Category Archives: 11. Opportunistic Infections

Opportunistic Infections (OIs)

-Christian Hoffmann –

In Western industrialized countries, many opportunistic infections (OIs) that in previous years were considered prevalent, are now quite rare. This is particularly true for infections associated with severe immunodeficiency, such as CMV and MAC disease. The incidence of these OIs has been reduced to less than one-tenth of their frequency in the pre-HAART era (Brooks 2009, Buchacz 2010). ART has not only decreased the incidence of the OIs, but it has also changed the course of OIs considerably. In early years of the AIDS epidemic, the life expectancy of individuals diagnosed with their first AIDS defining illness was two to three years, at most. Today, however, many patients now live with AIDS for 15 years or longer. In our own clinical study of 144 patients with cerebral toxoplasmosis, data from 1990-1993 indicated a 5-year survival rate of 8%; it climbed to 30% by 1994-1996, and then to 80% since 1997 (Hoffmann 2007).

Up to 90% of patients who develop AIDS or severe opportunistic infections are unaware of their HIV infection status. Typically, these patients seek medical attention late and when their overall health condition is serious. Since AIDS remains life-threatening, every HIV clinician should be familiar with the diagnosis OIs and their respective therapy. Even with recent improvements, over the years, many challenges still exist. First, there is still no adequate treatment available for diseases such as PML or cryptosporidiosis. Second, resistance to treatment has become an increasing problem in other OIs such as PCP. Even today OIs like PML have a mortality rate comparable to that of a non-Hodgkin-lymphoma (ART-CC 2009). Third, ART does not always lead to immediate improvement. ART may even complicate things, given the atypical course of a variety diseases under ART (see below a separate sub-chapter on the so-called “immune reconstitution inflammatory syndrome” IRIS). Moreover, there are no documented guidelines for OI prophylaxis outside of the US, and the US recommendations last updated in 2008 (www.aids.info), cannot always be adopted elsewhere, since the seroprevalence rates of many infectious agents often differ.

Moreover, in small HIV centers or regions with low HIV prevalence, diagnostic problems for many OIs may occur, due to a lack of familiarity with and inability to recognize these rare pathogens. Therefore, it is highly recommended that specimens be sent to specialized reference laboratories. If needed, then further advice can also be sought from a specialized clinician or a clinical HIV center.

The predominant rule for nearly all OIs is that the poorer the immune status of the patient, the earlier the invasive diagnostic procedures should begin. The primary aim should not be to spare patients of the unpleasant procedures associated with extensive diagnostic test.  Moreover, diagnostic tests must be repeated, if the results are inconclusive and nothing can be identified the first time. Also, treatment should be initiated almost immediately.

The second rule is that many OIs can be excluded if the immune status is known. Table 1 indicates the CD4 cut-off values and the expectancy of certain OIs.

Table 1: Important cut-offs for CD4 T cells, above which particular AIDS illnesses are improbable. However, exceptions are always possible.

No cut-off

Kaposi’s sarcoma, pulmonary tuberculosis, HZV, bacterial pneumonia, NHL

< 250/ml

PCP, esophageal candidiasis, PML, HSV

< 100/ml

Cerebral toxoplasmosis, cryptococcosis, miliary tuberculosis

< 50/ml

CMV retinitis, atypical mycobacteriosis

The third OI rule is that if ART is not already in place, then it should be started as quickly as possible. Immune reconstitution is the best protection against relapses or other OIs. For patients with some OIs, such as PML or cryptosporidiosis, which have no specific therapy, starting ART is essentially the only hope. Especially in these cases there is no time to waste. ART should also be started rapidly in cases of PCP or toxoplasmosis. Although OI therapy is not without toxicity and problems regarding interactions the choice of antiretroviral drugs has increased making it easier to react to side effects. In ACTG 5164, a total of 282 subjects with an acute OI (63% PCP) were randomized to initiate ART immediately or after OI treatment (Zolopa 2009). At 48 weeks significantly less mortalities and AIDS-infections occurred in the group starting ART immediately. CD4 T cell counts also increased more rapidly. The risk of changing ART was slightly higher in immediate group, however, not the number of adverse events, hospitalization or cases of IRIS. With such results ACTG A5164 provides clear arguments for an immediate initiation of ART in the face of an existing PCP. However, this does not necessarly apply to all OIs (Lawn 2011): Two randomized studies in patients with cryptococcal meningitis (Makadzange 2010) and tuberculous meningitis (Torok 2009) showed unfavorable effects when starting ART too early (see also chapter on late presenters).

The following chapter is intended to be a relevant practical overview and does not include clinical rarities. The literature cited refers to interesting reviews and, almost exclusively, to controlled studies and when applicable, randomized studies.

References, OI reviews

Antiretroviral Therapy Cohort Collaboration (ART-CC). Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51

Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. AIDS 1997, 11:1731-8.

Brooks JT, Kaplan JE, Holmes KK, et al. HIV-associated opportunistic infections—going, going, but not gone: the continued need for prevention and treatment guidelines. Clin Inf Dis 2009, 48:609–611

Buchacz K, Baker RK, Palella FJ Jr, et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS 2010, 24:1549-59.

Hoffmann C, Ernst E, Meyer P, et al. Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses. Clin Microbiol Infect 2007, 13:510-5.

Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunis-tic pathogens during potent antiretroviral therapy. Ann Intern Med 2002, 137:239-50.

Lawn SD, Török ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011, 24:34-42.

Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA 1999, 282: 2220-6.

Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010, 50:1532-8.

McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. AIDS 1999, 13:1687-95.

Sepkowitz KA. Effect of HAART on natural history of AIDS-related opportunistic disorders. Lancet 1998, 351: 228-230.

Torok ME. Randomized controlled trial of immediate versus deferred antiretroviral therapy in HIV-associated tuberculous meningitis. Abstract H-1224, 49th ICAAC 2009, San Francisco.

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS 2009, 4:e5575.

800×600

Leave a comment

Filed under 11. Opportunistic Infections, Part 3 - AIDS

Pneumocystis Pneumonia (PCP)

– Christian Hoffmann –

This interstitial pneumonia attributed to the majority of AIDS deaths in the early years of the HIV epidemic. In the last 20 years, there has been significant progress made in understanding this organism, especially through DNA analysis (review: Thomas 2004). Although pneumocystis was previously classified as a protozoan, it was established in 1988 that it is in fact an unusual type of fungus (Edman 1988). In the 1990s, it was recognized that every host, whether rat, mouse, monkey or human, had its own specific pneumocysts. It also became clear that Pneumocystis carinii (P. carinii), which was first described in 1910, does not occur in humans at all, but only in rats. The Pneumocystis species that affects humans is now referred to as Pneumocystis jiroveci, and “carinii” has now been taken out of the name for the pneumonia, although the abbreviation PCP remains the same (Stringer 2002).

Today, the majority of patients diagnosed with PCP are not pre-treated with antiretroviral drugs, because many of them either do not know of their HIV infection status or do not want to know it. In Europe between 1997-2004, among 760 cases of so-called “late presenters” who were diagnosed with HIV infection and AIDS diagnosed at the same time,  PCP was the by far most frequent OI (Mussini 2008).

PCP is a life-threatening disease, which should be treated by an HIV specialist. It often requires mechanical ventilation and then still continues to have a high fatality rate of up to 10% (Morris 2008, Walzer 2008). Factors associated with mortality are older age, low hemoglobin level, and low partial pressure of oxygen breathing room air at hospital admission (Walzer 2008, Miller 2010). Moreover, relapses seen frequently in the past have become rare, thanks to ART and prophylaxis. Scar tissue formation may result in susceptibility to recurring pneumothoraces. While PCP may rarely occur in relation to an immune reconstitution inflammatory syndrome (see below). Extrapulmonary manifestations of pneumocystis infections are also considerably rare. They may affect the liver, but many other organs may be involved.

Signs and symptoms

Every clinician should be familiar with the classic triad of PCP symptoms that include dry cough, subfebrile temperatures, and dyspnea on exertion; should ask patients specifically about their symptoms; and should measure the patients’ respiratory rates. A subacute course that allows differentiation from the productive cough, acutely high fever, pain and less common dyspnea associated bacterial pneumonia is a typical practice. Oral thrush is a frequent symptom in patients with PCP. Also, substantial weight loss of several kilograms in the weeks before PCP diagnosis is also common. These and other symptoms may be more subtle in cases with suboptimal prophylaxis (rare).

Weeks and sometimes even months may go by before the diagnosis of PCP is made. It is noteworthy to state that decompensation – as with all interstitial pneumonias – often occurs much faster than expected. It is not rare for a patient to suddenly require ventilation after weeks of antibiotic therapy prescribed by the primary health care provider, especially when even “broad spectrum” antibiotics do not help. A patient with significant exertional dyspnea or even resting dyspnea should be directed immediately to a hospital.

Diagnosis

If there is clinical suspicion of PCP determined by a physical examination with attention give to respiratory rate, oral thrush, and significant findings on auscultation, then a chest x-ray should follow without delay and, if possible, a high resolution computed tomography (HRCT) of the lungs. The chest x-ray often shows relatively characteristic findings with a butterfly-shaped (perihilar) interstitial infiltrate. In the early stages, the focus is on the mid- and lower fields. Indistinct, diffuse changes are more easily visible on HRCT than on chest x-ray. A CT scan also allows a fairly certain distinction from other pulmonary infections (Hidalgo 2003). However, in cases where nothing pathological is visible on CT scan to an experienced radiologist, then rapid initiation of treatment is still justified even without a definitive diagnosis – particularly in the presence of the classic triad of symptoms, low CD4 T cell count and no previous PCP prophylaxis. Almost always present is partial respiratory insufficiency, which should be confirmed by arterial blood gas analysis. Lactate dehydrogenase (LDH) is often elevated and may have limited use as a predictive parameter for the course of disease. A high LDH is an unfavorable sign and may reflect the severity of the PCP. In contrast, CRP is often normal, provided there are no other concurrent infections.

Sputum specimens are generally not useful (review: Cruciani 2002), so that a bronchoalveolar lavage (BAL) is usually necessary. This can lead to detection of pneumocysts even after several days of treatment. Therefore, it is not essential to wait for the BAL to start treatment. The laboratory should be specifically alerted to the suspicion of PCP. The routine test for detecting Pneumocystis in the BAL is direct immunofluorescence assay (DFA). A real-time PCR assay also seems to be an accurate diagnosis method and could replace the DFA (Fillaux 2008).

Performing the BAL as early as possible also allows for the timely diagnosis of co-infections (CMV, pneumococci). It should be noted that respiratory insufficiency can deteriorate with BAL. Full blood count, transaminases and kidney function must be monitored during treatment and baseline values should be determined at this point. Newer diagnostic approaches include antibody testing (Bishop 2003) and measurement of S-adenosylmethionine, a agent that pneumocysts require but cannot produce. S-adenosylmethionine levels are significantly reduced in patients with PCP (Skelly 2008). It is currently not foreseeable, whether these tests, which spare patients the discomfort of bronchoscopy, will be available for routine diagnostic testing in the future. This also applies to other serum markers such as beta-d glucan or antibody tests (Desmet 2009, Watanabe 2009, Djawe 2010, Gingo 2011).

Treatment

General

Treatment should be initiated immediately if there is clinical suspicion. In cases of mild PCP (BGA: PO2 > 70-80 mm Hg), ambulatory treatment can be attempted. In very mild cases, even oral medication can be considered. This may well be possible in cooperation with a competent HIV nursing service. If such monitoring is not possible, if respiratory deterioration occurs, and in every case with resting dyspnea, immediate hospitalization is advised. If ventilation becomes necessary, patients have a poor prognosis, even today (Crothers 2005, Walzer 2008). Non-invasive methods (like CPAP) may be beneficial if used from an early stage. This helps particularly in prevention of pneumothoraces (Confalonieri 2002).

While with ART naïve patients initiation of ART was mostly deferred until PCP was cured, a randomized study showed advantages of an early start (Zolopa 2009, see above). Another retrospective study showed improved survival in patients who began ART while hospitalized (Morris 2003). Possible cumulative toxicities and allergies with this approach, which may necessitate discontinuation of both PCP and HIV treatment can be largely avoided today (Watson 2002).

Drugs

Acute therapy should last for 21 days. The drug of choice is co-trimoxazole. The dose of three 960 mg tablets three times daily is possible in milder cases. However, these higher oral doses are also associated with poor gastrointestinal tolerability. Some case reports have observed positive effects with lower doses, but controlled studies are missing (Thomas 2009). All severe cases should be treated intravenously in hospital. Due to possible clinical deterioration, which is probably a result of the bursting of pneumocysts in the alveoli, 1 mg/kilogram prednisone bid should always be simultaneously co-administered with the PCP therapy for 5-10 days. There should be no hesitation to use steroids especially in patients with poor blood gases. On steroids, significantly less patients need intubation (Briel 2006). Important: clinical deterioration during the first week of treatment is still not uncommon. Initial treatment should be re-evaluated after one week at the earliest, and only after exclusion of co-infections such as CMV.

The high doses of co-trimoxazole require monitoring of full blood count, electrolytes, renal function parameters and transaminases at least three times weekly. The main problems in addition to myelotoxicity as well as liver and kidney problems include a rash that usually occurs after the middle of the second week of treatment and is often accompanied by drug fever. The rash occurred in up to 30% of patients (Fisk 2009) – patients should be checked daily for skin changes! If an exanthema occurs, one can attempt to interrupt treatment for one or two days, and then continue with half the dose under steroids. Otherwise, co-trimoxazole must be discontinued and replaced with alternative treatments.

All alternatives to co-trimoxazole are less effective. In cases of intolerability or history of sulfonamide allergy, intravenous pentamidine is recommended as the drug of second choice. An induction therapy is administered over the first few days (200-300 mg in 500 ml 5% glucose or 0.9% NaCl), and half the dose can then be given from day 6. This treatment is very toxic, which is why we have not used it for many years. Severe decompensations of electrolyte and blood glucose levels (both hyper- and hypoglycemia) are possible, as well as pancreatitis, arrhythmia and renal failure. Initially, daily monitoring of blood glucose, electrolytes and renal parameters is necessary.

In very mild cases of PCP, inhalative treatment with daily pentamidine inhalations (300-600 mg daily for three weeks) can be attempted (Arasteh 1990, Montgomery 1995). However, the experiences have not all been positive (Conte 1990, Soo 1990), and the current US-guidelines advise against inhalatory acute therapy (Benson 2004). Instead of pentamidine, treatment with atovaquone suspension (better than the tablets used in the past) or a combination of clindamycin and primaquine is possible. However, data on these alternative therapies is only available for mild to moderately severe cases of PCP (Hughes 1993, Dohn 1994, Toma 1998). According to a meta-analysis, clindamycin-primaquine seems very promising as second-line treatment for PCP in patients who fail treatment with co-trimoxazole (Benfield 2008) and is superior to pentamidine (Helweg-Larsen 2009).

In the past few years, these alternative agents (intravenous pentamidine, atovaquone, clindamycin, primaquine) have been used only in exceptional cases. It should be mentioned that a 10-day initial therapy of a high dose co-trimoxazole is achievable in almost all patients, most of whom are then already significantly better. If exanthema or toxicity forces the interruption of co-trimoxazole between day 10 and 14, daily pentamidine inhalation is called into question in the third and last week of acute therapy. As this is not toxic, it can usually be started in parallel to ART. However, a study on this strategy has yet to be published.

Prophylaxis

Patients with less than 200 CD4 T cells/µl (<14%) are at high risk of PCP. Above these values, the occurrence of PCP is rare. Therefore, these patients are treated prophylactically, ideally with co-trimoxazole. Daily dosages may be slightly more effective than giving the dosages three times weekly (El Sadr 1999). The gradual lead-in administration over a period of 14 days is supposed to prevent allergic reactions, but is cumbersome (Para 2000). In cases of a mild or moderate allergy to co-trimoxazole, desensitization after several weeks is possible (Leoung 2001), and should definitely be attempted. Although dapsone and pentamidine inhalations are almost equally effective (Bozzette 1995, Bucher 1997), co-trimoxazole prophylaxis is better for preventing bacterial infections such as enteritis, sinusitis and pneumonia (DiRienzo 2002). More importantly, co-trimoxazole simultaneously provides reliable protection for cerebral toxoplasmosis. Pediatric co-trimoxazole suspension can be used for desensitization, by slowly increasing exposure within six days from 12.5, 25, 37.5, 50 and 75 to 100% of the dose in the 480 mg tablet. In a study of almost 200 patients, no cases of severe allergy occurred, and there was a reduction of fever and headaches. Approximately three quarters of all patients are thus able to tolerate co-trimoxazole again. However, re-exposure should only be attempted after an interval of eight weeks (Leoung 2001).

Monthly inhalation of pentamidine is a well-tolerated alternative. However, coughing may occur. Asthma attacks are rare, and pneumothoraces are even rarer. A suitable inhalation system should be used, after administration of a beta-sympathomimetic to dilate the bronchi. The loading dose (300 mg tid for the first 5 days) frequently used in the past is no longer a universal standard. In patients with severe pulmonary disease, inhalation is probably less effective.

Further options are problematic. Dapsone has poor gastrointestinal tolerability, is quite myelotoxic and often leads to elevation of LDH. LDH, an important diagnostic parameter, can therefore not be utilized under treatment with dapsone (Ioannidis 1996). Atovaquone was proven to be of comparable efficacy to co-trimoxazole, dapsone and pentamidine in two multicenter studies (El-Sadr 1998, Chan 1999), and since then, is considered to be a good alternative for PCP prophylaxis. The oral suspension has better tolerability than the tablet formulation (Rosenberg 2001). A significant disadvantage of atovaquone for long-term prophylaxis is the disproportionately high cost (in some European countries approximately 1,000 Euro/month).

PCP prophylaxis regimens can be discontinued fairly safely with sufficient immune reconstitution: more than 200 CD4 T cells/µl for three months (Schneider 1999, Weverling 1999, Lopez 2001, Ledergerber 2001). PCP has only rarely been described in cases with CD4 T-cell counts greater than 200 cells/µl after stopping prophylaxis (Degen 2002, Mussini 2003). If the viral load is suppressed, even lower CD4 cells are possible. In an analysis of 23,412 patients from 12 European cohorts who started taking ART after 1997, the incidence of primary PCP was low among patients who had virologically suppressed HIV infection, were receiving ART, and who had CD4 cell counts >100 cells/µl. Discontinuation of prophylaxis may be safe in patients with CD4 counts of 101-200 cells/µL and suppressed viral load (COHERE 2010). However, there a no controlled studies addressing this issue.

Treatment/Prophylaxis of PCP (daily doses, if not specified otherwise)

Acute therapy

Duration: always at least three weeks

Severe to moderately severe PCP

Co-trimoxazole

Co-trimoxazole 5-6 amp. at 480 mg tid plus

prednisolone 2–2–0 tbl. at 20 mg (5-10 days)

Mild PCP

Co-trimoxazole

Co-trimoxazole 3 tbl. at 960 mg tid

Alternatives

Pentamidine

Pentamidine 200-300 mg i.v. for 5 days (4 mg/kg), then halve dose

In very mild cases: daily inhalations with 300 mg

Atovaquone

Atovaquone suspension 5-10 ml bid (750–1500 mg bid)

Clindamycin + Primaquine

Clindamycin 1 amp. at 600 mg i.v. q 6-8 h plus primaquine 1 tbl. at 30 mg qd

Prophylaxis

Below 200 CD4 T cells/µl; after PCP episode

First choice

Co-trimoxazole

Co-trimoxazole 1 tbl. at 480 mg qd or

co-trimoxazole 1 tbl. at 960 mg 3 x/week

Alternatives

Pentamidine

Pentamidine inhalation 300 mg 1-2 x/month

Dapsone

Dapsone 2 tbl. at 50 mg qd

Dapsone + Pyrimethamine

Dapsone  1 tbl. at 50 mg qd plus pyrimethamine 2 tbl. at 25 mg/week plus leucovorin 2 tbl. at 15 mg/week

Atovaquone

Atovaquone suspension 5 ml bid (750 mg bid)

Resistance issues, current controversies

Stopping prophylaxis not only reduces side effects and costs, but also avoids other negative developments: the proportion of co-trimoxazole-resistant bacteria is constantly increasing among HIV infected patients (Martin 1999). The worldwide use of co-trimoxazole has also affected pneumocysts. Resistance analyses were previously difficult since this particular organism, even almost 100 years after its discovery, can still not be cultured. However, it is now possible to sequence sections of the genome encoding for dihydropteroate synthetase (DHPS). DHPS is an important enzyme involved in the folate metabolism of many organisms, and is targeted by sulfonamides such as sulfamethoxazole (SMX) and dapsone. The first mutations in the DHPS gene in pneumocysts were discovered in 1997. A further study showed DHPS mutations in 43%, while the gene region for dihydrofolate reductase (DHFR), targeted by trimethoprim (TMP) and pyrimethamine, did not show a single relevant mutation. In contrast to SMX, there seems to be no selective pressure associated with TMP – a suspicion that has to be analyzed, that TMP is not effective against pneumocysts (Ma 1999). Recently, however, even DHFR-mutations have been proven (Nahimana 2004). In addition, studies in large groups of patients have demonstrated that the frequency of sulfa resistance mutations has significantly increased in recent years. Resistance correlated significantly with the duration of prior prophylaxis and its failure (Helweg-Larsen 1999). However, it remains unclear, whether DHPS mutations should affect decisions on PCP therapy or lead to a change in treatment (Review: Matos 2010).

The sequencing of the Pneumocystis genome has uncovered other possibly relevant findings: it seems highly likely that PCP is caused by a new infection, rather than the reactivation of an existing infection as previously assumed (Wakefield 2003). Asymptomatic HIV patients with frequent detection of pneumocysts may be reservoirs (Wakefield 2003), but also HIV-negative patients on corticosteroid therapy (Maskell 2003) and patients with active PCP. Reports also exist on nosocomial infection with pneumocysts (Schmoldt 2008). However, other authors doubt patient-to-patient transmission (Wohl 2002), and isolation of PCP patients is still not generally recommended (Thomas 2004).

Pneumocysts do not always cause a manifest pneumonia: in healthy patients pneumocystis colonization has been observed (Ponce 2010, Vargas 2010), which also play a role in chronic obstructive lung diseases (Morris 2008).

References

Arasteh K, Heise W, L’age M. Treatment of mild to moderately severe pneumocystis carinii pneumonia with cotrimoxazole versus pentamidine aerosol. Med Klin 1990, 85 Suppl 2:260-3.

Benfield T, Atzori C, Miller RF, Helweg-Larsen J. Second-Line Salvage Treatment of AIDS-Associated Pneumocystis jirovecii Pneumonia: A Case Series and Systematic Review. J AIDS 2008.

Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the NIH, and the IDSA. MMWR Recomm Rep 2004, 53(RR-15):1-112.

Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antipneumocystis agents in patients with advanced HIV. N Engl J Med 1995, 332:693-9.

Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev 2006, 19;3:CD006150.

Bucher HC, Griffith L, Guyatt GH, Opravil M. Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients. J AIDS Hum Retrovirol 1997, 15:104-14.

Chan C, Montaner J, Lefebvre EA, et al. Atovaquone suspension compared with aero-solized pentamidine for prevention of PCP in HIV-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis 1999, 180:369-76.

COHERE. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/microL? Clin Infect Dis 2010, 51:611-9.

Confalonieri M, Calderini E, Terraciano S, et al. Noninvasive ventilation for treating acute respiratory failure in AIDS patients with Pneumocystis carinii pneumonia. Intensive Care Med 2002, 28:1233-8.

Conte JE Jr., Chernoff D, Feigal DW Jr., Joseph P, McDonald C, Golden JA. Intravenous or inhaled pentamidine for treating PCP in AIDS. A randomized trial. Ann Intern Med 1990, 113:203-9.

Crothers K, Beard CB, Turner J, et al. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS 2005, 19:801-5.

Cruciani M, Marcati P, Malena M, et al. Meta-analysis of diagnostic procedures for Pneumocystis carinii pneumonia in HIV-1-infected patients. Eur Respir J 2002, 20:982-9.

Degen O, van Lunzen J, Horstkotte MA, Sobottka I, Stellbrink HJ. Pneumocystis carinii pneumonia after the discontinuation of secondary prophylaxis. AIDS 2002, 16:1433-4.

Desmet S, Van Wijngaerden E, Maertens J, et al. Serum (1-3)-beta-D-glucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy. J Clin Microbiol 2009, 47:3871-4.

DiRienzo AG, van Der Horst C, Finkelstein DM, et al. Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection. AIDS Res Hum Retroviruses 2002, 18:89-94.

Djawe K, Huang L, Daly KR, et al. Serum antibody levels to the Pneumocystis jirovecii major surface glycoprotein in the diagnosis of P. jirovecii pneumonia in HIV+ patients. PLoS One 2010, 5:e14259.

Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med 1994;121:174-80.

Edman JC, Kovacs JA, Masur H, et al. Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi. Nature 1988, 334:519-522.

El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of PCP in HIV-infected persons. Clin Infect Dis 1999, 29:775-783.

El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med 1998, 339:1889-95.

Fillaux J, Malvy S, Alvarez M, et al. Accuracy of a routine real-time PCR assay for the diagnosis of Pneumocystis jirovecii pneumonia. J Microbiol Methods 2008, 75:258-61.

Fisk M, Sage EK, Edwards SG, Cartledge JD, Miller RF. Outcome from treatment of Pneumocystis jirovecii pneumonia with co-trimoxazole. Int J STD AIDS 2009, 20:652-3.

Gingo MR, Lucht L, Daly KR, et al. Serologic responses to Pneumocystis Proteins in Human Immunodeficiency Virus Patients With and Without Pneumocystis jirovecii Pneumonia. J AIDS 2011 Mar 3. [Epub ahead of print]

Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother 2009, 64:1282-90.

Helweg-Larsen J, Benfield TL, Eugen-Olsen J, Lundgren JD, Lundgren B. Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated PCP. Lancet 1999, 354:1347-51.

Hidalgo A, Falco V, Mauleon S, et al. Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non-Pneumocystis carinii pneumonia in AIDS patients. Eur Radiol 2003, 13:1179-84.

Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumo-nia in patients with AIDS. N Engl J Med 1993, 328:1521-7.

Ioannidis JP, Cappelleri JC, Skolnik PR, Lau J, Sacks HS. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996, 156:177-88.

Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole dose escalation versus direct rechallenge for PCP prophylaxis in HIV-infected patients with previous adverse reaction to TMP-SMZ. JID 2001, 184:992-7.

Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against PCP after HAART in patients with HIV infection. NEJM 2001, 344:159-67.

Ma L, Borio L, Masur H, Kovacs JA. Pneumocystis carinii dihydropteroate synthase but not dihydrofolate reductase gene mutations correlate with prior trimethoprim-sulfamethoxazole or dapsone use. J Inf Dis 1999, 180:1969-78.

Martin JN, Rose DA, Hadley WK, et al. Emergence of trimethoprim-sulfamethoxazole resistance in the AIDS Era. J Infect Dis 1999, 180:1809-18.

Maskell NA, Waine DJ, Lindley A, et al. Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study. Thorax 2003, 58:594-7.

Matos O, Esteves F. Epidemiology and clinical relevance of Pneumocystis jirovecii Frenkel, 1976 dihydropteroate synthase gene mutations. Parasite 2010, 17:219-32.

Miller RF, Evans HE, Copas AJ, Huggett JF, Edwards SG, Walzer PD. Seasonal variation in mortality of Pneumocystis jirovecii pneumonia in HIV-infected patients. Int J STD AIDS 2010, 21:497-503.

Montgomery AB, Feigal DW Jr., Sattler F, et al. Pentamidine aerosol versus trimethoprim-sulfamethoxazole for Pneumocystis carinii in AIDS. Am J Respir Crit Care Med 1995;151:1068-74.

Morris A, Sciurba FC, Norris KA. Pneumocystis: a novel pathogen in chronic obstructive pulmonary disease? COPD 2008;5:43-51.

Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 2003, 17:73-80.

Morris A. Is there anything new in Pneumocystis jirovecii pneumonia? Changes in P. jirovecii pneumonia over the course of the AIDS epidemic. Clin Infect Dis 2008;46:634-6.

Mussini C, Manzardo C, Johnson M, et al. Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. AIDS 2008, 22:2461-9.

Mussini C, Pezzotti P, Antinori A, et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in HIV-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis 2003, 36:645-51.

Nahimana A, Rabodonirina M, Bille J, et al. Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother 2004; 48:4301-5.

Para MF, Finkelstein D, Becker S, et al. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia. J AIDS 2000, 24:337-43.

Ponce CA, Gallo M, Bustamante R, Vargas SL. Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population. Clin Infect Dis 2010, 50:347-53.

Rosenberg DM, McCarthy W, Slavinsky J, et al. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 2001, 15:211-4.

Schmoldt S, Schuhegger R, Wendler T, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol 2008; 46:966-71.

Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with HAART. Lancet 1999, 353: 201-3.

Skelly MJ, Holzman RS, Merali S. S-adenosylmethionine levels in the diagnosis of Pneumocystis carinii pneumonia in patients with HIV infection. Clin Infect Dis 2008;46:467-71.

Soo Hoo GW, Mohsenifar Z, Meyer RD. Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia in AIDS. A randomized trial. Ann Intern Med 1990;113:195-202.

Stringer JR, Beard CB, Miller RF, Wakefield AE. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis 2002, 8:891-6.

Thomas CF Jr, Limper AH. Pneumocystis pneumonia. NEJM 2004, 350: 2487-98.

Thomas M, Rupali P, Woodhouse A, Ellis-Pegler R. Good outcome with trimethoprim 10 mg/kg/day-sulfamethoxazole 50 mg/kg/day for Pneumocystis jirovecii pneumonia in HIV infected patients. Scand J Infect Dis 2009,17:1-7.

Toma E, Thorne A, Singer J, et al. Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe PCP in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004). Clin Infect Dis 1998, 27:524-30.

Vargas SL, Pizarro P, López-Vieyra M, et al. Pneumocystis colonization in older adults and diagnostic yield of single versus paired noninvasive respira-tory sampling. Clin Infect Dis 2010, 50:e19-21.

Wakefield AE, Lindley AR, Ambrose HE, Denis CM, Miller RF. Limited asymptomatic carriage of pneumocystis jiroveci in HIV-infected patients. J Infect Dis 2003, 187: 901-8.

Walzer PD, Evans HE, Copas AJ, et al. Early predictors of mortality from Pneumocystis jirovecii pneumonia in HIV-infected patients: 1985-2006. Clin Infect Dis 2008;46:625-33.

Watanabe T, Yasuoka A, Tanuma J, et al. Serum (1–>3) beta-D-glucan as a noninvasive adjunct marker for the diagnosis of  Pneumocystis pneumonia in patients with AIDS. Clin Infect Dis 2009, 49:1128-31.

Watson J. Pneumocystis carinii: where are we now? J HIV Ther 2002, 7:8-12.

Weverling GJ, Mocroft A, Ledergerber B, Kirk O, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of HAART in HIV-1 infection. Lancet 1999, 353:1293-8.

Wohl AR, Simon P, Hu YW, Duchin JS. The role of person-to-person transmission in an epidemiologic study of Pneumocystis carinii pneumonia. AIDS 2002, 16:1821-5.

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS 2009, 4:e5575.

 

Leave a comment

Filed under 11. Opportunistic Infections, Part 3 - AIDS, Pneumocystis Pneumonia (PCP)

Cerebral toxoplasmosis

– Christian Hoffmann –

Although the incidence in Europe has been drastically reduced as a result of ART (Abgrall 2001), cerebral toxoplasmosis (or toxoplasmic encephalitis, TE) remains the most important neurological OI in HIV-infected patients. At present, it is typically diagnosed in patients with hitherto unknown HIV infection or in those not under regular routine care (Hoffmann 2007). TE almost always results from the reactivation of a latent infection with Toxoplasma gondii, an intracellular parasite that infects birds, mammals and humans. Prevalence rates vary considerably worldwide (Porter 1992). Whereas Toxoplasma gondii is relatively rare in the US, seroprevalence rates in some regions within central Europe are as high as 90%. Toxoplasma gondii has an affinity to the CNS. Extracerebral organ manifestations (heart, muscle, liver, intestine, lung) are rare and often only detected at autopsy.

Cerebral toxoplasmosis is potentially life threatening, and treatment is complicated. In severe cases, there may be residual neurological syndromes with significant disabilities, like hemiparesis. It is not rare to see a remaining lifelong susceptibility to seizures as a result of defective healing. It should be noted that relapses may occur even after long periods of time due to intracerebral persistence.

In Western countries, there is some evidence that the situation of an HIV-infected patient developing TE in recent years differs from TE patients seen during the early years of the HIV epidemic (Hoffmann 2007). Patients with TE today usually do not take antiretroviral therapy or any prophylaxis. They are likely to be diagnosed with HIV at the time of TE diagnosis, and TE is much more frequently the AIDS-defining illness in these patients than in the pre-HAART era.

Signs and symptoms

Clinical symptoms depend on the localization of lesions with acute or peracute onset within a few days. The major signs include focal neurological deficits such as paresis, speech problems or sensory loss (Porter 1992). A febrile psychosyndrome with confusion is also frequently an early sign. It is not unusual to see an epileptic seizure as the initial presentation, in the absence of other symptoms. Headaches with fever or subfebrile temperatures are always suspicious. Meningitic signs, however, are less typical. Atypical manifestations in patients with immune reconstitution under ART have been described (Ghosn 2003).

A fairly rare, but important manifestation is Toxoplasma chorioretinitis. It causes impairment of vision, is an important differential diagnosis to CMV retinitis and may occur on its own (Rodgers 1996). Toxoplasma chorioretinitis should be treated in exactly the same way as cerebral toxoplasmosis.

Diagnosis

Cerebral toxoplasmosis seldomly occurs above a CD4 T cell count of 100 cells/µl; over 200 CD4 cells/µl it is very rare (Bossi 1998). In contrast, it should always be expected below 100 CD4 T cells/µl. A CT or MRI scan of the head should be performed promptly with in a week in every case of focal neurological deficit, but also if seizures occur in significantly immunocompromised patients. In this instance, a MRI is superior to a CT scan and almost always shows more visible lesions. A third of cases have either solitary, several (2-5) or multiple lesions, respectively. In approximately nine out of ten cases, ring enhancement is found around the lesions, often accompanied by edema. Hemorrhage may occasionally occur.

For all radiologically detected lesions, the most likely diagnosis is cerebral toxoplasmosis. In addition, the most important differential diagnosis is an “atypical” cerebral toxoplasmosis. Furthermore, the more lesions there are, the more likely the diagnosis of toxoplasmosis. However, the distinction between toxoplasmosis and a bacterial abscess or a cerebral lymphoma may be difficult. Other rare differential diagnoses include PML, infarcts, tuberculomas and cryptococcomas. “HIV-unrelated” diseases such as brain tumors or vascular diseases should also be considered.

A brain biopsy is not obligatory. Suspicion of toxoplasmosis (clinically and radiologically) justifies a treatment attempt without before it comes to this. Response to therapy then confirms the diagnosis. However, if the patient does not improve clinically within one week, or even worsens, then stereotactical brain biopsy cannot be avoided, and in this case, should not be postponed. The cerebrospinal fluid (CSF), which also does not necessarily have to be analyzed if there are clear radiological findings (several lesions with contrast enhancement), usually shows moderate pleocytosis and slightly elevated total protein. Our experience with Toxoplasma PCR from CSF has not been good. A negative result never excludes toxoplasmosis.

An updated serology should be available for every patient. Up to 97% of patients with cerebral toxoplasmosis have IgG antibodies, and so a negative result, which should be repeated in another laboratory if there is any doubt, makes toxoplasmosis unlikely. Some clinicians use levels of IgG titers or increased titers as indicators (Derouin 1996), but this approach has not been properly validated. IgM is only rarely positive, and therefore usually does not help. PCR from the blood also has little relevance (review: Bretagne 2003).

Treatment

Treatment of cerebral toxoplasmosis is difficult. The most frequently used combinations are usually effective (resistance has not yet been convincingly described), but require modification in at least half of the patients due to side effects – particularly allergies. Sulfadiazine and clindamycin are presumably equally effective in combination with pyrimethamine (Dannemann 1992). However, one large European study demonstrated a trend, though not significant, in favor of sulfadiazine (Katlama 1996). Co-trimoxazole may also be an option. According to a Cochrane analysis, the available evidence fails to identify a superior regimen which can be considered as the gold standard (Dedicoat 2006).

We recommend that sulfadiazine and pyrimethamine be used for an initial attempt as oral treatment. In cases of sulfonamide allergy, sulfadiazine should be substituted with oral or intravenous clindamycin from the beginning. In addition, all disoriented patients should receive clindamycin infusions, at least for adherence reasons. Because of the high rate of allergies under sulfadiazine, however, some clinicians oppose this treatment. We do not share this perspective, since clindamycin is also allergenic. Moreover, clindamycin can cause pseudomembranous colitis.

A loading dose for pyrimethamine during the first few days has been propagated since the first published study (Leport 1988). However, it has not yet been proven whether or not it is necessary. Even the dosages vary. For example, in the US, 200 mg is recommended for the first day (followed by 50-75 mg depending on the body weight); in many European countries, 100 mg is often given for three days, followed by 50 mg. It should be noted that, in contrast to clindamycin, pyrimethamine is also active in the presence of an intact blood brain barrier, and therefore, is sometimes the only effective agent.

Due to the myelotoxicity of sulfonamides and pyrimethamine, which inhibits transformation of folic acid to folinic acid, it is imperative to substitute sufficiently with folinic acid which unfortunately is expensive. Folic acid which is much cheaper is ineffective since it cannot be converted in the presence of pyrimethamine (Luft 2000).

Good results have also been reported with intravenous co-trimoxazole, with administration of the same dosages as for PCP (Canessa 1992, Béraud 2009). In two randomized studies on patients with ocular or cerebral toxoplasmosis, co-trimoxazole was as effective as sulfadiazine/pyrimethamine (Torre 1998, Soheilian 2005). If allergies or intolerance to both sulfonamides and clindamycin occur, then a combination of atovaquone and pyrimethamine is a possible alternative (Chirgwin 2002). A combination of azithromycin plus pyrimethamine could be another alternative (Bosch-Driessen 2002).

Acute therapy lasts for a period of four weeks and at best, six weeks duration or possibly even longer for the less effective reserve therapies. Treatment success can be assessed clinically in the first 14 days. While often an improvement in the symptoms can be observed within a few days. A patient who has not improved at all after two weeks of therapy or has even deteriorated, probably does not have toxoplasmosis. If this occurs, the the diagnosis has to be reviewed and an urgent brain biopsy must be performed. Changing the TE therapy is not useful in such cases and just expends valuable time. Antiretroviral therapy should be initiated as soon as possible. Drugs with the potential of allergic reactions (abacavir, when HLA-testing is not possible, but also NNRTIs, fosamprenavir, darunavir) should be avoided.

A control MRI is recommended for stable patients after two weeks at the earliest. Significant resolution of lesions is often only visible after four weeks. In cases of increased intracranial pressure or extensive edema, steroids are given (8 mg dexamethasone q 6-8 h). Steroids also should be given for a limited duration, as there is a significantly increased risk of aspergillosis. All treatment combinations require initial monitoring of blood count, glucose, transaminases and renal parameters at least three times weekly. Maintenance therapy with the reduced dose should only be initiated if lesions have resolved by at least 75%.

Prophylaxis

Exposure prophylaxis: IgG-negative patients can protect themselves from primary infection by not eating raw or undercooked meat (lamb, beef, pork, game, etc.). It has not been proven, despite widespread opinion, that infection occurs by mere contact with cats, the definitive hosts of Toxoplasma gondii. To date, the only study that has seriously investigated this conjecture could not prove endangerment as a result of proximity to cats (Wallace 1993). Nevertheless, stricter measures of hygiene should be followed (e.g. gloves should be used when handling for the cat litter box, details in: Kaplan 2002).

Primary prophylaxis: All IgG-positive patients with less than 100 CD4 T cells/µl require primary prophylaxis. The drug of choice is co-trimoxazole. In cases of co-trimoxazole allergy, desensitization may be considered (see PCP). An alternative is dapsone plus pyrimethamine or high-dose dapsone. Primary prophylaxes can be discontinued safely if CD4 T cells are above 200/µl for at least three months.

Maintenance therapy/secondary prophylaxis: In the absence of immune reconstitution, patients with cerebral toxoplasmosis require lifelong maintenance therapy or secondary prophylaxis, as there are otherwise recurrences in nearly all cases. It usually consists of half the dose of the acute therapy (Podzamczer 2000). However, clindamycin is presumably less suitable, as it cannot cross the intact blood-brain barrier (Luft 2000). Co-trimoxazole seems to be not as effective for secondary prophylaxis, but should be considered because it is simple. However, it definitely requires higher doses than those used to treat PCP (Ribera 1999, Duval 2004). With immune reconstitution (at least six months above 200 CD4 T cells/µl), secondary prophylaxis can probably be stopped (Benson 2004, Miro 2006). When possible, an updated MRI scan should be available beforehand. If there is enhancement, then it may mean that lesions have become active even after years – and there is a risk of a recurrence. A recurrence even after five years has been observed, despite CD4 T cells levels being around 200/µl.

Treatment/prophylaxis of cerebral toxoplasmosis (daily doses, if not specif. otherwise)

Acute therapy

Duration: always at least four weeks

First choice

Sulfadiazine+
Pyrimethamine

Sulfadiazine 2-3 tbl. at 500 mg qid plus

pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week

First choice

Clindamycin +
Pyrimethamine

Clindamycin 1 amp. at 600 mg i.v. qid or 1 tbl. at 600 mg qid plus

pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week

Alternative

Atovaquone +
Pyrimethamine

Atovaquone suspension 10 ml bid (1500 mg bid) plus pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week

Maintenance therapy

 

As for acute
therapy

As for acute therapy, but halve dose

Discontinue if > 200 CD4 cells/µl for > 6 months (if MRI is normal or without contrast enhancement)

Possibly

Co-trimoxazole

Co-trimoxazole 1 tbl. at 960 mg qd

Primary prophylaxis

First choice

Co-trimoxazole

Co-trimoxazole 1 tbl. at 480 mg qd

Alternative

Dapsone

Dapsone 2 tbl. at 50 mg qd

Alternative

Dapsone +
Pyrimethamine

Dapsone1 tbl. at 50 mg qd plus pyrimethamine2 tbl. at 25 mg/week plus leucovorin 2 tbl. at 15 mg/week

This and other cases (Stout 2002, Ghosn 2003) have shown that quantitative measurement of CD4 T cells on ART does not always reflect the quality of the TG-specific immune response. As a result, there have been increasing efforts in recent years to improve the characterization of this specific immune response via ELISPOT. Studies have made known that the Toxoplasma-specific immune response remains poor in approximately 10-20% of patients on ART, despite good CD4 T cell counts (Fournier 2001, Miro 2003). In the future, ELISPOT testing may allow identification of patients who are at risk of recurrence despite good CD4 counts and who should therefore continue with secondary prophylaxis.

References

Abgrall S, Rabaud C, Costagliola D. Incidence and risk factors for toxoplasmic encephalitis in HIV-infected patients before and during the HAART era. Clin Infect Dis 2001, 33: 1747-55.

Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the NIH, and the IDSA. MMWR Recomm Rep 2004, 53(RR-15):1-112.

Béraud G, Pierre-François S, Foltzer A, et al. Cotrimoxazole for treatment of cerebral toxoplasmosis: an observational cohort study during 1994-2006. Am J Trop Med Hyg 2009, 80:583-7.

Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MS. A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol 2002, 134:34-40.

Bossi P, Caumes E, Astagneau P, et al. Epidemiologic characteristics of cerebral toxoplasmosis in 399 HIV-infected patients followed between 1983 and 1994. Rev Med Interne 1998, 19:313-7.

Bretagne S. Molecular diagnostics in clinical parasitology and mycology: limits of the current polymerase chain reaction (PCR) assays and interest of the real-time PCR assays. Clin Microbiol Infect 2003, 9:505-11.

Bucher HC, Griffith L, Guyatt GH, Opravil M. Meta-analysis of prophylactic treatments against PCP and toxoplasma encephalitis in HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997,15:104-14.

Canessa A, Del Bono V, De Leo P, Piersantelli N, Terragna A. Cotrimoxazole therapy of toxoplasma gondii encephalitis in AIDS patients. Eur J Clin Microbiol Infect Dis 1992, 11:125-30.

Chirgwin K, Hafner R, Leport C, et al. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with AIDS: ACTG 237/ANRS 039 Study. Clin Infect Dis 2002, 34:1243-50.

Dannemann B, McCutchan JA, Israelski D, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern Med 1992, 116:33-43.

Dedicoat M, Livesley N. Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Cochrane Database Syst Rev. 2006 Jul 19;3:CD005420. Review.

Derouin F, Leport C, Pueyo S, et al. Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. AIDS 1996, 10:1521-7.

Duval X, Pajot O, Le Moing V, et al. Maintenance therapy with cotrimoxazole for toxoplasmic encephalitis in the era of highly active antiretroviral therapy. AIDS 2004, 18:1342-4.

Fournier S, Rabian C, Alberti C, et al. Immune recovery under highly active antiretroviral therapy is associated with restoration of lymphocyte proliferation and interferon-y production in the presence of toxoplasma gondii antigens. J Inf Dis 2001, 183:1586-1591.

Furco A, Carmagnat M, Chevret S, et al. Restoration of Toxoplasma gondii-specific immune responses in patients with AIDS starting HAART. AIDS 2008, 22:2087-96.

Ghosn J, Paris L, Ajzenberg D, et al. Atypical toxoplasmic manifestation after discontinuation of maintenance therapy in a HIV type 1-infected patient with immune recovery. Clin Infect Dis 2003, 37:112-114.

Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993, 328:1514-20.

Hoffmann C, Ernst M, Meyer P, et al. Evolving characteristics of toxoplasmosis in patients infected with HIV-1: clinical course and Toxoplasma gondii-specific immune responses. Clin Microbiol Infect 2007;13:510-5.

Jones JL, Hanson DL, Chu SY, et al. Toxoplasmic encephalitis in HIV-infected persons: risk factors and trends. AIDS 1996, 10:1393-9.

Katlama C, De Wit S, O’Doherty E, Van Glabeke M, Clumeck N. Pyrimethamine-clindamycin vs. pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic encephalitis in patients with AIDS. Clin Infect Dis 1996, 22:268-75.

Leport C, Raffi F, Matheron S, et al. Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the AIDS. Efficacy of long-term continuous therapy. Am J Med 1988, 84:94-100.

Luft BJ, Chua A. Central Nervous System Toxoplasmosis in HIV. Pathogenesis, diagnosis, and therapy. Curr Infect Dis Rep 2000, 2:358-362.

Miro JM, Lejeune M, Claramonte X. Timing of reconstitution of toxoplasma gondii-specific T-cell responses in AIDS patients with acute toxoplasmic encephalitis after starting HAART: A prospective multi-center longitudinal study. Abstract 796, 10th CROI 2003, Boston, USA.

Miro JM, Lopez JC, Podzamczer D, et al. Discontinuation of primary and secondary Toxoplasma gondii prophylaxis is safe in HIV-infected patients after immunological restoration with highly active antiretroviral therapy: results of an open, randomized, multicenter clinical trial. Clin Infect Dis 2006;43:79-89.

Podzamczer D, Miro JM, Ferrer E, et al. Thrice-weekly sulfadiazine-pyrimethamine for maintenance therapy of toxoplasmic encephalitis in HIV-infected patients. Eur J Clin Microbiol Infect Dis 2000, 19:89-95.

Porter SB, Sande MA. Toxoplasmosis of the central nervous system in AIDS. NEJM 1992, 327:1643-8.

Ribera E, Fernandez-Sola A, Juste C, et al. Comparison of high and low doses of Trimethoprim-Sulfamethoxazole for primary prevention of toxoplasmic encephalitis in HIV-infected patients. Clin Infect Dis 1999, 29:1461-6.

Rodgers CA, Harris JR. Ocular toxoplasmosis in HIV infection. Int J STD AIDS 1996, 7:307-9.

Ruf B, Schurmann D, Bergmann F, et al. Efficacy of pyrimethamine/sulfadoxine in the prevention of toxoplasmic encephalitis relapses and PCP in HIV-infected patients. Eur J Clin Microbiol Infect Dis 1993, 12:325-9.

Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology 2005, 112:1876-82.

Stout JE, Lai JC, Giner J, Hamilton CD. Reactivation of retinal toxoplasmosis despite evidence of immune response to highly active antiretroviral therapy. Clin Infect Dis 2002, 35:37-39.

Torre D, Casari S, Speranza F, et al. Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Antimicrob Agents Chemother 1998, 42:1346-9.

Torres RA, Barr M, Thorn M, et al. Randomized trial of dapsone and aerosolized pentamidine for the prophylaxis of pneumocystis carinii pneumonia and toxoplasmic encephalitis. Am J Med 1993, 95:573-83.

Wallace MR, Rossetti RJ, Olson PE. Cats and toxoplasmosis risk in HIV-infected adults. JAMA 1993, 269:76-7.

Weigel HM, de Vries E, Regez RM, et al. Cotrimoxazole is effective as primary prophylaxis for toxoplasmic encephalitis in HIV-infected patients: a case control study. Scand J Infect Dis 1997, 29:499-502.

1 Comment

Filed under Cerebral toxoplasmosis, Part 3 - AIDS

CMV Retinitis

– Christian Hoffmann –

Infections with cytomegalovirus are widespread. In many countries, seroprevalence is around 50-70%, and above 90% in MSM. In severely immunocompromised individuals, (CD4 count below 50 cells/µl), reactivation of CMV infection can lead to retinitis. In the past, CMV retinitis was a common AIDS-associated illness, leading to blindness in up to 30% of patients. It occurs mainly in untreated patients, who are often first diagnosed with HIV infection on presentation (Jacobson 2000). An inflammatory CMV retinitis, usually with severe vitritis, is also possible in the course of an IRIS (see below). If CMV retinitis is not diagnosed and treated promptly, then the patient’s sight is at risk. Impairment of vision is almost always associated with lesions, which are no longer reversible even with adequate treatment. This is why CMV retinitis remains a dangerous illness, although the prognosis has been significantly improved by ART (Goldberg 2003, Salzberger 2005, Thorne 2006).

Other manifestations of disseminated CMV infection are rare (15%), and can affect every organ. The lung (pneumonia), esophagus (ulcers), colon (colitis) and CNS (encephalitis) are most frequently involved. Sinusitis may also occur (Jutte 2000). The clinical signs of these CMV diseases depend on the organ affected. Diagnosis is often difficult and may only be possible on histology (Goodgame 1993). There is insufficient data on the treatment of these manifestations, so that systemic therapies are usually chosen in analogy to treatment for CMV retinitis (Whitley 1998).

Signs and symptoms

Any visual impairment occurring peracutely or acutely, such as blurred vision or floaters – especially unilaterally – should prompt an immediate (same day, if possible) ophthalmological examination of the patient. Symptomatic CMV retinitis is an emergency. Once there is a black spot in the visual field, it will be permanent.  Involvement of the posterior pole (zone 1 retinitis) accounts for approximately one half of incident visual acuity loss. Cataract and retinitis-related retinal detachment are also common causes of vision loss (Thorne 2006).

All CMV treatment regimens can prevent progression of lesions, but not reverse them.  Eye pain, burning, increased production of tears, and conjunctival irritation are not typical. However, many patients suffer from systemic symptoms such as fever and weight loss.

Diagnosis

Diagnosis is made by fundoscopy. Assessment of the usually peripheral, whitish exudates is dependent on the experience of the ophthalmologist. However, this can frequently be a problem, due to the rare occurrence of CMV retinitis nowadays. Unfortunately, incorrect diagnoses that are ill-fated due to the valuable time and, in worst case scenarios, retina lost are no exception. Therefore, if the primary ophthalmologist remains undecided, then it is best to start with oral valgancyclovir and transport the patient to a larger clinical center with ophthalmologists who are experienced in HIV. Furthermore, it is essential that the ophthalmologists receive information about the patient’s immune status. In cases of poor immune status and CD4 count less than 100/µl, chorioretinitis caused by Toxoplasma gondii is the most important differential diagnosis. CMV retinitis can almost be excluded at CD4 T cell counts above 100/µl; other viral infections (HSV, VZV) or even neurosyphilis should then be considered. CMV lesions may also be confused with cotton wool spots, which are not rare in HIV patients with high HIV viral load. Multiple small lesions without hemorrhage or exudates are almost always cotton wool spots, and almost never CMV retinitis. Bilateral involvement is also usually the exception. Vitritis is rare, except with immune reconstitution syndrome.

CMV serology (IgG almost always positive, IgM variable) is only seldomly helpful for diagnosis. CMV PCR or a blood test for pp65 antigen to detect antibodies against a CMV-specific phosphoprotein may be more useful. CMV retinitis or a recurrence is unlikely with a negative PCR or pp65 result. The higher the levels of CMV viremia, the higher the risk of CMV disease. Patients with positive CMV PCR have a 3-5-fold elevated risk (Casado 1999, Nokta 2002). Positive CMV PCR is also independently associated with a poor prognosis for the patient (Deayton 2004, Jabs 2005, Wohl 2005). As with Toxoplasma gondii, there have been efforts to determine the antigen-specific immune response more precisely (Jacobsen 2004), although such testing is not yet routine.

Treatment

CMV treatment should always be initiated promptly and strictly monitored by fundoscopy  at least once a week in the beginning. Photodocumentation is advisable. Initially, an intensive induction therapy is administered for two to three weeks, until there is scar formation of the lesions. HIV clinicians and ophthalmologists should work closely together, particularly during the induction therapy, and when possible, communicate several times a week. Induction therapy is followed by maintenance therapy at a reduced dose.

ART in particular has dramatically improved the prognosis of patients. That said, all diagnosed patients should start ART without delay. This can restore CMV-specific immune responses (Komandouri 1998), so that CMV viremia may disappear even without specific therapy after a few weeks (Deayton 1999, O’Sullivan 1999). However, if retinitis is present, CMV-specific treatment should nevertheless be started, as immune reconstitution may take several months.

Systemic treatment

Valgancyclovir, a prodrug of gancyclovir with good oral absorption, is the first choice in CMV treatment. In a randomized study (Martin 2002) on 160 patients with retinitis, the results were impressive: valgancyclovir tablets were just as effective as gancyclovir infusions. However, the toxicity profile of both agents was comparable. This means, in cases of oral treatment, that the blood count has to be as frequently monitored as for infusions and that the indication has to be equally carefully set. Treating a positive IgM serology (without any further diagnosis) with valgancyclovir is not only expensive, but also usually an unnecessary risk.

Other options for systemic treatment have become less important, and are only used in cases of recurrence. If there is intolerability or more rarely (Martin 2007) resistance to valgancyclovir (Drew 1999), then foscarnet remains an option. This, however, requires daily infusions. Further problems with this drug include nephrotoxicity, and very painful penile ulcers. Very intensive hydration of the patient is therefore necessary under all circumstances. However, there a some experts in the field who prefer intravenous CMV treatment in advanced cases.

There are no direct comparative studies available for cidofovir, which is also used occasionally. The benefit of the long half-life (once weekly dosing possible) is outweighed by the considerable renal toxicity of this drug (Plosker 1999). We observed creatinine elevations in every second patient treated, despite the fact that a strict infusion plan was closely followed (see Drugs section).

New anti CMV drugs are not expected for the next years. Maribavir recently failed to show a benefit in phase III studies (Marty 2011, Snydman 2011). Monoclonal antibodies (MSL-109) or compounds such as cyclopropavir or BAY 38-4766 are still in early phases of development.

Additional treatment with G-CSF (filgrastim) improved survival in one analysis of three large studies enrolling patients with CMV retinitis in the years 1990-1997. In particular, there was a reduction of bacterial infections. However, the reason for this positive effect remains unclear. Thus, administration of filgrastim is presently not generally recommended (Davidson 2002).

Local treatment

Several options for local treatment of CMV retinitis have been tested (review in: Smith 1998). Although such treatments can be safely administered by experienced ophthalmologists and are associated with few complications (infections, hemorrhage), disadvantages remain. Weekly intravitreal injections of gancyclovir or foscarnet, or pellet implantation (Vitrasert®, must be replaced every 6-9 months) do not protect from infection of the contralateral eye or from extraocular manifestations (Martin 1999). The same is true for fomivirsen (Vitravene®), an antisense-oligonucleotide for intravitreal injection, which is astonishingly effective even with multiresistant CMV strains (Perry 1999). These local treatments have become less important since ART and valgancyclovir, and some have been taken off the market.

Treatment/prophylaxis of CMV retinitis (daily doses, if not specified otherwise)

Acute therapy

Duration: always at least three weeks

Treatment of choice

Valgancyclovir

Valgancyclovir (ValcyteÒ) 2 tbl. at 450 mg bid (note: some experts prefer intravenous therapy in advanced cases)

Alternative

Gancyclovir

Gancyclovir 5 mg/kg i.v. bid

Alternative

Foscarnet

Foscarnet 90 mg/kg i.v. bid

Alternative

Gancyclovir +

Foscarnet

Half of the doses above

Maintenance therapy

Discontinue from > 100-150 CD4 cells/µl > 6 months

Treatment of choice

Valgancyclovir

Valgancyclovir (ValcyteÒ) 1 tbl. at 450 mg bid

Alternative

Foscarnet

Foscarnet 120 mg/kg i.v. qd on 5 days/week

Alternative

Cidofovir

Cidofovir 5 mg/kg i.v. qd every 14 days (plus probe-necid, hydration see Drugs section)

Primary prophylaxis

Not recommended

Prophylaxis

Primary prophylaxis: In the prospective studies that have been performed, no primary prophylaxis regimen has been convincing. There is also no effective vaccine. Therefore, the most important method for prevention in patients with CD4 counts less than 200 cells/µl is still fundoscopy every three months. With good immune reconstitution, intervals between examinations can be extended. It is important to perform a fundoscopy in severely immunocompromised patients prior to starting ART. This allows detection of smaller lesions, which may later present with severe inflammation during the course of immune reconstitution.

Secondary prophylaxis: After approximately three weeks of acute therapy, but at the earliest with scar formation of lesions, a reduced dose secondary prophylaxis (maintenance therapy) should begin, preferably with oral valgancyclovir (Lalezari 2002). However, the drug is not only very expensive but also just as myelotoxic as gancyclovir infusions. Discontinuation of secondary prophylaxis as quickly as possible, is therefore also desirable for this OI (MacDonald 1998, Tural 1998, Jouan 2001), but it also requires strict ophthalmologic monitoring. According to US guidelines, discontinuation should occur at the earliest after six months of maintenance therapy and with an immune reconstitution above 100-150 CD4 T cells/µl. However, we have even successfully stopped gancyclovir at lower CD4 T cell counts, if both HIV and CMV PCR in blood were below the level of detection. One study showed that stopping after 18 months of ART/maintenance therapy can be safe above 75 CD4 T cells/µl (Jouan 2001). After stopping maintenance therapy, funduscopy should be performed every four weeks over the first months.

The previously required life-long daily infusions of gancyclovir or foscarnet via port, pumps and nursing service are luckily now a thing of the past. If there are relapses under oral valgancyclovir, it is proposed that re-induction and maintenance therapy with foscarnet or possibly with cidofovir.

References

Casado JL, Arrizabalaga J, Montes M, et al. Incidence and risk factors for developing cytomegalovirus retinitis in HIV-infected patients receiving protease inhibitor therapy. AIDS 1999, 13:1497-1502.

Davidson M, Min YI, Holbrook JT, et al. Use of filgrastim as adjuvant therapy in patients with AIDS-related cytomegalovirus retinitis. AIDS 2002, 16: 757-65.

Deayton J, Mocroft A, Wilson P, et al. Loss of cytomegalovirus viraemia following HAART in the absence of specific anti-CMV therapy. AIDS 1999, 13:1203-6.

Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving HAART. Lancet 2004, 363:2116-21.

Goldberg DE, Wang H, Azen SP, Freeman WR. Long term visual outcome of patients with cytomegalovirus retinitis treated with highly active antiretrovi-ral therapy. Br J Ophthalmol 2003, 87:853-5.

Goodgame RW. Gastrointestinal cytomegalovirus disease. Ann Intern Med 1993, 119:924-35.

Jabs DA, Martin BK, Forman MS, et al. Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant CMV in patients with CMV retinitis. J Infect Dis 2005, 192:640-9.

Jabs DA, Martin BK, Ricks MO, Forman MS. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006, 193:1728-37.

Jacobson MA, Maecker HT, Orr PL, et al. Results of a cytomegalovirus (CMV)-specific CD8+/interferon- gamma+ cytokine flow cytometry assay correlate with clinical evidence of protective immunity in patients with AIDS with CMV retinitis. J Infect Dis 2004, 189:1362-73.

Jacobson MA, Stanley H, Holtzer C, et al. Natural history and outcome of new AIDS-related cytomegalovirus retinitis in the era of HAART. Clin Inf Dis 2000, 30:231-3.

Jouan M, Saves M, Tubiana R, et al. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving HAART. AIDS 2001, 15: 23-31.

Jutte A, Fätkenheuer G, Hell K, Salzberger B. CMV sinusitis as the initial manifestation of AIDS. HIV Med 2000, 1:123-4.

Komanduri KV, Viswanathan MH, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and HAART in individuals infected with HIV-1. Nature Med 1998, 8:953-6.

Lalezari J, Lindley J, Walmsley S, et al. A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr 2002, 30:392-400.

Macdonald JC, Torriani FJ, Morse LS, et al. Lack of reactivation of CMV retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4+ T cells in response to HAART. J Infect Dis 1998, 177:1182-7.

Martin DF, Kuppermann BD, Wolitz RA, et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999, 340: 1063-70.

Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002, 346:1119-26.

Martin BK, Ricks MO, Forman MS, Jabs DA. Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis. Clin Infect Dis 2007;44:1001-8.

Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis 2011, 11:284-292.

No authors listed. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial: 5. Clinical features of cytomegalovirus retinitis at diagnosis. Studies of ocular complications of AIDS Research Group in collaboration with the ACTG. Am J Ophthalmol 1997,124:141-57.

Nokta MA, Holland F, De Gruttola V, et al. Cytomegalovirus polymerase chain reaction profiles in individuals with advanced HIV infection: relationship to CMV disease. J Infect Dis 2002, 185:1717-22.

O’Sullivan CE, Drew WL, McMullen DJ, et al. Decrease of cytomegalovirus replication in HIV infected-patients after treatment with HAART. J Infect Dis 1999, 180:847-9.

Perry CM, Balfour JA. Fomivirsen. Drugs 1999, 57:375-80.

Plosker GL, Noble S. Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS. Drugs 1999, 58:325-45.

Salzberger B, Hartmann P, Hanses F, et al. Incidence and prognosis of CMV disease in HIV-infected patients before and after introduction of combination antiretroviral therapy. Infection 2005, 33:345-9.

Smith CL. Local therapy for cytomegalovirus retinitis. Ann Pharmacother 1998, 32:248-55.

Snydman DR. Why did maribavir fail in stem-cell transplants? Lancet Infect Dis 2011, 11:255-7.

Thorne JE, Jabs DA, Kempen JH, et al. Causes of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006, 113:1441-5.

Thorne JE, Jabs DA, Kempen JH, et al. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006, 113:1432-40.

Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in HIV-infected patients. J Infect Dis 1998, 177:1080-3.

Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Arch Intern Med 1998, 158:957-69.

Wohl DA, Zeng D, Stewart P, et al. cytomegalovirus viremia, mortality, and end-organ disease among patients with AIDS receiving potent antiretroviral therapies. JAIDS 2005, 38:538-544.

Leave a comment

Filed under 11. Opportunistic Infections, CMV Retinitis, Part 3 - AIDS

Candidiasis

– Christian Hoffmann –

Candidiasis is an infection with yeast-forming fungi. Of the 150 Candida species known to date, only approximately 20 cause disease. By far the most frequent species is C. albicans. Other species such as C. tropicalis, C. glabrata and C. krusei are rare, but may respond less readily to treatment with azoles. Although it is commonly assumed that azole resistance is a problem particularly with albicans strains, this has not been the case to date (Sanglard 2002).

Candidiasis is an important indicator of immunodeficiency and should be seen as a reason to consider starting ART, even with a good immune status. Esophageal candidiasis and even oral thrush often occur following other OIs. Fever, which is not a classic symptom of candidiasis, is a particular indication to be on the alert. If immune status is good, it must be remembered that there are also other reasons for thrush – alcoholism and steroid treatment are only two of many possibilities. In addition to candidiasis of the oropharynx and esophagus, vaginitis is a frequent problem in women (also occurring in healthy individuals). Candidemia occurs only rarely in HIV-infected patients, even with severe immunodeficiency.

Signs and symptoms

The oropharynx is usually affected, with taste disturbances and sometimes, a burning sensation on the tongue. White, non-adherent plaques on the buccal mucosa, tonsillar ring and tongue confirm the diagnosis. Involvement of the tongue alone is rare. Occasionally, there may be atrophic candidiasis, which presents only with an erythematous mucosa.

Candida esophagitis usually occurs with oropharyngeal involvement, but in about one third of cases there is no oral thrush. It often presents with dysphagia (“drinking is ok, but food can’t go down”) and retrosternal pain. Some patients complain of nausea, although vomiting occurs only rarely.

Diagnosis

Diagnosis in the oropharynx can be made based on the clinical appearance. A swab is not usually required. Characterization by culture or even determination of drug susceptibility (beware laboratory uncertainty!) is only advised if one treatment attempt with fluconazole or itraconazole has failed. Oral candidiasis is not to be confused with oral hairy leukoplakia (OHL). In contrast to candidiasis, the whitish, hairy plaques of OHL, on the sides of the tongue, cannot be scraped off. OHL is not caused by fungi but by EBV, and is an important disease marker for HIV, even if it is harmless and does not require treatment.

Candida esophagitis can also initially be diagnosed clinically. Dysphagia, retrosternal pain and oral candidiasis make the diagnosis very probable. Empiric fluconazole therapy reduces costs (Wilcox 1996). Upper GI endoscopy is only required if complaints persist. To distinguish fluconazole-resistant esophageal candidiasis from herpes or CMV esophagitis, samples of lesions should always be taken. In contrast, determination of serum antibodies or antigen is always unnecessary.

Treatment

With relatively good immune status and presentation for the first time, treatment with topical antimycotics such as nystatin, amphomoronal or miconazole can be attempted. However, systemic treatment is usually necessary. This is more effective and prevents relapses for longer (Pons 1997).

Fluconazole is the treatment of choice, and one week of oral treatment is usually sufficient (Sangeorzan 1994). According to a recently published trial, shorter treatment duration with higher dosages seems to be an option. In this large randomized study, a single dose of 750 mg of fluconazole was safe, well tolerated, and as effective as the standard 14-day fluconazole therapy (Hamza 2008).

If symptoms persist for more than a week, then a swab should be taken and the daily fluconazole dose may be increased up to 800 mg for the second attempt.  Itraconazole should only be used if the second treatment attempt fails and non-albicans strains have been found. It will be effective in approximately two thirds of cases (Saag 1997). Although itraconazole suspension is as effective as fluconazole (Graybill 1998), we do not primarily use it as plasma levels are unreliable and there are problems with numerous interactions.

Several new and promising antimycotics have been developed in recent years. However, these should only be used in clear cases of fluconazole resistance. There is insufficient evidence on the superiority of these drugs in the treatment of non-resistant candidiasis (Pienaar 2006). Voriconazole is expected to be as effective as fluconazole, but is possibly not tolerated as well (Ruhnke 1997, Ally 2001). This may be also true for posaconazole (Vasquez 2006). Like amphotericin B, these new azoles should only be used for treatment of multi-azole resistant mycoses. The new antimycotic class of echinocandins has also good efficacy, among them drugs such as caspofungin, micafungin or anidulafungin (Keating 2001, Villanueva 2001, Arathoon 2002, de Wet 2004, Reboli 2007). These drugs which can only be administered intravenously, showed similar efficacy and tolerability to intravenous fluconazole for treatment of candida esophagitis in randomized studies (Villaneuva 2001, de Wet 2004, Reboli 2007). Antiretroviral therapy should be initiated when such mycoses occur, particularly with multiresistant strains, as these usually disappear with sufficient immune reconstitution (Ruhnke 2000).

Treatment/prophylaxis of candidiasis  (daily doses)

Acute therapy

Duration: 5-10 days

In mild cases

Topical

e.g. amphotericin B 1 lozenge qid or

nystatin suspension 1 ml qid

Treatment of choice

Fluconazole

Fluconazole 1 x 1 cap at 100 mg for oral candidiasis

Fluconazole 1 x 1 cap at 200 mg for esophageal candidiasis (twice the dose on the first day in each case)

Alternative

Itraconazole

Itraconazole 1-2 cap. at 100 mg bid or

Itraconazole suspension 10-20 ml bid (1 ml = 10 mg)

Prophylaxis

Not recommended

Prophylaxis

No survival benefit has been demonstrated for any Candida prophylaxis to date (McKinsey 1999, Rex 2000, Goldmann 2005). In probably the largest randomized study on this theme, a reduction in oral candidiasis episodes as well as in invasive candidiasis was observed on long-term prophylaxis (Goldman 2005). The hypothesis that long-term prophylaxis will lead to the selection of resistant non-albicans strains (Vazquez 2001) was not confirmed in this study. Azole resistant infections were not seen more frequently in the long-term therapy group. Nonetheless, every immunocompromised patient should be screened for oral thrush at every visit.

References

Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voriconazole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect Dis 2001, 33:1447-54.

Arathoon EG, Gotuzzo E, Noriega LM, et al. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother 2002, 46:451-7.

de Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose-response study of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients. Clin Infect Dis 2004, 39:842-9.

Goldman M, Cloud GA, Wade KD, et al. A randomized study of the use of fluconazole in continuous versus episodic therapy in patients with advanced HIV infection and a history of oropharyngeal candidiasis: AIDS Clinical Trials Group Study 323/Mycoses Study Group Study 40. Clin Infect Dis 2005, 41:1473-80.

Graybill JR, Vazquez J, Darouiche RO, et al. Randomized trial of itraconazole oral solution for oropharyngeal candidiasis in HIV/AIDS patients. Am J Med 1998, 104:33-9.

Hamza OJ, Matee MI, Brüggemann RJ, et al. Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial. Clin Infect Dis 2008, 47:1270-6.

Keating GM, Jarvis B. Caspofungin. Drugs 2001, 61:1121-9; discussion 1130-1.

McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced HIV infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.

Pienaar ED, Young T, Holmes H. Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children. Cochrane Database Syst Rev 2006, 3:CD003940. Review.

Pons V, Greenspan D, Lozada-Nur F, et al. Oropharyngeal candidiasis in patients with AIDS: randomized comparison of fluconazole versus nystatin oral suspensions. Clin Infect Dis 1997, 24:1204-7.

Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007;356:2472-82.

Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000, 30:662-78.

Ruhnke M, Adler A, Muller FM. Clearance of a fluconazole-resistant Candida albicans strain after switching antifungal therapy and initiation of triple therapy for HIV infection. Clin Microbiol Infect 2000, 6:220-3.

Ruhnke M, Schmidt-Westhausen A, Trautmann M. In vitro activities of voriconazole (UK-109,496) against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients with HIV infection. Antimicrob Agents Chemother 1997, 41:575-7.

Saag MS, Fessel WJ, Kaufman CA, et al. Treatment of fluconazole-refractory oropharyngeal candidiasis with itraconazole oral solution in HIV-positive patients. AIDS Res Hum Retroviruses 1999, 15:1413-7.

Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am J Med 1994, 97:339-46.

Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002, 2:73-85.

Vazquez JA, Peng G, Sobel JD, et al. Evolution of antifungal susceptibility among Candida species isolates recovered from HIV-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001, 33:1069-75.

Vazquez JA, Skiest DJ, Nieto L, A multicenter randomized trial evaluating posaconazole versus fluconazole for the treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis 2006, 42:1179-86.

Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis 2001, 33:1529-35.

Walsh TJ, Gonzalez CE, Piscitelli S, et al. Correlation between in vitro and in vivo antifungal activities in experimental fluconazole-resistant oropharyngeal and esophageal candidiasis. J Clin Microbiol 2000, 38:2369-73.

Wilcox CM, Alexander LN, Clark WS, Thompson SE 3rd. Fluconazole compared with endoscopy for HIV-infected patients with esophageal symptoms. Gastroenterology 1996, 110:1803-9.

Leave a comment

Filed under 11. Opportunistic Infections, Candidiasis, Part 3 - AIDS

Tuberculosis

– Christoph Lange, Christian Herzmann, Giovanni Battista Migliori, Andrea Gori –

About 12% of all infections with the Mycobacterium tuberculosis complex (MTB, including M. tuberculosis, M. africanum, M. bovis, M. canetti and M. microti) occur in people living with HIV. In some African countries, up to 80% of tuberculosis (TB) patients are HIV seropositve, making it the most important opportunistic infection worldwide (WHO 2010, UNAIDS 2010). Although numbers of co-infection have been declining in the latest WHO report, the prevalence of HIV among TB patients remains extremely high in Africa (46%), the Americas (17%) and South-East Asia (13%). High rates of co-infection are also found in some smaller European countries like Portugal (12%), Estonia (10%), Malta (9%) and Latvia (8%) as well as in the urban metropolitan areas of European low prevalence countries (e.g. Brussels 9%). (ECDC 2011, Pimpin 2011, WHO 2010).

The spread of the TB epidemic is closely related to the HIV prevalence in the general population (Corbett 2003). The incidence of TB is more than eight times higher in HIV-positive than in HIV-negative people (Corbett 2006). In addition, there is concern that HIV may enhance the spread of multidrug resistant (MDR) TB (Dubrovina 2008, Cox 2010). With about 30.000 MDR-TB cases notified worldwide in 2009, its prevalence among all TB cases is high with up to 19% in Eastern Europe, 14% in Central Asia and 16% in the Russian Federation in comparison to 1.3-1.8% in Africa (WHO 2010).

Figure 1: HIV prevalence (%) in new TB cases (WHO 2010)

Figure 2: Percentage of HIV positive TB cases in Europe, 2009 (ECDC 2011)

Despite a steadily increasing prevalence of HIV-1 infection in Western Europe and North America in recent years, the incidence of TB has continuously declined in countries where ART is available (Kirk 2000, Girardi 2000, Nahid 2006). However, clinical management of MTB/HIV-coinfected patients is complicated due to a wide range of drug interactions, overlapping side effects of ART and anti-tuberculosis medications and low compliance caused by pill burden.

Interaction of HIV and MTB

HIV and MTB infections have synergic influence on the host immunoregulation. HIV infection impairs cell-mediated immunity largely through depletion of CD4 T cells. The impaired immunity leads to a higher susceptibility to MTB infection. In turn, it is likely that TB enhances the immunodeficiency related to HIV-infection (Toossi 2003). The incidence of primary TB and reactivated TB is greater in HIV-infected patients in comparison with HIV-seronegative individuals (Havlir 1999, Badri 2001). Although HIV-infected patients have a more than 50 times higher risk of TB reactivation, it is now clearly demonstrated that most patients develop disease after recent transmission, emphasizing the need for patient-to-patient infection control measures (Sonnenberg 2001, Horsburgh 2010, Houben 2011).

The incidence of post-primary TB ranges from 5-30% in HIV-infected subjects. The risk of active TB in patients with latent TB infection (LTBI) is approximately 8% per year in HIV-infected patients compared with a lifetime TB risk of 5-10% in HIV-seronegative individuals. In countries with a low TB prevalence HIV infected subjects have a 37-fold increased risk for TB, in countries with a high TB prevalence the risk is 21-fold increased (Getahun 2010). It has been shown that the risk of TB is already enhanced in the first year after HIV-seroconversion (Sonnenberg 2005). Low CD4 T cells, late presentation, low body mass index, anemia and a high HIV RNA despite ART are known risk factors for the development of TB (Van Rie 2011).

Despite adequate TB and HIV therapy, both morbidity and mortality remain increased in HIV-infected patients (Manas 2004, Whalen 2000). In the USA, TB mortality in 2006 was 9% in the general population but 20% in HIV-infected subjects (CDC 2010).

While most opportunistic infections, including non-tuberculosis mycobacterial infections (NTM), occur almost exclusively in advanced stages of HIV-infection, TB is prevalent at any stage regardless of the CD4 T cell counts (Ackah 1995). More than 50% of pulmonary TB cases occur in patients having more than 200 CD4 T cells/µl (Badri 2001). However, the incidence of disseminated TB is much higher in patients with advanced immunodeficiency (Wood 2000). TB is the leading cause of death among people with HIV infection (UNAIDS 2010)

Clinical manifestations

In the early stages of HIV-infection the clinical symptoms of TB are similar to those in HIV-negative patients. Fever, fatigue, night sweats and weight loss are common.

Pulmonary TB: As in HIV-negative cases, typical lesions of pulmonary TB in HIV-patients with more than 200 CD4 T cells/µl are upper-lobe lung infiltrates (with or without cavities). Tuberculosis granulomas are always present in these lesions. Cough and hemoptysis are frequent. Undefined lung opacities are often present on chest radiography as well as enlarged mediastinal lymph nodes. As immunodeficiency progresses, atypical pulmonary presentations or TB pleuritis become more frequent. Bronchopulmonary symptoms, such as cough and haemoptysis are often absent when TB occurs in the advanced stages of HIV infection. Because CD4 T cells are required for granuloma formation their cellular structure changes with increasing immunodeficiency (Diedrich 2011, Nambuya 1988). With the progression of immunodeficiency, hematogenous and lymphatic spread of mycobacteria is more common leading to miliary or disseminated TB or localized extrapulmonary TB (Elliott 1993, Kingkaew 2009).

Extrapulmonary TB occurs predominantly in patients with CD4 T cells below 200/µl, most commonly affecting the cervical lymph nodes (Schutz 2010). Lymph nodes are enlarged, hard and generally not painful on palpation. The formation of abscesses and draining fistulas as well as fever and malaise are common.

Tuberculosis meningitis often emerges with ambiguous prodromal symptoms such as headache, nausea and vomiting followed by elevated temperature and clinical signs of meningeal irritation. The basal meninges are usually involved and cranial palsies of the III and VI nerves are common. Mono-, hemi- or paraparesis as well as loss of consciousness and seizures can occur. In any patient with symptoms and signs of meningitis, a lumbar puncture should be performed without delay.

Other extrapulmonary localizations include pericarditis, osteoarthritis, the urogeni-tal tract and the skin. Tuberculosis lesions may involve adrenal glands causing Addison’s disease. Practically, any organ can be involved.

Miliary or disseminated TB: Clinical manifestations depend on multiple small granular lesions (lat. milium effusum) and their localization. Lungs may be involved and micro-nodular opacities are evident on chest x-ray. On radiological criteria alone, these lesions cannot be distinguished from pulmonary cryptococcosis. Miliary dissemination of TB can also involve the abdomen. In febrile patients with abdominal pain and ascites, peritoneal TB must be included in the differential diagnosis.

Diagnosis

The diagnosis is established based on clinical, radiological and microbiological findings. Diagnostic steps in the management of an HIV-infected patient with suspected TB do not differ from those with HIV-negative cases (Lange 2004). The differential diagnosis includes other infections such as NTM (e.g. M. avium complex), cryptococcosis, histoplasmosis, leishmaniosis, but also sarcoidosis, lymphoproliferative diseases, in particular non-Hodgkin lymphoma, and solid malignant neoplasia.

Radiology: Radiographic images of pulmonary TB can vary substantially. Pulmonary TB can mimic a variety of other pulmonary diseases and can be present without evident changes on chest radiography. However, typical chest radiographic findings are ill-defined single or multiple opacities in the upper lobe, with or without cavities inside the opacities, and enlarged mediastinal lymph nodes. Calcifications and fibrotic scar formation may be either a sign of healed pulmonary TB or a clue of re-activated disease. In miliary TB, the chest radiography shows disseminated micro-nodular opacities. Patients with low CD4 cell counts are less likely to present with typical radiographic changes but may have a normal chest X-ray, no cavities or a pleural effusion (Chamie 2010). In case of doubt, a chest CT scan is recommended whenever possible. If extrapulmonary TB is diagnosed, lung radiographic imaging as well as abdominal ultrasound should be performed to identify possible pulmonary disease, liver and spleen abscesses, thickening of the intestinal mucosa or ascites.

Respiratory samples: When pulmonary TB is suspected, three sputum samples should be collected on consecutive days for mycobacterial culture and direct sputum smear examination for acid fast bacilli (AFB). Sputum quantity (>3-5 ml) and its origin from the lower respiratory tract is essential, since smear microscopy for AFB and mycobacterial cultures remain sterile otherwise.

If patients are unable to cough deeply or cannot produce sputum, induced sputum should be provoked by 10-15 minutes inhalation of hypertonic sodium (3%) chloride. The collection of early morning gastric aspirate is an alternative if bronchoscopy is not available. The aspirate should be buffered in phosphate solution immediately. Bronchoscopy is indicated when the clinical findings remain highly suspicious for TB. Bronchial secretions or bronchoalveolar lavage obtained by bronchoscopy do not allow a more sensitive or specific diagnosis of TB than sputum smear in patients with HIV infection (Conde 2000). However, bronchoscopy is very helpful in the differential diagnosis of TB and other diseases particularly since co-existence of several pulmonary diseases is frequent in patients with HIV-infection (Narayanswami 2003). Furthermore, histopathological examination of transbronchial biopsies may show typical tuberculosis granulomas. On the day after bronchoscopy, sputum should be collected as the microscopic yield is higher following the intervention even if no mycobacteria were detected in lavage fluid.

Mycobacterial culture: Sputum and all other biological materials (including heparinised blood, urine, fluids, biopsies) should always be sent for culture that detects MTB with a high sensitivity and specificity. The gold standard for the diagnosis of TB is culture identification of MTB after incubation of biological samples preferentially in liquid media or alternatively in solid media. Liquid media take less time (2-4 weeks) than solid media (3-5 weeks) until a positive result can be obtained. A mycobacterial culture is only considered negative if no mycobacteria are identified after 6-8 weeks of incubation. Non-tuberculous mycobacteria (NTM) usually grow much faster than MTB and can often be identified within two weeks of incubation. All new clinical isolates of MTB should undergo drug susceptibility testing for first-line and in case of MDR TB for second-line antibiotic regimens.

Microscopy: For sputum and all other biological materials direct microscopy should be performed after staining to detect AFB. The sensitivity of fluorescence microscopy (49%) is superior to conventional light microscopy (38%) (Cattamanchi 2009). Specificity of direct sputum microscopy is poor. At least 5,000-10,000 mycobacteria per slide are necessary to achieve a positive result in a routine setting. Approximately 50% of all patients with culture positive pulmonary TB are AFB smear negative on three consecutive sputum samples. AFB positive smears are present in approximately 5% of cases where pulmonary lesions are not visible on standard chest radiography (Ackah 1995). In addition, discrimination between MTB and other acid fast bacteria is not possible by microscopy. The differential diagnosis includes infections with NTM, nocardiae and rhodococci. Microscopy in HIV-infected patients with >200 CD4 T cells /µl and typical radiographic changes has the same yield as in HIV-seronegative patients. With advanced immunodeficiency, the likelihood of an AFB positive smear decreases (Chamie 2010).

Biopsies of lymph nodes, pleura, peritoneum, synovia and pericardium and diagnostic fluid aspirates from all anatomic compartments are suitable for AFB microscopy and histological examination for typical granulomas.

Nucleic acid amplification (NAAT): Mycobacterial nucleic acid (DNA or RNA) can be detected in biological samples by a routine PCR test. MTB PCR test is faster than culture and more sensitive and specific than acid-fast staining. NAAT is especially helpful for differentiation of mycobacterial species when AFB are visible on microscopy. Under these circumstances, the sensitivity of MTB PCR is >95%. Unfortunately, the sensitivity decreases to 36-82% even for new diagnostic tools like the Cepheid Xpert when smear negative morning sputa are analysed directly (Rachow 2011, Boehme 2010). Because PCR can yield false negative results, reports should always be interpreted within the clinical context. A major advantage of modern NAAT is the detection of resistance mutations within a few hours, enabling the physician to initiate an adequate antituberculosis drug regime.

In extrapulmonary TB, for example tuberculosis meningitis, where direct microscopy is often negative but a rapid diagnosis is needed, MTB PCR testing should be performed as part of the initial evaluation. For PCR analysis, biopsy samples should not be kept in formalin but rather be preserved in “HOPE” (Hepes-glutamic acid buffer-mediated organic solvent protection effect) media (Olert 2001).

Tuberculin skin test (TST): If no AFB are visible on microscopy but TB is still suspected, a TST, also known as purified protein derivative (PPD) test is recommended. A positive TST (or PPD) indicates an immunological memory to previous or ongoing contact with MTB. Positive TST results may also be found in patients who were BCG-vaccinated or who had contact with NTM. On the other hand, the TST in HIV positive patients with active TB has a sensitivity of only 31%. The sensitivity of TST is  even more decreased, when CD4 cell counts decline (Syed Ahamed Kabeer 2009).

The TST should only be administered intradermally according to the method described by Mendel and Mantoux. The standardized dose recommended by WHO and the International Union against Tuberculosis and Lung Diseases (IUATLD) is 2 Tuberculin Units (TU)/0.1ml PPD RT23/Tween 80. In the US and other countries, the standardized dose is 5 TU/0.1ml PPD-S, which is thought to be similar in strength. 48-72 hours after intradermal injection, the diameter of induration (not redness) of the injection site is measured along the short axis of the forearm (Sokal 1975). According to the Infectious Diseases Society of America (IDSA), the TST is positive if the induration diameter is >5mm in HIV infected persons (≥5 mm in HIV negative subjects). The IDSA guidelines for interpretation of the TST result are based on results of clinical studies that were conducted with 5 TU PPD-S in the US and therefore cannot be directly applied to other countries where different antigens are used.

Interferon-γ Release Assay (IGRA): Recently, IGRAs have been introduced for the diagnosis of MTB infection. They detect the secretion of IFN-γ by peripheral blood mononuclear cells (PBMC) that is induced by specific MTB peptides (ESAT-6 and CFP-10). However, the tests were developed to detect latent tuberculosis infection (LTBI, see below), not active disease (Chen 2011). Accordingly, the sensitivity of the Quantiferon TB-Gold in-tube test has a sensitivity of only 65% in HIV patients with active tuberculosis and shows no additional value in the diagnostic workup of HIV positive, AFB negative TB suspects (Syed Ahamed Kabeer 2009, Rangaka 2011). However, IGRAs are more sensitive and specific than the TST for diagnosis of MTB infection in patients with immunodeficiency (Chapman 2002, Pai 2004, Ferrara 2006, Rangaka 2007b, Jones 2007, Luetkemeyer 2007, Leidl 2009). Two IFN-gamma blood tests are currently available: an ELISA (Quantiferon TB-Gold in-tube test) and an ELISPOT (T-SPOT.TB Test). Two trials demonstrated a better sensitivity for the ELISPOT assay in HIV infection (Lawn 2007, Mandalakas 2008). Importantly, the ELISPOT test result is much less dependent on the level of CD4 T cells (Rangaka 2007a, Hammond 2008, Stephan 2008, Kim 2009), while the IFN-gamma response in the ELISA strongly correlates to the CD4 T cell count (Leidl 2009). In patients with advanced immunodeficiency ELISA can therefore not be recommended for the diagnosis of LTBI. The sensitivity and specificity of the ELISPOT assay can possibly be improved further by relating them to the CD4 T cells of the patient (Oni 2010). Sequential IGRA measurements to monitor tuberculosis activity or treatment are not useful (Connell 2010, Lee 2010).

The detection of antibodies against mycobacterial components has no role in modern tuberculosis diagnostics.

Therapy

First-line drugs include rifampicin (RMP), isoniazid (INH), ethambutol (EMB) pyrazinamide (PZA) and streptomycin (SM). SM is only available as IM or IV formula and may thus not be considered “first-line”. INH and RMP are the most potent drugs. Second-line drugs include amikacin, capreomycin, cycloserine, levofloxacin, linezolid, moxifloxacin, prothionamide and rifabutin (RB).

Common cases of pulmonary TB can be treated with a standard 6-month treatment course, regardless of the HIV status. To prevent the development of drug resistance, active TB should always be treated with a combination of four drugs in the initial phase. The standard therapy consists of a 2-months course of RMP, INH, EMB and PZA, followed by a continuation phase therapy of 4 months with RMP and INH. Drug dosages are listed in Table 1. The four initial drugs should be administered until culture test results show drug susceptibility of MTB isolates.

Hospitalization is generally indicated to prevent the spread of the infection. As long as AFB are detected in the sputum or in the bronchoalveolar lavage, the patient should be treated in isolation. The duration of the infectious period in pulmonary TB depends on the extent of pulmonary lesions and cavities. Sputum should be regularly collected (weekly in the initial phase), evaluated for AFB by direct microscopy and for viable MTB by culture until the end of treatment. The infectiousness is considered to be very low once AFB are repeatedly absent in sputum smears. When at least three sputum samples obtained on different days are AFB negative, therapy can be continued as an outpatient. There appears to be no difference between HIV negative and HIV positive patients in the duration of therapy until the sputum becomes AFB negative and cultures remain sterile (Bliven 2010, Senkoro 2010). However, viable MTB can usually be cultured from sputum for a few weeks after microscopy has become AFB negative. Patients with MDR TB should be kept in isolation until both microscopy and sputum cultures remain negative.

Failure of therapy is associated with drug resistance, poor drug compliance or insufficient treatment duration (Sonnenberg 2001, Korenromp 2003). If sputum cultures are still positive after the initial phase of treatment or if the initial drug regimen was different from standard therapy (e.g. did not include RMP and INH), therapy should be extended to 9 months or longer (i.e., the continuation phase should be extended to 7 months or longer). Treatment is also longer than a standard 6-months course for AIDS patients, cavitary pulmonary TB and TB meningitis.

Adverse events

The most frequent and significant adverse events of antituberculosis drugs are listed in Table 1. INH should routinely be co-administered with prophylactic pyridoxine (vitamin B6) to prevent peripheral polyneuropathy .

Before and during therapy with EMB, colour vision should be examined and monitored as this drug may affect the optic nerve. Dosages of EMB and PZA need to be adjusted in patients with impaired renal function. In patients with liver disease (including drug induced hepatitis), the choice of first-line drugs is limited as RMP, INH and PZA can worsen the liver injury. In these cases, a combination of EMB, streptomycin, cycloserine, moxifloxacin and/or linezolid may be administered. Since this second-line therapy is no different from that of MDR TB, these patients should be treated in specialized centres. Audiometric monitoring should be performed when streptomycin is used. Following the start of TB therapy, liver enzymes, serum creatinine and complete blood count should be monitored on a regular basis (e.g. in the initial phase every week, then every 4 weeks). Hyperuricemia is common when PZA is used. A mild polyarthralgia can be treated with allopurinol and non-steroidal antiphlogistic drugs. Arthralgia can also be induced by RMP and RB.

Table 1: Antituberculosis drug doses, side effects and drug interactions

Antituberculosis drugs

Recommended daily dose

Common adverse events

Drug interactions

Comments

Rifampicin

(RMP)

 

Also available for IV injection

10 mg/kg

 

> 50 kg: 600 mg

< 50 kg: 450 mg

Elevation of liver enzymes, toxic hepatitis; aller-gy, fever; gastrointestinal disorders; disco-loration (orange or brown) of body fluids; thrombopenia

Many drug interactions: induces cytochrome p450

(for ART drug interactions see Table 3)

Monitor LFTs*

Isoniazid

(INH)

 

Also available for IV or IM injection

5 mg/kg

maximum
300 mg/day

 

Administer with vitamin B6

Peripheral neuropathy; eleva-ted liver enzy-mes, toxic hepatitis; CNS side effects: psychosis, seizures

Avoid d4T, ddI

Avoid administration if pre-existing liver damage; avoid alcohol

Ethambutol (EMB)

40-55 kg: 800 mg/day

56-75 kg: 1.2 g/day

76-90 kg: 1.6 g/day 

Optic neuritis; hyperuricemia; peripheral neuropathy (rare)

 

Antiacids may decrease absorption

Baseline screen for visual acuity and colour perception (repea-ted monthly);

contraindicated in pts with pre-existing lesions of optic nerve

Pyrazinamide (PZA)

30 mg/kg/day

 

maximum 2.0 g/day

Arthralgia, hyperuricemia, toxic hepatitis, gastro-intestinal discomfort

 

Hyperuricemia: uricosuric drug (allopurinol); monitor LFTs.

Streptomycin

IV/IM administra-tion only

0.75-1 g/day

< 50 kg: 0.75 g/day

> 50 kg: 1 g/day

maximum cumulative dose 50 g!

Auditory and vestibular nerve damage; renal damage; allergies, nausea, skin rash, pan-cytopenia

 

Audiometry; monitor renal function; should not be used in pregnancy

Amikacin

IV/IM administra-tion only

1 g/day

Maximum cumulative dose 50 g!

Auditory and vestibular nerve damage

 

Audiometry; monitor renal function; do not use in pregnancy

Capreomycin

IV/IM administra-tion only

15 – 30
mg/kg/day
max 1 g/day
> 50 kg: 1 g
< 50 kg: 0.75 g
maximum cumulative dose: 50 g

Renal damage, Bartter-like syndrome, auditory nerve damage

 

Audiometry; cumulative dose should not be exceeded; monitor renal function; should not be used in pregnancy

Cycloserine

10-15 mg/kg day

 

maximum
1,000 mg/day

CNS disorders,
anxiety, confus-ion,  dizziness,
psychosis, seizures, headache.

Aggravates CNS side effects of INH and prothionamide.

Contraindicated in epileptics; CNS side effects occur usually within the first 2 weeks

Levofloxacin

 

Also available for IV injection

500 or 1,000 mg/day

 

Gastrointestinal discomfort, CNS disorders, tendon rupture (rare)

 

Not approved for treatment in children; in adults rather use Moxifloxacin

Linezolid

600 mg /day

Thrombopenia, anemia, CNS disorders

 

Evidence for cli-nical use relies on case reports; expensive

Moxifloxacin

 

Also available for IV injection

400 mg/ day

Gastrointestinal discomfort, headache, dizziness, hallucinations

 

Similar activity as rifampin, drug resistance is still rare

Prothionamide

0,75–1 g/day

CNS disorders; liver damage, gastrointestinal discomfort

 

Slowly increase dosage; monitor LFTs

Rifabutin

(RB)

 

300 mg/day

Gastrointestinal discomfort; discoloration (orange or brown) of urine and other body fluids; uveitis; elevated liver enzymes; arthralgia

Weaker inducer of  cp450 than rifampin;

(for ART drug interactions see Table 3).

Monitor LFTs;

generally preferred instead of rifampin in patients treated with ART drugs (see Table 3)

*LFTs: Liver function tests.
**CNS: Central nervous system.

Patients who exhibit severe adverse events should always be hospitalized for diagnosis and treatment. Drugs thought to be responsible for a given adverse event ought to be discontinued. If visual disturbance occurs on EMB, renal failure or shock or thrombocytopenia on RMP and vestibular dysfunction on streptomycin therapy, re-exposure to these agents must be avoided. Other drugs can be reintroduced one by one when symptoms resolve, beginning with the drug that is least likely to cause the adverse event. All drugs should be restarted at low dosages and dosages should be increased stepwise (Table 2). When no adverse effects occur after 3 days, additional drugs can be added. The drug that is most likely to be responsible for an adverse effect should be the last one to be restarted if no alternative is available.

If toxic hepatitis occurs, then all drugs should be stopped until the serum bilirubin and liver transaminases have normalized. In many cases, it is possible to re-introduce the causative drug (usually INH, RMP or PZA) with increasing dosage without further hepatic complications.

When second-line drugs are used it is usually necessary to prolong the standard treatment duration.

Table 2: Re-introduction of TB drug following drug adverse event

Drug

Day 1

Day 2

Day 3

INH

50 mg

300 mg

5 mg/kg/day (max 300 mg/day)

RMP

75 mg

300 mg

10 mg/kg/day (max 600 mg/day)

PZA

250 mg

1,000 mg

25 mg/kg/day (max 2 g/day)

EMB

100 mg

500 mg

25 mg/kg/day for 2 months then 15 mg/kg/day

Streptomycin

125 mg

500 mg

15 mg/kg/day (max 1 g/day)

ART and TB therapy

Independent of the status of ART, uncomplicated non-cavitary pulmonary TB in HIV-infected patients can be treated using standard 6-months course with a similar success rate as in HIV-negative individuals (Burman 2001, Chaisson 1996, Hung 2003). If the therapeutic response is delayed (i.e. when sputum cultures are still MTB positive after 2 months of the initial phase), the TB therapy should be extended to at least 9 months.

A few issues must be considered regarding simultaneous ART and TB therapy.

Paradoxical reaction: Following initiation of TB therapy, patients already treated with ART present with paradoxical reactions (lymphadenopathy, fever or increasing pulmonary infiltrates) five times more often than ART naïve patients (Breen 2005). An acute exacerbation of a TH1 immune response against mycobacterial antigens seems to be responsible for the paradoxical reaction in ART experienced HIV/MTB co-infected patients (Bourgarit 2006).

Unmasked TB and immune reconstitution inflammatory syndrome (IRIS): Unmasked TB represents the progression of an undiagnosed subclinical TB disease which is already present before starting ART. The recovery of pathogen-specific immune responses during the initial months of ART trigger the unmasking of a subclinical disease. Screening strategies for underlying TB need to be carefully emphasized in order to prevent severe unmasking manifestations. All patients starting ART with an advanced immunodeficiency and principally those with access to ART programs in resource-limited settings, should undergo microscopic and culture screening for TB regardless of the presence or absence of symptoms.

A similar immunopathogenic mechanism is responsible for a form of tuberculosis progression termed IRIS. Patients with TB and advanced HIV infection can show a clinical progression of tuberculosis after ART is commenced. Even in the presence of TB treatment, ART is associated with immunereconstituion  and dysregulation resulting in the deterioration TB, mainly due to a strong inflammatory component (Lawn 2008). IRIS has been reported to occur in 25-60% of severely immunodeficient patients in the first three months of ART treatment and has been associated with a rapid immunologic and virologic response to ART (Michaelidis 2005, Lawn 2005a). The mortality of TB-IRIS was 10% in one Ugandan study (Worodria 2011). The criteria for the diagnosis of IRIS have been defined in an international consensus statement 2008 (Meintjes 2008). In summary, classic symptoms of TB are required (fever, lymphadenopathy, pulmonary consolidations, neurological symptoms, serositis). Notably, more than 10% of TB-IRIS cases in high prevalence countries are due to mycobacteria showing a previously undetected resistance to RMP (Meintjes 2009).

Although IRIS can lead to paradoxical exacerbations, the diagnosis of TB must trigger the introduction of ART in HIV infected patients (OARAC 2011). During IRIS, both ART and TB therapy should be continued (OARAC 2011). A trial performed in South Africa found a clinical benefit of prednisolone administration for the treatment of IRIS (1.5 mg/kg for 2 weeks, followed by 0.5 mg/kg for 2 weeks) (Meintjes 2010). However, data on IRIS therapy is sparse and no evidence based recommendations can be made yet.

Adherence to therapy is difficult to achieve due to the large number of ART and anti-tuberculosis drugs administered simultaneously and their overlapping toxicities. The most decisive determinant for the success of TB treatment is a good drug adherence for the entire duration of therapy. When compliance is impaired, the development of drug resistance and relapses are common. Therefore, WHO recommends that all patients with TB should be enrolled in directly observed therapy (DOT) programs.

Drug interactions: There are many pharmacological interactions between ART and anti-tuberculosis drugs (Table 3 and 4). Both RMP and protease inhibitors (PIs) are metabolized by cytochrome P450 3A. Concomitant therapy with PIs and RMP is generally not recommended (OARAC 2011, EACS 2009) (Table 3). The preferred antiretroviral regimen is efavirenz (<60kg: 600 mg QD; >60kg 800 mg QD) in combination with TDF+FTC when rifampin therapy is mandatory. In individual patients, screening for a CYP2B6 516G→T polymorphism may be justified to determine the interaction between efavirenz and RMP (Kwara 2011). Alternatively efavirenz (standard dose) can be combined with rifabutin (450 mg QD) that has less cytochrome P450-3A inducing potential (OARAC 2011). The combination of nevirapine and RMP appears to achieve similar outcomes (Moses 2010).

A combination of 3-4 NRTIs (AZT, Abacavir, 3TC ± TDF) could represent a short-term option for patients with a viral load <100,000 copies/ml until TB treatment with RMP is completed. Rifabutin (150 mg three times weekly) can also be combined with boosted PIs, but one trial reported increased rates of neutropenia when combined with atazanavir/r (Table 4) (Zhang 2011). Other (off-label first line) regimens may include T-20 as it has no interactions with rifamycins (Boyd 2003).

There are limited data about the combination of rifampicin and some other antiretroviral agents like tipranavir and maraviroc. Maraviroc should only be given under close observation. Rifampicin also induces the enzyme UGT1A1, leading to in-creased glucoronidation and reduced plasma levels of raltegravir (Wenning 2009) while Rifabutin increases the raltegravir AUC by 19% (OARAC 2011). No significant pharmacokinetic interactions were reported with tenofovir (Droste 2005).

Table 3: Recommendations for co-administering ART with Rifampin*

Drug

Antiretroviral dosage adjustment

Rifampin dosage adjustment

Comment

Boosted PIs

No co-administration

No co-administration

Efavirenz

600 mg (<60 kg weight) or 800 mg (>60 kg weight) OD

None

Nevirapine

No co-administration

No co-administration

Etravirine

No co-administration

No co-administration

Rilpivirine

No data

No data

Maraviroc

600 mg BID

None

Raltegravir

800 mg BID

None

TDM if possible as RAL levels decrease by 61 %

NRTI

Standard dose

Standard dose

Triple NRTI therapy not recommended

* EACS 2009, OARAC 2011, CDC 2007 (modified)
Priority: Treatment of active TB always has clinical priority over ART.

Several studies suggested that simultaneous use of ART and anti-TB treatment in patients with less than 200 CD4 T cells, and most significantly in patients with less than 50 CD4 T cells (Havril 2011, Abdool 2011), could have a significant impact on survival (Schiffer 2007, Velasco 2009, Blanc 2010).

Moreover, a recent randomized trial demonstrated that, at least in resource-limited settings, ART has the potential to reduce mortality even in patients with relatively conserved immune function (CD4 T cells 200-500 cells/µl) (Abdool 2010).

When TB occurs in ART-naïve patients with 50-100 CD4 T cells/µl the mortality is high. Therefore simultaneous treatment of both infections is indicated (Dean 2002, EACS 2009, Velasco 2009, OARAC 2011). It is recommended that TB therapy is initiated first. If TB therapy is tolerated, ART can be introduced within two weeks. Patients need to be monitored closely as the risk of paradoxical reaction is high and there are some overlapping toxicities.

In TB patients with CD4 T cells of 100-350/µl, anti-tuberculosis therapy must be started as soon as possible. The initiation of ART can be delayed for 4 weeks according to US guidelines and 8 weeks according to European guidelines (EACS 2009, OARAC 2011). At a CD4 T cell count >350/µl, the US guidelines still recommend initiation of ART within 4-8 weeks after TB therapy was started. The European guidelines leave this decision at the physician’s discretion. Patients who are already on ART when TB develops should remain on ART, although antiretroviral regimen may need to be modified depending on the compatibility with anti-tuberculosis drugs (Dean 2002).

Patients with advanced immunodeficiency remain at high risk of developing TB despite ART, as function of the immune system is not fully restored by ART (Lange 2003, Lawn 2005a+b, Bonnet 2006, Sutherland 2006).

Table 4. Recommendations for co-administering ART with rifabutin*

Drug

Antiretroviral dosage adjustment

Rifabutin dosage adjustment

Comment

Boosted PIs (LPV/r, FPV/r, DRV/r, SQV/r, ATV/r)

Standard dose

150 mg every other day or 150 mg three times weekly

Efavirenz

Standard dose

450 mg / day

Nevirapine

Standard dose

Standard dose

Liver toxicity

Etravirine

No co-administration

No co-administration

Rilpivirine

No data

No data

Maraviroc

ART without PI: standard dose

With TPV/r or FOS-APV/r: 300mg BID

With other PI/r: 150mg BID

Standard dose

Raltegravir

Standard dose

Standard dose

* EACS 2009, OARAC 2011 (modified)

Therapy of latent TB infection (LTBI)

Latent tuberculosis infection (LTBI) is defined by a positive MTB specific immune response in the TST or an IGRA in the absence of active tuberculosis (Mack 2009). It is not clear which proportion of individuals with a positive MTB-specific immune response is indeed infected with viable MTB. Nevertheless, preventive chemotherapy is recommended for all HIV-infected individuals with a positive MTB-specific immune response in order to prevent active TB (Akolo 2010). HIV-infected persons should be given treatment if their reaction to the TST is ≥5mm. ELISPOT (T-SPOT.TB test) testing is superior to the TST and ELISA (Quantiferon-Gold in tube test) in HIV-infected individuals with low CD4 T cells (Leidl 2009).

The efficacy of prophylactic INH treatment in HIV-infected patients with LTBI has been demonstrated in several randomized studies (Bucher 1999, Elzi 2007). A 6-months prophylactic course of INH reduced the incidence of TB among HIV infected subjects from about 11.5 to 4-9 per 100 person-years (Grant 2005, Charalambous 2010). Therefore, a 6-9 months course of INH (300 mg daily) and pyridoxine is usually recommended for the treatment of LTBI. Alternatively, treatment with RMP (600 mg daily) can be offered. Other regimes consisting of rifapentine / INH weekly for 12 weeks, RMP / INH twice weekly for 12 weeks or INH daily for up to 6 years were not superior to the standard 6-months INH regime in HIV infected adults (Martinson 2011). In contrast, one study reported a 36-months INH regime to be superior to the standard 6-months course (Samandari 2011).  A two-months course of RMP+PZA was associated with adverse hepatic effects and is not recommended (Woldehanna 2004).

ART-naïve patients with negative TST do not benefit from either primary or secondary preventive chemotherapy of TB (Bucher 1999, Churchyard 2003). In addition, preventive chemotherapy with INH has no effect on the overall mortality (Woldehanna 2004). Although ART has a beneficial effect on the prognosis of HIV-positive patients with active TB, the effects of ART in LTBI are still unknown.

Multidrug resistant (MDR) TB and extensively drug resistant (XDR) TB

MDR TB means TB caused by MTB isolates resistant to at least RMP and INH, the two most efficient anti-TB drugs. Despite declining numbers of TB cases in many industrialized nations in recent years, the proportion of MDR TB is rising in many countries. For example, in Germany, 2.2% of all MTB isolates were MDR in 2004, compared to 2.5% in 2004 (Eker 2008). Of these, 90% were isolated from migrants from the Russian Federation. In this geographical region, up to 50% of MTB show INH resistance, and up to 21% show multidrug resistance (WHO 2010). In these cases, selection of the correct drug regimen for treatment of LTBI and active TB becomes problematic.

XDR TB is defined by the WHO as to be resistant to at least RMP, INH, fluoroquinolones (moxifloxacin and levofloxacin) and to at least one injectable drug (amikacin, capreomycin or kanamycin). Initial reports of a near 100% mortality of XDR-infected patients could not be confirmed in a meta-analysis (Gandhi 2006). However, a retrospective study from South Africa reported 30-day and 1-year mor-tality rates of 51% and 83%, respectively (Gandhi 2010). MDR TB continues to spread in South Africa despite good treatment adherence (Calver 2010). XDR TB has been already reported in at least 58 countries (WHO 2010). Until now, data on the management and prognosis of HIV/XDR TB coinfection is sparse.

Where possible, patients with MDR and XDR TB should be treated in specialized centers with second-line anti-tuberculosis drugs. Patients should not be discharged before repeated sputum cultures yield MTB negative results. In general, at least five anti-tuberculosis drugs that are in vitro active against the causative strain of MTB should be administered for 18–24 months after the sputum culture conversion. Long-term treatment with linezolid against MDR- and XDR TB has been associated with a high frequency of severe adverse drug events. Thus, linezolid should only be used when better options are not available (Migliori 2009).

Given the limited number of drugs available for the treatment of resistant MTB, the importance of tracing contact persons cannot be underestimated.


References

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010 Feb 25;362(8):697-706.

Abdool Karim S, et al. Abs 39LB, 18° CROI, Boston 2011

Akolo C, Adetifa I, Shepperd S, et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000171.

Ackah AN, Coulibaly D, Digbeu H, et al. Response to treatment, mortality, and CD4 lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Cote d’Ivoire. Lancet 1995, 345:607-10.

Badri M, Ehrlich R, Wood R, et al. Association between tuberculosis and HIV disease progression in a high tuberculosis prevalence area. Int J Tuberc Lung Dis 2001;5:225-32.

Blanc FX, Sok T, Laureillard D, et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Paper presented at: XVIII International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract THLBB106.

Bliven E., Burman W., Goldberg S. et al. Effect of HIV Infection on Outcomes of Therapy for Pulmonary TB in 2 Clinical Trials. 17th Conference on retroviruses and opportunistic infections, San Francisco, CA, 16.-19.2.2010, Abstract 782

Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. Epub 2010 Sep 1.

Bonnet MM, Pinoges LLP, Varaine FFV, et al. Tuberculosis after HAART initiation in HIV-positive patients from five countries with a high tuberculosis burdon. AIDS 2006; 20:1275-79.

Bourgarit A, Crcelain G, Martinez V, et al. Explosion of a tuberculin-specific TH1 immuneresponse induces immune restoration syndrome in tuberculosis and HIV-coinfected patients. AIDS 2006; 20:F1-F7.

Boyd MA, Zhang X, Dorr A, et al. Lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide. J Clin Pharmacol 2003, 43:1382-91.

Breen RA, Smith CJ, Cropley I, et al. Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy? AIDS 2005;19:1201-6.

Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials. Aids 1999;13:501-7.

Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001;164:7-12.

Calver AD, Falmer AA, Murray M, et al. Emergence of increased resistance and extensively drug-resistant tuberculosis despite treatment adherence, South Africa. Emerg Infect Dis 2010, 16:264-71.

Cattamanchi A, Davis JL, Worodria W, et al. Sensitivity and specificity of fluorescence microscopy for diagnosing pulmonary tuberculosis in a high HIV prevalence setting.Int J Tuberc Lung Dis 2009, 13:1130-6.

CDC 2007. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis Division of Tuberculosis Elimination National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC December 2007. http://www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/PDF/tbhiv.pdf (Last accessed 24.07.2011)

CDC 2010. Mortality Among Patients with Tuberculosis and Associations with HIV Status — United States, 1993–2008. MMWR Morb Mortal Wkly Rep. 2010 Nov 26;59(46):1509-13.

Chaisson RE, Clermont HC, Holt EA, et al. 6-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154:1034-8.

Chamie G, Luetkemeyer A, Walusimbi-Nanteza M, et al. Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata. Int J Tuberc Lung Dis. 2010 Oct;14(10):1295-302.

Chapman AL, Munkanta M, Wilkinson KA, et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by enumeration of Mycobacterium tuberculosis-specific T cells. AIDS 2002;16:2285-93.

Charalambous S, Grant AD, Innes C, et al. Association of isoniazid preventive therapy with lower early mortality in individuals on antiretroviral therapy in a workplace programme. AIDS. 2010 Nov;24 Suppl 5:S5-13.

Chen J, Sun J, Zhang R, et al. T-SPOT.TB in the diagnosis of active tuberculosis among HIV-infected patients with advanced immunodeficiency. AIDS Res Hum Retroviruses. 2011 Mar;27(3):289-94. Epub 2010 Oct 26.

Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy? AIDS 2003;17:2063-70.

Conde MB, Soares SL, Mello FC, et al. Comparison of sputum induction with fiberoptic bronchoscopy in the diagnosis of tuberculosis: experience at an AIDS reference center in Rio de Janeiro, Brazil. Am J Respir Crit Care Med 2000;162:2238-40.

Connell TG, Davies MA, Johannisen C, et al. Reversion and conversion of Mycobacterium tuberculosis IFN-gamma ELISpot results during anti-tuberculous treatment in HIV-infected children. BMC Infect Dis. 2010 May 27;10:138.

Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003;163:1009-21.

Corbett EL. Marston B, Churchyard GJ et al. Tuberculosis in sub-Saharan Africa: Opportunities, challenges and change in the era of antiretroviral treatment. Lancet 2006; 367: 926-37.

Cox HS, McDermid C, Azevedo V, et al. Epidemic levels of drug resistant tuberculosis (MDR and XDR-TB) in a high HIV prevalence setting in Khayelitsha, South Africa. PLoS One. 2010 Nov 15;5(11):e13901.

Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:75-83.

Diedrich CR, Flynn JL. HIV-1/mycobacterium tuberculosis coinfection immunology: how does HIV-1 exacerbate tuberculosis? Infect Immun. 2011 Apr;79(4):1407-17. Epub 2011 Jan 18.

Droste JA, Verweij-van Wissen CP, Kearney BP, et al. Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2005;49:680-4.

Dubrovina I, Miskinis K, Lyepshina S, et al., Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics? Int J Tuberc Lung Dis. 2008 Jul;12(7):756-62.

EACS Guidelines. European AIDS Clinical Society: Clinical management and treatment of HIV infected adults in Europe (Version 5-4, November 2009). http://www.europeanaidsclinicalsociety.org. (Last accessed 24.07.2011)

ECDC 2011. European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance in Europe 2009. Stockholm: European Centre for Disease Prevention and Control, 2011. ecdc.europa.eu/en/publications/Publications/1103_TB_SUR_2009.pdf (last accessed 23.07.2011)

Eker B, Ortmann J, Migliori GB, et al. Multidrug- and extensively drug-resistant tuberculosis, Germany. Emerg Infect Dis 2008, 14:1700-6.

Elliott AM, Halwiindi B, Hayes RJ, et al. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. J Trop Med Hyg 1993;96:1-11.

Elzi L, Schlegel M, Weber R, et al. Reducing tuberculosis incidence by tuberculin skin testing, preventive treatment, and antiretroviral therapy in an area of low tubercu-losis transmission. Clin Infect Dis 2007; 44:94-102.

Ferrara G, Losi M, DÁmico R, et al. Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospec-tive study. Lancet 2006; 367: 1328-34

Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006, 368:1575-80.

Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, Weissman D, Marra C, Lalloo UG, Friedland GH; Tugela Ferry Care and Research (TF CARES) Collaboration. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med. 2010 Jan 1;181(1):80-6. Epub 2009 Oct 15.

Getahun H, Gunneberg C, Granich R, et al. HIV infection-associated tuberculosis: the epidemiology and the response. Clin Infect Dis. 2010 May 15;50 Suppl 3:S201-7.

Girardi E, Antonucci G, Vanacore P, et al. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000; 14:1985-91.

Grant AD, Charalambous S, Fielding KL, et al. Effect of routine isoniazid preventive therapy on tuberculosis incidence among HIV-infected men in South Africa: a novel randomized incremental recruitment study. JAMA 2005;293:2719-25.

Hammond AS, McConkey SJ, Hill PC, et al. Mycobacterial T cell responses in HIV-infected patients with advanced immunosuppression. J Infect Dis 2008, 197:295-9.

Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999;340:367-73.

Havlir D, et al. Abs 38, 18° CROI, Boston 2011

Horsburgh CR Jr, O’Donnell M, Chamblee S, et al. Revisiting rates of reactivation tuberculosis: a population-based approach. Am J Respir Crit Care Med 2010, 182:420-5.

Houben RM, Crampin AC, Ndhlovu R, et al. Human immunodeficiency virus associated tuberculosis more often due to recent infection than reactivation of latent infection. Int J Tuberc Lung Dis 2011, 15:24-31.

Hung CC, Chen MY, Hsiao CF, et al. Improved outcomes of HIV-1-infected adults with tuberculosis in the era of highly active antiretroviral therapy. AIDS 2003, 17:2615-22.

Jones S, de Gijsel D, Wallach FR, et al. Utility of QuantiFERON-TB Gold in-tube testing for latent TB infection in HIV-infected individuals. Int J Tuberc Lung Dis 2007; 11:1190-5.

Karim SA, Naidoo K, Grobler A, et al. Initiating ART during TB treatment significantly increases survival: results of a randomized controlled clinical trial in TB/HIV-co-infected patients in South Africa. Abstract 36a, 16th CROI, Montreal.

Kim SH, Song KH, Choi SJ, et al. Diagnostic usefulness of a T-cell-based assay for extrapulmonary tuberculosis in immunocompromised patients. Am J Med 2009, 122:189-95.

Kingkaew N, Sangtong B, Amnuaiphon W, et al. HIV-associated extrapulmonary tuberculosis in Thailand: epidemiology and risk factors for death. Int J Infect Dis. 2009 Feb 2.

Kirk O, Gatell JM, Mocroft A, et al. Infections with Mycobacterium tuberculosis and Mycobacterium avium among HIV-infected patients after the introduction of highly active antiretroviral therapy. Am J Respir Crit Care Med 2000, 162:865-72.

Korenromp EL, Scano F, Williams BG, et al. Effects of HIV infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003;37:101-12.

Kwara A, Lartey M, Sagoe KW, Court MH. Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy. AIDS 2011, 25:388-90.

Lange C, Lederman MM, Medvik K, et al. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS 2003; 17: 2015-23.

Lange C, Schaaf B, Dalhoff K. [HIV and lung]. Pneumologie 2004;58:416-27.

Lawn SD, Bekker LG, Wood R. How effective does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS 2005a; 19:1113-24.

Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005b, 5:361-73.

Lawn SD, Bangani N, Vogt M, et al. Utility of interferon-gamma ELISPOT assay responses in highly tuberculosis-exposed patients with advanced HIV infection in South Africa. BMC Infect Dis 2007 Aug 28;7:99.

Lawn SD, Wilkinson RJ, Lipman MC, Wood R. Immune reconstitution and “unmasking” of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med 2008, 177:680-5.

Lee SW, Lee CT, Yim JJ. Serial interferon-gamma release assays during treatment of active tuberculosis in young adults. BMC Infect Dis 2010, 16;10:300.

Leidl L, Mayanja-Kizza H, Sotgiu G, et al. Relationship of immunodiagnostic assays for tuberculosis and numbers of circulating CD4+ T-cells in HIV infection. Eur Respir J 2010, 35:619-26.

Luetkemeyer AF, Charlebois ED, Flores LL, et al.  Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals. Am J Respir Crit Care Med 2007, 175:737-42.

Mack U, Migliori GB, Sester M, et al. LTBI: latent tuberculosis infection or lasting immune response to Mycobacterium tuberculosis. A TBNET consensus statement. Eur Respir J 2009; 33:956-73.

Manas E, Pulido F, Pena JM, et al. Impact of tuberculosis on the course of HIV-infected patients with a high initial CD4 lymphocyte count. Int J Tuberc Lung Dis 2004;8:451-7.

Mandalakas AM, Hesseling AC, Chegou NN, et al. High level of discordant IGRA results in HIV-infected adults and children. Int J Tuberc Lung Dis 2008, 12:417-23.

Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with HIV infection. N Engl J Med 2011, 365:11-20.

Meintjes G, Lawn SD, Scano F, et al.Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008, 8:516-23.

Meintjes G, Rangaka MX, Maartens G, et al. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. CID 2009, 48:667-76.

Meintjes G, Wilkinson RJ, Morroni C et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitu-tion inflammatory syndrome. AIDS 2010, 24:2381-90.

Migliori GB, Eker B, Richardson MD, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur Respir J 2009, 34:387-93.

Moses M, Zachariah R, Tayler-Smith K, et al. Outcomes and safety of concomitant nevirapine and rifampicin treatment under programme conditions in Malawi. Int J Tuberc Lung Dis 2010, 14:197-202.

Nahid P, Daley CL. Prevention of tuberculosis in HIV-infected patients.Curr Opin Infect Dis 2006, 19:189-93.

Nambuya A, Sewankambo N, Mugerwa J, et al. Tuberculous lymphadenitis associated with hiv in Uganda. J Clin Pathol 1988;41:93-6.

Narayanswami G, Salzman SH. Bronchoscopy in the human immunodeficiency virus-infected patient. Semin Respir Infect 2003;18:80-6.

OARAC 2011. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents January 10, 2011. aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf (last accessed 24.7.2011)

Olert J, Wiedorn KH, Goldmann T, et al. HOPE fixation: a novel fixing method and paraffin-embedding technique for human soft tissues. Pathol Res Pract 2001;197:823-6.

Oni T, Patel J, Gideon HP, et al..Enhanced diagnosis of HIV-1 associated tuberculosis by relating T-SPOT.TB and CD4 counts. Eur Respir J. 2010 Jan 14.

Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761-76.

Pimpin L, Drumright LN, Kruijshaar ME, et al. TB-HIV co-infection in EU and EEA countries. Eur Respir J. 2011 Jul 7.

Rachow A, Zumla A, Heinrich N, et al. Rapid and Accurate Detection of Mycobacterium tuberculosis in Sputum Samples by Cepheid Xpert MTB/RIF Assay-A Clinical Validation Study. PLoS One 2011, 6:e20458.

Rangaka MX, Diwakar L, Seldon R, et al. Clinical, immunological, and epidemiological importance of antituberculosis T cell responses in HIV-infected Africans. CID 2007a, 44:1639-46.

Rangaka MX, Wilkinson KA, Seldon R, al. Effect of HIV-1 infection on T-Cell-based and skin test detection of tuberculosis infection. Am J Respir Crit Care Med. 2007b; 175:514-20.

Rangaka MX, Gideon HP, Wilkinson KA, et al. No discriminatory value of interferon release added to smear negative HIV-tuberculosis algorithms. Eur Respir J. 2011 Jun 30.

Samandari T, Agizew TB, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet 2011, 377:1588-98.

Syed Ahamed Kabeer B, Sikhamani R, Swaminathan S, et al. Role of interferon gamma release assay in active TB diagnosis among HIV infected individuals. PLoS One 2009, 4:e5718.

Schiffer JT, Sterling TR. Timing of antiretroviral therapy initiation in tuberculosis patients with AIDS: a decision analysis. J AIDS 2007, 44:229-34.

Schutz C, Meintjes G, Almajid F, et al. Clinical management of tuberculosis and HIV-1 co-infection. Eur Respir J 2010, 36:1460-81..

Senkoro M, Mfinanga SG, Mørkve O. Smear microscopy and culture conversion rates among smear positive pulmonary tuberculosis patients by HIV status in Dar es Salaam, Tanzania. BMC Infect Dis 2010, 10:210.

Sokal JE. Editorial: Measurement of delayed skin-test responses. N Engl J Med 1975;293:501-2.

Sonnenberg P, Murray J, Glynn JR, et al. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001, 358:1687-93.

Sonnenberg P, Glynn JR, Fielding K, et al. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis 2005, 191:150-8.

Stephan C, Wolf T, Goetsch U, et al. Comparing QuantiFERON-tuberculosis gold, T-SPOT tuberculosis and tuberculin skin test in HIV-infected individuals from a low prevalence tuberculosis country. AIDS 2008, 22:2471-9.

Sutherland R, Yang H, Scriba P, et al. Impaired IFN-g sectering capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long term HAART. AIDS 2006, 20:821-29.

Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis 2003, 188:1146-55.

UNAIDS 2010. Global report: UNAIDS report on the global AIDS epidemic 2010. http://www.unaids.org/globalreport/documents/20101123_GlobalReport_full_en.pdf (last accessed 23.07.2011)

Van Rie A, Westreich D, Sanne I. Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors, and prevention strategies. J Acquir Immune Defic Syndr 2011, 56:349-55.

Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis. J AIDS 2009, 50:148-52.

Wenning LA, Hanley WD, Brainard DM et al. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother 2009, 53:2852-6.

Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000, 14:1219-28.

WHO 2010. Global Tuberculosis Control. WHO report 2010.  whqlibdoc.who.int/publications/2010/9789241564069_eng.pdf (last accessed 23.07.2011)

Woldehanna S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev 2004:CD000171.

Wood R, Maartens G, Lombard CJ. Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis. J AIDS 2000; 23:75-80.

Worodria W, Massinga-Loembe M, Mazakpwe D, et al. Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. J Acquir Immune Defic Syndr. 2011 Jun 13.

Zhang J, Zhu L, Stonier M, et al. Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir. J Antimicrob Chemother. 2011 Jun 28.


2 Comments

Filed under 11. Opportunistic Infections, Part 3 - AIDS, Tuberculosis

Atypical Mycobacteriosis

– Christian Hoffmann –

Atypical mycobacterioses are usually synonymous for infections with Mycobacterium avium complex (MAC). Although MAC is by far the most frequent pathogen, numerous other atypical mycobacterioses exist that cause a similar disease pattern, such as M. celatum, M. kansasii, M. xenopi or M. genavense. MAC bacteria are ubiquitous and can be found in diverse animal species, on land, in water and in food. Exposure prophylaxis is therefore not possible. Consequently, isolation of infected patients is not necessary. While MAC may be detectable in the sputum or stool of asymptomatic patients (colonization), only patients with massive immunodeficiency and less than 50 CD4 T cells/µl develop disease (Horsburgh 1999). This used to include up to 40% of AIDS patients in the pre-HAART era (Nightingale 1992).

The infection has now become very rare in industrialized countries (Karakousis 2004). However, it remains important, as it has developed into a completely new disease in the ART era. It previously occurred mainly with a chronic, disseminated course of disease, often in patients with wasting syndrome. MAC infections under ART are now almost always localized and related to an immune reconstitution inflammatory syndrome. The disease now occurs with manifestations that were previously never seen (see below).

Signs and symptoms

The symptoms of disseminated MAC infection are unspecific. When the CD4 count is less than 100 cells/µl, fever, weight loss and diarrhea should always lead to consideration of atypical mycobacteriosis. Abdominal pain may also occur. As described above, disseminated MAC infection has now become rare.

Localized forms of atypical mycobacterioses are far more frequent. These include, above all, lymph node abscesses, which may occur practically everywhere. We have seen abscesses in cervical, inguinal and also abdominal lymph nodes, some of which developed fistulae and resolved only slowly even after surgical intervention. Any abscess appearing whilst on ART (with severe immunosuppression) is highly suspicious of MAC! In addition to skin lesions, localized forms include osteomyelitis, particularly of the vertebrae, and septic arthritis (observed: knee, hand, fingers).

Diagnosis

Diagnosis of the disseminated form is difficult. Blood cultures (heparinized blood) should always be sent to a reference laboratory. Although atypical mycobacteria usually grow more rapidly than TB bacteria, the culture and differentiation from TB may take weeks. In cases presenting with anemia, bone marrow aspiration is often successful. If atypical mycobacteria are detected in the stool, sputum or even BAL, it is often difficult to distinguish between infection requiring treatment and mere colonization. In such cases, treatment should not be initiated if general symptoms are absent. This is also true for Mycobacterium kansasii (Kerbiriou 2003).

Laboratory evaluations typically show elevated alkaline phosphatase (AP) – a raised AP in severely immunosuppressed patients is always suspicious of MAC. Similarly, MAC infection should be considered in any cases of anemia and constitutional symptoms. Cytopenia, particularly anemia, often indicates bone marrow involvement. Ultrasound reveals enlargement of the liver and spleen. Lymph nodes are often enlarged, but become apparent due to their number rather than their size (Gordin 1997). Here, differential diagnoses should always include TB or malignant lymphoma.

Direct specimens should always be obtained for localized forms, as identification of the organism from material drained from the abscess is usually successful.

Treatment

Treatment of MAC infection detected from culture is complex. Similarly to TB, monotherapy does not suffice. Since 1996, many clinicians prefer the combination of a macrolide (clarithromycin or azithromycin) with ethambutol and rifabutin (Shafran 1996). In the past, this treatment was given lifelong; today it is generally considered sufficient to treat for at least six months and until a ART-induced increase in the CD4 T cell count to above 100 cells/µl has been achieved. After publication of data indicating that rifabutin may be omitted from the regimen (Dunne 2000), the multicenter, randomized ACTG 223 Study demonstrated survival benefit with the triple combination C+R+E compared to C+E and C+R – mortality rates were halved in the triple combination arm (Benson 2003).

Due to the high potential for interactions, however, rifabutin can be discontinued after several weeks when clinical improvement is observed. The clarithromycin dose should not exceed 500 mg bid. In at least two randomized studies, there was a significantly higher number of deaths in treatment arms with a higher clarithromycin dose, for reasons that remain unclear (Chaisson 1994, Cohn 1999). Instead of clarithromycin, azithromycin can also be given, which is cheaper and interacts less with cytochrome P450 enzymes. Azithromycin and clarithromycin have comparable efficacy in combination with ethambutol (Ward 1998).

In disseminated illnesses, treatment should be monitored through regular blood cultures. Cultures must be negative after eight weeks, at the latest. In the localized from, the response can be assessed better clinically. Every MAC therapy has a high potential for side effects and drug interactions. The concomitant medications, including ART, should be carefully examined – dose adjustments are frequently required and there may be contraindications (see Drugs section).

Reserve drugs such as amikacin, quinolones or clofazimine are only required in rare cases today. It is important to perform resistance testing for all atypical mycobacterial infections with species other than M. avium complex.

We have generally stopped treatment of localized MAC infections when the abscess has healed – this usually takes several months. In individual cases, steroids may be helpful temporarily. However, there are no specific guidelines for treatment of local MAC infections.

Prophylaxis

In the US, large placebo-controlled trials have shown that the macrolides, clarithromycin and azithromycin, as well as rifabutin, significantly reduce MAC morbidity and mortality when used for primary prophylaxis in severely immunocompromised patients (Havlir 1996, Nightingale 1992, Pierce 1996, Oldfield 1998). Prophylaxis also saves costs (Sendi 1999). However, MAC infections are more rare in Europe. As a result, and because of concerns over compliance and development of resistance, few patients in Europe receive primary MAC prophylaxis (Lundgren 1997).

For patients failing currently available ART regimens and without new treatment options, prophylaxis with a macrolide should be considered at low CD4 T cell counts (below 50 cells/µl). Weekly dosing with azithromycin is convenient for patients and has comparable efficacy to daily rifabutin (Havlir 1996).

Primary prophylaxis and maintenance therapies can be discontinued quite safely at CD4 T cell counts above 100/µl (Currier 2000, El Sadr 2000, Shafran 2002, Aberg 2003). It is possible that even partial viral suppression suffices for MAC-specific immune reconstitution (Havlir 2000). Complete recovery as a result of immune reconstitution is possible (Aberg 1998).

Treatment/prophylaxis of MAC (daily doses, if not specified otherwise)
Acute therapy    
Treatment of choice Clarithromycin +ethambutol +

possibly rifabutin

Clarithromycin 1 tbl. at 500 mg bid plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Alternative Azithromycin +ethambutol +

possibly rifabutin

Azithromycin 1 tbl. at 600 mg qd plusethambutol 3 tbl. at 400 mg qd plus

rifabutin 2 tbl. at 150 mg qd

Maintenance therapy As for acute therapy, but without rifabutinDiscontinue if > 100 CD4 T cells/µl > 6 months
Primary prophylaxis Consider for CD4 cells below 50/µlDiscontinue if > 100 CD4 T cells /µl > 3 months
Treatment of choice Azithromycin Azithromycin 2 tbl. at 600 mg/week
Alternative Clarithromycin Clarithromycin 1 tbl. at 500 mg bid

References

Aberg JA, Williams PL, Liu T, et al. A study of discontinuing maintenance therapy in HIV-infected subjects with disseminated Mycobacterium avium complex. J Infect Dis 2003; 187: 1046-52.

Aberg JA, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with HAART. J Infect Dis 1998, 178:1446-9.

Benson CA, Williams PL, Currier JS, et al. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons. Clin Infect Dis 2003; 37:1234-43.

Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994, 121:905-11.

Cohn DL, Fisher EJ, Peng GT, et al. A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose clarithromycin. Clin Infect Dis 1999, 29:125-33.

Currier JS, Williams PL, Koletar SL, et al. Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. Ann Intern Med 2000, 133:493-503.

Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with HIV. Clin Infect Dis 2000, 31:1245-52.

El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex disease in HIV-infected patients who have a response to ART. N Engl J Med 2000, 342:1085-92.

Gordin FM, Cohn DL, Sullam PM, et al. Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997, 176:126-32.

Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996, 335:392-8.

Havlir DV, Schrier RD, Torriani FJ, et al. Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in HIV-infected subjects. J Infect Dis 2000, 182:1658-63.

Horsburgh CR Jr. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS. J Infect Dis 1999, Suppl 3:S461-5.

Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis 2004, 4:557-65.

Kerbiriou L, Ustianowski A, Johnson MA, Gillespie SH, Miller RF, Lipman MC. HIV type 1-related pulmonary Mycobacterium xenopi infection: a need to treat? Clin Infect Dis 2003; 37: 1250-4.

Lundgren JD, Phillips AN, Vella S, et al. Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997, 16:153-60.

Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bacteremia in HIV-positive patients. J Infect Dis 1992, 165:1082-5.

Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial. Clin Infect Dis 1998, 26:611-9.

Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated Mycobacterium avium complex infection in patients with advanced AIDS. N Engl J Med 1996, 335:384-91.

Sendi PP, Craig BA, Meier G, et al. Cost-effectiveness of azithromycin for preventing Mycobacterium avium complex infection in HIV-positive patients in the era of HAART. J Antimicrob Chemother 1999, 44:811-7.

Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996, 335:377-83.

Shafran SD, Mashinter LD, Phillips P, et al. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002;137:734-7.

Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with HIV infection. Clin Infect Dis 1998, 27:1278-85.

Leave a comment

Filed under 11. Opportunistic Infections, Atypical Mycobacteriosis, Part 3 - AIDS