Category Archives: Tuberculosis

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.


Advertisements

2 Comments

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