– Christiane Schieferstein-Knauer, Thomas Buhk –
Patients on ART commonly suffer from side effects. As a result, treatment of HIV infection has become a complicated balancing act between the benefits of durable HIV suppression and the risks of drug toxicity. Adherence problems, regimen changes or even withdrawal from therapy are often the result of drug toxicity. In former times at least 25% of patients stopped therapy within the first year on ART because of side effects (d’Arminio Monforte 2000, Yuan 2006). Between 2003 and 2007, the rate was still about 20% (Cicconi 2010). Only over the last three years tolerability of ART has been improved, thanks to new drugs becoming available. Treatment cessation due to side effects has become less frequent (Carr 2009).
Factors for poor or non-adherence include poverty, intravenous drug abuse, young age, Afro American origin, hepatitis co-infection and regular alcohol consumption (Robison 2008, Hendershot 2009). The patient should be counseled in detail on the potential side effects, so that he or she is in a position to recognize them and to contact their physician in time. This can save lives, for example in the case of abacavir hypersensitivity reaction, or prevent the irreversible damage of some side effects, such as polyneuropathy. Being prepared for the occurrence of possible problems and providing potential solutions improves both the acceptance of treatment and adherence. This information needs to be presented by the provider to the patient in a user-friendly and accessible manner – the extensive package inserts tend to frighten patients. It must be stressed that the majority of patients are able to tolerate ART well, even for years. Nevertheless, the regular monitoring of treatment by an HIV clinician, even in asymptomatic patients, is recommended through at least quarterly visits, and even more frequently at the beginning of any new regimenwhen visit schedules may be weekly or fortnightly. Standard evaluations include a thorough history (including allergies and other side effects), a physical examination and measurement of vital signs and body weight. Routine investigations include a full blood count, liver, pancreas and renal function tests, electrolytes (plus phosphate in patients on tenofovir) as well as fasting cholesterol, triglycerides and glucose levels. A urine dipstick can detect proteinuria in patients on tenofovir.
It is often difficult to distinguish between symptoms related to HIV infection and those caused by ART. An accurate history considering the intensity, variation and reproducibility of complaints is mandatory.
Gastrointestinal side effects
Gastrointestinal (GI) problems are the most common side effects even if they have fortunately become less frequent, as older NRTIs like AZT or ddI are no longer part of the current recommendations for ART (Robinson 2008, Chubineh 2008). GI side effects appear more frequently during the early stages of therapy. Typical symptoms include abdominal discomfort, loss of appetite, diarrhea, nausea and vomiting, heartburn, abdominal pain, gas in the abdomen or intestines and constipation. Diarrhea occurs frequently with all PIs, also but more rarely with 3TC.
In addition to the often considerable impact on everyday life, gastrointestinal side effects can lead to dehydration, malnutrition with accompanying weight loss, and low plasma drug levels with the risk of development of resistant viral strains.
In most cases, symptoms occur early on in therapy. Patients should be informed that these side effects usually resolve after some weeks (4–6) of treatment. If gastrointestinal side effects appear for the first time after longer periods on ART, other causes such as gastritis and infectious diarrhea need to be considered.
Nausea and vomiting
If administration on an empty stomach leads to nausea and vomiting, most drugs can be taken together with meals. Only the NNRTI efavirenz has to be administered on an empty stomach; small quantities of low-fat salty crackers may lessen nausea. Ginger, peppermint or chamomile teas or sweets may also be helpful, as well as more frequent but smaller meals. Care should be taken with fatty foods and dairy products. Coffee, smoking, alcohol, aspirin and very spicy foods should be avoided.
If treatment is necessary, metoclopramide has been proven to be useful. Dimenhydrinate, cimetidine, ranitidine or ondansetrone can also be taken. Antiemetic drugs can not only be administered if the patient is feeling ill, but taken regularly prophylactically, ideally 30 to 45 minutes before taking ART. If taken on a regular basis, attention should be paid to side effects such as dyskinesia. After a few weeks, doses can generally be slowly reduced. If nausea persists for more than two months, a change of treatment should be considered – otherwise adherence problems will certainly occur.
In patients with acute or severe diarrhea, the priority is to treat dehydration and loss of electrolytes. Other causes such as GI infection or lactose intolerance should be excluded. Difficult-to-digest foodstuffs (particularly those high in fat or glucose) should be avoided and those that are easy to digest (e.g., potatoes, rice, noodles) eaten instead. It makes sense to remember approved “homespun” remedies (see table 1). If significant dehydration and loss of electrolytes occur, coke and salty crackers, sports drinks, herbal teas or electrolyte solutions may be taken. Oral rehydration solution can be easily made from the juice of 5 oranges, 800 ml of boiled water or tea (cooled to room temperature), a teaspoon of iodized salt and two tablespoons of sugar.
Oat bran tablets have been proven to be useful and cheap for PI-associated diarrhea. They are taken together with antiretroviral therapy (daily dose 1500 mg). Pancrelipase, a synthetic pancreatic enzyme, has also been shown to be effective for PI-associated diarrhea.
PI-associated diarrhea can also be alleviated by calcium (Turner 2004), taken as calcium carbonate, at a dose of 500 mg BID. However, as calcium binds with many other agents, it should be taken 2 hours apart from HIV medication.
Oral supplements of glutamine (10–30 g/day) or alanyl–glutamine (up to 44 g/day) alleviate diarrhea and can also boost levels of antiretroviral drugs in the blood (Bushen 2004, Heiser 2004). Glutamine can be purchased in drugstores or ordered online. The probiotics Saccharomyces boulardii and Lactobacillus acidophilus are used in infectious diarrhea and for the prevention of antibiotic-associated diarrhea. They can sometimes ameliorate medication-associated diarrhea. Alternatively, psyllium may be effective. It should not be taken together with loperamide or opium tincture, or at the same time as HIV medication. Charcoal tablets might be helpful.
The cornerstone of symptomatic treatment is loperamide which inhibits bowel movement (initially 2–4 mg, followed by 2 mg, up to a maximum of 16 mg daily). If loperamide is not effective, opium tincture is an alternative (initially 5 drops, maximum 15 to 20 drops), and attention should be paid to the risk of intestinal obstruction, especially if overdosed. In some cases, a combination of different antidiarrheal drugs may be appropriate.
Table 1: “Approved” homespun remedies
|Pectin in apples (raw with paring), bananas (purée), carrots (purée, cooked, soup), St. John’s bread (oatmeal gruel or rice gruel with St. John’s flour). Pectin is a dietary fiber, which is not digested, it binds water and toxic agents and lessens the diarrhea.
Soups made of oatmeal or rice gruel
Black or green tea, dried blueberries (tea, powder), dark chocolate
ART led to a substantial reduction in the number of deaths related to AIDS. However this has been accompanied by an increase in liver-related morbidity and mortality which now is the most common cause of deaths among HIV – infected patiens not related to AIDS (Joshi 2011, Price 2010).
Elevated liver enzymes are common with ART, and severe hepatotoxicity occurs in up to 10% of patients (Price 2010). Liver failure is rare (Nunez 2005). Hepatotoxicity occurs more often in patients with pre-existing liver dysfunction (Soriano 2008). Severe, sometimes fatal liver damage has been associated with nevirapine, ritonavir and tipranavir, with several fatalities linked to nevirapine and tipranavir (Bjornsson 2006, Rachlis 2007, Chan-Tack 2008). Case reports also exist about liver failure occurring on darunavir, indinavir, lopinavir, ritonavir, tipranavir, atazanavir, efavirenz, nelfinavir and different NRTIs (Carr 2001, Clark 2002, Nunez 2010). Liver enzyme elevation up to severe hepatotoxicity has also been reported for maraviroc and raltegravir.
Risk factors for severe hepatotoxicity are elevated liver enzymes before initiating treatment, chronic hepatitis B or C, concomitant hepatotoxic medication, PI therapy, older age, higher BMI, female gender, thrombocytopenia, high alcohol intake, high viral load or renal dysfunction (Sulkowski 2002, Servoss 2006, Nunez 2010). Patients with pre-existing liver disease should use these drugs only along with strict monitoring. Four possible mechanism of hepatotoxicity are: Hypersensitivity reaction, mitochondrial toxicity/steatohepatitis, direct drug toxicity/drug metabolism or immune reconstitution syndrome. These hepatotoxic reactions occur at different time points for different drug classes.
Hypersensitivity reactions are typical for NNRTIs, not dose related and symptoms resolve usually after stopping the drug (Joshi 2011). They occur within the first 4 to 12 weeks. There are black box warnings for hypersensitivity for nevirapine, abacavir as well as the CCR5-inhibitor maraviroc. NNRTIs can also cause direct drug toxicity which appears within a couple of months (Price 2010).
Nucleoside analogs lead to hepatic steatosis, which is probably caused by mitochondrial toxicity and usually occurs after more than 6 months on treatment. PIs and boosted atazanavir, indinavir and tipranavir can lead to hepatotoxicity at any stage during the course of treatment – once again, patients with chronic viral hepatitis are particular at risk (Sulkowski 2004). One possible cause is immune reconstitution syndrome while on ART, with increased cytolytic activity against hepatitis virus infected liver cells usually within the first two months on ART accompanied by a decline in HIV-RNA and a rise in CD4 T cell count (Price 2010).
Liver toxicity occurs more commonly on nevirapine than on other antiretroviral drugs. Clinically asymptomatic and symptomatic liver toxicity, including rapidly occurring fatal liver failure have been observed (Bjornsson 2006). Serious and fatal liver toxicity has been reported even during post-exposure prophylaxis (PEP), but not after single-dose nevirapine (McKoy 2009). Therefore the use of nevirapine in occupational or non-occupational PEP is contraindicated. Symptomatic hepatotoxicity seems to depend on different risk factors, such as female gender, a body mass index lower than 18.5 (Sanne 2005) or chronic hepatitis C (Torti 2007).
A higher risk of serious liver toxicity was also observed in patients with higher CD4 T cell counts prior to initiation of therapy. A retrospective analysis of the Boehringer Ingelheim database showed a higher risk for females with CD4 T cell counts > 250 cells/µl (males: > 400/µl). Although these findings could not be confirmed by other studies (Manfredi 2006, Peters 2010), the Indications and Usage section of the Viramune® label advises against starting nevirapine treatment above these CD4 T cell counts unless the benefits clearly outweigh the risks. The increased risk seems to be particular to ART-naïve patients. Virologically suppressed patients switching to nevirapine seem not to have a significantly higher risk (Mallolas 2006, De Lazarri 2008). These findings were confirmed by an evaluation of seven observational clinical cohorts. Initiating nevirapine in antiretroviral-experienced patients with high CD4 cell counts was well tolerated provided there is no detectable viremia (Kesselring 2009). For pregnant women, data are inconsistent. One study showed a significant association between CD4 T cell count and hepatotoxicity with nevirapine (Jamisse 2007) whereas another study did not (Ouyang 2010). However, pregnancy itself is significantly associated with increased hepatotoxocity (Ouyang 2009).
NNRTIs should be used with caution in patients with HCV coinfection. They should be avoided in patients with liver cirrhosis Child–Pugh class B or C (Nunez 2010). Liver toxicity occurs usually early during ART (within 18 weeks of starting) and may progress to liver failure despite laboratory monitoring, which is not characteristic of other antiretrovirals. If liver enzymes increase to > 3.5 times upper limit of normal (ULN) during treatment, nevirapine should be stopped immediately. If liver enzymes return to baseline and if the patient has had no clinical signs or symptoms of hepatitis, rash, flu-like symptoms, fever or other findings suggestive of organ dysfunction, it may, on a case-by-case basis, be possible to reintroduce NVP. However, frequent monitoring is mandatory in such cases. If liver function abnormalities recur, nevirapine should be permanently discontinued. If clinical hepatitis (anorexia, nausea, jaundice, etc.) occurs, nevirapine must be stopped immediately and never readministered.
In patients treated with efavirenz minor enzyme elevations are generally safe and usually resolve so that a treatment change usually is not necessary (Gutierrez 2008, Kontorinis 2003). This also applies to tenofovir (Lattuada 2008).
Atazanavir and indinavir inhibit the hepatic enzyme UDP-glucuronosyltransferase, increasing the level of bilirubin in up to 50% of patients (Torti 2009). Hyperbilirubinemia is not usually associated with signs or symptoms of hepatocellular injury. It clinically resembles Gilbert’s syndrome. The levels of bilirubin return to normal following discontinuation of the drugs. If bilirubin is only mildly elevated (3 – 5 times ULN) and the serum liver enzyme levels are normal, treatment change is not mandatory. If the bilirubin is constantly markedly elevated, medication should be discontinued: no one knows about the long-term consequences of hyperbilirubinemia (Sulkowski 2004). Pre-existing liver fibrosis or cirrhosis seem to not increase substantially the risk of severe transaminase elevations with atazanavir/r in co-infected patients (HIV plus hepatitis) (Pineda 2008). In patients with end-stage liver disease, unboosted atazanavir did not worsen liver disease; in fact, atazanavir allowed patients to maintain or gain immunovirological eligibility for orthopic liver transplantation (Guaraldi 2009).
Tipranavir/r is associated with a risk of transaminase elevations. In the RESIST trials, grade 3 or 4 transaminase elevations were significantly more common in tipranavir/r than in all other boosted PIs (Hicks 2006). From June 2005 to March 2007, twelve cases of liver-associated deaths were identified (Chan-Tack 2008). Tipranavir/r should not be administered to patients with hepatic impairment Child-Pugh Class B or C. Extreme caution should be exercised when administering it to patients with mild hepatic impairment or patients with chronic hepatitis, as treatment-experienced patients with chronic hepatitis B or C co-infection or elevated transaminases are at approximately 2-fold elevated risk for developing grade 3 or 4 transaminase elevations or hepatic decompensation. Frequent monitoring is mandatory in such cases.
Besides serological tests for viral hepatitis, an abdominal ultrasound should be performed in order to recognize structural liver dysfunction early, e.g., non-alcoholic steatohepatitis or liver cirrhosis, before initiating ART. Liver function should be monitored biweekly at the start of treatment with nevirapine and PIs and even more frequently in patients with pre-existing liver disease. Monthly tests are generally sufficient for all other drugs. If liver enzymes (ALT, AST) are moderately elevated (< 3.5 times ULN) in the absence of clinical symptoms, treatment can be continued under close monitoring. If liver enzymes are elevated to more than 3.5 times ULN, additional diagnostic tests should be performed, including an abdominal ultrasound. In cases of co-infection with hepatitis B or C, treatment of these conditions should be considered. With other pre-existing liver conditions, it may be useful to determine drug plasma levels. Discontinuation of treatment may not be necessary except in the case of nevirapine (see above).
If liver enzymes are elevated in a later phase of therapy (after more than 6 months after initiation), a thorough investigation including serology for viral hepatitis, CMV, and EBV, as well as an abdominal ultrasound, should be performed. Lactic acidosis, hypersensitivity reactions to abacavir and other hepatotoxic drugs should also be considered. A liver biopsy can reveal macro- and microvesicular steatosis and mitochondrial alterations in NRTI-induced steatosis and is therefore helpful to identify a nucleoside-induced hepatopathy and to distinguish it from other causes of liver injury.
In patients with HCV co-infection, hepatitis C should, if possible, be treated before the initiation of ART (see chapter on Hepatitis C). In HBV co-infection, the ART regimen should include FTC or 3TC with tenofovir. Patients with pre-existing liver dysfunction should undergo drug plasma level monitoring, especially during treatment with PIs. Doses can be adjusted according to the plasma levels to help keep the patient on therapy.
Finally, drug interactions and hepatotoxicity related to other drugs or herbal medication taken concomitantly, should not be overlooked (Van den Bout-van den Beukel 2008).
Renal problems occur in particular with tenofovir as well as with atazanavir and the nowadays rarely used PI Indinavir. Indinavir and Atazanavir cause neprohlithiasis through excretion of unchanged drug in the urine. (see Chapter HIV and Kidney)
Tenofovir is a potentially nephrotoxic drug. Although experience over several years shows that severe renal toxicity occurs rarely, Tenofovir has an effect on renal function. One study showed that elevations in serum creatinine occurred in 2.2% of patients (Nelson 2007). In ART-naïve patients initiating ART with tenofovir was associated with a greater decline in renal function and a higher risk of proximal tubular dysfunction: 4.8% of patients on tenofovir had a more than 50% decline of GFR compared to 2.9% without tenofovir (Horberg 2010). A meta-analysis of 17 studies confirmed an association with a statistically significant loss of renal function with tenofovir, however the clinical magnitude of this effect was modest (Cooper 2010).
Severe cases have been reported with acute renal failure, proximal tubulopathy with Fanconi’s syndrome and nephrogenic diabetes insipidus and rarely hypophosphatemic osteomalacia (Rollot 2003, Saumoy 2004). Renal toxicity occurs after some months, rarely at the beginning of therapy. Risk factors include a relatively high TDF exposure due to pre-existing renal impairment, low body weight or co-administration of nephrotoxic drugs (Nelson 2007).
PIs can interact with the renal transport of organic anions, leading to proximal tubular intracellular accumulation of tenofovir (Izzedine 2004 and 2007, Rollot 2003). Whether combination with boosted PI has a higher risk for nephrotoxicity is unclear. Some studies did not observe increased tenofovir-associated nephrotoxicity in patients with concomitant PI therapy (Antoniou 2005, Crane 2007) others showed that treatment with TDF and a boosted PI was associated with greater declines in renal function compared with tenofovir and NNRTI-based regimens (Goicoechea 2008, Gallant 2009).
Furthermore, extensive pre-treatment with nucleoside reverse transcriptase inhibitors seems to be another risk factor (Saumoy 2004). However, even in patients without any predisposing factors, nephrotoxicity may occur (Barrios 2004).
In case of renal dysfunction, especially in patients with low body weight, tenofovir should be avoided, or the dosing interval should be adjusted. The manufacturer recommends administering TDF every 48h in patients with a creatinine clearance of between 30 and 49 ml/min. In case of severe renal dysfunction (creatinine clearance < 30 ml/min) it should not be administered. Normal creatinine levels may be misleading especially in subjects with low body weight, which is why creatinine clearance should be measured before initiating tenofovir treatment. Renal function tests including creatinine, urea, creatinine clearance, proteinuria, glycosuria, blood and urine phosphate should be monitored every other week.
The majority of the incident renal dysfunction in tenofovir patients is related to preexisting renal disorders (Brennan 2011). Therefore it is not recommended for use in patients with pre-existing renal insufficiency. It should also be avoided with concomitant or recent use of nephrotoxic agents such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2. Usually, abnormalities resolve upon discontinuation of the drug (Izzedine 2004, Roling 2006).
Neurological side effects
Most important neurological side effects are peripheral polyneuropathy caused by NRTI and CNS side effects caused by Efavirenz; see also chapter neuromuscular disorders.
Peripheral polyneuropathy (PNP) is mainly caused by NRTIs that are no longer prescribed as first- or second-line drugs in most Western Countries, although still frequently used in Africa or Asia, such as ddI, d4T or AZT. Because of their continued use in poor-resource areas, we will review the symptoms and possibilities for palliation. PNP usually presents with a distal symmetrical distribution and sensorimotor paralysis. Patients complain of paresthesia and pain (“tingling”) in hands and feet and perioral dysesthesia. The symptoms often begin gradually after several months of therapy. HIV infection itself can lead to PNP, but the drug-induced form becomes apparent much earlier and may develop within a shorter period of time. Patients must be informed that they should consult their treating physician as soon as possible if these complaints develop. Additional risk factors for polyneuropathy, such as vitamin B12 deficiency, alcohol abuse, diabetes mellitus, malnutrition, or treatment with other neurotoxic drugs, e.g., INH, should be addressed as well. In any case, the nucleoside analogs ddI and d4T have been dropped from first-line therapy recommendations (ddC is no longer manufactured). If possible they should be avoided for salvage therapy as well. Symptoms frequently improve within the first two months following discontinuation of the drugs responsible, but may initially increase in intensity and are not always fully reversible. Because treatment is difficult, and there is no specific therapy, it is extremely important that peripheral polyneuropathy is recognized early by the doctor, resulting in a rapid change of treatment. The causative agent needs to be stopped.
An easy test, in practice, is to test vibration with a tuning fork. A 64-Hz tuning fork (Rydel-Seiffer) is applied to the appropriate bony surface (e.g., distal hallux, medial malleolus or lateral malleolus) bilaterally. The patient is asked to report the perception of both the start of the vibration sensation and the cessation of vibration on dampening. As the intensity of the vibration starts to diminish the two triangles move closer together again. The intensity at which the patient no longer detects the vibration is read as the number adjacent to the intersection. It can thus be quantified and compared to the results of other tests. Through this simple method first signs of polyneuropathy can be recognized easily and early.
Apart from symptomatic treatment with metamizole, acetaminophen (paracetamol), carbamazepine, amitriptyline, gabapentine and opioids, methods such as acupuncture or transcutaneous nerve stimulation have been tried with varying success. Vitamin B supplementation can help to improve peripheral polyneuropathy faster. Tight shoes or long periods of standing or walking should be avoided; cold showers may relieve pain before going to bed.
CNS side effects
In up to 40% of patients, treatment with efavirenz may lead to CNS side effects such as dizziness, insomnia, nightmares, mood fluctuations, depression, depersonalization, paranoid delusions, confusion and suicidal ideation. These side effects are observed mainly during the first days and weeks of treatment. Discontinuation of therapy becomes necessary in approximately 3% of patients. There is an association between high plasma levels of efavirenz and the occurrence of CNS symptoms (Marzolini 2001). Genetic predisposition also seems to play a role. Different variations described in the enzyme system CYP2B6 may be responsible for the elimination of efavirenz (Haas 2004). Certain genetic variations more frequent in Afro-Americans than in Europeans raise the levels of efavirenz (Wyen 2007). High plasma levels can also be caused by medication interactions, so a thorough drug history should be taken; perceptions of drug tolerance by the patients can play an important role. It has been shown that efavirenz changes the sleeping pattern (Moyle 2006).
Patients should be informed thoroughly about the nature of these side effects and that they are usually expected to resolve after a relatively short period of time. Driving cars or operating machinery can be impaired in the first weeks. Treatment with efavirenz should not be started before exams or other important events.
If the CNS side effects persist for more than two to four weeks, it is reasonable to prescribe 200 mg pills, so that the dose can be divided into a 400 mg night dose and a 200 mg morning dose. With this schedule, we observed a reduction in unpleasant CNS side effects in 50% of patients in our center. The daily dose should not be reduced from 600 mg to 400 mg because of the higher risk of therapy failure and development of drug resistance.
Lorazepam can diminish the CNS side effects, and haloperidol can be given for panic attacks and nightmares, but both drugs should be restricted to severe cases, because of their side effects and addictive potency (lorazepam). If they persist with efavirenz even after splitting the dosage as described above for more than six weeks, efavirenz should be replaced.
CNS side effects are possible with etravirine, too (Madruga 2007), although they are less intensive and less frequent. Depression, insomnia and even psychosis rarely occur or get worse on 3TC or abacavir therapy. If the patient complains of CNS-related side effects, 3TC or abacavir should be considered as a possible cause (Foster 2004).
HIV infection itself may cause neurocognitive impairment, for which the earliest possible start of ART is a good preventative measure (Fessel 2009).
Allergic reactions are frequent during HIV therapy. They occur with all NNRTIs, as well as with the nucleoside analog abacavir and the PIs fosamprenavir, tipranavir, atazanavir and darunavir. Because fosamprenavir, tipranavir and darunavir are sulfonamides, they should be given with caution to patients with sulfonamide allergies. When there are limited alternative treatment options, desensitization may permit continued use of fosamprenavir or darunavir in patients with a history of allergy (Marcos Bravo 2009). Atazanavir-associated macular or maculopapular rash is reported in about 6% of patients and is usually mild, so that treatment withdrawal is not necessary (Ouagari 2006).
Nevirapine may cause a rash in 15 to 30% of patients, leading to discontinuation in about 5%. The rash is seen less frequently during efavirenz and etravirine therapy, where only rarely patients discontinue the drug (Carr 2001). With etravirine, fatal cases of toxic epidermal necrolysis have been reported as well as hypersensitivity reactions which were sometimes accompanied by hepatic failure (Borrás-Blasco 2008). It should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.
The NNRTI allergy is a reversible, systemic reaction and typically presents as an erythematous, maculopapular, pruritic and confluent rash, distributed mainly over the trunk and arms. Fever may precede the rash. Further symptoms include myalgia (sometimes severe), fatigue and mucosal ulceration. The allergy usually begins in the second or third week of treatment. Women are more often and more severely affected (Bersoff-Matcha 2001). If symptoms occur later than 8 weeks after initiation of therapy, other drugs should be suspected. Severe reactions such as Stevens Johnson Syndrome, toxic epidermal necrolysis (Lyell’s syndrome) or anicteric hepatitis are rare.
Treatment should be discontinued immediately in cases with mucous membrane involvement, blisters, exfoliation, hepatic dysfunction (transaminases > 5 times the upper limit of normal) or fever > 39°C.
Approximately 50% of NNRTI allergies resolve with continuation of therapy. Antihistamines may be helpful. Prophylactic treatment with glucocorticosteroids or antihistamines has no protective effect; rashes were even more common in some studies (Montaner 2003, The Grupo Estudio 2004). Following a severe allergic reaction, the drug responsible for the reaction should never be given again.
Abacavir causes a hypersensitivity reaction (HSR), which may be life-threatening if not recognized in time. It occurs in approximately 4-8% of Caucasian patients (Hughes 2008). A higher rate is noted in patients on a once-daily regime, in art-naïve patients, in patients with a nevirapine allergy, and in acute HIV infection. In over 90% of cases, the HSR occurs after a median of 8 days, and within the first 6 weeks. Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele, which has a prevalence of approximately 6% in Caucasians, and a very low prevalence in black population (Orkin 2010). The prospective PREDICT study involving 1,956 patients from 19 countries showed that HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir (Mallal 2008). HLA-B*5701 screening should be incorporated into routine care for patients who may require abacavir (Phillips 2009). It can prevent significant HSR-related costs and is likely to lead to overall net savings (Wolf 2010). Nevertheless, HLA-B*5701-negative patients should be informed about HSR, as it can rarely present also in these patients.
The rash associated with the abacavir HSR is often discrete, in contrast to the skin reactions caused by nevirapine or efavirenz; in 30% of patients it may not occur at all. 80% of patients have fever. In addition to general malaise (which grows worse day to day), other frequent symptoms include gastrointestinal side effects such as nausea, vomiting, diarrhea and abdominal pain. Respiratory symptoms, such as dyspnea, cough and sore throat, are rare. Changes in the blood count, elevation of liver transaminases, alkaline phosphatase, creatinine and LDH may accompany the HSR. There is usually no eosinophilia. One case of Stevens Johnson Syndrome has been described (Bossi 2002).
The simultaneous start of abacavir with NNRTIs is unfavorable because of the difficulties of differentiating between allergic reactions to NNRTIs and HSR. If abacavir is part of the initial therapy and flu-like symptoms occur, it is difficult to distinguish between immune reconstitution syndrome (IRIS) and HSR; HSR is diagnosed clinically. The differential diagnosis from an intercurrent infection is often difficult. Criteria in favor of HSR include the development of symptoms within the first 6 weeks of treatment, deterioration with each dose taken and the presence of gastrointestinal side effects. If abacavir is discontinued in time, the HSR is completely reversible within a few days. HSR may be fatal if not diagnosed. Following discontinuation of abacavir, further supportive treatment includes intravenous hydration and possibly steroids.
If the suspicion of HSR is only vague, and abacavir is not stopped, the patient should be seen or spoken to daily, to be able to react immediately in case of clinical worsening. Once the diagnosis of HSR has been established and abacavir stopped, rechallenge with abacavir can be fatal and is strictly contraindicated. If there is only a vague suspicion of HSR and abacavir stopped, rechallenge under in-patient conditions is possible. Whenever treatment is interrupted, it needs to be noted that the HSR can occur for the first time after restarting treatment, even without a prior HSR.
Treatment with abacavir requires detailed counseling on the possible occurrence and symptoms of the HSR. Patients should know whom to contact in case of possible HSR. It is important, however, to emphasise to patients that unnecessary discontinuation must also be avoided. Due to the implementation of routine HLA-B*5701 screening the diagnosis of HSR is becoming increasingly rare.
The incidence ofasymptomatic avascular necrosis is approximately 4.4% in HIV-positive patients, significantly more frequent than in the general population (Lawson-Ayayin 2005, Cazanave 2008). The postulated association with PIs has not been confirmed (Loiseau-Peres 2002). Risk factors for avascular necrosis are alcohol abuse, hyperlipidemia, steroid treatment, hypercoagulability, hemoglobinopathy, trauma, nicotine abuse and chronic pancreatitis. Virological (viral load) or immunological parameters are not associated with a risk of developing avascular necrosis (Mondy 2003).
The most common site of the necrosis is the femoral head and, less frequently, the head of the humerus. Initially, patients complain of pain when bearing weight on the affected joint, with symptoms worsening over the following days and weeks. The initial stages may be asymptomatic, but are followed by severe bone pain and reduced mobility. Necrosis of the femoral head produces pain in the hip or groin, which may radiate to the knee.
All patients on ART, especially those with additional risk factors like steroids should be monitored closely when hip pain occurs for the first time. Even in subjects with moderate bone or joint pain, an MRI should be performed early on, as this is more sensitive than conventional radiography. Early diagnosis and treatment can spare patients pain, loss of mobility and surgical intervention.
If the diagnosis is confirmed, patients should be referred to an orthopedic surgeon as soon as possible. Different treatment strategies are available for reducing bone and joint damage as well as pain, depending on the stage of disease, localization and grade of severity. In the early stages, reduced weight bearing with crutches is often sufficient. Surgical core decompression is an option: several holes are drilled in the femoral neck or head, causing new blood vessels to develop and thereby reducing the pressure within the bone. In the more advanced stages, the chances of success decrease with the size of the necrosis. The alternative, osteotomy, has the disadvantage of reducing the mobility of patients over long periods of time. In severe cases, a total endoprothesis (TEP) is usually necessary.
Further risk factors need to be identified and eliminated. If possible, steroids should be discontinued. Sufficient data are missing as to whether treatment modification on non–PI therapy is successful (Mondy 2003). Physiotherapy is recommended. Non-steroidal anti-inflammatory drugs (e.g., ibuprofen) are the treatment of choice for analgesia.
Osteopenia and Osteomalacia
HIV-infected individuals have a lower bone density than uninfected individuals (Loiseau-Peres 2002). Bone density is determined by the measurement of X-ray absorption (e.g., DEXA scan). Results are given as the number of standard deviations (the T-score) from the mean value in young, healthy individuals. Values between -1 and -2.5 standard deviations (SD) are referred to as osteopenia, values above -2.5 SD as osteoporosis. Osteomalacia is the softening of the bones. Osteopenia and osteomalacia may occur in combination. In addition to HIV infection, other factors such as malnutrition, diminished fat tissues, steroid treatment, hypogonadism, immobilization and treatment with PIs and (N)NRTIs, seem to play a role in the pathogenesis of this disorder (Herzman 2009). One study showed a loss of bone mineral density after antiretroviral therapy initiation, independent of which antiretroviral regimen was given (Brown 2009). For the association between tenofovir and bone metabolism see chapter Rheumatic disorders and bone disorders ).
Osteopenia and osteoporosis are often asymptomatic. Osteoporosis occurs mainly in the vertebrae, lower arms and hips. A bone fracture in a HIV patient should always make one suspect osteopenia or osteoporosis.
The following tests should be performed in all patients with AIDS: a lumbar spine X-ray in the standard anteroposterior and lateral views, bone density measurement (DEXA scan) of the lumbar spine and hip; and laboratory blood tests, including calcium, phosphate and alkaline phosphatase. Osteopenia should be treated with 1000 I.E. vitamin D daily and a calcium-rich diet or calcium tablets at a dose of 1200 mg/day. Patients should be advised to exercise and offered methods on how to give up alcohol and nicotine. In cases of osteoporosis, bisphosphonates (e.g., alendronate at 70 mg QW) should be added (McComsey 2007, Huang 2009). The tablets should be taken on an empty stomach 30 minutes before breakfast, and an upright position should be maintained for at least 30 minutes. No calcium should be taken on this day. Antiretroviral therapy should not be taken together with calcium. Because testosterone suppresses osteoclasts, hypogonadism should be treated. Alcohol and smoking should be avoided; regular exercise is an essential part of the therapy.
The most common side effect of T-20 is an injection site reaction (ISR) with erythema, induration, nodules, pruritus, ecchymosis, pain and discomfort. Almost every patient is affected, most of them, however, only mildly. ISR rarely limits treatment, and only 3-7% of patients discontinue therapy (Lazzarin 2003). The practitioner and the patient have to get used to the injection technique and the management of ISRs. Good injection technique (see Table 2), may be most effective in minimizing the incidence and severity, as well as the incidence of associated events, including infections. The appropriate management of ISR can lessen the reaction (Clotet 2004). Desensitization therapy is available for the skin rash that occurs rarely with T-20 (Shahar 2005). Patients traveling to foreign countries should be prepared for questions about their injection material. Taking along a medical certificate stating that the patient is on injection therapy can help to avoid unpleasant situations.
Table 2: Suggestions for prevention and management of injection site reactions (ISR) and other injection-related adverse events (Clotet 2004)
|Good injection technique
Interventions for ISR
1. Injection pain
2. Management of pruritus
Changes in blood count
HIV infection itself may cause pancytopenia. A very low CD4 T cell count may therefore be rarely due to a severe leukopenia. In this case, the percentage of the CD4 T cells and the CD4/CD8 ratio is normal.
Some antiretroviral drugs (especially AZT) are myelosuppressive, especially with respect to red cells, and lead to anemia (de Jesus 2004). Most commonly affected are patients with advanced HIV infection and pre-existing myelosuppression, on chemotherapy or co-medication with other myelotoxic drugs such as cotrimoxazole, pyrimethamine, amphotericin B, ribavirin, and interferon, or with other antiretroviral drugs.
5 to 10% of patients taking AZT develop anemia – usually during the first 3 months of therapy, but sometimes even after years on treatment (Carr 2001). AZT should be discontinued in severe cases, and a blood transfusion may be necessary. MCV is always elevated, even in patients on AZT without anemia, and is therefore a measure of adherence. It sometimes makes sense to change from Combivir® to the single drugs Retrovir® and Epivir® in anemic patients, because of the lower AZT dose in Retrovir® (250 mg) compared to Combivir® (300 mg). Because there are many alternatives to this third-line myelotoxic drug we see no reason to give high cost medications like erythropoietin.
Due to drug-induced neutropenia, it is possible that despite viral suppression the CD4 T cells remain low after an initial rise. In these cases treatment should be changed to less myelotoxic antiretroviral drugs and AZT should be avoided. Leukopenia may also occur on abacavir, tenofovir or indinavir. A low CD4 T cell count is also seen on combination of tenofovir and ddI.
For thrombocytopenia see also chapter HIV asscociated thrombocytopenia.
Increased bleeding episodes
HIV-infected patients with hemophilia A or B, after some weeks of treatment with PIs, may have increased episodes of spontaneous bleeding into joints and soft tissues. Rarely, intracranial and gastrointestinal bleeding has occurred. The etiology is unclear (Review: Wilde 2000).
During clinical trials with tipranavir/r, the manufacturer received 14 reports of intracranial hemorrhage, among them 8 fatal cases, in 13 out of 6,840 HIV-1 infected individuals. Most of them occurred more than one year after initiating therapy. So far, there have been no more spontaneous reports of intracranial hemorrhage on marketed tipranavir. Many of the patients affected had other risk factors for intracranial hemorrhage such as CNS lesions, head trauma, recent neurosurgery, coagulaopathy, hypertension or alcohol abuse, or were receiving anticoagulant or antiplatelet agents. Tipranavir was observed in vitro to inhibit human platelet aggregation (Graff 2007). No pattern of abnormal hematologic or coagulation parameters was observed. Therefore, routine measurement of coagulation parameters is not indicated. Tipranavir/r should be avoided if possible in patients with the above mentioned risk factors. This applies also for patients on antiplatelet agents or anticoagulants. Patients should be informed about the possible risk of intracranial hemorrhage.
Lactic acidosis is a rare but life-threatening complication due to mitochondrial toxicity. It occurs most frequently on treatment with d4T and ddI, and less so in patients on AZT, abacavir and 3TC (Garrabou 2009). Risk factors are obesity, female sex, pregnancy and therapy with ribavirin or hydroxyurea, a diminished creatinine clearance and a low CD4 T cell nadir (Bonnet 2003, Butt 2003, Wohl 2006).
Cases of severe lactic acidosis can occur without prior symptomatic hyperlactatemia. Lactate levels do not need to be monitored routinely, as increases are not predictive and may lead to unnecessary changes in treatment (Brinkman 2001, Vrouenraets 2002). In contrast, lactate levels should be tested immediately in symptomatic patients complaining of fatigue, sudden weight loss, abdominal disturbances, nausea, vomiting or sudden dyspnea, in pregnant women on NRTI treatment and in patients on NRTIs post-lactic acidosis (Carr 2003).
For clinical symptoms, pathogenesis, and treatment please see chapter on Mitochondrial Toxicity.
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