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6. Management of Side Effects

by Christiane Schieferstein and Thomas Buhk

Patients on HAART 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. About 25 % of patients stop therapy within the first year on HAART because of side effects (d'Arminio Monforte 2000). About the same number of patients does not take the recommended dosages of their medication due to concerns regarding the side effects ( Chesney 2000). Patients, who report significant side effects, are more often non-adherent to therapy (Ammassari 2001).

The patient should be counseled in detail about potential side effects, in order to be able to recognize them and to consult his physician in time. This can save lives, for example in the case of the abacavir hypersensitivity reaction, or prevent irreversible damage, such as polyneuropathy. Being prepared for the occurrence of possible problems and providing potential solutions improves both the acceptance of treatment and the adherence. However, patients should not be frightened by all this information - the extensive package inserts are often ominous enough. It may be difficult to distinguish between symptoms related to HIV infection and those caused by antiretroviral therapy. An accurate history, including any co-medication (not forgetting over-the-counter and "natural" products!) is paramount. It is important to consider the intensity, variation and reproducibility of complaints, as other possible causes should be excluded before symptoms are judged as being side effects of treatment.

It must be stressed that the majority of patients are able to tolerate HAART well, even over years. Nevertheless, the monitoring of treatment by an HIV clinician, is recommended in at least three-monthly intervals, even in asymptomatic patients, and more often at the beginning of a new HAART, when it should be weekly or fortnightly. Standard evaluations include a thorough history (allergies?, other side effects?), 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.




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HIV Medicine
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818 pages
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Gastrointestinal side effects Gastrointestinal problems are the most common side effects of almost all antiretroviral drugs - nucleoside analogs, NNRTIs and particularly protease inhibitors - and occur especially during the early stages of therapy. Typical signs and symptoms include abdominal discomfort, loss of appetite, diarrhea, nausea and vomiting. Heartburn, abdominal pain, meteorism and constipation may also occur. Nausea is a common symptom with zidovudine-containing regimens; diarrhea occurs frequently with zidovudine, didanosine and all PIs, particularly with lopinavir, fosameprenavir, nelfinavir and "baby dose" ritonavir. Treatment with zidovudine rarely leads to a severe form of gastritic pain, nausea and vomiting in the early phase of therapy, in which case it should be discontinued. In addition to the often considerable impact on everyday life, gastrointestinal side effects can lead to dehydration, malnutrition with ensuing weight loss, and low plasma drug levels with the risk of development of resistant viral strains. In most cases, symptoms occur at the beginning of therapy. Patients should be informed that these side effects usually resolve after four to six weeks of treatment. If gastrointestinal side effects occur for the first time after longer periods on HAART, other causes such as gastritis and infectious diarrhea are likely. Nausea and vomiting If administration on an empty stomach leads to nausea and vomiting, most drugs can also be taken together with meals. When a drug (e.g. didanosine, indinavir, rifampin) has to be administered on an empty stomach, small quantities of low-fat salty crackers may lessen the nausea. Ginger, peppermint or chamomile teas or sweets may also be helpful, as well as frequent small meals. Care should be taken with fatty foods and dairy products. Coffee, smoking, alcohol, aspirin and very spicy foods should be avoided if possible. If symptomatic treatment is necessary, metoclopramide has been proven to be useful. Dimenhydrinate, cimetidine, ranitidine or ondansetron can also be taken. Antiemetic drugs should not be administered only when the patient is already feeling sick, but rather taken regularly, ideally 30 to 45 minutes before HAART. If taken on a regular basis, attention should be paid to side effects such as dyskinesia. After a few weeks, doses can generally be reduced slowly. If nausea persists for more than two months, a change of treatment should be considered - otherwise adherence problems will certainly occur. Diarrhea In patients with massive diarrhea, the priority is to treat dehydration and loss of electrolytes. Other causes such as gastrointestinal infections or lactose intolerance should be excluded. Difficult to digest foodstuffs (particularly those rich in fats or glucose) should be avoided and those that are easy to digest (e.g. potatoes, rice, noodles), eaten instead. It makes sense to remember 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 (reviews in: Highleyman 2000, Sherman 2000). Oral rehydration solution can be easily made from the juice of 5 oranges, 800 ml of boiled water or tea (cooled to room temperature), one 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 is alleviated by calcium (Turner 2004), taken as calcium carbonate, at a dosage of 500 mg bid. However, as calcium binds many other substances, 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 the levels of antiretroviral drugs in the blood (Bushen 2004, Heiser 2004). 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. Case reports have implicated S. boulardii as an etiologic agent of possibly fatal invasive fungal infection. Particularly at risk were patients with an intravascular catheter or on antibiotic therapy (see review in: Enanche-Angoulvant 2005). Alternatively, psyllium may be effective. It should not be taken together with loperamide or opium tincture, or at the same time as HIV medication. 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), 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 skin), 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 substances and lessens the diarrhea. Gruel Soups made of oatmeal or rice gruel Tanning agents Black or green tea, dried blueberries (tea, powder), dark chocolate Hepatotoxicity Elevated liver function tests are common with HAART, and severe hepatotoxicity occurs in up to 6 % of patients (Becker 2004), but liver failure is rare (Nunez 2005). Occurrence of hepatotoxicity depends on the drug classes or agents used as well as on pre-existing liver dysfunction. Nevirapine, ritonavir and tipranavir have been associated with severe hepatotoxicity. Several fatalities due to liver failure habe been linked to nevirapine (Bjornson 2006, De Maat 2003, Law 2003). Case reports also exist about liver failure due to indinavir, atazanavir, efavirenz, nelfinavir and different nucleoside analogs (Carr 2001, Clark 2002). Risk factors for the occurrence of severe hepatotoxicity are baseline elevation in serum aminotransferases, chronic hepatitis B or C coinfection as well as concomitant hepatotoxic medication, protease inhibitor therapy, thrombocytopenia and renal insufficiency (Servoss 2006, Sulkowski 2002). Patients with pre-existing liver disease should receive the above mentioned drugs only under strict monitoring (Sulkowski 2004). Hepatotoxic reactions occur at different time points for different drug classes: NNRTIs often cause a hypersensitivity reaction within the first 12 weeks, nucleoside analogs lead to hepatic steatosis, which is probably caused by mitochondrial toxicity and usually occurs after more than 6 months on treatment (Montessori 2003). PIs can lead to hepatotoxicity at any stage during the course of treatment -,patients with chronic viral hepatitis are particularly at risk. One possible cause is an immune reconstitution syndrome on HAART, with increased cytolytic activity against the hepatitis virus-infected liver cells. Among the PIs, toxic hepatitis is seen most frequently in patients on boosted atazanavir, indinavir and tipranavir (Sulkowski 2004). Nevirapine 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, but not after single doses of nevirapine (Jackson 2003). Data had shown a higher risk of symptomatic hepatotoxicity for females compared to males, and in females with CD4+ T-cell counts > 250/µl, as well as for males with CD4+ T-cell counts > 400/µl. The data was mainly derived from a retrospective analysis of the Boehringer Ingelheim data-bases, including almost exclusively antiretroviral-naïve patients. In a cohort of antiretroviral-naïve pregnant women in Mozambique severe hepatotoxicity from nevirapine-containing HAART was likewise more common at higher CD4 counts (Jamisse 2007). The Indications and Usage section of the Viramune label therefore advises against starting nevirapine treatment in women with CD4+ T-cell counts greater than 250/µl unless benefits clearly outweigh risks (http://www.fda.gov/cder/drug/advisory/nevirapine.htm). Different studies have now shown that in virologically suppressed patients switching to nevirapine as a part of a simplification regimen has no higher risk of hepatotoxicity or rash independent of gender or CD4 + T cell count (Mallolas 2006). Another open-label comparison of 742 patients with nevirapine or efavirenz based regimen found no increased hepatotoxicity in nevirapine treated subjects with regard to gender or CD4 + T cellcount (Manfredi 2006). One risk factors was hepatitis C coinfection, if possible nevirapine should be avoided (Tossonian 2006, de Lazzari 2006). Another study showed that a body mass index (BMI) < 18.5 kg/m² in women is associated with a high risk of hepatotoxicity (Sanne 2005). Liver toxicity occurs usually early during therapy (within 18 weeks of starting). If liver enzymes levels increase to > 3.5 times upper limit of normal (ULN) during treatment, nevirapine should be stopped immediately. If liver enzymes return to baseline values and if the patient has had no clinical signs or symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ dysfunction, it may, on a case-by-case basis, be possible to reintroduce nevirapine. 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. Protease inhibitors Atazanavir and indinavir inhibit the hepatic enzyme UDP-glucuronosyltransferase, increasing bilirubinlevels in up to 47 % of patients. Hyperbilirubinemia is not usually associated with signs or symptoms of hepatocellular injury, and clinically resembles Gilbert's syndrome. Hyperbilirubinemia is associated with higher atazanavir plasma levels (Smith 2006). Individualshomozygous for UGT1A1*28 are at particular risk of atazanavir or indinavir associated hyperbilirubinemia. Genotyping for UGT1A1*28 before initiation of therapy would identify individuals at risk, but might not be cost-effective (Rotger 2005, Rodriguez-Novoa 2007). The levels of bilirubin return to normal following discontinuation of the drugs. If bilirubin is only mildly elevated (< 3 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: nobody knows about the long-term consequences of hyperbilirubinemia (Sulkowsky 2004). Tipranavir is associated with clinical hepatitis and hepatic decompensation including some fatalities. In a phase III study with 1458 patients grade 2 to 4 liver enzyme elevation was more frequent observed in patient treated with tipranavir compared with other PIs (both with ritonavir boosting) (17,5 % versus 9,9 % within 24 weeks, 24,4 % versus 12,8 % within 48 weeks) Patients with chronic hepatitis B or C co infection or baseline elevation in transaminases have an approximately 2.5 fold higher risk for developing further transaminase elevation or hepatic decompensation (Aptivus® Prescribing Information 2006). As Tipranavir is mainly metabolized by the liver, tipranavir concentrations might be increased in patients with hepatic impairment. It is contraindicated in patients with hepatic insufficiency Child- Pugh Class B and C). Liver function test as well as close clinical monitoring are mandatory prior initiating and during therapy. Besides serological and if necessary molecular testing for viral hepatitis, an abdominal ultrasound should be performed to recognize structural liver dysfunction, e.g. non-alcoholic steatohepatitis or liver cirrhosis early, before initiating HAART. 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 (exception: nevirapine). If liver enzymes are elevated in a later phase of therapy (after more than 6 months), 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. Furthermore, analysis of blood gases including pH, base excess and bicarbonate concentration, lactate levels and a thorough drug history can help. Liver biopsy reveals 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 HAART, to reduce the frequency of severe hepatotoxicity (see Chapter "Hepatitis C"). In HBV co-infection, the HAART regimen should include lamivudine and/or 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 so that a premature discontinuation of therapy can be avoided. However, no relationship has been found between hepatic injury and plasma levels of nevirapine. Finally, drug interactions and hepatotoxicity related to other drugs (e.g. ACE inhibitors or antidepressants), taken concomitantly, should not be overlooked. Renal problems Tenofovir Tenofovir has been approved since 2001 and is, like the two nephrotoxic drugs, adefovir and cidofovir, a nucleotide analog. Animal studies showed a dose-related nephrotoxicity. Severe renal toxicity occurs rarely, but a significant proportion of patients develop kidney dysfunction (Crane 2007, Sax 2007). In one study graded elevation of serum creatinine occurred in 2,2 % of the patients (Nelson 2007) ). Acute renal failure and proximal tubulopathy with Fanconi's syndrome and nephrogenic diabetes insipidus and rarely hypophosphatemic osteomalacia have been reported Rollot 2003,Saumoy 2004). Proximal tubular damage manifests as proximal tubular acidosis, normoglycemic glycosuria, hypophosphatemia, hypouricemia, hypokalemia, generalized aminoaciduria, and proteinuria. Renal toxicity occurs after some months, rarely at the beginning of therapy (Hansen 2004, Izzedine 2004, Rifkin 2004). Risk factors include a relatively high tenofovir exposure, pre-existing renal impairment, low body weight, increased age, co-administration of nephrotoxic drugs, amprenanvir and didanosine. 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). Case reports suggested that the use of lopinavir/ritonavir, atazanavir and ritonavir with tenofovir is associated with a higher risk of kidney dysfunction through the interaction of PIs with the renal transport of organic anions, leading to proximal tubular intracellular accumulation of tenofovir (Izzedine 2004, Rollot 2003, Zimmermann 2006). However, three studies did not find an increase in tenofovir-asscociated kidney dysfunction among patients receiving lopinavir/ritonavir, atazanavir, or ritonavir (Gallant 2005, Antoniou 2005, Crane 2007) In case of renal dysfunction, especially in patients with low body weight, tenofovir should be avoided if possible, or the dosing interval should be adjusted. The manufacturer recommends administering tenofovir every 48 hours in patients with a creatinine clearance between 30 and 49 ml/min and twice a week between 10 and 29 ml/min.In these cases therapeutic drug monitoring is recommended. 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. Urine-beta2 microglobuline might be a more sensitive marker of renal tubular injury caused by tenofovir (Gatanaga 2006). Renal function tests including creatinine, urea, creatinine clearance, proteinuria, glycosuria, blood and urine phosphate should be monitored every other week. Tenofovir 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 the abnormalities resolve after discontinuation of the drug (Izzedine 2004, Rifkin 2004, Roling 2006). An increase in creatine kinase (CK, CK-MB) is common with tenofovir (Shere-Wolfe 2002). Analysis of CK-MB isoenzyme activity and mass concentration revealed evidence for Macro CK 2 (Schmid 2006). Therefore, the elevated CK might not be an indicator of ischemic heart disease but Macro CK-2 appearance on tenofovir treatment. The CK elevation resolves after discontinuation of tenofovir. Indinavir Renal problems occur particularly on indinavir treatment, and are caused by indinavir crystals, which may be found in the urine of up to 20 % of patients. Approximately 10 % of patients develop nephrolithiasis, which is not visible on X-ray, accompanied by renal colic. Nephrolithiasis is primarily caused by high indinavir levels in relation to a low BMI, drug interactions and individual fluctuations of the drug plasma level. In one study, the intake of indinavir/ritonavir 800/100 mg with a light meal reduced the indinavir plasma concentration, probably reflecting a food-induced delay in the absorption of indinavir (Aarnoutse 2003). In case of suspected high indinavir levels, therapeutic drug monitoring should be performed and the dose adjusted (Collin 2007). Interruption of therapy, following a single incidence of colic, is not usually necessary. More than 20% of patients have persistent asymptomatic leukocyturia associated with a gradual loss of renal function without urological symptoms (Dielemann 2003). However, renal failure is rare (see also chapter HIV and Renal Function). Atazanavir Similar to Indinavir where 19% of the drug is excreted unchanged in the urine, 7% of Atazanavir is found in the urine of healthy persons. In contrast to indinavir, nephrolithiasis seems to be a very rare adverse event with atazanavir. Hitherto, three case reports have been published (Chang 2006, Pacanowski 2006, Anderson 2007), and the US Food and Drug Administration's Adverse Event Reporting System identified 30 cases of symptomatic nephrolithiasis (Chan-Tack 2007). Neurological side effects Peripheral polyneuropathy Peripheral polyneuropathy is mainly caused by the NRTIs, zalcitabine, didanosine and stavudine. It usually presents with a distal symmetrical distribution and sensorimotor paralysis. Patients complain of paresthesia and pain in their hands and feet, and often, with zalcitabine, about perioral dysesthesia. The symptoms often begin gradually after several months of therapy. HIV infection itself can lead to peripheral polyneuropathy, 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 the typical 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 in the appropriate manner. 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 an early change of treatment. The causative agent has to be abandoned. 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 variable 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 disorders In up to 40 % of patients, treatment with efavirenz leads to CNS side effects such as dizziness, insomnia, nightmares; even mood fluctuations, depression, depersonalization, paranoid delusions, confusion and suicidal ideation may occur . Efavirenz changes the time spent in several key sleep stages, therefore patients report about persistence of dream recollection and morning sluggishness (Moyle 2006). These side effects are observed mainly during the first days and weeks of treatment. Discontinuation of therapy becomes necessary in only 3 % of patients. There is an association between high plasma levels of efavirenz and the occurrence of CNS symptoms (Marzolini 2001). On the one hand, high efavirenz plasma levels can be caused by medication interactions, so a thorough drug history should be taken; on the other hand the different perception of drug tolerance of the patients can play an important role. Patients should be informed about the nature of these symptoms, and that they are usually expected to resolve after a short period of time. Driving cars or bicycles or operating machinery can be impaired in the first weeks. If dizziness or drowsiness is experienced, these activities should be avoided. 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. We experienced a reduction in unpleasant CNS side effects in 50 % of our patients. 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. Measurement of drug levels makes sense from the second week of therapy to verify overdosage, but the only consequence is the splitting of the 600 mg dosage (by no means should the dose be reduced to 400 mg). Taking 400 mg/200 mg can reduce the Cmax levels and therefore the toxic potential becomes milder. 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). Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). An American study showed that an allelic variant CYP2B6, which is more common in African-Americans than in Caucasians, was associated with significantly greater efavirenz plasma exposure during HIV therapy (Haas 2004). CNS side effects are rarely seen with other NNRTIs. If they persist even after splitting the dosage for more than six weeks, efavirenz should be replaced, for example by nevirapine. Lamivudine/abacavir Depression, insomnia and even psychosis rarely occur or get worse on lamivudine or abacavir therapy. If the patient complains of CNS-related side effects, lamivudine or abacavir should be considered as a possible cause (Foster 2004). Haematological changes 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 are nearly normal. Some of the antiretroviral drugs (especially zidovudine) are myelosuppressive, especially with respect to the red cells, and therefore 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 zidovudine develop anemia - usually during the first 3 months of therapy, but sometimes even after years on treatment (Carr 2001). Zidovudine should be discontinued in severe cases, and a blood transfusion may be necessary. MCV is always elevated, even in patients on zidovudine without anemia, and is therefore a good proof of adherence. It sometimes makes sense to change from Combivir™ to the single drugs Retrovir™ and Epivir™ in anemic patients, because of the lower zidovudine dose in Retrovir™ (250 mg) compared to Combivir™ (300 mg). In patients with advanced HIV infection and multiple viral resistance, and therefore no options to change to less myelotoxic drugs, erythropoietin is an option, but should be avoided as a long-term option if possible, due to the associated high costs (Henry 2004). Due to drug-induced neutropenia, it is possible that despite viral suppression the CD4+ T-cell count remains low after an initial rise. In these cases treatment should be changed to less myelotoxic antiretroviral drugs such as stavudine, lamivudine, most of the PI and all NNRTIs. Zidovudine should be avoided. Leukopenia may also occur on indinavir, abacavir or tenofovir. In Patients on tenofovir and didanosine as the nuke backbone a gradual decrease in the CD4+ T-cell count was observed (see chapter Antiretroviral Therapy). Increased bleeding episodes HIV patients with hemophilia A or B may have increased episodes of spontaneous bleeding into joints and soft tissues after some weeks of treatment with protease inhibitors. Rarely, intracranial or gastrointestinal bleeding has occurred. The etiology remains unclear (Review: Wilde 2000). Over the course of all clinical trials with tipranavir/r the manufacturer received 14 reports of intracranial hemorrhage (ICH), including 8 fatalities, in 13 out of 6,840 HIV-1 infected individuals. So far, there have been no more spontaneous reports of intracranial hemorrhage on marketed tipranavir. The median time to onset of an ICH event was 525 days on Tipranavir/r. Many of the patients 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. In an in-vitro experiment, tipranavir was observed to inhibit human platelet aggregation. No pattern of abnormal hematologic or coagulation parameters was observed. Therefore, routine measurement of coagulation parameters is not currently 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 (Important Safety Information, Boehringer Ingelheim 2006). Allergic reactions Allergic reactions are frequent during HIV therapy. They occur with all NNRTIs, as well as with the nucleoside analog, abacavir (see below) and the PIs, amprenavir, atazanavir, tipranavir and darunavir. Because amprenavir, tipranavir and darunavir are sulfonamide, they should be given with caution to patients with sulfonamide allergies. When there are limited alternative treatment options, desensitization may permit continued use of amprenavir in patients with a history of amprenavir-induced maculopapular eruptions (Kohli-Pamnani 2005). 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). NNRTIs Nevirapine and delavirdine may cause a slight rash in 15 to 20 % of patients, 5 to 10 % of which discontinue treatment. The rash is seen less frequently on efavirenz therapy, where only 2 % of the patients discontinue the drug (Carr 2001). 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 the Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) or anicteric hepatitis are rare (Rotunda 2003). 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. If patients present with a suspected nevirapine-associated rash, additional hepatotoxicity and liver failure should be considered and liver function tests should be performed. Patients with rash-associated AST or ALT elevations should be permanently discontinued from nevirapine. Approximately 50 % of NNRTI allergies resolve despite continuation of therapy. Antihistamines may be helpful. Prophylactic treatment with glucocorticosteroids or antihistamines has been shown to be of no benefit for the prevention of nevirapine allergy; in fact, rashes were even more common in some studies (Knobel 2001, Montaner 2003, The Grupo Estudio 2004). Following a severe allergic reaction, the drug responsible for the reaction should never be given again. Abacavir hypersensitivity Abacavir causes a hypersensitivity reaction (HSR), which may be life threatening if not recognized in time. It occurs in approximately 4-5 % of patients (reviews: Hewitt 2002, Clay 2002). 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 . The HSR occurs after a median of 8 days, more than 90% within the first 6 weeks. Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA-B*-5701 allele, probably mediated through HLA-B*5701-restricted CD8 cells (Phillips 2005). Exclusion of HLA-B*5701 individuals from abacavir treatment could therefore largely prevent HSR (Rauch 2006, Zucman 2007, Mallal 2007). Pre-prescription routine HLA typing or flow cytometry for HLA-B57 (Martin 2006) may be reasonable and cost-effective in the future. A more simple and therefore cheaper alternative approach might be a screening of HIV reverse transcriptase for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245 as part of routine drug- resistance testing (Chui 2007). The rash associated with the abacavir hypersensitivity reaction is often discrete, in contrast to the skin reactions caused by nevirapine and efavirenz; in 30 % of patients it may not occur at all. 80 % of patients have fever. In addition to general malaise (which gets worse from 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 synchronous start of therapy with abacavir and NNRTIs is not recommended 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 inflammatory syndrome (IRIS) and HSR; hence HIV therapy should be carried out by experienced doctors. The HSR is diagnosed clinically but often difficult to distinguish from an intercurrent infection. Criteria in favor of HSR include the development of symptoms within the first six 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 not stopped, the patient should be seen or spoken to (by telephone) daily, to be able to react immediately in case of clinical deterioration. Once the diagnosis of HSR has been established, rechallenge with abacavir can be fatal and is strictly contraindicated. If there was only a vague suspicion of HSR, rechallenge under in-patient conditions is possible. Whenever treatment has been interrupted, it should be noted that the HSR can occur for the first time after restarting treatment, even without a prior HSR or after switching from the twice-daily to the once-daily formulation (Gervasoni 2007). Treatment with abacavir requires detailed counseling (and documentation!) on the possible occurrence and symptoms of the HSR. Patients should know whom to contact in cases of suspected HSR, preferably also at night and at weekends. It is important, however, not to frighten patients to the extent that they themselves discontinue treatment too early. Lactic acidosis In comparison to asymptomatic hyperlactacidemia, which occurs in approximately 15-35 % of NRTI-treated patients (Carr 2001, Hocqueloux 2003), lactic acidosis is a rare but life-threatening complication. NRTIs are thought to cause mitochondrial toxicity via inhibition of the mitochondrial DNA polymerase (see also chapter on Mitochondrial Toxicity). It occurs most frequently on treatment with stavudine and didanosine, less often in patients on zidovudine, abacavir and lamivudine. 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). In case treatment with ribavirin is necessary, didanosine has to be replaced.The clinical symptoms, including fatigue, nausea and vomiting, abdominal pain, weight loss and dyspnea, are non-specific and may develop acutely or more gradually. Blood results show elevated lactate levels with or without metabolic acidosis (blood should be taken without using a tourniquet in a cooled fluoride oxalate tube, with transport on ice and the lactate measured within 4 hours). CPK, LDH, lipase, amylase, liver enzymes and the anion gap may be increased; serum bicarbonate may be decreased. Hepatic steatosis can be seen on ultrasound or CT. Cases of severe lactic acidosis can occur without prior symptomatic hyperlactacidemia. Lactate levels should therefore not be monitored routinely, as increases are not predictive and may lead to unnecessary changes in treatment (Brinkman 2000, Tan 2006, 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, who receive NRTIs again after having suffered a lactic acidosis (Carr 2003). For lactate levels between 3 and 5 mmol/l, "watchful waiting" with regular monitoring is recommended (see Brinkman 2001). If the resistance profile allows, NRTI treatment may be modified, e.g. switch from stavudine/didanosine to abacavir, zidovudine or tenofovir. At levels above 5 mmol/l, NRTI treatment should be stopped immediately and supportive treatment initiated; such as correction of the acidosis. For the treatment of lactic acidosis see chapter on Mitochondrial Toxicity. Mortality of patients with lactate levels above 10 mmol/l is approximately 80 % (Falco 2002). Avascular necrosis The incidence of asymptomatic avascular necrosis is approximately 0.4 % of HIV patients, significantly more frequent than in the general population (Lawson-Ayayin 2005). The postulated association with PIs could not be confirmed (Miller 2002, 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 (Miller 2002, Mondy 2003, Lawson-Ayayin 2005). The most common site of the necrosis arethe 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 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 HAART, especially those with additional risk factors (steroids!) should be monitored closely if 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. Once 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 endoprosthesis (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/osteoporosis 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. In addition to HIV infection, other factors such as malnutrition, diminished fat tissues, steroid treatment, hypogonadism, immobilization and treatment with PIs and NRTIs, seem to play a role in the pathogenesis of this disorder. Osteopenia and osteoporosis are often asymptomatic. Osteoporosis occurs mainly in the vertebrae, lower arms and hips. The following tests should be performed on 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 with a dose of 1200 mg/day. Patients should be advised to exercise and give up alcohol and nicotine. In cases with osteoporosis, bisphosphonates (e.g. alendronat 70 mg once a week) should be added. The tablets should be taken on an empty stomach 30 min before breakfast, and an upright position should be maintained for at least 30 min. 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. Specific side effects Enfuvirtide (T-20) The typical side effect of enfuvirtide 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, therefore, rarely limits treatment, and only 3 to 7 % of patients discontinue therapy ( Lazzarin 2003). The practitioner and the patient have to get used to the injection technique and the management of ISR. Good injection technique (including aseptic conditions) in conjunction with rotating injection sites (see Table 1), 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 (see Table 1, Clotet 2004, Buhk 2004). Desensitization therapy is available for the skin rash that occurs rarely with enfuvirtide (Shahar 2005). Another side effect, observed after 48 weeks in the TORO study, was a higher rate of bacterial pneumonia (gram+/ gram-) in patients taking enfuvirtide. The cause is unclear. Thus, patients undergoing enfuvirtide therapy should be monitored for pneumonia (Clotet 2004, Tashima 2003). Patients taking enfuvirtide and traveling to foreign countries should be prepared for questions about the injection material. Taking along a medical certificate stating that the patient is on subcutaneous injection therapy can help to avoid unpleasant situations. Table 1: Suggestions for prevention and management of injection site reactions (ISR) and other injection-related adverse events (Clotet 2004) Good injection technique § Ensure solution is at room temperature § Avoid muscle by bevelling needle at 45-90 degrees, depending on body habitus § Inject slowly § Maintain sterile technique (wash hands, use gloves, clean injection area and vial caps with alcohol swabs, never touch needle) § Feel for hard, subcutaneous bumps, avoid injecting into sites of previous ISR § Avoid indurated or erythematous areas § Avoid injections on the belt line § Rotate sites (abdomen, thighs, arms) and never inject two consecutive doses into the same place § Gentle manual massage after every injection Interventions for ISR 1. Injection pain § Topical anesthetic (e.g. lidocaine gel) § Oral analgesics pre-injection (e.g. ibuprofen or metamizole) § Numb area with ice or a cool pack before injecting 2. Management of pruritus § Oral antihistamines § Emollient creams or lotions (non-alcohol based and fragrance-free) Emtricitabine About 2% of patients on emtricitabine have skin discolouration, which is typically reported as hyperpigmentation and usually affecting either the palms of the hands or the soles of the feet. It is more frequent in patients of African origin (Nelson 2004) . References 1. Aarnoutse RE, Wasmuth JC, Faetkenheuer G, et al. Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir. Antivir Ther. 2003; 8:309-14. http://amedeo.com/lit.php?id=14518700 2. Ammassari A, Murri R, Pezzotti P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr 2001; 28:445-9. http://amedeo.com/lit.php?id=11744832 3. Anderson PL, Lichtenstein KA, Gerig NE, et al. 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