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HIV Medicine 2007
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6. Management of Side Effects
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.
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
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
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.
Soups made of oatmeal or rice gruel
Black or green tea, dried blueberries (tea, powder), dark chocolate
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).
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
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.
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.
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
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
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.
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
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 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.
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
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
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.
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).
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
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
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 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).
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
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 >
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 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.
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
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).
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.
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
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,
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
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)
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) .
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. Atazanavir-containing renal calculi in an
HIV-infected patient. AIDS 2007,21:1060-2. http://amedeo.com/lit.php?id=17457108
4. Antoniou T, Raboud J, Chirhin S, et al. Incidence of and risk factors for tenofovir-induced
nephrotoxicity: a retrospective cohort study. HIV Med. 2005; 6:284-90.
5. Aptivus® Prescribing Information. Boehringer Ingelheim 2006.
6. Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J et al. Tenofovir-related nephrotoxicity in
HIV-infected patients. AIDS 2004; 18:960-3. http://amedeo.com/lit.php?id=15060449
7. Becker S. Liver toxicity in epidemiological cohorts. Clin Infect Dis 2004; 38:S49-55.
8. Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect
Dis 2001; 32:124-9. http://amedeo.com/lit.php?id=11118391
9. Bjornsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig
Liver Dis 2006, 38:33-8. http://amedeo.com/lit.php?id=16054882
10. Bonnet F, Bonarek M, Morlat P, et al. Risk factors for lactic acidosis in HIV-infected patients
treated with nucleoside reverse-transcriptase inhibitors: a case-control study. Clin Infect Dis
2003; 36:1324-8. http://amedeo.com/lit.php?id=12746780
11. Bossi P, Roujeau JC, Bricaire F, et al. Stevens-johnson syndrome associated with abacavir
therapy. Clin Infect Dis 2002; 35:902. http://amedeo.com/lit.php?id=12228837
12. Brinkman K, Vrouenraets S, Kauffmann R, et al. Treatment of nucleoside reverse transcriptase
inhibitor-induced lactic acidosis. AIDS 2000; 14:2801-2. http://amedeo.com/lit.php?id=11125906
13. Brinkman K. Management of hyperlactatemia: no need for routine lactate measurements. AIDS 2001;
14. Buhk T. Einsatz von Fusionsinhibitoren. In: Hoffmann C, Jäger H (Hrsg.): AIDS Kongressband der
Münchner AIDS-Tage 2004. Landsberg/ Lech: Verlag Moderne Industrie, 2004
15. Bushen OY, Davenport JA, Bezerra Lima A , et al. Diarrhea and Reduced Levels of Antiretroviral
Drugs: Improvement with Glutamine or Alanyl-Glutamine in a Randomized Controlled trial in Northeast
Brazil. Clin Infect Dis 2004, 38:1764-70 http://amedeo.com/lit.php?id=15227625
16. Butt AA. Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine
therapy. AIDS Read 2003; 13:344-8. http://amedeo.com/lit.php?id=12889452
17. Callens S, De Roo A, Colebunders R. Fanconi-like syndrome and rhabdomyolysis in a person with
HIV infection on highly active antiretroviral treatment including tenofovir. J Infect 2003;
18. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2001; 356:1423-30.
19. Carr A, Morey A, Mallon P, et al. Fatal portal hypertension, liver failure, and mitochondrial
dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia. Lancet 2001;
20. Carr A. Lactic acidemia in infection with human immunodeficiency virus. Clin Infect Dis 2003;
21. Chesney MA, Ickovics JR, Chambers DB, et al. Self-reported adherence to antiretroviral
medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient Care
Committee & Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials
Group (AACTG). AIDS Care 2000; 12:255-66. http://amedeo.com/lit.php?id=10928201
22. Chang HR, Pella PM. Atazanavir urolithiasis. N Engl J Med 2006, 355:2158-9.
23. Chan-Tack KM, Truffa MM, Struble KA, et al. Atazanavir-associated nephrolithiasis: cases from
the US Food and Drug Administration's Adverse Event Reporting System. AIDS 2007, 21:1215-8.
24. Chui CK, Brumme ZL, Brumme CJ, et al. A simple screening approach to reduce B*5701-associated
abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase. Clin
Infect Dis 2007; 44:1503-8. http://amedeo.com/lit.php?id=17479950
25. Cirino CM, Kan VL. Hypokalemia in HIV patients on tenofovir. AIDS 2006; 20:1671-3.
26. Clark SJ, Creighton S, Portmann B, et al. Acute liver failure associated with antiretroviral
treatment for HIV: a report of six cases. J Hepatol 2002, 36:295-301.
27. Clay PG. The abacavir hypersensitivity reaction: a review. Clin Ther 2002; 24:1502-14.
http://amedeo.com/lit.php?id=12462283lotet B, Raffi F, Cooper D, et al. Clinical management of
treatment-experienced, HIV infected patients with the fusion inhibitor enfuvirtide: consensus
recommendations. AIDS 2004; 18:1137-1146.http://amedeo.com/lit.php?id=15166529Collin F, Chene G,
Retout S, et al. Indinavir trough concentration as a determinant of early nephrolithiasis in
HIV-1-infected adults. Ther Drug Monit 2007; 29:164-70. http://amedeo.com/lit.php?id=17417069
28. Creput C, Gonzalez-Canali G, Hill G, et al. Renal lesions in HIV-1-positive patient treated with
tenofovir. AIDS 2003;17:935-7. http://amedeo.com/lit.php?id=12660548
29. D'Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of
the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve
patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naïve Patients. AIDS 2000;
30. De Jesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and
efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis 2004;
31. De Lazzari E, Leon A, Arnaiz JA et al. Risk of Hepatotoxicity in Virologically Suppressed HIV
Patients Switching to Nevirapine According to Gender and CD4 Count. ICAAC in SF 2006, Abstract
32. De Maat MM, ter Heine R, van Gorp EC, et al. Case series of acute hepatitis in a non-selected
group of HIV-infected patients on nevirapine-containing antiretroviral treatment. AIDS 2003;
33. Dieleman JP, van Rossum AM, Stricker BC, et al. Persistent leukocyturia and loss of renal
function in a prospectively monitored cohort of HIV-infected patients treated with indinavir. J
Acquir Immune Defic Syndr 2003; 32:135-142. http://amedeo.com/lit.php?id=12571522
34. Enache-Angoulvant A, Hennequin C. Invasive Saccharomyces infection: a comprehensive review. Clin
Infect Dis 2005; 41:1559-68. http://amedeo.com/lit.php?id=16267727
35. Falco V, Rodriguez D, Ribera E, et al. Severe nucleoside-associated lactic acidosis in human
immunodeficiency virus-infected patients: report of 12 cases and review of the literature. Clin
Infect Dis 2002; 34:838-46. http://amedeo.com/lit.php?id=11850865
36. FDA Public Health Advisory for Nevirapine (Viramune).
37. Foster R, Taylor C, Everall IP. More on abacavir-induced neuropsychiatric reactions. AIDS 2004;
38. Gallant J, Parish M, Keruly J, et al. Changes in renal function associated with tenofovir
disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment.
Clin Infect Dis 2005; 40:1194-8. http://amedeo.com/lit.php?id=15791522
39. Gatanaga H, Tachikawa N, Kikuchi Y, et al. Urinary beta2-microglobulin as a possible sensitive
marker for renal injury caused by tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses
40. Gervasoni C, Vigano O, Grinelli E, et al. Abacavir hypersensitivity reaction after switching
from the twice-daily to the once-daily formulation.AIDS Patient Care STDS 2007; 21:1-3.
http://amedeo.com/lit.php?id=17263652Haas DW, Heather JR, Richard BK, et al. Pharmacogenetics of
efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS
2004; 18:2391-2400. http://amedeo.com/lit.php?id=15622315
41. Hansen AB, Mathiesen S, Gerstoft J. Severe metabolic acidosis and renal failure in an HIV-1
patient receiving tenofovir. Scand J Infect Dis 2004; 36:389-92.
42. Heiser CR, Ernst JA, Barrett JT, et al. Probiotics, soluble fiber, and L-Glutamine (GLN) reduce
nelfinavir (NFV)- or lopinavir/ritonavir (LPV/r)-related diarrhea. J Int Assoc Physicians AIDS Care
(Chic Ill) 2004; 3:121-9. http://amedeo.com/lit.php?id=15768732
43. Henry DH, Volberding PA, Leitz G. Epoetin Alfa for Treatment of Anemia in HIV-Infected Patients
Past, Present, and Future. JAIDS 2004; 37:1221-7. http://amedeo.com/lit.php?id=15385728
44. Hewitt RG. Abacavir hypersensitivity reaction. Clin Infect Dis 2002; 34:1137-42.
45. Highleyman L. Adverse Effects Associated with Antiretroviral Therapy. BETA 2000.
46. Hocqueloux L, Alberti C, Feugeas JP, et al. Prevalence, risk factors and outcome of
hyperlactataemia in HIV-infected patients. HIV Med. 2003; 4:18-23.
47. Important Safety Information; Intracranial Hemorrhage in Patients Receiving Aptivus®
(tipranavir) capsules. June 30 2006. Boehringer Ingelheim Pharmaceuticals, Inc.
48. Izzedine H, Isnard-Bagnis C, Hulot JS, et al. Renal safety of tenofovir in HIV
treatment-experienced patients. AIDS 2004; 18:1074-6. http://amedeo.com/lit.php?id=15096814
49. Jackson JB, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared
with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month
follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362:859-68.
50. Jamisse L, Balkus J, Hitti J, et al. Antiretroviral-associated toxicity among
HIV-1-seropositive pregnant women in Mozambique receiving nevirapine-based regimens. J Acquir Immune
Defic Syndr 2007. 1;44:371-6. http://amedeo.com/lit.php?id=17259905
51. Knobel H, Miro JM, Domingo P, et al. Failure of a Short-Term Prednisone Regimen to Prevent
Nevirapine-Associated Rash: A Double-Blind Placebo-Controlled Trial: The GESIDA 09/99 Study. J
Acquir Immune Defic Syndr 2001; 28:14-18. http://amedeo.com/lit.php?id=11579272
52. Kohli-Pamnani A, Huynh P, Lobo F. Amprenavir-induced maculopapular exanthem followed by
desensitization in a patient with late-stage human immunodeficiency virus. Ann Allergy Asthma
Immunol 2006; 96:620-3. http://amedeo.com/lit.php?id=16680935
53. Law WP, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the
HIV-NAT Cohort, Thailand, 1996-2001. AIDS 2003; 17:2191-9. http://amedeo.com/lit.php?id=14523276
54. Lawson-Ayayin S, Bonnet F, Bernardin E, et al. Avascular necrosis in HIV-Infected patients: A
case-control study from the Aquitaine Cohort, 1997-2002, France. Clin Infect Dis 2005; 40:1188-93.
55. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of Enfuvirtide in Patients Infected with
Drug-Resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348:2186-95.
56. Loiseau-Peres S, Delaunay C, Poupon S, et al. Osteopenia in patients infected by the HIV. A case
control study. Joint Bone Spine 2002; 69:482-5. http://amedeo.com/lit.php?id=12477232
57. Mallolas J. Nevirapine-associated hepatotoxicity in virologically suppressed patients-role of
gender and CD4+ cell counts. AIDS Rev 2006; 8:238-9. http://amedeo.com/lit.php?id=17219738
58. Mallal S. PREDICT-1: a novel randomised prospective study to determine the clinical utility of
HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study
CNA106030). 4th IAS Sydney. http://www.ias2007.org/pag/PSession.aspx?s=150
59. Manfredi R, Calza L. Nevirapine versus efavirenz in 742 patients: no link of liver toxicity
with female sex, and a baseline CD4 cell count greater than 250 cells/microl. AIDS 2006;
60. Martin AM, Krueger R, Almeida CA, et al. A sensitive and rapid alternative to HLA typing as a
genetic screening test for abacavir hypersensitivity syndrome. Pharmacogenet Genomics 2006,
61. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment
failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001; 15:71-75.
62. Miller KD, Masur H, Jones ED, et al. High prevalence of osteonecrosis of the femoral head in
HIV-infected adults. Ann Intern Med 2002; 137:17-25. http://amedeo.com/lit.php?id=12093241
63. Montaner JS, Cahn P, Zala C, et al. Randomized, controlled study of the effects of a short
course of prednisone on the incidence of rash associated with nevirapine in patients infected with
HIV-1. J AIDS 2003; 33:41-6. http://amedeo.com/lit.php?id=12792354
64. Mondy K, Tebas P. Emerging bone problems in patients infected with HIV. Clin Infect Dis 2003;
36:S101-5. http://amedeo.com/lit.php?id=12652379Montessori V, Harris M, Montaner JS. Hepatotoxicity
of nucleoside reverse transcriptase inhibitors. Semin Liver Dis 2003; 23:167-72.
65. Moyle G , Fletcher C, Brown H, et al. Changes in sleep quality and brain wave patterns following
initiation of an efavirenz-containing triple antiretroviral regimen. HIV Med 2006, 7:243-7.
66. Nelson M, Schiavone M. Emtricitabine (FTC) for the treatment of HIV infection. Int J Clin Pract
2004; 58:504-10. http://amedeo.com/lit.php?id=15206508
67. Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the
treatment of HIV infection in adults: the first 4 years. AIDS 2007; 21:1273-81. .
http://amedeo.com/lit.php?id=17545703Nunez M, Soriano V. Hepatotoxicity of
Antiretrovirals:Incidence, Mechanisms and Mangement. Drug Saf. 2005, 28:53-66.
68. Ouagari Z, Tubiana R, Mohand HA, et al. Skin rash associated with atazanavir: report of three
cases. AIDS 2006, 20:1207-8. http://amedeo.com/lit.php?id=16691076
69. Pacanowski J, Poirier JM, Petit I, et al. Atazanavir urinary stones in an HIV-infected patient.
AIDS 2006, 20:2131. http://amedeo.com/lit.php?id=17053366
70. Parsonage MJ, Wilkins EG, Snowden N, et al. The development of hypophosphataemic osteomalacia
with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med 2005, 6:341-6.
71. Phillips EJ, Wong GA, Kaul R, et al. Clinical and immunogenetic correlates of abacavir
hypersensitivity. AIDS 2005; 19:979-81. http://amedeo.com/lit.php?id=15905681
72. Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases the incidence of
abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis
2006, 43:99-102. http://amedeo.com/lit.php?id=16758424
73. Rifkin BS, Perazella MA. Tenofovir-associated nephrotoxicity: Fanconi syndrome and renal
failure. Am J Med 2004; 117:282-4. http://amedeo.com/lit.php?id=15308442
74. Rodriguez-Novoa S, Martin-Carbonero S, Barreiro P et al. Genetic factors influencing atazanavir
plasma concentrations and the risk of severe hyperbilirubinemia. AIDS 2007, 21:41-6.
http://amedeo.com/lit.php?id=17148966 Roling J, Schmid H, Fischereder M, et al. HIV-associated
renal diseases and highly active antiretroviral therapy-induced nephropathy. Clin Infect Dis 2006;
75. Rollot F, Nazal EM, Chauvelot-Moachon L, et al. Tenofovir-related Fanconi syndrome with
nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of
lopinavir-ritonavir-didanosine. Clin Infect Dis 2003;
76. Rotger M, Taffe P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral
therapy-associated hyperbilirubinemia.J Infect Dis 2005, 192:1381-6.
77. Rotunda A, Hirsch RJ, Scheinfeld N, et al. Severe cutaneous reactions associated with the use of
HIV medications. Acta Derm Venereol 2003; 83:1-9. http://amedeo.com/lit.php?id=12636014
78. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use
in hiv-infected Subjects. J Infect Dis 2005; 191 :825-829. http://amedeo.com/lit.php?id=15717255
79. Saumoy M, Vidal F, Peraire J, et al. Proximal tubular kidney damage and tenofovir: a role for
mitochondrial toxicity? AIDS 2004; 18:1741-2. http://amedeo.com/lit.php?id=15280790
80. Sax PE, Gallant JE, Klotman PE. Renal safety of tenofovir disoproxil fumarate. AIDS Read 2007;
17:90-2, 99-104, C3. . http://amedeo.com/lit.php?id=17323508
81. Schmid H, Muhlbayer D, Roling J, et al. Macroenzyme creatine kinase (CK) type 2 in HIV-infected
patients is significantly associated with TDF and consists of ubiquitous mitochondrial CK. Antivir
Ther 2006;11:1071-80. http://amedeo.com/lit.php?id=17302377
82. Servoss JC, Kitch DW, Andersen JW et al. Predictors of antiretroviral-related hepatotoxicity in
the adult AIDS Clinical Trial Group (1989-1999). J Acquir Immune Defic Syndr. 2006; 1;43:320-3.
83. Shahar E, Moar C, Pollack S. Successful desensitization of enfuvirtide-induced skin
hypersensitivity reaction. AIDS 2005; 19:451. http://amedeo.com/lit.php?id=15750403
84. Smith DE, Jeganathan S, Ray J. Atazanavir plasma concentrations vary significantly between
patients and correlate with increased serum bilirubin concentrations. HIV Clin Trials 2006.;7:34-8.
85. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated Nevirapine or
Efavirenz-containing antiretroviral therapy: role of Hepatitis C and B Infection. Hepatology 2002;
86. Sulkowski MS. Drug-induced liver injury associated with antiretroviral therapy that includes
HIV-1 protease inhibitors. Clin Infect Dis 2004; 38:S90-7. http://amedeo.com/lit.php?id=14986280
87. Sulkowski MS, Mehta SH, Chaisson RE, et al. Hepatotoxicity associated with protease
inhibiotor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004;
88. Tashima KT, Carpenter CC. Fusion inhibition-a major but costly step forward in the treatment of
HIV-1. N Engl J Med 2003; 348:2249-50. http://amedeo.com/lit.php?id=12773653
89. Tan D, Walmsley S, Shen S, et al. Mild to moderate symptoms do not correlate with lactate levels
in HIV-positive patients on nucleoside reverse transcriptase inhibitors. HIV Clin Trials 2006;
90. The Grupo Estudio Syndrome Immunodeficiencies Adquirida 26/02 Study Group. Failure of cetirizine
to prevent nevirapine-associated rash: A double-blind placebo-controlled trial for the GESIDA 26/01
Study. J AIDS 2004; 37:1276-1281. http://amedeo.com/lit.php?id=15385735
91. Tossonian H, Raffa J, Grebely J, et al. Hepatotoxicity in injection drug users (IDUs) and
non-IDUs receiving nevirapine-based HAART. AIDS 2006 - XVI International AIDS Conference, Toronto
2006, Abstract no. WEPE0176. http://www.iasociety.org/abstract/show.asp?abstract_id=2194279
92. Turner MJ, Angel JB, Woodend K. The efficacy of calcium carbonate in the treatment of protease
inhibitor-induced persistent diarrhea in HIV-infected patients. HIV Clin Trials 2004; 5:19-2
93. Vrouenraets SM, Treskes M, Regez RM, et al. Hyperlactataemia in HIV-infected patients: the role
of NRTI-treatment. Antivir Ther 2002; 7:239-44. http://amedeo.com/lit.php?id=12553477
94. Wilde JT. Protease inhibitor therapy and bleeding. Haemophilia 2000; 6:487-90.
95. Wohl DA, McComsey G, Tebas P, et al. Current concepts in the diagnosis and management of
metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006, 43:645-53.
96. Zucman D, Truchis P, Majerholc C et al. Prospective screening for human leukocyte
antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV
population. J Acquir Immune Defic Syndr. 2007; 45:1-3. http://amedeo.com/lit.php?id=17356469
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