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Review

Synthèse

Adverse effects of antiretroviral therapy
for HIV infection

Valentina Montessori, Natasha Press, Marianne Harris, Linda Akagi, Julio S.G. Montaner
Abstract nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV).
The dosages and adverse effects of all 3 classes of medica-
LONG-TERM REMISSION OF HIV-1 DISEASE CAN BE READILY ACHIEVED by tions are listed in Table 1.
combinations of antiretroviral agents. The suppression of plasma In this article we review the adverse effects of HAART
viral loads to less than the limit of quantification of the most sen- therapy, with specific attention to the metabolic abnormali-
sitive commercially available assays (i.e., less than 50 copies/mL) ties associated with HIV treatment, including dyslipi-
and the coincident improvement in CD4 T cell counts is associ- demias, diabetes mellitus, insulin resistance, and the lipody-
ated with resolution of established opportunistic infections and a strophy syndrome and lactic acidosis associated with NRTI
decrease in the risk of new opportunistic infections. However,
mitochondrial toxicity. Our aim is to help physicians gain a
prolonged treatment with combination regimens can be difficult
working knowledge of these adverse effects, with the ulti-
to sustain because of problems with adherence and toxic effects.
mate goal of improving the tolerability and effectiveness of
All antiretroviral drugs can have both short-term and long-term
adverse events. The risk of specific side effects varies from drug HIV treatment, promoting the early recognition and rever-
to drug, from drug class to drug class, and from patient to pa- sal of potentially serious adverse effects, and reducing the
tient. A better understanding of the adverse effects of antiretrovi- potential for adverse drug interactions.
ral agents is of interest not only for HIV specialists as they try to
optimize therapy, but also for other physicians who care for HIV- Significant antiretroviral adverse effects
positive patients.
Antiretroviral therapy can have a wide range of adverse
CMAJ 2004;170(2):229-38
effects on the human body (Fig. 1). Common but mild ad-
verse effects occurring early in most antiretroviral regimens

T
he introduction of highly active antiretroviral ther- include gastrointestinal effects such as bloating, nausea and
apy (HAART) has led to a significant reduction in diarrhea, which may be transient or may persist throughout
AIDS-related morbidity and mortality.1–3 Unfortu- therapy.6 Other common nuisance adverse effects are fa-
nately, up to 25% of patients discontinue their initial tigue and headache caused by AZT and nightmares associ-
HAART regimen because of treatment failure (inability to ated with EFV. Several uncommon but more serious ad-
suppress HIV viral replication to below the current limit of verse effects associated with antiretroviral therapy,
detection, 50 copies/mL), toxic effects or noncompliance including AZT-associated anemia, d4T-associated periph-
within the first 8 months of therapy.4,5 Several strategies eral neuropathy, PI-associated retinoid toxicity (exempli-
have been implemented to improve treatment duration. fied by pruritus and ingrown toenails) and NNRTI-associ-
While development of new antiretroviral agents continues, ated hypersensitivity reactions, are treated according to
efforts to maximize the effectiveness of currently available accepted therapy for these conditions in patients not re-
treatments include attempts to better understand and man- ceiving HAART. However, the subtle and serious nature of
age adverse effects. Each antiretroviral medication is associ- other adverse effects — lactic acidosis, hepatic steatosis, hy-
ated with its own specific adverse effects or may cause perlactatemia, hepatotoxicity, hyperglycemia, fat maldistri-
problems only in particular circumstances. Similarly, class- bution, hyperlipidemia, bleeding disorders, osteoporosis
specific adverse effects may occur. One of the drug classes and skin rash — warrant more detailed discussion.
used in HAART is the nucleoside reverse transcriptase in-
hibitors (NRTIs), which commonly form the “backbone” Lactic acidosis, hepatic steatosis and
of the antiretroviral cocktail; this class includes zidovudine hyperlactatemia
(AZT), lamivudine, didanosine (ddI), stavudine (d4T), aba-
cavir (ABC) and the newly released nucleotide analogue NRTIs are nucleoside analogues that prevent DNA
tenofovir. Two NRTIs are often combined with 1 medica- elongation and viral reproduction. These drugs are triphos-
tion from either of the 2 remaining classes, the non- phorylated intracellularly to become nucleotides and are
nucleoside reverse transcriptase inhibitors (NNRTIs) and then incorporated into the viral DNA chain by the viral re-
the protease inhibitors (PIs). The NNRTI class comprises verse transcription enzyme; their presence in the DNA

CMAJ • JAN. 20, 2004; 170 (2) 229

© 2004 Canadian Medical Association or its licensors

elevation of liver enzyme levels Full daily dose can be given once 2 wk. have a decreased anaerobic threshold.3 slow. 2.18 although resolution may be the incidence of NRTI-associated lactic acidosis was 1. which in turn enters ten vague complaints of malaise. Unfortunately. nausea and vomiting. malaise is rechallenged Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine NVP 200 mg once daily for Rash.17 The hyperlac- Lactic acidosis has been associated with AZT. In a recent case series (20 patients) the mean time to per 1000 person-years. awareness shown in Fig. Recent work has described disruption of mito.21 incidence of NRTI-associated lactic acidosis in the current The mechanism of NRTI-associated lactic acidosis is era of triple therapy. these researchers re.19 Hyperlactatemia viewed patients who had each been treated with a single an. ferred into the mitochondria. rash.16 followed by liver failure. which is then trans- dosis (Box 1) is important in the management of HIV.75 mg tid Reversible peripheral neuropathy. However. elevation of liver enzyme levels. headache. elevation of lactic acid level. medication is continued or patient myalgias. has been independently associated with exposure to d4T tiretroviral agent. Should not be combined with ddC.20. there is the only enzyme involved in the replication of mitochondr. gout. Full daily dose can be given 200 mg bid once daily Didanosine-EC ddI-EC Body weight > 50 kg: 400 mg once daily Zalcitabine ddC 0. which is a surrogate patic steatosis. rash 230 JAMC • 20 JANV. pancreatitis or ddI. these drugs can theoret. Given its potential lethality. divided Nausea.Montessori et al halts transcription. Relatively weak risk–benefit ratio limits usefulness Stavudine d4T Body weight 40–60 kg: Reversible peripheral neuropathy.. The clinical course is characterized by of.e. most of the pyruvate infected patients.17–22 Patients with hyperlactatemia may ranging from nucleoside-associated lactic acidosis to he. which may Reaction may be fatal if be characterized by fever. rash. tigue and tachypnea. with subsequent adverse events containing regimens. anemia.” drowsiness). evidence of a persistent mild to moderate elevation of ve- ial DNA. verted to pyruvate (in the cytosol).6–14 Fortgang and associates15 estimated that NRTIs are discontinued. Should not be combined with d4T (i. pancreatitis. the tricarboxylic acid cycle to form NADH (the reduced Table 1: Antiretroviral medications and their adverse effects Drug Abbreviation Dosage Most common adverse effects Comments Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine AZT 400–600 mg/d. cardiac dys- ically also function as substrates for other enzymes capable rhythmias and death. low phosphate levels Abacavir ABC 300 mg bid Hypersensitivity reaction. Should not be combined with d4T mouth ulcers. glucose is con- of the signs and symptoms of NRTI-associated lactic aci. including human DNA polymerase γ. then increase to daily 200 mg bid Delavirdine DLV 400 mg tid Rash Efavirenz EFV 600 mg once daily Central nervous system toxicity (or 300 mg bid) (“hangover. ddI and tatemia and associated symptoms tend to resolve when d4T therapy. 100 mg bid reversible peripheral neuropathy Should be taken separately from Body weight > 50 kg: food. fa. elevation of CPK level Lamivudine 3TC 150 mg bid Neutropenia (rare) Didanosine ddI Body weight 35–49 kg: GI intolerance. 2004. nous lactic acid (hyperlactatemia) in 10% to 20% of pa- chondrial function through NRTI-mediated inhibition of tients undergoing long-term treatment with NRTI- human DNA polymerase γ. of DNA formation. resolution was 62 (range 7 to 176) days. 170 (2) . administered bid) leukopenia. Should not be combined with AZT 30 mg bid lactic acid elevation (rarely fatal) Body weight > 60 kg: 40 mg bid Tenofovir TDF 300 mg once daily GI upset. There. During normal glycolysis.7 In addition to this serious but rare syndrome. is converted into acetylcoenzyme A.8–13 for underlying mitochondrial dysfunction. and their results may underestimate the and hydroxyurea. arthralgias.

which may lead mitochondrial DNA of the general population. the lactic acidosis. nutritional depletion of cofactors and vitamins required for phate through oxidative phosphorylation. Alternatively. 20. The mito. Other risk factors may include obesity and chondria use the NADH to produce adenosine triphos.28–30 However. severe NRTI-associated lactic acidosis. These excess chondria caused by HIV infection makes these patients more triglycerides may accumulate in the liver. meta- viral agents are more likely than others to cause mitochondr. ther as a result of concurrent acid–base disturbances or be- clear.g. Dose should be increased to 4 capsules bid if used with EFZ or NVP and in the presence of moderately to highly PI-resistant HIV virus Amprenavir APV 1200 mg bid. The risk factors for lactic acidosis are currently unknown. GI upset with RTV boosting: APV 600 mg/RTV 100 mg bid Nelfinavir NFV 750 mg tid GI upset.26 cially oxidative phosphorylation. which diminishes mitochondrial function. circumoral Most common use at present is as a paresthesias. hyperlipidemias or lipodystrophy (limb and face wasting and accumulation of abnormal fat deposits). CPK = creatine phosphokinase. ei- ial dysfunction. with RTV boosting: IDV nephrolithiasis.g. Furthermore. Better 400 mg/400 mg bid tolerability (e. GI = gastrointestinal. with Elevation of liver enzyme levels Very poor bioavailability unless SQV/RTV ratio as follows: combined with RTV. As described normal mitochondrial function. DNA polymerase γ is inhibited in the presence of boflavin.31 Thus. hypertension. are subjected to further damage by NRTIs. there is significant polymorphism in the cause of factors such as hypoalbuminemia. Can be given Elevation of liver enzyme levels. with enzyme levels absence of RTV SQV/RTV ratio as follows: 1000 mg/100 mg bid or 1600 mg/100 mg once daily Ritonavir RTV 600 mg bid GI upset. 2004. Free fatty acids then accumu. EC = enteric coated. Mitochondrial necrosis is caused by HIV infection in vitro. susceptible to significant problems when the mitochondria acteristic hepatic steatosis.24 In addition. without HIV infection. Adverse effects of antiretroviral therapy form of nicotinamide adenine dinucleotide). to underestimation of the anion gap. 100– levels. ingrown 800 mg/RTV 100 mg bid toenails. tid = 3 times daily. increase with age.. GI toxic effects. GI) and similar or pharmacokinetics to FTV when used 1000 mg/100 mg bid with RTV boosting or 1600 mg/100 mg once daily Brand Fortovase FTV 1200 mg tid.25 and a spe.23. *PIs have multiple drug interactions and may be associated with various metabolic adverse effects such as diabetes mellitus. Impaired oxidation may also lead to a de. Can be given Rash. NRTIs.27 The depletion of cellular mito- late and are metabolized to triglycerides. diarrhea. elevation of liver Better bioavailability than INV in the administer with RTV. espe. This allows pyruvate and and HIV-infected patients who have never taken NRTIs NADH to accumulate. 170 (2) 231 .. benign hyperbilirubinemia Lopinavir/ritonavir LPV/RTV 3 capsules bid GI upset Two drugs combined in a single capsule. the anion gap cific form of the DNA may place certain individuals at is less attractive as a screening tool for NRTI-associated higher risk for mitochondrial dysfunction. causing the char. bolic acidosis may also present with a normal anion gap. because it can be an indicator of multiple number of possible forms of mitochondrial DNA appears to concurrent illnesses or malnutrition. CMAJ • JAN. DNA in the peripheral blood cells than control subjects crease in fatty acid oxidation. have a significantly lower ratio of mitochondrial to nuclear vate to lactate. Table 1 continued Drug Abbreviation Dosage Most common adverse effects Comments Protease inhibitors (PIs)* Saquinavir SQV Brand Invirase INV Administer with RTV. Finally. the clinical relevance of these findings is un. such as thiamine and ri- above. elevation of liver enzyme PI booster at low doses (e. hypertriglyceridemia 400 mg/d) Indinavir IDV 800 mg tid. Elevation of the anion gap (see Box 1) is characteristic of Although in vitro studies have suggested that some antiretro. HIV infection itself may be a risk factor. enhancing the conversion of pyru. mostly diarrhea Note: bid = twice daily.

20 mg depanthenol). physicians treating a case of severe lactic DNA to nuclear DNA may provide a more sensitive and spe.35. but they do not reliably dis. The antiretroviral therapy should be discontinued immedi- drial damage in patients with severe lactic acidosis..23 The ratio of mitochondrial tive data are lacking. twice as high as among patients without (efavirenz) efavirenz) hepatitis C infection. thiamine and riboflavin) in the management of severely avir (RTV) but only 6% to 7% of those who initiated ther- apy with saquinavir. pyridoxine. asymptomatic.g.26 Plymale ately. mg daily and L-carnitine 1000 mg IV twice daily. In some cases. 100 lower among patients with symptomatic. The authors concluded that long-term use of PIs Chesley Sheppard Peripheral neuropathy may have a beneficial impact on the progression of liver fi- brosis in patients infected with HIV and hepatitis C. 20 mg hyperlactatemia than among controls (without HIV infec. Because defini- with chronic hyperlactatemia. treatment-naive pa. Montessori et al Peripheral venous lactate levels are currently used as a ill patients. there have been recent attempts to under- Lactic acidosis stand the hepatic histologic changes. as well as coenzyme Q10 50 tion) and HIV-infected. vomiting gested that successful treatment of hepatitis C in dually in- Pancreatitis fected patients may facilitate the introduction of Nephrolithiasis PI-containing antiretroviral therapy. 1: Adverse effects of antiretroviral therapy. Consideration could be given to twice-daily intra- and associates26 found that mitochondrial DNA levels were venous (IV) administration of vitamin B complex (e. the Central adiposity Diarrhea newest member of the class represents a coformulation of lopinavir and low-dose RTV (see Table 1).42 Coadministration of (indinavir) Thinning extremities low-dose RTV with other PIs is now common. infection was 12%.3%). In addition. The hepatotoxicity of this drug has been largely supportive. exploring the effectiveness of these and other agents for pro- tinguish patients at risk for severe lactic acidosis from those phylaxis and treatment of this adverse effect. most of the antiretroviral agents.77. 2. Benhamou and associates43 reviewed liver biopsy samples from 182 patients with both HIV and he- patitis C.40 The rate of severe hepatotox- icity associated with any PI among patients with hepatitis C Insomnia.32–36 but there is an urgent need for formal trials screening tool in some centres.41 The risk of liver enzyme Anemia (AZT) elevation among patients with chronic hepatitis B or C was. Hepatotoxicity Measurement of mitochondrial DNA remains a research tool but may eventually become important in the management of Transaminitis and hepatotoxicity are associated with patients receiving antiretroviral therapy.3% to 18. Case reports have suggested a class varies with the specific drug: in a prospective cohort possible role for supplementation with essential cofactors study. 170 (2) . 200 mg nicotinamide.2%) and 10. In addition. although with variable success. mitochondrial chondrial disorders. These tients. 6. other than elevation of transaminases. the treatment of NRTI-associated lactic acidosis concern focused on the PIs. The decrease in mitochondrial DNA preceded an in. Reisler and colleagues44 found that the rate Fig. D4T. acidosis should seek expert consultation whenever possible. in fact. agents have been studied in the treatment of other mito- crease in venous lactate levels. The liver fibrosis stage was lower among patients receiving PIs than among those who had never received PI therapy.9% (95% confidence interval [CI] only a certain drug causes the effect (drug name in parentheses).6% to 11.or 2. cific tool to evaluate the risk of toxic effects due to mitochon.37–39 DNA levels increased in all patients with symptomatic hyper- lactatemia when antiretroviral therapy was discontinued.g.47-fold greater after initiation of a Cardiomyopathy Breast hypertrophy PI-containing regimen than among patients without evi- dence of viral hepatitis. it has been sug- Hepatotoxicity Nausea.. nelfinavir (NFV) or indinavir (IDV) experienced severe hepatotoxicity (defined as a grade 3 or 4 change in the serum levels of alanine aminotransferase and Alopecia aspartate aminotransferase).8% (95% CI 3. respec- 232 JAMC • 20 JANV. The extent to Skin rash Pruritic skin which such combinations will affect the safety profiles of the individual agents remains to be fully characterized. although initially most To date. depression Headache (AZT. Similar findings have been reported by den Brinker and colleagues. 20 mg riboflavin. 2004.41 In this context. of hepatotoxicity was 8. nucleoside-related mg thiamine. 30% of patients who initiated treatment with riton- (e. Ingrown toenails The NNRTIs are also associated with transaminitis and hepatotoxicity. respectively. that occur with PI-containing antiretrovi- Osteoporosis ral regimens.

as discussed in the previous section. Dashed lines indicate steps occurring within the mitochondria. NADH = reduced form of NAD.47 How- grade 3 or 4 elevation of transaminases than DLV (DLV v. for antiretroviral-associated lactic acidosis NVP is no longer used for postexposure prophylaxis and is used with caution in the setting of liver disease. Elevated random serum lactate level: > 3 mmol/L Decreased ratio of mitochondrial DNA to nuclear DNA* Hyperglycemia *Currently a research tool. bone loss. Signs and symptoms Finally. These 2 mens. DLV v. Lipodystrophy affecting HIV-positive patients Glucose LDH Pyruvate Lactate + + NADH + H NAD Gluconeogenesis AcetylCoA NADH ATP Tricarboxylic Oxidative acid cycle phosphorylation Fig. pyruvate and NADH accumulate.46 Therefore. In one study in which NVP was used for pos. LDH = lactate dehydroge- nase. CMAJ • JAN.01). which ultimately leads to lactic acidosis. New-onset diabetes mellitus. which highlights the complexity and difficulty of Laboratory tests evaluating and managing hepatotoxicity associated with an- Elevated anion gap: [Na] – ([Cl] + [HCO3]) > 10 tiretroviral therapy. insulin resistance may also be associated with HIV NVP: OR 2. the overall rate of severe hepatotoxicity Nausea. leading to lactic acidosis.45 The hypersensitivity reaction observed with NVP (char. 2: Postulated mechanism by which nucleoside reverse transcriptase inhibitor (NRTI) therapy interferes with glycolysis. Others have ob. ever. resulting from the direct effects of the HIV virus on pan- served similar rates of hepatotoxicity for NVP and EFV but creatic β cell function and insulin secretion. ATP = adenosine triphosphate. among patients receiving NVP and EFV.48 found that elevation of CD4 cell count of more than 50/µL was most strongly linked to hepatotoxicity. insulin resistance and accelerated transaminitis. p = 0.7 [95% CI 1. Lipodystrophy is part of a metabolic syndrome that in- acterized by rash and fever) can also include severe cludes dyslipidemias. rather than a common screening method. perhaps due to Fat maldistribution adherence or immune reconstitution.2 to 5. weight loss with NRTI therapy reported by Reisler and colleagues44 was 12%. Adverse effects of antiretroviral therapy texposure prophylaxis. the NRTIs Fatigue are associated with risk of mitochondrial toxicity and he- Diminished exercise tolerance patic steatosis. affects a small proportion (1% to 6%) of HIV- infected patients treated with PI-based antiretroviral regi- tively.5].6 to 4. While these may be particular problems Shortness of breath. enhancing the conver- sion of pyruvate into lactate. If such impairment occurs. tachypnea with d4T and ddI. AcetylCoA = acetylcoenzyme A. Many more patients receiving PI therapy have evi- drugs were significantly more likely to be associated with dence of insulin resistance without frank diabetes. These steps are subject to impairment by NRTI therapy. NAD = nicotinamide adenine dinucleotide. 2 patients experienced liver failure.003. 2004. for which normal mitochondrial function is required. 170 (2) 233 . EFV: infection itself in patients not receiving PI therapy.7]. 20. Box 1: Signs and symptoms of and laboratory tests and 1 of them required liver transplantation.5 [95% CI 1. perhaps OR 2. clinically similar to type 2 diabetes. p = 0.

high LDL cholesterol Diabetes High fasting blood sugar and HbA1c levels Insulin resistance Increased insulin and C-peptide levels Fig. been estimated at about 50% after more than a year of anti- tocks. puts these patients at increased risk for pre- mature cardiovascular disease. with Note: HDL = high-density lipoprotein. particularly in high-risk individu- als. coupled with other factors pre- sent in HIV patients such as insulin resistance and vascular inflammation. high LDL cholesterol level. Table 2). increasing age and advanced drome.Montessori et al was first described in 1998. Several case reports have de- Table 2: Features of the antiretroviral-associated metabolic syndrome Condition Observation or test Clinical Central fat accumulation Intra-abdominal. LDL = low-density lipoprotein. lipomas Peripheral lipoatrophy Face. HIV disease.53 domen and breasts and over the dorsocervical spine (the Attempts to identify patients most likely to experience “buffalo hump”) and lipomas (Fig. Reproduced. accompanied by central fat accumulation in the ab.5. although NRTIs. limbs and but. especially d4T. breast hypertrophy. with combined en- docrine and metabolic abnormalities having profound ef- fects on the distribution of body fat.55 sociated with lipodystrophy. Risk factors may include a has been most strongly linked to the lipodystrophy syn. buttocks Laboratory Dyslipidemia Hypertriglyceridemia.5 PI therapy lipodystrophy are in progress. 170 (2) . high triglyceride level) is ex- tremely atherogenic and. longer duration of PI therapy. low HDL cholesterol.49 The main clinical features are least one physical abnormality related to lipodystrophy has peripheral fat loss (lipoatrophy) in the face. low levels of high-density lipoprotein (HDL) cholesterol and elevation of low-density lipoprotein (LDL) cholesterol. 2004. legs. 3: Clinical features of lipodystrophy. dorsocervical spine. have also been as.51. The dyslipidemia is more profound among those receiving PIs and in those with fat redistribu- tion (lipoaccumulation or lipoatrophy). 234 JAMC • 20 JANV. the cause is multifactorial. retroviral therapy. essentially result in a visible manifestation of HIV posi- tivity. Most likely. Inability to manage lipodystrophy and its associated risks threatens the effectiveness of antiretroviral therapy by discouraging patients from continuing treatment. Dyslipidemia Dyslipidemia to levels associated with increased risk of cardiovascular disease occurs in about 70% of HIV-1 in- fected patients receiving antiretroviral therapy. from the Canadian Respiratory Journal.5 The dyslipidemia pattern (low HDL cholesterol level. In addition. HbA1c = hemoglobin A1c permission.54. Bottom: Central fat accumulation with abdominal Lactic acidosis skin striae and thinning of the extremities. arms.56 Features of the dyslipidemia in this syndrome include severe hyper- triglyceridemia.50 (glycosylated hemoglobin). Top: Dorsocervical Osteoporosis Bone densitometry fat pad. 3.52 The overall prevalence of at The pathogenesis of lipodystrophy is poorly understood.47 Lipodystrophy is rec- ognized as the source of significant cosmetic concerns and threatens the confidentiality of HIV serostatus: the typical changes of lipodystrophy. an increase in visceral and abdominal fat has been associated with an increased risk for glucose intol- erance.

and the beneficial effects of antiretroviral therapy in tients (of whom 280 were receiving triple therapy).73 Treatment of not a specific entity but a final common pathway of several osteoporosis in the setting of antiretroviral therapy is evolv- conditions that may impair blood supply to the bone. in one series 6 cases occurred among 508 HIV pa- low. and referral for specialist assessment. Review of the patient’s CMAJ • JAN. defined only recently and patients have been prospectively all previously described risk factors for osteonecrosis. HIV-infected patients presenting with persistent hip. warranted. The ing.02). min D to 1.61. osteoporosis. and inhibition of 2 cytochrome P450 mixed- increased bleeding. For However. the overall risk of myocardial infarction remains example.60 care and the most widely accepted method is dual-energy x-ray absorptiometry (DEXA) at the spine and hip. though unusual. when it was thought to be secondary with hemophilia to poor nutrition or perhaps increased cytokine levels re- lated to chronic infection. a non-PI regimen should RTV and NFV all inhibited conversion of 25-hydroxy vita- be considered for these patients. Standard therapy. the patients’ coag. and variety of techniques. 170 (2) 235 .. the current standard of other mechanisms may also be involved. (e. bleeding occur more frequently. patients with additional risk factors for osteoporosis Osteonecrosis results in cell death of various bone com. 2004. is first report of osteonecrosis in association with HIV infec. However. Dusso and associates72 found that the PIs IDV.5 The cardiovascular event rate is difficult to calcu. followed for just a short period of time (approximately 4 to There is no apparent difference in the overall use of PIs 5 years).62 50% of the HIV-positive patients receiving PIs. knee PIs may bind to or interfere with LDL receptor-related or shoulder pain. If undergoing surgery. The need for formal osteoporosis evaluation and ther- Osteonecrosis. as well as pharmaco- partum with avascular necrosis of multiple bones. including fat marrow and mineralized tissue. teonecrosis. a situation in which phosphate may act as a buffer. When possible. corticosteroid therapy and hypercoagulability. Although most PIs have been implicated. these patients may bene.25-dihydroxy vitamin D in vitro. especially in the absence of trauma. protein and cytoplasmic retinoic acid binding protein type should undergo MRI to evaluate for possible osteonecrosis. some linked to hyperlipidemia and others to alcoholism. bleeding increased within the first few 23% of HIV-positive patients not receiving PIs and 29% of weeks of PI therapy. operative period.70 The mechanism is unknown.71 The PIs are metabolized by cytochrome mophiliac patients taking PIs should be monitored for P450 enzymes. HAART was associated among HIV-infected patients with and without os- with a 27% relative increase in the rate of myocardial in. additional cases emerged. as well as logic measures such as hormone replacement and bisphos- a similar case in a young HIV-positive man with no other phonate therapy. curred in conjunction with antiretroviral-associated lactic RTV in particular is associated with this adverse effect. lumbar spine and creased frequency and severity of bleeding in patients with proximal femur bone mineral density in 112 male subjects: hemophilia. several case reports HAART.63 He. In some studies osteoporosis oc- sues of the palms. and PI therapy should be discontinued function oxygenases that mediate vitamin D activation has if it occurs. However. osteopenia and osteoporosis apy in HIV-infected patients remains to be clarified. 1. HIV infection is unclear. and factor VIII re. acidosis. but the onset ranged from a few days healthy seronegative controls. but only In most patients. late at present because the metabolic syndrome has been pancreatitis. postmenopausal) should be consid- ponents. including vitamin D and cal- tion described an HIV-infected woman who presented post cium supplementation and exercise.65 farction per year of exposure over the first 7 years of use. therapy. the interaction of of bone mineral density. osteonecrosis is a serious bone abnormal- diovascular effects. The pathogenesis of dyslipidemia is poorly understood. but it occurred at unusual The pathophysiology of osteoporosis in the setting of sites such as the small joints of the hands and the soft tis. both of which are lipid regulatory proteins involved in The diagnosis of osteoporosis is based on measurement fat storage and lipid release.58 In at least one cohort. Others have postulated that PIs may inhibit new bone for- ulation parameters are typically normal. which can be accomplished by a PIs with these proteins has not been fully elucidated.64 patients with few or no risk factors who were receiving PI After HAART became available.59 Osteonecrosis occurs only rarely in HIV patients. 68 After the introduction of Soon after the introduction of PIs. Tebas and collaborators 69 reported a cross- suggested an association between these drugs and in. when possible. However.67 Increased bleeding episodes among patients Osteoporosis in HIV-infected patients was reported in the pre-HAART era.66 Al- preventing HIV progression outweigh the deleterious car. been suggested as a possible mechanism for development of fit from temporary cessation of PI therapy during the peri. teoblast activity. It is ered for evaluation with DEXA scanning. How- ever. sectional DEXA analysis of whole body.57. corticosteroid use. Not only did nia (p = 0. 20.g. mation by stimulating osteoclast activity or inhibiting os- placement is not efficacious in resolving the bleeding. Adverse effects of antiretroviral therapy scribed premature coronary artery disease in HIV-infected risk factors who was not receiving antiretroviral therapy. had osteoporosis or osteope- to many months after initiation of therapy. ity that can lead to the need for joint replacement. may be indicated.

The many adverse effects of mately every 3 months to determine whether the patient therapy may cause symptoms affecting a variety of organ has asymptomatic abnormalities. which can result in toxic effects or ineffectiveness of The nucleoside analogue ABC causes a hypersensitivity therapy. Akagi.78. on the trunk. but is not widely recommended. Risk factors for eral Hospital’s Immunodeficiency Clinic at www. Montessori. treating physicians must triglyceride and fasting blood glucose levels. although the links between specific medications and lation. comitant medications that are metabolized by this system Johnson syndrome and toxic epidermal necrolysis in less can be dramatically altered if these agents are given to- than 1% of all patients treated with NVP. sori.74 Clinically significant interactions usually involve additive If the rash occurs during the initial 2-week dose lead-in toxicity (e. Vancouver.edu).78. are not recommended for routine monitoring.81 Diabetes and insulin resistance should also be treated in accordance with national guidelines. and hence bilirubin and amylase levels. This article has been peer reviewed.83 with or without pruritus.. LDL cholesterol. favourable adverse effect profiles. and all were antiretrovirals. Akagi all con- imens because their infection is resistant to other classes of tributed substantially to the conception and design of the manuscript. Harris.Montessori et al current antiretroviral combination should also be consid. such as abdominal CT to detect visceral fat. not all switch studies have shown beneficial effects. 236 JAMC • 20 JANV. clinicians must focus on preventing adverse effects. should be the same as for dyslipidemia in the general popu- ered. Approximately 16% of patients taking this rophy and liposuction for buffalo humps. Monitoring laboratory systems. Rechallenge patients take 3 or more medications. Patients switching from PI-based therapy to NNRTI or triple-nucleoside regimens have shown improvements in From the British Columbia Centre for Excellence in HIV/AIDS (Montessori. drug interaction information.g. Intense exercise can decrease central fat accumulation but may increase pe- Rash is a common adverse effect of the NNRTIs.74 gether. treatment for dyslipidemia involved in drafting and revising the article. bone marrow suppression or neuropathy) or period.75 Although most rashes are self-limited. clinic. Imaging tests. within the first 6 weeks on therapy.5% of NVP-treated patients. As well. such as implants for facial at- ularly NVP. liver transaminase. San Francisco at hivinsite. whereas most HIV-infected gradually after discontinuation of the drug.75 Severe rashes tochrome P450 enzyme system and can also be inducers or occur in about 6.tthhiv- ABC hypersensitivity have not been identified. mainly dur. 2004. and distinguishing those that are self-lim- for dyslipidemia.4. including toxic effects. patient nonadherence. Harris. the dose should be held at 200 mg daily until the problems with drug absorption (e. they often fail because of measurement of electrolyte. In this situation. RTV is the most potent inhibitor of the cy- syndrome in 3% to 5% of patients. Patients remain aware of new and developing syndromes associated should be asked about and examined for changes in fat dis. with or other medications. creatinine. 80.79 How. ited from those that are potentially serious. the Toronto Gen- life-threatening hypotension and death. and lipoaccumulation or lipoat. partic. can be found online (e. As efforts con- rophy. tored at regular intervals (approximately every 3 months) when possible..g. Surgery.82 Lipodys- Skin rash trophy has no easy and proven treatment. inhibitors of this system. including lifestyle modifications and pharmacother- risk of osteoporosis have yet to be defined. ddI buffered tablets rash resolves. NVP when given with fluoroquinolones. tribution. about drug interactions.g. Montaner) and the University of British Columbia (Montes- lipodystrophy. 170 (2) . NRTIs have few interactions with other medications. BC ever. ripheral fat wasting. Press. Montaner). This laboratory work should include determination tinue in the development of medications with more of total cholesterol. efficacy. Caution is advised when interpreting without rash) starting during the first 6 weeks of treatment. as severe symptoms may occur rapidly. Levels of antiretrovirals and con- ing the first 4 weeks of treatment. including Stevens. some patients have no alternatives to PI-based reg- Contributors: Drs.5 To optimize adherence. Patients should also be moni. Press. Monitoring of patients who are receiving Conclusions HAART Antiretroviral therapy is becoming increasingly effective Routine laboratory monitoring should be done approxi. Press. dyslipidemia and insulin resistance..79 Competing interests: None declared.ucsf. is another option agent experience a mild to moderate maculopapular rash.com or the HIV InSite of the University of Califor- nia. with antiretroviral use. Harris and Montaner and Ms.76.77 who present with tochrome P450 system and the most likely to interact with nonspecific symptoms (including malaise and fever. but also increasingly complex. Although current antiretroviral regimens are po- tests include complete and differential blood counts and tent from an antiviral perspective. diabetes.) should be permanently discontinued if the rash is severe or PIs and NNRTIs are metabolized through the cy- accompanied by constitutional symptoms. including summaries of important tempted. HDL cholesterol. apy. Valuable information with ABC after a hypersensitivity reaction should not be at. face and extremities. Most such information cov- The symptoms worsen with continued therapy and resolve ers only 2-way interactions.

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