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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-
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

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. 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 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.

Gang DL. Am J Med 1999. et al. Garas BA. Eur J Anaesthesiol 1999. 9. prophylaxis after HIV exposures—worldwide. myopathy. Burger DM.131:81-7. Murphy R. 44. 31. 34. et al. et al. Weisdorf T. Goodman SI. Kaehny WD. Chan K.160(5):659-65. 11. Alexander CS. Satten GA. Chan Yan C. Adverse effects of antiretroviral therapy. Clin Infect Dis 2000. 2000 Jan 30 to 2000 Feb 2. obic threshold and random venous lactate levels among HIV-positive patients 46. Chevallier M. Medina DJ. CMAJ 1999. Freund J. al. Chassard D. ciency virus and the role of hepatitis C or B virus infection. 42. AN. 35. Treatment al. ated with stavudine treatment in an HIV patient: a case report. Chariot P. Nat contribution to protease inhibitor-related lipodystrophy syndrome. Thompson CR. nucleoside analogs on human DNA polymerases and mitochondrial DNA 52. ence on Retroviruses and Opportunistic Infections. Brown CE.356:1423-30. AIDS CMAJ • JAN. Behling C. Respiratory failure due to 23. Lee ECC.C.21: 10(Suppl 1):129–46. Tsai CH. Partisani M. O’Shaughnessy MV.283 Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as (1):74-80. Del Bravo P. 5. Habersetzer F. Gabow PA. 50. Przyrembel H. Luzzati R. levels in HIV-infected patients on combination antiretroviral therapy. Thiamine for the treatment of nucleo- ated with 2’. 38. et al.235:367-71. 1st International fect Dis 2000. cidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment fected patients receiving nucleoside analogue combination regimens. N Engl J 4. Garry RF. Hsiung GD. Tesiorowski A. hyperlipidaemia and insulin resistance in Chronic hyperlactatemia in HIV-infected patients taking antiretroviral ther. NNRTI use: role of drugs and chronic hepatitis [abstract 618]. Fuhre J. Wanitschke R. Delaney KM. 8. A. AIDS 1999. Aparicio M.15:717-23. Bruneel F. Disorders associated with an altered anion gap. Kauffmann R. Dieterich DT. et 36. Adverse effects of antiretroviral therapy References Med 1996. et al. Reves R. 2000. The fall of the tive antiretroviral therapy (HAART) regimen in a cohort of antiretroviral serum anion gap. French MA. Bissuel F. Law M. Moore R. ACTG Liver Diseases Focus Group. Luzzani A. liver failure. Diagnostic importance of an increased serum anion gap. A syn- 22. Plymale DR. Lucas GM. Hyperlac. Galle PR. Yip B. ter Hofstede HJM. 170 (2) 237 . Weigel H. Rezza G. 973-6. Kingsley LA. AIDS Cohort Study Investigators. Bochet M. Hepatic steatosis and lactic acidosis associ. 26. Benhamou Y. 43. Liou A. and cell viability in cultured cells lung function.346(11):811-20.5(Suppl 2):31.352:291-2. Delgado J. Comardelle AM.30:156–60. Gutierrez E. RW. and mitochondrial (mt) DNA depletion 2000. Upton RP. Harris M. I. et al. Zidovudine-induced mitochondrial disorder with massive hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. syndrome: report of two patients and review of the literature. Carr A. Dalakis MC. Colombet G. Chazaud B.107(6B):79S-84S. Sulkowski. treated with three anti-human immunodeficiency virus dideoxynucleosides.56:38-54. et al. Crit Care Med 39. Weel J. Lai KK. Riboflavine and se- a large urban clinic: risk factors for virologic failure and adverse drug reac. Koopmans PP.14:2801-2. Lewis DE. Chaisson RE. mitochondrial DNA content. Theodore D. Vrouenraets S. Gabow PA. Bruno F. 29. 8–11. Nolan D. Suarez M. Pfander H. Hyperlactatemia in 20 patients receiving NRTI combination regimens 48. Antoniou T.3’-dideoxyinosine (ddI). Serious adverse events attributed to nevirapine regimens for postexposure on antiretroviral therapy. Fouty B. et al. naïve patients. Chaisson RE. Mitchell W. Hepatomegaly and steatosis in issues in coinfection. van Leeuwen R. Detels R. 10. 1977. Factors affecting liver fibrosis in human immunodeficiency virus. Reisler R.115:283-4. de Lacroix-Szmania I. vere lactic acidosis. apy. J Intern Med 1994. Hassenein T. Sulkowski MS. 49. Belitsos P. AIDS 1998.31(2):250-1. Dube MP. Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in pa- tic acidosis and hepatic failure in patients with acquired immunodeficiency tients with mitochondrial myopathy. in an HIV-infected child treated with combination antiretroviral therapy 7. 2004. Lang JM. immunodeficiency virus. Sundar K. Emmett M. ciated with antiretroviral therapy in adults infected with human immunodefi- 13. Fortgang I. Munoz A. Brinkman K. Gabow PA. Smeitink JAM.8(4):279-82. Clinical use of the anion gap. Mehta S. duced lactic acidosis. Carr A. Lewis W. Ann Intern Med 1991. 1997–2000. J Med 2002.27:472-83. Sherwin 1997. Winter SD. O’Connor D. Banogon PE. Matthews-Davis N. Lancet 1998. HIV Outpatient Study Investigators. Fantus IG. Insights into the reasons for discontinuation of the first highly ac. Lactic acidosis complicating antiretroviral therapy: frequency and correlates 45. Near- 6. Law M. MMWR Morbid 20. Mathews WC. 17. Di Perri G. James IR. CMAJ 1999. al. Mathews WC. Narins RG. Cotte L. John M. Pfander H. Clin In. Borucki MJ. Johns D. Hepatotoxicity asso- 1997. Highly active antiretroviral therapy in 33. Moore RD. AIDS 1998.12:1735-44.43:884–90. Schultz AL. lactic acidosis. review.49(51):1153-6. Fennessey PV. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients of nucleoside reverse transcriptase inhibitor-induced lactic acidosis. Bai T. Reardon JE. Brinkman K.338:853-60. Anaer. Matthews PM. Cooper DA. 7th Conference on Retroviruses and Opportunistic Infec. Harris M. Harris M. Tesiorowski A. Poizot-Martin I. Di Martino V. daemia and liver dysfunction associated with nucleoside analogue therapy: 25. Lorenzo G. Antivir Ther 2000.161(2):161-4.A. Cheng YC. Wetheim-van Dillen PME. Martin JL. Palella FJ Jr. Frerman F. Behling C.2:1065-8. Montaner JSG.43:884–90. et al. Robbins G.280:1497-503. ment of mitochondrial disease. Rosenberg R. Jurriaans S. in a patient with AIDS who was receiving zidovudine. McKinnon EJ. 20. Dandurand RJ.13:1827-39. Can Respir J 2001. Vu T. 14. AIDS 2001. Huertas R. Antimicrob Agents Chemother 1994. Margolick JB. HIV-infected patients receiving nucleoside analogue antiretroviral therapy. et Am J Gastroenterol 1995. Neurology 1993. Fermin CD. Chaisson R. Gough K. Cooper DA.90:1433-6. San Francisco. JAMA 1998. fections. Coenzyme Q10 with multiple vitamins is generally ineffective in treat- 12. Comparison of mitochondrial protease inhibitor related lipodystrophy in an HIV patient with compromised morphology.168(2):195-8.33:2072-4. et al. Chicago. Hepatitis B and C virus co-infection and the risk for Lombes A. Zawacki JK.31:1467-75. Church J. Wit FNM. Cote H. man immunodeficiency virus infection. Moore CB. Wen JW.353:901-2. Miller J. drome of peripheral lipodystrophy. Lepoff RB. 32. AIDS 2000. Disorders of glucose metabolism in patients infected with human [poster. M. Clin Infect Dis 2001. den Brinker M. Thibault V. Press N. Campos Y. New-onset diabetes mellitus associated individuals — a case series. In- tatemia and hepatic abnormalities in 10 human immunodeficiency virus-in. Chisholm DJ. Pezzotti P. Italian Cohort of Antiretroviral. Ann Intern Med 1999. Massive hepatic steatosis and lactic acidosis 37. Arch Intern Med 1990. Nat Med (ART) [abstract 58]. McFarlane G. Cooley TP. Application of a novel assay to monitor peripheral blood mitochondrial DNA N Engl J Med 1998. tions. Drogou I. Concia E. Schrier drug antiretroviral regimens. et al. Lancet 1999. Lenzo NP. CMAJ 2003. tions. Ting L. 7th Conference on Retroviruses and Opportunistic In- 1995. Riboflavin to treat nucleoside analogue-in- Naïve Patients. Moore RD. Montessori VC.150:311-3. Kully C. Gonzalez-Gomez I. Fulminant hepatic failure associ. Moore R. Rouviere O. Buenos Aires. Medicine (Baltimore) men with known HIV infection duration. Tesiorowski AM. Lepri AC. 2001 Jul 18. Symptomatic elevations Mortal Wkly Rep 2001. Tang DS. Thomas DL. Boles R. 30. Hepatol 1999. Chan KJ. et al. Brumme ZL. 2001 Feb 4–8. with protease inhibitor therapy in an HIV-positive patient: case report and 21. Lonergan JT. Moorman AC. AIDS 40. Hepatotoxicity associated with [abstract 36]. Frissen J. 41. Bautista J. of lactic acid and their response to treatment manipulation in HIV infected 47. 2000 Jan 30 to 2000 Feb 2. J Acquir Immune Defic Syndr 2002. Antimicrob Agents Chemother 1994. Hassanein TI. Study Group. A syndrome of lipoatrophy. patients receiving HIV protease inhibitors. Gross PA. Craib KJP. AIDS Society Conference on HIV Pathogenesis and Treatment.34(2):283-7. et al. Hepa- HIV-positive patient: a case report and discussion. Carr A. AIDS on didanosine therapy. Mitochondrial toxicity of antiviral drugs. Thomas D. cells. Schechter MT. Effects of antiviral ing long-term nucleoside analogue therapy. Improved survival among HIV-infected patients after initiation of triple. 51. J Inherit Metab Dis 1987. Montaner JSG. Muscle Nerve 1993. common pathway. San Francisco. N Engl 2. Burton S.12:F51-8. Zidovudine-induced fatal lac. Olano JP. Shapiro JP. Antinori A.16:733-5.38:2743-9. Wynhoven B. side analogue-induced severe lactic acidosis. Hogg R. trials [abstract 43]. Eliezer-Vanerot MC. The other human genome: mitochondrial DNA and disease. 8th Confer- 19.14(18):2895-902. lactic aci- synthesis. Hogg RS. Therapy of mitochondrial disorders. Wetzel R. Lonergan JT.303:854-8. Effectiveness of potent antiretroviral therapy on time to AIDS and death in 28. Both necrosis and apoptosis contribute to HIV-1 induced killing of CD4 1.38(8):1824-8. Eidelman DH. Saint-Marc T. Ford B.N. J AIDS 2000. d’Arminio Monforte A.11:1294-6. Samaras K. Hepatitis C virus and human immunodeficiency virus: clinical 15. Havlir D.31(1):162-6. Pearson R. Lancet fatal metabolic acidosis. 27. Phillips Med 1980. Craib KJ. Servoss JC. Giorgi J.25:1425-30.and he- 16. Liou S. Kidney Int 3. liver steatosis.O. et al. AIDS 1999. Loveless MO. and mitochondrial DNA depletion. JAMA 2000. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiv- 24.14:499-507. Montaner JSG. Declining morbidity and mortality among patients with advanced hu. Walmsley S. Schramm C. Clin Infect Dis 1995. Symptomatic hyperlactatemia in an patitis C virus-coinfected patients: impact of protease inhibitor therapy. et 1985.1:417-21. session 9]. tology 2001.13:1359-67.

(10):1502-14. CMAJ 2000. J. 2002 Feb 24-28. Osteonecrosis of the hip. prediction. Clin Infect Dis 698-T]. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. single-centre study. Beck SB. 8th Conference on Retroviruses and Opportunistic Infections. 71. Tam H. 2nd International Workshop on Adverse Drug Reac- tions and Lipodystrophy. Ward D. Lactic acidemia is associated with spinal osteopenia in HIV-infected men [abstract 631].18(2):300-2. 69. Henry WK. 70. Kaufmann G. Cox BA. Teitelbaum SL. for the HIV Outpatient Study (HOPS) Investigators. for the Scientific Advisory Council of the Osteoporosis Society of Canada. Weber R. D’Arminio Monforte A. Giangrande PLF. Osteonecrosis in HIV: a case–control study. Dabis 80. Reiss P. 24-28. Mocroft A. Multiple site avascular necrosis in HIV infected patients. Chisholm DJ. Koeger AC. Viboud C. Eur J Med Res 2001. Hamid F. Powderly WG. AIDS Patient Care STDS 2001. 2002 Feb 24-28. Brown JP. 1999. Mockenhaupt M. 78. Collins P. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. Soriano V. Naldi L. Carpenter A. St. Clin Infect Dis 2002. Garcia-Viejo MA. Kendler DL.31:1216-24. A.167(11):1261-6. Powderly WG. Lentle BC. Calcif Tissue Int 1997.Montessori et al 2000. Risk of lipodystrophy in HIV-1-infected patients treated with fected subjects under long-term successful triple combination therapy. Klein D. Miller J. Cooper DA. 83. Breur JP. 2000. Tebas P. 170 (2) . The strategy of antiretroviral switch studies — a review [ab- 54. Risk stract 1375]. Correspondence to: Dr. CMAJ 2022. CMAJ 2002. de la Cruz JJ.162(10):1441-7. Hurley L. 61:30-2. Khan AA. Clay PG. Dusso A. et al. Sprecher D. Liposuction 59. Brown JP.14:807-12. Toronto.15:1843-8. Josse RG. Martinez E.167(10 suppl):S1-34. Severe bleeding complications in HIV-posi- tive haemophiliac patients treated with protease inhibitors. Teitelbaum SL. Bartlett JG. Recommendations for the dial infarction: the DAD Study [abstract 130]. Seattle. Gerster JC. Ostrosky-Zeichner L. Chicago. Fung MA. fax 604 806-8527. 62. Carr A. Ake C. Griffin GE. 73. Black K. Kremer G.25(1):19-25. Blanco F. Fodor JG. Keiser P. Fauci AS. Schwenk A. Pazianas M. In- creased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders. Ross FP. Vancouver BC V6Z 1Y6. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Possible linkage of am- prenavir with intracranial bleeding in an HIV-infected hemophiliac.766 US veterans [abstract LB-9]. Chave JP. 72. Valentina Montessori. The abacavir hypersensitivity reaction: a review.ubc. Pahwa S. Hospitalizations for coronary heart disease and myocardial 81. 58. Moorman. Greenberg AE. 2001 Feb 4–8. Dube MP. Bakashi S. Pathogenesis of HIV-1 pro- tease inhibitor-associated lipodystrophy. et al. Abacavir hypersensitivity reaction. 667-1081 Burrard 60. Wood K. Samaras K. hyperlipidemia. Guidelines for using an- tiretroviral agents among HIV-infected adults and adolescents. Tong. Indinavir in- hibits bone formation while ritonavir inhibits osteoclast differentiation and function [abstract 541]. 74. J Rheumatol 1991. Paton NI. Gonzalez-Lahoz 55. Br J Haematol 1999. 76.14(13):2056. Lewiecki EM. 2002 Feb 2000. et al.14:F63-7. valm@hivnet. 82. Roujeau JC. Yarasheski KE. Scimeca P.24 53. Tebas P. Boston. 2004. 61. Scribner AN. Clin Ther 2002. Pau AK. Chisholm DJ. AIDS 2000. Eisman JA. Romer K. T. Hypercholesterolemia and Other Dyslipidemias. Shiach CR. et al. Recommendations of use and adverse cardiovascular outcomes in ambulatory HIV patients [abstract the Adult ACTG Cardiovascular Disease Focus Group. Bone mineral density in patients with human immunodeficiency virus infection. Hypercholesterolemia and Other Dyslipidemias. 63. 2000 Sep 17–20. Fagot JP. 2003 Feb 10–14. triglyceridemia. Cooper DA. Hodis HN. Frohlich JJ. Ponce-de-Leon S. 68. Chicago.353:1244. Iglesias M.5(10):443-8. McPherson PR.357(9256):592-8. Franzen C. Thorisdottir A. et al. Carr A. Rappoport G. 57.25(OH)2-vita- min D [abstract 030]. Wang M. Diagnosis. Lancet (8):1137-42. for Working Group on F. Hewitt RG. et Preliminary guidelines for the evaluation and management of dyslipidemia in al. 77. Powderly WG. Barreiro P. Lancet 1998. 40th Interscience Conference on Antimicrobial Agents and factors for the HIV-associated lipodystrophy syndrome in a cross-sectional Chemotherapy. Leslie WD. Blanco JL. for protease-inhibitor-associated lipodystrophy [letter]. Bozzette SA. Roudiere L. et al.351:1881-3. Lee CA. Dybul M. 10th Conference on Retro. et al. Hollmig KA. Vidal M.15(7):347-52. CMAJ 2002. Macallan DC. 64. Samaras K. 9th Con.. AIDS 2000.107:556-9. Bethe U. The 2002 Canadian bone densitometry recommendations: take-home messages. Camus JP. 56. Kaplan JE. Ceballos J. Torriani FJ. Carr A. Lancet 1999. Ann Intern Med 2002. AIDS protease inhibitors: a prospective cohort study. Wilde JT. management and treatment of dyslipidemia: report of the Working Group on viruses and Opportunistic Infections. Bommakanty U. Friis-Moller N. Aberg JA. 66. Toronto. 6(3):112-4. Lancet 2001.167(10):1141-5. J Acquir Immune Defic Syndr 2000. Casimiro C. El-Sadr W. and insulin resis. Troia-Cancio PV. and natural course of HIV protease-inhibitor-associ. Marin D. hyperlipidemia. Claxton S. Kodoth S. Eur J Med Res 2000. and diabetes mellitus.353:2893-9. Winter M. 238 JAMC • 20 JANV. AIDS 2001. Doll DC. Frolich JJ. Powderly WG. 2000 Sep 13–15. Leung V.34 ated lipodystrophy. Seattle. Protease inhibitor HIV-infected adults receiving antiretroviral therapy. Seattle.14:F25-32. 2001 Feb 4–8. ference on Retroviruses and Opportunistic Infections. 67. Tebas P. Cooper DA. Cardio and cerebrovascular outcomes with changing process of anti-HIV therapy in 36. Perez-Cuevas JB. lipodystrophy and antiretro- viral treatment [letter]. Bouwes-Bavnick JN. Protease in- hibitors inhibit in vitro conversion on 25(OH)-vitamin D to 1. tance. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-in- lolas J.137(5 pt 2):381-433. 9th Conference on Retro- viruses and Opportunistic Infections. Marcantonio D. et al. Tantisiriwat W. 9th Conference on Retroviruses and Opportunistic Infections. 65. Holmberg S. 75. Genest JJG Jr. Exposure to HAART is associated with an increased risk of myocar. 8th Conference on Retroviruses and Opportunistic Infections. Viard JP. Common problems in the management of hyper- infarction among HIV+ patients in the HAART era [abstract 696-T]. Mal.