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Clinical update: adverse eff ects of antiretroviral therapy
See New Drug Class page 81
The adverse eff ects of antiretroviral therapy (ART) cause history, lipoatrophy and fat accumulation (and the ARTs substantial morbidity and compromise adherence, which that cause them), metabolic syndrome, and hepatitis C can lead to drug resistance. Treatment guidelines recom- infection.8 Stavudine, indinavir, ritonavir (even at the mend against universal immediate ART, partly because of low boosting dose) and lopinavir, but not atazanavir or See Online for webtable
toxicities (table). The webtable lists licensed ARTs.
amprenavir, induce insulin resistance acutely, but long- HIV lipodystrophy is characterised by peripheral sub- term eff ects are unknown. Fasting blood glucose is a cutaneous lipoatrophy, relative central fat accumulation, poor measure of insulin resistance and diagnoses less lipomatosis, dyslipidaemia, insulin resistance, and hyper- than half of all diabetes in HIV-infected adults. When lactataemia. Over the fi rst 6 months of ART, limb and other cardiovascular risks factors are present, an oral visceral fat increase, often followed by a progressive and glucose tolerance test should be considered. Metformin selective loss of limb fat.1 Zidovudine and stavudine are improves insulin sensitivity and systolic blood pressure, the drugs most associated with lipoatrophy. About 30% and may reduce visceral fat. Thiazolinediones also of patients receiving stavudine for 2 years developed improve insulin sensitivity; rosiglitazone, but not pio-lipoatrophy compared with 6% of tenofovir recipients.2 glitazone, aggravates dyslipidaemia.
Abacavir, emtricitabine, lamivudine, and tenofovir do A large prospective cohort study reported a 16% not seem to induce much lipoatrophy; the protease relative increase in the incidence of myocardial in-inhibitor nelfi navir accelerated lipoatrophy, but another farc tion per year of ART exposure, an eff ect mainly such drug, lopinavir, might prevent it.3 Lipoatrophy associated with the duration of protease inhibitor can be largely prevented by avoidance of stavudine therapy.9 About half of this association was explained and zidovudine. Switching stavudine or zidovudine by hypercholesterolaemia, hypertriglyceridaemia, and to tenofovir or abacavir improves lipoatrophy, but low HDL-cholesterol. Nevertheless, traditional risk normalisation can take years.4 Cessation of protease factors (older age, being male, smoking, hypertension, inhibitor therapy may improve visceral adiposity.
diabetes, pre-ART dyslipidaemia) are collectively more Thiazolidinediones have a small or no eff ect on HIV important than ART. The overall cardiovascular risk lipoatrophy.5 Uridine and pravastatin may improve associated with ART is declining, possibly because of lipoatrophy more rapidly and substantially than the increasing use of lipid-lowering drugs, less smoking, zidovudine or stavudine switching.6,7 Cosmetic inter- and use of more lipid-neutral ART.9 Surprisingly, ventions, such as poly-L-lactic acid injec tions, modestly however, intermittent ART modestly increased rather improve facial lipoatrophy. Growth hor mone and a than decreased the cardio vascular event rate compared growth-hormone releasing-hormone analogue improve with continuous ART. This increase may relate to the visceral abdominal fat accumulation, but aggravate observed slight increase in the ratio of total cholesterol lipo atrophy and, at least for growth hormone, insulin to HDL-cholesterol with intermittent ART.10resistance and dyslipidaemia.1 Met formin also improves All cardiovascular risk factors should be assessed before visceral adiposity, but the eff ect is modest.
starting ART and about annually thereafter. Cessation Most protease inhibitors (except unboosted ata- of smoking is likely to be the single most eff ective zanavir, but including low-dose ritonavir), efavirenz, intervention. Intensive diet and exercise over 6 months stav udine, and zidovudine increase total cholesterol, improved central obesity and systolic blood pressure in LDL-cholesterol, and triglyceride concentrations.1 The HIV-infected adults with metabolic syndrome, but lipid change in risk of cardiovascular disease with ART (esti- mated by the Framingham equation) is generally not For hypercholesterolaemia, pravastatin is most used substantial unless other cardiovascular risk factors are because its metabolism is unaff ected by ART, although present, perhaps partly because most potent ART also its eff ects may be less than in HIV-uninfected adults. increases HDL-cholesterol concentrations.
Plasma concentrations of more potent statins, such Diabetes mellitus occurs in 6–10% of those receiving as rosuvastatin and atorvastatin, can be increased by ART. Risk factors include increasing age, obesity, family protease inhibitors, which increases the risk of statin www.thelancet.com Vol 370 July 7, 2007
toxicity. If used, these statins should be started at lower Side-eff ect
New learning points
Most promising therapies*
than normal doses. Ezetimide is also eff ective at lowering LDL-cholesterol. The other option for dyslipidaemia is to switch boosted protease inhibitors, efavirenz, and/or Contribution of protease inhibitors less some nucleoside analogues to other virologically active lipid-neutral ART. Because ART is generally given long- stavudine, zidovudine, or protease inhibitor Treatment directions limited by uncertainty term, switching is an attractive option because it avoids about whether central fat accumulation is permanently treating drug toxicity with another drug.
direct drug eff ect or secondary to lipoatrophy analogue Mechanisms of hepatotoxicity include direct anti- Protease inhibitor and/or tNRTI cessation retroviral toxicity, hypersensitivity, immune recon- Pravastatin, low-dose atorvastatin, or rosuvastatin stitution in those with chronic viral hepatitis, and Fasting glucose is poor tool for diagnosis of hepatitis secondary to mitochondrial toxicity caused by nucleoside reverse-transcriptase inhibitors. Consider oral glucose tolerance testing in higher-risk patients Liver toxicity is generally more frequent in patients Withdrawal of ART increases risk, perhaps Address all risk factors, such as smoking, with chronic viral hepatitis or increased baseline hepatic Traditional risk factors aff ect risk more aminotransferases and in people who abuse alcohol. 5% of nevirapine-exposed patients develop hepatitis in Nevirapine be initiated only in ART-naive the fi rst 3 months of therapy, and in half of these a rash counts <400 and 250 cells per µL, respectively also occurs. Because immunocompetence is a signifi cant Didanosine associated rarely with hepatic fi brosis, nodular regenerative hyperplasia, risk factor, guidelines recommend that nevirapine be started only in ART-naive men and women with CD4+ Abacavir hypersensitivity strongly linked to lymphocyte counts less than 400 and 250 cells per µL, Tenofovir associated with small increased respectively.12 Patients already receiving ART who switch risk of osteopenia over 3 years, but not with to nevirapine above these CD4 thresholds may not have increased fracture rateRole of routine screening (bone mineral this greater risk of hepatitis.13 Idiopathic hepatic fi brosis was found in 2% of HIV-infected adults and was related Tenofovir associated with small increased to cumulative didanosine exposure. Moreover, long- Maybe less severe with use of needle-free term didanosine therapy is rarely linked to nodular Has substantially aff ected use of enfuvirtide Tenofovir can induce nephrotoxicity. In two phase III DEXA=dual-energy X-ray absorptiometry. tNRTI=thymidine nucleoside reverse-transcriptase inhibitor. *In addition to drug withdrawal and avoidance in higher-risk patients. trials, no tenofovir-induced grade 3 or 4 nephrotoxicity (estimated glomerular fi ltration rate [eGFR] less than Table: Recent advances in understanding of antiretroviral toxicity
50 mL per min per 1·73 m²) was observed, although eGFR fell by a mean 10%.15 In cohorts, however, about in black Americans and Africans. Deaths have occurred 4% of tenofovir recipients had decreased creatinine clear- after unsupervised rechallenge, which is contraindicated. ance of more than 50% after a median 12 months, a rate Adults with the HLA-B*5701 haplotype are at very high about 60% greater than that without tenofovir.16 Risk risk of abacavir hypersensitivity. Molecular screening factors for this signifi cant GFR decline were a low CD4+ for HLA-B*5701 has positive and negative predictive count, hypertension, anaemia, impaired renal function, values of about 80% and 96%, respectively. Screening injection drug use, diabetes, and the use of a boosted decreased hypersensitivity from 9% to 2%, and lowered protease inhibitor, which increases tenofovir levels by the cessation rate in those with uncertain symptoms.17about 30%. Consensus guidelines recommend that eGFR HIV-infected adults receiving ART have more osteo- be estimated before ART and at least every 6 months in penia than uninfected adults. The relative contributions those receiving tenofovir.
of ART, HIV, and patients’ characteristics are unknown. Abacavir causes a hypersensitivity reaction, including Tenofovir is associated with signifi cantly more osteo- fever, rash, fatigue, and gastrointestinal symptoms after penia than stavudine. No study has been large enough to a mean 10 days in 8% of unselected white adults, but less assess whether the low bone-mineral density (BMD) will www.thelancet.com Vol 370 July 7, 2007
translate into an increased fracture rate. Measurement A Calmy declares that she has no confl ict of interest. BH has received travel of BMD should be considered in high-risk patients. grants and speakers’ honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, and Roche. DAC has received Alendronate for 48 weeks signifi cantly increased BMD advisory and consultancy fees, honoraria, and grant support from GlaxoSmithKline, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Abbott, Boehringer Ingelheim, Johnson & Johnson, and Gilead Sciences. A Carr has There are some important diff erences in the pattern of received research grants or funding from Abbott and Roche; consultancy fees from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, and GlaxoSmithKline; toxicity in resource-poor settings, in which most patients and lecture sponsorships from Abbott, Boehringer-Ingelheim, Bristol-Myers start ART with nevirapine, lamivudine, and either stavu- Squibb, Gilead, and GlaxoSmithKline; and has served on advisory boards for Abbott and Roche.
dine or zidovudine. Because of the few altern atives, 1 Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in patients often endure chronic toxicity to receive the bene- HIV-infected adults. N Engl J Med 2005; 352: 48–62.
fi ts of ART. A South African study showed a 1·5% annual 2 Law M, Puls R, Cheng AK, Cooper DA, Carr A. Evaluation of the HIV lipodystrophy case defi nition in a placebo-controlled, 144-week trial in risk of symptomatic hyperlactataemia with stavudine antiretroviral-naive adults. Antivir Ther 2006; 11: 179–86.
(al though rechallenge with zidovudine in some patients 3 Haubrich R, Riddler S, DiRienzo G, et al. Metabolic outcomes of ACTG 5142. 14th CROI, 2007: 38 (abstr).
was reported as safe).18 Risk of nevirapine rash was 4 Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of 2·8 times higher in Thai adults than white adults.19 In Africa, tenofovir DF or abacavir as replacement for a thymidine analogue in
persons with lipoatrophy. AIDS 2006; 20: 2043–50.
grade 2–4 anae mia occurred in 12% of adults, compared 5 Slama L, Lanoy E, Valentin MA, et al. Eff ect of pioglitazone on HIV-1 related lipoatrophy. 13th CROI, 2006: 151LB (abstr).
with 2% in Europe and the USA.20 Low CD4+ count, female 6 Sutinen J, Walker UA, Sevastianova K, et al. Uridine supplementation sex, anaemia, low body-mass index, and being ART-naive increases subcutaneous fat in patients with HAART-associated lipodystrophy (HAL). 7th Int Workshop on Adverse Events and were the main risk factors. Issues of toxicity led WHO to Lipodystrophy in HIV, 2005: 7 (abstr).
change its ART guidelines in 2006 and exclude stavudine 7 Mallon PW, Miller J, Kovacic JC, et al. Eff ect of pravastatin on body composition and markers of cardiovascular disease in HIV-infected men. from fi rst-line ART. If used, the recommended dose of AIDS 2006; 20: 1003–10.
stavudine is now 30 mg twice daily, regardless of weight.
Brar I, Shuter J, Thomas A, Daniels E, Absalon J. A comparison of factors associated with prevalent diabetes mellitus among HIV-infected, 10–25% of patients starting ART develop an immune antiretroviral-naive individuals versus individuals in the National Health and Nutritional Examination Survey Cohort. reconstitution infl ammatory syndrome: fever, a constitu- J Acquir Immune Defi c Syndr 2007; 45: 66–71.
tional illness, and infl ammation at the site of previously 9 DAD Study Group. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356: 1723–35.
unrecognised replication of an opportunistic pathogen, 10 Phillips A, Carr A, Neuhaus J, et al. Interruption of ART and risk of such as Mycobacterium tuberculosis. This illness is more cardiovascular disease: fi ndings from SMART. 14th CROI, 2007: 41 (abstr).
11 Fitch KV, Anderson EJ, Hubbard JL, et al. Eff ects of a lifestyle modifi cation common in patients with advanced immunosuppression. program in HIV-infected patients with the metabolic syndrome. The syndrome is not a drug-specifi c side-eff ect, rather a AIDS 2006; 20: 1843–50.
12 DHSS. Guidelines for the use of antiretroviral agents in HIV-1-infected consequence of rapidly improving immune function.
adults and adolescents. Oct 10, 2006. http://aidsinfo.nih.gov/contentfi les/AdultandAdolescentGL.pdf (accessed May 5, 2007).
More potential toxicities are now studied preclinically, 13 Mocroft A, Staszewski S, Weber R, et al. Risk of discontinuation of in particular mitochondrial toxicity. Several drugs have nevirapine due to toxicities in antiretroviral-naive and experienced patients with high and low CD4 counts. XVI Int AIDS Conf, 2006: THAB0104 (abstr).
been or will soon be withdrawn from the market, in part 14 Mallet V, Blanchard P, Verkarre V, et al. Nodular regenerative hyperlpasia is for toxicity: soft-gel saquinavir (diarrhoea, nausea), zalcita- a new cause of chronic liver disease in HIV-infected patients. AIDS 2007; 21:
bine (peripheral neuropathy), and extended-release stavu- 15 Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and dine (pancreatitis, lipoatrophy, and periph efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med
2006; 354: 251–60.
neuro pathy). A continuing issue for a disease requiring life- 16 Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function long therapy is the short duration of registra tional ran dom- associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005; ised trials, usually no more than 2 years. There is a need for 40: 1194–98.
17 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.
18 Osler M, Stead D, Rebe K, Boulle A, Meintjes G. Severe hyperlactatemia *Alexandra Calmy, Bernard Hirschel, David A Cooper, complicating ART with stavudine fi rst-line therapy in South Africa: incidence, risk factors, and outcomes. 14th CROI, 2007: 792 (abstr).
19 Kappelhoff BS, van Leth F, Robinson PA, et al. Are adverse events of St Vincent’s Hospital, Sydney 2010, NSW, Australia (A Calmy, DAC, nevirapine and efavirenz related to plasma concentrations? Antivir Ther A Carr); Service des Maladies Infectieuses, Hôpital Cantonal 2005; 10: 489–98.
Universitaire de Genève, Geneva, Switzerland (A Calmy, BH); and 20 Ssali F, Stohr W, Munderi P, et al. Prevalence, incidence and predictors of severe anaemia with zidovudine-containing regimens in African adults National Centre in HIV Epidemiology and Clinical Research, with HIV infection within the DART trial. Antivir Ther 2006; 11: 741–49.
University of New South Wales, Sydney, NSW, Australia (DAC)acalmy@gmail.com www.thelancet.com Vol 370 July 7, 2007

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