8481.aids

Perspective
Metabolic Complications of Antiretroviral Therapy
Donna E. Sweet, MD
HIV–infected patients receiving long-term antiretroviral treatment experience a num- ber of metabolic abnormalities, including lipid abnormalities, dysregulation of glu- cose metabolism, body-fat redistribution, mitochondrial abnormalities, and bone tase inhibitors (nRTIs), a number of stud- abnormalities, as well as the sequelae of these disorders. These complications can be severe and life threatening, disrupt adherence to antiretroviral therapy, limit options in therapy, and profoundly affect quality of life. Risk for such complications should be considered in selection of antiretroviral therapy, and patients should be monitored for the occurrence of abnormalities and changes in risk factors. This article summa- Clinical Trials Group [ACTG] 384 study) or rizes a presentation by Donna E. Sweet, MD, on the metabolic complications of long- term antiretroviral therapy at the IAS–USA course in New York in March 2005. Management of Antiretroviral Therapy–Terry Beirn Community Programs for initial therapy, and the selection should gression of HIV disease, developing effec- lowering the pill burden of regimens, and which threatens efficacy, and their pres- patients on long-term effective antiretro- viral therapy are the long-term metabolic as simplification of regimens, need to be Lipodystrophy
Clinical Implications of
Metabolic Abnormalities
HIV-infected patients receiving long-term quality of life. The lack of a standardized case definition for lipodystrophy compli- lipid abnormalities, dysregulation of glu- cose metabolism, body-fat redistribution, tracking of the disorder. The etiology of Opportunistic Infections. In brief, find- ings in these studies indicate that substi- abnormalities, as well as the sequelae of and influenced by specific antiretroviral inhibitor (NNRTI) appears safe, decreases insulin resistance, usually reduces triglyc- there are probably multiple causes of fat eride levels, has inconsistent effects on redistribution, it is unlikely that a single lipoprotein (HDL) cholesterol levels, and the timing of initiation of antiretroviral therapy, since the risk of long-term toxic- switching of antiretroviral drugs, anabol- cavir substitution for stavudine results in glitazone treatment, lipid-lowering thera- Dr Sweet is a Professor of Medicine at the University of Kansas School of Medicine in effects of rosiglitazone in lipodystrophy Volume 13 Issue 2 June/July 2005
fat mass in those with both insulin resis- pravastatin 40 mg or atorvastatin 5 or 10 needed if patients are taking efavirenz.
els, but may result in increased total and ered, with careful dose titration; fluvas- low-density lipoprotein (LDL) cholesterol tatin should not be used if the patient is levels. Further studies with newer glita- taking saquinavir/ritonavir or nelfinavir.
Dyslipidemia and Coronary
infarction (MI), 28% of which were fatal, also be used to treat dyslipidemia. Other Heart Disease
HIV-infected patients on long-term thera- py was 1.26 per year of therapy; a recent HIV-infected patients and these risk fac- update after an additional year of follow- large decrease in triglycerides in hyper- tors need to be managed aggressively.
triglyceridemic patients, although levels year of antiretroviral therapy (Sabin et al, Expert Rev Cardiovasc Ther, 2004). For (CHD), as well as for diabetes and hyper- tension, both major risk factors for CHD.
relative risk of 10.4 for stroke. Another sent before beginning antiretroviral ther- Antiretroviral therapy appears to acceler- ate the progression of insulin resistance coronary disease, is greater and increas- ate to have less effect on lipid profiles. As indicated that HIV infection alone, prior to initiation of therapy, is associated with and efavirenz-based therapies resulted in adverse effect on insulin sensitivity (El- Sadr et al, HIV Med, 2005). HIV-mediated reduce cardiovascular risk include follow- general population, including institution steroid treatment on lipid profiles and fat toxicity in association with HIV–hepatitis B or C virus coinfection need to be taken into careful consideration when selecting Truncal Fat
Subcutaneous
Adipose Tissue
Appendicular Fat
Visceral
Adipose Tissue
Body Fat (kg)
Abdominal Fat (cm
Figure 1. Changes in body fat (left) on dual energy x-ray absorptiometry (DEXA) and in abdominal fat (right) on computed tomography (CT)
over 48 weeks of efavirenz-based (EFV) or atazanavir-based (ATV) treatment in the BMS-034 study. Adapted with permission from Noor et al,
XV Int AIDS Conf, 2004.
P = .01
P = NS
P = NS
P = NS
P = NS
P = NS
P = .01
P = .02
Oxandrolone
Oxandrolone
Triglyceride
Lean Mass
Figure 2. Changes in body fat and lipid measures over 12 weeks with oxandrolone treatment plus exercise (oxandrolone) or exercise alone
(placebo). Abd SAT indicates abdominal subcutaneous adipose tissue; Abd VAT, abdominal visceral adipose tissues; Chol, cholesterol; HDL,
high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; NS, not significant. Adapted with permission from Smith et al, XV
Int AIDS Conf, 2004.
pared with exercise alone (Figure 2); how- patients (Valcour et al, J Acquir Immune osteoporosis. Clinicians need to be aware Defic Syndr, 2005). The study indicated that diabetes is an independent risk fac- should treat them early; however, routine tor for HIV-associated dementia, with the Glucose Metabolism
study is needed to identify the etiology of decreased bone mineral density, risk fac- in patients on antiretroviral therapy, with >50 years), older patients with diabetes over 144 weeks in initially antiretroviral- patients had osteopenia at baseline, but, adjustment for age, education, ethnicity, to osteoporosis over the course of follow- insulin-sensitizing agents may be benefi- significantly associated with risk for HIV- patients were lost to follow-up, making it cial; diabetes treatment guidelines should difficult to interpret the study findings.
be followed in HIV-infected individuals. Mitochondrial Disorders
dorsocervical fat deposit termed “buffalo hump” in HIV-infected patients (Mallon et Bone Disorders
al, J Acquir Immune Defic Syndr, 2005).
This finding indicates that patients with these agents. Older nRTIs (eg, stavudine, for insulin resistance and diabetes. It also associated with a greater risk of toxicity suggests that caution should be exercised emtricitabine, abacavir, tenofovir).
Mitochondrial toxicity has been implicat- ies call this into question. Various risk Volume 13 Issue 2 June/July 2005
loss. The disorder is primarily seen with dine, zalcitabine, didanosine); pancreati- reversible after stopping nRTI therapy.
citabine); peripheral fat wasting (stavu- severe lactic acidosis is relatively rare, a associated with HIV infection per se. Risk acidosis. The role of HIV per se in mito- ing of lactate levels. Risk factors include clear cells (PBMCs) increased in patients Pancreatitis
was significant only after switching from hyperlactatemia is unclear. Of concern is with the findings being similar to what is observed in nonalcoholic steatohepatitis.
Hyperlactatemia and Lactic Acidosis
Questions that remain to be answeredinclude whether the condition poses Myopathy and Cardiomyopathy
As noted, hyperlactatemia and lactic aci- potential for progression to cirrhosis and ly with zidovudine, although it is less fre- associated with older nRTIs, such as zal- Peripheral Neuropathy
tic acidosis observed is a “type B” lactic oxygen supply to tissue), for which mito- is characterized by bilateral, symmetric, ciated myopathy is difficult to distinguish painful tingling sensations (dysesthesias) from that caused by HIV infection per se.
Mean mtDNA (copies/cell)
Mean mtDNA (copies/cell)
Figure 3. Changes in mitochondrial DNA (mtDNA) level in fat (left) and in peripheral blood mononuclear cells (PBMCs; right) over 48 weeks
after switch to nRTI-sparing regimen. After stratification for prior nRTI, increase in fat mtDNA was significant only with switch from stavudine
(not zidovudine) and increase in PBMC mtDNA was significant only with switch from zidovudine (not stavudine). Adapted with permission
from Boyd et al, XV Int AIDS Conf, 2004.
grant and research support from Bristol- Table 1. Guidelines for Reducing Risk
Myers Squibb, Gilead, and GlaxoSmithKline. She has also served as a scientific advisor toor is on the speakers’ bureaus of Abbott, Smith BA, Raper JL, Weaver MT, et al.
Agouron, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, and ViroLogic. exercise and oxandrolone on lean mass, fat distribution, blood lipids, bone density andtraining markers in HIV infected men and • Assess the patient’s risk factors and Suggested Reading
XV International AIDS Conference. July 11- Boyd MA, Bien D, Ruxrungtham A, et al.
• Lipodystrophy is easier to prevent than al. Diabetes, insulin resistance, and demen- • Treat dyslipidemia, insulin resistance, efavirenz 600mg qd after failing NRTI com- tia among HIV-1-infected patients. J Acquir Immune Defic Syndr. 2005;38:31-36.
• Think about lactate levels in patients syndrome. Expert Rev Cardiovasc Ther. • Be vigilant for bone disease—investigate El-Sadr WM, Mullin CM, Carr A, et al.
Effects of HIV disease on lipid, glucose and Top HIV Med. 2005;13(2):70-74.
insulin levels: results from a large antiretro- Copyright 2005, International AIDS Society–USA viral-naive cohort. HIV Med. 2005;6:114- thy, clinical and histologic changes arereported to be reversible. Mallon PW, Wand H, Law M, Miller J,Cooper DA, Carr A; HIV Lipodystrophy Case Definition Study; AustralianLipodystrophy Prevalence Survey Patients should be assessed for risk fac- associated lipodystrophy is associated with antiretroviral therapy prior to initiation of hyperinsulinemia but not dyslipidemia. J Acquir Immune Defic Syndr. 2005;38:156- after starting treatment, at the time ofswitching therapy, and at least annually Noor MA, Maa J, Giordano MF, Hodder SL.
after initiation of atazanavir-based therapy: International AIDS Conference. July 11-16, Sabin C, Morfeld L, Friis-Moller N, et al.
HIV-1 RNA levels to below 50 copies/mL.
Changes over time in the use of antiretrovi- ral therapy and risk factors for cardiovascu- therapy threaten the clinical benefits of lar disease in the D:A:D study. [Abstract 866.] 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, Presented in March 2005. First draft pre- Shlay JC, Visnegarwala F, Bartsch G, et al.
pared from transcripts by Matthew Stenger. Reviewed and updated by Dr Sweet in June in antiretroviral-naive patients randomized to didanosine and stavudine (ddI+d4T) vs.
abacavir and lamivudine (ABC +3TC).
Financial Disclosure: Dr Sweet has received

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