Management of Metabolic Complications Associated With Antiretroviral Therapy for HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel

Alterations in glucose and lipid metabolism, lactic acidemia, bone disorders, and abnormal fat distribution have been recognized recently as frequent complications associated with HIV-1 infection and potent antiretroviral therapy, but limited data are available regarding the appropriate management of these disorders.

A 12-member panel representing international expertise in HIV-1 patient care, antiretroviral therapy, and endocrine and metabolic disorders was selected in the spring of 2000 by the International AIDS Society-USA, a not-for-profit physician education organization. Panel members met in closed meetings beginning May 2000, reviewing published results of clinical, epidemiologic, and basic science studies and data and abstracts presented at research conferences, primarily from 1997-2002. The panel also considered studies involving metabolic abnormalities in noninfected persons. Emphasis was placed on results from prospective, randomized, controlled clinical trials when available. The following summarizes the recommendations the panel developed to guide physicians actively involved in HIV care in the management of metabolic complications that occur primarily within the context of potent antiretroviral therapy (PAT). Assessment and Monitoring

• Glucose and lipid abnormalities: Before the initiation of PAT, three to six months after starting or switching therapy, and at least annually during therapy, assess fasting glucose (if therapy includes a protease inhibitor [PI]) and fasting lipid panel (total cholesterol, HDL and LDL cholesterol [calculated or direct], and triglyceride levels). A blood glucose level after oral administration of 75g of glucose may be used to identify impaired glucose tolerance in patients with risk factors for type 2 diabetes mellitus or those with severe body fat changes.

• Body fat distribution abnormalities: No specific technique can be recommended at the present time for routine assessment and monitoring of body fat distribution changes.
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• Lactic acidemia: Routine measurement of lactic acid levels is not recommended. Lactic acid levels should be monitored in those receiving NRTIs who have clinical signs or symptoms of lactic acidemia, and in pregnant women receiving NRTIs. If alternative NRTIs are resumed in those who have interrupted antiretroviral therapy for lactic acidemia, lactate levels should be monitored every four weeks for at least three months.

• Osteopenia, osteoporosis, and osteonecrosis: Routine screening for osteoporosis or osteonecrosis is not recommended. Radiographic examination of involved bone is recommended for those with symptoms of bone or joint pain; the contralateral joint should also be assessed. Treatment

• Glucose intolerance and diabetes mellitus: Weight loss for overweight subjects is recommended. Follow established guidelines for treating diabetes in the general population, with preference given to insulin sensitizing agents such as metformin (except for those with renal disease or history of lactic acidemia) or thiazolidinediones (except for those with preexisting liver disease). Avoid use of PI as initial therapy in patients with preexisting glucose intolerance or diabetes mellitus.

• Lipid and lipoprotein abnormalities: Follow National Cholesterol Education Program (NCEP) III guidelines for assessment of risk factors for cardiovascular disease, and dietary and lifestyle alterations for lowering cholesterol and triglyceride levels. Avoid PI use, if possible, in those with preexisting cardiovascular risk factors, family history of hyperlipidemia, or elevated lipid levels. Follow NCEP guideline thresholds for lipid-lowering therapy. Fibrates are recommended as initial therapy for those with isolated fasting hypertriglyceridemia. Pravastatin or atorvastatin are preferred statin agents for those with isolated fasting hypercholesterolemia requiring treatment in the setting of PI or other CYP3A4 inhibitor therapy. If combination therapy for hypercholesterolemia and hypertriglyceridemia is indicated, therapy should begin with a statin, followed by the addition of a fibrate if there is insufficient response after three to four months of treatment.

• Body fat distribution abnormalities: No therapies for fat distribution abnormalities in the absence of other metabolic complications can be routinely recommended.

• Lactic acidemia: Antiretroviral therapy should be withheld for all patients with confirmed lactate levels more than 90mg/dL (10mmol/L) or those with confirmed lactate levels more than 45 mg/dL (5mmol/L) who are symptomatic. No intervention apart from NRTI cessation is recommended. Restart combination NNRTI and PI therapy after lactate levels return to normal and symptoms resolve.

• Osteopenia, osteoporosis, and osteonecrosis: Surgical resection of involved bone is the only effective therapy for symptomatic osteonecrosis. If osteoporosis is demonstrated by radiography or regional dual-energy X-ray absorptiometry (DEXA) scanning, or if a pathological fracture occurs in the setting of osteoporosis, therapy with a biphosphonate should be considered.

"Metabolic complications of PATs have only been recently recognized, and prospective studies to determine the incidence, etiology, risk factors, and most appropriate treatments for these complications are only now under way or being initiated. There remains a pressing need for guidance in managing these complications while definitive data to establish firm recommendations accrue. Extrapolation from preliminary results of ongoing studies and experience garnered from management of similar metabolic abnormalities in patients who do not have HIV-1 infection serve as the basis for many of these recommendations," the authors concluded.

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