Seronegatives and Metabolic Abnormalities Protocol 2 (SAMA002): Study to Compare the Effect of Kaletra and Combivir® in HIV-Negative Healthy Subjects

• To determine:
• - the effect of six weeks antiretroviral therapy with LPVr and CBV, alone and in combination, in HIV negative healthy subjects with respect to changes from baseline in genes related to mitochondrial and lipid and glucose metabolism in monocytes
• - the effect of six weeks antiretroviral therapy with LPVr and CBV, alone and in combination, in HIV negative healthy subjects with respect to changes from baseline in adipocyte structure.
• - the effect of six weeks LPVr and CBV, alone and in combination, in HIV negative healthy subjects with respect to changes in serum lipids and glucose.
• - the safety of LPVr and CBV, alone and in combination,in HIV negative healthy subjects by evaluating the incidence and severity of adverse events and abnormal laboratory values.
• To compare:
• - the effects of six weeks therapy with LPVr/CBV on the parameters listed above with six weeks of LPVr alone or CBV alone in HIV negative subjects.
• To assess:
• - changes in body composition and plasma concentrations of LPVr over the course of the trial in subjects taking LPVr and CBV, alone and in combination, and compare them to changes in gene expression in monocytes and/or adipose tissue.
• - possible increased risk of cardiovascular disease (CVD) by measurements of changes in brachial artery endothelial reactivity over the course of the trial in individuals taking LPVr and CBV, alone and in combination.
• - the reversibility of any abnormalities developing during the course of the six weeks of dosing, by performing repeat assessments at weeks 12 and 24.

This is a randomised study of the effect of treatment with Combivir (zidovudine [AZT] and lamivudine [3TC]) and Kaletra (lopinavir [LPVr]), alone and in combination, on the development of abnormalities in lipid and glucose metabolism in HIV negative healthy subjects.

Antiretroviral medications, used to treat HIV infection, cause side effects. These include changes in the way that fat is laid down on the body. This results in fat loss from some parts of the body, with fat deposits at other sites, giving a characteristic look known as "HIV associated lipodystrophy" or HIVLD. With these changes, there are also abnormalities in glucose and fat metabolism (collectively termed metabolic abnormalities). In HIV negative populations, these metabolic changes are associated with an increased risk of developing cardiovascular disease (CVD). The aim of this study is to investigate if changes in the body's handling of fats and glucose occur with a short course of treatment in HIV negative subjects and if these correlate to an increased risk of CVD.

• HIV Infections
• Dyslipidemias
• Glucose Metabolism Disorders
• Metabolic Diseases
• Lipodystrophy
• Cardiovascular Disease

• Drug: Combivir (zidovudine [AZT] / lamivudine [3TC])
• Drug: Kaletra (lopinavir [LPVr])

Inclusion Criteria:

• Age >18
• Be able to provide written consent to perform in the trial.
• HIV antibody negative and HIV DNA negative at time of entry to the study.

Exclusion Criteria:

• Any history of, or ongoing, mental or physical condition (including suspected or known diagnosis of ischaemic heart disease), which, in the opinion of the investigator, would impede the subject's ability to participate in the trial.
• History of type I or type II diabetes mellitus or previous treatment with antidiabetic medication.
• Prior use of testosterone, oestrogen, growth hormone or other oral glucocorticoid or anabolic steroid products within the previous six months.
• Alcohol or substance abuse which in the opinion of the investigator would affect the subject's ability to participate in the trial.
• Prior use of anti-retroviral agents (including protease inhibitors, nucleoside or non-nucleoside reverse transcriptase inhibitors, investigational antiretroviral agents or fusion inhibitors either in a previous study, as treatment or as part of post-exposure prophylaxis).
• Prior use of any retinoid-containing compound within the previous six months.
• Abnormal coagulation.
• Previous allergic reaction or known allergy to local anaesthetic.
• Previous use of psychotropic medications.
• Concomitant use of medications, including those metabolised by CYP3A4 enzyme system, which, in the opinion of the investigator, would affect the subject's ability to participate in all activities involved in the trial.
• Any grade-three laboratory abnormality recorded from screening bloods.
• Any grade-two laboratory abnormality recorded from screening bloods, which, in the opinion of the investigator, would impede the subject's ability to safely complete all study requirements.
• Gastrointestinal disorders, which may affect drug absorption.
• Any finding on screening clinical examination, which, in the opinion of the investigator, would impede the subject's ability to participate in the rest of the trial.
• Pregnancy
• Evidence of acute or chronic active hepatitis B virus infection by serology performed at baseline.
• Evidence of hepatitis C infection by serology performed at baseline.

• St Vincent's Hospital, Sydney
• National Heart, Lung, and Blood Institute (NHLBI)
• Garvan Institute of Medical Research
• Prince of Wales Hospital, Sydney