HIV Infections Clinical Trial
Official title:
Effect of Change to a Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Sparing Regimen of Efavirenz (EFV) and Lopinavir/Ritonavir (LPV/r) on Liver Histology in HIV-1-Infected Individuals With Lactic Acidemia and Persistent Alanine Aminotransferase (ALT) Elevations on NRTI-Containing Antiretroviral Therapy
The purpose of this study is to look at how 2 different anti-HIV drug treatments affect the
liver.
The use of anti-HIV drugs like the nucleoside reverse transcriptase inhibitors (NRTIs) may
be linked to liver problems like fatty changes, scarring, abnormal liver function tests
(LFTs), and lactic acidemia (an increase in lactic acid in the blood). Increased liver
enzymes may mean liver damage. The way that the liver changes in people with abnormal LFTs
and lactic acidemia is not completely understood.
This study provides a unique opportunity to prospectively assess the relationship of lactic
acidemia with liver dysfunction and to determine whether lactic acidemia and liver
dysfunction are likely to be secondary to NRTI-induced mitochondrial toxicity. If lactic
acidemia and hepatic fatty infiltration (steatosis) in this study population are secondary
to NRTI-induced mitochondrial toxicity, withdrawal of NRTI medications can be expected to
result in partial improvement or resolution of these findings. Furthermore, this study will
examine the possible additive ill effects of NRTI-induced mitochondrial toxicity on liver
function in individuals coinfected with hepatitis C.
This study is designed both as a stand-alone ACTG protocol providing an NRTI-sparing regimen
and as a study coenrollable simultaneously with A5116.
Patients enrolling in A5133 as a stand-alone study: Patients on NRTI-containing regimens
with elevated lactates and ALTs are enrolled into a single open-label NRTI-sparing treatment
regimen of efavirenz (EFV) plus lopinavir/ritonavir (LPV/r), which are provided by the
study. These patients follow virologic failure/toxicity management guidelines as detailed in
the protocol.
Patients coenrolling in A5116: Patients are studied on their assigned A5116 antiretroviral
regimens with medication as provided by A5116. Those randomized in A5116 to the NRTI-sparing
regimen of EFV and LPV/r identical to that offered by A5133 will be assessed together with
patients who entered A5133 as a stand-alone study. Individuals assigned in A5116 to the
continued NRTI arm of 2NRTIs plus EFV are enrolled into a separate observational arm of
A5133. The impact of continued NRTI therapy on liver histology is assessed in this
observational arm. Virologic failure/toxicity management is in accordance with the A5116
protocol. The definition of virologic failure in A5116 is identical to the definition used
in A5133.
Arm 1 consists of patients assigned to an NRTI-sparing regimen without evidence of HCV
coinfection.
Arm 2 consists of patients assigned to an NRTI-sparing regimen with evidence of HCV
coinfection.
Arm 3 consists of patients coenrolled in the NRTI-containing arm of A5116 with or without
evidence of HCV coinfection.
All patients are evaluated for safety and for virologic and immunologic responses. In
addition, individuals undergo liver biopsy and upper abdominal CT scans within 30 days prior
to entry and within 30 days prior to week 24. The biopsied tissue is reviewed for evidence
of fatty infiltration, inflammation, and fibrosis. The CT scans are assessed for degree of
fatty infiltration. If sufficient liver tissue is available, the biopsied tissue will be
assessed for other parameters. Plasma, PBMCs, and sera are collected to explore the role of
oxidative stress and other parameters in the development of hepatic fatty infiltration
(steatosis) and hyperlactatemia. The effect of changes in liver fatty infiltration and
plasma lactate on lipoproteins will be explored. Finally, PBMC mtDNA content will be
correlated with liver mtDNA content.
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