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Clinical trials conducted by HIV Dynamics and Replication Program
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The clinical arm of the HIV Dynamics and Replication Program is under the direction of Frank Maldarelli, M.D., Ph.D.  Its primary research focus is to understand the population genetics, evolution, and dynamics of HIV infection in patients, particularly as related to the development of resistance and possible ways to overcome it.  In collaboration with the NIAID/CCMD AIDS clinic and the NCI HIV and AIDS Malignancy Branch, Dr. Maldarelli develops and secures IRB approval for clinical trials, and implements them using the support of these groups.  At present, there are five active protocols:

HIV expression in patients with viral loads suppressed on HAART (Protocol 02-I-0232).  The goal of this study is to determine the level and nature of viremia in HIV-1-infected patients.  Using the single-copy assay, we are following patients on therapy whose virus load is undetectable by standard assays.  We have found that about two-thirds of such patients have detectable, stable viremia in the range of 1-40 copies of RNA/ml.  The level of this viremia appears to be related to regimen potency, suggesting that it is maintained by ongoing replication.  We will test this relationship further by applying this analysis to stored samples from large-scale trials of regimens with different expected potencies.  In another randomized, prospective trial, we will test the effect of intensification of therapy on level of viremia.  The latter study should directly test whether ongoing replication is responsible for maintaining the low, but steady, load in suppressed patients.

Analysis of HIV-1 replication during antiretroviral therapy (Protocol 08-I-0221).  Combination antiretroviral therapy (ART) for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality.  Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance.  How drug resistance emerges during suppressive ART remains poorly understood.  Investigating the characteristics of HIV-1 replication during suppressive ART will yield important insights in understanding the emergence of resistance, and requires patients who have suppressed viral RNA levels.  Prior NIH protocols have made important observations regarding the kinetics of HIV-1 decline in response to therapy, the levels of HIV-1 viremia during suppressive therapy, and the nature of HIV-1 genetic diversity before and after initiation of ART.  In the process, these studies have generated a useful cohort of patients with suppressed viral RNA levels, who have been extensively characterized from a virologic and immunologic standpoint.  Similarly, patients from other NIH protocols have been followed for prolonged periods before and after therapy has been initiated, and they also have stored sample sets that would be useful in new studies of HIV replication.  The HIV Dynamics and Replication Program has studied samples from protocols 00-I-0110 and 97-I-0082 to develop a number of new, sensitive laboratory techniques to measure and quantitate genetic variation and to investigate immune response parameters.  To further advance understanding of HIV-1 replication during suppressive ART and the emergence of drug resistance, we have developed a new protocol to study these 2 patient cohorts (from the above-cited protocols) and selected patients in other protocols with a new series of studies.  The primary objective of this protocol is to investigate the virologic and immunologic characteristics of HIV-infected individuals undergoing ART.

An assessment of the relationship between antiretroviral drug genotype/phenotype (IC50) and antiretroviral activity in HIV-infected, drug-experienced patients with suboptimal suppression of plasma viral load (Protocol 01-I-0004).  This study analyzes the correlation between phenotype/genotype to selected antiretroviral agents and short-term change in viral load upon discontinuation of a single antiretroviral agent from a failing regimen.  One drug in a failing multidrug regimen is withdrawn for a limited period of time, and then restored.  By monitoring changes in both viremia and genotype (by the limiting-dilution assay), we can discern whether the drug was contributing to partial suppression of virus, and also determine which mutations are associated with resistance to that drug, and their effect on both fitness of the virus and resistance to the drug.

A randomized placebo controlled trial of atorvastatin in HIV positive patients not on antiretroviral medications with the specific aims of studying the effects of atorvastatin on HIV viral load and immune activation markers (Protocol 06-I-0197).  This protocol is a randomized, double-blind, placebo-controlled trial designed to study the effects of the lipid-lowering statin atorvastatin on HIV-1 viremia.  Untreated HIV-1 infection results in an incurable, progressive immunodeficiency and death, usually from opportunistic infections.  Combination ART has been successful in suppressing HIV replication and reducing morbidity and mortality.  Long-term ART is associated with the development of HIV-1 drug resistance and significant adverse side effects, including metabolic and cardiovascular complications.  Prolonged therapy with certain antiretrovirals is associated with increased risk of cardiovascular disease and a number of dyslipidemic syndromes, including increased levels of cholesterol, LDL, and triglycerides in peripheral blood.  New therapeutic strategies to suppress HIV-1 infection are essential.

Previously, in vitro studies suggested that exposure to cholesterol-lowering statins results in decreases in HIV-1 replication.  The mechanisms of inhibition remain uncertain, but possibilities include disrupting membrane trafficking or cytoskeletal processes necessary for intracellular transport of viral proteins, or altering the cellular activation state necessary for viral gene expression.  Initial in vivo studies of the effects of statins on HIV-1 have been largely anecdotal in nature and have yielded conflicting results.  Although statin therapy is commonly used in HIV-1 infection, adverse effects from the combination of antiretrovirals and statins are possible.  A more thorough understanding of the effects of statins on HIV-1 replication is essential to determine the potential therapeutic effect and to investigate the risks and benefits of this approach in vivo.

We plan to conduct a double-blind, randomized, placebo-controlled trial, with a crossover design, to study the effects of atorvastatin in 22 HIV-infected patients not currently taking ART.  Patients will be randomized to receive either a placebo or atorvastatin (80 mg) for 8 weeks.  After a 4-week wash-out period, patients on the atorvastatin arm will crossover to placebo, and vice versa patients in the placebo arm will cross over to atorvastatin for an additional 8 weeks.  Upon completion of study medications, all patients will be followed for 4 weeks.  Each arm will have a minimum of 11 patients.  The primary outcome measure in this study is the effect of lipid-lowering agents on HIV-1 RNA levels; additional secondary outcome measures include effects of lipid-lowering agents on lipid profile, markers of inflammation and immune activation, and investigations of host and viral genetic factors.

Effect of interferon alpha 2b intensification on HIV-1 residual viremia in individuals suppressed on antiretroviral therapy (Protocol 11-I-0057).  As a result of combination ART, morbidity and mortality from AIDS has declined significantly in the past 12 years, at least in developed countries.  HIV-1-infected individuals now live longer, but must undergo continuous therapy that has substantial consequences on quality of life.

ART suppresses HIV-1 viremia below the limits of detection in current commercial assays (50 copies/ml plasma).  Although therapy is not immediately curative, previous studies were optimistic, suggesting that prolonged duration of suppressive therapy could result in eventual viral eradication.  More recent data suggest, however, that HIV-1 RNA persists even after prolonged suppressive therapy.  The origin of this residual viremia is yet not defined, but data from several sources, including our own, indicate that persistent viremia may be the product of viral genome production from chronically infected long-lived reservoirs, and not from new ongoing cycles of HIV-1 infection.

Antiretrovirals are extremely active against replicating cells, and can thus successfully stop viral replication, but have no effect on long-lived viral reservoirs of cells already infected with HIV-1 at the time ART is initiated.  As a result, new strategies may be necessary to reduce or eradicate long-lived reservoirs.

Interferon alpha is a natural cytokine with antiviral activity.  Prior to the introduction of ART, several studies demonstrated the modest effect of interferon alpha on HIV-1 viremia in active cycles of infection in infected individuals.  Interferon alpha was also effective in vitro in decreasing virus production from cells chronically infected with HIV-1.  With the introduction of potent ART, interferon was not developed as a direct anti-HIV drug.  Interferon alpha is relatively effective in therapy of hepatitis C virus (HCV) infection, and has been used in HIV-1/HCV-coinfected individuals.  Recently, Kottilil and coworkers in the Laboratory of Immunoregulation, NIAID, have shown a decrease in HIV-1 RNA levels in HCV-coinfected participants treated with pegylated interferon alpha and ribavirin.  In stored samples from that study, we conducted a retrospective trial on samples from participants with HIV-1 RNA levels of <50 copies/ml, showing a further reduction in residual viremia using an ultrasensitive single-copy assay developed in our laboratory.

In this protocol, we will conduct a prospective, nonrandomized, single-arm pilot study to investigate the effect of pegylated interferon alpha 2b on HIV-1 RNA levels as an additional drug in participants undergoing suppressive ART with viral RNA levels suppressed to less than 50 copies/ml plasma.  We will determine whether interferon alpha therapy will reduce residual viremia in participants on suppressive ART, which will expand our understanding of persistent low-level viremia in HIV-1-infected individuals.

For further information about these clinical trials, please contact Dr. Maldarelli (e-mail 

Last modified: 11 April 2017


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