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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, samples from the following protocols are undergoing investigation:

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 two 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 have 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.

A double blind randomized placebo controlled study examining the effects of a non-absorbable (rifaximin) antibiotic on the chronic immune activation observed in HIV-infected subjects (Protocol 13-I-0062).  The introduction of ART has resulted in dramatic reductions in AIDS-related morbidity and mortality. Therapy is not curative, however, and the nature of HIV replication during therapy remains unclear. Understanding mechanisms involved in HIV persistence will be useful in identifying effective strategies for HIV eradication. Immune activation (IA) plays a central role in the pathogenesis of HIV infection, and may play a critical role in HIV persistence during therapy. In comparison with the levels detected in HIV-uninfected subjects, both cellular markers of activation and biomarkers of inflammation are elevated in HIV-infected individuals. Levels of inflammatory cytokines and cellular markers of activation independently correlate with disease progression in HIV-infected subjects. Chronic, persistent IA is associated with the observed CD4 depletion in untreated subjects and among ART-treated and virologically suppressed subjects and may contribute to the failure to reconstitute CD4 counts. IA also plays a role in the pathogenesis of non-AIDS-related complications such as chronic kidney disease and coronary artery disease (CAD).

Although chronic persistent IA may play a role in HIV persistence, the source of IA itself is unknown. Low-level viremia may represent a virologic stimulus for IA. Viremia persists at low levels during therapy, but it is not known whether HIV infection is maintained by ongoing cycles of replication in sanctuary sites, production from long-lived cells with integrated proviruses, or both. Using sensitive assays for HIV-1 viremia, we and others have detected the presence of persistent HIV viremia in the majority of subjects throughout prolonged ART. Drug intensification studies suggest little contribution of active replication to levels of persistent viremia, suggesting that factors other than complete cycles of HIV replication may contribute to HIV-1 persistence. Activation of HIV-1 from long-lived cells in reservoir sites is another potential source of viremia, but the nature of such reservoirs is not yet well understood.

The mechanism of IA in HIV infection remains to be clarified and is likely multifactorial. Additional potential mechanisms of persistence include a central role for the gastrointestinal tract. The gastrointestinal epithelium and gut-associated lymphoid tissue (GALT) are thought to represent important barriers to microbial translocation, but HIV infection results in substantial destruction of both barriers. The reservoir of bacteria in the gastrointestinal tract is substantial, and small amounts of bacterial products are reported to translocate across the gastrointestinal tract into the bloodstream; microbial translocation across this defective GALT is an important driver of the observed IA in HIV infection. The precise effects of ART on gut microbial translocation remain uncertain; some studies suggest that ART incompletely reverses the effects of microbial translocation, others have failed to demonstrate any effect, yet other studies have demonstrated complete reversal with ART. In this study, we will examine the potential role of bacterial translocation on IA by studying the effects of the antibiotic rifaximin on markers of microbial translocation, IA, and HIV viremia in the gut reservoir in ART-treated aviremic subjects. Rifaximin is an orally administered antibiotic with potent qualitative and quantitative effects on gut bacterial flora. Rifaximin is not systemically absorbed, and drug effects appear to be confined to the gastrointestinal tract. Rifaximin has been studied as maintenance therapy in both inflammatory bowel disease (IBD) and hepatic encephalopathy (HE), disease states in which endogenous gut flora play an important role in the pathogenesis. It is anticipated that the use of rifaximin will result in an alteration and reduction in gut bacterial flora. We hypothesize that the reductions in gut bacterial flora will result in a corresponding reduction in bacterial translocation and reductions in biologically active LPS levels leading to reductions in IA in HIV-infected persons receiving ART.

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

Last modified: 15 October 2018

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