The Predictive and Clinical Value of Proviral HIV-1 DNA Quantification and Understanding HIV Genetic Subtypes

Symposium participants also heard a report on the SENTRY project in the UK and its role in revealing a significant prevalence of all non-B subtypes in the United Kingdom.  This study is also exploring the possible implications viral subtypes have for diagnosis, monitoring and correlation to treatment response among patients.

Potential Key Role of Proviral HIV-1 DNA in Treatment Decisions

Other Symposium Highlights

Potential Further Sensitivity of Modified Roche HIV-1 RNA Test

Potential Key Role of Proviral HIV-1 DNA in Treatment Decisions

At the symposium, Professor Christine Rouzioux of the Laboratory of Virology, CHU Necker-Enfants Malades in Paris, described how the quantity of proviral HIV-1 DNA is an independent marker for clinical outcomes of HIV-1 patients, and that this marker could potentially be a key in making treatment decisions for these individuals.

This finding is of significant interest because, while highly active antiretroviral therapy (HAART) has profoundly reduced mortality rates among HIV-infected patients, it is not able to eradicate the HIV-1 virus. HAART can also produce serious adverse side effects. 

Professor Rouzioux’s research indicates that levels of proviral HIV-1 DNA may be an important predictive marker – independent from plasma RNA and CD4 cells – and significant in that it represents the “stock” of latently-infected cells capable of producing new viral particles in the body.  In this regard, measurement of proviral HIV-1 DNA could potentially be used to base decisions on starting, interrupting, and restarting therapy. As a new marker, it could potentially help to optimize the effectiveness of HAART for the clinical management of HIV, and also aid in  maintaining the quality of life among infected patients.

Professor Rouzioux’s research entailed the analysis of patient specimens from several HIV-1 studies within France.  Her team of investigators measured proviral HIV-1 DNA in peripheral blood mononuclear cells (PBMC) from samples collected for these studies, which revealed a diversity of clinical situations.

Each of the studies that she reviewed focused on a specific aspect of proviral HIV-1 DNA.  Samples from the SEROCO Cohort study suggested that proviral HIV-1 DNA was predictive of the risk of disease progression to AIDS, independent of the number of CD4+ cells or the level of HIV RNA in plasma.

Quantitative analysis of proviral HIV-1 DNA in samples from the French PRIMO cohort (individuals at the time of HIV-1 primary infection) showed that the stock of latently infected cells is established at the very beginning of HIV infection.  Samples of long-term asymptomatic patients within the French ALT Cohort study confirmed the predictive value of proviral HIV-1 DNA on the risk of evolution to AIDS, and also showed a protective role of specific immune responses. 

Analysis of samples obtained in three different ANRS trials in France measured the impact of HAART on proviral HIV-1 DNA.  Samples of PRIMOFERON patients (Peg-Interferon associated to HAART at time of primary infection) showed a significant impact of HAART when initiated early.  Samples from ANRS 079 (IL2+HAART) indicated the absence of expansion of the stock of infected cells when treated with IL2.  Samples from PRIMSTOP indicated a weaker effect from HAART in pre-treated subjects compared to that observed in naïve subjects. 

Finally, analysis of samples collected at the Necker Hospital in Paris from patients treated during more than five years and presenting continuous control of viral replication confirmed that the effect of HAART on cellular stock occurs primarily during the first two years of treatment.

In composite, the results of Professor Rouzioux’s study lead to the belief that the stock of circulating HIV-infected blood cells is representative of the total reservoir of HIV virus present in the body, and that this stock of virus integrated into the cellular genome is the major obstacle to a cure.  However, living a sustained time with the HIV virus is clearly possible, provided the expansion of cellular viral stock is controlled.

In the overall context of HIV-1 treatment, Professor Rouzioux’s findings may serve to create a different treatment paradigm with the control of the expansion of latently-infected cells as an important new objective.  The use of quantitative proviral HIV-1 DNA measurements along with other markers could potentially help clinicians to customize HIV treatment with the goals of improving clinical effect and enhancing patient life quality over very long periods. 

Professor Rouzioux concluded that, while reducing the adverse effects of HAART, limiting long exposure, and alternating “on” and “off” therapy periods may not be completely realistic at this time, it is clear that understanding the utility of the proviral HIV-1 DNA marker may play a critical role in making individualized choices about HAART.

Other Symposium Highlights 

In another presentation at this symposium, Clive Loveday, MD, PhD, Clinical Director for the International Clinical Virology Centre (ICVC) in Buckinghamshire, United Kingdom, reported how the SENTRY project is revealing a significant prevalence of all non-B subtypes in the United Kingdom.  This study is also exploring the possible implications viral subtypes have for diagnosis, monitoring and correlation to treatment response among patients.

Dr. Loveday explained that the presence of multiple subtypes in any given community has revealed the ability of HIV-1 to genetically recombine in one host.  The evolutionary capacity of the virus has resulted in the selection of recombinant forms that are biologically more successful than existing viruses, which raises considerable implications for management of HIV-1/AIDS and clinical care.

His study group has leveraged molecular diagnostics for national and international surveillance of HIV-1 diversity, with the goal of characterizing the distribution and ongoing spread of subtypes throughout the world.

Information on HIV-1 subtypes and their genetic origin, as well as specific viral sequences, combined with viral load testing to determine possible correlations among certain subtypes to treatments, has helped to understand new clinical implications in managing HIV-1-positive patients of all subtypes.  This research is also providing information for the development of next generation molecular tests that provide result integrity despite constant mutation of the HIV-1 virus.

Potential Further Sensitivity of Modified Roche HIV-1 RNA Test

Brooks Jackson, MD, MBA, Chairman of Pathology at the Johns Hopkins Medical Institutions, presented research findings that showed how a modified version of Roche’s AMPLICOR HIV-1 MONITORÒ Test, version 1.5, could be made at least twice as sensitive in detecting HIV-1 RNA, through a modified viral extraction process.

The AMPLICOR HIV-1 MONITORÒ Test, version 1.5, which is pending approval by the U.S. Food and Drug Administration, can measure HIV-1 RNA down to 50 copies per milliliter, and detect Group M subtypes A-G.  Further sensitivity, as achieved by Dr. Jackson’s research team, may prove to enhance the value of this technology in quantifying very low levels of HIV-1 virus, monitoring viral suppression and determining the relative efficacy of drug regimens.

Also at the symposium, Thomas W. Myers, PhD, Associate Director, Program in Core Research for Roche Molecular Diagnostics, presented a newly-developed assay using RT/PCR, which is able to reliably amplify over 1.3 kb of HIV-1-RNA.  This could open the door to breakthrough applications of PCR, offering more robustness in the context of sequencing and resistance testing for HIV.

07/24/02

Symposium sponsored by Roche Diagnostics Systems. July 9, 2002. Barcelona, Spain.