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Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.

ABSTRACT: Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolved viral genomes. Episodes of LLV (plasma HIV-1 RNA, 50 to 379 [median, 77] c/ml) were detected in 21/37 (57%) HIV-1-infected children with median plasma HIV-1 RNA levels of <50 c/ml during 79 patient years of HAART. Viral sequences were derived by direct sequencing of PCR products from 21 plasma specimens diluted to end point. In phylogenetic analysis, LLV viral sequences grouped with virus from early in the course of infection in 8/11 subjects. Six specimens had multiple identical viral sequences, suggesting origin from clonally expanded infected cells. LLV plasma virus evolved over time, indicating viral replication, in 3/11 subjects. Two of these had frequent LLV, including the selection of drug-resistant mutants. In summary, plasma virus from episodes of LLV during effective HAART appeared to originate from two distinct processes, (i) clonal outgrowth from long-lived HIV-1-infected cells, presumably following activation and proliferation of these cells, and (ii) ongoing viral replication that included the selection of new drug-resistant mutants. These observations provide a plausible explanation for the divergent clinical outcomes previously associated with LLV.

SUBMITTER: Tobin NH

PROVIDER: S-EPMC1181593 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.

Tobin Nicole H NH Learn Gerald H GH Holte Sarah E SE Wang Yang Y Melvin Ann J AJ McKernan Jennifer L JL Pawluk Diane M DM Mohan Kathleen M KM Lewis Paul F PF Mullins James I JI Frenkel Lisa M LM

Journal of virology 20050801 15

Episodes of low-level viremia (LLV), with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels ranging from 50 to 400 copies (c)/ml, occur commonly during highly active antiretroviral therapy (HAART). LLV has been associated with virologic failure of HAART in some studies, while in others LLV did not appear to affect the clinical outcome. To understand the processes leading to LLV, genetic analyses were used to determine whether plasma virions emanated from archived or from newly evolve ...[more]

PMID: 16014925

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Project description:BackgroundWidespread HIV screening and access to highly active antiretroviral treatment (ART) were cost effective in mathematical models, but population-level implementation has led to questions about cost, value, and feasibility. In 1996, British Columbia, Canada, introduced universal coverage of drug and other health-care costs for people with HIV/AIDS and and began extensive scale-up in access to ART. We aimed to assess the cost-effectiveness of ART scale-up in British Columbia compared with hypothetical scenarios of constrained treatment access.MethodsUsing comprehensive linked population-level data, we populated a dynamic, compartmental transmission model to simulate the HIV/AIDS epidemic in British Columbia from 1997 to 2010. We estimated HIV incidence, prevalence, mortality, costs (in 2010 CAN$), and quality-adjusted life-years (QALYs) for the study period, which was 1997-2010. We calculated incremental cost-effectiveness ratios from societal and third-party-payer perspectives to compare actual practice (true numbers of individuals accessing ART) to scenarios of constrained expansion (75% and 50% probability of accessing ART). We also investigated structural and parameter uncertainty.FindingsActual practice resulted in 263 averted incident cases compared with 75% of observed access and 676 averted cases compared with 50% of observed access to ART. From a third-party-payer perspective, actual practice resulted in incremental cost-effectiveness ratios of $23 679 per QALY versus 75% access and $24 250 per QALY versus 50% access. From a societal perspective, actual practice was cost saving within the study period. When the model was extended to 2035, current observed access resulted in cumulative savings of $25·1 million compared with the 75% access scenario and $65·5 million compared with the 50% access scenario.InterpretationART scale-up in British Columbia has decreased HIV-related morbidity, mortality, and transmission. Resulting incremental cost-effectiveness ratios for actual practice, derived within a limited timeframe, were within established cost-effectiveness thresholds and were cost saving from a societal perspective.FundingBC Ministry of Health, National Institute of Drug Abuse at the US National Institutes of Health.

Project description:UnlabelledA number of men receiving prolonged suppressive highly active antiretroviral therapy (HAART) still shed human immunodeficiency virus (HIV) in semen. To investigate whether this seminal shedding may be due to poor drug penetration and/or viral production by long-lived cells within male genital tissues, we analyzed semen and reproductive tissues from macaques chronically infected with simian immunodeficiency virus mac251 (SIVmac251) who were treated for 4 months with HAART, which was intensified over the last 7 weeks with an integrase inhibitor. We showed that a subset of treated animals continued shedding SIV in semen despite efficient HAART. This shedding was not associated with low antiretroviral drug concentrations in semen or in testis, epididymis, seminal vesicles, and prostate. HAART had no significant impact on SIV RNA in the urethra, whereas it drastically reduced SIV RNA levels in the prostate and vas deferens and to a lesser extent in the epididymis and seminal vesicle. The only detectable SIV RNA-positive cells within the male genital tract after HAART were urethral macrophages. SIV DNA levels in genital tissues were not decreased by HAART, suggesting the presence throughout the male genital tract of nonproductively infected cells. In conclusion, our results demonstrate that 4 months of HAART induced variable and limited control of viral infection in the male reproductive organs, particularly in the urethra, and suggest that infected long-lived cells in the male genital tract may be involved in persistent seminal shedding during HAART. These results pave the way for further investigations of male genital organ infection in long-term-treated infected individuals.ImportanceA substantial subset of men receiving prolonged HAART suppressing viral loads in the blood still harbor HIV in semen, and cases of sexual transmission have been reported. To understand the origin of this persistence, we analyzed the semen and male reproductive tissues from SIV-infected macaques treated with HAART. We demonstrated that persistent seminal shedding was not linked to poor drug penetration in semen or semen-producing prostate, seminal vesicle, epididymis, and testis. We revealed that HAART decreased SIV RNA to various extents in all male genital organs, with the exception of the urethra, in which SIV RNA(+) macrophages were observed despite HAART. Importantly, HAART did not impact SIV DNA levels in the male genital organs. These results suggest that infection of male genital organs, and particularly the urethra, could be involved in the release of virus in semen during HAART.

Dataset Information

Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.

Publications

Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus.

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