Plasma HIV‐1 RNA Dynamics in Antiretroviral‐Naive Subjects Receiving either Triple‐Nucleoside or Efavirenz‐Containing Regimens: ACTG A5166s

Kuritzkes, Daniel R.; Ribaudo, Heather J.; Squires, Kathleen; Koletar, Susan L.; Santana, Jorge; Riddler, Sharon A.; Reichman, Richard C.; Shikuma, Cecilia; Meyer, William A.; Klingman, Karin L.; Gulick, Roy M.; Team, Actg A Study

doi:10.1086/512619

Cited by 39 publications

(47 citation statements)

References 32 publications

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“…Firstphase decay of RT-SHIV mne during ART (t 1/2 ϭ 1.0 day) closely mimicked initial decay in HIV-1-infected persons receiving a 3-drug EFV protocol in which the t 1/2 value was 1.03 days (33). When ART was reinitiated in 5/6 animals after treatment interruption, a t 1/2 value of approximately 1.3 days for RT-SHIV mne was calculated based on the plasma viremia reduction observed 1 week later (not shown).…”

Section: Discussionmentioning

confidence: 71%

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Ambrose

Palmer

Boltz

et al. 2007

J Virol

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Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does notclear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

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Section: Discussionmentioning

confidence: 71%

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Ambrose

Palmer

Boltz

et al. 2007

J Virol

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“…This prior study, however, did not involve chronically infected patients treated in parallel for direct comparisons of treatment responses to the same intervention. Data from representative subsets of acute/ early and chronic patients treated with the same drug regimens from the study by Louie et al [21] also demonstrate no difference in first-phase decay rates (Table 2) [25][26][27][28]. Table 2 compares viral kinetic results found in a variety of studies in which drug was given to patients presumably at or near setpoint viral loads so that Eq.…”

Section: Discussionmentioning

confidence: 92%

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

Kilby¹,

Lee

Hazelwood³

et al. 2008

Aids

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Objective-Compare the initial phases of virologic decay when acute/early and advanced HIVinfected adults are administered the same treatment regimen.Design-Mathematical modeling of a previously completed prospective treatment pilot study involving treatment-naive patients with early and advanced immunosuppression.Methods-We analyzed data from a treatment protocol in which 18 individuals with acute or recent HIV-1 seroconversion and six patients with advanced AIDS were administered the same four-drug antiretroviral regimen. Initial treatment responses were compared by fitting a mathematical model to frequent viral load measurements in order to calculate the first and second phase kinetics of viral clearance, and also by comparing viral load suppression over 24 weeks. Patients were also comprehensively compared in terms of protease inhibitor drug levels, HIVspecific immune responses at baseline, and the presence of drug resistance-conferring mutations.Results-There was no statistically meaningful difference in first phase clearance of comparable high-level viremia in the two groups, whether protease inhibitor levels were inserted into the model or 100% antiviral drug effectiveness was assumed. In contrast, acute/early patients had inferior sustained responses than advanced patients, reflecting erratic adherence.Conclusions-Despite many years of intervening immune destruction, the initial virologic decay on therapy appears to be the same at the extremes of the HIV disease spectrum. [6]. The natural history of untreated infection then involves years of clinical stability, followed by inexorable CD4+ Tcell count decline (reviewed in [7]). In the advanced immunosuppression setting, antiretroviral therapy (ART) results in rapid plasma viremia decline, CD4+ T-cell count improvement, and decreased disease progression and mortality [8]. Treatment during acute seroconversion also hastens the viremia decline beyond the natural equilibration seen in untreated patients [9,10], but there is no consensus regarding the long-term risks and benefits of early treatment [7,8,11].Very limited data directly compare treatment responses among individuals with early and late stage disease. It remains unclear whether comparably high viremia levels observed at the opposite ends of the disease spectrum would decline at the same rate in response to identical treatment interventions. Previously, we completed a pathogenesis-driven study involving both acute/early and highly advanced HIV-infected patients [12]. We revisited this unique dataset to compare and contrast treatment responses at the disease spectrum extremes. We hypothesized that virologic suppression would be more rapid and complete during acute than advanced disease, perhaps because of rescue of immune clearance mechanisms [13] or incomplete population of viral reservoirs [14]. MethodsAll studies were approved by the Institutional Review Board. Eligibility required no prior ART, Karnofsky performance of at least 80, and safety laboratory results were within acceptable rang...

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“…The slowing of first-phase decay can be explained by a number of scenarios: (i) some drugs were given at low dosages which resulted in the number of HIV RNA copies/ml stabilizing and/or rebounding for certain individuals; (ii) later time points may be partially influenced by viral production from the traditional second phase seen with CART; (iii) some drug studies used branched DNA assays which have a limited dynamic range especially at the lower end and therefore can lead to HIV RNA measurements at later time points that are artificially elevated; (iv) there is ongoing replication that adds to viral load (10) sult in a spectrum of viral replication and loss that can be reflected in different decay rates. Half-lives of productively infected CD4 ϩ T cells have previously been calculated through a variety of procedures and have led to estimates that range from 0.9 to 1.6 days (20,26,30,32,39). Our estimate of a 17-h half-life for cells responsible for the majority of HIV RNA production is an average across all drugs, and these calculations take into account the initial delay for each drug and any slowing of decay that may reflect a process other than the loss of productively infected CD4 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

Murray

Kelleher

Cooper

2011

J Virol

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We estimate the time required for HIV to complete separate stages of its infection cycle in productively infected CD4؉ T cells in vivo by comparing initial delays after administration of single antiretroviral drugs until HIV RNA reduction in peripheral blood. Data were obtained from monotherapy studies of eight antiretroviral drugs from all currently licensed HIV drug classes: CCR5 blockers (maraviroc), fusion inhibitors (enfuvirtide), nucleoside and nonnucleoside reverse transcriptase inhibitors (abacavir, tenofovir, and rilpivirine), integrase inhibitors (raltegravir), and protease inhibitors (ritonavir and nelfinavir). We find that HIV requires an average of 52 h between export of virions in one generation to export in the next, with most of this (33 h) taken up by reverse transcription. Reverse transcription in vivo was three times longer than in vitro and began soon after virion fusion, as we determined no difference in mean times for commencement of reverse transcription and virion fusion as calculated by timing of the effects for tenofovir and maraviroc. Approximately 7 h is required between HIV integration and virion production. First-phase HIV RNA decay (half-life of 17 h over all drugs) seemed to slow as the stage being inhibited by the drug was further from viral production. The mean estimated half-life of plasma virions was 5 min, significantly shorter than previous estimates.

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Plasma HIV‐1 RNA Dynamics in Antiretroviral‐Naive Subjects Receiving either Triple‐Nucleoside or Efavirenz‐Containing Regimens: ACTG A5166s

Cited by 39 publications

References 32 publications

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals

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Plasma HIV‐1 RNA Dynamics in Antiretroviral‐Naive Subjects Receiving either Triple‐Nucleoside or Efavirenz‐Containing Regimens: ACTG A5166s

Cited by 39 publications

References 32 publications

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline

Timing of the Components of the HIV Life Cycle in Productively Infected CD4 + T Cells in a Population of HIV-Infected Individuals

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Timing of the Components of the HIV Life Cycle in Productively Infected CD4 ⁺ T Cells in a Population of HIV-Infected Individuals