To assist in the search for therapies that might contribute to curing HIV infection, scientists are seeking to identify biomarkers that are associated with control of viral load after an antiretroviral therapy (ART) interruption. If reliable predictors of viral load control could be identified, the effect of candidate therapies on these biomarkers could be evaluated without necessarily having to ask clinical trial participants to undergo ART interruptions (which can pose risks to health). Two recent papers report that certain measurements of the HIV reservoir show statistically significant associations with viral load rebound, although the results are not entirely consistent.
The SPARTAC trial studied the effects of a 48-week course of ART in people with acute HIV infection. The primary results were reported in the New England Journal of Medicine last year. In a paper in the journal Elife, the trial investigators describe assessments of whether the amount of HIV DNA in blood samples at ART interruption was linked to the time it took for HIV viral load to rebound to detectable levels, or the trial’s primary endpoints (CD4 T cell count less than 350 or restart of ART). The level of total HIV DNA was significantly correlated with time to a viral load above 400 copies; the higher the HIV DNA level, the quicker the time to rebound. Significant associations were also observed between HIV DNA levels and time to reach a CD4 T cell count of less than 350 or ART restart. However, when an assay with a lower viral load cut-off of 50 copies was used, HIV DNA levels were no longer significantly associated with time to rebound.
The second paper, by Jonathan Li and colleagues, is based on analyses of participants in a randomized, placebo-controlled therapeutic HIV vaccine trial involving Merck’s Ad5-based vaccine candidate (since discontinued). The study design involved a 16-week analytical treatment interruption (ATI). The researchers were able to document statistically significant correlations between pre-ATI HIV RNA and DNA measurements and the viral load set point during the ATI. However, neither measure was significantly associated with time to viral load rebound above 200 copies.
Taken together, the papers indicate that HIV reservoir measurements have some promise for predicting viral load rebound after ART interruption, but uncertainties remain. In both studies HIV DNA assays did not show significant correlations with time to rebound when a lower viral load cut off was used (<50 or <200 compared to <400). The explanation for this finding is unclear, but could potentially relate to greater viral load test result variability at lower copy numbers. The AIDS Clinical Trials Group (ACTG) is now developing a research protocol with the specific aim of identifying biomarkers of viral load control, designated the PR 691 Monitored Antiretroviral Pause [MAP] Biomarker study.
As part of the preparation for this protocol, Jonathan Li has performed an analysis of six prior ACTG trials involving ATIs to gain an understanding of what proportion of individuals are able to maintain undetectable viral loads for an extended period. The results were presented at the IDSA conference last month, showing that overall 6% of 263 participants had levels below 200 copies at week 12 of an ATI. The phenomenon was more common among those treated during acute or recent HIV infection compared to chronically infected individuals. Galit Alter has collaborated with Li to look at possible correlates of control in these study participants, identifying the presence of specific antibody subclasses that are associated with enhanced natural killer cell activity (this preliminary work was presented at the NIAID Strategies for an HIV Cure meeting the week following the IDSA conference). The forthcoming ACTG MAP biomarker study should hopefully be able to build on these findings.
Elife. 2014 Sep 12:e03821. doi: 10.7554/eLife.03821. [Epub ahead of print]
Williams JP, Hurst J, Stöhr W, Robinson N, Brown H, Fisher M, Kinloch S, Cooper D, Schechter M, Tambussi G, Fidler S, Carrington M, Babiker A, Weber J, Koelsch KK, Kelleher AD, Phillips RE, Frater J; on behalf of the SPARTAC Trial Investigators.
In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials.
Elife. 2014 Oct 16;3:e04742. doi: 10.7554/eLife.04742.
Biomarker reveals HIV's hidden reservoir. (open access)
Cockerham LR, Deeks SG.
Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection.
AIDS. 2014 Sep 23. [Epub ahead of print]
Li JZ, Heisey A, Ahmed H, Wang H, Zheng L, Carrington M, Wrin T, Schooley RT, Lederman MM, Kuritzkes DR; the ACTG A5197 Study Team.
OBJECTIVES: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics.
DESIGN: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine.
METHODS: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4/CD8 activity was assessed by an intracellular cytokine staining assay.
RESULTS: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4 interferon-γ producing cells (CA-RNA: r = -0.23, P = 0.03 and CA-DNA: r = -0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4 activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4 and CD8 interferon-γ producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4 cells/10 lymphocytes, P = 0.03 and 1326 versus 669 CD8 cells/10 lymphocytes, P = 0.04). Pre-ATI CA-RNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01).
CONCLUSION: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics.