A study published in Nature Communications has drawn a fair amount of press coverage—and some hyperbolic headlines—by reporting that certain immunological biomarkers may be able to predict the likelihood of maintaining a low viral load after an antiretroviral therapy (ART) interruption.
The research involves a subset of participants from the SPARTAC trial, which randomized individuals with primary HIV infection to one of three arms: no treatment (the standard of care at the time the trial was conducted) or 48 or 12 weeks of ART followed by an interruption (the primary results were published in NEJM in 2013). Drawing on samples from a subset of participants who received 48 weeks of ART, analyses were conducted to assess if there were associations between a multitude of immunological biomarkers and the time it took for viral load to rebound to detectable levels after ART interruption (these analyses were not planned in the original SPARTAC protocol and are thus considered exploratory). Senior author John Frater from Oxford University originally described the work at CROI earlier this year (the webcast of his talk is available online).
The crux of the results is that baseline (pre-ART) levels of three biomarkers linked to T cell exhaustion—PD-1, Tim-3 and Lag-3—were statistically associated with time to viral load rebound to over 400 copies after ART interruption. Participants with baseline levels of these exhaustion biomarkers on CD4 and CD8 T cells that were below the median for the cohort took longer to rebound, on average, compared to those with levels above the median. However, no such association was seen when the biomarkers were measured in samples taken immediately prior to the ART interruption (the only predictor of time to viral load rebound at this timepoint was total HIV DNA, as reported previously).
The researchers suggest that the study represents a step toward the development of biomarker algorithms capable of identifying ideal candidates for ART interruptions, based on the likelihood of post-treatment control of viral load. However, it is a very early step, as is stressed by the UK website NHS Choices, which published a commentary in response to a wildly overstated Daily Mail headline about the paper (“HIV breakthrough could lead to a CURE: Scientists identify markers on immune cells that 'predict who can stop drug therapy and stay well'”). There are also uncertainties as to whether post-treatment control necessarily equates to a state of health equivalent to that obtained by ART-mediated HIV suppression (see “The Challenge of Defining HIV Remission” in the most recent TAGline).
In the discussion section of the paper, the authors note that anti-PD-1 antibodies have shown success as cancer immunotherapies and that there is interest in studying their therapeutic effects in HIV. In laboratory studies, anti-PD-1 antibodies have been shown to stimulate HIV production by latently infected CD4 T cells, and restore functionality to exhausted HIV-specific T cells. There are concerns, however, about the potential for adverse effects, particularly the induction of autoimmune responses (which has been observed in some cancer trials).
The uncertainty about the risk/benefit of anti-PD-1 antibodies in otherwise healthy HIV-positive people has prompted a research team led by Thomas Uldrick at the National Cancer Institute to design a trial that will enroll HIV-positive individuals with relapsed, refractory, or disseminated cancers. The main aims are to evaluate safety and anticancer effects; assessments of the HIV reservoir and HIV-specific T cell immunity are included as tertiary endpoints. The anti-PD-1 antibody that will be administered is pembrolizumab (trade name Keytruda), which recently gained FDA approval for the treatment of certain forms of melanoma and non-small cell lung cancer. With helpfully coincidental timing, the trial was recently entered in clinicaltrials.gov and is due to launch in January.
Nat Commun. 2015 Oct 9;6:8495. doi: 10.1038/ncomms9495.
Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, Meyerowitz J, Willberg C, Koelsch KK, Robinson N, Brown H, Fisher M, Kinloch S, Cooper DA, Schechter M, Tambussi G, Fidler S, Babiker A, Weber J, Kelleher AD, Phillips RE, Frater J.
Treatment of HIV-1 infection with antiretroviral therapy (ART) in the weeks following transmission may induce a state of 'post-treatment control' (PTC) in some patients, in whom viraemia remains undetectable when ART is stopped. Explaining PTC could help our understanding of the processes that maintain viral persistence. Here we show that immunological biomarkers can predict time to viral rebound after stopping ART by analysing data from a randomized study of primary HIV-1 infection incorporating a treatment interruption (TI) after 48 weeks of ART (the SPARTAC trial). T-cell exhaustion markers PD-1, Tim-3 and Lag-3 measured prior to ART strongly predict time to the return of viraemia. These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription. Our results may open new avenues for understanding the mechanisms underlying PTC, and eventually HIV-1 eradication.