A news release issued today by the National Institute of Allergy and Infectious Diseases (NIAID) reports the disappointing news that viral load has rebounded in the child in Mississippi who had been considered possibly cured of HIV infection. The child is now nearly four years of age and HIV had remained undetectable without treatment for over two years, but recent routine laboratory testing revealed a viral load of 16,750 copies that was confirmed 72 hours later with a second measurement of 10,564 copies. HIV-specific antibodies are also now detectable and CD4 T cell numbers have declined. The child has been restarted on antiretroviral therapy and is said to be responding well. Genetic sequencing was used to establish that the rebounding HIV was derived from the virus present in the mother.
The news obviously has implications for the IMPAACT trial mentioned in my last blog post, but it is not yet clear what the effect on the trial will be; the NIAID release simply states: “the researchers planning the clinical trial will now need to take this new development into account.” In an interview with Forbes, Daniel Kuritzkes notes that the first goal of the trial is the initiation of early treatment in HIV-infected newborns and decisions about whether to interrupt ART will not be made until later.
The outcome in the Mississippi baby case suggests that early HIV treatment greatly reduced the number of latently infected cells, but some remained present and ultimately rekindled viral replication. There are parallels with the two adults known as the Boston patients, whose latent HIV reservoirs were significantly reduced by stem cell transplant procedures, leading to an extended delay in viral load rebound after stopping ART (but not a cure). The idea that reducing the number of latently infected cells can lead to a delay in reappearance of viral load after ART interruption has recently been proposed by Alison Hill and colleagues from the laboratory of Robert Siliciano. Hill’s mathematical modeling work was presented at CROI 2013 and has since been published in Quantitative Biology (see abstract and link to free full text PDF below). The results indicate that large reductions in the latent HIV reservoir can delay viral load rebound for many years or even decades. To completely prevent viral load rebound in most individuals, Hill estimates that a greater than six log (million-fold) diminution of the HIV reservoir would be required. The findings argue that in cases where HIV does not rebound after ART interruption, extremely long-term follow-up will be required in order to ascertain if a cure has been achieved.
Alison L. Hill, Daniel I. S. Rosenbloom, Feng Fu, Martin A. Nowak, Robert F. Siliciano
(Submitted on 17 Mar 2014)
Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4+ T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that approximately 2,000-fold reductions are required to permit a majority of patients to interrupt ART for one year without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the lab to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients.