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Early ART led to long-term remission after treatment discontinuation
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A group of 14 patients with HIV experienced long-term infection control upon discontinuing treatment after starting antiretroviral therapy early during primary HIV infection, researchers from France reported.
“Although in most cases, these advantages wane soon after treatment interruption, the existence of individuals in whom the viral load remains undetectable for several years after interruption of prolonged therapy that was initiated very early after infection (post-treatment controllers) was reported in 2010,” the researchers wrote in PLoS Pathogens. “These individuals hold important clues in the search for a functional HIV cure.”
All of the patients were diagnosed with primary HIV infection in the late 1990s or early 2000s. They received the standard ART and had an undetectable viral load within a median of 3 months. The median treatment duration was 36.5 months. All but two patients experienced an increase in CD4+ T-cell counts before treatment interruption. After treatment interruption, viral control continued for a median of 89 months and the CD4+ T-cell counts remained stable.
The researchers compared the post-treatment controllers with spontaneous HIV controllers, patients with uncontrolled viremia and patients receiving ART. Among the post-treatment controllers, there was a higher prevalence of risk alleles HLA-B*07 and HLA-B*57, but little presence of the protective alleles HLA-B*27 and HLA-B*57. The post-treatment controllers also had weak HIV-specific CD8+ T-cell responses.
“Here, we show that in some HIV-infected individuals with symptomatic primary infection and no favorable genetic background, off-therapy viral control for several years may be associated with a very early and prolonged antiretroviral treatment,” the researchers wrote. “These findings argue in favor of early ART initiation and open up new therapeutic perspectives for HIV-infected patients.”
Disclosure: The researchers report no relevant disclosures.
Perspective
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W. David Hardy, MD
There has been great attention surrounding the case of the baby that seems to have been cured of HIV infection, following mother-to-child transmission (reported at the 2013 Conference on Retroviruses and Opportunistic Infections) and this report of 14 cases from the VISCONTI cohort. Both have focused on the latently-infected viral reservoir —HIV-infected cells that aren’t actively replicating, and therefore are not affected by antiretroviral therapy. This reservoir typically contains about one million cells, which we believe is the “final frontier” that we much eradicate for someone to be functionally cured and be able to live without needing continuous lifelong treatment. These recent data, both from the VISCONTI cohort and the baby, seem to indicate that if we treat people very early in the course of HIV infection, with potent ART long enough to clear the actively-replicating virus, we may, at least in certain cases, be able to cure the newly-infected person. For reasons that remain to be discovered, the latently-infected reservoir in these patients seems to be smaller or made up of different kinds of immune cells, compared to the latently-infected reservoir in almost all chronically-infected persons. Thus, the remaining, residual virus that can’t be eradicated with ART, is small enough or is in different cells and can be eradicated. In the case of the baby, this reservoir was probably formed, but was so small or was present in such immature immune cells that within the 15 to 18 months of treatment the baby received, the reservoir was purged.
In this study, the 14 VISCONTI patients all received ART during primary HIV infection (within 6 months of the estimated initial exposure). When they stopped treatment, they all had viral control for a median of at least 89 months. What was so interesting about this study is that when these post-treatment controllers (PTCs) were compared with a group of eight spontaneous (without receiving ART) HIV controllers (HICs) from the PRIMO cohort, significant differences, but also some similarities were found. The researchers found, curiously, that the 14 PTCs did not have any of the usual good prognostic indicators that characterized the HICs. Twelve of the PTCs experienced a symptomatic acute retroviral illness, which generally is a poor prognostic sign. The PTCs also had high viral loads and low CD4+ T cell counts before they began medication, which are also typically poor prognostic indicators. In addition, the HICs exhibited similar HLA genotypes that are commonly associated with HIV control (HLA B*57 and B*27). In the PTCs, it was just the opposite. They exhibited low frequencies of these protective HLA genotypes and, in fact, had high frequencies of HLA genotypes associated with rapid HIV progression (HLA B*07 and B*35). But where the two groups were similar, which may be a major piece of the HIV “functional cure” puzzle, is that the latently-infected viral reservoirs in the patients in both cohorts were small. This raises the question: How did these patients, who had all of the poor prognostic indicators, actually do very well? This paper suggests that perhaps it was the early initiation of potent combination ART that protected their immune cells from the virus, so that the formation of the viral reservoir was minimized. A small viral reservoir seems to be the consistent theme among the baby at CROI, the VISCONTI PTCs and the PRIMO HICs. These data seem to be telling us that it’s the size of the reservoir, and the characteristics of the T cells that make up the reservoir, that probably determine whether a functional cure can be accomplished.
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