Biomarkers predict post-treatment controllers

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Only four individuals out of nearly 5000 people receiving care at US military health facilities were found to exhibit immune control of HIV after starting antiretroviral therapy (ART), achieving viral suppression and interrupting treatment, according to a presentation at the recent IDWeek 2015. A recently published related study identified several biomarkers that may help predict who will be post-treatment controllers, a useful tool for HIV cure research.

Post-treatment controllers are people with HIV who start antiretroviral therapy (in some cases during acute or primary infection), reach a very low or undetectable viral load and then stop treatment, either as part of structured treatment interruption research or for other reasons such as patient choice or loss to follow-up. The French VISCONTI cohort is the most well-known group of post-treatment controllers. Infants treated very early, like the “Mississippi Baby”, seem to be a different phenomenon, as are so-called “elite controllers” who maintain viral control without ever going on treatment.

Matthew Perkins of Walter Reed National Military Medical Centre and colleagues from several other military health facilities around the US aimed to determine how many post-treatment controllers were among participants in the HIV Natural History Study Cohort, which has followed people living with HIV since 1986 at six major military treatment facilities. Participants are seen about once every six months, at which time they have a physical examination, give a sample of blood for viral load testing and their ART regimen is documented.

The researchers retrospectively analysed medical records from 4,685 cohort participants with clade B HIV. The analysis was limited to 3,480 people who had a pre-treatment viral load of at least 1000 copies/ml, indicating that they were not elite controllers. Within this group, 2,115 had been on ART and had suppressed viral load (400 copies/ml) after ART discontinuation. But four individuals maintained viral suppression for six months or more off treatment. Of these, two were classified as “transient controllers”, having viral suppression for at least six months but less than two years, while the other two were “durable controllers”, having suppressed virus for two years or longer.

Three of the people with post-treatment viral suppression were men, all were black and their ages ranged from 21 to 38 years. All had started taking ART during chronic infection, about one to five years after seroconversion. Their pre-treatment viral loads were low: 1,008; 2,011; 35,454; and 46,773 copies/ml. All had viral loads <50 copies/ml at six months after treatment discontinuation.

The two transient controllers maintained viral suppression off ART for approximately nine months (267 days) and about a year and a half (575 days). One durable controller had suppressed virus for nearly three years (1,058 days). The other restarted ART after more than two years (794 days), having not yet experienced viral rebound, because his partner wanted to become pregnant.

“The results of our study are consistent with the rarity of post-treatment controllers reported in the literature,” the researchers concluded. “While our numbers are too small to suggest any associations between demographic characteristics or medical history and post-treatment control, it is interesting to note that all four post-treatment controllers were African American, one had previously been treated for lymphoma, and one was undergoing treatment for hepatitis C.”

They noted that these are the first known reports of post-treatment control in people who started ART during chronic infection – other post-treatment controllers identified to date, including the VISCONTI cohort and SPARTAC participants (see below), started ART very soon after infection.

“The existence of patients who spontaneously control HIV infection suggests that a functional HIV cure may be possible and investigations into these patients’ immunologic characteristics may yield clues to how this could be achieved,” they suggested.

In a related study, Jacob Hurst and John Frater of the University of Oxford and colleagues looked for biomarkers that could help predict post-treatment control. These findings were previously presented in part at this year’s Conference on Retroviruses and Opportunistic Infections (CROI).

The researchers analysed outcomes in the SPARTAC trial, in which people with primary HIV infection either received immediate ART lasting for 12 or 48 weeks, or else deferred treatment until their CD4 count fell below 350 cells/mm3. They found that three markers of T-cell exhaustion – PD-1, Tim-3 and Lag-3 – measured prior to ART initiation strongly predicted the time to viral rebound.

“These data indicate that T-cell exhaustion markers may identify those latently infected cells with a higher proclivity to viral transcription,” the study authors concluded. “Our results may open new avenues for understanding the mechanisms underlying post-treatment control, and eventually HIV-1 eradication.”

“Our work has identified that there are certain markers on the immune cells of patients which seem to help predict who can stop therapy and stay well,” Frater explained. “We hope now to find out more about these markers – and others – to discover if new strategies for treating or even curing HIV might be possible.” “We want to be able to predict how the virus will behave before we take patients off ART to test drug therapies aimed at eradicating HIV,” Anthony Kelleher from the University of New South Wales added.

Abstract 1
Background: Post-treatment controllers (PTCs) are a rare group of HIV-infected individuals with transient (TC) or durable viral control (DC) off antiretroviral therapy (ART) after a period of treatment most commonly initiated during acute HIV infection. Given the durable viral control off ART, these patients are of particular interest for HIV functional cure research. We used data from the US Military Natural History Study (NHS) to assess the prevalence and demographics of PTCs.
Methods: We retrospectively identified patients who had had a set-point viral load (VL) >1000 copies/ml [cpm], achieved virologic suppression [<400 cpm] for ≥48 weeks after initiating ART, who subsequently discontinued ART for ≥ 6 months and had VL determinations available after discontinuation. Subjects with virologic suppression for ≥6 months but <2 years off of ART were considered TC, while DC were individuals with virologic suppression for ≥2 years off of ART. We examined baseline demographics and VL prior, during, and after ART was discontinued.
Results: 27 of the 4623 subjects examined met our screening criteria. 23 of the 27 subjects, who had a median set-point VL of 37061cpm [range: 2645, >75,000], became rapidly viremic within 6 months of ART cessation {median VL 26439 cpm [range: 581, 97387]}. Four subjects met criteria for PTC (2 DC), all 4 were African American, and 3 were male. All four PTCs initiated ART during chronic infection (range: 1.28-5.44 yrs after their estimated seroconversion), their median set-point VL was 21312 cpm [range: 1008, 46773], and VL six months after cessation of cART was <50cpm. The 2 TCs had suppression for 9 and 12 months. While 1 DC had suppression for 35 months, the other suppressed for 26 months before restarting ART (for pregnancy planning) without ever developing a viremia to >400 cpm while off of ART.
Conclusion: We identified 4 PTC in the NHS; the results of our study are consistent with the rarity of PTCs reported in the literature.  Of note, thus far most identified PTCs have initiated ART in the acute stage of infection, while our study reports the first cases of PTC after initiating ART in chronic infection. The identification of PTCs and further inquiry into their immunologic and genetic characteristics will prove important in the search for a functional cure for HIV.

Abstract 2
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.

Aidsmap material
ID Week abstract
Nature Communications abstract

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