Post-treatment control of HIV appears rare, biomarkers may help predict viral rebound

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 IDWeek 2015 last month in San Diego. 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 Center 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.

Glossary

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

biomarker

Genes, proteins or chemicals that can act as signals for certain diseases.

elite controllers

A small subset of people living with HIV who are able to control HIV replication in the absence of antiretroviral treatment for an unusually long period of time (also known as HIV controllers). However, because HIV continues to replicate even in elite controllers, ART is recommended for elite controllers who have declining CD4 counts or who develop HIV-related complications. Around half of elite controllers can also be described as long-term non-progressors. 

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

The researchers retrospectively analysed medical records from 4685 cohort participants with clade B HIV. The analysis was limited to 3480 people who had a pre-treatment viral load of at least 1000 copies/ml, indicating that they were not elite controllers. Within this group, 2115 had been on ART and had suppressed viral load (<400 copies/ml) for at least two years. Of these, 85 stopped ART and had an available viral load measurement done at least 30 days after treatment discontinuation.

Among the 85 people who stopped treatment, 81 experienced rapid viral rebound (>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: 1008; 2011; 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 (1058 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.

Biomarkers for post-treatment control

In a related study, published in the October 9 edition of Nature Communications, 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 in a University of Oxford press release. “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 in a separate press release.

References

Perkins M et al. Post-treatment control of HIV infection in an early diagnosed well-characterized military cohort of chronically HIV-1 infected subjects. IDWeek 2015, abstract 1072, 2015.

Hurst J et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nature Communications 6:8495, 2015.