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HIV remission: more clues, but still many questions

, by Liz Highleyman

HIV scienceResearchers have explored a variety of approaches for achieving a functional cure for HIV. Most experts agree that complete eradication of HIV from the body will be very difficult—or even impossible. But a functional cure, or long-term remission, could allow people with HIV to stay off of ART for prolonged periods without the harmful consequences of viral replication.

Long-term HIV remission was among the themes at the International AIDS Society Conference on HIV Science, held in July in Paris. Researchers reported on a child who has maintained viral suppression for more than eight years after stopping antiretroviral therapy (ART), as well as a man who had delayed viral rebound after interrupting very early treatment. A third study showed that the broadly neutralizing antibody VRC01 could delay viral rebound following ART interruption in people who started treatment very early.

Prior research has shown that people who start antiretroviral treatment very early have a smaller latent HIV reservoir, as well as a less diverse set of HIV types, giving them a better chance of achieving viral remission.

A child, born with HIV, now in HIV remission

Avy Violari, MD, of the University of the Witwatersrand in Johannesburg presented the case of a South African child who started ART as a baby and has maintained viral suppression off of ART for eight and a half years after stopping treatment.

In 2007 the girl received a confirmed diagnosis of HIV infection at the age of one month and started ART about a month later as part of the CHER trial, which compared early treatment strategies for infants. She was randomly assigned to receive lopinavir/ritonavir (Kaletra), zidovudine (AZT), and lamivudine (3TC) for 40 weeks.

After starting ART the girl’s viral load went from a high level (more than 750,000 copies/mL at 39 days old) to below 50 copies/mL, and it fell further, to less than 20 copies/mL, after she stopped ART. She received blood tests every three months for four years to monitor CD4 levels, which remained high. A later analysis of the stored blood samples showed that her viral load remained undetectable during this time.

A more extensive evaluation at age 9.5 showed that the girl had evidence of HIV DNA in a small number of immune cells. This means that the girl had a small and stable viral reservoir. She also had weak HIV Gag-specific CD4 cell responses but not CD8 killer T-cell responses, which may indicate the presence of a small amount of hidden virus. The girl showed no evidence of replication-capable HIV.

This case is similar in some respects to that of the Mississippi Baby. In that case, an infant born to an HIV-positive mother was started on a full ART regimen about 30 hours after birth. After a year on treatment with good viral suppression, she was temporarily taken off treatment by her caregivers. When she was brought back for care at age two, her viral load was still undetectable despite being off ART for several months.

Extensive testing failed to find replication-competent HIV after two years off treatment, leading many to hope that the girl had been cured. But eventually her virus rebounded and she was put back on treatment.

Another related case involved a young woman who was infected with HIV at birth and received very early ART. Again, the child was taken off treatment around age six, and when she returned to care her viral load was undetectable despite being off ART. She has since stayed off treatment and was still maintaining viral suppression at age 18.5, according to a 2015 conference report.

The new case offers further evidence that although early time-limited treatment of children may not cure HIV, it can potentially lead to long-term remission.

“[T]his new case strengthens our hope that by treating HIV-infected children for a brief period beginning in infancy, we may be able to spare them the burden of life-long therapy and the health consequences of long-term immune activation typically associated with HIV disease,” said Anthony Fauci, MD, of the National Institute of Allergy and Infectious Diseases, which sponsored the CHER trial.

HIV remission after PrEP

Timothy Henrich, MD (Photo: Liz Highleyman)

Timothy Henrich, MD (Photo: Liz Highleyman)

Timothy Henrich, MD, of the University of California at San Francisco (UCSF) reported on another case of long-term HIV remission occurring under unusual circumstances.

This case involved a gay man who joined a pre-exposure prophylaxis (PrEP) trial, tested HIV-negative using the usual tests, and began taking Truvada (tenofovir/emtricitabine). However, it was soon determined that he had been infected very recently, before starting PrEP. He then started a complete multidrug ART regimen while still in the “hyperacute” phase, around 10 days after infection.

After nearly three years on treatment, the man showed no evidence of HIV in his blood and body tissues, and had no HIV DNA in his T-cells. The researchers estimated that his latent viral reservoir might have consisted of only around 200 cells.

At that point the man opted to try a carefully monitored treatment interruption. He maintained an undetectable viral load for just over seven months, but ultimately he did experience viral rebound, with a high viral load, and successfully restarted treatment.

“Very small numbers of infected cells following very early ART may prolong ART-free remission,” Henrich’s group concluded.

It remains unclear why a small proportion people are able to maintain HIV suppression off of ART, Fauci told reporters. It may have to do with an individual’s particular virus or the types of immune responses they are able to generate. But early treatment appears to be an “important common denominator” because it keeps the viral reservoir small, he said. 

“From a cure perspective, the biggest story at the conference was proof that very early antiretroviral therapy is not curative, but that early ART—but perhaps not too early—can lead to a remission in some people,” said study co-investigator Steven Deeks, MD, of USCF. 

Can antibodies prolong HIV remission? 

Another conference presentation showed that a broadly neutralizing antibody could delay the return of viral replication following ART interruption in people who started treatment very early, but it ultimately did not prevent viral rebound.

Trevor Crowell, MD (Photo: Liz Highleyman)

Trevor Crowell, MD (Photo: Liz Highleyman)

Trevor Crowell, MD, of the U.S. Military HIV Research Program presented findings from a study of VRC01, a monoclonal antibody that targets HIV’s CD4 binding site, preventing the virus from latching on to susceptible CD4 cells.

The RV397 study included 18 men in Thailand who started ART during acute infection and had undetectable viral load on treatment for at least two years.

Participants were randomly assigned to receive intravenous infusions of VRC01 (13 men) or placebo (five men) every three weeks; they stopped ART at the time of their first infusion. Treatment with VRC01 continued for 24 weeks, and at that point those who still had viral suppression could continue observation without further treatment for up to 24 more weeks.

To minimize the risks of treatment interruption, study participants were monitored every three to seven days and ART was restarted if they had a confirmed viral load above 1,000 copies/mL, their CD4 count fell below 350 cells/mm3, or they showed signs of clinical disease progression.

Participants who received VRC01 showed a “modest” delay in viral rebound, according to Crowell. A majority of VRC01 recipients reached the viral load threshold for resuming ART within three to five weeks, while most placebo recipients experienced viral rebound within one to three weeks. The median time to rebound was 26 days in the VRC01 group and 14 days in the placebo group.

One man in the VRC01 group maintained undetectable viral load through 42 weeks. This 24-year-old gay man started ART during Fiebig stage III and had undetectable viral load for about three years on a regimen of tenofovir, lamivudine, and efavirenz. However, he had his first detectable HIV RNA measurement just days before the presentation, Crowell reported.

The results from this study show that VRC01 alone is unable to maintain viral suppression after stopping ART, but it may play a role in a combination strategy for achieving long-term HIV remission.

Sources: 

Violari A et al. Viral and host characteristics of a child with perinatal HIV-1 following a prolonged period after ART cessation in the CHER trial. IAS 2017. Abstract TUPDB0106LB. 

Henrich T et al. Prolonged HIV-1 remission and viral rebound in an individual treated during hyperacute infection. IAS 2017. Abstract TUPDB0103.

Crowell T et al. HIV-specific broadly-neutralizing monoclonal antibody, VRC01, minimally impacts time to viral rebound following treatment interruption in virologically-suppressed, HIV-infected participants who initiated antiretroviral therapy during acute HIV infection. IAS 2017. Abstract TUAB0106LB.

Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.

 

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