DURBAN, South Africa,— Disappointing results from a trial of a latency-reversing strategy for HIV underscore the challenges researchers are facing in their search for a functional cure for the infection, said experts here at the International AIDS Conference 2016.
“This is not like any other infection that we have ever faced,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Disease (NIAID) in Bethesda, Maryland.
“In the end, the body can clear virtually every other virus that attacks the body — even the most serious of infections, like smallpox — and leave a patient with sustained long-lasting immunity,” he said during a news conference at the meeting.
“But we don’t have that experience with HIV, so we have to do things that nature has never done before to eradicate it,” he explained.
One of the main strategies used to try to achieve a classic cure is the so-called “shock and kill” approach.
HIV has a pernicious ability to hole up in latent reservoirs, undetected by normal surveillance mechanisms, Steven Deeks, MD, from the University of California, San Francisco, explained during the news conference. If the pressure from antiretroviral therapy is not there to keep a lid on replication, the virus inevitably rebounds.
Over the years, various latency-reversing agents have been used to “wake” the virus up in its reservoir. Some 20 years ago, Dr Fauci was involved in research in which interleukin-2 was used to try to reconstitute the immune system in patients in whom antiretroviral therapy had been discontinued.
“Despite the reservoir being below detectable levels, there was consistent viral rebound a few weeks after withdrawing ART,” Dr Fauci reported. “So flushing the virus out of the reservoir is going to be very difficult.”
The SEARCH 19 study involved 15 patients in whom the virus had been well suppressed for more than 2 years. For all the patients, antiretroviral therapy had been initiated during acute HIV infection.
SEARCH 19 Trial
Ten patients were randomized to latency-reversing therapy, and received three cycles of vorinostat 400 mg/day (14 days on and 14 days off) plus hydroxychloroquine 400 mg daily and maraviroc 1200 mg daily.
The remaining five patients served as the control group. After 10 weeks, treatment was interrupted in both groups.
One of the two patients in the latency-reversing group who developed serious adverse events dropped out of the study because of toxic effects.
Median time to viral-load rebound was 22 days. Time to first viral-load detection was the same in the two groups.
However, there were no instances of virologic failure in either group, and upon the reintroduction of treatment, repression of viral load occurred very quickly, reported Jintanat Ananworanich, MD, PhD, from the Thai Red Cross AIDS Research Centre in Bangkok.
Clearly, a new strategy to reduce or eliminate HIV in reservoirs is needed, said Dr Ananworanich. As was shown in the case of the now-famous Berlin patient, it is possible to clear HIV from reservoirs, but extreme measures are needed.
The HIV-infected Berlin patient received an allogeneic stem cell transplant for the treatment of leukemia. It turned out that the donor carried a mutant variant of the CCR5 gene, and the patient became refractory to HIV infection in the absence of antiretroviral therapy.
Stem Cell Transplantation
The EpiStem consortium was created to capitalize on this unique experience and to provide guidance to clinicians caring for HIV-infected patients who undergo stem cell transplantation for the treatment of a hematologic malignancy.
Preliminary findings from an observational study, indicating that the procedure can lead to steep decreases in HIV reservoirs, were presented by Annemarie Wensing, MD, from University Medical Center in Utrecht, the Netherlands.
To date, 15 HIV-infected patients with concurrent malignancy have undergone stem cell transplantation, and many received the same type of procedure as the Berlin patient. For ethical reasons, antiretroviral therapy has been continued in all patients.
In the six patients who are still alive, ultrasensitive HIV DNA viral quantification has shown a systemic reduction in HIV reservoirs to very low levels.
“In two cases with long-term follow-up, we were unable to detect infectious virus in blood, independent of the CCR5 status of the donor,” Dr Wensing reported. “And in tissue, only traces of HIV DNA could be detected.”
The greatest hope for a functional cure might be in infants and children.
Although infants infected with HIV at birth still need some sort of immune system enhancement, the fact that physicians usually know when an infant is infected means that treatment can be initiated immediately, when children have naïve T-cells, which might be harder for HIV to infect.
In addition, “the child’s developing immune system may make it harder for HIV to replicate and hide in the body,” Dr Ananworanich reported.
And because “children are more able to make new immune cells than adults, they might be able to respond better to a vaccine or immune therapy,” he added. “As a pediatrician, I am hopeful for these children.”
Sustained Virologic Remission
Working toward sustained virologic remission might be more successful, and more feasible, than the shock and kill strategy.
“We know that the body does not make an adequate immune response against HIV,” said Dr Fauci.
The chances for sustained virologic remission are better when patients are treated when they have a small HIV reservoir and a competent immune system. This constellation of factors is most likely to be seen immediately after a diagnosis of HIV.
Ideally, a therapeutic vaccine could be used to prime the immune system to stand on guard against HIV replication.
A trial in which a therapeutic vaccine was compared with placebo has been conducted, but the data have yet to be analyzed, Dr Fauci reported.
Passive immunotherapy, where broadly neutralizing HIV-specific antibodies are periodically infused to control the virus, could be another way to boost the immune response to HIV.
One such study, which involved ten patients with chronic HIV infection who had been well suppressed for more than 3 years, was conducted by NIAID researchers.
All received infusions of the broadly neutralizing HIV-specific antibody VRCO1 3 days before and 14 and 28 days after the interruption of antiretroviral therapy, and for 7 months thereafter, Dr Fauci explained.
“Ultimately, everybody rebounded,” he reported, but the time from discontinuation of antiretroviral therapy to rebound was extended.
Median time to plasma viral rebound was 39 days in the VRCO1 patients, whereas in historic control subjects, the interval ranged from 11 to 28 days.
Although it was “very limited,” there was an increase in time to viral rebound, Dr Fauci said. The use of more potent antibodies, vector-based antibody expression, or combinations of antibodies might improve the success of this approach, he pointed out.
CRISPR Gene Editing Tool
State-of-the-art CRISP/Cas9 gene editing techniques might enable researchers to create a cellular environment that is incompatible with HIV replication. The permanent silencing of the HIV provirus, and therefore its ability to replicate, could allow HIV-infected patients to discontinue antiretroviral therapy.
“Combination antiretroviral therapy can profoundly control viral replication, but conventional treatment lacks the ability to stop viral production and clear the latent reservoir, which remains the major obstacle toward cure,” explained Monique Nijhuis, MD, from University Medical Center in Utrecht.
The CRISPR system involves the use of endonuclease, which can digest double-stranded DNA, much like scissors, and guide RNA, which is a small string of nucleotides that are identical to the sequence that researchers specifically want to target, such as HIV DNA.
“We have designed several guide RNA sequences targeting different regions of the viral genome and steps in the viral lifecycle,” Dr Nijhuis told Medscape Medical News. “And we showed that some of the guide RNAs in combination with the scissors are more potent than others.”
The researchers demonstrated that the use of single guide RNA and scissors is not very effective because the virus can rapidly escape. However, they also demonstrated that the combination of two potent HIV guide RNAs and scissors can prevent viral replications and could become a promising tool in the control of HIV infection, she explained.
In the meantime, cure research must always take ethical issues into account, and progress must be balanced against the potential harm treatments can cause HIV-infected people who are essentially well.
“We want to make sure that what we are doing for cure is better for the patient than what they are already receiving,” Dr Fauci cautioned.
“We have got to push for a cure, but it’s got to be safe, it’s got to be less toxic than what the person is already on, and it needs to be scalable to a large number of people,” he said.
Dr Ananworanich reports receiving travel support from Cooper Human System and honoraria from ViiV Healthcare and Merck. Dr Fauci and Dr Nijhuis have disclosed no relevant financial relationships.
International AIDS Conference 2016. Abstract LBPE005, to be presented July 19, 2016; Abstract THAA0105, to be presented July 21, 2016; Abstract WEPEA022, to be presented July 19, 2016.
By Pam Harrison