Progress on Prevention and Cure

The 21st edition of the Conference on Retroviruses & Opportunistic Infections brought encouraging news on several fronts.

The data presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI), which attracts thousands of HIV clinicians and researchers, always draws headlines. And this year was no exception. The 2014 CROI, held March 3-6 in Boston, Massachusetts, brought news of a possible second case of a US baby cured of HIV infection by incredibly early initiation of antiretroviral therapy (ART). There was also an update on the first possibly cured baby in the US, now an almost three-and-a-half year old who still remains HIV free without treatment.

While this news stoked enthusiasm over HIV cure research, the field also received sobering news that suggests the road to curing HIV may be a long and arduous one.

In the prevention realm, three studies of long-acting antiretrovirals (ARVs) offered hope of more user-friendly pre-exposure prophylaxis (PrEP) options—the use of ARVs in uninfected individuals to prevent HIV acquisition. Other evidence emerged suggesting that suppression of virus by ART in HIV-infected individuals massively reduces, or even obliterates, the risk of HIV transmission. Vaccines contributed only quietly to the busy symphony of science this year, primarily through the incremental advances reported in the accelerating quest to induce antibodies capable of inactivating or neutralizing many HIV variants, so-called broadly neutralizing antibodies (bNAbs).

Baby makes two?

The headlines from last year’s CROI were dominated by the report of an infant from Mississippi who may have been cured of HIV infection as a result of receiving ART soon after birth. This year, Deborah Persaud, associate professor of pediatrics at Johns Hopkins University School of Medicine, reported that this now 41-month-old child has been off ART for close to two years, and yet continues to have either undetectable or such low levels of HIV that it borders on the limits of extremely sensitive tests. Still, Persaud characterized this outcome not as a cure, but rather as ongoing “remission” of HIV infection.

Persaud also presented on another baby that may be in a similar situation. At the time of delivery, the second baby’s mother had rather advanced HIV infection and she had not adhered to a prescribed ART regimen. Although ART was administered to the mother during labor, the baby was ascertained to be HIV infected at four hours after birth. Based on knowledge of the Mississippi baby, the infectious disease specialist treating the newborn instituted a three-drug ART regimen immediately, which was supplemented with an additional ARV two weeks later. The infant is now nine months of age and remains on a three-ARV regimen.

However, the possibility of a cure is suggested by the results of analyses showing that the baby’s viral load—a measure of the amount of virus in a sample of blood—was persistently undetectable after 11 days. Multiple other tests to find HIV were also negative and the infant now tests negative for HIV antibodies. Given these results, doctors are considering interrupting ART in this baby if HIV remains undetectable at two years of age.

In addition to the excitement generated by these reports, a poster presentation about a possible adult equivalent also drew much attention. The case report by Hiroyu Hatano, assistant professor of medicine at the University of California-San Francisco School of Medicine, involved a man who was recruited into a PrEP demonstration project in San Francisco and acquired HIV infection during the 13-day interval between his last screening visit and the initiation of the ARV Truvada for PrEP.

A baseline sample taken on the day he started Truvada showed he had a viral load of 220 copies of HIV/ml of blood. As soon as this result became available, seven days later, he was switched from Truvada to a conventional multi-drug ART regimen. His viral load at the time of the switch was 120 copies and was followed by a reading of “detected,” but below 40 copies after 22 days. All subsequent viral load tests have been negative, and no HIV can be detected now. A treatment interruption is planned after one year to assess if this man’s infection may have been cleared.

In the vast majority of cases, where HIV is not cleared so dramatically, early treatment may still have benefits in reducing the long-lived hideouts of HIV that form quickly after infection, and remain the biggest obstacle to a cure. Persaud emphasized that children and adolescents who receive early ART are good candidates for inclusion in cure research studies because the number of HIV-infected cells that remain latent in the body and would need to be cleared to achieve a cure is likely very small.

The Boston patients

While all this news was encouraging, other research presented at CROI by Timothy Henrich, associate physician at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, should give pause to anyone inclined to assume that the absence of detectable HIV equates to a cure.

Henrich previously reported on two HIV-infected individuals from Boston, who after receiving stem cell transplants to treat cancers while on continuous ART showed no measurable levels of virus over a period of several years. Last spring, after ART was interrupted in both individuals under a careful research protocol involving monitoring for viral load rebound every one to two weeks, early signs were promising as multiple tests continued to find no detectable HIV. But after three months, one individual had detectable virus that rapidly increased in just three to four days.

HIV remained undetectable in the second individual for a longer period of time after interrupting ART—eight months as opposed to three—but about a week after the last negative HIV test, symptoms of acute HIV infection developed and viral load was measured at just under two million copies. ART was immediately restarted.

Henrich highlighted several lessons from these data, including that despite the potential risks, analytical ART interruptions followed by long-term clinical monitoring represent the only definitive means for establishing whether a cure of HIV infection may have been obtained.

PrEP with long-acting ARVs

Last year at CROI, results from an experiment in monkeys offered an encouraging indication that a long-acting ARV called GSK744, an analog of the ARV dolutegravir that is approved by the US Food and Drug Administration for therapy, could also have a future as an intermittently administered drug for PrEP. Both dolutegravir and GSK744 are so-called integrase inhibitors that work by blocking the enzyme that HIV uses to integrate its genetic material into a cell’s genome—an early and vital step in the virus’s replication process. This year, three new studies bolstered the possibility that GSK744 may work for preventing HIV infection, generating considerable excitement and a slew of mainstream media stories.

Chasity Andrews, a postdoctoral fellow at the Aaron Diamond AIDS Research Center in New York City, who presented the first monkey study of GSK744 for PrEP last year, described new work that aimed to establish the minimum drug levels that would be protective against rectal infection with a hybrid simian/human immunodeficiency virus (SHIV) in monkeys. Based on her results, Andrews was able to conclude that protective concentrations can be achieved by quarterly injections of the drug, administered by two shots, one into each gluteal muscle. A Phase II safety and tolerability trial of this drug as PrEP in high-risk men who have sex with men (MSM) is slated to start this spring.

J. Gerardo Garcia-Lerma, a research microbiologist at the US Centers for Disease Control and Prevention, debuted findings from a study exploring the efficacy of GSK744 against vaginal transmission in monkeys. In Garcia-Lerma’s study, all six female pigtailed macaques that were given monthly injections of GSK744 over a three-month period were protected against a low-dose, intra-vaginal SHIV challenge. Garcia-Lerma concluded that these results strongly support further efforts to establish the efficacy of GSK744 for PrEP in women.

In a complementary poster presentation by Andrews’s group, protection against a single, high-dose, intra-vaginal SHIV challenge was also reported in six of eight monkeys that received GSK744 and were treated with the injectable hormonal contraceptive Depo-Provera, which thins the cervicovaginal epithelium and mimics the most vulnerable phase of the menstrual cycle.

The development of long-acting ARVs that could represent potentially more user-friendly PrEP options is timely given that several trials have recently found that PrEP recipients appear to struggle with adherence to daily regimens. “Daily dosing is burdensome to the user,” said Ariane van der Straten, director of the Women’s Global Health Imperative at RTI International, an independent, nonprofit institute.

Zeroing transmission

While it’s now well accepted that ART reduces the risk of sexual transmission of HIV, it is unclear how protective ARVs are if condoms aren’t used. The PARTNER study, which has recruited over 1,000 discordant couples (in which one individual is HIV infected and the other is not) at 75 European clinical trial centers, was designed to address this question and interim results were presented at CROI.

Alison Rodger, senior lecturer and honorary consultant in Infectious Diseases, Infection & Population Health at University College London, described data from 767 eligible couples. Of these, 282 were MSM, 245 were heterosexual couples in which the female partner was HIV infected, and 240 were heterosexual couples in which the male partner was HIV infected.

Among the 767 couples, there were zero documented transmissions from HIV-infected individuals on suppressive ART to their uninfected partners, even in the absence of condom use. However, Rodger stressed that the limited duration of follow up—an average of around a year per couple—still leaves some uncertainty. She said the data are compatible with up to a four percent risk of transmission over 10 years for any sex, or a 10 percent risk over 10 years for anal sex. The PARTNER study is now being extended until 2017 for the MSM couples in order to try to collect more precise data.

Advancing vaccine research

HIV vaccine researchers recently overcame one of the major roadblocks to the development of vaccines that can induce antibodies that can effectively neutralize or inactivate the virus. This advance was creating a stable version of HIV’s cagey outer protein, known as the envelope trimer (see VAX Nov. 2013 Spotlight article, Barcelona, in Essence). Accurately recapitulating this critical component of HIV, the target of bNAbs, has been enormously challenging, with many attempts resulting in disappointment. Recreating a stable HIV trimer was, loosely speaking, the biochemical equivalent of baking a soufflé—researchers would think they had succeeded only to have it collapse into disarray the moment it was removed from the oven.

The hope is that this new trimer protein structure, known as BG505 SOSIP.664, developed by the laboratory of John Moore, professor of microbiology and immunology at Weill Cornell Medical College, will provide a better platform for the design of vaccine antigens—the main ingredients of a vaccine that induce an immune response. Early studies using BG505 SOSIP.664 to immunize rabbits suggest there is still a long way to go. “We haven’t gotten anywhere close to where we want to get,” said Moore.

But based on a retrospective analysis comparing the new trimer proteins to previous trimer antigens, it appears researchers are on the right track. Efforts are now underway to try to improve the immune responses induced by BG505 SOSIP.664, as well as to develop other trimer proteins based on different versions of HIV so that they can be tested in combination and hopefully induce a broader neutralizing antibody response.

This article was adapted for VAX by Kristen Jill Kresge, based on a feature in the forthcoming edition of IAVI Report by Richard Jefferys, coordinator, Michael Palm Basic Science, Vaccines & Prevention Project at the Treatment Action Group.