Cure or Remission—What’s in a word?
Positively Aware Jeff Berry
By Jeff Berry @paeditor

Progress toward a cure continued at this year’s International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment, and Prevention. Eradication of the virus from the body will be difficult if not nearly impossible to achieve, but remission (defined as HIV remaining in the body but viral load is undetectable in the absence of antiviral therapy, or ART), is possible and likely much more attainable. With one case of remission discovered in an HIV-positive teenager in Paris who has been off ART for 12 years and remains undetectable, research continues to adapt in this ever-evolving area of science.

In an outstanding plenary overview of cure research to date, Nicholas Chomont, Ph.D., outlined how HIV hides in reservoirs found in the brain, lymphatic system, gut, and genital tract even when a patient is on treatment and undetectable. Mechanisms of viral persistence include the active reservoir where there is residual replication such as in the tissue; the latent reservoir found in memory CD4 T-cells; and T-cell proliferation, which is a major mechanism of viral persistence (proliferation, or increase, of T-cells is part of homeostasis, a process of the immune system which keeps the individual components in balance over a person’s lifetime).

Chomont put forth two main cure strategies currently being pursued. The first would be to limit the establishment of the reservoir in the first place, such as with a vaccine prior to exposure or ART during early or acute infection. The second strategy would be to reduce or limit the reservoir in chronic infection, by either rendering the uninfected cells resistant to HIV; depleting the reservoir cells (such as with the drug auranofin); or flushing out the reservoir (shock and kill).

The latest strategy, which was presented at this conference, is silencing the reservoir or putting it into a deep sleep, so that it never awakens (as opposed to shock and kill).

In a study presented at CROI earlier this year, those treated early during infection had a smaller active reservoir, which predicted a longer time to viral rebound once ART was stopped. This is important, and has been described by leading researcher Sharon Lewin and others as the holy grail of cure research. Being able to predict the time to viral rebound, and the ability to extend that, will be crucial when performing treatment interruptions in HIV-positive adults. A structured, or analytical, treatment interruption is so far the only way to measure whether or not the strategy or method you are testing is actually working in the absence of ART, which of course is the ultimate goal in HIV remission or cure—being and staying off ART while maintaining viral control. Combinations of treatments and/or strategies will ultimately be needed to reach that goal.

At this conference there was one highly publicized case of prolonged remission in a young woman, 18 years old, who was born with HIV and has had undetectable virus (less than 50 copies) for 12 years after stopping therapy. She did experience a blip upwards measured at 515 when she was 12.

According to the IAS organizers the case, presented by Asier Sáez-Cirión of the Pasteur Institute in Paris, was “the first evidence that long-term HIV remission is possible in a perinatally infected child who received early treatment.”

In their report, the researchers said this was the first evidence that “very long-term” remission was possible in these children. They also noted that the case study shows it’s possible to have similar characteristics as reported in adult post-treatment controllers. Dr. Sáez-Cirión noted that the girl has none of the genetic factors typically associated with those who naturally control the virus.

The young woman’s mother had uncontrolled virus with a very high viral load at the time of birth and the baby was given AZT for prevention. After she was found to have HIV herself, she was put on combination therapy at three months of age. Her family stopped her therapy, however, when she was around age six.

During the first 500 days of life the infant had several blips in her viral load. Is it possible that these blips could have induced or elicited a response from the developing immune system that contributed to her remission? Was it the treatment she received, her genetic profile, or because the child was still developing her immune system? While we can’t know for sure, HIV physician and leading researcher Dr. Stephen Deeks stated during a press conference that we need to look at all of these possibilities.

The IAS is currently rewriting their Towards an HIV Cure Strategy, first introduced in 2012, and it will be presented at the International AIDS Conference in Durban, South Africa next year.

Starting treatment, new drugs, and prevention

 by Enid Vázquez

Final data from the SMART study confirmed previous results trumpeted around the world: starting HIV therapy sooner provides significant health benefits, regardless of how strong the person’s immune system is (basically, how high their T-cell count). A person’s chance of staying healthy and living longer more than doubles with immediate treatment. Moreover: if treatment is delayed, the risk of other diseases (cancer was the most common) doubles.

When to Start? NOW

For years there’s been debate about how soon to start therapy, but other data in addition to SMART have shown the benefits of starting earlier rather than waiting. Many experts—and treatment guidelines—have adopted the position that, in general, people should start treatment as soon as they’ve been diagnosed if they can—that is, have access to treatment, are ready to adhere to therapy, etc.

“IAS 2015 will be remembered as the definitive moment when the world agreed earlier initiation of treatment is the best way to preserve the health of people living with HIV, and one of the best tools we have to slow HIV transmission to others,” said Julio Montaner, MD, in a press release. Dr. Montaner was the IAS 2015 Local Co-Chair and is Director of the British Columbia Center for Excellence in HIV/AIDS. “The new data presented [here] will inform HIV treatment guidelines worldwide, and inspire governments, funders, and health systems to act to save millions more lives.”

Treatment prevents transmission

Serodiscordant couples—in which one partner is HIV-positive—were able to significantly reduce the risk of transmission out to 10 years when the positive partner had undetectable virus while on therapy, according to the large, landmark international study HPTN 052. “The new data confirms the significant ‘treatment as prevention’ benefit to early ART [antiviral therapy] for HIV prevention that was previously reported in 2011,” the IAS 2015 organizers noted in a press release. Although no linked transmissions were seen within the couples when the positive partner had undetectable viral load, researchers cannot put the risk at zero.

Doravirine

An HIV medication still in development, doravine continued to do well in early 24-week results against efavirenz (Sustiva, which is contained in Atripla).

Both medications are from the same drug class, non-nucleoside reverse transcriptase inhibitors (NNRTIs). As a new drug, doravirine may still work for people who have developed resistance to efavirenz or rilpivirine. Rilpivirine (Edurant) is also an NNRTI, and is found in Complera.

Viral load results were the same for both groups, but there were fewer discontinuations in the study with doravirine: 4.6% of people given the newer drug vs. 12% for those on efavirenz.

The researchers noted that “the common NNRTIs are associated with suboptimal efficacy and/or safety profiles,” with rilpivirine use restricted to people with lower viral loads (of less than 100,000) and efavirenz leading to “frequent CNS [central nervous system] adverse events,” and neither drug is recommended under current U.S. guidelines for first-time treatment of HIV.

Maturation inhibitor BMS-955176

BMS-955176 is a second-generation maturation inhibitor, a drug class not yet on the market. Since synergy was seen with atazanavir (Reyataz) in the test tube, a small safety study of 28 individuals looked at combining the two drugs. The combination was well tolerated, with major drops in viral load. A similar early (Phase 2) study in treatment-experienced patients is planned. It’s hoped that the combination can be used without a booster dose for Reyataz or a background of nucleoside medications, thereby simplifying treatment.

Switching to TAF

Once a new drug has been found to work as well as an old one, the question becomes: Can you switch from the old to the new?

The largest switch study to date in HIV looked at switching to a newer version of tenofovir DF (TDF, or Viread, found in Truvada). The study found that people had greater success with the new version, tenofovir alafenamide fumarate (or TAF). At the one year mark, they were significantly more likely to maintain suppression of their HIV viral load (to undetectable levels).

Specifically, the study compared Stribild to a newer version that contains TAF instead of TDF. The study also looked at switching to the new combo from Atripla (which contains TDF) or a regimen of Norvir-boosted Reyataz plus Truvada. Nearly 1,000 persons were switched and compared to nearly 500 who were kept on a TDF-containing regimen.

Switch participants also saw improvements in their spine and hip bone mineral density, as well as in proteinuria and other markers of kidney function, in addition to reductions in osteopenia and osteoporosis (both indications of loss in bone mass). Although tenofovir DF is considered very tolerable, TAF was created to overcome the medication’s potential damage to the kidneys and bones, as seen by some patients.

“This is the first large study to demonstrate that switching from a TDF-based regimen to E/C/F/TAF can help improve patients’ bone and kidney measures,” said Tony Mills, MD, lead author of this advanced Phase 3 study and Medical Director of the Southern California Men’s Medical Group in Los Angeles.

A separate switch study with 242 individuals also showed renal and bone improvements with TAF at 48 weeks.

A poster presentation (WELBPE13) also showed that the TAF regimen was able to maintain suppression of hepatitis B virus (HBV) in co-infected patients. (TDF is effective against HBV, as is emtricitabine, which is also found in Truvada. Patients who also have hepatitis B should generally be placed on HIV therapy that can also treat their hep B.)

The new single-tablet regimen containing TAF is awaiting FDA approval.

Thais and lower dose of Reyataz

Thai researchers reported that lower doses of Reyataz and Norvir were able to adequately suppress HIV in Thais living with the virus when compared to standard doses. Pharmacokinetic data had previously found that the standard dose of boosted Reyataz (300 mg plus 100 mg Norvir) is associated with higher exposures in Thais, while a lower dose of 200 mg/100 mg led to adequate dosing with fewer side effects.

In the LASA study comparing the two doses among 500 patients, the higher drug levels also led to a greater number of treatment discontinuations.

The research group said that applicability to other ethnicities and larger body weights is not known, and that results are not generalizable to patients who are treatment-naïve or failing first-line therapy. Results are at one year, with patients who had undetectable virus levels for at least three months before entering the study.

Young men and PrEP

Data from the PrEP Demonstra-tion Project of the Adolescent Trials Network (ATN) were presented by Sybil Hosek, PhD, of Stroger Hospital in Chicago.

The ATN 110 study provided Truvada PrEP (pre-exposure prophylaxis) for HIV prevention to young men who have sex with men (MSM) ages 18 to 22, at 12 sites across the country.

The high level of risk behaviors seen when the young men entered the study continued throughout it. There was, however, a statistical trend for those who engaged in condomless sex to be consistently more adherent in taking their Truvada. Also, those who reported condomless receptive (bottom) anal sex had higher blood levels of Truvada, although there was no statistically significant difference.

White and Latino study participants (21% and 17% respectively of the total) took more than four doses of Truvada a week, which is considered to be very protective against HIV (the prevention pill is supposed to be taken every day). African American participants (53% of the total) and those self-identifying as mixed race (7% of participants) overall did not reach that level after 24 weeks in the 48-week study.

“Our African American participants, on average, did not reach the highly protective levels that PrEP can afford them at all across the study,” Hosek said. Still, “The vast majority of participants had detectable drug throughout the course of the study, so they were all trying to take drug at some level,” she said, and pointed out that all groups showed a drop-off in adherence at 12 weeks. It was at that point, she noted, that study visits changed from monthly to quarterly. More contact in person or mobile technology might help, the study team reported. Some groups went back up in adherence, but only whites had a higher adherence level at 48 weeks than when they began. Latinos also remained above the four-dose-a-week level.

There were four HIV infections during the study (out of 400 participants enrolled from more than 2,000 youths contacted), with two of the young men having been positive at study entry but testing HIV antibody negative, and none of the four having detectable blood levels of Truvada. Therefore, no drug resistance was found.

Given the high level of risk and STIs overall, the ATN expected a higher level of HIV infections had the participants not been on Truvada PrEP. Also, the study noted that young MSM are at highest risk of HIV in this country.

In addition to looking at PrEP acceptability, patterns of use, adherence, and drug levels, ATN 110 also used evidence-based behavioral interventions (either Many Men, Many Voices, or 3MV; or Personalized Cognitive Counseling, or PCC) as well as provided information on the safety and efficacy of PrEP from prior studies (which may help improve adherence).

Data from ATN 113, which provides Truvada PrEP to young MSM ages 15 to 17, is expected next year.

Among its conclusions, the research team reported that the young men most at risk may be the most adherent, but called the results a “call to action for more in-depth understanding of the historical, societal, behavioral, and attitudinal barriers to PrEP access and adherence among those most impacted in the U.S.—black/African American young MSM.”

“How can we dig deep to avoid growing the gap in disparities?” Hosek asked.

More on young men and PreP

A survey of young black MSM (YBMSM), looking at their knowledge and uptake of PrEP, was presented in a poster report by John A. Schneider, MD, of the University of Chicago Medicine and its Chicago Center for HIV Elimination.

According to the poster abstract, “In the United States, early evidence exists of racial disparities in PrEP knowledge, seeking behavior, and uptake. Young black MSM in particular have lower PrEP engagement when compared to other racial/ethnic groups, even in the context of increased health care access due to the Affordable Care Act.”

More than 600 YBMSM participated. Half were younger than 22, and 28% were HIV-positive. Of the 252 respondents considered eligible for PrEP, only 40% knew about it and only 9% had used it.

Factors associated with knowledge of PrEP included completing college, having a medical provider, living with HIV, previously participating in an HIV prevention program, and membership in the House/Ball community. There was no significant association found with closeness to the black or gay community, socializing in Boystown (Chicago’s main gay neighborhood), or behavioral risk factors such as condomless sex with male partners and group sex.

“Several clinical factors were associated with PrEP knowledge suggesting that accelerating access to health care and HIV prevention programming may increase PrEP knowledge,” according to the abstract’s conclusion. “In addition some YBMSM sub-groups, such as the House/Ball community and HIV infected individuals, may be exposed more to PrEP information. Engaging YBMSM not engaged with HIV prevention/clinical systems and those with sex behaviors associated with HIV risk is urgently required if PrEP uptake is to have public health impact on the U.S. HIV epidemic.”

Go to ias2015.org to view webcasts of Dr. Cáceres’ overview and other presentations. slides presented are available for download, along with the abstract book for the conference.