Top Menu Items From the Boiling Cauldron of HIV Clinical Research

These featured words are from Phil Peters, M.D., the primary author of a paper published in The New England Journal of Medicine (NEJM) exploring an outbreak of HIV infections in a rural section of southeastern Indiana in late 2014 and 2015. The paper recounted the scale of the outbreak -- a total of 181 new diagnoses in an area that had reported just five new cases in the decade prior -- as well as a common theme: Of the new diagnoses, 96% were among recent injection drug users, most of whom injected oxymorphone, a prescription opioid.

The outbreak didn't just highlight the vulnerability of this rural population to HIV and other infectious diseases, Del Rio said; it also highlighted how public health officials could have responded much earlier to avert a broader outbreak. By the time a public health emergency was declared in the area, roughly two months had passed since the first cluster of HIV infections had been identified.

More at TheBodyPRO.com: "Tragedy in Scott County, Indiana: A Top HIV Clinical Development of 2015"

The Indiana HIV outbreak naturally yielded a critical question: What areas are at greatest risk for a similar event -- and, thus, are where intervention efforts should be focused? To answer that question, John T. Brooks, M.D., (who provided the quote at left), Michelle Van Handel, M.P.H., and colleagues authored a study published in the Journal of Acquired Immune Deficiency Syndromes (JAIDS) in which they looked at local acute hepatitis C (HCV) infection rates across the U.S. as a tipoff that use of unsterilized injection drug equipment was occurring in an area.

The researchers identified six variables closely tied to acute HCV infection, including drug overdoses rates, prescription opioid sales, income levels, unemployment rates and race. They also identified 220 counties across 26 U.S. states that appeared to be particularly vulnerable to an Indiana-style outbreak. More than half of those counties were located within the Appalachian region.

More at The Wall Street Journal: "CDC Identifies Counties at Risk of HIV Outbreaks"

Shifting from epidemiology to prevention, Del Rio highlighted research by Jared Baeten, M.D., Ph.D., (quoted at left) and colleagues that explored the potential preventive benefits of an antiretroviral ring that could be inserted into the vagina. Published in NEJM, the study found that the ring's overall efficacy was modest at best: It achieved just a 27% reduction in new HIV infections compared with a placebo group.

Here's the catch, though: Similar to early research on pre-exposure prophylaxis (PrEP) among women, the findings indicated that adherence and study retention were likely pulling the efficacy rate down -- possibly by quite a bit. One key piece of data supporting that contention: Among women over age 21, efficacy jumped to 56%, compared with no efficacy among younger women.

In other words, Del Rio said, the "big challenge" in biomedical HIV prevention turns out to be the same as the big challenge in HIV treatment, generally: ensuring that people adhere to their medication.

More on TheBodyPRO.com: "Vaginal Ring Reduces HIV: Making Sense of the Initial Results"; "Consistent Use of Dapivirine Vaginal Ring Could Offer More Than 75% HIV Protection, New Data Suggests"

Though it's been slow to gain acceptance and availability among the general population, the HIV care community has heard a ton about HIV PrEP over the past year or so. One of the more important new pieces of information came out of the IPERGAY study, the results of which appear in an article by Jean-Michel Molina, M.D., and colleagues published in NEJM.

The study's purpose was to see whether "on-demand" PrEP -- in which tenofovir/emtricitabine (Truvada) is taken by an HIV-negative person only in the vicinity of a sexual act -- was as effective an HIV prevention method as taking PrEP once daily without fail. Molina's analysis of the study results is quoted on the left.

The study found a risk-reduction rate of 86% among on-demand PrEP takers compared with a placebo group; just two infections occurred in the on-demand arm compared with 14 in the placebo arm. Del Rio noted that the participants actually averaged about 15 PrEP doses per month or nearly four per week -- near the adherence threshold found necessary to ensure efficacy in earlier studies involving once-daily PrEP.

More on TheBodyPRO.com: "On-Demand PrEP Effective Among MSM, but High Rates of STIs Observed"

Speaking of groundbreaking biomedical prevention studies, is there one more significant for the HIV community than HPTN 052, the study that put the "treatment as prevention" concept firmly on the map?

This year, NEJM published the final results of this historic study, which include more than five years of follow-up data. In the concluding analysis, HIV-positive people who started treatment early had a 93% lower risk of transmitting HIV to their sexual partners than HIV-positive people who waited to start treatment until their immune health had declined. The key to that other 7%? As lead author Myron Cohen, M.D., puts it in the quote to the left, adherence and complete virologic suppression.

More on TheBodyPRO.com: "Early HIV Treatment Lowers Transmission Risk by Up to 93%: HPTN 052 Final Results"

If HPTN 052 put "treatment as prevention" on the map, the PARTNER study made it a must-see destination. The study was massive: nearly 1,200 serodiscordant couples split between heterosexual partnerships in which the man was positive, heterosexual partnerships in which the woman was positive and partnerships between men who have sex with men. Despite a significant number of condomless sex acts, the risk of transmission from the positive partner to the negative partner -- provided the positive partner was on suppressive HIV treatment -- was about as close to zero as you can get: 0.3 infections per 100 couple-years.

The words of lead study author Alison Rodger, M.D., on the left drive home the transformative power of these study results, which were published in the Journal of the American Medical Association this year. It's not just about the numbers or the justification of the concept. It's the realization of what "essentially zero risk" means for HIV-positive people: freedom, in just about every sense of the term.

More on TheBodyPRO.com and TheBody.com: "Zero: No Linked HIV Transmissions in PARTNER Study After Couples Had Sex 58,000 Times Without Condoms"; "Q&A on the PARTNER Study: How to Interpret the Zero Transmission Results"

Of course, antiretrovirals aren't just about HIV prevention: Believe it or not, they're still about treatment, too. As a kindler, gentler version of tenofovir -- tenofovir alafenamide (TAF) -- increasingly replaces its forebear -- tenofovir disoproxil fumarate (TDF) -- a question has lingered as to whether the new drug would share a unique side benefit of the old: an ability to treat hepatitis B (HBV), a commonly occurring HIV coinfection. In fact, TDF-based regimens are widely recommended for the treatment of HIV/HBV coinfection.

As Joel Gallant, M.D., M.P.H., attests in the quote to the left, TAF is indeed an effective HBV fighter. Gallant is the primary author of an open-label study published in JAIDS earlier this year in which coinfected patients were switched from their existing regimen to the single-tablet regimen of elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF for short, more efficiently known by the brand name Genvoya). Forty-eight weeks after the switch, 92% of the 72 volunteers had either maintained their existing virologic suppression or achieved it anew. Improvements were also seen in renal function and bone turnover markers.

More on HIVandHepatitis.com: "IAS 2015: HIV and Hepatitis B Coinfected People Can Safely Switch to Simpler TAF Single-Tablet Regimen"

Much has rightly been made of the high efficacy and low toxicity of our current generation of first-line HIV antiretrovirals. But modern-day treatment is certainly not perfect -- side effects remain a concern, as do the cost and chemical complexity of typical three- or four-drug regimens. Scientists have toyed with the idea of two-drug regimens for years, and as Pedro Cahn, M.D., Ph.D., notes in the quote to the left, they may have finally hit pay dirt.

The PADDLE study, the most recent results of which were presented by Cahn in a late-breaker session at the 2016 International AIDS Conference, explores the viability of a first-line regimen consisting entirely of dolutegravir (Tivicay) and lamivudine (3TC, Epivir). Virologic suppression was achieved by week 24 in all 20 of the pilot study's treatment-naive volunteers; all but two remained suppressed at week 48. Larger clinical trials of the combination are now underway.

More from TheBodyPRO.com: "Once-Daily Raltegravir and Dolutegravir-Based Dual-Drug Regimen Show Promise"

Of course, if we really want to simplify treatment, why stop at a dose of two drugs taken once a day? Why not prescribe a dose of drugs once a week -- or once every two months or so?

Enter the long-acting HIV antiretroviral and the LATTE-2 study, in which treatment-naive volunteers begin therapy with a daily oral antiretroviral regimen and then transition to an injectable regimen of cabotegravir and rilpivirine (Edurant). Study arms include one group of patients that receive the injectable combination once every four weeks and another group that receives the combination once every eight weeks.

As David Margolis, M.D., who presented 32-week study results at CROI earlier this year, notes in the quote to the left, the data look promising: 95% of people receiving one dose every four weeks were virologically suppressed after 32 weeks, as were 94% of people receiving a dose every four weeks. Both rates were higher than the control group (which remained on daily oral treatment), of which 91% were suppressed. One potential issue: Injection site pain was an extremely common complaint.

More from TheBodyPRO.com: "Long-Acting Injectable HIV Treatment Safe and Effective at 32 Weeks"; "Long-Acting Cabotegravir + Rilpivirine for Induction Then Maintenance Therapy"

Formerly known as the "HIV treatment cascade," the continuum of HIV care has become a focal point of conversations about ending the global pandemic. Ensuring that people are tested and treated for HIV quickly and successfully is now generally accepted to be a wise approach. But how quickly should clinicians move? Is it wise, for instance, to begin a person on antiretroviral therapy the same day they're diagnosed?

Recent research suggests it's quite wise. A noteworthy study published in JAIDS this year offered proof of concept for same-day observed initiation of HIV treatment based on the findings from a pilot program in San Francisco. At the International AIDS Conference, Serena Koenig, M.D., M.P.H., (quoted at left) presented a study out of South Africa that yielded similar findings -- and, as importantly, pointed to the psychological benefits of same-day treatment initiation for the newly diagnosed study participants.

More from TheBodyPRO.com: "RAPID Program Leads to Faster HIV Suppression"

Of course, even as we continue to hail the value of HIV treatment initiation, we must remain keenly aware of the adverse effects that antiretroviral therapy can have. Degradation of bone mineral density is today among the more frequently discussed comorbidities.

While the rise of TAF as a replacement for TDF may curb one key cause of bone loss, a basic question remains regarding what HIV-positive people can do to reduce -- or possibly even to reverse -- bone loss while on antiretroviral therapy.

A potential solution was published in Clinical Infectious Diseases this year: bisphosphonates, which act as an inhibitor of bone resorption. Ighovwerha Ofotokun, M.D., is lead author of a small study in which 63 people starting treatment with a TDF-containing regimen were simultaneously randomized to receive either a single infusion of zoledronic acid or a placebo solution. At 48 weeks, that single-dose bisphosphonate intervention was found to completely counter any loss of bone mineral density in the lumbar spine, as noted in the quote from Ofotokun on the left. The approach is now moving on to a larger clinical trial, Del Rio said.

More on Aidsmap: "CROI: Alendronate Effectively Treats Bone Loss in Men and Women With HIV"

Reducing cancer incidence among people with HIV may have an even easier solution than reducing bone loss. According to a paper by lead author Álvaro Borges, M.D., MSc, Ph.D., (quoted at left) published this year in Clinical Infectious Diseases, antiretroviral therapy itself appears to act as a cancer prevention agent.

The intriguing finding, which comes from an analysis of START study data, found that study volunteers who began HIV treatment immediately had a 74% reduced risk of developing an HIV-related cancer and a 51% reduced risk of developing a cancer unrelated to HIV -- although only the former finding reached statistical significance.

Investigators found some additional variables affecting cancer incidence, Del Rio noted: older age, higher body mass index, baseline HIV viral load, baseline CD8 cell count and living in a low- or middle-income region. But the precise reasons that tie HIV treatment initiation to reduced cancer risk have yet to be conclusively identified.

More on HIVandHepatitis.com: "CROI 2016: Early Antiretroviral Therapy Reduces the Risk of Infection-Related Cancers"

It has been a revolutionary past few years in the HCV treatment realm. And the revolution is not yet over: Though the current generation of HCV treatment regimens is more effective and less toxic than ever, there tend to be wide variations in success rates across viral genotypes. That is, except for the experimental combination sofosbuvir/velpatasvir (Epclusa), according to research presented at the European Association for the Study of the Liver conference earlier this year.

The phase 3 study, known as ASTRAL-5, found that pair of direct-acting antivirals effective against all HCV genotypes in patients coinfected with HIV. Twelve weeks of therapy yielded a 95% sustained virologic response in HIV-positive volunteers with HCV genotypes 1 though 4 -- including a 100% response rate among cirrhotic volunteers and a 97% response rate among people who had failed HCV therapy in the past. The combination also appeared to get along well with HIV antiretroviral therapies.

The reaction quote from study co-author Mark Sulkowski, M.D., on the left highlights one major benefit of this regimen's success, should it be ultimately approved: It could eliminate the need for HCV genotype testing, since it works so well against all viral types. In a subtle reference to the ongoing controversies over HCV drug pricing, Del Rio also mentioned that the availability of a generic version of the regimen outside the U.S. would likely yield a therapy cost that was "globally acceptable."

More from HIVandHepatitis.com: "EASL 2016: Sofosbuvir/Velpatasvir Cures 95% of HIV/HCV Coinfected People"

Del Rio wound down his talk with a gaze toward what is arguably the greatest hurdle we now face to ending the HIV pandemic: access to care. The scale-up of HIV treatment access continues, spurred by UNAIDS' "90-90-90" target for 2020 -- and there are already some resounding successes.

An article published in HIV Medicine this year reports that Sweden has become the world's first country to achieve the 90-90-90 goals -- and a separate article in The Lancet notes that Botswana is not far behind.

However, many countries are struggling to move from the first target (90% of all people with HIV being diagnosed) to the third (90% of all people on HIV treatment being virologically suppressed). Del Rio highlighted ANRS 12249, a study presented at both the International AIDS Conference and the HIVR4P meeting this year, which found that a "test and treat" strategy piloted in a rural part of KwaZulu-Natal province in South Africa did just as well as the typical intervention strategy at meeting UNAIDS' 90% targets for HIV testing and viral suppression -- and that it did just as poorly at engaging diagnosed people in care, with percentages only in the mid 40s.

The quote on the left from Francois Dabis, M.D., Ph.D., who presented the study results at the International AIDS Conference, further explains the lack of success of the "test and treat" approach. Del Rio called the results "depressing," but if the reasons behind the poor linkage to care can be better elucidated, new interventions can be explored to close that care gap.

More on Aidsmap: "'Test and Treat': Large Study Fails to Show an Impact on New HIV Infections"

Not content with that piece of sobering news, Del Rio closed his review of major clinical studies from the past 12 months with a particularly stark warning: Within the next few years, the U.S. may not have enough trained health care providers to adequately treat the country's HIV-positive population.

This year, Clinical Infectious Diseases published a paper by John Weiser, M.D., M.P.H., and colleagues reporting results from a survey conducted in 2013 and 2014 that was completed by 1,234 U.S. HIV care providers (out of an estimated 8,257 practicing at the time). Among the mountain of intriguing survey findings, Del Rio noted that an analysis of trend data revealed that, although the overall number of HIV care providers was forecast to increase over the coming years, that increase would not be sufficient to offset a more rapid increase in HIV prevalence caused by plummeting mortality rates.

We are, in effect, victims of our own HIV treatment success, Del Rio said. Weiser added his own takeaway in the quote to the left, which refers to survey data indicating that just 11% of HIV care providers are black and another 11% are Hispanic -- as well as data showing that the aspects of their jobs with which HIV care providers expressed the least amount of satisfaction were salary levels and the amount of time they had to spend on documentation and administrative duties.

More from NEMJ Journal Watch: "Future Needs for the HIV Workforce in the U.S."