November 15, 2012
It is virtually impossible to point to a single piece of research or conference presentation as the seminal study in a particular subfield this year, so we won't attempt to pass such a judgment.
Instead, we take you on a guided tour through important conference presentations in several of HIV's key subfields: cure research, vaccine development, HIV prevention, HIV treatment strategy, antiretrovirals in development, access to HIV care and comorbidities/complications. Each of these highlighted presentations has the potential to change our understanding of, or our approach to, HIV science and clinical practice.
The Search for a Cure
For years, Timothy Brown -- the "Berlin patient" -- had been the lone individual in existence who could justifiably claim to have been cured of his HIV infection. This summer, he may have been joined by two others.
At the XIX International AIDS Conference, Daniel Kuritzkes, M.D., presented a study outlining how two HIV-infected men showed no traces of the virus in their blood more than two years after receiving an autologous stem cell transplant.
The procedure differed from the one Brown received in a pivotal way: While Brown's donor cells lacked the CCR5 receptor, the primary means by which HIV attaches to CD4+ cells, the two men received donor cells that did have the CCR5 receptor and were fully susceptible to HIV. If there were no need to find a CCR5-deficient matching donor for the transplant to be successful, it would make such a procedure far more realistic.
In addition, unlike Brown, the two men remained on antiretroviral therapy during the transplant period, which is believed to be key to their immune system's ability to completely suppress viral replication.
"The importance of our findings is that we have evidence now that we can protect uninfected cells from becoming infected when they're transplanted into an HIV-infected patient, a form of PrEP at the cellular level, if you will," Kuritzkes said.
These findings arguably made the loudest noise in the cure subfield this year, but they are by no means the only movement on the cure research front. Research continues in many directions as the world waits for further proof that latent HIV reservoirs can be activated and eliminated once and for all.
HIV Vaccine Development
A successful HIV vaccine remains a light at the end of the tunnel, but that light may be growing brighter. Among the best examples of this renewed hope can be found in the research conducted by the HIV Vaccines Trial Network (HVTN), which has made incremental but important developments with some of its latest HIV vaccine candidates.
In a presentation at the AIDS Vaccine 2012 Conference, Nicole Frahm, Ph.D., highlighted the latest research developments by comparing the immunogenicity -- the ability to induce immune responses -- of some of these HVTN vaccine candidates.
Two of the DNA vaccines seemed to elicit better T-cell responses when combined with an adjuvant (a substance that enhances immune-stimulating properties) and electroporation (a process that creates temporary holes in cell membranes for better permeability), Frahm said. This suggests a synergistic effect in which the sum is better than each separate approach.
Poxvector vaccines elicited a better T-cell response when heterologous regimens were given -- i.e., when different vaccine candidates were administered to the same volunteer in succession, the first as a "prime" and the second as a "booster." Prime-boosting is a common method used in vaccine research to induce different immune reactions and enhance overall response.
Compared to heterologous vaccine regimens, higher antibody response rates were seen when homologous regimens (just one vaccine candidate as both prime and booster) were given. Again, these results support the contention that it will be crucial to find the combination that has the best synergistic effect.
Frahm also discussed two of the most promising vaccine candidates, NYVAC and MRKAd5 (or simply "Ad5"), each of which uses a weakened pathogen as a vector. The NYVAC vaccine candidate (a weakened poxvirus) works better as a booster, rather than a prime, when combined with Ad5 (a weakened cold virus), Frahm said, suggesting that the order in which vaccine doses are given play a role in immune response.
Ad5 remains the most potent vaccine candidate, in terms of eliciting T-cell and antibody responses. Out of all the candidates, it is the farthest along: It is currently in a phase 2b trial, with results expected next year.
While work on an HIV vaccine continues to ramp up, the biggest HIV prevention story of the year involves a more prosaic intervention method: the very antiretrovirals we already know and love as a critical form of treatment.
This year brought the U.S. Food and Drug Administration's seal of approval on the use of HIV pre-exposure prophylaxis (PrEP) -- specifically, the use of tenofovir/emtricitabine (Truvada) by HIV-uninfected people to reduce their risk of contracting the virus.
As the health care community commences its rollout of PrEP, there are a huge number of issues to address. One of the most critical elements to the success of PrEP will be adequate adherence to the regimen -- an element that appeared to be distinctly missing from the FEM-PrEP study, as was discussed at CROI 2012 earlier this year.
Additional research presented at CROI testifies to just how effective PrEP can be when it's done right. The lingering question (and challenge), as we begin the PrEP era in earnest, is: Will we, and our patients, do it right? Proper funding, organization, preparation and education will be key to ensuring the answer is "yes."
HIV Treatment Strategy
For a fair amount of time during the 2000s, the debate over when to start antiretroviral therapy was frequently referred to as a "pendulum," as dueling studies stoked the debate over the value of early initiation (to reduce viral load and stave off immune decline) versus its risks (namely, the toxicities of HIV medications and the risks of emergent resistance due to imperfect adherence).
2012 may prove to be the year that the pendulum finally stopped swinging.
A growing number of studies (and the guidelines based on their findings) support HIV treatment initiation at higher and higher CD4+ cell counts. There may be none more important than the landmark HPTN 052 study, which last year stunned the clinical and research communities by revealing a 96% reduction in HIV transmission risk among serodiscordant couples in which the HIV-infected partner initiated treatment early and maintained virologic suppression.
At this year's International AIDS Conference, new HPTN 052 data were unveiled that demonstrated benefits for the HIV-infected partner as well: significant reductions in comorbidities and significantly delayed mortality among those who begin HIV treatment with a CD4+ cell count above 350.
It is findings such as these that make geniuses out of people such as the San Francisco public health officials who instituted a "treat everyone with HIV" policy back in 2010. That program has, of course, been strikingly successful. While antiretroviral therapy should never be prescribed blindly or without taking into account a patient's capability to take medications safely and adhere to them, the reasons to hold off on at least recommending treatment initiation to all patients appear to be dwindling.
Antiretrovirals in Development
As soon as the approval of the long-awaited "quad" (elvitegravir/cobicistat/emtricitabine/tenofovir, Stribild) added a valuable new integrase inhibitor and boosting agent (as well as a new efavirenz [Sustiva, Stocrin] alternative) to the first-line therapy pantheon, eyes almost immediately turned to seek out the next exciting drug in the antiretroviral pipeline.
It didn't take long for those eyes to settle on dolutegravir, an integrase inhibitor whose safety and efficacy profile impressed in early clinical trials.
In a series of phase 3 studies presented or published throughout the year (including at the International AIDS Conference and ICAAC), dolutegravir continued to shine, sporting treatment response levels similar to or greater than that of a number of standard-of-care regimens.
The bar continues to climb for HIV antiretrovirals, with expected efficacy rates for first-line regimens now nearing the 90% mark -- a level almost unthinkable less than a decade ago. And yet the pipeline, while arguably not as rich as it was several years ago, continues to feature promising drugs, with dolutegravir as the present-day vanguard.
Access to (and Continuity of) HIV Care
If you haven't heard the phrase "treatment cascade" yet, now's the time to get on board. The concept is likely to shake out as one of the transformative moments in our understanding of the HIV epidemic in the U.S., while also provides a reminder about how powerful it can be to portray data visually.
Originally published in Clinical Infectious Diseases last March, the treatment cascade casts in stark relief exactly where the largest gaps are that need to be filled when it comes to the process of getting HIV-infected individuals onto successful antiretroviral therapy. The cascade notes that, of the approximately 1.2 million individuals living with HIV in the U.S., 82% have been diagnosed; 66% have been linked to HIV care; just 37% are retained in care; 33% are prescribed antiretroviral therapy; and 25% have an undetectable viral load.
As Michael Horberg, M.D., discussed at CROI; Irene Hall, Ph.D., discussed at the International AIDS Conference; and Greg Millett, M.P.H., discussed at IDWeek 2012, there is a tremendous amount we have yet to learn about the best ways to fill these gaps, and the factors that lead to them being so wide (particularly for harder-hit populations, such as African Americans). But the conversation has begun in earnest, and it raises hopes that we can transform the landscape of HIV care before more individuals fall through the cracks.
Comorbidities and Complications
There are few more heated topics among frontline HIV care providers than the concept of "premature aging" among individuals living with the virus. As the ever-increasing efficacy and tolerability of antiretroviral therapy reduces mortality rates and increases lifespans, the impact of HIV -- and the medications we use to treat it -- on senescence will inevitably gain more attention. In fact, the number of studies in 2012 that touched on the issue is staggering, and is bound to increase further as we move into 2013 and beyond.
And yet, when it comes to the intersection of aging and HIV, we still have far more questions than answers. In a captivating presentation at CROI 2012, Amy Justice, M.D., Ph.D., questioned some of the fundamental conclusions that many in the research community have reached on the subject in recent years. Although "there certainly is more of a trend for HIV-positive people to be a bit younger" when they develop certain health problems, as Justice said in a recent interview, "we're talking about somewhere between one and six years -- we're not talking about 20 or 30 years," which is what earlier research seemed to suggest.
We are still only gazing out at the sunrise when it comes to gaining a better understanding for how HIV and antiretrovirals impact the rate and severity of complications we commonly think of as related to aging -- cardiovascular disease, bone fractures, cirrhosis, renal failure, lung cancer and so forth. Presentations such as Justice's point to the importance of keeping a level head and a reasonable approach when discussing with HIV-infected patients and clients the risks and realities of aging with HIV.