CROI 2012: Changing Winds in HIV/AIDS Research
The evolution of HIV/AIDS research is taking place in a faster pace than ever before. Attending this year's conference was an amazing experience and the conference was full of promising endeavors in the search for the cure and biomedical prevention. Humankind has arrived at a tipping point of the HIV/AIDS epidemic and we have the opportunity to get rid of the virus and offer the promise of a generation that's HIV-free.
One symposium -- HIV Latency and Eradication: Clinical Perspectives -- was a main attraction for a large number of researchers, healthcare providers and advocates attending the conference. The topic addressing the "C" word (cure) included the following: mechanisms of viral latency (or how the viral genetic material stays dormant within cells), the identification of compounds that are able to bring out latent virus and force their expression, ways to prevent the dissemination of reactivated HIV and the search for drugs that bring the virus out of its latency state.
As we all know everything began with the serendipitous "Berlin patient" Timothy Brown, who now lives in San Francisco. Five years after receiving bone marrow transplants, Mr. Brown had no sign of HIV infection. A very important factor of these transplants is that they came from a donor with a mutation (CCR5-delta 32) which makes T cells resistant to HIV. However, we still don't know if the eradication of HIV infection in Mr. Brown was provoked by these transplants or other factors.
Several attempts to replicate Mr. Brown's circumstances are now in development at multiple research centers in the world. A small study was presented at CROI 2012 (Abst. 154) with ten subjects diagnosed with AIDS-related lymphoma. They received autologous hematopoietic stem cell transplants and were taking antiretroviral therapy (ART) with plasma viral load <50 copies/mL. After the transplants, viremia persisted (virus in blood stream) in nine out of ten subjects. This study somehow indicates that stem cell transplantation alone does not eradicate HIV, but we need to consider that these ten people did not receive total body irradiation and chemotherapy. It is possible that they carried over HIV from their own transplanted cells.
Another way to replicate the "Berlin patient" is through the use of gene therapy. Sangamo Biosciences Inc. is using zinc finger nuclease technology to produce T-cells resistant to HIV by erasing the CCR5 gene. Data from the first cohorts using modified T-cells were presented at CROI this year (Abst. 155). It is important to note that previous reports of this study have been presented at CROI 2011 and ICAAC 2011.
This report included the results of immunological responders to antiretroviral therapy and immunological non-responders. The difference was based on CD4 counts (>450 cells/mm3 and <500 cells/mm3). All participants received one infusion of CD4 cells modified SB-278. No serious side effects have been reported, only one post-transfusion reaction that resolved after a few days.
After 12 months, CD4 cell increases were observed in these two groups. A very important finding was the normalization of CD4/CD8 T-cell ratios in the majority of subjects. These SB-278 T-cells were also identified in peripheral blood from 90 through 700 days -- a very long time for a transfusion of blood cells. These cells were found in rectal mucosa, which is quite important in the process of immune reconstitution. A subset of participants of these cohorts stopped ART. After an initial increase of viral load, all subjects had significant drops in viral load before reinitiating ART.
On a side note, I'd like to share that I am a participant of this study and that the intervention allowed me to reach a normal ratio of CD4/CD8 (1.11) situation that has been characterized as "functional cure" of the immune system. I did not experience any side effects after the transfusion, and the research team is the most dedicated and professional I have ever worked with since my diagnosis in 1990.
One important step in identifying ways to eradicate HIV is to find compounds that can force viral expression in latent infected resting cells. Several drugs have the potential to activate latent HIV and are currently in study.
A group of Johns Hopkins found a new group of compounds (Abst. 156). The benefits of these new compounds are that they not only induce viral expression in resting latent cells, but do not provoke dangerous global T-cell activation.
One specific compound presented was Vorinistat (Zolinza or SAHA, Abst. 157 LB), which is an HDAC inhibitor and used as an anticancer. Six people who had been stable taking ART with undetectable viral load <50 copies/mL and CD4 cell count >500 cells/mm3 were studied after a single dose of Vorinistat. There was a two-fold increase in histone deacetylation eight hours after the dose. All six participants had intracellular HIV RNA increases, a demonstration that a single dose was able to activate latent virus. The participant did not experience drug-related adverse events or toxicities. There were presentations about similar interventions that seek the activation of "sleeping" HIV RNA using Vorinistat and Disulfiran (Antabuse).
This is an incredible time for research on viral eradication. However, several critical matters should be addressed in the process of this research: the presence of constant funding, validation, and standardization of assays to test HIV latency and reservoirs; and, of course, coordination and collaborative work of researchers and institutions.
Prevention Revolution/Biomedical Prevention in Action/Treatment as Prevention
Pre-exposure prophylaxis (PrEP) is the utilization of antiviral drugs by HIV negative people in order to prevent HIV infection. This topic has been controversial. In recent studies the effectiveness of this intervention was between 42 to 76%. One study was halted early for failure to produce any protective effect (FEM-PrEP).
One of the pivotal studies was Partner PrEP, which enrolled 4,758 sero-discordant couples (one positive and the other negative); the HIV negative was assigned by chance to receive one of two regimens -- Tenofovir alone or Tenofovir/Emtricitabine (Truvada) or placebo. Overall PrEP decreased new infections by 70%. One presentation at CROI 2012 was dedicated to present the analysis of people who became infected during the study Partners PrEP, while taking ART drugs. Twenty-nine people were infected in the two PrEP active drug arms. Interestingly, only 35% of people taking Tenofovir alone had detectable drug levels in blood. In the Truvada group only 25% has detectable drug levels in blood. It is important to acknowledge that a sub analysis found that new infections were reduced by 86% and 90% in the Tenofovir and Truvada arms respectively.
IPrEx is another study on PrEP targeting men who have sex with men (MSM) and transgender women. In this multinational study, 2,499 people participated and were randomly assigned to Truvada or placebo once daily. These people were tested every 12 weeks. There were 132 new HIV infections, 84 in the placebo arm and 48 in the Truvada PrEP arm. These results indicated a 42% effectiveness rate in an overall intent-to-treat analysis. However the effectiveness rate was 92% among those with detectable drug levels in their blood. Further studies identified how frequently Tenofovir should be administered in order to have a protective effect. For instance, taking Tenofovir seven days a week confers a 99% reduction of HIV infection.
PrEP is still controversial despite of its promising results. Adherence is going to become a major obstacle to overcome in order to achieve acceptable levels of protection. Also, recent studies have identified that a large proportion of people living with HIV who needs antiretroviral therapy do not access to these medications in the United States. According to NASTAD there are over 4,000 people on waiting lists for AIDS drug assistance programs (ADAP). The situation is more precarious around the world. In general, health disparities are a major issue and PrEP will make these disparities deeper. There is a lot of work to done before the PrEP benefits will become a reality.
For the last five years, the term "community viral load" (the average viral load of people known to be HIV+ in a community) became a buzz word in the arena of intervention that seeks the control of the HIV epidemic. During CROI 2012, data from San Francisco Early HIV Treatment Policy was presented. This policy offers ART to everyone who tests positive for HIV regardless of CD4 cell count. Elvin Geng from UCSF presented the findings from a study of clinical practice and patient outcomes since the new policy took effect in 2010. The main finding is that the likelihood of HIV suppression more than doubled after the adoption of this new policy, with rapid suppression and less rebound of viral load in comparison with those who started with lower CD4 counts.
However, this universal early treatment policy has the potential to increase the depth of disparities between those who receive the current standard of care and those who participate in the new policy. For instance, people who started ART with CD4 cells counts >500 were significantly more likely to be white MSM and diagnosed by private clinicians, and less likely to be at the poverty level. Evidence of the benefits of this intervention exposes a new potential inequality for populations already disproportionately affected by HIV, including youth, African Americans, the poor, and those diagnosed at facilities other than private providers. According to the authors, unless these gaps are closed through specific efforts for earlier diagnosis, care, and ART initiation, we may observe increasing health and survival disparities among people living with HIV.
We are facing incredible times with the work on HIV/AIDS. Although we are seeing remarkable achievements in biomedical prevention (treatment as prevention) and the search for the cure (human viral eradication), we are also facing severe challenges due to financial constraints and changes in the political landscape of this country. The return of the International AIDS Conference (IAC) to American territory will offer the opportunity for HIV activists to reignite commitment and passion in the work of HIV/AIDS and secure the financial resources to confront our new challenges. This is the right time to become involved and participate in public forums, sign petitions, and contact your elected officials. Also, you can join Being Alive and be part of its advocacy initiatives.