Preventive Technologies, Immune-Based and Gene Therapies and Research Toward a Cure

Table of Contents

• Introduction
• Preexposure Prophylaxis
• Microbicides
• Immune-Based and Gene Therapies
• Conclusion
• References

Introduction

The phrase "product pipeline" typically conjures up the notion of multiple experimental candidates incrementally advancing along a pre-plumbed path toward licensure and widespread availability. But for most of the approaches described in this section of the report, the route toward a pharmacy shelf is far more convoluted and uncertain. Few large pharmaceutical companies are involved in the development of the candidates listed here; the majority are collaborative efforts between small biotech firms, academic researchers, non-profits, and government funders. And even those with the support of a major manufacturer can face unique obstacles related to their novelty, because there are as yet no approved precedents in any of these realms.

The current state of the biomedical prevention pipeline offers illustrative examples. After decades of disappointment and frustration, the past few years have seen low but statistically significant efficacy reported for each of the main approaches: vaccines, microbicides, and, most recently, preexposure prophylaxis (PrEP). The vaccine trial, named RV144, involved an ALVAC canarypox vector made by Sanofi-Pasteur combined with an envelope protein booster shot, AIDSVAX. While Sanofi-Pasteur remains committed to following up on the marginal degree of protection (31.2%) observed among recipients of the regimen (Rerks-Ngarm 2009), the company that made AIDSVAX, VaxGen, ceased to exist several years ago after the product failed to show efficacy given alone. Attempts to duplicate and improve upon the results have thus been slowed by the need to secure a new manufacturer for the envelope protein boost.

Greater success was reported last year with a microbicide consisting of a 1% vaginal gel form of the antiretroviral drug tenofovir (Viread), which demonstrated 39% protective efficacy in the CAPRISA 004 trial in South Africa (Abdool Karim 2010). However, the next steps toward licensure have proven surprisingly slippery. The U.S. Food and Drug Administration (FDA) has indicated that at least one more confirmatory trial (in addition to an ongoing study called VOICE) will be sufficient for them to consider the product for approval, but securing the relatively small amount of funding necessary for the new efficacy evaluation proved difficult and time-consuming. The trial, FACTS 001, is now expected to get underway in August 2011. The maker of Viread, Gilead Sciences, has licensed the gel form to the nonprofit organization CONRAD, so the development of the microbicide also represents a test case for the viability of nonprofit manufacturing and marketing.

Among the most significant biomedical prevention news since the last TAG pipeline report in 2010 was the announcement of the long-awaited first efficacy results of PrEP in HIV negative gay men and transsexual women at high risk of infection (Grant 2010). The iPrEx study found that individuals assigned to receive Truvada (a pill combining two antiretroviral drugs, tenofovir and emtricitabine) experienced a 44% reduction in risk of HIV infection, with additional analyses indicating that protection was significantly better among participants who closely adhered to the regimen. While Gilead donated Truvada for this and other PrEP studies, it was not otherwise involved and it was unclear whether the company would pursue a prevention indication for the drug. After the iPrEx findings were announced, Gilead expressed its intent to submit the data to FDA for consideration, which provoked a vociferous and at times acrimonious debate regarding whether such a filing would be appropriate or premature. Subsequently, the picture was further complicated when news emerged that a trial of Truvada as PrEP in women was being stopped after an interim analysis found it would be unable to show efficacy. A broad lesson from all these biomedical prevention developments is that an approach can get tantalizing close to the end of the pipeline, yet still face significant impediments to actually emerging from it.

Immune-based therapies (IBTs) and gene therapies for HIV have long been entrenched in a distant corner of the research field. This is partly due to uncertainties about mechanisms of action and how best to define and measure success, particularly in light of the dramatically beneficial effects of HIV suppression with antiretroviral drugs. But resurgent interest in curing HIV infection is now helping to move these types of approaches toward the mainstream. In particular, the widely reported case of Timothy Brown, who has remained off antiretroviral therapy and free of detectable HIV for four years and counting after a complex series of high-risk treatments for cancer -- including stem cell transplants from a donor lacking the CCR5 receptor -- is viewed as a compelling proof of concept that a cure for chronic HIV infection is possible (Allers 2011). The goals for potentially curative therapies are relatively straightforward: either eradicate HIV completely (to the extent that this can be verified with current testing technologies) or induce long-term control of the virus in the absence of ongoing treatment (referred to as a functional cure). In addition to IBTs and gene therapies, cure research includes treatments -- most notably histone deacetylase (HDAC) inhibitors -- that aim to awaken the latent HIV that otherwise can persist for life in dormant form, integrated into the host cell's DNA, invisible to the immune system, yet subject to reactivation by immune stimuli or to renewed replication when the resting infected cell divides.

Another potential role for IBTs and gene therapies is addressing the immune system dysfunction that can persist in some individuals despite HIV suppression. Examples include inadequate CD4 T cell recovery, elevated levels of immune activation and inflammation, and an accelerated aging of the immune system called immunosenescence. Studies have linked all of these phenomena to an increased risk of ill health (Marin 2009; Tan 2008; Tien 2010; Deeks 2011), suggesting that an IBT and/or gene therapy capable of addressing them could conceivably offer clinical benefits.

Results from three groundbreaking biomedical prevention trials were presented at the International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention in July 2011. HIV Prevention Trials Network trial 052 (HPTN 052) was a randomized comparison of the effects of earlier initiation of antiretroviral therapy (at CD4 T-cell counts of between 350 and 550 vs. <350) on sexual transmission of HIV among serodiscordant couples. The trial was stopped ahead of schedule by the Data Safety Monitoring Board (DSMB) after an interim analysis revealed that earlier treatment reduced HIV transmission by 96% and also significantly reduced the incidence of extrapulmonary TB. The results have now been published in the New England Journal of Medicine and are available free online (Cohen 2011).

Results also became available from two independent clinical trials evaluating the efficacy of PrEP among heterosexuals at risk of HIV infection. Initially announced by press release, details were presented at the IAS conference in July 2011. In both cases, a statistically significant reduction in risk of HIV acquisition was documented in the trial participants receiving daily PrEP (consisting of the antiretroviral drugs Viread or Truvada) compared to placebo. The larger of the trials, named Partners PrEP, enrolled 4,758 HIV-serodiscordant couples in Kenya and Uganda and randomized the HIV-negative partners to receive either Viread, Truvada, or placebo. A total of 78 HIV infections occurred: 47 in the placebo group, 18 in the Viread group, and 13 in the Truvada group. This equated to a 73% reduction in risk of HIV acquisition for those assigned to Truvada and a 62% reduction among those in the Viread arm (Baeten 2011).

The second trial (called TDF2) was conducted by the U.S. Centers for Disease Control (CDC) in Botswana. The population was not couples in this case, but 1,200 sexually active men and women aged 18-39 (54.7% male/45.3% female) in Gaborone and Francistown. Participants were randomized to receive either Truvada or placebo. There were a total of 33 HIV infections during follow-up: 9 among the 601 individuals in the Truvada group and 24 among those assigned to placebo. The reduction in risk of HIV acquisition was 62.6%, a statistically significant result. In an analysis restricted to participants known to have a supply of Truvada (i.e. those who had not missed a study visit at which 30-day supplies of drug were dispensed), efficacy was reported to be 77.9%. Similar efficacy was observed in both men and women. The side effects reported more often in the Truvada arm compared to placebo were nausea, vomiting, and dizziness (Thigpen 2011).

The results of Partners PrEP and TDF2 contrast with the trial of Truvada as PrEP in women (the FEM-PrEP study), which was unable to show efficacy due to similar HIV infection rates in the active and placebo arms. The reason for the divergent outcome of FEM-PrEP remains to be fully elucidated, but could relate to differences in adherence and/or an enhanced risk of HIV acquisition associated with the use of hormonal contraceptives (Heffron 2011).

Taken together with prior results from iPrEx and CAPRISA 004, the new findings underscore the efficacy of antiretrovirals in preventing HIV infection. Along with the demonstrated effectiveness of circumcision in reducing risk of HIV acquisition in men (Weiss 2010), there is clearly potential to greatly reduce HIV incidence if the political will and funding support can be mustered to appropriately implement the tools now available.