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

September 2011

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Microbicides are substances that aim to prevent HIV infection via application to the vagina or rectum prior to (and in some cases also after) sex. Last year witnessed the first major microbicide breakthrough with the announcement of the results of CAPRISA 004, a phase IIb trial of tenofovir gel conducted in South Africa (Abdool Karim 2010). Women randomized to receive the gel had a statistically significant 39% reduction in risk of acquiring HIV infection. In raw numbers, there were 38 infections in the group of 445 tenofovir gel recipients and 60 among the 444 placebo recipients over an average of 18 months of follow up. The product was well tolerated and there was a strong association between drug levels in cervicovaginal fluid and protection from HIV (Kashuba 2010), echoing the findings from iPrEx and adding to the plausibility of the result.

Unexpectedly, CAPRISA 004 also showed that tenofovir gel offers significant protection against HSV-2 infection. Risk of acquiring HSV-2 was reduced by 51% (95% confidence interval: 30-78%) among women assigned to the active gel arm. This impressive finding suggests that tenofovir gel could have a dual impact on susceptibility to HIV, because HSV-2 infection is associated with an approximately 3-fold increase in relative risk of HIV acquisition in women (Freeman 2006). Tenofovir only inhibits HSV-2 at very high concentrations that cannot be achieved with oral dosing, but pharmacologist Angela Kashuba has shown that the gel form can reach sufficient levels in the genital tract (Kashuba 2010).

Since the initial presentation of the CAPRISA 004 results at the International AIDS Conference in Vienna in July 2010, the US Food and Drug Administration (FDA) has indicated that two additional confirmatory trials would provide sufficient data for the agency to consider the product for licensure. One trial, VOICE (described in the previous section), is ongoing. A second, called FACTS 001, has taken longer to secure funding than was anticipated, but is now expected to begin in South Africa in August 2011. The fate of a third tenofovir gel efficacy trial planned by the UK's Microbicide Development Programme, MPD 302, is less certain.

Gilead Sciences has licensed the rights to produce tenofovir gel to the non-profit organization CONRAD, which is exploring options for manufacturing and marketing globally. CONRAD has recently announced that the South African government's Technology Innovation Agency (TIA) will be granted the rights to manufacture and distribute tenofovir gel in Africa. TIA has, in turn, set up a joint venture called ProPreven consisting of TIA, Cipla Medpro and iThemba Pharmaceuticals. ProPreven will handle the registration, manufacturing and marketing of the gel if and when the data accrue to support licensure. A recent modeling study based on the results of CAPRISA 004 concluded that, over a twenty year period, the use of tenofovir gel in South Africa could avert up to two million new HIV infections and a million AIDS deaths (Williams 2011).

The next microbicide product that appears likely to undergo efficacy testing is a gel form of the nonnucleoside reverse transcriptase inhibitor drug dapirivine, which is being developed by the International Partnership for Microbicides (IPM). Phase I/II trials have shown that dapirivine gel can be safely delivered via a matrix intravaginal ring (Nel 2009), and IPM has ambitious plans to conduct two phase III efficacy trials of the approach involving a total of 6,000 women.

Table 3. Research Toward a Cure
Clinical Identifier(s)Manufacturer/Sponsor
SB-728-T, autologous CD4 T-cells genetically modified at the CCR5 gene by zinc finger nucleasesNCT01044654
Sangamo Biosciences
Vorinostat (SAHA)NCT01319383
Merck/University of North Carolina Chapel Hill/NIAID/Bayside Health
Disulfiram (Antabuse)NCT01286259University of California, San Francisco/Johns Hopkins University
IL-7, DNA/Ad5 HIV vaccine, ART intensificationNCT01019551
Cytheris/Vical/GenVec, NIH Vaccine Research Center/Objectif Recherche Vaccins SIDA (ORVACS)
Alpha interferon intensificationNCT01295515NIAID

Not so long ago, prospects for an HIV cure were deemed so dim that even mentioning the word was generally frowned upon, lest it create false hopes. But it is important to appreciate that this semantic reticence did not equate to an absence of research; most of the trials and approaches included in the table above were in development long before the breakthrough case of Timothy Brown was reported. What Brown's experience has done, however, is provide invaluable momentum for the research effort while at the same time bringing the possibility of a cure into the public consciousness. The elevated profile of the field has also spurred a flurry of review articles and opinion pieces in the scientific literature, delineating the challenges that lie ahead (Deeks 2010; Lafeuillade 2011; Lewin 2011a; Lewin 2011b; Margolis 2011; Siliciano 2010).

While the term "cure research" is now increasingly invoked, it is not well defined. In terms of human trials, current strategies can be divided into three broad categories:

  • Cell-protecting: approaches designed to protect potential target cells from HIV infection, e.g. via gene therapy.
  • Reservoir-depleting: approaches that aim to reduce the amount of residual HIV that persists after viral replication is suppressed by ART.
  • Immune-enhancing: approaches to bolster the immune response to HIV in hopes of enabling the body to control or even gradually eliminate residual viral reservoirs.

Sangamo Biosciences is pursuing a cell-protecting strategy based on a proprietary technology that allows targeting of specific genes. By pairing zinc finger proteins with enzymes called nucleases that can break up DNA, Sangamo's approach disrupts the CCR5 gene and thus prevents expression of the CCR5 co-receptor on modified cells (Urnov 2010). In current trials, CD4 T cells are extracted from participants via apheresis, subjected to the zinc finger nuclease procedure in the laboratory, and then expanded in number and re-infused. Presentation of preliminary phase I results early in 2011 generated considerable excitement because the researchers were able to document significant CD4 T cell count increases and persistence of CCR5-deleted CD4 T cells at low but detectable levels in peripheral blood (Lalezari 2011). In a small subset of participants who underwent sampling from the gastrointestinal tract there was evidence that the majority of CD4 T cells in their gut were CCR5-deleted, suggesting that the modified cells had a particular survival advantage in this location, which is known to be a major site of HIV replication (Tebas 2011). Further results from these trials are eagerly anticipated. Unlike many cashstrapped biotech companies, Sangamo is better positioned to move its candidate HIV therapy through the pipeline due to a robust revenue stream obtained from licensing their gene modification technology for laboratory and agricultural use. Researchers are also collaborating with Sangamo to study the effects of CCR5-deleted stem cells in individuals with HIV who require stem cell transplants for AIDS-related lymphoma; the trial is not yet open for enrollment but is slated to take place at the City of Hope in Los Angeles (Cannon 2011).


While Sangamo ultimately has marketing ambitions for its gene therapy, the other examples of cure-related trials are more exploratory in nature. Laboratory experiments indicate that a class of anticancer drugs called HDAC inhibitors can activate the otherwise silent latent HIV reservoir and one such drug -- vorinostat (SAHA) -- is now being studied for this purpose in both the US and Australia (the principal investigators are David Margolis at the University of North Carolina and Sharon Lewin at Monash University, respectively). The downside of HDAC inhibitors is a daunting toxicity profile that has led these trials to proceed with extreme caution. The goal is not to develop vorinostat but rather to find out if HDAC inhibition can have measurable effects on the HIV reservoir in humans; a positive outcome would justify investment in the development of safer candidates with similar mechanisms of action. Two large pharmaceutical companies, Merck and Gilead, have publicly acknowledged having research programs looking at HIV latency reversal and Merck is involved in the vorinostat trials for this reason.

Disulfiram (Antabuse) is an approved drug used to treat alcoholism, its HIV latency-reversing properties emerged from a large drug screening study conducted by the laboratory of Robert Siliciano at Johns Hopkins University (Xing 2011). The discovery is a testament to the impact of the recently formed amfAR Research Consortium for HIV Eradication (ARCHE), which funded the work of Siliciano and collaborator Steve Deeks at the University of California San Francisco; Deeks's group is now conducing a small trial to investigate whether disulfiram has an effect on latent HIV reservoirs in vivo.

Objectif Recherche Vaccins SIDA (ORVACS) is a foundation based in France that was originally established to support therapeutic HIV vaccine research. ORVACS is sponsoring two trials, Eramune 01 and 02, that are investigating combination approaches to HIV reservoir reduction. Eramune 01 will look at intensifying standard antiretroviral therapy (ART) with the integrase inhibitor raltegravir and CCR5 inhibitor maraviroc, with or without the addition of the cytokine IL-7. Eramune 02 employs the same ART intensification, with or without the addition of a DNA/Ad5 prime-boost therapeutic vaccine developed by the Vaccine Research Center at the National Institutes of Health.

At the National Cancer Institute, an alternate means of ART intensification is being explored. Frank Malderelli's research group is conducting a pilot study of the cytokine alpha interferon as an adjunct. The trial was motivated by an observation that individuals co-infected with HIV and hepatitis C may have declines in residual HIV viral load levels during alpha interferon treatment.

Although only a limited number of clinical trials can reasonably be described as curerelated at the current time, this is likely to rapidly expand. Plans are afoot at the AIDS Clinical Trials Group (ACTG) to investigate a PD-1 inhibitor made by Merck; this approach is intriguing as it may have the potential to both enhance the immune response to HIV and activate latent viral reservoirs (Kaufmann 2009; DaFonseca 2010). The company VIRxSYS has therapeutic vaccine candidate, VRX1273, that is on the verge of phase I; the construct is unusual in that it consists of a lentiviral vector based on HIV itself (Lemiale 2010). Many older gene therapies and therapeutic vaccines that remain in the pipeline (see Table 4 and Table 5) could potentially fit under the new rubric of "cure-related" (and may eventually feature in trials for that purpose), because they aim to protect susceptible cells from HIV or improve immune responses to the virus.

If appropriate circumstances arise, researchers also intend to try and duplicate the case of Timothy Brown. This is a complex goal as it involves identifying people with HIV and cancer requiring stem cell transplantation, then finding a matched donor who lacks the CCR5 receptor (in genetic terms, a donor homozygous for the CCR5Δ32 mutation). The doctors involved in Brown's case, led by clinician Gero Hütter, are spearheading this ongoing effort (Hütter 2011).

On 11 July 2011, the National Institutes of Allergy and Infectious Diseases (NIAID) announced the award of three large grants to support HIV cure research under the aegis of a program called the Martin Delaney Collaboratory (named after the late activist and founder of Project Inform who championed the cause of cure-related research). The recipients comprise teams organized by the University of North Carolina, the Fred Hutchinson Cancer Research Center in Seattle, and the University of California, San Francisco in collaboration with the Vaccine and Gene Therapy Institute of Florida. The total amount of funding is anticipated to be $70 million over five years. Additional information on the projects is being made available via a new website:

Immune-Based and Gene Therapies

The developmental pathway for these types of candidate HIV therapies is particularly complex. Because of the effectiveness of antiretroviral drugs in treating HIV, IBTs and gene therapies needs to be able to supplement their effects, or replace them (either intermittently or permanently); the latter goal obviously overlaps with the idea of a "functional cure" described in the previous section.

There are potential opportunities for supplementing ART because a proportion of HIV-positive individuals experience persistent immune dysfunction despite suppression of viral replication to undetectable levels. The features of this dysfunction typically include poor recovery of CD4 T cell numbers in peripheral blood, persistent skewing of the CD4:CD8 T cell ratio (usually around 2:1 in healthy individuals but often <1 in people with HIV), elevated immune activation and inflammation, decreased numbers of naive CD4 and CD8 T cells and increased numbers of dysfunctional, worn-out CD4 and CD8 T cells that are termed "senescent" (Deeks 2011; Erikstrup 2010; Fernandez 2006; Massanella 2010; Robbins 2009). The senescent cells resemble those that have been shown to accrue in very elderly individuals without HIV infection. The most significant risk factor for experiencing these persistent immunological perturbations on ART is initiating treatment at a low CD4 T cell count. Importantly, research shows that there is a link between these phenomena and an increased risk of illness and mortality (Kesselring 2011; Schechter 2006; Zoufaly 2011); therefore, therapies capable of enhancing the restoration of the immune system might be able to improve the prognosis for this subset of people with HIV. Currently the cytokine IL-7 appears to be the only IBT with any prospect of being evaluated for clinical benefit in this setting. There are however several other approaches that attempt to address different aspects of immune dysfunction, including anti-inflammatories and bone marrow stimulants.

Table 4. Immune-Based & Gene Therapy Pipeline 2011
Maraviroc (Selzentry)CCR5 inhibitorPfizerPhase IV
Chloroquine phosphateAnti-inflammatory, anti-inflammatoryNIAID/ACTGPhase II
HydroxychloroquineAntimalarial, antirheumatic, anti-inflammatoryMedical Research Council/Wellcome Trust/St Stephens Aids TrustPhase II
Phase I
Pegasys (peginterferon alfa-2a)CytokineNIAID/Hoffmann-La RochePhase II
Interleukin-7 (CYT 107)CytokineCytherisPhase II
HLA-B*57 cell transferCell infusionNIH Clinical CenterPhase I
TXA127Bone marrow stimulant, angiotensin 1-7Tarix PharmaceuticalsPhase I
Mesalamine (5-aminosalicylic acid)Oral anti-inflammatory drug approved for the treatment of inflammatory bowel diseaseUniversity of California-San Francisco/Salix PharmaceuticalsPhase IV
Umbilical Cord Mesenchymal Stem Cells (UC-MSC)Adult stem cells originating from the mesenchymal and connective tissuesBeijing 302 HospitalPhase I//II
Ganeden BC30, GBI-30, PTA-6086Probiotic Dietary SupplementAIDS Healthcare Foundation/Ganeden Biotech, Inc.Phase II
EtoricoxibCox-2 inhibitor, anti-inflammatoryOslo University HospitalPhase II
SimvastatinHMG-CoA reductase inhibitor, anti-inflammatoryUniversity of Pennsylvania, NIAIDPhase IV
OZ1 ribozyme gene therapyAntiviral ribozyme targeted against the tat gene, introduced into CD4 T cells via stem cellsJohnson & JohnsonPhase II
Lexgenleucel-T (formerly referred to as VRX496)Lentiviral vector encoding antiretroviral antisense, introduced into CD4 T cells ex vivoVIRxSYSPhase II
HGTV43Vector encoding antiretroviral antisense, introduced into CD4 T cells ex vivoEnzo BiochemPhase II
M87oEntry inhibitor gene encoded by a lentiviral vector, introduced into CD4 T cells ex vivoEUFETS AGPhase I
SB-728Autologous T cells genetically modified at the CCR5 gene by zinc finger nucleasesUniversity of Pennsylvania/Sangamo BiosciencesPhase I
Gene Transfer for HIV Using Autologous T CellsInfusions of autologous CD4 T cells modified with by a lentivirus vector encoding 3 forms of anti-HIV RNA: pHIV7-shI-TAR-CCR5RZCity of Hope Medical Center/Benitec LtdPhase I
Redirected high affinity Gagspecific autologous T cells for HIV gene therapyGene therapy that introduces an HIV-specific T-cell receptor into CD8 T cells and re-infuses themUniversity of PennsylvaniaPhase I

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.
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