Reason for hope in microbicide research? An interview with Zeda F. Rosenberg, ScD.
Article Type: Interview
Subject: Anti-infective agents (Usage)
Anti-infective agents (Health aspects)
Disease transmission (Health aspects)
Disease transmission (Control)
HIV infection (Risk factors)
HIV infection (Drug therapy)
HIV infection (Research)
International agencies (Officials and employees)
Author: Mascolini, Mark
Pub Date: 06/22/2009
Publication: Name: Research Initiative/Treatment Action! Publisher: The Center for AIDS: Hope & Remembrance Project Audience: General; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 The Center for AIDS: Hope & Remembrance Project ISSN: 1520-8745
Issue: Date: Summer, 2009 Source Volume: 14 Source Issue: 1
Topic: Event Code: 310 Science & research; 540 Executive changes & profiles
Product: Product Code: 2834800 Antiinfective Preparations NAICS Code: 325412 Pharmaceutical Preparation Manufacturing SIC Code: 2834 Pharmaceutical preparations
Persons: Named Person: Rosenberg, Zeda F.
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220766446
Full Text: Dr. Rosenberg is Chief Executive Officer of the International Partnership for Microbicides (IPM), Silver Spring, Maryland.

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Mascolini: Why have microbicide candidates failed with such regularity?

Rosenberg: The reasons differ for the two types of microbicides tested in trials so far. The early-generation microbicide candidates were either surfactants or polyanions. The surfactants, such as nonoxynol-9 (1) and SAVVY, (2,3) are membrane surface-active agents. Although surfactants kill HIV in vitro, their limited activity in humans probably reflects their impact on human cells: Anything that is membrane active will also probably affect human cells as well as HIV. As a result, in trials of surfactant microbicides there may have been a competition between killing the virus and harming the mucosal surface. These products were formulated so that they had to be used every time a woman had sex. Therefore, if a woman used these products many times a day, they could disrupt the mucosal surface and increase the risk of infection, which may be what happened in the nonoxynol-9 trial. (1)

The polyanions, such as Carraguard, (4) cellulose sulfate, (5) and PRO 2000, (6) have relatively low potency against HIV. You need to realize that microbicide research began in the early 1990s, before we knew how to treat HIV infection with highly active antiretrovirals. The polyanions are very large molecules that don't get absorbed well systemically, and that limits systemic toxicity. But their potency against HIV is relatively low because they do not specifically target either HIV proteins or target cell receptors. Also, after work on polyanions began, research showed that viruses using the CCR5 coreceptor are preferentially transmitted, and polyanions had even lower potency against those R5 viruses. In short, the reason some of those early polyanion products didn't work was probably because they just were not potent enough. And, as with surfactants, they were formulated to be used every time a woman had sex, so imperfect adherence would lower their impact.

Mascolini: What's your assessment of the PRO 2000 results presented at this year's Conference on Retroviruses? (6)

Rosenberg: This was a phase 2b trial designed as a proof-of-concept study to show that a product can prevent HIV transmission. Because the trial was relatively small, the confidence interval around the 30% level of efficacy crossed 0 at the lower end, which means that 0.5% PRO 2000 may be not effective at all, or it may be more than 30% effective. But at the end of the day the study was not large enough to show with statistical accuracy that PRO 2000 was effective.

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Luckily, there is a larger efficacy study with the same dose of PRO 2000, MDP301, (7) and results of that trial will be available by the end of 2009.

Mascolini: In the smaller trial, PRO 2000 did appear to protect certain subgroups of women from HIV infection. (6)

Rosenberg: Again, this is a product that must be used every time a woman has sex. Analyses of women with high levels of self-reported compliance to PRO 2000 did find higher levels of efficacy, which is what you want to see. But when you start doing subgroup analyses, you lose the original randomization of your population. Subgroup analyses are supportive data; they cannot be used to generate the comfort level that comes with statistical significance in the primary analysis.

The main result regulators look at when deciding whether to license a product is the intent-to-treat analysis, which includes every woman randomized to each arm in the study. That includes women who may not have used the product a lot, and women who did use the product a lot. Randomization takes care of the distribution of those women within each group. So those subgroup results are very intriguing; they're what you want to see to support a protective effect, but you can't go with those numbers.

Mascolini: So you're reserving judgment on PRO 2000 until you see results of the larger trial?

Rosenberg: Exactly. I think the results so far are a hint of efficacy. And that 30% point estimate, even with the large confidence interval, made us all quite happy, because previous trial data showed either no benefit with microbicides or even a trend favoring placebo. But happiness is not the same as statistical significance.

Mascolini: Where do things stand with testing antiretrovirals as vaginal microbicides?

Rosenberg: Tenofovir gel was originally tested by the NIH in safety studies in the late 1990s and again earlier in this decade. (8) Now it's in a phase 2b trial in South Africa, and results of that trial will be available in the middle of 2010. Tenofovir is one component of very successful antiretroviral regimens and it has a good safety profile, which would be a benefit in a gel microbicide.

Mascolini: What other antiretroviral classes are being considered as microbicide candidates?

Rosenberg: Here I can speak directly from IPM's experience because that is what we have been focusing on. The product most advanced in the pipeline is a nonnucleoside reverse transcriptase inhibitor, dapivirine. (9) Dapivirine is a highly potent drug, relatively easy to make, and relatively inexpensive, which is important for a microbicide. Because it is a small molecule and very hydrophobic, dapivirine lends itself very nicely to a variety of formulations, one being an intravaginal ring that can be used monthly. Another is a daily-use gel. We believe these are important benefits that will improve compliance, ensuring there is drug around when virus comes in.

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We also have a license from Pfizer for maraviroc, a CCR5 blocker approved as a therapeutic agent. It is being formulated both as a single-drug product and as a combination microbicide. We have a license from Bristol-Myers Squibb for a gp120 binder that is also being formulated for microbicide use right now.

There have been discussions about formulating integrase inhibitors (such as Merck's raltegravir and Gilead's elvitegravir) as microbicides. I don't think anyone is working on this class as microbicides right now. Originally we thought protease inhibitors work too late in the viral life cycle to be useful microbicides. Ideally, you want a microbicide to stop HIV from entering the cell, either by hitting the virus, like gp120 binders or gp41 binders, or by hitting the target cell, like CCR5 antagonists. But certain in vitro studies with explant models suggest that a protease inhibitor could add something to a microbicide combination. So there is some discussion about potential protease inhibitor microbicide candidates as well.

Mascolini: Are there resistance risks in using the same antiretrovirals in microbicides, pre-exposure prophylaxis (PrEP), and chronic treatment of infected people?

Rosenberg: The question of resistance is always raised whenever antiretrovirals are used. The real answer to your question is that we don't know--yet. Microbicide trials are designed to minimize the risk of resistance. In the trials, women are tested for HIV monthly. If they are infected, they are taken off the product immediately. So an infected woman would be on drug for a month or less, and that will limit the risk of resistance.

With all studies of antiretroviral-based microbicides, once there is a proof of concept that the product does prevent infection, then further studies will be done to look specifically at whether consistent use of the product by women who already have HIV infection will result in resistance to that antiretroviral and complicate treatment effects.

Mascolini: What are the specific resistance concerns with microbicides?

Rosenberg: There are two resistance issues people worry about with antiretroviral microbicides. One is, if there are circulating resistant strains in the population, will the product be effective in preventing new infections? To address this question, we need to remind ourselves that resistance is never an all-or-none phenomenon. What resistance means is that it takes more drug to kill the virus. It's rare that the drug just stops working completely. In treatment, you are normally limited in increasing the dose to overcome resistance because of toxicity. That's why you change drugs, because you can't raise the dose to deal with resistance. In prevention, however, the drug levels locally present in the vagina are very high. So if a resistant virus comes into the vagina, there should be enough drug there to prevent the infection. Researchers in the microbicide field don't believe resistance will be a big issue in effectiveness of the product.

The real question is, what happens when a woman taking a microbicide is infected with HIV but doesn't know it? Either she may be infected and start using a microbicide, or she may not use the product consistently, or it may not be 100% effective, and as a result she may get infected and continue using the product. In that case, we need follow-up studies to define the risk of resistance.

Very low levels of vaginal microbicide drugs are generally absorbed systemically. The rationale for using antiretrovirals locally to prevent infection is that you can keep high levels of drug where you need it--at the point of viral entry. It could be that not enough drug is absorbed systemically to exert selective pressure on the virus to create resistance. But we won't know those answers until we do the study in HIV-infected women. And we believe that study could be started ethically when we know the product is effective. If it doesn't work, why assess the resistance potential?

Those are the plans to answer these resistance questions. And those plans are being made in a very thoughtful, ethical manner, with consensus among the World Health Organization, women living in developing countries, and investigators.

Mascolini: If tenofovir or some other antiretroviral proves effective as a microbicide and enters wider use for that purpose, can there be effective monitoring in the field to prevent wide emergence of resistance in a population?

Rosenberg: Yes, because there is already a lot of ongoing monitoring for treatment. That infrastructure has been developing over time. Also, a fair amount of modeling has been done on this question. We know that if women become infected and start antiretroviral therapy, resistant virus will evolve in a certain percentage of them. Modeling suggests that if you prevent infection with a 50% or 60% protective microbieide, then fewer women will become infected and you will end up with less resistant virus circulating in that population. In other words, you never get resistance if you have no infection.

Several ongoing PrEP trials are testing oral antiretrovirals for prevention. Those researchers work very closely with the microbicide field, and we're looking closely at their modeling studies. You would expect to see more resistance occurring with oral antiretrovirals for prevention than with topical antiretrovirals, because with oral agents you do get the systemic levels that we know may result in selection of resistant virus during treatment. Those modeling studies show that, depending on the level of protection with the product, you end up with a net public health benefit in terms of resistance because you're preventing new infections.

Mascolini: If you were put in charge of global microbicide planning this afternoon, what would be your first steps?

Rosenberg: I'd make sure the product development effort is sufficiently funded to be able to move the products along as quickly as possible. We know drug development in any field is fraught with challenges, and it's the rare drug that actually makes it to approval. To mitigate against the expected failures in drug development, you need a robust pipeline, and you need to fund that pipeline to move things along as quickly as possible. You want to be able to learn why products fail, and you want the successes to move as quickly as possible into the clinic.

In the prevention field, these trials are incredibly expensive because HIV incidence is thankfully rather low, even in high-transmission settings. As a result, these trials must be very, very large. Every person in a therapeutic drug trial delivers an endpoint. It is very different in prevention trials. If you have a 4% HIV incidence rate, only 4% of your entire trial population will contribute an endpoint, which means 96% do not. So you need a very large study to give that 4% the statistical power to discriminate between effective and ineffective products. Drug companies and biotechs generally are not involved in prevention trials. The nonprofit approach drives this field, so cost considerations are critical.

Mascolini: Are there other points about microbicide research or about the biomedical prevention field in general that you'd like to stress?

Rosenberg: I think it's clear that there is not going to be a single, stand-alone prevention method, unless there were to be a highly effective HIV vaccine. But the challenges of HIV vaccine development are such that most experts feel a partially protective vaccine would be something to strive for at this point. Once you have that and you have a number of other partially protective prevention technologies, as well as partially effective strategies that are already being implemented, the goal must be combination prevention.

I believe the prevention field as a whole acknowledges this and realizes that these interventions need to be developed in tandem. When we think about access and the future, we need to think of a future in which a number of different approaches can be used together to try to end the epidemic.

References

(1.) Van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002;360:971-977.

(2.) Peterson L, Nanda K, Opoku B, et al. SAVVY (C31G) gel for prevention of HIV infection in women: a phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS One. 2007;2:e1312.

(3.) Feldblum P, Adeiga A, Bakare R, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS One. 2008;3:e1474.

(4.) Skoler-Karpoff S, Ramjee G, Ahmed K, et al. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1977-1987.

(5.) Van Damme L, Govinden R, Mirembe FM, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med. 2008;359:463-472. Erratum in: N Engl J Med. 2008;359:877.

(6.) Abdool Karim S, Coletti S, Richardson B, et al. Safety and effectiveness of vaginal microbicides BufferGel and 0.5% PRO 2000/5 gel for the prevention of HIV infection in women: results of the HPTN 035 trial. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 48LB.

(7.) ClinicalTrials.gov. Trial to evaluate PRO 2000/5 gels for the prevention of vaginally acquired HIV infection (http://clinicaltrials.gov/ct2/show/NCT00262106).

(8.) Mayer KH, Maslankowski LA, Gai F, et al. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS. 2006;20:543-551.

(9.) Fletcher P, Harman S, Azijn 11, et al. Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2009;53:487-495.

(10.) Romano J, Variano B, Copian E et al. Safety and availability of dapivirine (TMC 120) delivered from an intravaginal ring. AIDS Res Hum Retroviruses. 2009;25:483-488.
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