Why do so many HIV prevention trials fail?
|Article Type:||Cover story|
Zidovudine (Product development)
|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: 331 Product development|
|Product:||Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs SIC Code: 2833 Medicinals and botanicals; 2834 Pharmaceutical preparations|
|Organization:||Company Name: Merck & Company Inc.|
|Geographic:||Geographic Scope: United States|
Prevention research gave H IV medicine its first ironclad success,
back in the days when few considered the words success and HIV medicine
in even remotely related brainwaves. It happened on February 17, 1994,
when a panel reviewing data from Pediatric AIDS Clinical Trials Group
(PACT(;) study 076 learned that zidovudine monotherapy taken during
pregnancy by previously untreated women slashed the risk of HIV
transmission by two thirds. (1,2) Since then, more muscular prophylactic
regimens have cut mother-to-child transmission risk to about 1%.
Other biomedical HIV prevention successes followed. Postexposure prophylaxis (PEP), if begun soon after viral contact and taken faithfully, protects most people exposed to HIV on the job or in the bed? Three randomized trials found that circumcision cuts the risk of sexually acquired HIV in heterosexual men. (4-6) And getting your sex mate to don a condom usually contains the virus, as long as the condom doesn't break.
But there's also a dark side to HIV prevention research, one that has yielded hardly a pinprick of light in more than two decades of labor. The bleak record of attempts to find an HIV vaccine has already provided enough fodder for a book-long catalog of woe, (7) and that book came out years before the latest headline-spangled failure. Three placebo-controlled trials of acyclovir to control herpes simplex virus type 2 (HSV-2) as a way to lower HIV risk ended in failure, (8-10) as did six trials aimed at identifying a vaginal microbicide to block HIV. (11-16) The most recent microbicide trial vouchsafed a glimmer of hope with an agent called PRO 2000. (17)
What explains this incessant string of failures in three critical prevention areas? Is it just that finding a vaccine, a microbicide, or an HSV-2 blocker that limits HIV risk is hard? Or, as more than one scientist suggests, is it that prevention planners have bull-headedly pushed through studies of candidates bound to fail? These explanations are not mutually exclusive. Indeed, evidence backing both possibilities is rife in the annals of prevention research.
No one doubts that HIV prevention remains an exigent priority. The latest global head count tallied 2.7 million new infections in 2007, and 1 million people starting antiretroviral therapy. "So do the math," suggests Ward Gates of Family Health International in an interview with RITA! "We're losing the battle against HIV unless we have more tools." Improving prevention is no less urgent in the United States, where the Centers for Disease Control (CDC) revamped its long-standing estimate that 40,000 people pick up HIV every year, jacking that annual reckoning to 56,000. (18)
This issue of RITA! ponders that evidence with assists from 12 experts in prevention research, three of whom spelled out their thinking in extended telephone interviews (see pp. 26.29, 34).
Rapidly cycling prospects for an HIV vaccine
More ink has been spilled than plasma in trying to figure why making even a modestly effective HIV vaccine has proved impossible for over two decades. The latest inky inundation followed failure of Merck's gag/pol/nef-adenovirus vector candidate in the STEP trial (19,20) and subsequent speedy shutdowns of two related studies, Phambili (testing the same vaccine in South Africa (21)) and PAVE 100 (testing an HIV DNA vaccine with the same adenovirus vector in the United States (22)).
This retrenchment is only the latest chapter in a largely inglorious history of HIV vaccine development. The endeavor began with bright hopes in 1984, when discovery of HIV-1 prompted US health chief Margaret Heckler to predict an HIV vaccine would be ready for testing in 2 years. Heckler, a long-time Republican pol considered for a NASA job just before becoming Ronald Reagan's Secretary of Health, learned to her regret that retrovirology is tougher than rocket science. Knowing little then about HIV's relentless mutability, few scientists stepped forward to challenge this brassy assertion. In fact, Heckler's office based the prediction on input from Robert Gallo, according to Science reporter Jon Cohen. (7) And many HIV vaccine researchers went on to suggest routinely that the world would have an HIV vaccine "in 10 years," though they offered that augury repeatedly as calendar pages flew by.
With the turn of the millennium come and gone and no vaccine in sight, some credible experts began counseling that an HIV vaccine may never be made. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID) and the country's most visible vaccine spokesman, counseled in 2004 that "all of us are working under the assumption that we will [develop a vaccine], but there's certainly the possibility that we're not going to be able to develop a truly effective preventive vaccine." (23)
And at the 2008 Conference on Retroviruses, after the Merck failure, Harvard's Ronald Desrosiers warned, "there is no rational basis for believing that any of the products in the pipeline have any chance of effectiveness. Dollars that could have been used for discovery research have been used to manufacture and test products that have little hope." (24)
What went wrong? Does HIV vaccine research resemble a staccato volley of "shots in the dark," as Jon Cohen suggested in titling his coruscating account of vaccine science in 2001. (7) Angus Dalgleish, who identified CD4 as HIV's primary cellular receptor and studies HIV and cancer immunology at St. George's University in London, thinks vaccine planning pros still shoot blindly, though he mostly eschews dainty metaphor:
"The people at the top of the research and funding agendas have an extreme version of tunnel vision," Dalgleish told RITA! by e-mail. They "ignore the strong signals that HIV is different from other viruses which can be successfully prevented by vaccines. Even most of the immunologists involved are blind men feeling an elephant."
The University of Pennsylvania's David Weiner, a champion of DNA vaccines, also believes ideology can derail research planning, though he suggests there's a good reason: "Scientists have strong opinions and these are important as they are asked to invent a safer future," he told RITA! "They live on the edge of the scientifically possible and they need the conviction to jump of f the edge." But, Weiner insists, scientists must remember "balance is key and not ideology."
Now, fewer than 2 years after STEP, Phambili, and PAVE investigators closed shop, some prevention mavens sound propitious once more. Anthony Fauci told RITA! "we are certainly not giving up" on devising a vaccine that confers sterilizing immunity. "I have cautious optimism that we will be able to do it." (See the interview with Dr. Fauci on p. 26.)
The University of North Carolina's Myron Cohen thinks "the vaccine field is making progress" because "the basic science is moving very fast right now." (See the interview with Dr. Cohen in this issue.)
Even Ronald Desrosiers, the last person one would call an HIV vaccine Pangloss, sees reason for hope, he told RITA! "I believe that the approach described by Phil Johnson at this year's CROI meeting (25) has the potential of conferring sterilizing immunity against the majority of strains circulating around the globe." (See below for more on Johnson's strategy.)
Dare one espouse a rosy outlook so soon after the resounding rout of a vaccine called "promising" so routinely that people assumed it was part of the vaccine's name? A look at how vaccine research got where it is today suggests no need to abandon all hope.
What should an HIV vaccine do?
As surprising as it sounds, that remains a contentious question. Some say the only sensible HIV vaccine must stimulate antibodies that recognize HIV and neutralize it before infection takes hold. Others say a vaccine that stirs up HIV-killing T cells, like the Merck vaccine, would be a big step forward. A third contingent insists a successful vaccine must do both. And a fourth party proposes skinning the virus some other way entirely.
HIV vaccine efficacy trials began (notoriously) with two trials of AIDSVAX, which tried to pique neutralizing antibodies by subjecting high-risk populations to a recombinant mimic of HIV's gp120 envelope protein (Table 1 on page 8), (26,27) Almost everyone--except, apparently, the investigators and the developer--believed from the start that AIDSVAX would flop because HIV's envelope mutates so avidly and because neither monoclonal antibodies to gp 120 (28) nor envelope subunit vaccines (29) neutralized viral isolates from people--they worked only on lab strains.
And flop it did, inspiring near unanimity on two points: First, mounting vaccine efficacy trials on a scaffold of shaky science is a dreadful waste of human and financial capital. And second, tricking the body into making antibodies that handcuff HIV is every bit as hard as predicted. Years after the AIDSVAX flameout, how to elicit neutralizing antibodies still vexes the most thoughtful scientists. Indeed, research has yielded few clues on which antibodies to summon, although several investigators doggedly pursue antibody vaccine leads.
Difficulties with the antibody approach did much to stoke interest in a vaccine that sparks cell-mediated immunity. Cell-mediated immunity won't protect a person from HIV, because HIV-specific T cells go after already-infected cells. But, in theory, cell-based immunity could keep HIV replication under wraps long enough to delay antiretroviral therapy, and well enough to keep infected people from spreading HIV to sex mates.
Merck's MRKAd5 vaccine aimed to harness HIV by stimulating HIV-fighting cells in a double-blind, placebo-controlled trial at 34 sites in North America, the Caribbean, South America, and Australia. (19,20) An interim analysis found that, among people with a prestudy adenovirus 5 (Ad5) antibody titer below 201, 24 of 741 people (3%) getting the vaccine and 21 of 762 (3%) getting dummy shots picked up HIV infection. (19) Looking at all study participants regardless of prestudy Ad5 antibody levels, the researchers found a 2-fold higher risk of HIV infection in Ad5-positive men who got the vaccine than in the placebo group (hazard ratio 2.3, 95% confidence interval 1.2 to 4.3). Even though the vaccine induced HIV-specific CD8 cells, (20) it did not lower the HIV load set point significantly more than placebo. (19)
Although the media reported the Merck failure in doomsday vernacular and scientists thrashed vigorously for explanations, more than a few vaccine savants saw little reason for surprise. Indeed, some had predicted failure before the bad news came. NIAID's Anthony Fauci and Margaret Johnston noted skepticism that the Merck vaccine or a prime-boost vaccine "will be effective in the prevention of HIV infection" in the May 17, 2007 New England Journal of Medicine. (30)
As long ago as 2001, Dutch virologist Jaap Goudsmit baldly stated that vaccines aimed at stirring cell-mediated immunity "will never do anything else than postpone AIDS ... [and] they will not block or hamper spread [of HIV] substantially." (31)
After the STEP trial bust, Fauci shut down an already-truncated version of the PAVE study, designed to test a similar vaccine. STEP's collapse, Fauci said in a Scientific American interview, led some to say, "Well maybe we can look at the immunological response and get some information from a subset of people in the trial who seem to have responded well." (32) But "that's a fallacious approach," he maintained. "If the vaccine doesn't work, doing immunological correlates, in my mind, and the minds of many many of my colleagues, is not worth doing."
Is there any reason to continue working on T-cell vaccines for HIV? "No," Angus Dalgleish told RITA! "Even my dog sees this one."
But David Weiner counters that "the same question could be raised for antibody approaches following the VaxGen studies (26,27) where antibodies had no impact." The University of Pennsylvania vaccine expert explains that the Merck vaccine "induced a low level of interferon-gamma ELISPOT response against perhaps only three [viral] epitopes at a very low magnitude, well below those levels in infected persons that control infection." On top of that, the vaccine stirred such responses in only 60% to 70% of vaccinated people, and higher HIV incidence in people with high Ad5 levels confused interpretation of results.
"But," Weiner adds, "as soon as a true cytotoxic T lymphocyte [CTL] vaccine is developed that in people drives CTLs at a greater rate, and stronger magnitude, and more breadth, I would be in favor of a small focused study."
Stanley Plotkin, who devised the rubella vaccine and worked on several other viral vaccines at Philadelphia's Wistar Institute, agrees with Weiner. "It is still clear that some forms of cellular immunity control viral load," he told RITA! In a post-STEP review article, Plotkin pointed to "numerous leads with regard to improving cellular immune responses to an HIV vaccine." (33) Failure of the Merck candidate, he added, "says only that the responses induced were inadequate to simulate those induced during natural infection that appear to control HIV temporarily."
Jorge Flores, deputy director of a vaccine research program at NIAID, confirms that "the field has been polarized pro/against continuing development of T-cell vaccines." But "such polarizations are not uncommon in science," he adds, "and at the end may be useful." Arguing that a combined antibody/T-cell vaccine would be "ideal," Flores cautions that "the T-cell concept should not be dropped prematurely."
But whether anyone will sponsor another T-cell vaccine trial, when no one expects that kind of vaccine to prevent infection, remains open to question. More data on T-cell and antibody-stimulating approaches will come from a nearly finished phase 3 Thai trial of a vaccine intended to excite T-cell responses with HIV-1 subtype E gag, pro, and env, and to elicit an antibody response with subtypes B and E gp 120. This prime-boost vaccine survived a preliminary efficacy review, but Fauci and Johnston observe that this candidate "does not induce broadly neutralizing antibodies" and they note scientific doubt about its chances. (30)
Looking for ways forward, looking for funds
With researchers at sixes and sevens over the rationale for stimulating cell-mediated immunity, work to find a stout antibody-stimulating vaccine is moving back to the front burner. In an interview in this issue of RITA!, NIAID chief Fauci confirms the renascent search for an antibody vaccine, pointing to research by NIAID investigator Peter Kwong (34) and Scripps Research Institute scientist Dennis Burton. (35)
The "reverse immunization" approach taken by Philip Johnson at Children's Hospital in Pennsylvania--touted by vaccine veteran Ronald Desrosiers--starts by pinpointing broadly neutralizing antibodies then synthetically fashions genes that produce those antibodies and ferries them to cells on an adenovirus vector. (25) This strategy produced high levels of simian immunodeficiency virus (SIV)-specific antibodies in monkeys after a single injection, and those levels persisted for up to a year. The antibodies protected six of nine moneys from intravenous SIV challenge 1 month after injection. All six unvaccinated monkeys became infected after challenge. Johnson plans to pursue approval for trials in humans.
Stimulating antibody responses, stimulating T cells, and doing both are not the only conceivable vaccine tactics. In his e-mail to RITA! Dalgleish proposed that "the way forward is a therapeutic vaccine based on the activating ligands which, because they are nonneutralising, have been ignored by the field." He suggests that a vaccine preventing ligand activation may prevent viral dispersal and "could be an ideal preventative as well."
Despite the back-to-basics bent stressed after STEP, several vaccine deans, including Fauci, caution against abandoning clinical research entirely until a strong candidate emerges. University of Pennsylvania scientist David Weiner believes "a focus on basic research without clinical research is not the best course." Animal models are useful, Weiner maintains, but studies in humans, "even vaccine efficacy trials, are critical to moving forward." Though disappointing, the AIDSVAX and STEP trials advanced the field by "forcing us to face our failures and move forward."
Stanley Plotkin told RITA! the need for more basic research is clear. "However," he added, "if a candidate looked really good in a robust simian model, I would consider a phase 2b trial."
Both basic and clinical research can be expensive. Monkeys for SIV studies carry a high price tag, and the bigger the human trial, the bigger the budget. Right now the National Institutes of Health spend about $600 million yearly on HIV vaccine research. (26) But is that enough, and is it going to the right labs?
NIAID's Flores thinks NIH and Gates Foundation dollars are flowing in the right direction. After STEP, both "promptly switched the discovery/development balance to attend to the new information in the field and support more basic innovative research," he told RITA! Still, Flores sees a need for "additional funding to engage folks outside the field with new ideas and perspectives to cross-fertilize with HIV vaccine researchers."
But David Weiner argues that "the entire NIH vaccine budget is a few fully equipped fighter planes, a few pork programs." He suggests that funders "consider the payoff" of investing in basic and clinical research: "Through this research we live longer, healthier lives and generate a tremendous number of jobs and help to support our economy and help America compete in the global economy."
Ultimately, though, "the problem is not lack of money," Plotkin maintains, "but biological complexity."
Stalling HSV-2 to stop HIV: a great idea falls flat
Suppressing HSV-2 to prevent HIV acquisition or transmission made as much sense as circumcising men to lower HIV risk. Volumes of epidemiologic data backed each strategy as a seemingly surefire bet to protect people from HIV. When researchers tested circumcision as a way to limit men's risk of picking up HIV, it worked consistently in three randomized trials of immediate versus deferred circumcision. (4-6) When researchers tested HSV-2-suppressive acyclovir therapy as a way to slow HIV in three placebo-controlled trials, it failed every time (Table 2 on page 1 2). (8-10)
Ate these contrasting trial results merely a stern object lesson on the limits of cohort data? Or do they also hold lessons on the value of treating any sexually transmitted infection (STI) as a tool to trim HIV incidence? Some experts are suggesting the second, broader implication may apply as well as the first.
Researchers cataloged a library of data suggesting that muzzling HSV-2 would slow HIV's spread. Myron Cohen and coauthors cited "overwhelming epidemiologic evidence" tying classical sexually transmitted infections (STIs) to HIV risk, (37) especially ubiquitous STIs (like Trichomonas and HSV-2), STIs that produce lifelong infection (like HSV-2), and STIs that trigger ulcers (like syphilis and HSV-2). A meta-analysis figured that prevalent HSV-2 infection triples the risk of heterosexually acquired HIV in the general population. (38)
Why did this sterling rationale tarnish so consistently in placebo-controlled trials of acyclovir? In an interview in this issue of RITA!, Myron Cohen suggests two prime possibilities:
1. The hypothesis was wrong.
2. The intervention was insufficient.
In an e-mail to RITA!, Johns Hopkins prevention expert Ronald Gray expands on these possibilities, suggesting that:
1. HSV, especially chronic HSV infection, "may play too small a role in HIV acquisition to be detectable" in trials.
2. HSV-2 "suppression with acyclovir may be incomplete, leaving residual microulceration/ inflammation and thus be insufficient to prevent infection."
3. "The associations between HSV and HIV infection reported in observational studies may not reflect causality, but rather may be due to confounding by high-risk behaviors which put individuals at risk of both HSV and HIV." In other words, herpes simplex infection may not lead to HIV acquisition, but rather high-risk behaviors lead to both infections, "and since HSV is more infectious [than HIV], people acquire it before they acquire HIV."
In an editorial with coworker Maria Wawer, Gray noted that African studies on what causes genital ulcers fail to pinpoint specific pathogens in many ulcers, "so ulceration unrelated to HSV-2 could have diluted the expected effect" of acyclovir. (39)
If acyclovir is too wimpy to affect HIV incidence, would valacyclovir do the job? Two randomized trials found that people taking valacyclovir instead of placebo shed less HIV in genital secretions, (40,41) a result implying that valacyclovir could dampen HIV transmission. But acyclovir also reduced HIV genital HIV shedding in some studies, (42,43) and the Partners in Prevention trial found that giving acyclovir to people already infected with HIV did nothing to protect their sex mates. (10) Whether valacyclovir would do better is anybody's guess.
Even if acyclovir therapy had helped block HIV infection, no one ever proposed rolling out a massive acyclovir program to dampen the HIV epidemic. "It seems unlikely that HSV-2 suppression interventions could be provided to all HSV2-infected individuals in low-resource settings," University of Washington investigator Scott McClelland explained in an e-mail to RITA! "Nonetheless," he added, "these types of interventions, if proven to be effective, could be useful if targeted towards those most at risk for sexual acquisition or transmission of HIV. For example, interventions targeting female sex workers and men who have sex with men could benefit these groups directly, and might also have population-level benefits." But now it seems even targeted intervention would prove futile.
Prevention experts hasten to stress that dim results of the acyclovir trials do not mean HIV physicians should forget about treating HSV-2 and other STIs in people with or at risk of HIV infection. Cohen and coauthors (37) observe that, besides the inherent clinical value of controlling non-HIV STIs, having these people in care can yield HIV benefits because they are more likely to have unrecognized HIV (44) or to become infected with HIV (45) than people without STIs.
But some prevention bigwigs are beginning to counsel that STI control should be dropped as an HIV prevention tactic. Dire data backing their argument go beyond the three hope-dashing acyclovir trials. In their editorial,: (39) Gray and Wawer note that five of six African trials testing bacterial infection therapy to slow HIV also found no impact on HIV incidence. (46-50) And the sixth trial involved a population with an HIV rate atypically low for Africa. (51) Adding the three acyclovir trials means seven of eight trials testing this tactic flopped.
Despite this record of failure, Gray and Wawer observe that many agencies and HIV programs continue to advise STI control as a way to bridle HIV. But the trial record strongly argues that pursuing this discredited strategy only robs funds from proved prevention measures. They quote Thomas Henry Huxley's apothegm that "the great tragedy of Science" is "the slaying of a beautiful hypothesis by an ugly fact." Ugly facts from the STI trials, Gray and Wawer propose, should inspire some fast adjustments in HIV prevention policy.
Microbicide hopes after first-generation failures
Microbicide trials have an even bleaker record than acyclovir trials. Whereas three acyclovir trials found no hint that treating HSV-2 cornered HIV, six microbicide trials came up empty. (11-16) Yet microbicide researchers remain brimful of hope that a vaginal gel can protect women from HIV. Three factors explain the starkly differing prospects for these two prevention schemes:
1. Microbicides that failed so far come in two classes that--at least in retrospect--have long odds against success.
2. Newer microbicides rely on antiretrovirals, which certainly stymie HIV when taken orally.
3. The most recent trial of a first-generation microbicide offered some hints of success, (17) and a much larger trial of that agent is nearly wrapped up.
As Zeda Rosenberg of the International Partnership for Microbicides explains in an interview in this issue of RITA!, the first microbicides tested in efficacy trials, nonoxyno (1-9) and SAVVY, (11-13) work on surface membranes. As a result, they can harm cells as readily as HIV, and in trials these so-called surfactants apparently ravaged cells more than they wracked HIV. Unlike surfactants, the polyanions--Carraguard, (14) cellulose sulfate, (15) and PRO 2000 (17)--have intrinsically limp antiretroviral activity.
So why did these agents ever make it into big efficacy trials? Rosenberg observes that microbicide studies started in the early 1990s, before anyone understood how profoundly the right antiretroviral mix can stifle HIV. Other experts are more critical. The Gladstone Institute's Robert Grant and a starry cast of coauthors blame "poor coordination among interested parties and the choice of nonvalidated scientific targets for phase III studies." (52)
In a trial comparing the polyanion PRO 2000, the spermicide BufferGel, and placebo in 3099 African and US women, 36 women using 0.5% PRO 2000, 54 using BufferGel, and 53 using placebo picked up HIV. (17) In the primary intention-to-treat analysis, those results meant PRO 2000 had a 30% protective effect compared with placebo, but the difference between PRO 2000 and placebo stopped short of statistical significance (P = 0.10). A 33% protective effect would have been statistically significant.
After a dispiriting string of microbicide failures, that hair's-breadth distance from unmitigated success looked pretty good to some prevention experts. In a phone interview, Ward Cates of Family Health International argued that "there is nothing magic about a 0.05 traditional level" for statistical significance. The 0.05 benchmark signifies a 1 in 20 probability that a result occurred by chance alone. The trial found that PRO 2000 had "about a 1 in 17 probability of occurring by chance alone--close enough to provide encouragement."
In an interview in this issue of RITA!, Cohen claims to be "very encouraged because PRO 2000 is incredibly better than nothing. As a vehicle, it's incredibly better than nothing." Notably, PRO 2000 researchers counted only 33 serious side effects of complications in 769 women using that microbicide--a rate of 4%. (17)
Whether Cates and Cohen can sustain their cheer will come clear later this year when results of MDP301, a trial of 0.5% PRO 2000 in more than 9000 people, are divulged. (53) Until then, microbicide advocates must make do with subgroup analyses of the completed trial. (17) Among 769 women randomized to PRO 2000, 81% reported better than 85% adherence to gel use, 72% reported faithful condom use by partners, and 68% reported better than 85% gel use when partners shunned condoms. Comparing women who used gel more than 85% of the time with women who used gel less, the investigators charted a 44% lower HIV rate with PRO 2000 than with placebo. Looking only at women who used gel consistently with partners who did not wear condoms, PRO 2000 reduced HIV incidence 78% compared with placebo.
Those results suggest that women who use PRO 2000 regularly, especially when their partners shirk condoms, may sidestep HIV 40% to 80% more of ten than women not using PRO 2000. But as Rosenberg observes in her RITA! interview, interpreting subgroup analyses gets dodgy because such analyses lose the objective power of randomization.
Cohen suggests one reason the PRO 2000 findings have not whipped up wider zeal is the high hope for trials using antiretroviral-containing microbicides. CAPRISA 004 enrolled 980 South African women with a high HIV risk and randomized them to use 1% tenofovir gel or placebo. (54) Results should be ready in 2010. A vaginal microbicide combining tenofovir and emtricitabine protected 6 of 6 monkeys challenged vaginally with a simian-HIV mix (SHIV). (55)
Clinical trials of the nonnucleoside dapivirine and the nonnucleoside UC-781 are under way. As Rosenberg notes, microbicide researchers are working with antiretroviral makers to plan microbicide studies of agents in other classes. The microbicide story may still be in its early chapters.
Preparing for success with PrEP
Antiretrovirals used in vaginal or rectal gels to prevent HIV are called microbicides; antiretrovirals taken by mouth to prevent infection are called pre-exposure prophylaxis, or PrEP. McGill University researcher Mark Wainberg and London clinician Mike Youle were among the first to espouse antiretroviral-based PrEP, back in 2003. (56,57) Specifically suggesting PrEP studies of tenofovir because of its low toxicity and success in postexposure prophylaxis (PEP), Wainberg and Youle cautioned that developing antiretroviral PrEP "will not be simple and will take time." (56)
They were right about the complexity, and they were right about the time. Many prevention pundits also believe they were right about the potential for success. In an interview in this issue of RITA!, Myron Cohen affirms a strong belief that antiretroviral PrEP trials "are going to demonstrate prevention of acquisition, especially heterosexual penile-vaginal acquisition." And Wainberg's ardor has not dimmed, he told RITA!, intrepidly predicting that tenofovir/emtricitabine PrEP trials "will succeed in a major way."
Tenofovir plus emtricitabine coformulated as Truvada has fomented particular PrEP fervor, partly because the drugs have a relatively clean safety record when used daily, partly because they have long intracellular half-lives, partly because two drugs erect a higher barrier to resistance than one, and partly because these drugs prevented rectal SHIV transmission in 4 of 6 monkeys receiving human-equivalent daily doses and challenged weekly with SHIV for 14 weeks. (58) The two animals that became infected picked up SHIV on the ninth and twelfth exposures.
Numerous phase 2 and 3 placebo-controlled trials of PrEP with tenofovir or tenofovir/emtricitabine are under way in gay men, heterosexual men and women, discordant heterosexual couples, and injecting drug users in North and South America, Africa, and Asia. (37) Mounting these trials wasn't easy. Two early tenofovir PrEP trials ended before they began, largely at the instigation of AIDS activists who convinced leaders in Cambodia and Cameroon that the studies were unethical. (59,60) The protesters claimed the trials lacked adequate prevention counseling, pre- and post-test HIV counseling, and medical services and insurance for people who became infected in the studies. (59)
The principal clinical concern with antiretroviral PrEP is resistance. If a person taking single- or double-drug PrEP does becomes infected without realizing it--or unknowingly has HIV before starting PrEP--the virus will have a splendid chance to replicate in the face of flimsy treatment, and resistant virus will probably evolve. When that person's HIV infection is diagnosed, regimens containing drugs to which the virus has become resistant probably won't work. And if that person passes HIV to a sex partner before getting suppressive therapy, the partner will probably pick up the resistant virus.
Resistance risks seem lower with topical microbicides than with oral PrEP drugs, because microbicides put overwhelming concentrations of drug at HIV's port of entry--the vagina or the rectum--while yielding minimal systemic drug levels. In theory, high local drug levels will keep HIV out, and no virus means no resistant virus. In a US study, resistant virus did not evolve during 14 days of tenofovir gel use by 24 HIV-infected women. (61) of course, gel adherence will differ in a 14-day controlled trial and in real-world use of vaginal or anal gels, and imperfect adherence will up the odds of resistance.
Resistance certainly poses a bigger threat with oral PrEP drugs than with topically applied antiretroviral gels. In the monkey study of tenofovir/emtricitabine PrEP, the investigators continued giving the drugs to animals that became infected. (58) The M184I mutation emerged in one of two animals that became infected while taking oral tenofovir/ emtricitabine. M184I confers resistance to emtricitabine and lamivudine. The tenofovir-associated K65R mutation did not emerge.
If a person is unknowingly infected before starting tenofovir-based PrEP or becomes infected despite PrEP, observes Mark Wainberg, circulating HIV may select resistant virus. "I believe that this highlights the need to carefully monitor for resistance" in people taking PrEP, Wainberg told RITA! But the resistance threat is "certainly not a reason to abandon PrEP." No one advocates banning antiretroviral therapy because resistant HIV may evolve in treated people.
PEP after sex or drug use: no waste with baste
Postexposure prophylaxis (PEP) with antiretrovirals has become a standard of care after health workers get poked with a needle that may bear HIV or otherwise have a bloody brush with the retrovirus? The Centers for Disease Control (CDC) also recommends PEP after "nonoccupational" sexual exposure or needle sharing. For both occupational and nonoccupational encounters, the CDC calls for PEP only when "exposure to an HIV-infected source is known or thought to be highly likely." (3) After contacting blood or other fluids from a person with uncertain HIV status, the CDC says PEP decisions should be made "on a case-by-case basis, considering the information available about the type of exposure, known risk characteristics of the source, and prevalence in the setting concerned."
When someone needs PEP, it should start as soon as possible, without waiting for HIV test results, the CDC advises. (3) The agency does not say which antiretrovirals to use for PEP, suggesting only that "regimens should aim for simplicity and tolerability," that pregnant women should not take efavirenz, that no one should take nevirapine, and that inexperienced physicians should tapan antiretroviral expert. PEP should continue for 4 weeks, and the PEP recipient should get tested for HIV within 72 hours if rapid HIV testing is not available.
Exactly how well PEP works after sex or needle sharing can never be established because a randomized trial is virtually impossible: Infection rates in both treated and untreated people would be so low that only a massive trial could distinguish any difference between PEP and no PEP. (37) And then there are ethical questions.
There's little doubt, though, that nonoccupational PEP candidates are legion across the world, according to results of studies in the United States, (62) Brazil, (63) and Kenya. (64) Researchers in New York state asked directors of 207 hospital emergency departments to answer a survey about nonoccupational PEP after sexual assault or consensual sex. The 188 directors who responded (91%) reported 3439 sexual assaults that may have exposed people to HIV and 6858 consensual sexual exposures in a single year, 2005. (62) And that leaves out the likely thousands exposed to HIV by needle or syringe sharing. Notably, PEP began for only 65% of sexual assault cases and after 43% of consensual liaisons, even though most hospitals had protocols recommending PEP.
In Rio de Janeiro, researchers gave 200 HIV-negative gay mena 4-day supply of zidovudine/ lamivudine and told them to start the drugs if they had sex with an HIV-infected person. (63) After 2 years of follow-up, 68 men (34%) started PEP 109 times, and 10 more men should have because they became infected after deciding not to start PEP. Kenya launched a national PEP policy in 2001. (64) Between November 2001 and December 2006, 355 people in western Kenya sought PEP after potential nonoccupational exposure to HIV, including 285 women and girls (80%) and 90 children (25%).
The few published studies on nonoccupational PEP efficacy show that it works well, as long as people start fast. A 2005 report from San Francisco General Hospital involved 877 people beginning a 28-day PEP course after exposure to HIV in the preceding 72 hours. (65) Among 702 people evaluated 12 weeks after potential exposure, 7 (1%) had HIV infection. Four of those 7 had another sexual adventure with an HIV-infected person while on PER The remaining 3 also had sex again, but they weren't sure of their partner's HIV status. The people who became infected despite PEP began treatment a median of 45.5 hours after exposure, while those who remained uninfected started a median of 32.5 hours after exposure. Although that difference falls short of statistical significance (P = 0.11), it supports advice to start PEP as soon as possible.
An earlier 401-person study of nonoccupational PEP at San Francisco General Hospital recorded no HIV diagnoses 6 months after suspected exposure to the virus. (66) The Brazilian study found only 1 HIV seroconversion after 109 PEP courses (0.9%). (63) Among 87 PEP patients with follow-up HIV antibody tests in Kenya, none had HIV infection. (64) A study of 112 gay men taking two-drug PEP after 116 potential exposures saw no seroconversions. (67)
The best PEP regimen will probably never be established and will probably change as antiretrovirals get stronger and safer. Although a standard three-drug regimen may seem the best bet to keep HIV at bay, three-drug combinations typically cause more side effects than double-drug pairs, and side effects dissuade people from completing their PEP course. So why use three drugs if two will prevent infection? Comparing tenofovir/emtricitabine or tenofovir/lamivudine with zidovudine/lamivudine, clinicians at the largest HIV clinic in New England caring for gay men found that none of 112 people taking tenofovir-based PEP after 116 exposures stopped of modified their regimen because of side effects. (67) PEP completion rates were 87.5% with tenofovir/lamivudine, 72.7% with tenofovir/ emtricitabine, 42.1% with zidovudine/lamivudine, and 38.8% with zidovudine/lamivudine plus a third drug.
Even prevention cooperation question breeds controversy
Would the world profit from more cooperation in prevention science? You'd think this vanilla question would inspire rhapsodic encomiums to far-flung scientists working shoulder-to-shoulder to halt transmission of HIV. But you'd be wrong.
As Rosenberg observes in her RITA! interview, health workers will probably have to cobble together several prevention strategies to keep HIV at bay--unless a highly effective HIV vaccine emerges. But does the likely need for manifold prevention tactics mean researchers must always work together to perfect those tactics? The very notion makes some scientists' skin crawl.
Johns Hopkins investigator Ronald Gray, who works on several HIV prevention fronts, doesn't think cooperative research will solve anything, but will further expand administrative burdens and mix conflicting agendas. "The current networks for prevention are already bogged down and underperforming," Gray explained in an e-mail to RITA! "What science needs is bold vision, careful thought and individual initiatives, not more committees and conference calls which waste time and lead to group-think lowest common denominators." Gray adds that these are precisely the reasons why the Hopkins team works independently and left a number of NIH networks.
Other prevention mavens only hinted at their disdain for the committee approach, answering RITA!'s question about cooperation with an apparently sardonic "I thought that all arms of prevention science got along well."
Scientists who answered questions for this issue of RITA
Willard Cates, Jr, MD, MPH, President, Research, Family Health International, Research Triangle Park, North Carolina
Myron S. Cohen, MD, J. Herbert Bate Distinguished Professor of Medicine and Microbiology, Immunology & Public Health, School of Medicine, University of North Carolina (UNC) at Chapel Hill; Chief, Division of Infectious Disease; Director, UNC Institute for Global Health and Infectious Diseases, Chapel Hill, North Carolina
Angus G. Dalgleish, MD, Foundation Professor of Oncology, St. George's University, St. George's Hospital Medical School, London, UK
Ronald Desrosiers, PhD, Professor of Microbiology and Molecular Genetics, Harvard Medical School, Director of the New England Primate Research Center, New England Regional Primate Research Center, Southborough, Massachusetts
Anthony S. Fauci, MD, Director, National Institute of Allergy and Infectious Diseases (NIAID), Chief, NIAID Laboratory of Immunoregulation, National Institutes of Health, Bethesda, Maryland
Jorge Flores, MD, Deputy Director, Vaccine Research Program, DAIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Ronald Gray, MD, Professor, William G. Robertson Jr. Professor in Population and Family Planning, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
R. Scott McClelland, MD, MPH, Associate Professor, Departments of Medicine and Epidemiology, University of Washington, University of Nairobi College of Health Sciences, Nairobi, Kenya
Stanley A. Plotkin, MD, Professor Emeritus of Virology, The Wistar Institute, Emeritus Professor of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania; Executive Advisor, Sanofi Pasteur, Doylestown, Pennsylvania
Zeda Rosenberg, ScD, Chief Executive officer, International Partnership for Microbicides, Silver Spring, Maryland Mark A. Wainberg, PhD, Director, McGill AIDS Centre, McGill University, Montreal, Quebec, Canada
David B. Weiner, PhD, Professor, Department of Pathology and Laboratory Medicine, Chair, Gene Therapy and Vaccine Program, CAMB, University of Pennsylvania, Philadelphia, Pennsylvania
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Table 1. Results of large placebo-controlled HIV vaccine trials Vaccine Purpose of vaccine Study participants AIDSVAX (26) Recombinant HIV subunit 5095 gay men (gp120) to prevent HIV and 308 women infection by stimulating at high risk of antibody- mediated HIV infection immunity AIDSVAX (27) Recombinant HIV subunit 2546 injecting (gp120) to prevent HIV drug users infection by stimulating antibody- mediated immunity MRKAd5, (19,20) HIV proteins Gag, Pol, 3000 STEP trial and Nef on adenovirus vectors to prevent HIV infection or limit HIV load by stimulating cell-mediated immunity Vaccine Sites Key results AIDSVAX (26) North Vaccine did not prevent America and HIV infection; HIV the incidence 6.7% with Netherlands vaccine and 7.0% with placebo AIDSVAX (27) Thailand Vaccine did not prevent HIV infection; HIV incidence 8.4% with vaccine and 8.3% with placebo MRKAd5, (19,20) North Vaccine did not prevent STEP trial America, HIV infection; among the Caribbean, people with adenovirus 5 South America antibody titer <200, HIV Australia incidence 3% with vaccine and 3% with placebo; risk of HIV 2.3 times higher with vaccine among adenovirus 5-positive men; HIV load set point equivalent with vaccine and placebo Table 2. Results of randomized trials of HSV-2 suppression to prevent HIV infection First author Goal Countries Participants Watson-Jones (8) Determine Tanzania 821 women whether working in 400 mg recreational of acyclovir facilities twice daily (vs placebo) will prevent HIV infection in women with HSV-2 Celum Determine South Africa, 1358 (HPTN 039) (9) whether Zimbabwe, women 400 mg Zambia and 1814 of acyclovir (women); gay men twice daily USA, (vs placebo) Peru will prevent (gay men) HIV infection in women and men with HSV-2 Celum Determine Botswana, 3408 HIV- (Partners in whether Kenya, discordant Prevention) (10) 400 mg Rwanda, couples of acyclovir South Africa, (one partner twice daily Tanzania, with HIV, (vs placebo) Uganda, the other will prevent Zambia partner transmission without of HIV from HIV) people with HSV-2 to their HIV-negative partner First author Duration Main findings Watson-Jones (8) Average Acyclovir has no 1.52 years impact on acquisition with of HIV; 27 infections acyclovir in the acyclovir and group, 28 in the 1.62 years placebo group; with median estimated placebo adherence 90% Celum 18 months Acyclovir has no (HPTN 039) (9) impact on acquisition of HIV; incidence 3.9 per 100 person- years in the acyclovir group, 3.3 per 100 person-years in the placebo group Celum Not Acyclovir has (Partners in reported no impact on Prevention) (10) yet * transmission of HIV; 41 infections of partners in the acyclovir arm, 43 infections of partners in the placebo arm * Results of Partners in Prevention were not formally presented when this article was written.
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