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HIV Prevention at CROI 2010
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Jared Baeten, MD PhD
Connie Celum, MD MPH
University of Washington
Continuing the trend in recent years, HIV prevention was central at CROI 2010, with important work presented relevant to populations both in the US and worldwide.
Antiretroviral Treatment for HIV Prevention
Arguably the strongest predictor of HIV transmission risk in epidemiologic studies is the level of HIV in blood. When HIV infected persons are treated with antiretroviral therapy (ART), plasma and genital viral concentrations decrease, usually to extremely low levels, which is expected to substantially reduce the infectiousness of HIV infected persons. Mathematical modeling studies have argued that increasing the number of persons on ART could substantially reduce new HIV transmissions, particularly if the number of persons who know their HIV serostatus is substantially increased, if they are effectively linked to HIV care, and if ART is initiated (together called the 'test and treat' strategy). The concept of treating more HIV-infected persons with ART as an HIV prevention strategy has generated great international scientific enthusiasm and debate during the past year.
The ultimate impact of ART on HIV spread is still a topic of debate. In a symposium on the global epidemic, Dr. Brian Williams from the South African Center for Epidemiologic Modelling and Analysis presented mathematical modeling work assessing the potential benefits of use of wide-spread ART to reduce HIV transmission (abstract 13). With wide-spread ART provision, substantial reductions in new HIV infections could be realized, although the modeling work assumes high levels of HIV testing, uptake of ART (specifically the ability to provide ART to millions more persons than are currently receiving therapy, including those with high CD4 counts and no HIV symptoms), and life-long adherence to therapy once initiated. Opportunities for HIV testing were highlighted in several presentations this CROI (see section on HIV testing below) and challenges with linkage of HIV infected persons to care and attrition in ART in resource-poor countries were presented as well (posters 825-834). Some of these issues are also relevant to resource-rich countries, as highlighted in a plenary by Dr. Kimberly Smith from Rush University (abstract 72).
Empiric data to assess the short- and long-term impact of ART on reducing HIV transmission risk are limited. Data from a large prospective cohort study among African HIV serodiscordant couples were analyzed to assess the effect of ART on reducing HIV transmission risk (Donnell, abstract 136). In total, nearly 3400 couples were followed for 1-2 years, during which time they received HIV risk-reduction counseling and free condoms, and HIV-infected partners were referred to local care centers for ART initiation when they met national ART initiation guidelines. In total HIV transmission occurred in 103 couples (notably, these transmission events were confirmed as occurring within the couples by sequence analysis of HIV from the transmitting and seroconverting members of the couple). Only 1 transmission event occurred in a couple in which the HIV-infected partner had initiated ART (HIV incidence 0.37 per 100 person-years), and transmission in that case occurred within the first 118 days after ART was started. In contrast, HIV incidence was 2.24 per 100 person-years among those couples in which the HIV-infected partner had not yet started ART, which translated into a calculated risk reduction of 92%, an effect that was highly statistically significant (p=0.004). The greatest risk of HIV transmission was from HIV-infected persons with CD4 counts <200 cells/µL, and the investigators emphasized that treatment of HIV-infected persons who meet guidelines for ART initiation should be the first priority, as less than half of persons worldwide with CD4 counts <200 are currently on ART. Empiric evidence of the effect of ART on HIV transmission continues to be required, particularly the magnitude of effect of ART in reducing HIV transmission from persons with CD4 counts >200. The ongoing HIV Prevention Trials Network (HPTN) study 052 is a clinical trial assessing the effect of early versus standard-of-care initiation of antiretroviral treatment on HIV transmission within discordant couples in which the HIV infected partner has a CD4 count between 350 and 550 cells/μL.
Two population-based studies were also presented that provide intriguing evidence to suggest that increasing use of ART in North America may be reducing new HIV transmissions. The first, from San Francisco, assessed "community viral load," defined as the average most recently-measured plasma viral load for all HIV+ persons in that city (Das, abstract 33). Between 2004 and 2008, community viral load decreased significantly and the proportion of HIV+ persons with undetectable viral load increased significantly, presumably reflecting effective ART use. Interestingly, new HIV diagnoses also decreased significantly during the same time period and estimates of incident HIV cases declined 33%, although this latter number was not statistically significant. In a second abstract, data from British Columbia on ART expansion and new HIV diagnoses between 1996 and 2009 were presented (Montaner, abstract 88LB). During that time period, there was rapid uptake of ART and statistically significant decrease in new HIV diagnoses, in particular a 50% decrease in diagnoses among injection drug users. Community plasma viral load decreased similarly. While the ecologic nature of these two studies cannot definitively establish a causal relationship between ART and decreases in population-level HIV transmission, they provide very encouraging suggestions that ART may have important effects in preventing HIV transmission.
Pre-Exposure Prophylaxis (PrEP)
Use of antiretrovirals for primary prevention in HIV uninfected persons has also generated great interest. This concept, in which HIV uninfected persons use an antretroviral agent (e.g., oral or formulated as a topical microbicide) prior to high-risk exposures in an effort to block initial HIV infection, is known as pre-exposure prophylaxis (PrEP) As part of an exciting symposium on new strategies for HIV prevention, Dr. Kenneth Mayer from Brown University presented an overview of antiretroviral-based HIV prevention, including on treatment of HIV+ persons to decrease infectiousness, post-exposure prophylaxis (PEP), and PrEP (abstract 63). Current PrEP trials are using oral tenofovir (Viread®), oral co-formulated emtricitabine-tenofovir (Truvada®), or intravaginal tenofovir gel; other agents are under consideration for PrEP and are undergoing early testing. There are eight large safety and efficacy trials of PrEP ongoing worldwide, a sign of high scientific enthusiasm for this novel potential HIV prevention strategy. With the first PrEP efficacy results expected potentially as soon as later this year, 2010 could be an important year for PrEP for HIV prevention.
As they did last year, investigators from the US Centers for Disease Control and Prevention presented data from non-human primate models mimicking the effect of PrEP on mucosal HIV transmission. Current PrEP trials are using daily dosing of the antiretroviral agents, in order to maximize the potential for demonstrating efficacy for prevention of HIV, but there is great interest about whether intermitted use could be effective. At last year's CROI, data were presented from a low-dose viral rectal mucosal challenge model that found that oral emtricitabine/tenofovir PrEP provided substantial protection against viral infection, when provided 22 hours to 7 days before an exposure, when coupled with another dose 2 hours after an exposure. Doses closer in time to the exposure (either 2 hours before or 2 hours after) was less effective, although viral risk was still somewhat reduced (these results recently published in the journal Science Translational Medicine).
In one abstract from this year's CROI (Dobard, abstract 949), the efficacy of 1% tenofovir gel was evaluated for intermittent use. Pig-tailed macaques underwent twice-weekly, low-dose vaginal challenge with a pathogenic simian-HIV virus for 10 weeks, with viral challenge occurring 30 minutes and 3 days after each get application. Nine of 10 animals receiving placebo gel became infected, after a median of 4 challenges; in contrast, 4 of 6 animals receiving tenofovir gel remained uninfected after 20 mucosal challenges, a finding that was highly statistically significant (p<0.0009). No evidence of drug-resistant virus was found in the 2 animals that were exposed to tenofovir gel and became infected. Thus, in this mucosal challenge animal model, 1% tenofovir gel had a wide window of protection, consistent with the oral findings from last year, suggesting non-daily use of vaginal gel might be possible. Results of an efficacy trial of coitally-dependent 1% tenofovir gel among South African women (CAPRISA 004) will be presented in mid-2010, which will indicate whether this challenge model is predictive of human efficacy.
In a second abstract, however, the data for intermittent PrEP use was not as encouraging (Garcia-Lerma, abstract 83). In this study, only a single pre-exposure dose of oral PrEP was used, 3 days prior to rectal challenge, with no post-exposure dose. Combination emtricitabine/tenofovir and a new agent, GS7340, a tenofovir pro-drug, were tested, separately. Both PrEP agents resulted in high levels of tenofovir diphosphate in rectal tissues and in peripheral blood mononuclear cells. In spite of this, the rate of viral transmission was similar in PrEP-exposed animals as in untreated controls. In comparison to data presented last year, these findings suggest that the post-exposure dose for PrEP is important for protection. These data emphasize that high drug levels, potent antiretroviral activity, and long persistence of an antiretroviral agent in tissues do not necessary translate into high intermittent PrEP efficacy. A better understanding of pharmacokinetics and pharmacodynamics of PrEP are needed in order to anticipate how to potentially design intermittent PrEP regimens.
Adherence to PrEP in ongoing trials is important for demonstrating PrEP efficacy, and being able to accurately measure adherence is equally important, in order to fully interpret the results of trials when they are completed. As part of an ongoing phase II study of tenofovir PrEP from the US, investigators measured tenofovir in plasma, peripheral blood mononuclear cells, and hair samples collected from 89 study participants (47 taking tenofovir, 42 placebo) as surrogate measure of adherence (Liu, abstract 86). The sensitivity and specificity of tenofovir detection for was comparable for the three specimen types: >90% for each. One participant who had been assigned placebo had tenofovir detected in all three specimen types, suggesting real exposure. There was only low or no correlation, however, between the concentration of tenofovir in samples and other measures of study drug adherence, such as pill counts and self-reported adherence. Ultimately, these data support that biologic measures of tenofovir exposure can be developed as possible surrogates of adherence, and these could serve as valuable contributions to understanding the results of the ongoing PrEP trials.
With respect to safety of tenofovir, data were presented that indicated tenofovir was without renal toxicity in vertically-infected HIV infected children (Giacomet, abstract 870) and updated information on safety of tenofovir use by pregnant women was also presented (Chidziva, abstract 924; Linde, abstract 925; Vigano, abstract 926). A critical aspect of use of tenofovir-based compounds for pre-exposure prophylaxis will be the incidence and clinical significance of K65R mutations in seroconverters. While awaiting empiric observations from ongoing PrEP efficacy trials, reassuring data were presented on low level of K65R in persons with subtypes B or C infection (Li, abstract 564) and indication from phenotypic assays with clinical and laboratory isolates that K65R is associated with hypersusceptibility to NNRTIs (Napolitano, abstract 549).
Several non-tenofovir based agents are currently undergoing early phase testing as potential oral or topical PrEP agents. One consideration in evaluating what agents might best be used for PrEP is whether those same medications are used for treatment of HIV infection in that population, and thus whether antiretroviral resistance might undermine the efficacy of the medication for PrEP (i.e., if resistance develops in HIV-infected persons because of inadequate treatment response) or the efficacy of that medication for treatment in the community (i.e., if significant resistance develops in persons who acquire HIV in spite of PrEP). In a late breaker abstract (Veazey, abstract 84LB, presented by co-author Moore), the efficacy of the CCR5 inhibitor maraviroc, which the investigators formulated into a vaginal gel, was tested in a macaque high-dose vaginal challenge model. Dose-dependent protection from maraviroc was seen, with complete protection achieved at the highest doses tested. The protective effect dissipated over time since application of the vaginal gel, with a half-life of just 4 hours. These data suggest that antiretroviral medications other than tenofovir might be able to serve as successful PrEP agents, although rigorous preclinical evaluation of GMP-formulated gel is needed, including challenges by R5 and X4 viruses and careful safety evaluation in early clinical studies.
Vaginal Microbicides
At last year's CROI, a phase IIb, placebo-controlled clinical trial (HPTN 035) found that 0.5% PRO2000 gel, a synthetic sulphonated polymer formulated as a topical vaginal microbicide, decreased the risk of HIV acquisition in women by ~30%. While these results were not statistically significant (p=0.10 in the primary intent-to-treat analysis), they were greeted with high enthusiasm as a "first signal" that PRO2000 in general and topical microbicides in particular could be successfully developed for prevention of HIV acquisition.
Unfortunately, a year later, a second trial of 0.5% PRO2000 vaginal gel has now been completed and failed to confirm the first trial's suggestively positive results (abstract 87LB, presented by Sheena McCormack). The second trial was conducted by the UK-based Microbicides Development Programme. The trial, named MDP 301, was a phase III, randomized, placebo-controlled parallel evaluation of two concentrations of PRO2000 gel: 0.5% and 2%. This large trial enrolled and followed 9385 women from sites in South Africa, Tanzania, Uganda, and Zambia, between September 2005 and September 2009. The average age was 30 years. In February 2008, the study's independent Data and Safety Monitoring Board (DSMB) recommended that the 2% PRO2000 arm be discontinued because it was statistically unlikely that the 2% concentration would demonstrate efficacy compared to placebo for the prevention of HIV-1 infection; the 0.5% PRO2000 and placebo arms were allowed to continue. Reported gel use was 90% with last sex, and loss to follow-up was modest, with 16% of maximum anticipated person-years lost.
PRO2000 0.5% gel demonstrated no efficacy for the prevention of HIV acquisition. Among 3156 women randomized to PRO2000 0.5%, 130 acquired HIV compared with 123 HIV acquisitions among 3112 women randomized to placebo (incidence 4.5 vs. 4.3 per 100 person-years, hazard ratio 1.05, 95% confidence interval 0.82-1.34, p=0.7). At the time the 2% PRO2000 arm was stopped, HIV incidence among women receiving 2% PRO2000 was 4.7 per 100 person-years (hazard ratio versus placebo 1.21, p=0.2).
PRO2000 0.5 also did not significantly reduce the risk of sexually transmitted infections in this study, including Neisseria gonorrhoeae, Chlamydia trachomatis, and herpes simplex virus type 2. PRO2000, at both the 0.5% and 2% concentrations, were safe; there was no significant difference in genital toxicity adverse events between the PRO2000 and placebo arms.
Thus, PRO2000 did not live up to the expectations raised at CROI 2009. The MDP 301 results illustrate the critical importance of having more than one clinical trial to evaluate novel biomedical HIV prevention strategies, particularly when one trial concludes with a marginal signal to suggest prevention benefit. The final PRO2000 results are arguably the last large efficacy studies of surfactant and other non-specific microbicide products, as multiple studies of compounds of these types have found no benefit in preventing HIV acquisition. Nevertheless, efforts to find new HIV prevention strategies for women must continue – the 4.5% annual HIV incidence among the women who participated in MDP 301, most of whom were drawn from the general community, testifies to an incredible unmet need. Current research in the microbicides field is now focused on antiretroviral-based compounds (analogous to PrEP), with both early and late stage studies underway and results expected in the next few years.
HIV testing and prevention of HIV transmission
A key component in implementing sexual and perinatal HIV prevention strategies, such as microbicides, PrEP, ART, and PMTCT, is knowledge of one's HIV serostatus. Both population- and clinic-based studies of HIV testing were presented this year. Wide-spread HIV testing is a central component of the test-and-treat strategy as well. Plenary and symposium talks highlighted new opportunities for HIV testing in Africa, including in the home-based and community-level HIV testing (Cherutich, abstract 61) and couples counseling and testing and other prevention interventions to reduce HIV transmission in serodiscordant couples (Bunnell, abstract14).
Washington, DC has one of the highest HIV prevalences of any city in the United States, on par with population prevalences in parts of Africa. Recent attention to high HIV risk has spurred innovative programs aimed at promoting HIV testing and access to HIV care in Washington, DC. Since 2006, a program by the DC Department of Health has promoted HIV testing, specifically expanding HIV rapid testing at multiple provider locations (particularly the city jail), empowering residents to seek testing, and linking persons with preliminarily positive rapid test results immediately to HIV clinics for confirmatory testing and long-term care (Castel, abstract 34). Implementation of expanded routine HIV testing resulted in an increase in the number of people tested for HIV and the number of new HIV cases diagnosed (by 17%). For newly-identified HIV infected persons, there was a significant decrease in time from HIV testing to entry into HIV care, an increase in average CD4 count at the time of HIV diagnosis (signaling testing was identifying HIV-infected persons earlier in infection, allowing earlier entry into care), and significantly fewer persons progressed to AIDS (suggesting earlier access to care allowed ART initiation and prevention of clinical disease progression). Continued attention to HIV testing is needed, and these data emphasize the opportunity with expanded promotion of HIV testing to identify HIV infected persons and to do so earlier so care can be initiated before advanced disease.
Two abstracts presented important data highlighting high HIV incidence during pregnancy and the early postpartum period among women in Africa. The first (Kinuthia, abstract 155) tested 2034 Kenyan women 6 weeks after delivery, when they attended routine immunization visits for their infants. 53 women (2.6%) were HIV positive, all of whom had documented negative HIV serologic results during pregnancy; the estimated annualized HIV incidence was 6.8%. The second, from Swaziland, was an operations research program that instituted a 1-day training in maternity wards focused on HIV testing during labor and delivery for women who had not been tested during pregnancy or whose test during pregnancy had been done >3 months prior to delivery (Kieffer, abstract 156). Of 1398 women tested, 58 were newly discovered to have HIV (4.4%, estimated incidence 16.75 per 100 woman-years). At maternity wards where the 1-day training had been completed, the proportion of women receiving repeat testing and the proportion of HIV infected women receiving prophylactic nevirapine increased significantly, compared with control maternity wards. Together, these two studies, from East and southern Africa, emphasize 1) an extremely high risk of HIV acquisition for women during pregnancy and the early post-partum period, 2) real opportunity to implement HIV testing during labor and during post-partum follow-up, and 3) the possibility to institute services to prevent mother-to-child HIV transmission from women who are discovered to be newly HIV infected.
Two abstracts were presented using data from the Kenya AIDS Indicator Survey (KAIS), a population-based serosurvey of HIV-1 and STI prevalence in the East African country done in 2007. In KAIS, 9691 households were included, including 15,853 individuals. HIV prevalence was 7.1% (8.4% for women and 5.4% for men), corresponding to an estimated 1.3 million infections nationwide among those aged 15-64. Among the 1104 HIV-infected persons identified, 63% were married, 73% lived in rural locations, and only 45% had ever been tested for HIV (Mwangi, abstract 38). Most notably, 85% did not know they were HIV-infected. Among those who had never tested, one-third felt themselves at low-risk for HIV. Half of HIV-infected women wanted a child. Most HIV-infected persons who did not know their serostatus engaged in unprotected sex. These data emphasize the importance of efforts to expand HIV testing in high prevalence areas.
In a second abstract (Kaiser, abstract 40), HIV prevalence among couples in KAIS was reported. A total of 2748 couples were tested: in 3.8% both members were HIV infected and in 5.8% one member was HIV infected while the other was HIV uninfected. Of married HIV-infected persons, 44% had an HIV uninfected spouse and 89% did not know their partner's HIV status. One in six discordant couples desired a child. Couples HIV testing offers an opportunity for HIV prevention.
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