Efficacy Trial Shows Combination of Two Antiretrovirals Can Prevent HIV Infection
A study of nearly 2,500 men and transgendered women who have sex with men at 11 clinical sites in the US, South Africa, Brazil, Thailand, Peru, and Ecuador showed that daily administration of the antiretrovirals (ARVs) emtricitabine (FTC) and tenofovir (TDF) was 44% effective in protecting men or transgendered women who have sex with men from HIV infection, according to a study published in November (N. Engl. J. Med . doi: 10.1056/NEJM0a1011205). This randomized, double-blinded, placebo-controlled study, known as iPrEx, is the first efficacy trial of oral pre-exposure prophylaxis (PrEP) to be completed.
Many researchers heralded the success of PrEP in this trial as an important development in HIV prevention research, a field that after years of gridlock has seen much progress. In September 2009 researchers reported results from the RV144 trial in Thailand that showed a prime-boost vaccine regimen provided about 31% protection against HIV infection. Then in July, microbicide researchers reported that vaginal application of a 1% gel formulation of tenofovir was 39% effective in blocking HIV infection.
The iPrEx results were statistically significant with a confidence interval that ranged from 15 to 63. In the group receiving ARVs, either TDF or FTC was detected in 22 of 43 seronegative volunteers (51%), and in only three of 34 volunteers (9%) who acquired HIV during the course of the study, indicating that detectable quantities of either of the study drugs in the blood was strongly correlated with the protective effect.
The news of the efficacy of PrEP did not come as a surprise to many researchers in the field. For years, researchers have suspected that the life-extending ARVs that have proven so successful in treating HIV/AIDS might also be useful in prevention. The first study in non-human primates that hinted this might be a promising approach for HIV prevention was done nearly 15 years ago (see PrEP Work, IAVI Report, Nov.-Dec. 2008). A study by Gilead, the pharmaceutical company that developed both TDF and FTC, showed that TDF was effective at preventing infection with simian immunodeficiency virus (SIV), the monkey equivalent of HIV, in rhesus macaques. Since then, several monkey experiments have shown that FTC-TDF was even better at protecting against SIV infection in models that more closely recapitulate HIV transmission.
One of the obstacles to implementing PrEP as an HIV prevention strategy will be adherence—for the drug to work, individuals at risk of HIV infection must take it faithfully. Among individuals in the FTC-TDF group who had detectable drug levels in their blood, the odds of HIV infection were 12.9 times lower, corresponding to a 92% reduction in risk of HIV infection as compared to volunteers in the FTC-TDF group who did not have detectable levels of the drugs in their blood.
In the iPrEx trial, all volunteers were counseled on a monthly basis to adhere to the daily dosing regimen. Investigators collected self-reported information on adherence as well as pill counts at these monthly visits. However, blood levels of the drugs, measured by an intracellular assay that was expected to detect TDF 14 days or more after the last dose was taken, indicated self-reported adherence was not an accurate measure of how often volunteers had actually taken the pill. “Although reported pill use was high, drug exposure that was measured objectively was substantially lower,” the study’s investigators noted.
The investigators speculate that side effects, including nausea and unintended weight loss, associated with initiation of FTC-TDF may have contributed to the overall low adherence to the study drugs. There was also a trend toward more elevated serum creatinine levels, which are known to impair renal function, in the FTC-TDF group than in placebo recipients. Although this side effect appeared to reverse upon discontinuation of FTC-TDF and only occurred in a small subset of volunteers, Nelson Michael, director of the US Military HIV Research Program, who wrote an editorial in the New England Journal of Medicine on the iPrEx study, concluded that “this finding raises both safety and monitoring concerns regarding possible cumulative toxic effects associated with large-scale exposure to daily FTC-TDF therapy for an extended period.” He also cautioned that the side-effect profile for FTC-TDF was probably diluted in this study because of low adherence to the drugs, suggesting the side effects could be even more substantial in volunteers who were compliant to the daily regimen.
In addition to side effects, another concern with PrEP is the potential for development of drug resistance if a person unknowingly becomes HIV infected and continues taking ARVs for PrEP. In the iPrEx study, none of the volunteers in the FTC-TDF group or the placebo group who became HIV infected during the course of the trial developed drug resistance. Two volunteers who were infected at enrollment but placed on FTC-TDF anyway, did develop FTC-resistant virus. Researchers speculate that the lack of any drug resistance may have been due in part to the overall low adherence to the study drugs.
Now that PrEP has also shown partial efficacy against HIV, there are certainly many thorny issues that will need to be resolved before it can be implemented, particularly in developing countries that continue to bear the greatest burden of HIV infection. With only a third of HIV-infected individuals in need of HIV therapy currently receiving it, there is bound to be some debate about how to dole out antiretrovirals for prevention. Robert Grant, an associate professor of medicine at the Gladstone Institute of Virology and Immunology and the principal investigator of the iPrEx study, says researchers must still address whether FTC-TDF is as effective in preventing HIV infection in other high-risk populations, such as injection drug users or women in areas of high HIV prevalence.
Grant says it will also be important to determine if daily dosing is needed, or whether intermittent dosing before and after sex will be sufficient to protect against HIV infection. “I think the durability of how long people can use this is also an open question,” says Grant. “The median duration of follow-up in the iPrEx trial was 1.2 years, the maximum was 2.8 years. It is conceivable though that people might want to use [FTC-TDF] for a longer period of time.”
Grant says there are also questions about whether using ARVs for prevention is economically feasible, even in rich countries. “There is no mechanism for reimbursing individuals for the cost of [using ARVs] as a preventive measure, which could dissuade potential users,” he adds.
Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), a funder of the study, says the iPrEx results are encouraging, but “in no way lessen the need for a vaccine, which would be a gigantic step in the fight against AIDS,” says Fauci.
In the meantime, the iPrEx trial results have prompted discussions among AIDS vaccine investigators and advocates over whether volunteers should be counseled and given access to PrEP in addition to the other risk-reduction methods that are currently standard in AIDS vaccine trials. There are even discussions about whether ongoing vaccine trials, such as the HVTN 505 trial of 1,350 men who have sex with men (MSM) in the US, should be adapted to include a PrEP arm.
Scott Hammer, principal investigator of the HVTN 505 trial, says US regulatory authorities should provide some clarity soon about if or how PrEP should be used. The US Centers for Disease Control and Prevention is expected to publish interim guidelines for healthcare providers in the coming weeks, followed by formal US Public Health Service guidelines. In the meantime, Hammer says an effort is underway by trial sites to address questions that the MSM community has regarding the iPrEx results.
The HVTN 505 trial is testing the safety and efficacy of a DNA/adenovirus serotype 5 prime-boost regimen developed at NIAID’s Vaccine Research Center. Volunteer enrollment in the HVTN 505 trial was slow at first, but the results of the iPrEx trial may actually have boosted the MSM community’s interest in vaccine trials, Hammer says. —Regina McEnery and Kristen Jill Kresge
Latest UNAIDS Report Shows Significant Advances in Combating HIV/AIDS
In its annual report on the status of the pandemic, the Joint United Nations Programme on HIV/AIDS (UNAIDS) gave everyone something to cheer about when it declared that the world has “halted and begun to reverse the spread of HIV.”
The 364-page report, released in advance of World AIDS Day on Dec. 1, highlighted several bright spots. Over the last decade, HIV incidence declined by more than 25% in 33 countries, 22 of them in sub-Saharan Africa. Globally, HIV incidence declined by 19% between 1999, when incidence likely peaked, and 2009.
Another area of progress was the continued scale-up of antiretroviral drugs in low- and middle-income countries. An additional 1.2 million people in low- and middle-income countries received antiretroviral therapy in 2009, bringing the total to 5.2 million, a 30% increase over 2008. Despite this increase, only 36% of the people who are eligible to receive antiretroviral therapy in developing countries at the end of 2009 were receiving it. Significant progress has also been made in preventing mother-to-child transmission of HIV and in reducing HIV-related stigma and discrimination.
The report also highlighted some major obstacles in combating HIV/AIDS, notably the alarming trends in Eastern Europe and Central Asia, where HIV incidence has increased by more than 25% between 2001 and 2009, a jump that UNAIDS attributes to both a lack of access to services and anti-drug use laws. Also, the global economic recession is seen as a major threat to HIV/AIDS treatment and prevention programs in developing countries.
In a foreword to the report, UNAIDS executive director Michel Sidibé said the world should be proud of the recent accomplishments in the fight to end AIDS, but cautioned that it is too soon to say mission accomplished. “Growth in investment for the AIDS response has flattened for the first time in 2009. Demand is outstripping supply. Stigma, discrimination, and bad laws continue to place roadblocks for people living with HIV,” said Sidibé. —Regina McEnery