CATIE News

24 September 2010 

PrEP—hope and excitement greet first successful microbicide

The burden of HIV infection is largely borne by people in sub-Saharan Africa, particularly girls and women. Behavioural messages that encourage abstinence, monogamy and use of condoms have had, according to researchers, only a limited long-term impact on the spread of HIV in that region. This situation arises in part because women do not have control over their sexuality and face many obstacles to achieve social, economic and political equality. So, more options for preventing HIV transmission are needed. 

A call for relevance

Strategies for HIV prevention “need to be made relevant” for adolescent girls as they transition to adults, noted Quarraisha Abdool Karim, a leading South African researcher, in an interview with the journal Lancet. Moreover, she added, “Any intervention after 18 years [of age] is too late.” This statement is supported by findings from a study done by The Centre for the AIDS Programme of Research in South Africa (CAPRISA). Researchers surveyed pregnant women attending clinics between 2005 and 2008 and here’s what they found: 

  • By the age of 16, 10% of women were HIV positive.
  • By the age of 18, 20% of women were HIV positive.
  • By the age of 24, 50% of women were HIV positive. 

Enter microbicides

Pre-exposure prophylaxis (PrEP) is a term given to any therapy that can be taken prior to exposure to HIV in the hope that it will protect the user from HIV infection. PrEP can take the form of pills taken orally or creams or gels applied to the vagina, anus or penis. Creams or gels that are applied to the genitals that have anti-HIV activity are called microbicides. Such forms of PrEP can be applied by women and are under their control. Microbicides have shown promise in animal experiments but until recently have not demonstrated sustained protection against HIV infection. Many forms of PrEP use the antiviral drug tenofovir (Viread) or combinations of tenofovir and another drug called FTC (sold as a fixed-dose co-formulation called Truvada). Tenofovir has antiviral activity against several sexually transmitted infections (STIs), including HIV, hepatitis B virus and a herpes virus called HSV-2. 

CAPRISA Trial 004

In Trial 004, researchers tested a vaginal gel containing 1% tenofovir vs. another gel containing placebo. Over two and a half years the tenofovir-containing gel reduced the risk of infection by 39%. This is a major advance in the field of HIV prevention, given the dismal track record of microbicide testing. Readers should note that these findings do not mean that a tenofovir-containing microbicide is ready for sale or distribution. There are issues related to Trial 004 that need to be resolved. The trial results should be viewed as a good first step and we will explain why later. 

Study details

Between May 2007 and January 2009, researchers recruited sexually active non-pregnant HIV-negative women who did not have active STIs. They were randomly assigned to one of two groups: 

  • vaginal gel containing tenofovir – 445 women
  • vaginal gel containing placebo – 444 women 

The gels were supplied in pre-filled vaginal applicators. Researchers asked the women to insert one dose of gel “within 12 hours before sex and a second dose as soon as possible within 12 hours after sex and no more than two doses of gel in a 24-hour period.” 

The study team provided what it called “a comprehensive adherence support program” to assist women so that they could cope with the “mechanics of applicator use, timing and dosing, avoidance of gel sharing, and incorporation of gel use into their daily routines.” Furthermore, several months after the trial started, individualized adherence support and counseling were added. Importantly, researchers repeatedly told women to “only use the gel vaginally,” as there was no safety data for rectal use.  

Women were monitored monthly for HIV infection and assessed for adherence and any side effects. Every four months they underwent vaginal examinations. 

The average profile of women when they entered the study was as follows: 

  • age – 24 years
  • in a stable partnership – 88%
  • age at sexual debut – 17 years
  • number of lifetime sexual partners – three
  • average age of oldest sexual partner – 27 years
  • had sex in the past week – 60%
  • always used a condom during sex – 29%
  • had anal sex in the past month – 0.5%
  • infected with HSV-2 – 50%
  • use of injectable contraception – 82% 

Results—Overall

After 30 months, the total number of new HIV infections was distributed as follows: 

  • tenofovir gel users – 38 women became HIV positive
  • placebo gel users – 60 women became HIV positive 

Overall, tenofovir gel reduced the risk of HIV infection by 39%. This difference was statistically significant; that is, not likely due to chance alone. 

The results of the study were not affected by the frequency of sex, gel or condom use because these were similar in both groups of women. 

Use of tenofovir gel also reduced the rate of new HSV-2 infections by 50%. 

Adherence makes a difference

Women who used the tenofovir-containing gel as directed more than 80% of the time increased their protection from HIV infection. Indeed, among these high adherers, the risk of infection was reduced by 54% compared to women who used placebo. 

Among women who used the gel less than 50% of the time they were supposed to, protection from HIV fell to 28%. 

Researchers found a worrying trend over time—adherence to the gel by many women decreased. 

Safety

Women who received tenofovir-containing gel reported more diarrhea (17%) than did women on placebo (11%). This difference was statistically significant. However, there were no serious side effects reported in Trial 004. 

About 67% of pregnancies among tenofovir gel users resulted in live births compared to 52% among placebo users. However, this difference was not statistically significant. No babies were born with birth defects. 

Viral load and resistance

The average viral load was not significantly different when HIV antibodies were detected in women who became infected whether they used tenofovir gel (45,000 copies/ml) or placebo (20,000 copies/ml).  

Researchers estimate that women who became HIV positive during the study were exposed from time to time to tenofovir gel for between three and four weeks after infection. In theory, this could have led to the development of strains of HIV with resistance to tenofovir and other anti-HIV drugs, such as 3TC, AZT or d4T. However, such resistance was not detected. 

Issues to consider

  • Adherence

CAPRISA Trial 004 included intensive adherence support. Despite this support, adherence decreased over the course of the study. Furthermore, according to the study team, “about 40% of the women in this study had below 50% adherence.” This suggests that future studies of microbicides and perhaps other forms of PrEP will need to also emphasize intensive adherence. If these or other microbicides are released for general use into the community in the future, decreased levels of adherence over time may pose a challenge to the sustained protection from microbicides.  

  • Proceed with caution

The results of Trial 004 are very encouraging given the previous lack of success of microbicides. However, reproductive specialist Sharon Hillier, who heads the Microbicide Trials Network in the U.S., says, “We want to see something more effective.” This latter point is an important one. Despite the encouraging results of Trial 004, a relatively large proportion of women became infected with HIV. Also, the ability of the gel to protect women apparently decreased over time (perhaps this was related to reduced adherence but it needs to be confirmed). The reasons for these two findings are not clear and are under investigation by the CAPRISA team.  

  • Confirmation required

Trial 004 was relatively small and so its results will need to be confirmed. This will take several years. Other hurdles may lie ahead. 

Due to the economic crisis in most high-income countries, raising the $100 million U.S. necessary to complete subsequent research to confirm Trial 004’s benefit has been difficult. 

  • Anal sex

There were relatively low rates of anal sex in the present study. Based on their trial design and results, CAPRISA researchers say that “it is not possible to [draw] any conclusions on the safety and effectiveness of tenofovir gel for anal sex.” 

A trial called MTN 007, in which researchers will assess the safety of the rectal use of tenofovir gel in men and women, is planned for the U.S.  

  • Timing

The gel in CAPRISA Trial 004 was applied 12 hours before and within 12 hours after sex. So the effectiveness of tenofovir gel when used with other schedules is not known. 

  • Another trial

There are other trials of microbicides for HIV prevention underway. One of these, MTN 003, involves the daily use of tenofovir gel by women. Results from this trial will become available in several years. 

Ready for which market?

All of the previous points mean that tenofovir vaginal gel will not be ready for wider distribution any time soon. Moreover, should another trial confirm the results of CAPRISA 004, the future sales and distribution of the gel will be prioritized for low- and medium-income countries where HIV is relatively common. This gel is unlikely to become available in high-income countries, where tenofovir in pill formulation is widely available and legal liability issues related to the use of tenofovir gel are financially daunting. 

Key findings

  • For more than two and half years, a vaginal gel containing 1% tenofovir protected 39% of women who used it from HIV infection. 
  • Adherence to the gel made a difference. Among women who had high rates of adherence, 54% were protected from HIV infection.
  • The gel was relatively safe, with mild diarrhea being the most commonly reported side effect (in 17% of women who used it). 
  • The ability of tenofovir gel to protect people from HIV and other germs transmitted during anal sex is not known. 
  • While highly promising, the results of the present study require confirmation. Testing other schedules of gels, such as daily use, is underway. 
  • Until further studies are done to confirm the effects of tenofovir gel it will not become available in low- and middle-income countries where HIV infection is common. 

To learn more about PrEP, please see the CATIE Fact Sheet on the subject, available at:

http://www.catie.ca/en/fact-sheets/prevention/pre-exposure-prophylaxis-prep

—Sean R. Hosein

REFERENCES:

  1. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010 Sep 3;329(5996):1168-74. 
  2. Baleta A. Antiretroviral vaginal gel shows promise against HIV. Lancet. 2010 Jul 31;376(9738):320. 
  3. Cohen J.  At last, vaginal gel scores victory against HIV. Science. 2010 Jul 23;329(5990):374-5.  
  4. Dugger CW. HIV prevention gel hits snag: money. New York Times, 4 September 2010. Available at: www.nytimes.com/2010/09/04/world/africa/04safrica.html?_r=1&scp=1&sq=tenofovir&st=cse