Pre-Exposure Prophylaxis: A New Focus For HIV Prevention

By Liz Highleyman

HIV prevention was a key theme at the recent XVI International AIDS Conference in Toronto, and pre-exposure prophylaxis (PREP) was among the new preventive technologies that generated the most interest. Unlike microbicides, which also hold considerable promise, PREP could protect against direct blood exposure (for example, through needle sharing) as well as sexual exposure.

PREP refers to use of antiretroviral agents by HIV negative individuals in an effort to prevent infection. To date, the drug that has been most extensively studied for this purpose is tenofovir DF (Viread). Some animal studies have shown that oral or injected tenofovir, possibly in combination with emtricitabine (FTC, Emtriva), provides partial protection from infection with simian immunodeficiency virus (SIV; a virus related to HIV) in monkeys.

In a late-beaker session at the conference, Leigh Peterson of Family Health International (FHI) presented the first preliminary evidence that PREP might be effective in humans.

Researchers conducted a double-blind study that enrolled 936 at-risk HIV negative women in Cameroon, Ghana, and Nigeria, between June 2004 and March 2005. Women were not pregnant and had normal liver and kidney function at study entry. The Cameroon site stopped enrollment early due to controversy over ethical issues (discussed below), while the Nigerian site was closed due to faulty laboratory monitoring.

Participants were randomly assigned to receive 300 mg daily tenofovir monotherapy or placebo. They received monthly HIV and pregnancy tests, risk-reduction counseling, and free condoms. Physical exams and laboratory tests were conducted quarterly.

Results

The mean age was about 24 years (range 18-35). Most women were not married or living with a partner; nearly 75% had prior pregnancies, and about 40% had a sexually transmitted infection in the past 6 months.

Results were presented for 731 women followed for 9 months.

A total of 8 women were infected with HIV:

- 2 out of 363 subjects in the tenofovir group (0.86 per 100 person-years);
- 6 out of 368 subjects in the placebo arm (2.48 per 100 person-years).

While those in the PREP group were 65% less likely to become infected, the difference did not reach statistical significance due to the small numbers involved (rate ratio 0.35; 95% CI 0.03-0.93; P = 0.24).

There were no significant differences in adverse events or treatment discontinuations between the tenofovir and placebo groups.

Severe (Grade 3-4) laboratory abnormalities were rare in both the tenofovir and placebo groups, including:

- Alanine and aspartate aminotransferase (ALT and AST) elevation - indicators of liver inflammation (a particular concern among patients coinfected with chronic hepatitis B);
- Elevated creatinine and decreased phosphorus - possible signs of kidney damage.

While the number of sex acts increased while using PREP, the number of sexual partners decreased.

The rate of condom use rose from 52% to 94%.

Conclusion

The researchers concluded that, "tenofovir did not increase the rate of adverse events or Grade 3-4 laboratory abnormalities in participants during or after use," but acknowledged that, "the number of HIV infections was insufficient to conclude that tenofovir protected against HIV infection."

Benefits and Risks of PREP

Although the FHI study was not able to show a statistically significant reduction in the risk of HIV infection, the low frequency of side effects through 9 months and the trend toward a lower rate of infection suggest that this approach holds promise.

However, use of antiretroviral PREP is fraught with unsolved medical and ethical issues, which were discussed at a special session at the conference entitled "What If PREP Works?"

On the medical side, there is concern about healthy people using a drug over the long-term that could cause side effects such bone loss or kidney or liver damage. There is also a risk than the use of any antiretroviral agent as monotherapy could lead to resistance, which may render the drug less effective or useless for later treatment of individuals who become infected despite PREP. Development of the K65R tenofovir-resistance mutation has, in fact, been demonstrated in animal PREP studies. Extensive tenofovir resistance due to PREP would be especially problematic for national antiretroviral treatment programs in resource-limited settings, since it is one of the most convenient antiretroviral medications and has few side effects.

On the ethical side, there is considerable concern that the availability of a prophylactic pill could cause people to abandon risk reduction practices such safer sex or use of sterile needles. If PREP is not completely effective, even a partial reduction in safer sex could actually lead to an increased rate of HIV transmission.

For example, Robert Grant, MD, from UCSF's Gladstone Institute of Virology and Immunology presented estimates from a mathematical model showing that a 50% increase in high-risk behavior could completely offset the benefits of partially (50%-80%) effective PREP.

Researchers from the San Francisco Department of Public Health (SFDPH) presented data from a survey of awareness of and attitudes toward PREP among 851 self-identified gay and bisexual men recruited at various social venues and a sexually transmitted disease clinic in San Francisco, and at a circuit party in Palm Springs.

About 18% of the men had heard of PREP, with the most common sources of information being the media and friends; men who reported recent unprotected anal sex were more likely to say they knew about PREP. Just one individual said he had used PREP, and 2 percent said they knew someone who had. (This conflicts with data from a prior survey of gay/bisexual men of color in 4 cities, which found that about 25% had heard of PREP, and about 7% said they had used it).

In the SFDPH study, 68% of the men said they would be likely to use PREP if it were shown to work. But, according to Albert Liu, MD, "It is critical that we wait for safety and efficacy data. It is important to stress that we don't know if it works."

The FHI study suggests that intensive risk reduction counseling can prevent such behavioral "disinhibition." However, effective counseling is likely to reduce the risk of infection on its own, making it more difficult to determine whether PREP works.

PREP studies have also been criticized because they target vulnerable populations, such as sex workers in poor countries (who are at highest risk for infection), and for providing inadequate care for participants who do become infected. There is also the issue of how PREP will be provided and paid for - and for whom - should it prove effective.

Currently, a PREP trial called "Project T" is underway studying men who have sex with men in San Francisco and Atlanta. Similar studies are looking at men who have sex with men in Peru, young heterosexuals in Botswana, and injection drug users in Thailand. Some of these studies have added emtricitabine, since results from a study in monkeys showed that the combination led to a greater reduction in viral transmission than either drug alone.

09/12/06

References

L Peterson, D Taylor, E E K Clarke, and others. Findings from a double-blind, randomized, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in women. XVI International AIDS Conference, Toronto. August 13-18, 2006. Abstract THLB0103.

A Liu, S Wheeler, E Vittinghoff. Low levels of pre-exposure prophylaxis awareness and use among HIV-negative/unknown gay/bisexual men: San Francisco Bay Area residents, circuit party attendees, and clients of an urban STD clinic. XVI International AIDS Conference, Toronto. August 13-18, 2006. Abstract THLB0101.

R Grant, J Lama, P Goicochea, and others. Cost-effectiveness analysis of HIV chemoprophylaxis. XVI International AIDS Conference, Toronto. August 13-18, 2006. Abstract THLB0102.