www.hivandhepatitis.com

Truvada PrEP Demonstration Project Debuts in San Francisco

The San Francisco Department of Public Health's new pre-exposure prophylaxis demonstration project opened for enrollment at City Clinic on Friday, September 21. Men who have sex with men (MSM) and transgender women with ongoing risk of HIV infection are eligible to receive Truvada PrEP for up to 1 year.

Pre-exposure prophylaxis, better known as PrEP, refers to use of antiretroviral drugs prior to unprotected sex or other exposures to prevent HIV from taking hold in the body. Most PrEP research has looked at an oral combination of tenofovir plus emtricitabine, the drugs in Truvada. Already a widely used component of HIV treatment, the U.S. Food and Drug Administration approved Truvada for PrEP on July 16, 2012.

"PrEP isn’t for everyone, but we're giving [people] options to keep themselves safe," said Susan Buchbinder, director of Bridge HIV (formerly the SFDPH HIV Research Section). "We don’t know if it's 100% effective, but it’s a tool that people can use if it's right for them."

While HIV incidence rates are declining in San Francisco -- even among young black gay men of color, who have the highest rates nationwide-- there still about 400 new cases per year, indicating that the prevention tools we have been using are not fully effective, according to Buchbinder.

Controlled trials have shown that Truvada PrEP can dramatically lower the risk of HIV infection in different population groups, but effectiveness depends on taking the drugs consistently.

The iPrEx trial, which enrolled nearly 2500 gay and bisexual men and a small number of transgender women in 6 countries (including San Francisco and Boston in the U.S.), found that daily Truvada reduced the risk of HIV infection by 42% overall, rising to 92% for participants who had drug levels in their blood indicating good adherence.

The Partners PrEP study, which looked at approximately 4700 heterosexual serodiscordant couples in Kenya and Uganda, found that the drugs in Truvada reduced the likelihood of infection by 75%. TDF2, another study of heterosexual men and women in Africa, showed a 62% risk reduction. A study of African women called FEM-PrEPshowed less impressive results, but further analysis revealed that less that half of participants where taking PrEP as directed.

"PrEP is not a homerun, and not everyone was protected, but the reason why it didn't always work was that people weren’t always taking the pill," Buchbinder summarized. "If you were to take it perfectly every day would it always work? We don’t know the answer."

While most HIV advocacy groups lauded the approval of Truvada for PrEP, skeptics have expressed doubts about whether healthy HIV negative people will consistently take a daily pill, and raised concerns about drug resistance, side effects, and an increase in unprotected sex.

But these concerns have not been borne out in trials to date. People who became infected while taking PrEP did not develop resistance (although this did happen among the small subset of participants who had unrecognized acute HIV infection at study entry). Tenofovir is known to cause kidney and bone toxicity in some people who take it for treatment, but no significant problems have been seen in PrEP trials to date.

In all these trials, participants received a comprehensive prevention package including risk-reduction counseling, regular HIV and sexually transmitted disease (STD) testing, and free condoms along with PrEP or placebo. Risk behavior actually decreased overall, with both PrEP and placebo recipients reporting fewer sexual partners and more condom use.

The Real World

Now that Truvada PrEP has demonstrated its effectiveness for carefully selected at-risk people in controlled studies, the question is whether it will also work in the real world, without the intensive support and monitoring available in a clinical trial setting.

To answer some of these questions, the National Institute of Allergy and

Infectious Diseases (NIAID) is partnering with local public health departments to set up PrEP demonstration projects like the one launched last week.

First out of the gate, San Francisco's Demo Project aims to enroll 300 HIV negative MSM and transgender women at City Clinic, while a sister project in Miami will enroll 200 participants.

The goals of the demonstration project include determining the level of community interest in PrEP, evaluating how well people adhere to a daily prevention regimen, seeing how long they stay on it, and assessing whether sexual practices change, according to City Clinic medical director Stephanie Cohen.

"So far everything we know [about PrEP] is from clinical studies in which people didn’t know whether they were taking PrEP or placebo," Cohen said. "There's still a lot to learn: Who will take it and how? Will risk factors change? How do we get PrEP out there safely? and Can we provide PrEP in the busy environment of City Clinic?"

Eligible participants are gay/bisexual men and transgender women who are sexually active and at risk of HIV infection. They must have a confirmed HIV-negative screening test and be tested for hepatitis B virus (the drugs in Truvada are also active against HBV), have normal kidney function and no serious medical conditions, and must not be taking any other experimental drugs or vaccines.

Demo Project participants will receive Truvada PrEP for up to 48 weeks, (the duration of NIAID funding) along with a prevention package that includes risk reduction counseling and free condoms. Every 3 months they will receive an HIV RNA test, which can detect very early infection. They will also get regular STD tests, adherence counseling, and monitoring of side effects including changes in kidney function.

"[PrEP] studies included mostly young, healthy people, but we see people who are older and at higher risk of kidney disease and bone loss," said Harry Lampiris, chief of infectious disease at the San Francisco Veterans Administration Medical Center, who prescribes Truvada PrEP in his clinical practice. "If they are hepatitis C coinfected they may be higher risk of kidney problems, and smokers or drinkers are more at risk of bone loss. Being more predisposed to bone or kidney [problems] doesn't mean you can't take PrEP, it just means you need to take more precautions."

Two men currently using Truvada PrEP described their experiences at the forum.

Michael (who did not give his last name), an iPrEx participant, has been taking PrEP for 4 years. He said that during this period he has only missed about a dozen pills. At age 56, he has not had any kidney or bone problems. His side effects include nausea -- "mild but pretty much every day" -- and "significant flatulence." Although Truvada's gastrointestinal side effects generally dissipate after several weeks, he said the problem has been chronic for him.

Derek Brocklehurst, an HIV clinic nurse, started PrEP in October 2011, having asked his doctor to prescribe it prior to approval. "I have been 100% adherent -- it's in my backpack every day," he said, adding "I haven't really noticed any side effects." One creatinine clearance kidney function test came back normal and he has not yet had a bone test.

Having had several exposures to HIV through unprotected sex (which he described at a forum on serosortingthe previous week), Brocklehurst said that using PrEP reduced his anxiety and "freak-outs" about becoming positive. "PrEP didn’t change my behavior, but it's eased my mind," he said.

Cost and access issues around Truvada PrEP are still being worked out. The Demo Project has funding to provide the drug and associated care and monitoring free for 1 year. "We don’t have funding to provide Truvada for everyone for their whole lives," Buchbinder stressed. Cohen added that the Healthy San Francisco health program is now considering whether to add Truvada PrEP to its formulary.

Brocklehurst said his insurance company, Anthem Blue Cross, covers PrEP, and Truvada manufacturer Gilead Sciences offers co-pay assistance, so he pays nothing out of pocket. Michael said he does not know whether Kaiser Permanente will cover the drug, and he may not be able to afford to stay on PrEP after his study ends in December.

In addition to the San Francisco and Miami demonstration projects, New York City just got funding for one as well, according to Buchbinder. Washington, D.C. and Los Angeles are in the process or starting similar projects, and preparatory work is underway in Chicago and Oakland.

Future Directions

Truvada PrEP should not be used as a sporadic or "morning after" pill. Controlled clinical trials so far only demonstrate the effectiveness of daily use, though an iPrEx analysispublished in the September 12, 2012, issue of Science Translational Medicine found that men taking Truvada at least 4 days per week achieved drug concentrations high enough to provide 90% risk reduction.

But daily Truvada may turn out not to be the optimal PrEP regimen. Albert Liu, director of HIV prevention intervention studies at Bridge HIV, described 2 trials looking at other types of PrEP that are now enrolling participants.

The NEXT-PREP trial (HPTN 069) will compare the safety and tolerability of 4 PrEP regimens for high-risk men who have sex with men at 12 sites in the U.S. Participants will be randomly assigned to take combinations of tenofovir, emtricitabine, maraviroc (Selzentry), or placebo; everyone will receive at least 1 active drug.

Maraviroc blocks the CCR5 receptor that most types of HIV use to enter cells. It reaches high levels in vaginal in rectal tissue, and has the advantage of not being commonly used for HIV treatment. But a study presented at the International AIDS Conference (AIDS 2012) this summer found that oral maraviroc did not protect monkeys from rectal infection with an HIV-like virus.

Study MTN-017 will look at another method of administration, a tenofovir-containing rectal gel. The CAPRISA 004 trialshowed that a 1% tenofovir vaginal gel was safe and reduced HIV infection in women by 39%. The same product was found to be safe for rectal use, but it caused gastrointestinal side effectsand bloating.

MTN-017 is testing a new formulation of the gel with less glycerin that appears to be better tolerated. Participants will be assigned to 1 of 3 regimens: oral tenofovir PrEP, daily tenofovir gel, or tenofovir gel applied before and after receptive anal sex.

"We're trying to give people as many options as possible," said Buchbinder. "For some, a monthly injection is the best option, for some using [an antiretroviral] lube during sex is a great option, some would rather take a daily pill."

Cohen ended the forum noting that Demo Project researchers "really don’t know what kind of demand we're going to get." An informal poll of the audience revealed that about half though the study would have potential participants breaking down doors, while the other half thought the DPH would have to work to convince people to take PrEP.

"It's really an individual decision for a person whether PrEP is something that makes sense in their life," Cohen concluded. "PrEP is a personal choice and we want to support people if they decide to start, if they want to stop, or if due to life changes they want to start again."

The San Francisco AIDS Foundation has collaborated with Bridge HIV, City Clinic, NIAID, Project Inform, and other organizations to develop a new website, PrEPfacts.org, to provide information about PrEP and the SF Demo Project. Individuals interested in taking part in the Demo Project should call 415-487-5537 or visit City Clinic.

[An earlier version of this report appeared in the September 27, 2012, Bay Area Reporter.]

9/28/12