PrEP at CROI – A review of some of the
discussions and key data presented
ARV-based Prevention: A Community and Research Forum on Recent Results and What Happens Next
“What needs to happen to ensure that PrEP doesn’t become a hard-to-get intervention?” Julie Davids (HIV Prevention Justice Alliance) posed this terrific question to the panel at a packed event at Fenway Health in Boston. The event included presentations from Salim Abdool Karim (CAPRISA, South Africa), Bob Grant (Gladstone Institute-UCSF) and a very lively discussion among panelists and the 150 audience members. In the interest of space, we’re including the answers to Julie’s question here—and will summarize other key points in a separate posting. Julie has also posted a video of this discussion. Take a look!
- In countries where PrEP research is not happening, the discussion of PrEP needs to move into policy circles, so that key decision makers know that important results are here and more are coming.
- Brazil, Ecuador and Peru haven’t licensed TDF/FTC for treatment yet, even though they hosted the iPrEx trial that studied this drug for PrEP. This registration needs to be handled in the short term. Bob Grant noted that the iPrEx team is working to help get the drug registered and said he was not sorry about doing the trial in these countries, as the result was now helping the registration process.
- In the US, the government needs to address the current crisis in the AIDS Drug Assistance Program (ADAP) which has waiting lists nationwide; negotiate/ensure insurance coverage for PrEP and make sure there is infrastructure to support PrEP as part of comprehensive response.
- Across the globe, donors, policy makers and community stakeholders need to create public demand. When the public says they want it and what they’re willing to do it get it, this can push things forward, like we’ve seen in treatment. Marketing and educational campaigns are needed to inform people to support this demand.
- It is time to raise funds for HIV—the G8 should declare war on HIV. Now is the time given that we have new and effective tools to combat the epidemic on every front.
- Support continued HIV prevention research in different populations and operational research on implementation.
- On the regulatory front, there’s a need to file for a prevention indication on the TDF/FTC label and to provide education to both providers and patient community about what the research data is and what recommendations are about appropriate use.
- Get demonstration projects and pilot programs designed, funded and implemented now. Anyone doing CDC-funded prevention work should know about PrEP.
CDC Pre-Conference Symposium on PrEP
The day before the conference opened, the US Centers for Disease Control and Prevention (CDC) hosted a symposium that featured presentations by Bob Grant (Gladstone Institute-UCSF), John Mellors (University of Pittsburg), Ron Valdisseri, (US Department of Health and Human Services) Jonathan Mermin (CDC), Ian McGowan (University of Pittsburgh), Dawn Smith (CDC); a mock debate on PrEP versus treatment as prevention; and a panel of state and local health authorities.
Need
Dawn Smith noted that lack of data on
consistent condom use among gay men and other
MSM in the US is a barrier to determining which
communities or individuals should be targeted
with PrEP. Consistency of condom use is one of
the CDC’s criteria for identifying potential
PrEP users in exploratory research designed to
estimate numbers of PrEP users in the US. Other
criteria include having had more than two male
sex partners in the past year and no condom use
at last anal sex. Based on these criteria and
national survey data, Smith estimated nearly
275,000 gay men and other men who have sex with
men in the US could benefit from PrEP. As AVAC
noted in AVAC
Report 2008, there are glaring knowledge
gaps in the social and behavioral data on gay
men, particularly men of color, that hinder
development of effective new prevention
programs.
Demand
Studies of need quantify how many people could
benefit from an intervention. Demand studies
look at how many people are asking for it.
There is scant concrete information on demand
for PrEP in the post-iPrEx era; the published
information that exists is from pre-iPrEx when
respondents were asked about their hypothetical
interest in PrEP. In discussions, some health
providers noted that there had been limited
interest in PrEP among their clients.
One lamentable barrier is many providers’
discomfort asking for detailed sexual histories
from their clients. This also affects the
ability to generate estimates of need (see
above). On an individual basis, providers will
not be able to identify potential PrEP users
among their clients if they cannot ask
questions about sexual practices and behaviors.
Likewise, individuals who are uncomfortable
raising these issues with providers will be
unlikely to seek PrEP prescriptions.
Once again, no biomedical intervention can move ahead without an enabling environment that engages with basic issues around communication, non-stigmatizing health care and the broader health needs of gay men and other sexual minorities. A suggestion to introduce paper or electronic surveys in advance of visits seemed to skirt and even entrench the issue, rather than tackling it head on.
Service provision
What’s the best way to deliver PrEP? Can it
be provided efficiently without losing out on
the intensive counseling needed to support
adherence and continued use of other
strategies? At this meeting, participants
discussed some of the evidence that could help
guide program design in the US. One speaker
mentioned Project
EXPLORE, a trial which showed that short
counseling sessions worked as well as intense
versions. Another participant suggested a Project
Respect-like model for risk-reduction
counseling—this trial, which enrolled 6,000
heterosexual men and women in the US found
that, perhaps not surprisingly, when providers
"encourage" and "discuss" prevention strategies
with people at risk, rather than simply
providing a "lecture" on HIV prevention, it
significantly reduces their risk of STDs.
Drug resistance
John Mellors presented modeling data on rates
of resistance that could emerge from PrEP and
ART use in South African epidemic. The model
and data were presented
at CROI by Ume Abbas and are detailed in
the conference report below. was based on the
South African epidemic.
Many presenters and participants noted the importance of HIV testing to confirm HIV-negative diagnoses in people starting PrEP and to rapidly identify new HIV infections among PrEP users. The cost and programmatic implications of increasing frequency of testing are significant. But there could be many collateral benefits. Increased testing as part of PrEP rollout could also help to identify more people in acute phase of infection. Studies have estimated that up to 50 percent of new infections involve transmission from individuals who are recently infected and so have very high viral loads.
Messaging and
positioning
Some debates about PrEP have, unfortunately,
revived old and—AVAC would argue—irrelevant
debates about the relative merits of treatment
versus prevention. Pitting one against the
other is not only a waste of time, it also
diverts attention from the tremendous
possibility of a comprehensive approach to
using ARVs for both treatment and
prevention.
Bob Grant emphasized the importance of messages that position PrEP as a bridge to universal access to treatment. He emphasized that well-designed PrEP programs might be able to get more people into testing. HIV-negative people would receive a new strategy plus proven interventions—perhaps giving them hope and increased incentive to remain negative. HIV-positive people would be referred to ARV treatment and care. Ideally, programs that had concrete, substantive offerings for both HIV-positive and negative people would destigmatize testing, ARVs and clinic visits. Grant noted that risk-reduction services were a “transformative experience” for some of the young iPrEx trial participants in the Andean region.
Grant’s vision is, admittedly, ideal if not utopian, and there are many steps to go through before it can even be considered a reality. AVAC Senior Program Manager Deirdre Grant said, “Numerous people commented on the need for community education, outreach and messaging around PrEP. Dawn Smith noted that CDC has some funding to do communications/messaging work with MSM, but she also noted that funds are limited so it is unlikely that they can support intensive health communications efforts for MSM. I would be interested in thinking about the role of advocacy organizations in moving this forward, either by providing information directly or advocating for resources and activity on the part of CDC and local health departments.”
What’s next and who’s running
the show?
The CDC plans is to release a preliminary
formal guidance in April or May and send it out
for review and comment. Final formal guidance
would be released at the end of the year.
Preliminary legal analysis suggests PrEP for
adolescents in the various states will need
parental consent.
AVAC’s Policy Director Kevin Fisher summarized the take-home message from the symposium as follows, “We learned some new things, particularly about resistance, and Dawn Smith also said that Kaiser Permanente had agreed to cover PrEP--and she thought other insurance companies would as well. This may be half the battle because employers also have to be willing to pay for those policies.
“My impression was that the next action item is to develop a few models of how to reach key MSM populations and how to provide PrEP in different settings. There wasn’t a clear consensus on HIV clinicians versus primary care, or HIV clinic versus reproductive health clinics, or social marketing campaigns versus public service announcements. At the end, Jonathan Mermin pointed to the HHS internal PrEP working group that was working with NIH, CDC, and HHS and coordinating with the states. It’s possible that right now that is the closest to a US PrEP coordinating body, and it’s all US government.”
CONFERENCE HIGHLIGHTS: A SELECTIVE SUMMARY
In addition to these selective updates, AIDSMAP, hivandhepatitis.com and Treatment Action Group’s Basic Science blog all provided excellent, comprehensive coverage.
MONDAY
In a Monday morning session “HIV Prevention: HSV-2, Topical and Oral PrEP, and Circumcision” there were a number of presentations on ARV-based HIV prevention research.
Charles Dobard from the CDC presented data from a non-human primate study of post-exposure prophylaxis (PEP) with a gel formulation of raltegravir, an integrase inhibitor. Five of six monkeys remained uninfected after low-dose vaginal challenges with SHIV162p3. The gel was inserted three hours after challenge—this happened twice weekly for ten weeks. The four control animals all became infected. Integrase inhibitors block the enzyme that allows HIV to integrate into the genome of the cell it has infected. Dobard speculated that the gel provided post-exposure protection because the drug acts at this late stage of the viral life cycle. In theory, such a product could retain effectiveness even if used after potential exposure to HIV. Adherence to and consistent use of any ARV-based prevention tool is a major issue. Identifying tools that could be used either before and/or after potential exposure is critical. Oral raltegrevir is licensed and used as an ARV among HIV-positive people. This gel formulation needs to be tested for safety in humans.
What are the comparative advantages and
disadvantages of oral versus topical ARV-based
prevention? There are many ways to answer this
question when considering user preference, ease
of adherence and side effects. Craig Hendrix,
(Johns Hopkins University) presented data from
MTN 001, an open-label study from the
Microbicide Trials Network, which looked at
acceptability, adherence and pharmacokinetics
and pharmacodyamics of PrEP in pill and gel
form. There were 144 women enrolled from sites
in South Africa, Uganda and the US. Each
participant spent six weeks in each trial
arm—daily oral TDF; daily tenofovir gel; both
daily tenofovir gel and TDF pill—with a
washout period between each.
There
were no significant differences in serious
adverse events across the study arms with some
low-grade side effects reported more frequently
in the oral and dual arms. Acceptability was
high across sites and trial arms with 93
percent of participants reporting that they
would likely use a pill and 83 percent for the
gel. US participants preferred the pill while
data from African participants showed no
preference, but they did note the added sexual
pleasure the use of gel provided. Studies of
drug concentrations in the blood and vaginal
tissues showed that the gel achieved a more
than 100-times higher concentration of active
drug in vaginal tissue than did the oral
tablet, while, compared to the gel, oral TDF
used daily was associated with a 20-times
higher active drug concentration in blood.
Hendrix noted that with topical dosing there may be more tolerance for missed dosing even though we don’t yet have a correlate of protection to know for sure. There is not yet data on what blood levels will be required for protection, but this data set will complement information that has been collected from trials like iPrEx and that will emerge from ongoing effectiveness trials. Self-reported adherence to the regimens was over 90 percent while drug level data showed that it was likely closer to 50 percent.
Peter Anton (University of California, Los
Angeles) presented a small, intensive trial of
18 participants (14 men, 4 women) looking at
rectal use of tenofovir gel and oral tenofovir.
As
reported by Gus Cairns from AIDSMAP, Anton
"told the conference that although the gel,
which was identical to the tenofovir-containing
gel used in last year’s CAPRISA 004 vaginal
microbicide trial, was 80% effective in
inhibiting HIV from infecting rectal cells, it
produced adverse gastrointestinal events such
as cramps and discomfort in some users and was
unpopular, with only 25% of users liking it.
The gel is now being reformulated specifically
for rectal use, with various compounds already
being tested on cell cultures, and a
formulation given as a douche or enema has also
been devised."
TUESDAY
There were a number of late-breaker
abstracts presented in a Tuesday oral abstract
session, “Advances
in PrEP”. This included a number of
updates from the iPrEx
trial. Much of the news was encouraging,
including a presentation from iPrEx Principal
Investigator Robert Grant, who presented data
that showed through 144 weeks of follow-up that
participants who received oral TDF/FTC had an
estimated 42 percent fewer infections compared
those who received placebo. No additional
cases of resistance were seen in the additional
follow-up. Other presentations, all
available via webcast and for downloading,
included further analysis of oral PrEP effects
on bone density (see details below), markers of
adherence among iPrEx participants, and more
detailed analysis of drug resistance using
assays to identify minor variant strains.
Several PrEP modeling abstracts were also
presented, one of which is detailed
below.
Albert Liu (San Francisco
Department of Public Health) reported on a
sub-study of the CDC trial of expanded safety
and acceptability of PrEP in MSM that reported
preliminary results in Vienna last year. In
this sub-study, 184 men were followed for up to
two years with at least two DEXA scans to
measure their bone mineral density (BMD). Some
ARVs, including TDF and TDF/FTC, can reduce BMD
in HIV-positive people. Learning more about BMD
effects of these drugs in HIV-negative people
is critical for evaluating long-term safety of
PrEP.
Liu reported that there was a
surprising prevalence of low BMD among
HIV-negative gay men at baseline—before they
were randomly assigned to take either TDF or
placebo. At the end of the sub-study, there was
a small but statistically significant decrease
in BMD among the men who were receiving active
drug, compared to those receiving placebo. Liu
said that the clinical significance of this
still needed to be determined—there were no
differences in rates of bone fractures among
the two groups, for example. The VOICE trial
has a BMD substudy built into its protocol in
heterosexual women in Africa. Learning more
about this potential side effect will be
critical as part of PrEP introduction and
implementation research.
Ume Abbas
(Cleveland Clinic) presented modeling on the
impact of PrEP and/or ART rollout on HIV
resistance and new infections in the South
African context. The models included scenarios
of ART alone, PrEP alone (an instance of
modeling departing from reality, since South
Africa is in the midst of a massive ART rollout
campaign) and ART + PrEP rollout. The
combination approach was modeled in two
scenarios—an "optimistic" one in which 50%
coverage of PrEP was achieved in two years with
high adherence and effectiveness. In the
“pessimistic” scenario with two scenarios,
PrEP coverage took five years to achieve, there
were drop-outs over time, adherence and
effectiveness were lower. In the ART scenario,
it was assumed a TDF-FTC-NNRTI first line
regimen, and PrEP was modeled as oral
TDF-FTC.
The take-home message from Abbas’ presentation was that ART combined with PrEP is likely to have a bigger prevention impact than either strategy alone. (The ART scenario included the assumption, supported by data, that effective ART treatment reduces infectiousness by 92 percent.) In this model, ART contributed more to prevalence of drug resistance than PrEP. For example, in the ART plus PrEP pessimistic scenario for cumulative resistance cases between 2012 and 2022, there were a projected 295,596 for ART alone, 23,489 for PrEP alone, and 323,421 for ART and PrEP. She also said that the model showed that the use of the same drug for ART and PrEP would increase cases of drug resistance and argued for non-overlapping drugs for ART and PrEP. The idea of reserving certain ARVs for PrEP continues to be widely discussed—but AVAC would argue against delaying PrEP rollout until such agents are identified as the prevention benefits using existing drugs must be explored. In the pessimistic PrEP + ART scenario, the number of new HIV infections averted over ten years was 696,020 for ART alone, 200,500 for PrEP alone, and 838,860 for ART + PrEP.
WEDNESDAY
On the last day of the conference, Connie Celum of the University of Washington and principal investigator of the Partners PrEP trial, gave a plenary presentation on ARVs for prevention. In addition to reviewing the rationale for ARV-based prevention and the clinical research to date, Celum outlined some thoughts for the way forward—the three “I”s: Investigation, Implementation and Integration. Investigation is ongoing in the form of numerous trials ongoing in varying populations, many of which expect to report results in late 2012/early 2013.
While the field eagerly anticipates these results, there are a number of questions that will remain unanswered around which additional research is required (e.g., data on populations not in trials, alternative dosing strategies, different agents). While additional investigation is ongoing, work is being done to consider implementation, including resistance and cost-effectiveness modeling, some of which was presented at the conference. Celum addressed the issue of treatment and PrEP rollout, noting the need to reframe the discussion and figure out what needs to happen to roll out PrEP and treatment in parallel. How can we reduce delivery costs, improve retention and improve programming for these efforts? And in conclusion, Celum highlighted the need for integration of ARV-based approaches to maximize benefit as part of “high-impact” combination approaches to combat the epidemic.
As was apparent through the data presented at the conference and highlighted in Celum’s presentation—the science is exciting. It’s also clear, based on a range of stakeholder dialogues and hallway conversations, that the field has much to do as it moves forward—and that the magnitude of the task cannot become an excuse for inaction. Quoting Samuel Johnson at the end of her presentation, Celum reminded the audience that, “Nothing will ever be attempted if all possible objections must first be overcome.”