MICROBICIDES AS AN HIV PREVENTION TOOL:
A REVIEW OF THE LITERATURE
by
Jennifer Nicole Bender
B.A., University of Nebraska at Omaha, 2008
B.S.N., Creighton University, 2009
Submitted to the Graduate Faculty of
Epidemiology
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Public Health
University of Pittsburgh
2012
i
UNIVERSITY OF PITTSBURGH
GRADUATE SCHOOL OF PUBLIC HEALTH
This essay is submitted
by
Jennifer Nicole Bender
on
December 10, 2012
and approved by
Essay Advisor:
Nina Markovic, Ph.D.
Associate Professor, Dental Public Health
School of Dental Medicine
Assistant Professor, Epidemiology
Graduate School of Public Health
University of Pittsburgh
_______________________________________
Essay Reader:
Ronald D. Stall, Ph.D., MPH
______________________________________
Professor and Director
Center for Lesbian, Gay, Bisexual and Transgender Health Research
Behavioral and Community Sciences
Graduate School of Public Health
University of Pittsburgh
ii
Copyright © by Jennifer Nicole Bender
2012
iii
Nina Markovic, Ph.D.
MICROBICIDES AS AN HIV PREVENTION TOOL:
A REVIEW OF THE LITERATURE
Jennifer Bender, MPH
University of Pittsburgh, 2012
Biomedical HIV prevention research findings are becoming increasingly prevalent in the
literature, but in order to get an accurate picture of prevention possibility, adherence and
environment must be carefully considered.
This essay reviews the available literature,
examining reported microbicide trials and participant adherence. Many microbicide trials fail to
show efficacy, but participants’ adherence is not examined in detail. Even though there have
been successes in trials testing microbicides as HIV prevention, the general trend is to dismiss
them and explore other opportunities for prevention. Because behavioral interventions have not
been entirely effective, microbicide research is significant to public health because it adds a
biomedical dimension to the existing prevention effort. This essay aims to show that further
studies of both microbicidal efficacy and means to increase participant adherence are needed to
move the field of HIV prevention forward.
iv
TABLE OF CONTENTS
1.0
INTRODUCTION ........................................................................................................ 1
1.1 IMPORTANCE TO PUBLIC HEALTH……………………………………………..2
1.2 METHODS……………………………………………………………………………...3
1.3 RESULTS…………………………………………………………………………….....5
1.4 DISCUSSION………………………………………………………………………….18
BIBLIOGRAPHY ....................................................................................................................... 21
v
LIST OF TABLES
Table 1. Clinical Trials: Articles Reviewed……………………………………………………….5
Table 2. Ongoing Microbicide Research.......................................................................................17
vi
1.0
INTRODUCTION
Historically, HIV transmission is preventable only by behavior change, if at all. Because
it is transmitted primarily through sex, prevention efforts have been focused on behavior changes
like abstinence, minimizing number of partners, and condom use. Those efforts have been
effective, but there are still 2.5 million new infections worldwide each year. (WHO, 2011) To
further decrease the incidence of newly acquired HIV infection, attention has recently turned to
biomedical prevention. This area of research focuses on a new arsenal of prevention tools:
vaccine development, pre- and post-exposure prophylaxis, and microbicides.
Vaccine
development has not produced any efficacious results as of yet, while antiretroviral medications
as prevention in the forms of both pills and microbicidal gels are promising. The FDA recently
approved Truvada, formerly used only as HIV treatment, as a pre-exposure prophylaxis drug.
Physicians can now prescribe it on-label to high-risk patients to reduce the likelihood of HIV
transmission. Microbicides may possibly be the most interesting and promising of the three
types of biomedical prevention. Although not a single one is approved for use in the general
population, many clinical trials testing the efficacy of microbicides have been done and even
more are currently underway or planned for the near future. Microbicides have shown efficacy
in some clinical trials evaluating them as a form of HIV prevention, but more research needs to
be done to have conclusive evidence. There is enough evidence to propose that microbicides
could be an important part of HIV prevention science.
1
A major factor in both the
developmental process of microbicides and testing their efficacy is the acceptability of their use
among clinicians and the populations in which they will be used
1.1
IMPORTANCE TO PUBLIC HEALTH
There are 34.2 million people living with HIV worldwide. (WHO, 2011) According to
the World Health Organization’s global health sector strategy on HIV/AIDS, women now
account for 52% of the HIV prevalence worldwide. Microbicides were initially developed as a
means for women to initiate prevention, as behavioral interventions traditionally involve a male
condom. The African epidemic always affected heterosexual men and women, but as more
women in the United States were infected with HIV through sexual transmission (when it was
previously mainly through intravenous drug use), a female-initiated prevention tool became more
and more in demand. (Hoffman et al., 2010)
Vaginal microbicides were introduced as a
prevention method that a woman could initiate if a man didn’t want to use a condom, and if
necessary, could be used without her partner knowing.
In the United States, the largest incidence of new infections is in men who have sex with
men (MSM). In 2009, MSM made up 61% of new infections in the US. They also account for
39% of all infections in the US. (CDC, 2009) The disproportionate burden carried by this
population creates a need for a microbicide that is safe when used in the rectum, and not just
vaginally. Development of a microbicide that is both rectally and vaginally safe is significant to
public health as it impacts both homosexual and heterosexual populations. Microbicides were
2
originally formulated for safe use only in the vagina, and research on formulas also safe for anal
is currently being done.
Although it is true that some of the increasing prevalence of people infected with HIV
can be attributed to successful development of HIV and AIDS treatment, that is not the only
reason so many people are living with HIV today. A staggering 2.5 million new infections are
detected each year, and that’s only the infections that are identified. (WHO, 2011) In the United
States, an estimated one-fifth of those who are HIV positive do not know their HIV status, and
are at risk to be actively spreading the virus to all sexual partners. (CDC, 2008) It is true that
more people living with the virus because of better treatment means that there are more people
that can transmit the virus to others, but that should not be an inevitable situation. Long before
there were drugs to fight HIV, the mechanics of its transmission were known. Behavioral
interventions were developed, but the incidence of HIV each year shows that people do not
abstain from sex, nor do they use a condom every time. Sometimes they choose not to, but in
many cases of rape or partner violence, there is not a choice to be made. It is for these reasons
that biomedical developments are an important part of prevention science. Development of
effective microbicide products, in combination with existing behavioral interventions and testing
initiatives, could help to stop transmission of HIV worldwide.
1.2
METHODS
To begin the review of literature, a search for full text articles on “microbicides” was
conducted through Medline, that resulted in identifying 248,230 articles. Narrowing the results
3
to humans only reduced the body of work by half, returning 134,614 articles. Further restricting
to the past ten years reduced the count to 74, 614. Adding the term “HIV” and selecting English
language only articles resulted in 9,588. 1,554 of these articles were clinical trials. The titles
and abstracts of the articles were skimmed, and articles were selected in order to have a
representation of different antiretroviral medications, clinical trials of different types of vaginal
microbicides (for example, rings, gels) and development of rectal microbicides. Many of the
articles were pharmacological studies on the safety of the antiretroviral drugs being used,
whether they were in pill or other form. Although these papers are undoubtedly important, the
focus of this search was on development of microbicidal formulas that could stop the virus at the
site of transmission, and papers that did not directly address this issue were discarded from the
search. There were also trials completed evaluating microbicides as prevention of other sexually
transmitted infections.
Ultimately, only phase III randomized clinical trials evaluating the
efficacy of microbicides as HIV prevention were reviewed. In total, there were only seven
articles that met the above criteria and were results of a phase III randomized clinical trial.
References in these papers were also investigated to be possible sources, and if they were
relevant to the literature review, they were included as well.
4
1.3
RESULTS
Table 1. Clinical Trials: Articles Reviewed
Author
Year
Description of
Population
Sample
Size
Type of Microbicide
Major Findings
Tenofovir
(antiretroviral)
Reduced HIV
acquisition by
39% overall
SAVVY
(surfactant)
No reduction
of HIV
incidence; no
harmful
treatment
effect
Insufficient
evidence of
prevention;
safe for use
Not efficacious
for HIV
prevention
Abdool
Karim
2010
Feldblum
2008
HIV-negative women 1085
ages 18-40,sexually
active
HIV negative women 2153
ages 18-35, multiple
sex partners in last
month
Halpern
2008
HIV negative “high 1644
risk” women
Cellulose sulfate
(blocker)
McCormack
2010
PRO2000
(blocker)
Peterson
2007
HIV-negative women 9385
18+ who are sexually
active
HIV negative women 2142
ages 18-35, multiple
sex partners in last
month
SkolerKarpoff
2008
Carraguard
(blocker)
Van Damme
2002
HIV-negative women 6202
ages 16+, sexually
active
HIV-negative female 892
sex workers ages 18+
SAVVY
(surfactant)
Nonoxynol-9
(surfactant)
Insufficient
evidence of
prevention;
more adverse
reproductive
events
No efficacy
shown; safe for
use
Enhances HIV1 infection; no
longer used
Microbicides are chemicals that are self-applied at either the vagina or rectum as a
prophylactic agent. They are intended to protect for receptive transmission, but they may also
prevent forward transmission. There are five categories of microbicides that have been tested so
far: buffers, surfactants, blockers, antiretroviral agents, and co-receptor blockers. (Abdool Karim
et al., 2012) Buffer agents lower the pH of the vagina to create an environment that is not ideal
5
for viral transmission.
Surfactants inactivate pathogens by increasing the porosity of cell
membranes. Blockers prevent the entire virus from entering host cells. Antiretroviral agents are
commonly used as treatment for HIV/AIDS. They work by preventing virus replication. Coreceptor blockers prevent specific molecules in the virus from attaching to the surface of host
cells. (Abdool Karim et al. 2012)
Cutler and Justman (2008) wrote that at the time of their publication, there were 118
studies on vaginal microbicides to date, 45 of which were clinical trials. Clinical trials to date
have been phases I, II, and III—and overall, the drugs used have been found to be safe and
“well-tolerated,” but efficacy has not been shown among the studies. (Cutler and Justman, 2008)
Some of the issues that deteriorate efficacy in clinical study are a lack of acceptability,
inconsistent use, and nonadherence to study protocols. (Abdool Karim, 2012) In order to
observe any kind of efficacy, these issues must be explored and addressed. When reviewing past
trials, it is important to not just study the results but also how they came to be—the drug and
application type of microbicide used, the participants chosen, whether or not the participants in
the trial followed the protocol, and if not, why that might be.
Trials
In Van Damme et al.’s 2002 study, the participants chosen were female sex workers in
four countries.
The drug being tested was nonoxynol-9, which was already proven as a
spermicide. The drug was formulated into a low-dose gel that was packaged in single-dose
vaginal applicators and supplied to the women in the treatment arm of the study. Condoms and
6
safe sex counseling were supplied to both arms. At the end of the study, the treatment arm had a
slightly higher loss to follow-up than the control arm. The study was stopped by the data safety
monitoring board (DSMB) at the minimum number of seroconversions to perform statistical
analysis, because the nonoxynol-9 group was showing a slightly increased risk of getting HIV.
This was related to lesions that the gel was causing. Participants in the placebo group had
lesions as well, but they did not develop as quickly in these participants as in the treatment
group. This could very well be a reason women were leaving the study. Another concern of
validity is inaccurate self-reporting of sex acts, which researchers had the women do by pointing
to different pictures on a graphic chart.
Two trials were done testing the SAVVY (C31G) vaginal gel in Africa.
In 2007,
Peterson et al. did a study of high-risk HIV-negative women in Ghana. Both the SAVVY (1.0%
C31G) and placebo gels were clear gels in single-dose applicators. This study was stopped early
because not enough HIV infections were taking place in either group to significantly show the
effectiveness of the trial drug. That fact aside, participants reported use of their assigned gel
only 75% of the time in the treatment group and 77% of the time in the control group. Reasons
for not using the gel were not directly addressed, but gel use did decrease over time in both
groups of this study. (Peterson et al., 2007) Feldblum et al. did another trial with the same gel in
2008, this time among high-risk HIV-negative women in Nigeria. Much like the trial in Ghana,
this study used a 1.0% SAVVY gel as compared to a placebo gel, both of which were distributed
to the women in single dose applicators. Usage of the gel was reported at 78% in the SAVVY
group and 79% in the placebo group. Gel use among all participants also decreased over time in
this study. It was found during the study that large number of additional participants would need
7
to be enrolled, so the DSMB watching this study also ended it prematurely. (Feldblum et al.
2008) Both trials using SAVVY were unable to show effectiveness of the drug. The barriers to
statistically significant outcomes in both of these studies are similar: low adherence, unreliable
self-reporting about sexual activity, consistent condom use by participants, and lower HIV
incidence among the population studied than the researchers had expected.
Halpern et al. also published a paper in 2008 about the study that they did in Nigeria, this
one testing the effectiveness of cellulose sulfate as HIV and STD prevention.
Instead of
enrolling high-risk women like the other studies mentioned, to participate in this study, the
women had to be HIV-negative, have an average of 3+ sex acts per week, and have multiple
partners within the last month. The methods of this study are much like that of the SAVVY
trials: all participants were provided with condoms, risk counseling, and a supply of single dose
applicators of either cellulose sulfate or the placebo gel. The reported use of gel in this study
was 81%, slightly higher than in the SAVVY trials. Like the other trials, the loss to follow-up
was more than expected—almost 1/3 of each arm of the trial—leading to difficulties in showing
the effectiveness of the drug tested. This study was also stopped prematurely. The researchers
directly attributed their difficulties to “the challenges associated with performing clinical
research among high risk women in poor settings.” (Halpern et al., 2008)
After the nonoxynol-9 and both SAVVY trials were stopped, another formulation called
Carraguard was tested. Skoler-Karpoff, et al. also published the results of their study of this
carrageenan-based compound in 2008. This compound acts as a barrier between infected and
non-infected cells, and was hoped to protect against HIV and other sexually transmitted diseases.
8
Women involved in this study were South African, age 16 or older, HIV-negative, and sexually
active. The inclusion criteria were not aimed at high-risk women, in fact, anyone who had sex
one time in the past three months was eligible. All women were given either the Carraguard or
placebo gel in individual applicators, and instructed to apply it up to one hour before vaginal sex.
All participants were given condoms and counseling as part of the trial protocol.
Unlike
previous trials, HIV incidence in this population was higher than the researchers had expected.
Even though other less inclusive studies tried to get the women at most risk, this shows that
being more open with enrollment criteria may produce the incidence needed to show efficacy of
a prevention method. This study did not show efficacy in the Carraguard treatment, possibly due
to low adherence. However, Carraguard was tested in a trial a few years later and was the first
vaginal microbicide that was shown to be efficacious against human papillomavirus (HPV).
(Malais et al., 2011) Carraguard was still shown to be a useful medication in preventing an STD,
just not HIV.
Even though this study did not show efficacy, it still had value in that it shows how
important adherence is to a trial and how important it is to measure any variable in the study as
objectively as possible.
A few things set this study apart from others when it comes to
addressing low adherence and other difficulties. Along with a self-report of usage, participants
were instructed to return both used and unused gel applicators to the study staff, and these were
counted and recorded as another measure of participant adherence. Self-reports of adherence by
the participants were high, and “data from applicator testing differed substantially from selfreports of gel use.” (Skoler-Karpoff et al. 2008) The researchers tested the applicators with a
stain assay to see if they had been vaginally inserted, and used the number of applicators inserted
9
divided by the average number of sex acts recorded from behavioral interviews to come up with
a more accurate adherence estimate. Using this estimate, the researchers found that on average
participants were using the gel for only 42.1% of their sex acts—by far the lowest adherence of
the vaginal microbicide trials. The low level of adherence measured by stain assay as compared
to the (much higher) level reported by participants could speak to the results of other studies as
well. Even if a medication works perfectly, effectiveness will never be seen if people are not
using it. This study showed us that more attention needs to be paid to both supporting and
measuring participant adherence to protocol in microbicidal HIV prevention trials.
In 2010, McCormack et al. published another gel trial study that was done in South
Africa, Tanzania, Zambia, and Uganda. The net was cast wider in this study as well, as if a
women was over 18, sexually active, HIV-negative, and willing to follow study protocol she was
eligible if none of the exclusion criteria were met. Exclusion criteria for this study are similar to
other gel studies: pregnancy, regular spermicide use, and HIV-positive status are among the
exclusion criteria. Unlike other trials so far, this study tested two doses of the PRO2000
treatment gel (0.5% and 2.0%) against a placebo. Participants in this study were also instructed
to return used and unused applicators as a measure of adherence. Reported adherence for this
study was 89%, which is high. These researchers used a “triangulation method” for measuring
adherence, which comprised of the self-reports, applicator counts, and the participants’ coital
diaries. All of these things suggested high adherence to gel use among participants, but in spite
of that, PRO2000 gel was not found to be efficacious in preventing HIV transmission. Like the
other studies done so far, this one was stopped early because the treatment had little chance of
ever showing significant reduction in HIV seroconversion.
10
However, the published paper
emphasizes study strengths like strong social integration and community partnerships, which
makes it stand out from previous trials.
Abdool Karim, et al. published the results of the CAPRISA trial in 2010. The CAPRISA
trial was innovative in that it was the first microbicide to use an antiretroviral medication in the
gel formulation. In this trial, tenofovir was used. Tenofovir is an adenoside nucleotide that was
already licensed for AIDS treatment in oral form, either alone (as Viread) or in a combination
with other drugs in a single pill (Truvada and Atripla). (De Clercq, 2007) Because tenofovir had
already been proven effective as AIDS treatment in humans and because it prevented HIV in
macaques when it was administered subcutaneously, De Clercq asserted that it has the potential
to be an effective prophylaxis in a microbicidal preparation for any route of HIV transmission—
for example, a microbicidal gel for vaginal transmission or inoculation/subcutaneous
administration for parenteral transmission, from something like sharing needles during
intravenous drug use or a bloodborne pathogen exposure in a healthcare setting. The CAPRISA
trial followed a similar format as previous microbicide studies. The tenofovir was formulated
into a 1% gel, and South African women ages 18-40 who were HIV-negative and sexually active
were recruited into the trial. Adherence was measured in a manner similar to the PRO2000 trial.
Along with self reports, the women returned both used and unused applicators to the study staff.
Applicators not returned were assumed to be unused for study calculations. This study had a
“comprehensive adherence support program” based on each participant’s last month of usage
history in addition to the instructions and counseling that were provided to all participants on an
ongoing basis. The retention rate in this study was extremely high, with 94.8% of the sample
population remaining in the study until the endpoint. However, adherence was lower than most
11
of the other microbicide trials to date, at 72%, even with the addition of an individualized
adherence support system. This could be attributed to the fact that an “adherent” sex act as it
pertained to study protocol was strictly defined according to the dosage instructions, with the gel
being used within the 12 hours before and the 12 hours after each sex act. If the gel was used
only once, that act would not be considered adherent. In those who were considered “highly”
adherent, the HIV incidence was 54% lower than in those who were not. The study was carried
out to completion and overall, the tenofovir gel in the study was estimated to reduce HIV
incidence by 39%, arguably the most successful result of any microbicide trial to date.
Even with this success, it is pointed out that at least 40% of the women in the study used
the gel adherently less than half of the time, and in order for tenofovir or any HIV prevention to
be effective, it must be used correctly and consistently. This lack of adherence is in place even
though the researchers went to great lengths to help participants achieve maximum adherence
with the individualized adherence support system and counseling.
Acceptability of a
microbicidal gel in the study was also very high, as “97.4% of the participants found the gel to be
acceptable, and 97.9% indicated that they would use it if it prevented HIV.” (Abdool Karim et
al., 2010) Despite the high acceptability and support provided in the study, adherence didn’t
reach the necessary levels for effective prevention. The researchers stress the importance of
continuing research to improve adherence, along with the combination of microbicidal gels with
other HIV prevention methods. They also stress the need for more effectiveness trials to be
done. Along with gathering more scientific evidence, more trials could improve adherence to
HIV prophylaxis methods in general, as the gel was found to be more highly acceptable among
participants in this trial once they know for sure that it prevents HIV.
12
Adherence
Acceptability is one of the major factors in the level of adherence to any therapy. Many
studies have been done to determine the level of acceptability of a topical microbicidal gel as an
HIV prevention method. The measure of acceptability of a microbicidal formulation includes
physical properties like texture and scent, but also the likeliness of women to use a vaginal
microbicide with their current partner(s).
(Morrow & Ruiz, 2008)
The best time to do
acceptability research is early in the development of a microbicide—that way, a formulation that
best suits the wants and needs of the population can be considered from the beginning. (Morrow
& Ruiz, 2008) Women interviewed in qualitative studies agreed that having a woman-initiated
form of prevention was important, saying that it gave women “responsibility to her own personal
body” and that the gel had a role in “helping women…have control over the sexual acts that
they…have to perform.” (Hoffman et al., 2010) Another issue brought forth in qualitative
interviews was the possibility of covert use. Most women said that using a microbicide secretly
with a casual or new partner would be possible, but those who were married or in long-term
relationships would disclose use to their partners. Women were uncomfortable with the idea of
hiding microbicide use from a long-term partner, and many believed that a long-term partner
would be able to tell that something was different during sex if a microbicide was being used.
(Hoffman et al., 2010)
Acceptability is not universal. One issue that divides populations when it comes to
acceptability of a formula is vaginal lubrication. In many African cultures, women use vaginal
drying agents to increase men’s sexual desire—a dry vaginal climate is preferred by many
13
African men, and in a study of Depo Provera (a birth control method), South African Women
reported vaginal wetness as an adverse effect. (Smit et al., 2002) This is just one example where
populations are divided on an issue that affects acceptability of a microbicide product, and it is
something that researchers need to consider when developing HIV prevention methods. In order
for a microbicide to be used consistently, it will need to be accepted in a society—and depending
on the target population, microbicides will need to be formulated differently. Increasing sexual
pleasure and performance both for themselves and their partner is something that most women
agree is integral to consistent microbicide use. (Hoffman et al., 2010) However, sexual pleasure
is not a one-size-fits-all concept, and in order to develop products that will be effective
worldwide, researchers will need to take into account the sexual culture of multiple societies, and
qualitative research is an important window into this issue.
Combined with data from
participants in early phase clinical trials, it can help researchers to develop products than can
achieve effective prevention as well as efficacy in a clinical trial.
Acceptability is also a major issue in the development of microbicides that are safe for
rectal use. Issues impacting the acceptability of these products are similar to those impacting the
development of vaginal microbicides, with lubrication being a concern for both insertive and
receptive anal sex partners. (Gross, 2001) In a phase I clinical trial done at UCLA, participants
tested a gel formulated for vaginal use in the rectum. The participants in this study responded
that on average, they would be highly likely to use a microbicide any time they had receptive
anal sex or any time they had sex without a condom. The gel tested in this study also received
high acceptability ratings on its physical properties like texture and smell. (Ventuneac et al.,
2010) Participants in the study did have some suggestions on how to make the product, but
14
overall, comments were favorable. The researchers state “the combined use of quantitative and
qualitative assessment tools proved quite rich.
We were able to establish that although
participants felt positive or neutral in their quantitative ratings of the application process and the
applicator, when given the opportunity to elaborate, during the qualitative interviews, they
pointed out a number of ways in [it] could be improved. This is useful information to take into
account for the design…to anticipate (and correct) situations that may interfere with adherence
not just in Phase 1 clinical trials but also in larger Phase 2 or 3 trials.” (Ventuneac et al., 2010)
Although many studies have been done about women’s preferences on vaginal
lubrication, little research has been conducted about preferences concerning rectal lubrication
among heterosexual or homosexual couples. (Ventuneac et al., 2010) This can be partially
attributed to the societal stigma surrounding anal sex, and the unwillingness of many societies to
address such an issue. In the studies that have been done on men’s lubrication preferences, the
high frequency of usage is a promising sign for microbicide research. In a study of Latin men
who have sex with men (MSM) in New York City, 93% of survey respondents said that they
used lubricants. The majority (59%) responded that they always used a product, and 74% used
lubricant during at least 80% of the time. (Carballo-Diéguez, 2000) Most MSM are already
using some kind of product during most of their sexual encounters—which means that it would
not be as far of a stretch to get them to use a microbicidal lubricant in place of a non-medicated
one. What’s more, 87% of the men in the same study said that they would be interested in
participating in an acceptability trial of an HIV preventative microbicide. Most of the men in this
study reported using the lubricant either on the penis or around the anus to facilitate penetration,
so in order to provide an environment for maximum protection from HIV, education about
15
lubricating the insider of the rectum would have to be provided to study participants. Still, the
prevention opportunities highlighted by this research are promising. (Carballo-Diéguez, 2000)
Barriers to rectal microbicide use have not been studied in detail, but considering barriers to
vaginal microbicide use gives us a good idea of what we can expect.
Participants in the
acceptability trial discussed previously clearly had suggestions on how to make the microbicides
in the trial more suitable to their tastes, and an aversion to the physical properties of the gel could
certainly cause a barrier to use.
MSM may also have reservations about covert use of
microbicidal formulations as prevention, especially if they have long-term partners with whom
they have a trusting relationship. Another possible barrier to use is that microbicides, whether
they are distributed through part of a clinical trial or as FDA-approved HIV prevention, will most
likely have to be prescribed by a physician to be obtained. Access to healthcare is a huge barrier
among many high-risk populations, especially sex workers. With this prescription will come
specialized care, testing, and questioning, and this has the potential to make many people
uncomfortable and is definitely a barrier to microbicide use among MSM. In fact, distrust of the
healthcare system is not just a barrier to prevention but also a driver of HIV infections among
minority populations. (Christopoulos et al., 2011) However, this barrier cannot be attributed to
distrust in the MSM population alone.
Years into the HIV epidemic, the connection to
healthcare from community-based AIDS organizations is unreliable at best. (Christopoulos et al.,
2011) If researchers want the MSM population to trust the science, there is much work to be
done at the system level and that trust is going to have to be earned. Clinicians will need to be
sensitive to the needs of their MSM patients and vigilant in prescribing prevention methods like
microbicides and pre-exposure prophylactic drugs when they are appropriate (and approved).
16
Current Research Trials
Although research on rectal microbicides is not quite as far along as the research being
done in vaginal formulations, there are many studies currently underway. The following table
outlines the work in rectal microbicide development currently being done by the Microbicide
Trial Network (MTN, 2012).
Table 2. Ongoing Microbicide Research
Protocol Number
MTN-007
MTN-012/IPM 010
MTN-014
MTN-017
Study Name
A Phase 1 Randomized, DoubleBlinded, Placebo-Controlled Rectal
Safety and Acceptability Study of
Tenofovir 1% Gel
Male Tolerance Study of Dapivirine
Gel Following Multiple Topical Penile
Exposures
A Phase 1 Crossover Trial Evaluating
the Pharmacokinetics of Tenofovir
Reduced-Glycerin 1% Gel in the
Rectal and Vaginal Compartments In
Women
A Phase 2 Randomized Sequence
Open Label Expanded Safety and
Acceptability Study of Oral
Emtricitabine/Tenofovir Disoproxil
Fumarate Tablet and Rectally-Applied
Tenofovir Reduced-Glycerin 1% Gel.
Study Status
Closed to Follow-Up
Closed to Follow-Up
Pending
Pending
These studies are all using antiretroviral medications, which showed high efficacy in the
CAPRISA trial. The results of the CAPRISA trial in combination with the high lubricant use of
many MSM provide the basis for the great excitement of many scientists about the potential that
rectal microbicides have for HIV prevention. Rectal microbicide groups like the International
Rectal Microbicide Advocates (IRMA) work hard to develop new studies and educate the
community about what’s going on in the research world. (McGowan, 2011) A grant program
17
called “Be the Generation Bridge,” funded by the National Institute of Allergy and Infectious
Diseases, helps community organizations that already provide HIV testing and AIDS case
management services to create and then integrate education materials about biomedical
prevention like vaccine development, pre- and post-exposure prophylaxis, and microbicides into
their existing programs. (NIH, 2012) These educational programs all exist in cities where there
is a site doing biomedical prevention research. Programs and advocacy groups can help the
development of microbicides and other biomedical prevention by educating the scientific and lay
communities about the ongoing research.
1.4
DISCUSSION
Throughout the past decade of microbicide research, we have learned that many things
don’t work and that some things do. The early vaginal microbicide trials with spermicides and
other compounds were discouraging, and for a while nothing seemed to be preventing
transmission. It was unclear if the compounds being tested were actually ineffective, or if the
major issue was a lack of adherence by study participants. Throughout this inquiry, qualitative
and quantitative studies were done, and great insight into participant adherence and how to
increase it was gained.
The CAPRISA trial changed everything.
Using tenofovir, an
antiretroviral medication, proved efficacious in preventing HIV transmission in a vaginal
microbicide trial. (Abdool Karim et al., 2010) Since then, a large quantity of research has been
done in a relatively short time to move both vaginal and rectal microbicide options further
towards US Food and Drug Administration (FDA) approval and widespread use by populations
at high risk of contracting HIV. Now that a more efficacious product is available, it is more
18
important than ever to understand all the factors that affect adherence, since it is still a possible
barrier to achieving positive results in a clinical trial. More studies should be done to find out
exactly what affects adherence during a microbicide trial, and what we can do to maximize
adherence level in future studies.
Another reason HIV prevention research is slow to produce results is that it is clearly
unethical to have high-risk participants engage in completely unprotected sex, so participants in
treatment and placebo arms of all HIV prevention receive standard care, usually consisting of a
condom supply and safe sex counseling. These things, when used correctly and consistently, are
effective at preventing HIV transmission—so incidence in trials has frequently been lower than
researchers needed to see to prove statistically significant efficacy of their trial method. Multiple
clinical trials testing microbicide efficacy have been stopped for this reason, and even in trials
that continued to their endpoint, it is important to look closely at the results for any differences in
the condoms and counseling provided to the different arms of the study. Any bias could alter the
results, and it is integral to have everything in a study except the microbicide formula be as close
to the same as possible in order to see the true effect of the drug.
For this reason, more research is needed in the development of both vaginal and rectal
microbicides. Now that efficacious combinations of medication have been discovered, larger
effect sizes can be seen once bigger trials are underway. Research in lesbian, gay, bisexual, and
transgender (LGBT) healthcare disparities can inform the development of microbicides and other
biomedical prevention by helping clinicians make their practice as accommodating, and therefore
attractive, to high-risk populations as possible.
19
Acceptability research has informed
development by suggesting that if a product is similar to a lubricant that is already used for sex,
high-risk populations, especially MSM, would be more likely to use the product as HIV
prevention. Physical properties of the microbicide need to be attractive to the population for
which its use is intended, and although some qualitative research has been done around this idea,
more studies are needed to develop a product that is desirable by populations worldwide. A form
of prevention that people are excited to use would be an incredible asset for those working in the
field of HIV prevention and all populations that can potentially benefit from such a product.
Education in the community needs to be ongoing. HIV is a worldwide epidemic that
biomedical prevention can help us end forever, but there is still a huge stigma surrounding sex,
and in order for these prevention methods to be effective we all need to be vigilant in our work to
get rid of this stigma. Prevention research is a lengthy process that requires participation from
everyone—without interested and engaged community partners, recruitment efforts will not be
successful. Community-based organizations, advocacy groups, and individuals can all work
together to help the cause. Community involvement is essential to advance the research process.
Biomedical research is just one piece of the puzzle that is HIV prevention. Further research in
biomedical prevention, especially in microbicide development, should be done in order to move
development toward an easily accessible prevention method forward. Combining research on
adherence, acceptability, and microbicide efficacy will result in a huge step forward for the field
of HIV prevention and possibly a new way to stop transmission of the HIV virus forever.
20
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