Introduction recent years.2 Globally, women accounted for 47%



With improved global coverage of antiretroviral therapy
and reduction in mother-to-child transmission, tremendous strides have been
made towards the United Nations target of ending the Acquired Immune Deficiency
Syndrome (AIDS) epidemic by 2030.1 This
progress, however, has been impeded by a stagnating decline in new Human
Immunodeficiency Virus (HIV) infections among adults since 2010.1 The
annual number of new HIV infections among adults (15 years and above) has
maintained at an average of 1.9 million in the recent years.2
Globally, women accounted for 47% of new adult HIV infections.2 This
number is at a much more disproportionate 81% in sub-Saharan Africa, where HIV
prevalence is higher, highlighting the pressing need for additional HIV
prevention options for women.1,3 In a
recent study, called ASPIRE (A Study to Prevent Infection with a Ring for
Extended use), Baeten et al. present their results on the use of the
first long-acting, female-controlled HIV prevention option.4 The
study aimed to investigate the efficacy and safety of a monthly vaginal ring
containing the antiretroviral drug dapivirine for protection against the sexual
transmission of HIV in African women.4 The
study findings raise critical questions about its potential benefits and level
of use, as well as how to optimize the HIV prevention efforts and support

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Need for a discreet, female-controlled, long-acting


Biologically, women have a higher risk than
men of being infected with HIV during vaginal intercourse.5 Gender
inequalities and sexual violence experienced by women limit their ability to
negotiate the use of HIV prevention options, further increasing their risk of
HIV infection.2 Yet,
current HIV prevention options such as female condoms and male circumcision are
mainly controlled by men, either directly or indirectly.2,3
Research into microbicides – topical products applied to the vagina and/or
rectum to prevent mucosal transmission of HIV during sexual intercourse –
started in 1992 to develop a prevention option which women can directly
However, none of the studied microbicides have been successfully licensed up
till today.7



Before the dapivirine vaginal ring (DVR), the
only other antiretroviral microbicide candidate which showed modest efficacy in
an earlier trial was the event-driven vaginal 1% tenofovir gel.8
Subsequent trials did not confirm its efficacy in HIV protection, in large part
due to non-adherence by study participants.9,10 The use
of the tenofovir gel, however, would also not be discreet and still be
subjected to partner negotiation in which women may have less control over.


With unprotected heterosexual sex as the main
driver of the AIDS epidemic in sub-Saharan Africa, there is hence a need for a
new discreet, female-controlled HIV prevention option that can directly reduce
HIV incidence in women.3,11 Today,
the only discrete prevention option women can control is a highly efficacious
oral combination tablet containing the antiretrovirals tenofovir and
emtricitabine (called pre-exposure prophylaxis, or PrEP).12 While
oral PrEP is a step in the right direction, it would not be a suitable or
preferred option for all women. Based on early experience, researchers noted
that non-adherence to daily PrEP greatly diminishes its effectiveness.9 This
underscores the need for a long-acting form of HIV protection, which is less
dependent on adherence, to ensure better effectiveness.13,14
Therefore, ASPIRE is a crucial study to evaluate the potential of microbicides
and the impact on adherence to HIV prevention by using a discreet product with
sustained release properties. Follow-up studies and introduction of other new
HIV prevention products in the development pipeline would be built on the
evidence provided by ASPIRE.



Key Findings from ASPIRE 


ASPIRE was a randomised, double-blind,
placebo-controlled Phase III trial conducted at 15 sites in Malawi, Uganda,
South Africa and Zimbabwe between August 2012 and June 2015.4 It enrolled 2,629 sexually active women ages 18-45, who were
randomized in a 1:1 ratio to receive either a vaginal ring containing 25mg of
dapivirine or a placebo vaginal ring.4 Dapivirine is an antiretroviral drug which acts as a
non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1.4 When placed inside the vagina, the ring
slowly releases dapivirine over the course of four weeks.4 Every
four weeks, women visit the centres to remove the used ring and insert a new


Data was analysed with an intention-to-treat (ITT)
approach using Cox regression.4
However, 15 women were excluded from the ITT-based analysis, including 3 women
in the placebo group who were HIV-positive at enrolment.4 The
authors also did not provide details for excluding the other 12 women lost to
follow-up. Nevertheless, the impact on the effect estimates, if any, will
likely be small since they were only a small proportion of the initial sample
size. At the end of the study period, 71 women in the dapivirine group acquired
HIV-1 infection incidence rate of 3.3 seroconversions per 100 person-years;
95% confidence interval (CI): 2.6 to 4.2, compared to 97 in the placebo group (incidence
rate of 4.5 seroconversions per 100 person-years; 95% CI: 3.7 to 5.5).4


Based on the
findings, Baeten et al. concluded that DVR
modestly reduced the risk of HIV-1 infection by 27% in women enrolled in the
trial.4 Similar results have since been
independently confirmed by another Phase III efficacy trial, called the Ring
Study.15 In the Ring Study, incidence
of HIV-1 infection was found to be 31% lower in the dapivirine group compared
to placebo.15 This is encouraging news for the
field since past microbicide trials failed to obtain repeatable results.9,10 While ASPIRE raises many new and
important questions, it ultimately shows DVR as the first long-acting and
discreet female-controlled microbicide that offers protection against HIV-1


On closer
examination, ASPIRE’s results are only borderline statistically significant
(P=0.046) and may not be clinically impactful.4 This is reflected in the wide 95%
CI of the hazard ratio (HR), comparing HIV-1 incidence in dapivirine group to
placebo, which is between 0.54 to 0.99.4 The upper limit of 0.99 is very
close to a null effect (HR = 1), and indicates there could be a clinically
negligible or no treatment effect compared to placebo.4 Comparable findings were also
reported in the Ring Study (HR 0.69; 95% CI: 0.49 – 0.99).15 However, there was a slightly
greater confidence in treatment effect (HR 0.63; 95% CI: 0.44 – 0.88)
only when Baeten et al. excluded from 2 sites where many
women were not returning for study visits or using the ring consistently.4 This raises questions about the
intrinsic efficacy of DVR, especially when compared to the evidence for oral
PrEP in which the effect estimates from multiple studies are all far from the
null effect (Figure 1).16




Figure 1
| Levels of efficacy from each major antiretroviral-based prevention trial and
the corresponding confidence intervals around the finding16 



Furthermore, even though DVR was
designed to be inserted once a month, it seemed that the ring was often taken
out between clinic visits by study participants. Baeten et
al. stated that this lower than expected efficacy may be related to
non-adherence by study participants after they were told that they might be
getting a placebo and that the product might or might not be efficacious.4 During
the trial, participants
were also provided with other HIV risk-reduction measures such as free condoms
and counselling.4 Since we
cannot rule out the use of other HIV prevention options during the trial, it is
possible that participants may turn to the use of proven alternatives, such as
condoms or daily PrEP, especially if they believe they are receiving a placebo.
Therefore, any treatment effect observed might have arose out of other
confounding factors.


from ASPIRE also points out a major limitation of DVR. HIV is known to transmit more readily through anal than
vaginal intercourse.17 However, dapivirine is unlikely to attain sufficient levels systemically
or in the rectal tissues to protect women against non-vaginal exposures such
anal sex or intravenous drug use.18 Although 2% of the participants
reported a previous exposure to anal sex in the earlier 3 months, investigators
did not routinely collect information during the study about the participants’
exposure to anal sex nor report on the likely causes of infection in women who
acquired HIV.4 Therefore, it is possible that a small proportion acquired
HIV-1 infection via anal sex and considerably reduced the efficacy of a product
which only has vaginal coverage.19


Although one of the primary objectives was also to
determine its safety, the authors did not categorically conclude if DVR was
safe to use for HIV prevention in women. Incidence of sexually transmitted
infections and adverse medical events did not show any significant difference
between both groups, suggesting that the use of DVR did not increase the
likelihood of risky sexual behaviours or side effects.4 There
is, however, concerns over treatment resistance in participants who acquired
HIV-1 infection. Although the rates of NNRTI mutations was similar in both
study arms, E138A was the most common NNRTI-associated drug resistance mutation
(DRM) found in ASPIRE.4 As in
vitro studies have shown E138A to cause 2-fold resistance to other NNRTIs like
etravirine and rilpivirine, mutations at codon 138 may be associated with
reduction in dapivirine susceptibility.20
Follow-up studies would be required to determine if resistance to dapivirine
develops in individuals who acquired HIV-1 infection after using DVR. The low
genetic barrier to NNRTI resistance may also lead to cross-resistance to other
NNRTIs, increasing the risk of therapy failure and limiting treatment options.21
Moreover, if DVR was not worn consistently by women, E138A may also be more
likely to occur as local levels of dapivirine would fall below the minimum
concentration required to prevent against mutation.21 In view of
the risk of resistance, there is no clear indication of the
likely level of protection and safety for an individual using DVR.



Insights for Microbicide Research


In view of the suspected non-adherence, Baeten et al.
pointed out a novel method for ascertainment.4
Initially, participants’ self-reported adherence was defined as blood
concentrations of dapivirine which tested greater than 95pg per millilitre.4 This
was based on the understanding from previous studies on oral PrEP where higher
drug concentrations were achieved with higher medication compliance.9
However, pharmacokinetic studies have shown that dapivirine is detectable in
plasma as early as 1 hour after ring insertion and achieves peak concentration
only after 8 hours of use.22
Therefore, study participants who only wore the ring just few hours before
testing could have been misclassified as adherent.4
Investigators then turned to testing of residual dapivirine levels in used
rings as a surrogate measure.4
Although phase I and II studies indicated that an average of 4mg of dapivirine
is released during four weeks of continuous use, Baeten et al. used a
slightly higher adherence criteria of below 23.5mg, instead of 22mg, of
residual dapivirine.4,23,24 Both
methods were acknowledged in the report as a potential reason for
overestimation of adherence which likely affected the study results.4
Post-hoc time-varying product adherence analysis of both ASPIRE and the Ring
Study has since assessed residual dapivirine levels below 22mg as a better
marker of adherence.15,25
Nevertheless, the initial findings of ASPIRE stresses the importance of
objective measures of adherence and provides useful insights on how to improve
future trial design to confirm adherence for a range of HIV prevention



More importantly, ASPIRE demonstrated that more must be
done to improve adherence and address the HIV prevention needs of adolescent girls and young women (AGYM), who remain as
one of the highest at-risk groups.3 While post-hoc analysis showed that rate of HIV-1 protection
was 56% higher in women over 21 years in the dapivirine group when compared to
placebo, there was little to no protection in women between 18 to 21 years.4 This difference in effect was likely associated with a lower
adherence to DVR in younger women. In earlier trials involving the use of daily
oral PrEP and tenofovir gel, older women also reported higher levels of
adherence.8,9 The varied results of ASPIRE strongly
indicates that DVR did not work in the context of young women’s lives. This
also underlines the need to assess effectiveness
in diverse groups, since a product that fails because of poor adherence in one
population could succeed in another.26


With AGYM accounting for up to 25% of
new adult infections globally and in sub-Saharan Africa, further
research is necessary to understand the age-related disparities in the observed
level of protection.1 Moving
forward, two open-label extension studies are underway to assess real-world
patterns of use and acceptability.27
Typically, adherence to HIV prevention options are found to be significantly
greater in open-label trials as participants are aware of what they are getting
as well as how efficacious and safe they are.28-30 With
better adherence, the true effectiveness of DVR can be better estimated. In
addition, continuing research focused on AGYM would be critical in
understanding their acceptability of the ring and specific prevention needs.
Recently, a study on 96 adolescent girls in the United States has found DVR to
be safe and highly acceptable, although some participants had concerns that
their partners would feel the ring during sex.31 This
paves the way for a planned study on approximately 300 AGYM aged 16-21 in
sub-Saharan Africa to evaluate the safety of, adherence and preference to both
DVR and oral PrEP.27 This
way, we can develop varying types of HIV prevention strategies or tailor health
care delivery to match the sexual behaviour and needs required by women at
different stages of life.26



Next Steps for HIV Prevention


future of microbicide come a time when the U.S. National Institutes of Health
(NIH), one of the largest public funder of biomedical research in the world, deliberates
on how best to allocate funding for HIV prevention research going forward.32 The
laggard status of various microbicides in development, including DVR, has thus
raised questions over whether the industry should shift away from research on
microbicides to support other forms of HIV prevention such as vaccines or new
types of PrEP that are much further along in the pipeline.19 As seen
from Figure 1, PrEP has set a high bar for other prevention modalities
to follow. In a major
study of men who have sex with men, called iPrEx, there was a substantial 92%
reduction in risk of HIV-infection for participants who adhered to the daily
PrEP regimen.33 In comparison, the efficacy of DVR
is well below that of daily oral PrEP, even in the context of good adherence.


As discussed earlier, the use of DVR
is also restricted to people with only vaginal
exposures. This excludes high risk groups such as female sex
workers and transgender men who frequently engage in anal sex.34,35 While vaginal
intercourse is currently accountable for most new infections in African women,
the proportion attributable to anal sex globally is expected to increase in
line with its increasing prevalence.36,37 Many women also did not use the
ring consistently during the study despite being designed with the hope to
improve adherence. This further drives the preference for prioritizing research on
long-acting systemic products which offer protection to the whole body and not
just the vagina or rectum, such as long-acting injection of PrEP, broadly
neutralizing HIV antibodies, or an implant providing prolonged release of a
preventive antiretroviral.19


However, as with
contraception, there is a need to offer an array of prevention options to fit
individual needs.27 For
instance, not all women who engage in unprotected sex are willing or able to
receive a long-term systemic medication (due to side effects, lack of access,
partner disapproval, cost and accessibility).19
Compared to having no protection at all, such real-life circumstances then
support the ethical design of even moderately effective microbicides as
reasonable alternatives.19 With
more options available to women, the likelihood that one will be used

Particularly, multi-purpose technologies (MPT), such as
the combination of a microbicide with a contraceptive into a single product,
would likely improve uptake and adherence of the vaginal ring.38 Recent
research have found that women prefer products that not only protect against
HIV, but also unintended pregnancy and other sexually transmitted diseases.39 Since
contraception goes hand in hand with HIV prevention in women, it would be more
reasonable and cost-effective to study microbicides as part of MPT research.


From a macro-perspective, microbicides may also provide
considerable population benefit at compelling economic value.3 Compared
to systemic prevention approaches, microbicides can be self-administered and
require less frequent monitoring due to its localized action.3 As
such, they can be cheaply distributed by workers without significant medical
training, and does not burden the resource-constrained health systems in the
developing world.19 After
accounting for a strong uptake of oral PrEP and low adherence to DVR (50%),
results from a cost-effectiveness analysis of scaling up DVR in South Africa
still show a possible prevention in 8.8% of new infections over ten years, with
cost savings of $8678 per infection (from healthcare and intervention costs).40 This
impact was even greater when the scale-up was targeted at women aged 20-29
years.40 A modelling
analysis on 13 African countries have also found that a modest reduction in
risk by DVR could still potentially avert an additional 170,500 HIV infections
by 2030.3 This
further supports the need for continued research on microbicides, including DVR,
as an additional prevention strategy to reduce HIV incidences.




Although we are
unable to know with any confidence the likely level of individual protection
which DVR offers, ASPIRE contributes important insights to the field of HIV
prevention research by highlighting the urgent need to deliver better tools and
programs that truly address prevention in AGYM and support adherence. With the
ongoing discussions on how to prioritize future HIV prevention research
funding, the role and benefit of microbicides in expanding the range of HIV
prevention options controlled by women cannot be disregarded despite their
modest efficacy. More work is certainly required before DVR can be added to the
short list of HIV prevention option. As HIV continues to be a public health
crisis, research into other promising approaches, including long-acting
injectable antiretrovirals and vaccines, must also continue. 


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