Scene A publication from Baeten et al.5 in the

Scene Setting

The Human Immunodeficiency Virus or HIV is a condition, when
untreated, leads to Acquired Immunodeficiency Disease Syndrome or AIDS. As
Benjamin Franklin once said, “An ounce of prevention is worth a pound of cure”.
Once infected by HIV, patients cannot be cured which emphasizes the need for
preventative methods especially with an estimated annual cost per person for
HIV treatment of 23,000$ in 20101. HIV infects the host’s CD4 immune
cells, decreasing their count and thus the patient’s ability to fight other
diseases. A weakened immune system gives rise to opportunistic infections and
cancers that further deteriorate the patient’s quality of life. HIV is
transmitted through certain body fluids such as blood, semen, rectal fluid, and
vaginal fluid. Hence, needle use and sexual behaviours are common modes of
transmission of the virus.

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Despite the fact that condoms are a very
effective method of preventing sexually transmitted diseases, many people
refuse, ignore or forget to wear them. Other prevention methods have already
been developed and studied for safety and efficacy, however the results are
conflicting. Emtricitabine/ Tenofovir disoproxil fumarate is an antiretroviral
combination therapy found to be very effective in preventing HIV transmission in
men who have sex with men and serodiscordant heterosexual couples, both of
which are considered high-risk populations2. Vaginal Tenofovir gel,
on the other hand, was less effective in preventing HIV infection in south
African women in CAPRISA 004 study3. However, all of the
above-mentioned drugs were ineffective in the VOICE study in African women4.

Also, Dapivirine is an investigational drug
being studied for the prevention of HIV-1. It is a potent non-nucleoside
reverse transcriptase inhibitor that blocks the multiplication of the virus and
its spread. One of the dosage forms under study is a silicone elastomer self-inserted
vaginal ring. It works locally and provides a long-term delivery of the drug. A
publication from Baeten et al.5 in the New England Journal of
Medicine describes the effectiveness and safety of the Dapivirine vaginal ring.

Need for Study

Sub-Saharan Africa accounts for over 70% of all new HIV infections
in the world, most of which are women. Although the prevalence of the infection
is higher in older people, young women have higher incidence. In fact, women between
the ages of 15 to 24 are not only at higher risk of HIV than their men peers but
also acquire the infection at earlier stages in life6. However, gender
discrimination in Sub-Saharan Africa hinders young women’s access to antiretroviral
medications due to many factors such as sexual abuse and lack of access to education
and health services. In this region, the main mode of HIV transmission is
through heterosexual sex, hence the need to find an effective preventive product
to be used by African women6.

One of the main drawbacks of tenofovir-based prophylaxis is
non-adherence, specifically in Sub-Saharan African young women4, which
further emphasizes the need to find new methods of prevention for this
population. Intravaginal rings (IVRs) have already been approved for other
conditions and have been correlated with increased adherence due to their
sustained delivery system and therefore higher efficacy and lower resistance. IVRs
may be more desirable than daily pills and thus possibly used more consistently.
Consequently, IVRs were hypothesized to solve the problem of non-adherence and
decrease HIV acquisition in Sub-Saharan Africa, a highly vulnerable population. 

Key Results

Baeten et al. performed a multi-site, double-blind, randomized,
placebo-controlled phase 3 trial to study the effectiveness and safety of a
monthly 25 mg Dapivirine vaginal ring in 2629 Sub-Saharan African women between
the ages of 18 and 45. Cumulative incidence was calculated using COX regression
to assess time to HIV-1 acquisition, and Hazard Ratios were obtained to
differentiate between the efficacy in sub-groups. A minimum of 120 incident
cases were required to achieve a 90% power that could detect a 60% effect size
excluding values less than 25% from the 95% confidence interval. However, results
were analysed against a null of 0%.

With regard to the results of the sub-analysis, statistically
significant hazard ratios were seen in South African women, those with
secondary school educational level or higher, un-married monogamous women with
no baseline sexually transmitted diseases and whose partner is aware of the
ring use.

The primary analysis consisted of an intention to treat (ITT)
principle that included all 15 sites. Due to very low adherence levels in 2
sites, authors also opted for a per-protocol (PP) analysis that included 13
sites. Both resulted in statistically significant but modestly effective levels:
there was a 27% decrease in HIV-1 acquisition in the Dapivirine group compared
to placebo in ITT with a 95% confidence interval (CI) ranging between 1 and 46,
and 37% in PP with a 95% CI ranging between 12 and 56. When divided according
to age groups, the desired decrease in risk was only achieved in women 25 years
of age and older with an efficacy of 61%  and a 95% CI ranging between 32 and 77, compared
to women younger than 25 who showed an efficacy of 10% and a 95% CI ranging
between -41 and 43. In terms of safety and resistance to Dapivirine, there wasn’t
a statistically significant difference between the placebo and treatment arm.

To assess adherence in participants, plasma Dapivirine levels were
collected during the first year of the trial and then, Dapivirine levels in both
plasma and returned rings were measured. Utilization increased after the first
months of using the ring then decreased at later stages, however it appeared to
be used more consistently among older women. The reasons behind non-adherence shown
in the qualitative study were suspected to be associated with participant
demographics, drug’s side effects, or concerns of the participant regarding
safety and effectiveness of the drug.   

Study Critique

Choosing to conduct a randomized control trial is appropriate for
the question being investigated. Even though multi-centre trials decrease
validity, they also increase generalisability. Nevertheless, the authors
decreased bias and therefore increased internal validity by blinding
participants and investigators. Comparing the new drug to placebo is suitable
in this case because it’s one of the first trials to test the drug. However, future
trials would have to test inferiority and superiority of Dapivirine ring to
other PrEP formulations.

The study had a large sample size and enough power to detect an
efficacy of 60% that excludes 25% from the confidence interval. Although Baeten
et al. originally aimed for a null of 25% in the protocol, they subsequently
opted for a null of 0% in the primary analysis while providing explanation
behind their choices.

The target population has been correctly chosen since the highest
risk of HIV-1 transmission in Sub-Saharan Africa is in women through
heterosexual sex. The results seem reliable seeing that they were reflected in
a similar study, the Ring Study7. However, in both studies, Dapivirine
ring was not effective in younger women. Considering that this was the age
group who needed the drug the most, we would argue about the impact of the
trial on current guidelines.

In addition, the authors have overlooked the fact that HIV-1
infections occurring during the trial might have been caused by anal rather
than vaginal sex8. They assumed that the percentage of anal sex is
negligible according to the participants’ self-reporting. Although Baeten et
al. stated the 2% reported sexual behaviors during in-person interviews, they
failed to do so with the 13% anal sex reported through the audio
computer-assisted system8. Authors should not have disregarded the
possibility of participants misreporting such behaviour, especially in a region
with high levels of stigma around sexual behavior.        

Economically, Dapivirine ring was found to be cost-effective in
South Africa when efficacy is 25% or more which is the case in the study in
question9. Nevertheless, affordability was not considered in the
analysis which apparently depends on user demand and adherence. As we have
seen, adherence was not high even in the vaginal ring formulation, especially
in younger women, so further analysis would have to be done to assess
affordability of the drug in Sub-Saharan Africa.

On another note, Baeten et al. failed to point out that the vaginal
ring was only effective in relatively educated non-married but monogamous South
African women with no sexually transmitted diseases at baseline and who’s
partners are aware of the ring use.

In attempts to estimate utilization of the ring, Baeten et al.
based their results on objective biologic measures. Dapivirine plasma levels
were collected during the first year but then became more precise by also
measuring residual Dapivirine levels in used rings. Knowing that the defined
cut-off point can be achieved by wearing the ring 8h prior to the clinic visit,
the authors could have prevented the imprecision in quantifying adherence. Although
both methods are better than the usual count of remaining pills4 or
applicators3, changing techniques without providing reasons behind
it decreases the credibility of the results. In addition, the authors stated that
utilization increased after the first months of use without mentioning its
decline in later stages.

On the other hand, considering the social barriers to the
improvement in Sub-Saharan Africa, conducting a qualitative study as was done
by Baeten et al. to understand the causes of non-adherence was critical for
future advancements. The authors provide possible reasons for non-adherence
from their qualitative study, but they fail to mention some of the causes which
could be of great interest for future investigation. In fact, some women
expressed concerns about their fear from their partner’s reaction, which could
possibly be abusive, when finding out about the ring10. This could
be a major limitation to the use of vaginal rings considering the high
prevalence of intimate partner violence in Sub-Saharan Africa11.

Next Steps

The discovery of antiretroviral therapy has drastically improved the
quality of life of HIV patients but still, the prevalence of HIV is increasing,
especially in Sub-Saharan Africa. Therefore, finding an effective prophylactic
drug in this population, specifically in women, might impact the global burden
of HIV. Recent studies haven’t shown an effect in this study population and
have identified non-adherence as one of the main limitations. Even though the
trial by Baeten et al. only showed modest efficacy, it is an innovative
delivery method for the prevention of HIV that targets the issue of
non-adherence and therefore should further be investigated.

On a final note, as stated by Baeten et al. further research should
be conducted to discover the distinctive attributes of younger women. The authors
propose conducting open-label studies to better evaluate concerns surrounding
the efficacy, safety and use of placebo in the trial. I believe that
understanding the imminent challenges to an effective HIV-1 prevention in young
African women is the most urgent matter to be explored. Non-effectiveness was speculated
to be caused by either non-adherence or underdeveloped genital tracts. Given these
assumptions, investigating the rationale behind the results could help choose
the most appropriate method of delivery for this population. Nevertheless, I also
believe that behavioural change must be considered either way. If the issue was
related to non-adherence, then efforts to reshape people’s perception of the
disease and to decrease stigma would possibly improve the outcome. Otherwise,
the obstacle to discovering an effective preventive product for young women would
be biological, and even then behavioural change would be needed to encourage
safe sex and better hygiene.