Scene chronic, often sexually transmitted disease that infects

Scene setting

Human
immune deficiency (HIV) is a chronic, often sexually transmitted disease that infects
a person for life and leads to acquired immunodeficiency syndrome (AIDS) if
left untreated (5). HIV is spread via blood, semen, breast milk, and vaginal
and rectal fluids. The disease weakens the immune system by attacking it,
leaving those infected more prone to disease (5).  Though HIV was once a death sentence, anti-retroviral
therapy (ART) has allowed HIV patients to keep the disease under control and
live otherwise normal lives (9). ART is proven to reduce HIV transmission
from one sexual partner to another by 93%, and the use and availability of ART
in low and middle-income countries has saved 5.2 million people from AIDS
related death (2,3). Unfortunately, ARTs have not been as effective in
sub-Saharan Africa, compromising 70% of the global burden of HIV infection (7).
As of 2013, the highest death rates per 1000 people living with HIV were in
Central African Republic with 91, South Sudan, with 82, Cote d’Ivore, with 75,
Cameroon with 72, and Chad, with 71 out of 1000 living with HIV (4). Though ART has reduced instances of HIV and
death in these five nations, they have almost ten times higher death rates than
high income countries, showing that there is a need for further intervention (4).

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In their study, Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in
Women, Baeten et al. indicate that young
sub-Saharan women shoulder most of the HIV-1 related burden (1). While
ARTs are proven to reduce HIV transmission, the authors cited three articles in
which ARVs were not effective in preventing HIV-1 incidences among African
women, hypothesized to be due to low adherence to daily or coital antiretroviral
gels, films, or pills (1). This subgroup of women may have difficulty
remembering to use these ARV measures, or may be prohibited from using these
technologies by their partners due to cultural beliefs or taboos. Given that
the greatest
mode of HIV-1 transmission in sub-Saharan Africa is unprotected heterosexual
intercourse, it is clear that young women in sub-Saharan Africa require an
innovative intervention to lower their chance of HIV-1 infection (3).

Baeten
et al. hypothesized that using vaginal rings for ARV administration would provide
longer term protection, thus making adherence easier for these young women,
ultimately decreasing new HIV-1 incidences (1). They decided to administer
dapivirine via the vaginal rings, as it is a topical antiretroviral medication
that blocks HIV-1 reverse-transcriptase enzymes, preventing a broad range of
HIV-1 subtypes from multiplying in the body and causing infection (11). Dapivirine
was chosen as it decreased susceptibility to HIV-1 in previous studies without
exposing the entire body to the drug (1).

 

Need for study

According
to the WHO, 20% of new global HIV cases were in women between the ages of 18
and 25, meaning that a fifth of new HIV incidences occurred in only 11% of the
adult population in 2015 (6). That same year, young women in sub-Saharan
Africa suffered from 56% of new HIV cases globally among all adults (6). This report demonstrates the gender gap in HIV
infection, while identifying sub-Saharan women as an especially vulnerable
group.

As
African women are the most affected by the HIV epidemic, Baeten et al’s study
addresses the need to decrease HIV incidence by protecting this at-risk
population (1). Though socioeconomic factors such as insufficient education,
lack of quality healthcare, poverty, and violence drive the high HIV incidence among
women in sub-Saharan Africa, it is clear that the HIV epidemic needs to be
controlled epidemiologically (6). Previous
studies have proven that monthly HIV and STI testing of women and their partners,
risk-reduction counselling, and free condoms were not enough to protect against
a positive HIV diagnosis (1). The need is to increase adherence to ART via a
longer acting option so women would not need to remember to take a daily pill or
apply a gel every time they have intercourse (1). As vaginal rings release
medication over a longer period of time, they offered promise in this regard (1).

The
authors conducted a phase 3, randomized, double-blind, placebo–controlled trial
of dapivirine vaginal rings in African women to determine whether vaginal ring
offered simpler, long term protection against HIV in comparison to a placebo
ring (1). Every month, participants were provided with new rings, condoms, clinical
consultations, HIV-1 and STI tests for themselves and their partners, safety
monitoring, and individual adherence counseling (1). It was important for the
authors to study whether vaginal rings, in conjunction with these other interventions,
had their intended effect of increasing adherence to ART while still providing
care and information to each participant.

 

 Key
details of the study and analysis

The
authors followed sexually active, non-pregnant women with a negative HIV
diagnosis between the ages of 18 and 45 years in Malawi, South Africa, Uganda,
and Zimbabwe (1). At baseline, 5516 women underwent HIV-1 screening, and the
2629 women who tested negative for HIV-1 were enrolled in the study. Baeten et.
al then assigned 1313 women to the dapivirine group and 1316 women to the
placebo (1). Within each country, half the participants were randomly assigned
to use the vaginal ring containing 25 mg of dapivirine while the other half was
allocated a placebo ring. The rings were indistinguishable, enabling both participants
and researchers to remain blinded to the condition assigned to each participant
(1). Women were taught to insert and remove the rings, and were provided a new
ring at each monthly appointment, along with HIV-1 risk reduction counselling
and free condoms.

Adherence
was assessed via a plasma dapivirine level of over 95 pg per millimeter (1).
Additionally, a used ring containing less than 23.4 mg of dapivirine objectively
indicated the participant was adherent (1).  Based on their definition, the authors reported
the rate of adherence in the study to be over 70% (1).

Baeten
et al. aimed for their test to correctly reject false positives 90% of the time
and used an end point driven study design to record a minimum of 120 HIV-1
diagnoses to achieve this statistical power (1). They aspired to record 60%
lower incidences of HIV-1 in the dapivirine group over the placebo (1). All
participants were followed for 12 months minimum or until they tested positive
for HIV-1. The results were modelled using cox regression showing cumulative
incidence to compare differences between the dapivirine and placebo groups in
each country. The authors claimed to use intention-to-treat (ITT) methods in
carrying out two analyses, one that showed cumulative incidence rates at all 15
sites, and one that excluded two sites with exceptionally low adherence (1).

Using
ITT analysis, the results showed 26% less incidence of HIV-1 in the dapivirine condition,
which was significant in all 15 sites. The 95% Confidence Interval showed HIV-1
incidence to be 1 to 46 percent lower in the dapivirine group, with a p value
of 0.046. The data was then analyzed by excluding two sites where adherence was
lower than expected. After exclusion, the authors reported 139 HIV-1 infections
among 2395 participants, 54 of which were in the dapivirine group and the other
85 incidences in the placebo group. This result showed that incidence of HIV
was 37% lower in the dapivirine condition, with a 95% confidence interval
between 12 and 56% decreased incidence in the dapivirine group with a strongly
significant p value of 0.007 (1). Baeten et al. noted that the efficacy of
HIV-1 protection of less than 25% was not ruled out in either analysis (1).

However,
efficacy of HIV-1 protection differed significantly based on age, which Baeten
et al. determined via a post-hoc analysis (1). They found dapivirine increased
HIV-1 protection by 61% as compared to placebo in women aged 25 years or older
(95% CI, 32 to 77; P

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