Scene women, hypothesized to be due to low adherence


Human immune deficiency (HIV) is a
chronic 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). The highest death rates per 1000 people living
with HIV were in Central African Republic (91), South Sudan (82), Cote d’Ivore
(75), Cameroon (72), and Chad (71) as recently as 2013 (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).


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). Vaginal rings, which release
medication over a longer period of time, 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