1. unequal burden of HIV infections accounting for

1. Background:

Human Immunodeficiency Virus
(HIV)1,
the causative agent for acquired immunodeficiency syndrome (AIDS), is a
significant contributor to the global burden of disease with undesirable
implications for individuals and countries (Want et al., 2016). As of 2016, there
were 36.7 million HIV-positive individuals worldwide (WHO, 2017). Half of the HIV-positive
individuals are adolescent girls and women aged 15 and older with about 60% of
cases among those aged 15-24 (UNAIDS, 2017). Sub-Saharan Africa (SSA) suffers
from an unequal burden of HIV infections accounting for 71% of all cases with
high proportions in Malawi (4%), Uganda (6%), Zimbabwe (6%) and South Africa
(25%) (Kharsany and Karim, 2016). The HIV epidemic in many countries has had
devastating effects on the economic growth of the nation, as HIV predominantly
affects individuals in their most productive years.

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Substantial efforts have been
made in behavioural, structural and biomedical strategies for HIV prevention
and treatment. As a result of the remarkable development and universal scale-up
of antiretroviral therapy (ART), there have been major reductions in HIV
associated mortality, morbidity, transmission and overall improvements in the
quality of life of those living with HIV (Bain et al., 2017).  To illustrate, there was a 48% decrease in
AIDS-related deaths from 2005 to 2016 (UNAIDS, 2017). Additionally, the rollout
of ART is considered highly effective in reducing sexual transmission of HIV,
where HIV-negative individuals living in high ART coverage regions were less at
risk of an HIV infection compared to those living in low coverage areas (Tanser
et al., 2013). However, the feasibility of attaining high ART coverage remains
a challenge. This is mainly because ART initiation requires an HIV diagnosis
and high ART coverage requires high retention of patients on treatment, both of
which have yet to be achieved in many countries (Maartens et al., 2014).

 

Despite global efforts to
strengthen HIV prevention and reduce transmission, the speed at which HIV
incidence is declining is far from reaching its target (Bain et al., 2017).

Infection trends continue to be high with about 1.9 million new infections
diagnosed in 2016 of which two-thirds were in SSA (UNAIDS, 2017). Unprotected
heterosexual sex it the primary manner of transmission in the region (Bain et
al., 2017). As a result, females aged 15 and older bear a disproportionate
burden of HIV infection, accounting for 56% of new cases (UN Women, 2016).

Furthermore, females aged 15-24 years acquire HIV infection 5 to 7 years
earlier than males of the same age group (Kharsany and Karim, 2016). While
global scale-up of treatment has provided a better quality of life to those
living with HIV and enabled reductions in transmission, the sustainability of
such progress now depends on reducing new infections, particularly among women.

 

2. The Need for the Study:

The gender disparity in HIV
prevalence and incidence in SSA can be attributed to multiple structural,
economic, sociocultural, behavioural and biological factors. Biologically,
women are more susceptible than men because during sexual intercourse (1) women
have a larger area of mucous membrane exposed to the virus and infectious fluid
for longer periods, and (2) greater quantities of possibly infected fluids are
transferred from men to women (Gilbert and Selikow, 2011). Placing these
biological factors within the broader sociocultural context of
gender-inequalities gives a more comprehensive understanding of the situation. A
multitude of factors including earlier sexual debut among females, high
proportions of transactional sex as a result of economic dependency on men,
multiple partners with concurrent sexual partnerships, gender-based violence
against females and low condom use contribute to increased vulnerability among adolescent
girls and young women (Ramjee and Daniels, 2013).

 

Currently, there are many
proven opportunities for HIV prevention including voluntary medical male
circumcision (VMMC), programming for behaviour change, promotion of condom use,
provision of post-exposure prophylaxis (PEP) and more recently pre-exposure
prophylaxis (PrEP) (Sued et al., 2016). The combination of these prevention
packages has excellent potential in preventing HIV infection from vaginal and
anal sexual intercourse. In particular, uptake of VMMC and consistent condom
use are considered two of the main interventions in reducing heterosexually
acquired HIV (Kharsany and Karim, 2016). However, VMMC and female and male
condom use require male consent, meaning the male partner determines the
preventative measures a woman can take against HIV. Among women considered at
higher risk of sexually transmitted HIV, the nature of female-male
relationships constricts women’s agency over their health and sexual rights (UNAIDS,
2017). Thus, prevention becomes ‘inaccessible’.

 

Realising the gendered nature
of current interventions and the need for more female-controlled options,
researchers have started looking into other possibilities. In the Partners PrEP
Study, the administration of PrEP – i.e. ART in HIV-negative individuals to
prevent HIV infection – showed promising results among serodiscordant
heterosexual couples with 75% reduction in HIV transmission among female
partners (Baeten et al., 2014). Another study found that PrEP resulted in 62%
reduction in HIV transmission (Thigpen et al., 2012). However, further investigation
into the potential of prevention using PrEP among younger single women in SSA proved
that it was ineffective (Van Damme et al., 2012). This was due to poor
adherence stemming from concerns around stigma associated with the use of drugs
intended for the treatment of HIV and fear of adverse side effects (ibid.). To address
some of these issues, vaginal microbicides – formulated as gels, creams,
suppositories or films – were developed (Cottrell et al., 2014). Despite the
efficacy of microbicides, the unpredictable pharmacokinetics of microbicides in
different individuals was concerning (ibid.). More importantly, the same issue present
in other female-centred interventions remained: adherence was low.

 

3. Study Summary:

Taking into consideration the
acute need for new and more convenient HIV prevention interventions, Baeten and
colleagues (2016) set out to test the efficacy and safety of a dapivirine
containing intravaginal ring, which is the first long-acting HIV prevention
product explicitly designed for women. The study –A Study to Prevent Infection
with a Ring for Extended Use (ASPIRE)– was a phase III randomised,
double-blind, placebo-controlled, multicentre and parallel arm trial. ASPIRE
was conducted with the primary objective of determining whether a sustained-release
form of an antiretroviral drug named dapivirine2
is effective and safe in protecting women at high risk of sexually transmitted
HIV. The vaginal ring is designed to be worn consistently for four weeks and
then exchanged at the end of the month for a new ring.

 

From August 2012 until June
2015, the study recruited and followed 2629 HIV-negative 18-to-45-year-old
women at 15 different sites in South Africa, Uganda, Malawi and Zimbabwe. The
median age of the study participants was 26 years with the majority having at
least a secondary school education or higher. The reported number of vaginal
intercourse in the three months before the study was about 26.5 in both control
and treatment groups with about 60% in both groups reporting use of a condom
during their last vaginal sex (see p.2126 for more details). The median
follow-up time was 1.6 years with 1024 women followed for over two years.

Retention during the follow-up period – up to month 33 – was high at 85%. The
participants were randomly allocated to placebo or intervention.

 

The primary endpoint for
efficacy is HIV-1 seroconversion. The study was designed to detect a 60% lower
risk of HIV-1 infection among the dapivirine group compared to those on
placebo. The primary endpoint for safety was assessed by clinicians and was
defined as “a composite of any serious adverse event, any grade 2 or 4 adverse
event” attributed to dapivirine. The researchers also investigated adherence as
a secondary objective of the study. Measurement of adherence was done through
drug level testing as well as testing remainder drug levels on the ring itself.

 

Overall, Baeten et al. (2016)
found that the vaginal ring resulted in a modest decrease in HIV incidence. More
specifically, women who wore the ring had 27% (95% CI, 1 to 46; P=0.045) lower
risk of HIV infection compared to the placebo group. After excluding two sites
from the primary analysis due to “lower-than-expected protocol and product
adherence” (p.2125), the relative reduction in HIV incidence from wearing the
dapivirine vaginal ring compared to placebo was 37% (95% CI, 12 to 56;
P=0.007). Post hoc analysis of the results demonstrated that increased efficacy
and protection against HIV was associated with increased level of adherence,
which was associated with age. On the one hand, a 61% (95% CI, 32 to 77;
P

 

In their primary analysis, the
authors used intention-to-treat (ITT) analysis. ITT analysis includes every
subject who is randomised as per original treatment assignment, ignoring issues
such as withdrawal, noncompliance and any deviations from protocol that occur
after randomisation (Gupta, 2011). As a result, ITT analysis usually provides a
more conservative treatment effect because of dilution due to deviations from the
protocol (ibid.). For their secondary analysis, the researchers used per-protocol
analysis to provide more sensitive analysis of conclusions obtained from the
ITT analysis. Per-protocol analysis only includes participants who adhered and
completed the treatment as allocated. Per-protocol analysis provides a better estimate
of treatment effect, ITT analysis provides a better reflection of practical
clinical/real-life setting.

 

4. Study Critique:

4.1
Limitations

The researchers state that the
dapivirine vaginal ring showed modest efficacy in protecting against HIV
infections at 27% relative reduction when including all 15 sites and 37% when
including 13 sites. While there is no agreed upon ‘cut-off’ point for HIV
prevention efficacy, clinical trials of HIV prevention tools are powered to
detect an efficacy of 50% and over (McNicholl, 2016). The ASPIRE study set efficacy
at 60% and in both analyses, the study did not reach the estimated effect size
or the typical 50% effect size. Furthermore, the trial was also powered to
exclude a 25% reduction in the lower boundary of the 95% confidence interval
(CI). This is done to confirm that the new prevention has a clinically
significant benefit. In both effect estimates the 95% CIs included the 25%
lower boundary with the 27% reduction 95% CI starting at 1 – indicating
clinically negligible results. More alarming were the results obtained for the
24 and younger age group with the ring being associated with a possible
increase in HIV-incidence. This group is considered the most ‘at-risk’ of new
infections and thus, interventions are urgently needed for those younger than
24.

 

The most discouraging
limitation is the inability to confidently ascertain the level of protection due
to the inaccurately measured adherence. While the researchers make extra effort
to measure adherence, interpretation of adherence based on the data they
collected is difficult. The primary measure of adherence was quarterly drug
level testing was conducted on the patients during follow-up visits. However,
the design of the ring itself ensured that target dapivirine levels were
reached within 8 hours. This would lead to overestimation of adherence, as the
ring could have been removed for a long time and only worn the day before the
follow-up appointment. Yet, the results of the measurement would imply that the
ring was worn for longer. Consequently, adherence would be overestimated and
true efficacy would be underestimated.  The
secondary method of quantifying adherence was conducted through measuring remaining
drug levels in the returned rings. However, the secondary measurement was only
preformed starting the 2nd calendar year of the trial, as rings from
the 1st year were unavailable. As such, interpretation of adherence
in the study is very difficult. Future studies should consider using a newly
developed vaginal ring by Moss et al. (2016). It provides real-time evaluation
of adherence through comparing measured ring temperature to a predefined
indicator value to establish insertion/removal trends.

1 Throughout
the commentary, HIV refers to HIV-1 and does not include HIV-2.

2 Dapivirine
is a highly potent antiretroviral drug originally developed as an oral
treatment for HIV. It acts as a non-nucleoside HIV-1 reverse-transcriptase
inhibitor. It works by preventing HIV from replicating its genetic material
after the virus has entered a healthy cell; thus, halting the development of an
HIV infection (IPM, 2018).