Aim: controlled trials provide solid evidence that the

Aim:

This essay will be a commentary on the
article “Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in
Women” written by Baeten et al. Its aim is to set the new article into context,
relay key information, critique the study, and describe the next steps.

 

Background:

Although there had been
remarkable efforts to manage the spread of the human immunodeficiency virus
type 1 (HIV-1) epidemic through therapeutics and behavioral changes, it still remains
a major public health concern.  Almost
36.7 million people are currently infected with HIV-1 worldwide (WHO, 2016).

Most of these cases occur in
low and middle-income countries.  Sub-Saharan Africa is severely affected by the
epidemic, having more than 19.4 million people living with HIV-1. Women
constitute 56% of the total adult population infected with HIV-1 in that region
(Avert, 2017).

 

The history of HIV-1
prevention witnessed a range of successful turning points. HIV-1 prevention
tools varied in the extent of current use and effectiveness. The development of
condoms was a major milestone in reducing infections.

Condoms were the
first physical barriers to be used against the transmission of HIV-1. They act
by preventing the passage of HIV-sized particles through intercourse.  HIV seroconversion studies and model-based
estimations indicate that condoms provide 90%-95% effective protection against
HIV among consistent users (Pinkerton et al., 1997).

 

After the
recognition of condoms as an effective prevention tool, male circumcision’s efficacy
was investigated in 2006. Results from three randomized controlled trials
provide solid evidence that the risk of HIV-1 is reduced by 50% – 60% through
this one-time surgical intervention. Despite its benefits, male circumcision provides
better protection when combined with the use of condoms (Newell et al., 2007).

 

The major breakthrough of
antiretroviral therapeutic drugs was in 2010. Pre-exposure Prophylaxis (PrEP)
is an antiretroviral medication taken by HIV-negative individuals with a
continuous risk of infection. It prevents HIV-1 infection by inhibiting the
reverse transcriptase enzyme from transcribing HIV genetic material into DNA
that can be inserted into the cells’ genome. When PrEP is taken on a regular
basis, the risk of getting infected with HIV is reduced by 70% (Fonner et al.,
2016). However, adherence is a very important topic to consider when discussing
effectiveness.  There should be
standardized measures of adherence in order to precisely understand the
relationship between adherence and effectiveness of PrEP. More focus should be
given to objective measures rather than individual self-report (Straten et al.,
2012).

 

Several studies revealed that
adherence to PrEP was low amongst African women.  Reasons for low adherence may include
difficulty in following the daily pill regimen, or perceived low risk (Van
Damme et al., 2012). It is important to note that low adherence may lead to
unprecedented resistance to antiretroviral therapy. Thus, continuous therapy is
the key to achieve long-term efficacy.

 

Need For Study:

There are many factors that
should be carefully studied before planning an intervention to maximize
adherence. These include treatment delivery, patients and clinicians, and
societal constraints. http://europepmc.org/abstract/med/10546786

Adherence is a major issue in
implementing certain interventions, especially when it is medication to be
taken on a daily basis. Stemming from the need to develop more options to
prevent new HIV-1 infections, this study aimed at determining the effectiveness
and safety of using dapivirine vaginal rings to prevent infectivity.

 

Despite their current
convenience and usefulness, the first vaginal ring was not marketed until 1992.
They are designed to be flexible and to provide a lasting and sustainable drug
delivery. They can be self-inserted and removed, which makes compliance more
attainable for women (Malcolm et al., 2010). Dapivirine is a non-nucleoside reverse
transcriptase inhibitor (NNRTI) used as a microbicide inhibiting HIV-1 with the
use of vaginal rings (Romano et al., 2009).

 

In 2 phase-1 safety trials, dapivirine
vaginal rings were tested on 25 healthy women aged 19 to 46 years. Adverse
events that occurred in both placebo and dapivirine groups included mild
vaginal hemorrhage, fatigue, abdominal ache, and urinary incontinence. No
adverse events were associated with antiretroviral drug dapivirine (Romano et
al., 2009).  Another clinical trial
tested the safety of dapivirine vaginal ring in healthy women aged 18 to 40
years for over 28 days. The trial showed similar results to previous studies.
The dapivirine vaginal ring had no safety problems and it sustainably released
dapivirine over the 28-period of study (Nel et al., 2014). Further testing was
required to evaluate the full-scale dapivirine vaginal ring treatment and to
compare it to standard therapy or placebo. Dapivirine vaginal rings have the
potential to make HIV-1 prevention controlled by women with longer-acting
results. Dapivirine vaginal rings can be more convenient than daily pills and
coitally dependent interventions.

 

Key details and analysis:

 

This study was a randomized,
double-blinded, controlled phase-3 trial that tested the efficacy of dapivirine
vaginal rings. Researchers recruited 2629 healthy, sexually active and
non-pregnant women between the ages of 18 and 45 years in Malawi, South Africa,
Uganda, and Zimbabwe. They were followed from August 2012 through June 2015.
The study used fixed-size block randomization and stratification was according
to site only. Almost
1313 participants received a silicone elastomer vaginal ring containing 25 mg
of dapivirine and 1316 received a placebo vaginal ring.

 

Study procedures required
women to come back every month for HIV-1 serologic testing, safety check-up,
and individualized adhering counseling. Participants were monthly provided with
a new ring along with multiple services that target HIV-1 prevention. These
services include partner HIV-1 testing, free condoms, and treatment of sexually
transmitted diseases in participants and their partners. The assessment of
adherence was done through collecting plasma samples that were tested for the
presence of dapivirine using liquid chromatography. The minimum level of
dapivirine present in samples was 20 pg per milliliter. Women were considered
adherent if plasma samples had 95 pg per milliliter. After the first year of
trial, another method for testing adherence was employed. Used rings were
tested for residual dapivirine by high-pressure liquid chromatography. Presence
of less than 23.5 mg of dapivirine in the used ring defined adherence.

 

Intention-to-treat analysis
using Cox regression provided a total of 168 new HIV-1 infections that were
diagnosed by the end of the study period. This included 71 cases in the
dapivirine group and 97 in the placebo group. Analysis of new cases from 15
sites gave statistically significant results that the incidence of HIV-1
infection in the dapivirine group is lower by 27% than the placebo group (95% confidence
interval (CI), 1 to 46; P-value=0.046).  However,
the p-value was shown to be slightly lower than 0.05, which implies that there
is weak evidence with a very wide confidence interval. Also, this study was
powered so that the lower boundary of the 95% CI would exclude 25% reduction.
The 95% CI of HIV-1 incidence in the dapivirine group included 25%, which failed
to match the study’s power requirement.

 

Moreover, two out of fifteen
sites were excluded during analysis because of lower than usual adherence and
participant retention. After exclusion, results showed a much stronger evidence
for the efficacy of dapivirine vaginal rings. The incidence of HIV-1 in the
dapivirine group was 37% lower than the placebo group (95% CI, 12 to 56;
P-value=0.007).  Again, 25% reduction is
included within the 95% CI.

 

However, the efficacy of
dapivirine vaginal rings varied with age of women. This interesting finding
needs more research to pin point the exact biological and social factors behind
it.  A post hoc exploratory analysis was
conducted by creating age-categorized subgroups with balanced statistical
power.  Results showed lower levels of
adherence and protection among participants aged between 18 and 21. In fact,
the efficacy of HIV-1 protection was -27% (95% CI, -133 to 31; P=0.45), which
shows that the dapivirine ring could potentially increase the risk for HIV-1
infection among this age group. It is clear that more research is needed in
that area.

A randomized controlled trial
done for women between the ages of 18 and 21 is necessary to identify
interventions that cater for their needs. Social determinants are important
areas to delve into to find the proper interventions for the proper age group. The
major social determinants of health are the conditions in which you grow, live
and age (WHO, 2018). However, all of these elements are not discussed throughout
the paper.

There are several available
frameworks than can be used to explain the pathway through which social factors
influence the incidence of HIV-1. For instance, before carrying out a study to
test effectiveness of dapivirine ring, the proximate determinant framework could
be used. It is presented as the indirect determinants that are the underlying biological
and behavioral causes such as poverty, lack of education, and access to
healthcare. These operate through the proximate determinants such as not
adhering to medication, not wearing condoms, or multiple sexual partners to get
to HIV-1 (Boerma & Weir, 2005). Evidence suggests that Sub-Saharan women’s
disproportionate risk for HIV-1 is because of women’s economic dependence on
men resulting in survival sex. More studies described “consumption sex” among
Sub-Saharan women as a way to gain more access to material possessions (Fox,
2010).

In some cases, it would be
more effective to tackle the underlying causes instead of preventing HIV-1. The
reason behind this is that underlying causes such as poverty may lead to
several health outcomes other than HIV-1 (Boerma & Weir, 2005).

 

5. Critique:

5.1. Strengths:

 

This is a randomized
controlled trial that was designed to have a very high power with 90% chance of
detecting a true reduction of risk. It is also, important to note that
participants in placebo and dapivirine group were matched on several
characteristics, which reduced interferences caused by confounding factors. The
randomization process reduced allocation bias resulting in a balanced
distribution of prognostic factors among the treatment and placebo groups.

 

One of the strengths of this
study is that community members from each of the 15 sites were involved in the
design and conduct of the trial. In areas with subgroups at an exceptionally high
risk such as women in Sub-Saharan Africa, interventions work best when they are
designed to fit with society’s customs. Community members notify the
researchers about existing policies, norms, and procedural considerations. High
efficacy of interventions does not necessarily translate into high
effectiveness, especially with non-adherent participants. Community members
might increase the degree of adherence to provide more accurate and reliable
results. Also, proposed interventions will be more effective and sustainable on
the long run (Bogart & Uyeda, 2009).

 

 This study’s main feature is that it targeted Sub-Saharan
women, a key population that is at high risk. Women were assisted throughout
the study period by providing them with many services that improved health
outcomes, including sessions to familiarize them with the insertion and removal
of the vaginal ring.

Although results varied with
age, the dapivirine vaginal ring was effective in women over the age of 21. The
efficacy of HIV-1 protection was 56% (95% CI, 31 to 71; P<0.001). This gives a promising prevention tool, especially that the adherence level was up to 70% or more. Limitations: The main limitation of the study is that it didn't provide protection to the youngest age group (18-21). Young women aged 15-24 are at a very high risk of HIV-1 infection. In sub-Saharan Africa, they account for 25% of the new HIV-1 infections (UNAIDS, 2016). Therefore, biological and behavioral differences must be carefully studied to further increase adherence and identify the proper intervention for this age group. Moreover, the study results might have been overestimated. This resulted from more adherent participants whether in the placebo or the dapivirine group. In general, study participants tend to be more adhesive than the general population. This idea raises questions about the generalizability of this study. Would it be effective to implement the vaginal dapivirine ring to the Sub-Saharan population? Also, all women from the study were provided with services to prevent HIV-1. These services might have overestimated the effectiveness of the dapivirine vaginal rings. The reported reduction in risk might be due to the combination of preventive interventions such as condoms. Additionally, the study completely excluded pregnant women from the study. Yet, they are in general a susceptible group that has a high chance of transmitting HIV-1 to their offspring during labor or breastfeeding. Recent studies show that pregnant women have a twofold increased risk of acquiring HIV-1 even after adjusting for behavioral and social behaviors (Quinn & Overbaugh, 2005). Further research is needed in order to find the suitable tools to safeguard mothers and their offspring from HIV-infection. The vaginal ring fails to protect against other HIV-1 infections due to anal or oral sex, and exchanging needles. However, self-reporting was used to assess the anal sex in the previous three months   Finally, there were some issues with defining adherence in the plasma samples taken from participants with dapivirine vaginal ring.  Participants were considered adherent if the detection of plasma dapivirine of more than 95 pg per milliliter. However, this concentration can be obtained after 8 hours of continuous use. Participants may be inclined to use the ring right before the clinic visit. This dapivirine concentration may overestimate the effectiveness of the intervention. Another objective method for assessing adherence was used after the first year. This method is more accurate and generates better results.       Ways forward: Most HIV-1 prevention tools have been proved to be partially effective against HIV transmission and acquisition. Hence, no single prevention tool will be enough to prevent new HIV-1 infections in Sub-Saharan Africa. The success of combining certain behavioral and medical prevention interventions was shown in several randomized controlled trials. Thus, when at high-risk populations are targeted such as Sub-Saharan women, multiple interventions should be chosen to match their profile. Researchers should take into consideration the efficacy, acceptability, and safety of any combination (Kurth et al., 2011).   When discussing new interventions, an economic evaluation is necessary to allocate the limited funds available. Implementing the vaginal ring in Sub-Saharan Africa needs careful consideration taking into account priority setting, limited budget, health system, and governance. We need to compare costs and benefits of interventions, because introducing a new intervention usually means cutting of expenditure on another. Only very few countries of Sub-Saharan Africa provide the minimum health care defined by World Health Organization (zekeng). Constraints like this need to be incorporated in the cost-effectiveness model. Also, implementation of the vaginal ring requires strong governance where priorities and implementation can be monitored. A phase-3 study should be repeated to confirm the results of efficacy, with more attention given to young and pregnant women that are at high risk of acquiring and transmitting HIV-1. Social determinants are a necessary component to understand the acceptability and efficacy of vaginal rings in certain age groups. Moreover, condoms were proven to be very effective against HIV-1 infection.  Almost 60% of participants in the dapivirine and placebo group used condoms during their last vaginal sex. Also, condoms were provided to the participants along with vaginal rings. Analysis of results could be improved and made more accurate if data was stratified according to use of condoms.   Conclusion: HIV-1 remains a major public health problem that still needs further research. The previous interventions seem to have a great impact in the reduction of HIV-1 infection in various parts of the world. However, in some countries the problem is still persistent and needs further research to include information from behavioral, biological, and economic aspects. 

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