Aim: controlled trials provide solid evidence that the

Aim:This essay will be a commentary on thearticle “Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention inWomen” 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 beenremarkable efforts to manage the spread of the human immunodeficiency virustype 1 (HIV-1) epidemic through therapeutics and behavioral changes, it still remainsa major public health concern.  Almost36.

7 million people are currently infected with HIV-1 worldwide (WHO, 2016).Most of these cases occur inlow and middle-income countries.  Sub-Saharan Africa is severely affected by theepidemic, having more than 19.4 million people living with HIV-1. Womenconstitute 56% of the total adult population infected with HIV-1 in that region(Avert, 2017).

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 The history of HIV-1prevention witnessed a range of successful turning points. HIV-1 preventiontools varied in the extent of current use and effectiveness. The development ofcondoms was a major milestone in reducing infections.Condoms were thefirst physical barriers to be used against the transmission of HIV-1. They actby preventing the passage of HIV-sized particles through intercourse.

  HIV seroconversion studies and model-basedestimations indicate that condoms provide 90%-95% effective protection againstHIV among consistent users (Pinkerton et al., 1997). After therecognition of condoms as an effective prevention tool, male circumcision’s efficacywas investigated in 2006. Results from three randomized controlled trialsprovide solid evidence that the risk of HIV-1 is reduced by 50% – 60% throughthis one-time surgical intervention.

Despite its benefits, male circumcision providesbetter protection when combined with the use of condoms (Newell et al., 2007). The major breakthrough ofantiretroviral therapeutic drugs was in 2010. Pre-exposure Prophylaxis (PrEP)is an antiretroviral medication taken by HIV-negative individuals with acontinuous risk of infection. It prevents HIV-1 infection by inhibiting thereverse transcriptase enzyme from transcribing HIV genetic material into DNAthat can be inserted into the cells’ genome. When PrEP is taken on a regularbasis, 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 discussingeffectiveness.  There should bestandardized measures of adherence in order to precisely understand therelationship between adherence and effectiveness of PrEP. More focus should begiven to objective measures rather than individual self-report (Straten et al.,2012).

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

 Need For Study: There are many factors thatshould be carefully studied before planning an intervention to maximizeadherence. These include treatment delivery, patients and clinicians, andsocietal constraints. http://europepmc.

org/abstract/med/10546786Adherence is a major issue inimplementing certain interventions, especially when it is medication to betaken on a daily basis. Stemming from the need to develop more options toprevent new HIV-1 infections, this study aimed at determining the effectivenessand safety of using dapivirine vaginal rings to prevent infectivity. Despite their currentconvenience and usefulness, the first vaginal ring was not marketed until 1992.They are designed to be flexible and to provide a lasting and sustainable drugdelivery. They can be self-inserted and removed, which makes compliance moreattainable for women (Malcolm et al., 2010). Dapivirine is a non-nucleoside reversetranscriptase inhibitor (NNRTI) used as a microbicide inhibiting HIV-1 with theuse of vaginal rings (Romano et al.

, 2009). In 2 phase-1 safety trials, dapivirinevaginal rings were tested on 25 healthy women aged 19 to 46 years. Adverseevents that occurred in both placebo and dapivirine groups included mildvaginal hemorrhage, fatigue, abdominal ache, and urinary incontinence. Noadverse events were associated with antiretroviral drug dapivirine (Romano etal., 2009).  Another clinical trialtested the safety of dapivirine vaginal ring in healthy women aged 18 to 40years for over 28 days.

The trial showed similar results to previous studies.The dapivirine vaginal ring had no safety problems and it sustainably releaseddapivirine over the 28-period of study (Nel et al., 2014). Further testing wasrequired to evaluate the full-scale dapivirine vaginal ring treatment and tocompare it to standard therapy or placebo. Dapivirine vaginal rings have thepotential to make HIV-1 prevention controlled by women with longer-actingresults. Dapivirine vaginal rings can be more convenient than daily pills andcoitally dependent interventions.

 Key details and analysis: This study was a randomized,double-blinded, controlled phase-3 trial that tested the efficacy of dapivirinevaginal rings. Researchers recruited 2629 healthy, sexually active andnon-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 accordingto site only. Almost1313 participants received a silicone elastomer vaginal ring containing 25 mgof dapivirine and 1316 received a placebo vaginal ring.  Study procedures requiredwomen to come back every month for HIV-1 serologic testing, safety check-up,and individualized adhering counseling. Participants were monthly provided witha new ring along with multiple services that target HIV-1 prevention. Theseservices include partner HIV-1 testing, free condoms, and treatment of sexuallytransmitted diseases in participants and their partners.

The assessment ofadherence was done through collecting plasma samples that were tested for thepresence of dapivirine using liquid chromatography. The minimum level ofdapivirine present in samples was 20 pg per milliliter. Women were consideredadherent if plasma samples had 95 pg per milliliter. After the first year oftrial, another method for testing adherence was employed. Used rings weretested for residual dapivirine by high-pressure liquid chromatography. Presenceof less than 23.

5 mg of dapivirine in the used ring defined adherence.  Intention-to-treat analysisusing Cox regression provided a total of 168 new HIV-1 infections that werediagnosed by the end of the study period. This included 71 cases in thedapivirine group and 97 in the placebo group. Analysis of new cases from 15sites gave statistically significant results that the incidence of HIV-1infection in the dapivirine group is lower by 27% than the placebo group (95% confidenceinterval (CI), 1 to 46; P-value=0.046).  However,the p-value was shown to be slightly lower than 0.

05, which implies that thereis weak evidence with a very wide confidence interval. Also, this study waspowered 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 failedto match the study’s power requirement.  Moreover, two out of fifteensites were excluded during analysis because of lower than usual adherence andparticipant retention. After exclusion, results showed a much stronger evidencefor the efficacy of dapivirine vaginal rings.

The incidence of HIV-1 in thedapivirine group was 37% lower than the placebo group (95% CI, 12 to 56;P-value=0.007).  Again, 25% reduction isincluded within the 95% CI. However, the efficacy ofdapivirine vaginal rings varied with age of women.

This interesting findingneeds more research to pin point the exact biological and social factors behindit.  A post hoc exploratory analysis wasconducted by creating age-categorized subgroups with balanced statisticalpower.  Results showed lower levels ofadherence 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), whichshows that the dapivirine ring could potentially increase the risk for HIV-1infection among this age group. It is clear that more research is needed inthat area.A randomized controlled trialdone for women between the ages of 18 and 21 is necessary to identifyinterventions that cater for their needs.

Social determinants are importantareas to delve into to find the proper interventions for the proper age group. Themajor social determinants of health are the conditions in which you grow, liveand age (WHO, 2018). However, all of these elements are not discussed throughoutthe paper.There are several availableframeworks than can be used to explain the pathway through which social factorsinfluence the incidence of HIV-1. For instance, before carrying out a study totest effectiveness of dapivirine ring, the proximate determinant framework couldbe used. It is presented as the indirect determinants that are the underlying biologicaland behavioral causes such as poverty, lack of education, and access tohealthcare. These operate through the proximate determinants such as notadhering to medication, not wearing condoms, or multiple sexual partners to getto HIV-1 (Boerma & Weir, 2005). Evidence suggests that Sub-Saharan women’sdisproportionate risk for HIV-1 is because of women’s economic dependence onmen resulting in survival sex.

More studies described “consumption sex” amongSub-Saharan women as a way to gain more access to material possessions (Fox,2010).In some cases, it would bemore effective to tackle the underlying causes instead of preventing HIV-1. Thereason behind this is that underlying causes such as poverty may lead toseveral health outcomes other than HIV-1 (Boerma & Weir, 2005). 5.

Critique:5.1. Strengths:  This is a randomizedcontrolled trial that was designed to have a very high power with 90% chance ofdetecting a true reduction of risk. It is also, important to note thatparticipants in placebo and dapivirine group were matched on severalcharacteristics, which reduced interferences caused by confounding factors. Therandomization process reduced allocation bias resulting in a balanceddistribution of prognostic factors among the treatment and placebo groups.  One of the strengths of thisstudy is that community members from each of the 15 sites were involved in thedesign and conduct of the trial. In areas with subgroups at an exceptionally highrisk such as women in Sub-Saharan Africa, interventions work best when they aredesigned to fit with society’s customs.

Community members notify theresearchers about existing policies, norms, and procedural considerations. Highefficacy of interventions does not necessarily translate into higheffectiveness, especially with non-adherent participants. Community membersmight increase the degree of adherence to provide more accurate and reliableresults.

Also, proposed interventions will be more effective and sustainable onthe long run (Bogart & Uyeda, 2009).  This study’s main feature is that it targeted Sub-Saharanwomen, a key population that is at high risk. Women were assisted throughoutthe study period by providing them with many services that improved healthoutcomes, including sessions to familiarize them with the insertion and removalof the vaginal ring.Although results varied withage, the dapivirine vaginal ring was effective in women over the age of 21. Theefficacy of HIV-1 protection was 56% (95% CI, 31 to 71; P<0.001).

This givesa promising prevention tool, especially that the adherence level was up to 70%or more. Limitations: The main limitation of thestudy is that it didn’t provide protection to the youngest age group (18-21). Youngwomen aged 15-24 are at a very high risk of HIV-1 infection. In sub-SaharanAfrica, they account for 25% of the new HIV-1 infections (UNAIDS, 2016). Therefore,biological and behavioral differences must be carefully studied to furtherincrease adherence and identify the proper intervention for this age group.Moreover, the study results might have been overestimated. Thisresulted from more adherent participants whether in the placebo or thedapivirine group.

In general, study participants tend to be more adhesive thanthe general population. This idea raises questions about the generalizabilityof this study. Would it be effective to implement the vaginal dapivirine ringto the Sub-Saharan population? Also, all women from thestudy were provided with services to prevent HIV-1. These services might haveoverestimated the effectiveness of the dapivirine vaginal rings. The reportedreduction in risk might be due to the combination of preventive interventions suchas condoms.Additionally, the studycompletely excluded pregnant women from the study. Yet, they are in general asusceptible group that has a high chance of transmitting HIV-1 to theiroffspring during labor or breastfeeding. Recent studies show that pregnantwomen have a twofold increased risk of acquiring HIV-1 even after adjusting forbehavioral and social behaviors (Quinn & Overbaugh, 2005).

Further researchis needed in order to find the suitable tools to safeguard mothers and their offspringfrom HIV-infection. The vaginal ring fails to protect against other HIV-1infections 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 someissues with defining adherence in the plasma samples taken from participantswith dapivirine vaginal ring.  Participants were considered adherent if thedetection of plasma dapivirine of more than 95 pg per milliliter. However, thisconcentration can be obtained after 8 hours of continuous use. Participants maybe inclined to use the ring right before the clinic visit. This dapivirineconcentration may overestimate the effectiveness of the intervention.

Anotherobjective method for assessing adherence was used after the first year. This methodis more accurate and generates better results.    Ways forward:Most HIV-1 prevention toolshave been proved to be partially effective against HIV transmission andacquisition. Hence, no single prevention tool will be enough to prevent newHIV-1 infections in Sub-Saharan Africa.

The success of combining certainbehavioral and medical prevention interventions was shown in several randomizedcontrolled trials. Thus, when at high-risk populations are targeted such asSub-Saharan women, multiple interventions should be chosen to match theirprofile. Researchers should take into consideration the efficacy,acceptability, and safety of any combination (Kurth et al., 2011). When discussing newinterventions, an economic evaluation is necessary to allocate the limitedfunds available.

Implementing the vaginal ring in Sub-Saharan Africa needscareful consideration taking into account priority setting, limited budget,health system, and governance. We need to compare costs and benefits ofinterventions, because introducing a new intervention usually means cutting ofexpenditure on another. Only very few countries of Sub-Saharan Africa providethe minimum health care defined by World Health Organization (zekeng). Constraints likethis need to be incorporated in the cost-effectiveness model. Also,implementation of the vaginal ring requires strong governance where prioritiesand implementation can be monitored. A phase-3 study should be repeated to confirmthe results of efficacy, with more attention given to young and pregnant womenthat are at high risk of acquiring and transmitting HIV-1.

Social determinantsare a necessary component to understand the acceptability and efficacy ofvaginal rings in certain age groups. Moreover, condoms were proven to be veryeffective against HIV-1 infection.  Almost 60% of participants in the dapivirineand placebo group used condoms during their last vaginal sex. Also, condomswere provided to the participants along with vaginal rings. Analysis of resultscould be improved and made more accurate if data was stratified according touse of condoms. Conclusion: HIV-1 remains a major publichealth problem that still needs further research. The previous interventionsseem to have a great impact in the reduction of HIV-1 infection in variousparts of the world. However, in some countries the problem is still persistentand needs further researchto include information from behavioral, biological, and economic aspects.