Scene women, hypothesized to be due to low adherence

ScenesettingHuman immune deficiency (HIV) is achronic sexually transmitted disease that infects a person for life and leadsto acquired immunodeficiency syndrome (AIDS) if left untreated (5). HIV isspread via blood, semen, breast milk, and vaginal and rectal fluids. Thedisease weakens the immune system by attacking it, leaving those infected moreprone to disease (5).  Though HIV wasonce a death sentence, anti-retroviral therapy (ART) has allowed HIV patientsto keep the disease under control and live otherwise normal lives (9).

ART is proven to reduce HIV transmission from one sexual partner to another by93%, and the use and availability of ART in low and middle-income countries hassaved 5.2 million people from AIDS related death (2,3). Unfortunately, ARTs havenot been as effective in sub-Saharan Africa, compromising 70% of the globalburden of HIV infection (7).

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The highest death rates per 1000 people livingwith 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 fivenations, they have almost ten times higher death rates than high incomecountries, showing that there is a need for further intervention (4). In their study,Use of a Vaginal Ring Containing Dapivirine for HIV-1 Preventionin Women, Baetenet al. indicate that young sub-Saharan women shoulder most of the HIV-1 relatedburden (1).

While ARTs areproven to reduce HIV transmission, the authors cited three articles in whichARVs were not effective in preventing HIV-1 incidences among African women, hypothesizedto be due to low adherence to daily or coital antiretroviral gels, films, orpills (1). This subgroup of women may have difficulty remembering to use theseARV measures, or may be prohibited from using these technologies by theirpartners due to cultural beliefs or taboos. Given that the greatest mode of HIV-1 transmission in sub-SaharanAfrica is unprotected heterosexual intercourse, it is clear that young women insub-Saharan Africa require an innovative intervention to lower their chance ofHIV-1 infection (3). Baeten et al. hypothesized that usingvaginal rings for ARV administration would provide longer term protection, thusmaking adherence easier for these young women, ultimately decreasing new HIV-1incidences (1). They decided to administer dapivirine via the vaginal rings, asit is a topical antiretroviral medication that blocks HIV-1reverse-transcriptase enzymes, preventing a broad range of HIV-1 subtypes frommultiplying in the body and causing infection (11). Dapivirine was chosen as itdecreased susceptibility to HIV-1 in previous studies without exposing the entirebody to the drug (1).

 Needfor studyAccording to the WHO, 20% of new globalHIV cases were in women between the ages of 18 and 25, meaning that a fifth of newHIV incidences occurred in only 11% of the adult population in 2015 (6). That sameyear, young women in sub-Saharan Africa suffered from 56% of new HIV cases globallyamong all adults (6). This report demonstratesthe gender gap in HIV infection, while identifying sub-Saharan women as anespecially vulnerable group. As African women are the most affectedby the HIV epidemic, Baeten et al’s study addresses the need to decrease HIV incidenceby protecting this at-risk population (1). Though socioeconomic factors such asinsufficient education, lack of quality healthcare, poverty, and violence drivethe high HIV incidence among women in sub-Saharan Africa, it is clear that the HIVepidemic needs to be controlled epidemiologically (6). Previousstudies have proven that monthly HIV and STI testing of women and their partners,risk-reduction counselling, and free condoms were not enough to protect againsta positive HIV diagnosis (1). The need is to increase adherence to ART via alonger acting option so women would not need to remember to take a daily pill orapply a gel every time they have intercourse (1). Vaginal rings, which releasemedication 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 ringsin African women to determine whether vaginal ring offered simpler, long termprotection against HIV in comparison to a placebo ring (1). Every month, participantswere provided with new rings, condoms, clinical consultations, HIV-1 and STI testsfor themselves and their partners, safety monitoring, and individual adherencecounseling (1). It was important for the authors to study whether vaginalrings, in conjunction with these other interventions, had their intended effectof increasing adherence to ART while still providing care and information toeach 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 45years in Malawi, South Africa, Uganda, and Zimbabwe (1). At baseline, 5516women underwent HIV-1 screening, and the 2629 women who tested negative forHIV-1 were enrolled in the study. Baeten et. al then assigned 1313 women to thedapivirine group and 1316 women to the placebo (1).

Within each country, halfthe participants were randomly assigned to use the vaginal ring containing 25mg of dapivirine while the other half was allocated a placebo ring. The ringswere indistinguishable, enabling both participants and researchers to remainblinded to the condition assigned to each participant (1). Women were taught toinsert 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 plasmadapivirine level of over 95 pg per millimeter (1).

Additionally, a used ringcontaining less than 23.4 mg of dapivirine objectively indicated theparticipant was adherent (1).  Based ontheir definition, the authors reported the rate of adherence in the study to beover 70% (1).Baeten et al.

aimed for their test to correctlyreject false positives 90% of the time and used an end point driven studydesign to record a minimum of 120 HIV-1 diagnoses to achieve this statisticalpower (1). They aspired to record 60% lower incidences of HIV-1 in thedapivirine group over the placebo (1). All participants were followed for 12months minimum or until they tested positive for HIV-1.

The results weremodelled using cox regression showing cumulative incidence to comparedifferences between the dapivirine and placebo groups in each country. The authors claimed to use intention-to-treat (ITT) methodsin carrying out two analyses, one that showed cumulative incidence rates at all15 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 inall 15 sites.

The 95% Confidence Interval showed HIV-1 incidence to be 1 to 46percent lower in the dapivirine group, with a p value of 0.046. The data was thenanalyzed by excluding two sites where adherence was lower than expected. Afterexclusion, 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 placebogroup. This result showed that incidence of HIV was 37% lower in the dapivirinecondition, with a 95% confidence interval between 12 and 56% decreasedincidence 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 protectiondiffered significantly based on age, which Baeten et al. determined via apost-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<0.

001). For women under 25, dapivirine hadan efficacy of 10% (95% CI, ?41 to 43; P = 0.64)(1). To better analyze the effect of age, theauthors stratified participants into 3 age groups: 18 to 21, 22 to 26, and 27to 45. Among the 18 to 21 year olds, 44 out of 451 were diagnosed with HIV-1 inthe placebo group, yielding an incidence of 5.4 out of 100 person years (1).

Withinthe 22 to 26 year olds, 51 out of 752 participants in the placebo group werediagnosed with HIV-1. The incidence rate was 6.1 per 100 person years (1). Finally,27 to 45 year olds had 44 out of 1192 participants diagnosed with HIV-1 in theplacebo group with an incidence rate of 3.0 out of 100 person years (1). These results imply that dapivirine waseffective in reducing new cases HIV-1 in women over 25, but was not effectivein reducing HIV-1 incidences in younger women, as shown by the non-significantp value of 0.64. Additionally, HIV-1 incidence rates were lowest in womenbetween 27 and 45, indicating the intervention was most successful in this demographic.

 StudycritiqueLimitations                                                                                While adherence was assessed via aplasma dapivirine level above 95 pg per millimeter, this level is usuallyachieved after using a dapivirine vaginal ring for 8 continuous hours (1). Aswomen were instructed to wear the ring for a month, they cannot be truly adherentif they wear the ring for a shorter time (1).  As the authors’ objective was to find a way toadminister ART in a way that young women will adhere to, it is important thatthey actually ensure whether or not their target population adhered to thevaginal rings and found them to be a more desirable form of ART over gels,pills, or films. Thought the authors reported that 70% adhered to wearing thering based on their definition, they can only speculate whether these womentruly wore the ring for the whole month.Baeten et al. seemed to modify theirresults to show as strong an effect as possible.

Originally, the nullhypothesis was set as dapivirine being no more than 25% effective in reducingincidence of HIV-1. The alternative hypothesis was that dapivirine would havean HIV-1 incidence difference up to 60% lower in the dapivirine group. Theauthors aimed to rule out effectiveness below 25%, however, they changed theparameters of statistical analysis when dapivirine reduced HIV-1 incidence by26% in order to obtain significant results. This difference was only moderatelysignificant in all 15 sites based on the p value of 0.

046, meaning this resultcould be due to chance. The 95% confidence interval of 1-46 includes the nulleffectiveness value of 25, confirming the authors had to compare their resultsto the standard null hypothesis of 0% difference in the dapivirine group versusthe placebo.Using ITT analysis while excluding participantsin certain sites due to noncompliance is a limitation of the study.

In ITTanalysis, all participants should be included in the analysis within thecondition to which they were randomly assigned, which would includenoncompliant participants in order to maintain randomization (9). Though Baetenet. al wrote that the majority of participants met the criteria for objectiveadherence to the vaginal ring, they analyzedtheir results while excluding two sites in which they believed adherence to below with little discussion as to why (1).

 As the authors originally set out to determinewhether dapivirine vaginal rings would be more effective and make complianceeasier for women in sub-Saharan Africa, it seems unethical for the authors topick and choose data to analyze under the guise of ITT analysis when it is morein line with per-protocol analysis. The exclusion of these sites showed HIVincidence to be 37% lower in the dapivirine condition, with a p value of 0.007,a strongly significant result. The confidence interval showed that dapivirineprotection was between 12% to 56% lower in dapivirine compared to the placebo,which still includes the original null hypothesis value of 25% lower HIV-1incidences in the dapivirine condition. Though there was a protective effectdue to dapivirine in the study, it seemed as if the authors were statisticallymanipulating data to force an effect.

Though Baeten et al. discussed youngerwomen has lower compliance rates and higher incidences of HIV-1 in theirintroduction, they did not stratify for age until after the study was over. Themedian age for the 2629 women between ages 18 and 45 was 26, meaning half theparticipants were younger than this age while half were older (1). Thus, it isclear that there were many more younger participants than older in this study, makingthe fact that women between 18 and 21 having a 27% increase in HIV-1 incidence inthe dapivirine group even more striking, as this age groups makes up a largeportion of the study population. This result was moderately significant with ap value of 0.45, showing that vaginal dapivirine rings were not an effectivetreatment to reduce HIV in young sub-Saharan women between 18 and 21. The authors stated that the lack ofprotection within the 18 to 21 year age group could be due to behavioral andbiological factors combined, citing low adherence and potentially more HIVsusceptible genital tracts (1). Seeing as the women were provided monthlysupport, STI testing, and free condoms along with the dapivirine rings, it ishard to imagine what more could be done to increase adherence in sub-Saharan Africa,especially as Baeten et al.

did not explain their reasoning. Thoughonly 2% of women reported engaging in anal sex within the last 3 months atbaseline, it is important to keep in mind that younger women may have higherrates of HIV because they are engaging in anal sex without reporting it due tofear of judgement (1).  Topicaldapivirine in the vagina would not be able to prevent HIV infection transmittedin the rectum (1). If this is the case, the vaginal ring’s concentratedprotection is not beneficial to young women, who would need a systemic ART.   Strengths            The authors used good randomizationtechniques in order to decrease confounding factors. Baeten et al. used blockrandomization to allocate research condition while stratifying by country,ensuring that confounding factors were reduced to a minimum (1). A strength of this study wasdemonstrating that incidence of HIV-1 was significantly lower in older womenwho adhered to the dapivirine study condition (1).

Dapivirinevaginal rings were effective in women over 21 years of age, with resultsshowing 56% less HIV-1 incidences as compared to the placebo. A p value of0.001 shows the result is strongly significant. Additionally, 27 to 45 yearolds had the lowest cumulative incidence rate of the three age groups withincidence of 3 out of 100 person-years. Conversely, 18-21 year olds were theonly group in which the cumulative incidence rate of HIV-1 in placebo was lowerthan in the dapivirine condition, meaning less people died on placebo.

Though Baetenet al. did not succeed in finding an intervention to help younger women insub-Saharan Africa reduce incidence of HIV-1, they may have found a potentialintervention to decrease HIV-1 transmission in older women. As many otherstudies could not yield any protective effects, a 26-37% decrease in HIVincidence is a promising start (8).   NextStepsWhile this study shows dapivirinereleasing vaginal rings increases efficacy in HIV-1 protection in women over21, who were much more adherent than younger women, there is still a publichealth need to develop an intervention to decrease HIV-1 incidence in youngsub-Saharan women. Clearly a vaginal ring would not be clinically feasible forthe young women who did not utilize them even with additional support. Policy makers and scientists shouldfocus on finding a long acting, systemic ARV to protect young women against allmethods of HIV transmission, as it remains a pertinent public health challenge.The women in this study should be followed up for qualitative interviews orquestionnaires regarding their experience with vaginal rings to determine ifthey were comfortable, culturally appropriate, easy to use, and whether therewere side effects. Women could also report their partners perspective on thevaginal rings, as a non-supportive partner may have contributed to decreasedadherence.

The results of these interviews could help researchers understandwhy younger women did not adhere to the rings as much as older women,ultimately leading to the development of a more clinically significantintervention.While vaginal rings may not help youngerwomen prevent HIV-1, scientists should continue to study vaginal rings todeliver ART to older women. Results from Baeten et al’s study shows promise oflonger term, efficient protection against HIV-1 for this population, which mayprove to be more economically feasible and clinically more significant in olderdemographics.  Though more work needs to be done toprotect young women living in sub-Saharan Africa, this study provided evidenceof dapivirine protecting women over 25 from HIV-1. Though the authors may nothave achieved their goal, they have developed a promising intervention that mayultimately decrease the number of women living with HIV-1 in the future.            Bibliography 1.

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, Gamble, T., Hosseinipour M., Kumarasamy, N. et al. AntiretroviralTherapy for the Prevention of HIV-1 Transmission. The New England Journal of Medicine. 2016; 375:830–839.

3.   Fettig,J., Swaminathan, M., Murrill, C., and J. Kaplan. Global Epidemiology of HIV. Infectious Disease Clinics of North America.

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, Young, B. and J. Zuniga. Trends in AIDS Deaths, NewInfections and ART Coverage in the Top30 Countries with the Highest AIDSMortality Burden; 1990-2013. PublicLibrary of Science.

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8.   McNicholl,J. Combining biomedical preventions for HIV: Vaccines with pre-exposureprophylaxis, microbicides or other HIV preventions. Human Vaccines & Immunotherapeutics. 2016; 12(12): 3202-3211.

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