Scene settingHumanimmune deficiency (HIV) is a chronic, often sexually transmitted disease that infectsa person for life and leads to acquired immunodeficiency syndrome (AIDS) ifleft untreated (5). HIV is spread via blood, semen, breast milk, and vaginaland 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-retroviraltherapy (ART) has allowed HIV patients to keep the disease under control andlive otherwise normal lives (9).
ART is proven to reduce HIV transmissionfrom one sexual partner to another by 93%, and the use of ART in low and middleincome countries has averted 5.2 million AIDS related deaths (2,3). Unfortunately,ARTs have not been as effective in sub-Saharan Africa, compromising 70% of theglobal burden of HIV infection (7). As of 2013, the highest death rates per1000 people living with HIV were in Central African Republic with 91, SouthSudan, with 82, Cote d’Ivore, with 75, Cameroon with 72, and Chad, with 71 outof 1000 living with HIV (4).Though ART has reduced instances of HIV and death in these five nations, theyhave almost ten times higher death rates than high income countries, showingthat there is a need for further intervention (4). In their study, Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention inWomen, Baeten et al. indicate that youngsub-Saharan women shoulder most of the HIV-1 related burden (1). WhileARTs are proven to reduce HIV transmission, the authors cited three articles inwhich ARVs were not effective in preventing HIV-1 incidences among Africanwomen, hypothesized to be due to low adherence to daily or coital antiretroviralgels, films, or pills (1).
This subgroup of women may have trouble rememberingto use these ARV measures, or may be prohibited from using these technologiesby their partners due to cultural beliefs or taboos. Given that the greatest mode of HIV-1 transmissionin sub-Saharan Africa is unprotected heterosexual intercourse, it is clear thatyoung women in sub-Saharan Africa require an innovative intervention to lowertheir chance of HIV-1 infection (3). Baetenet al.
hypothesized that using vaginal rings for ARV administration would providelonger term protection, thus making adherence easier for these young women,ultimately decreasing new HIV-1 incidences (1). They decided to administerdapivirine via the vaginal rings, as it is a topical antiretroviral medicationthat blocks HIV-1 reverse-transcriptase enzymes, preventing a broad range ofHIV-1 subtypes from multiplying in the body and causing infection (11). Dapivirinewas chosen as it decreased susceptibility to HIV-1 in previous studies withoutexposing the entire body to the drug (1). Need for studyAccordingto the WHO, 20% of new global HIV cases were in women between the ages of 18and 25, meaning that a fifth of new HIV incidences occurred in only 11% of theadult population in 2015 (6). That same year, young women in sub-SaharanAfrica suffered from 56% of new HIV cases globally among all adults (6). This report demonstrates the gender gap in HIVinfection, while identifying sub-Saharan women as an especially vulnerablegroup.
AsAfrican women are the most affected by the HIV epidemic, Baeten et al’s studyaddresses the need to decrease HIV incidence by protecting this at-riskpopulation (1). Though socioeconomic factors such as insufficient education,lack of quality healthcare, poverty, and violence drive the high HIV incidence amongwomen in sub-Saharan Africa, it is clear that the HIV epidemic needs to becontrolled 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). As vaginal rings releasemedication over a longer period of time, they offered promise in this regard (1).Theauthors conducted a phase 3, randomized, double-blind, placebo–controlled trialof dapivirine vaginal rings in African women to determine whether vaginal ringoffered simpler, long term protection against HIV in comparison to a placeboring (1). Every month, participants were provided with new rings, condoms, clinicalconsultations, HIV-1 and STI tests for themselves and their partners, safetymonitoring, and individual adherence counseling (1).
It was important for theauthors to study whether vaginal rings, in conjunction with these other interventions,had their intended effect of increasing adherence to ART while still providingcare and information to each participant. Keydetails of the study and analysis Theauthors followed sexually active, non-pregnant women with a negative HIVdiagnosis 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 the2629 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 theplacebo (1). Within each country, half the participants were randomly assignedto use the vaginal ring containing 25 mg of dapivirine while the other half wasallocated a placebo ring. The rings were indistinguishable, enabling both participantsand 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 newring at each monthly appointment, along with HIV-1 risk reduction counsellingand free condoms.Adherencewas 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 objectivelyindicated the participant was adherent (1). Based on their definition, the authors reportedthe rate of adherence in the study to be over 70% (1).
Baetenet al. aimed for their test to correctly reject false positives 90% of the timeand used an end point driven study design to record a minimum of 120 HIV-1diagnoses to achieve this statistical power (1). They aspired to record 60%lower incidences of HIV-1 in the dapivirine group over the placebo (1). Allparticipants were followed for 12 months minimum or until they tested positivefor HIV-1. The results were modelled using cox regression showing cumulativeincidence to compare differences between the dapivirine and placebo groups ineach country.
The authors claimed to use intention-to-treat (ITT) methods incarrying out two analyses, one that showed cumulative incidence rates at all 15sites, and one that excluded two sites with exceptionally low adherence (1). UsingITT 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-1incidence to be 1 to 46 percent lower in the dapivirine group, with a p valueof 0.046.
The data was then analyzed by excluding two sites where adherence waslower than expected. After exclusion, the authors reported 139 HIV-1 infectionsamong 2395 participants, 54 of which were in the dapivirine group and the other85 incidences in the placebo group. This result showed that incidence of HIVwas 37% lower in the dapivirine condition, with a 95% confidence intervalbetween 12 and 56% decreased incidence in the dapivirine group with a stronglysignificant p value of 0.007 (1). Baeten et al. noted that the efficacy ofHIV-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 Baetenet al. determined via a post-hoc analysis (1). They found dapivirine increasedHIV-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 had an efficacyof 10% (95% CI, ?41 to 43; P = 0.64) (1). Tobetter analyze the effect of age, the authors stratified participants into 3 agegroups: 18 to 21, 22 to 26, and 27 to 45. Among the 18 to 21 year olds, 44 outof 451 were diagnosed with HIV-1 in the placebo group, yielding an incidence of5.
4 out of 100 person years (1). Within the 22 to 26 year olds, 51 out of 752participants in the placebo group were diagnosed with HIV-1. The incidence ratewas 6.
1 per 100 person years (1). Finally, 27 to 45 year olds had 44 out of1192 participants diagnosed with HIV-1 in the placebo group with an incidencerate of 3.0 out of 100 person years (1). Theseresults imply that dapivirine was effective in reducing new cases HIV-1 in womenover 25, but was not effective in reducing HIV-1 incidences in younger women,as shown by the non-significant p value of 0.64. Additionally, HIV-1 incidencerates were lowest in women between 27 and 45, indicating the intervention wasmost successful in this demographic. Study critiqueLimitations While Baetenet al.
assessed adherence via a plasma dapivirine level above 95 pg permillimeter, this level is usually achieved after 8 continuous hours of dapivirinering exposure (1). As women were instructed to wear the ring for a month, they cannotbe truly adherent if 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.Baetenet al. seemed to modify their results to show as strong an effect as possible. Originally,the null hypothesis was set as dapivirine being no more than 25% effective inreducing incidence of HIV-1.
The alternative hypothesis was that dapivirine wouldhave an 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 byonly 26% (1). In order to obtain significant results, 0% was used as thestandard reference parameter. This difference of 26% was only moderately significantin all 15 sites based on the p value of 0.046, meaning this result could be dueto chance.UsingITT analysis while excluding participants in due to noncompliance is alimitation of the study. In ITT analysis is the gold standard and includes allparticipants within the condition to which they were randomly assigned, includingthe noncompliant, in order to maintain randomization (9). Though Baeten et.
al wrotethat the majority of participants met the criteria for objective adherence, theyanalyzed their results while excluding two sites, because they believedparticipants in these places to be non-compliant with little discussion as totheir reasons for thinking so (1). Analyzing participants based on whether theyfollowed the parameters of their assigned condition is known as per-protocolanalysis (9). As the authors originally set out to determine whether dapivirinevaginal rings would be more effective and make compliance easier for women insub-Saharan Africa, it seems unethical for the authors to pick and choose datato analyze under the guise of ITT analysis when it is more in line withper-protocol analysis. The per-protocol analysis showed HIV incidence to be 37%lower in the dapivirine condition, with a p value of 0.007, a stronglysignificant result. The confidence interval showed that dapivirine protectionwas between 12% to 56% lower in dapivirine compared to the placebo, which stillincludes the original null hypothesis value of 25% lower HIV-1 incidences inthe dapivirine condition. Though there was a protective effect due todapivirine in the study, it seemed as if the authors were statisticallymanipulating data to show a stronger effect.
Though Baetenet al. discussed younger women having lower compliance rates and higherincidences of HIV-1 in their introduction, they did not stratify for age untilafter the study was over. The median age for the 2629 women between ages 18 and45 was 26, meaning half the participants were younger than this age while halfwere older (1). Thus, there were many more younger participants in this study, makingthe fact that women between 18 and 21 having a 27% more HIV-1 incidences in thedapivirine group even more striking, as this age groups makes up a largeportion of the study population (1). This result was moderately significantwith a p value of 0.
45, showing that vaginal dapivirine rings were not aneffective treatment to reduce HIV in young sub-Saharan women between 18 and 21(1). Theauthors stated that the lack of protection within the 18 to 21 year age groupcould be due to behavioral and biological factors combined, citing lowadherence and potentially more HIV susceptible genital tracts (1). Seeing asthe women were provided monthly support, STI testing, and free condoms alongwith the dapivirine rings, it is hard to imagine what more could be done toincrease adherence in sub-Saharan Africa, especially as Baeten et al. did notexplain potential biological factors in detail. Though only 2% of women reported engaging inanal sex within the last 3 months at baseline, it is important to keep in mindthat younger women may have higher rates of HIV because they are engaging inanal sex without reporting it due to fear of judgement and socialstigmatization (1). Topical dapivirinein the vagina would not be able to prevent HIV infection transmitted in therectum (1). If this is the case, the vaginal ring’s concentrated protection is notbeneficial to young women, who would need a systemic ART. Strengths Theauthors used good randomization techniques in order to decrease confoundingfactors.
Baeten et al. used block randomization to allocate research conditionwhile stratifying by country, ensuring that confounding factors kept to aminimum (1). Astrength of this study was demonstrating that incidence of HIV-1 wassignificantly lower in older women who adhered to the dapivirine studycondition (1).Dapivirine vaginal rings were effective inwomen over 21 years of age, with results showing 56% less HIV-1 incidences ascompared to the placebo. A p value of 0.001 shows the result is stronglysignificant.
Additionally, 27 to 45 year olds had the lowest cumulativeincidence rate of the three age groups with incidence of 3 out of 100person-years. Conversely, 18-21 year olds were the only group in which thecumulative incidence rate of HIV-1 in placebo was lower than in the dapivirinecondition, meaning less people died on placebo. Though Baeten et al. did notsucceed in finding an intervention to help younger women in sub-Saharan Africareduce incidence of HIV-1, they may have found a potential intervention to decreaseHIV-1 transmission in older women. As many other studies could not yield anyprotective effects, a 26-37% decrease in HIV incidence is a promising start (8). Next StepsWhilethis study shows dapivirine releasing vaginal rings increases efficacy in HIV-1protection in women over 21, who were much more adherent to the rings thanyounger women, there is still a public health need to develop an interventionto decrease HIV-1 incidence in young sub-Saharan women.
Clearly a vaginal ringwould not be clinically feasible for the young women who did not utilize them evenwith additional support. Policymakers and scientists should focus on finding a long acting, systemic ARV toprotect young women against all methods of HIV transmission, as it remains apertinent public health challenge. The women in this study should be followedup for qualitative interviews or questionnaires regarding their experience withvaginal rings to determine if they were comfortable, culturally appropriate,easy to use, and whether there were side effects. Women could also report theirpartners perspective on the vaginal rings, as a non-supportive partner may havecontributed to decreased adherence. These interviews could help researchersunderstand why younger women did not adhere to the rings as much as olderwomen, ultimately leading to the development of a more clinically significantintervention.While vaginalrings were not proven to be clinically significant in helping younger womenprevent HIV-1, scientists should continue to study vaginal rings potential todeliver ART as an option for more adherent women.
Results from Baeten et al’sstudy shows promise of longer term, efficient protection against HIV-1 for thepopulation of older women, which may prove to be more economically feasible andclinically more significant in this demographic. Thoughmore work needs to be done to protect young women living in sub-Saharan Africa,this study provided evidence of dapivirine protecting women over 25 with longerterm HIV-1 protection. Though the authors may not have achieved their goal ofdecreasing HIV-1 incidences in younger women, they have developed a promisingintervention that may ultimately decrease the number of women living with HIV-1in the future. Policy makers and scientists should work together in developingdapivirine rings as a new intervention, while further exploring new potentialinterventions targeted towards the young women in sub-Saharan Africa.