Ethical considerations for involving adolescents in biomedical HIV prevention research.

BACKGROUND: Involvement of adolescent girls in biomedical HIV research is essential to better understand efficacy and safety of new prevention interventions in this key population at high risk of HIV infection. However, there are many ethical issues to consider prior to engaging them in pivotal biomedical research. In Uganda, 16-17-year-old adolescents can access sexual and reproductive health services including for HIV or other sexually transmitted infections, contraception, and antenatal care without parental consent. In contrast, participation in HIV prevention research involving investigational new drugs requires adolescents to have parental or guardian consent. Thus, privacy and confidentiality concerns may deter adolescent participation. We describe community perspectives on ethical considerations for involving adolescent girls in the MTN 034 study in Uganda. METHODS: From August 2017 to March 2018, we held five stakeholder engagement meetings in preparation for the MTN 034 study in Kampala, Uganda (NCT03593655): two with 140 community representatives, two with 125 adolescents, and one with 50 adolescents and parents. Discussions were moderated by the study team. Proceedings were documented by notetakers. Summary notes described community perspectives of adolescent participation in HIV research including convergent, divergent or minority views, challenges, and proposed solutions. RESULTS: Most community members perceived parental or guardian consent as a principal barrier to study participation due to concerns about adolescent disclosure of pre-marital sex, which is a cultural taboo. Of 125 adolescent participants, 119 (95%) feared inadvertent disclosure of sexual activity to their parents. Community stakeholders identified the following critical considerations for ethical involvement of adolescents in HIV biomedical research: (1) involving key stakeholders in recruitment, (2) ensuring confidentiality of sensitive information about adolescent sexual activity, (3) informing adolescents about information to be disclosed to parents or guardians, (4) offering youth friendly services by appropriately trained staff, and (5) partnering with community youth organizations to maximize recruitment and retention. CONCLUSIONS: Stakeholder engagement with diverse community representatives prior to conducting adolescent HIV prevention research is critical to collectively shaping the research agenda, successfully recruiting and retaining adolescents in HIV clinical trials and identifying practical strategies to ensure high ethical standards during trial implementation.

Experiences with simultaneous use of contraception and the vaginal ring for HIV prevention in sub-Saharan Africa.

BACKGROUND: Clinical trials have found that a monthly dapivirine vaginal ring was well-tolerated and reduced HIV-1 risk among women in sub-Saharan Africa. However, in order for the ring or other novel prevention methods to have optimal impact, it is necessary to understand and address women's challenges to uptake and adherence. This paper provides insight into a few key challenges noted by women using the ring and contraceptives simultaneously. METHODS: The qualitative portion of the MTN-020/ASPIRE study consisted of data collection using single in-depth interviews, serial in-depth interviews, and focus group discussions, conducted with 214 participants across 15 sites in Malawi, South Africa, Uganda and Zimbabwe. A coding team used qualitative analysis software to identify themes within the interviews. RESULTS: The primary qualitative themes among participant data pertained to side effects. Participants reported negative side effects related to menses, in some cases attributing these effects to their contraceptives and in others to the vaginal ring. Participants also expressed concern over the long-term impact of contraception and ring use on fertility, including the reversibility of the contraceptive, especially among nulliparous women. CONCLUSIONS: Women's attitudes toward contraceptives can impact their willingness to concurrently use and adhere to a novel HIV prevention product. To optimize the potential of both prevention products, researchers should pre-emptively address concerns about contraceptive impact on fertility and counsel women about the expected side effects of contraceptives versus the ring. Clinical trials identifier NCT01617096. Registered on 6-12-2012 at clinicaltrials.gov https://clinicaltrials.gov/ct2/show/NCT01617096.

Feasibility and Safety of IUD Insertion by Mid-Level Providers in Sub-Saharan Africa.

CONTEXT: The copper IUD is safe and effective, but underutilized in Sub-Saharan Africa, in part because of a lack of trained providers. The World Health Organization recommends training mid-level providers-including nurses and midwives-to insert IUDs; however, the safety of such task shifting has not been evaluated in Sub-Saharan Africa. METHODS: Data were drawn from baseline surveys and study charts of 535 sexually active women aged 18-45 who used a copper IUD while participating in an HIV-prevention clinical trial conducted from August 2012 through June 2015 in Malawi, South Africa, Uganda and Zimbabwe. IUDs were inserted by study physicians, nurses and midwives trained as part of the trial, and by local nonstudy providers. Chi-square and Fisher's exact tests were used to compare women's experiences of adverse events-such as irregular bleeding, pelvic pain or device expulsion-by provider type. RESULTS: Half (54%) of women reported experiencing an adverse event; the most common were irregular bleeding and pelvic pain (45% and 25%, respectively). Compared with women who had received an IUD from a study physician or study nurse, greater proportions of women who had received one from a nonstudy provider reported any adverse event (76% vs. 49% and 51%, respectively), irregular bleeding (57% vs. 41% and 45%) and pelvic pain (35% vs. 15% and 32%); the difference between study physicians and nurses was significant only for pelvic pain. Expulsion rates were comparable for study nurses and nonstudy providers (12.3 and 11.9 per 100 woman-years, respectively), but lower for study physicians (7.3 per 100 woman-years). CONCLUSIONS: The findings support task shifting of IUD insertion to mid-level providers to improve IUD access in Sub-Saharan Africa.

RESUMEN Contexto: Aunque el DIU de cobre es seguro y efectivo, está subutilizado en África subsahariana, en parte debido a la falta de proveedores de servicios de salud capacitados. La Organización Mundial de la Salud recomienda capacitar a los proveedores de nivel medio ­incluidas las enfermeras y parteras­ para insertar los DIU; sin embargo, la seguridad de tal cambio de tareas ha sido evaluada en África subsahariana. Métodos: Se obtuvieron datos de encuestas de línea de base y cuadros de un estudio de 535 mujeres sexualmente activas, de 18 a 45 años, que usaron un DIU de cobre en un ensayo clínico de prevención del VIH realizado entre agosto de 2012 y junio de 2015 en Malaui, Sudáfrica, Uganda y Zimbabue. Los DIU fueron insertados por médicos participantes en el estudio, enfermeras y parteras capacitadas como parte del ensayo, así como por proveedores de servicios de salud locales no relacionados con el estudio. Las pruebas exactas de Chi-cuadrado y Fisher se usaron para comparar las experiencias de las mujeres con eventos adversos ­como sangrado irregular, dolor pélvico o expulsión del dispositivo­ por tipo de proveedor. Resultados: La mitad (54%) de las mujeres reportaron haber experimentado algún evento adverso; los eventos más comunes fueron sangrado irregular y dolor pélvico (45% y 25%, respectivamente). En comparación con las mujeres que habían recibido un DIU de un médico o de una enfermera del estudio, una gran parte de las mujeres que lo habían recibido de un proveedor no relacionado con el estudio reportaron algún tipo de evento adverso (76% vs. 49% y 51%, respectivamente), sangrado irregular (57 % vs. 41% y 45%) y dolor pélvico (35% vs. 15% y 32%); La diferencia entre los médicos y las enfermeras del estudio fue significativa solo para el dolor pélvico. Las tasas de expulsión fueron comparables para las enfermeras del estudio y los proveedores no relacionados con el estudio (12.3 y 11.9 por 100 años-mujer, respectivamente), pero más bajas para los médicos del estudio (7.3 por 100 años-mujer). Conclusiones: Los hallazgos respaldan el cambio de tareas de inserción del DIU a proveedores de nivel medio para mejorar el acceso al DIU en África Subsahariana.

RÉSUMÉ Contexte: Bien qu'il soit sûr et efficace, le DIU au cuivre est sous-utilisé en Afrique subsaharienne, faute, en partie, de prestataires formés. L'Organisation mondiale de la Santé recommande la formation de prestataires de niveau intermédiaire ­ personnel infirmier et sages-femmes ­ pour la pose du DIU. La sécurité de cette délégation de tâches n'a cependant pas été évaluée en Afrique subsaharienne. Méthodes: Les données proviennent d'enquêtes de base et de graphiques d'étude concernant 535 femmes sexuellement actives âgées de 18 à 45 ans qui utilisaient un DIU au cuivre dans le cadre d'un essai clinique de prévention du VIH réalisé d'août 2012 à juin 2015 en Afrique du Sud, au Malawi, en Ouganda et au Zimbabwe. Les DIU avaient été posés par les médecins, infirmières et sages-femmes de l'étude, formés dans le cadre de l'essai, ainsi que par des prestataires locaux extérieurs à l'étude. Le test chi carré et la méthode exacte de Fisher ont servi à comparer l'expérience d'effets indésirables ­ tels que saignements irréguliers, douleurs pelviennes ou expulsion du DIU ­ vécus par les femmes suivant le type de prestataire. Résultats: La moitié (54%) des femmes ont signalé un effet indésirable, les plus courants étant les saignements irréguliers et les douleurs pelviennes (45% et 25%, respectivement). Par rapport aux femmes dont le DIU avait été posé par un médecin ou une infirmière de l'étude, de plus grandes proportions de celles qui avaient obtenu leur dispositif d'un prestataire extérieur à l'étude ont signalé un effet indésirable quelconque (76% contre 49% et 51%, respectivement), des saignements irréguliers (57% contre 41% et 45%) et des douleurs pelviennes (35% contre 15% et 32%). La différence entre les médecins et le personnel infirmier de l'étude n'est significative que pour les douleurs pelviennes. Les taux d'expulsion sont comparables pour les infirmières de l'étude et les prestataires extérieurs (12,3 et 11,9 pour 100 femmes-années, respectivement), mais il est moindre pour les médecins de l'étude (7,3 pour 100 femmes-années). Conclusions: Les résultats sont favorables à la délégation de la pose du DIU aux prestataires de niveau intermédiaire pour améliorer l'accès au DIU en Afrique subsaharienne.

Contraceptive method switching among women living in sub-Saharan Africa participating in an HIV-1 prevention trial: a prospective cohort study.

OBJECTIVE: Long-acting reversible contraceptive (LARC) method uptake has been low within the context of HIV prevention trials. Within a multinational study (MTN-020/ASPIRE), the Contraceptive Action Team improved LARC accessibility and uptake. In this secondary analysis, we determined the rate of contraceptive method continuation among the women enrolled. STUDY DESIGN: ASPIRE was a randomized, double-blinded, placebo-controlled phase III safety and effectiveness study of the Dapivirine Vaginal Ring for HIV-1 prevention. Between 2012 and 2014, sexually active women aged 18-45 from Malawi, South Africa, Uganda and Zimbabwe were enrolled. All participants were required to use contraception for enrollment to the study and could choose between all highly effective contraceptive methods available in their respective countries. Women were seen monthly and could change methods at any time. Continuation rates from study enrollment to 6 and 12 months were determined. RESULTS: The overall contraceptive method continuation rate was 77% (1972/2551) at 6 months and 66% (1694/2551) at 12 months. The 6- and 12-month continuation rates were highest for implantable contraceptives (89%, 82%) followed by copper intrauterine device (83%, 77%). Rates of continuation for injectable contraceptives depot medroxyprogesterone acetate (80%, 69%) and norethisterone enanthate (71%, 54%) were higher than for oral contraceptives, which were continued at 47% at 6 months and 35% at 12 months. The continuation rates of all methods did not differ by users with and without previous contraceptive experience. CONCLUSIONS: LARC methods have the highest rates of continuation at 12 months and should be routinely offered in the context of HIV prevention trials in sub-Saharan Africa. IMPLICATIONS: Intrauterine devices and contraceptive implant continuation was high at 12 months among women participating in an HIV prevention trial in sub-Saharan Africa and LARCs and should be routinely offered.

Maximizing participant retention in a phase 2B HIV prevention trial in Kampala, Uganda: The MTN-003 (VOICE) Study.

BACKGROUND: The success of longitudinal trials depends greatly on using effective strategies to retain participants and ensure internal validity, maintain sufficient statistical power, and provide for the generalizability of study results. OBJECTIVE: This paper describes the challenges and specific strategies used to retain participants in a Phase 2B safety and effectiveness study of daily oral and vaginal tenofovir formulations for the prevention of HIV-1 infection in the MTN-003 (VOICE) trial in Kampala, Uganda. METHODS: Once enrolled, participants were seen every 28 days at the research site and their study product was re-filled. Challenges to retention included a mobile population, non-disclosure of study participation to spouse/family, and economic constraints. Strategies used to maintain high participation rates included the use of detailed locator information, a participant tracking database, regular HIV/STI testing, and the formation of close bonds between staff and subjects. RESULTS: We enrolled 322 women out of the 637 screened. The overall retention rate was 95% over a 3 year follow up period. Only 179 (3%) out of the 6124 expected visits were missed throughout study implementation. Reasons for missed visits included: participants thinking that they did not need frequent visits due to their HIV negative status, time constraints due to commercial sex work, and migration for better employment. CONCLUSIONS: With the implementation of multi-faceted comprehensive follow-up and retention strategies, we achieved very high retention rates in the MTN-003 study. This paper provides a blueprint for effective participant retention strategies for other longitudinal HIV prevention studies in resource-limited settings in Sub-Saharan Africa.

Human papillomavirus prevalence and cytopathology correlation in young Ugandan women using a low-cost liquid-based Pap preparation.

Screening for HPV-driven cervical dysplasia and neoplasia is a significant public health concern in the developing world. The purpose of this study was to use a manual, low-cost liquid-based Pap preparation to determine HPV prevalence in HIV-positive and HIV-negative young women in Kampala, Uganda and to correlate cervical cytopathology with HPV-DNA genotype. About 196 post-partum women aged 18-30 years underwent rapid HIV testing and pelvic examination. Liquid-based cervical cytology samples were processed using a low-cost manual technique. A DNA collection device was used to collect specimens for HPV genotyping. HIV and HPV prevalence was 18 and 64%, respectively. Overall, 49% of women were infected with a high-risk HPV genotype. The most common high-risk HPV genotypes were 16 (8.2%), 33 (7.7%), 35 (6.6%), 45 (5.1%), and 58 (5.1%). The prevalence of HPV 18 was 3.6%. HIV-positive women had an HPV prevalence of 86% compared to 59% in HIV-negative women (P = 0.003). The prevalence of HPV 16/18 did not differ by HIV status. HIV-positive women were infected with a significantly greater number of HPV genotypes compared to HIV-negative women. By multivariate analysis, the main risk factor for HPV infection was coinfection with HIV. HIV-positive women were four times more likely to have abnormal cytology than HIV-negative women (43% vs. 11.6%, P < 0.001). These data highlight that HIV infection is a strong risk factor for HPV infection and resultant abnormal cervical cytology. Notably, the manual low-cost liquid-based Pap preparation is practical in this setting and offers an alternate method for local studies of HPV vaccine efficacy.