Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.

BACKGROUND: The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE. METHODS: In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50. FINDINGS: Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines. INTERPRETATION: HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination. FUNDING: The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Durability of single-dose HPV vaccination in young Kenyan women: randomized controlled trial 3-year results.

Cervical cancer burden is high where prophylactic vaccination and screening coverage are low. We demonstrated in a multicenter randomized, double-blind, controlled trial that single-dose human papillomavirus (HPV) vaccination had high vaccine efficacy (VE) against persistent infection at 18 months in Kenyan women. Here, we report findings of this trial through 3 years of follow-up. Overall, 2,275 healthy women aged 15-20 years were recruited and randomly assigned to receive bivalent (n = 760), nonavalent (n = 758) or control (n = 757) vaccine. The primary outcome was incident-persistent vaccine type-specific cervical HPV infection. The primary evaluation was superiority analysis in the modified intention-to-treat (mITT) HPV 16/18 and HPV 16/18/31/33/45/52/58 cohorts. The trial met its prespecified end points of vaccine type-specific persistent HPV infection. A total of 75 incident-persistent infections were detected in the HPV 16/18 mITT cohort: 2 in the bivalent group, 1 in the nonavalent group and 72 in the control group. Nonavalent VE was 98.8% (95% CI 91.3-99.8%, P < 0.0001) and bivalent VE was 97.5% (95% CI 90.0-99.4%, P < 0.0001). Overall, 89 persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: 5 in the nonavalent group and 84 in the control group; nonavalent VE was 95.5% (95% CI 89.0-98.2%, P < 0.0001). There were no vaccine-related severe adverse events. Three years after vaccination, single-dose HPV vaccination was highly efficacious, safe and conferred durable protection. ClinicalTrials.gov no. NCT03675256 .

HPV vaccination in Kenya: a study protocol to assess stakeholders' perspectives on implementation drivers of HPV vaccination and the acceptability of the reduced dose strategy among providers.

Background: Cervical cancer is the leading cause of cancer-related deaths among Kenyan women. Persistent infection with high-risk oncogenic Human papillomavirus (HPV) genotypes is a necessary cause of cervical cancer. HPV vaccines are safe, durable, and efficacious in preventing incident HPV infections. In Kenya, despite efforts to increase HPV vaccination, coverage remains low. We sought to assess: (1) barriers and facilitators of HPV vaccination from the perspective of adolescent girls and young women (AGYW), their guardians as well as stakeholders involved in HPV vaccine delivery, and (2) the acceptability of the single dose of the HPV vaccination among healthcare providers (HCPs). Methods: Our study is nested within the KENya Single-dose HPV-vaccine Efficacy study (KEN SHE) that sought to test the efficacy of single-dose bivalent (HPV 16/18) and single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11) vaccination. We are conducting this study in Kiambu, Nairobi, and Kisumu counties. In these counties, we are interviewing stakeholders (n = ∼25), selected based on their role in HPV vaccination at the county and national levels. Interviews are audio recorded and conducted in English or Swahili. The semi-structured interview guides were designed based on: (1) the Theoretical Domains Framework (TDF) for AGYW and guardians and (2) the Consolidated Framework for Implementation Research (CFIR) for other stakeholders. The Theoretical Framework of Acceptability (TFA) was leveraged to design the survey administered to HCPs (n = ∼309) involved in HPV vaccination. We will develop a codebook based on emerging codes from the transcripts and constructs from the TDF and CFIR. Emerging themes will be summarized highlighting similarities and differences between and within the different stakeholder groups and counties. Descriptive statistics and a χ2 test will be used to assess the distribution of responses between the different sites and regression analysis will be used to assess factors associated with high acceptability of the single-dose strategy while controlling for confounding variables. Discussion: Our study will describe key barriers and facilitators that affect HPV vaccination from the perspective of multiple stakeholders as well as insights on the perspective of HCPs towards the single-dose strategy to inform the designing of strategies to increase HPV vaccination uptake in Kenya and comparable settings.

Efficacy of single-dose HPV vaccination among young African women.

Background: Single-dose HPV vaccination, if efficacious, would be tremendously advantageous; simplifying implementation and decreasing costs. Methods: We performed a randomized, multi-center, double-blind, controlled trial of single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11) or bivalent (HPV 16/18) HPV vaccination compared to meningococcal vaccination among Kenyan women aged 15-20 years. Enrollment and six monthly cervical swabs and a month three vaginal swab were tested for HPV DNA. Enrollment sera were tested for HPV antibodies. The modified intent-to-treat (mITT) cohort comprised participants who tested HPV antibody negative at enrollment and HPV DNA negative at enrollment and month three. The primary outcome was incident persistent vaccine-type HPV infection by month 18. Results: Between December 2018 and June 2021, 2,275 women were randomly assigned and followed; 758 received the nonavalent HPV vaccine, 760 the bivalent HPV vaccine, and 757 the meningococcal vaccine; retention was 98%. Thirty-eight incident persistent infections were detected in the HPV 16/18 mITT cohort: one each among participants assigned to the bivalent and nonavalent groups and 36 among those assigned to the meningococcal group; nonavalent Vaccine Efficacy (VE) was 97.5% (95%CI 81.7-99.7%, p=<0.0001), and bivalent VE was 97.5% (95%CI 81.6-99.7%, p=<0.0001). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: four in the nonavalent group and 29 in the meningococcal group; nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95%CI 68.5-96.1%, p<0.0001). The rate of SAEs was 4.5-5.2% by group. Conclusions: Over the 18 month time-frame we studied, single-dose bivalent and nonavalent HPV vaccines were each highly effective in preventing incident persistent oncogenic HPV infection, similar to multidose regimens.

Impact of catch-up human papillomavirus vaccination on cervical cancer incidence in Kenya: A mathematical modeling evaluation of HPV vaccination strategies in the context of moderate HIV prevalence.

BACKGROUND: Cervical cancer incidence is high in Kenya due to HIV and limited access to cancer prevention services. Human papillomavirus (HPV) has been shown to increase HIV acquisition; however, the potential impact of HPV vaccination on HIV is unknown. We modeled the health impact of HPV vaccination in the context of the HIV epidemiology in Kenya. METHODS: Using a validated compartmental transmission model of HIV and HPV set in Kenya, we evaluated five scenarios of nonavalent HPV vaccination: single-age-vaccination of 10-year-old girls at 90% coverage; multi-age-cohort (MAC) vaccination of 10-14-year-old girls at 90% coverage; MAC plus moderate-coverage (50%) catch-up vaccination of 15-24-year-old women; MAC plus high-coverage (80%) catch-up of 15-24-year-old women; and MAC plus catch-up of 15-44-year-old women at 80% coverage (HPV-FASTER). We compared cervical cancer incidence, HIV prevalence, and cumulative cervical cancer and HIV cases averted after 50 years to a baseline scenario without vaccination. In all scenarios, we assumed the UNAIDS 90-90-90 goal for HIV treatment is attained by 2030. FINDINGS: In 2021, model-estimated cervical cancer incidence is 44/100,000 and HIV prevalence among women is 6·5%. In 2070, projected cancer incidence declines to 27/100,000 and HIV prevalence reaches 0·3% without vaccination. With single-age-vaccination, cancer incidence in 2070 is reduced by 68%, averting 64,529 cumulative cancer cases. MAC vaccination reduces cancer incidence by 75%, averting 206,115 cancer cases. Moderate and high-coverage catch-up and HPV-FASTER reduce cancer incidence by 80%, 82%, and 84%, averting 254,930, 278,690, and 326,968 cancer cases, respectively. In all scenarios, HIV prevalence in 2070 is reduced by a relative 8-11%, with 15,609-34,981 HIV cases averted after 50 years. INTERPRETATION: HPV vaccination can substantially reduce cervical cancer incidence in Kenya in the next 50 years, particularly if women up to age 24 are vaccinated. HIV treatment scale-up can also alleviate cervical cancer burden. However, HPV vaccination has modest additional impact on HIV when antiretroviral therapy coverage is high. FUNDING: National Institutes of Health, Bill and Melinda Gates Foundation.

Single-dose HPV vaccination efficacy among adolescent girls and young women in Kenya (the KEN SHE Study): study protocol for a randomized controlled trial.

BACKGROUND: HPV infection is the primary cause of cervical cancer, a leading cause of cancer among women in Kenya and many sub-Saharan African countries. High coverage of HPV vaccination is a World Health Organization priority to eliminate cervical cancer globally, but vaccine supply and logistics limit widespread implementation of the current two or three dose HPV vaccine schedule. METHODS: We are conducting an individual randomized controlled trial to evaluate whether a single dose of the bivalent (HPV 16/18) or nonavalent (HPV 16/18/31/33/45/52/58/6/11) HPV vaccine prevents persistent HPV infection, a surrogate marker for precancerous lesions and cervical cancer. The primary objective is to compare the efficacy of immediate, single-dose bivalent or nonavalent vaccination with delayed HPV vaccination. Kenyan women age 15-20 years old are randomized to immediate bivalent HPV and delayed meningococcal vaccine (group 1), immediate nonavalent HPV vaccine and delayed meningococcal vaccine (group 2), or immediate meningococcal vaccine and delayed HPV vaccine (group 3) with 36 months of follow-up. The primary outcome is persistent vaccine-type HPV infection by month 18 and by month 36 for the final durability outcome. The secondary objectives include to (1) evaluate non-inferiority of antibody titers among girls and adolescents (age 9 to 14 years) from another Tanzanian study, the DoRIS Study (NCT02834637), compared to KEN SHE Study participants; (2) assess the memory B cell immune response at months 36 and 37; and (3) estimate cost-effectiveness using the trial results and health economic models. DISCUSSION: This study will evaluate single-dose HPV vaccine efficacy in Africa and has the potential to guide public health policy and increase HPV vaccine coverage. The secondary aims will assess generalizability of the trial results by evaluating immunobridging from younger ages, durability of the immune response, and the long-term health benefits and cost of single-dose HPV vaccine delivery. TRIAL REGISTRATION: ClinicalTrials.gov NCT03675256 . Registered on September 18, 2018.

The Kanyakla study: Randomized controlled trial of a microclinic social network intervention for promoting engagement and retention in HIV care in rural western Kenya.

BACKGROUND: Existing social relationships are a potential source of "social capital" that can enhance support for sustained retention in HIV care. A previous pilot study of a social network-based 'microclinic' intervention, including group health education and facilitated HIV status disclosure, reduced disengagement from HIV care. We conducted a pragmatic randomized trial to evaluate microclinic effectiveness. METHODS: In nine rural health facilities in western Kenya, we randomized HIV-positive adults with a recent missed clinic visit to either participation in a microclinic or usual care (NCT02474992). We collected visit data at all clinics where participants accessed care and evaluated intervention effect on disengagement from care (≥90-day absence from care after a missed visit) and the proportion of time patients were adherent to clinic visits ('time-in-care'). We also evaluated changes in social support, HIV status disclosure, and HIV-associated stigma. RESULTS: Of 350 eligible patients, 304 (87%) enrolled, with 154 randomized to intervention and 150 to control. Over one year of follow-up, disengagement from care was similar in intervention and control (18% vs 17%, hazard ratio 1.03, 95% CI 0.61-1.75), as was time-in-care (risk difference -2.8%, 95% CI -10.0% to +4.5%). The intervention improved social support for attending clinic appointments (+0.4 units on 5-point scale, 95% CI 0.08-0.63), HIV status disclosure to close social supports (+0.3 persons, 95% CI 0.2-0.5), and reduced stigma (-0.3 units on 5-point scale, 95% CI -0.40 to -0.17). CONCLUSIONS: The data from our pragmatic randomized trial in rural western Kenya are compatible with the null hypothesis of no difference in HIV care engagement between those who participated in a microclinic intervention and those who did not, despite improvements in proposed intervention mechanisms of action. However, some benefit or harm cannot be ruled out because the confidence intervals were wide. Results differ from a prior quasi-experimental pilot study, highlighting important implementation considerations when evaluating complex social interventions for HIV care. TRIAL REGISTRATION: Clinical trial number: NCT02474992.

Cervical Cancer Stigma in Rural Kenya: What Does HIV Have to Do with It?

Cervical cancer is a leading cause of cancer-related death amongst women in sub-Saharan Africa, largely due to the lack of early screening and treatment. In addition to poor access to screening services, inadequate uptake of available services is a barrier to early identification of precancerous lesions. Given that cervical cancer is caused by a sexually transmitted virus and is associated with HIV positivity, stigma is one of the potential barriers to the utilization of cervical cancer programs in sub-Saharan Africa. We conducted a cross-sectional survey of 419 women attending health facilities in rural western Kenya to measure levels of cervical cancer and HIV stigma and to measure the associations between cervical cancer stigma, HIV stigma, and HIV status. Women who qualified for cervical cancer screening were asked to complete an oral questionnaire using a modified 9-point HIV stigma scale. Low cervical cancer stigma was reported in this study, with only 85/419 (20.3 %) of respondents answering yes to at least one cervical cancer stigma question. However, cervical cancer stigma was highly correlated with HIV stigma (correlation coefficient 0.72) and was significantly lower in HIV-positive women (p < 0.001). Reducing cervical cancer stigma in the general population is an important part of promoting screening in sub-Saharan Africa.

Changing knowledge, attitudes, and behaviors regarding cervical cancer screening: The effects of an educational intervention in rural Kenya.

OBJECTIVE: Cervical cancer screening uptake may be influenced by inadequate knowledge in resource-limited settings. This randomized trial evaluated a health talk's impact on cervical cancer knowledge, attitudes, and screening rates in rural Kenya. METHODS: 419 women attending government clinics were randomized to an intervention (N=207) or control (N=212) group. The intervention was a brief health talk on cervical cancer. Participants completed surveys at enrollment (all), immediately after the talk (intervention arm), and at three-months follow-up (all). The primary outcomes were the change in knowledge scores and the final screening rates at three-months follow-up. Secondary outcomes were changes in awareness about cervical cancer screening, perception of personal cervical cancer risk, cervical cancer and HIV stigma, and screening acceptability. RESULTS: Mean Knowledge Scores increased by 26.4% (8.7 points increased to 11.0 points) in the intervention arm compared to only 17.6% (8.5 points increased to 10.0 points) in the control arm (p<0.01). Screening uptake was moderate in both the intervention (58.9%; N=122) and control (60.9%; N=129) arms, with no difference between the groups (p=0.60). CONCLUSION: A brief health talk increased cervical cancer knowledge, although it did not increase screening over simply informing women about free screening. PRACTICAL IMPLICATIONS: Screening programs can increase patient understanding with just a brief educational intervention.

Barriers to Cervical Cancer Screening in Rural Kenya: Perspectives from a Provider Survey.

Although cervical cancer is highly preventable through screening, it remains the number one cause of cancer-related death in Kenyan women due to lack of funding and infrastructure for prevention programs. In 2012, Family AIDS Care and Education Services in partnership with the Kenya Ministry of Health began offering free screening at eleven rural health facilities. We sought to explore why screening coverage remains low at some sites. We examined the barriers to screening through a survey of 106 healthcare staff. The most frequently cited barriers to service delivery included staffing shortages, lack of trained staff, insufficient space, and supply issues. The patient barriers commonly perceived by the staff included inadequate knowledge, wait time, discomfort with male providers, and fear of pain with the speculum exam. Despite multilateral efforts to implement cervical cancer screening, staff face significant challenges to service provision and increased education is needed for both providers and patients.

Cervical Cancer Screening Knowledge and Behavior among Women Attending an Urban HIV Clinic in Western Kenya.

Cervical cancer is a highly preventable disease that disproportionately affects women in developing countries and women with HIV. As integrated HIV and cervical cancer screening programs in Sub-Saharan Africa mature, we have an opportunity to measure the impact of outreach and education efforts and identify areas for future improvement. We conducted a cross-sectional survey of 106 women enrolled in care at an integrated HIV clinic in the Nyanza Province of Kenya 5 years after the start of a cervical cancer screening program. Female clinic attendees who met clinic criteria for cervical cancer screening were asked to complete an oral questionnaire assessing their cervical cancer knowledge, attitudes, and screening history. Ninety-nine percent of women had heard of screening, 70 % felt at risk, and 84 % had been screened. Increased duration of HIV diagnosis was associated with feeling at risk and with a screening history. Nearly half (48 %) of women said they would not get screened if they had to pay for it.

Knowledge about cervical cancer screening and perception of risk among women attending outpatient clinics in rural Kenya.

OBJECTIVE: To evaluate cervical cancer knowledge, risk perception, and screening intention among women attending outpatient clinics in rural Kenya. METHODS: A cross-sectional oral survey was conducted among non-pregnant women aged 23-64 years who attended one of 11 western Kenyan health facilities for any reason between March 25 and April 26, 2013. Demographic and clinical predictors were identified using bivariate and multivariate regression analyses. RESULTS: Among 419 participants, 327 (78.0%) had heard of cervical cancer screening. Nevertheless, their specific knowledge was low (mean score 8.6±2.4 [out of 15.0]). Overall, 288 (68.7%) women felt at risk for cervical cancer, and 333 (79.5%) stated that they would undergo screening if offered. Women who intended to undergo screening were less likely to attend a district hospital (adjusted odds ratio [AOR] 0.4; 95% confidence interval [CI] 0.2-0.6) and more likely to have been diagnosed with HIV more than 4 years previously (AOR 0.4; 95% CI 0.2-0.6). Additionally, increased screening acceptance was associated with high knowledge scores (P=0.004). CONCLUSION: Educational interventions to increase knowledge about cervical cancer might increase screening uptake in low-income settings. Additionally, improvements in services at local health facilities could have a large effect.

Medicalization of HIV and the African response.

Since the discovery of HIV, the advent of anti-retrovirals in the late 80s heralded an era of medicalization of HIV and fostered major advancements in the management of the disease. Africa, despite its high HIV burden, lagged behind in the adoption of these advancements due to major resource and logistical constraints. Innovative responses such as family-centered models of care, community systems strengthening, integration of HIV care with existing health services, and economic and mobile phone- based approaches have been critical in the successful roll-out of evidence-based HIV/AIDS treatment even in the most resource- limited settings.

Diaphragm for STI and HIV prevention: is it a safe method for women at high risk?

Female sex workers (n = 140) were enrolled in a 6-month acceptability trial of the diaphragm. We randomized a subset (n = 40) to receive colposcopies after 1 month of diaphragm use or after 1 month of observation before commencing diaphragm use. Adverse events were mild in nature. Frequency of colposcopic findings did not differ between women randomized to immediate versus delayed diaphragm use (P = 0.25).

Sustained changes in sexual behavior by female sex workers after completion of a randomized HIV prevention trial.

INTRODUCTION: Behavioral interventions in female sex workers (FSWs) are associated with changes in sexual behavior and reduced rates of sexually transmitted infections (STIs) and HIV We examined the sustainability of such interventions. METHODS: HIV-uninfected Kenyan FSWs were enrolled in a clinical trial that provided free male condoms, community and clinic-based counseling, and STI management. After trial completion, scaled-back community-based resources remained in place. More than a year later, women were invited to complete a follow-up behavioral questionnaire and to undergo STI/HIV counseling and testing. Individual changes in sexual behavior were assessed by paired analysis. RESULTS: One hundred seventy-two women participated in the resurvey 1.2 years after trial termination. Client numbers had risen (paired t test, P < 0.001), but condom use had also increased (P < 0.001); both remained substantially lower than at enrollment. Regular partners accounted for a greater proportion of unprotected FSW sexual encounters (35% vs. 10%; P < 0.001). Only 9 (5.2%) of 172 women had a conventional STI, and the follow-up HIV incidence of 1.6 per 100 person-years (PYs) was similar to that during the trial period (3.7 per 100 PYs). Incident STIs and HIV were associated with the frequency of unprotected sex and younger age. CONCLUSIONS: Less intensive community-based risk reduction services after clinical trial termination may support ongoing reductions in STIs and HIV among high-risk FSWs.