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Background Cytology-based cervical cancer screening followed by confirmation and treatment of biopsy-proven high-grade squamous intraepithelial lesions (bHSIL) is difficult to implement in resource-constrained settings. We hypothesized that high-risk human papillomavirus (hrHPV) testing followed by immediate cryotherapy of women with hrHPV (HPV screen-and-treat) may improve outcomes. Methods Randomized, open-label, phase 2, multinational clinical trial enrolling women with human immunodeficiency virus (HIV) age 18 or older with cervical hrHPV and having no cervical lesions or lesions appropriate for cryotherapy. Women were randomized to immediate cryotherapy (Arm A) or cytology-based screening (Arm B). For Arm A, cervical biopsies were obtained followed by cervical cryotherapy, and in Arm B, women with abnormal cytology underwent colposcopy followed by loop electroexcision procedure (LEEP) if bHSIL was detected. Women were followed through 30 months. The primary outcome was time to bHSIL detected from Month 6 through study completion. Results In total, 288 women (145 in Arm A, 143 in Arm B) were randomized: median age 35 years, 84% on antiretroviral therapy, median CD4 501 cells/mm3. In Arm A, 39 (27%) of women had bHSIL at entry, and in Arm B, 88 (62%) had abnormal cytology, 22 (15%) were diagnosed with bHSIL, 12 (8%) underwent LEEP. In follow-up, 30 (21%) and 31 (22%) developed bHSIL; time to bHSIL was similar between arms (P=.94). The prevalence of hrHPV at Month 6 was similar between arms (61% and 70%, P=.13). Conclusions HPV test-and-treat was not associated with improved bHSIL outcomes as compared to cytology-based screening. More effective treatment options are required to improve outcomes from screen-and-treat programs. Clinical Trials Registration NCT01315363.

Background: Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial. Methods: HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks. Results: Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%–100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH. Conclusions: TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

The objective of this study was to describe the impact of intense counseling to reduce vaginal hygiene practices and its effect on bacterial vaginosis. A secondary data analysis of the HIV Prevention Trials Network 035 study was undertaken, focusing on HIV-negative, nonpregnant women who were at least 18 years old, in seven African sites and one US site. At enrollment and during follow-up quarterly visits, vaginal hygiene practices were determined by face-to-face administration of a behavioral assessment questionnaire. Vaginal hygiene practices were categorized as insertion into the vagina of (1) nothing, (2) water only, and (3) other substances with or without water. Each practice was quantified by frequency and type/combination of inserted substances. At quarterly visits, diagnosis of bacterial vaginosis was made using the Nugent score. Trends for vaginal hygiene practices and bacterial vaginosis were evaluated using generalized estimating equation models. A total of 3087 participants from the HIV Prevention Trials Network 035 study were eligible for this analysis. At enrollment, 1859 (60%) reported recent vaginal hygiene practices. By one year, this figure had decreased to 1019 (33%) with counseling. However, bacterial vaginosis prevalence remained consistent across the study observation period, with 36%–38% of women testing positive for the condition ( p for trend = 0.27). Overall, those who reported douching with water only (AOR = 1.03, 95%CI: 0.94–1.13) and those who reported inserting other substances (AOR= 0.98, 95%CI: 0.88–1.09) in the past quarter were not more likely to have bacterial vaginosis compared to those who reported no insertions. However, in South Africa, an increase in bacterial vaginosis was seen among those who reported inserting other substances (AOR: 1.48, 95%CI: 1.17, 1.88). In conclusion, targeted counseling against vaginal hygiene practices resulted in change in self-reported behavior but did not have an impact on bacterial vaginosis diagnosis in all but one site.

There is a paucity of normative bone mineral density (BMD) data in healthy African women. Baseline total hip and lumbar spine BMD was measured in premenopausal women. BMD distribution was comparable to that of a reference population and was impacted by several factors including contraception and duration of lactation.Normative data on bone mineral density (BMD) and the cumulative impact of lactation, contraceptive use, and other factors on BMD in healthy African women have not been well studied.The objective of this study was to determine the factors associated with BMD in healthy premenopausal women in Uganda and Zimbabwe.Baseline total hip (TH) and lumbar spine (LS) BMD was measured by dual x-ray absorptiometry in 518 healthy, premenopausal black women enrolling in VOICE, an HIV-1 chemoprevention trial, at sites in Uganda and Zimbabwe. Contraceptive and lactation histories, physical activity assessment, calcium intake, and serum vitamin D levels were assessed. Independent factors associated with BMD were identified using an analysis of covariance model.The study enrolled 331 women from Zimbabwe and 187 women from Uganda. Median age was 29 years (IQR 25, 32) and median body mass index (BMI) was 24.8 kg/m(2) (IQR 22.2, 28.6). In univariate analyses, lower TH BMD values were associated with residence in Uganda (p 0.001), lower BMI (p 0.001), and any use of and duration of depot-medroxyprogresterone acetate. Use of oral contraceptives, progestin-only implants, and higher physical activity levels were protective against reduced BMD. Similarly, lower LS BMD values were associated with these same factors but also higher parity and history of breastfeeding. In a multivariable analysis, lower TH and LS BMD values were associated with enrollment in Uganda, lower BMI, and lower physical activity level; contraceptive use was associated with lower spine BMD, and breastfeeding contributed to lower total hip BMD.Among healthy premenopausal women, TH and LS BMD was higher in Zimbabwe than Uganda. Additional factors independently associated with BMD included BMI, physical activity level, contraceptive use, and lactation.

Human papillomavirus (HPV) genotype 52 is commonly found in Asian cases of cervical cancer but is rare elsewhere. Analysis of 611 isolates collected worldwide revealed a remarkable geographical distribution, with lineage B predominating in Asia (89.0% vs 0%-5.5%; P(corrected) < .001), whereas lineage A predominated in Africa, the Americas, and Europe. We propose that the name "Asian lineage" be used to denote lineage B, to signify this feature. Preliminary analysis suggested a higher disease risk for lineage B, although ethnogeographical confounders could not be excluded. Further studies are warranted to verify whether the reported high attribution of disease to HPV52 in Asia is due to the high prevalence of lineage B.

Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas.

Objective. Cervical human papillomavirus (HPV) infection has been associated with human immunodeficiency virus (HIV) acquisition in populations with a high prevalence of both infections. Procedures performed in the management of cervical dysplasia may facilitate HIV entry via mechanical injury. We sought to investigate the association between cervical procedures and incident HIV. Methods. Data on cervical cancer screening and procedures were collected in a cohort study evaluating the diaphragm for HIV prevention in 2040 women. In this secondary analysis, we investigated the association between cervical procedures and HIV acquisition. Results. Out of 2027 HIV-negative women at baseline, 199 underwent cervical procedures. Cumulative risk of HIV was 4.3% over 21 months of median followup (). Compared with women without cervical procedures, we observed no difference in HIV incidence after a cervical biopsy (RR 0.92, 95% CI 0.39–2.16), endocervical curettage (RR 0.29, 95% CI 0.07–1.22), or loop electrosurgical excision procedure (RR 1.00, 95% CI 0.30–3.30). Conclusions. In this cohort, cervical procedures were not associated with HIV incidence. This lack of association could be due to the small number of events.

Background. Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. Methods and results. This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014–6539) and LCR (nucleotides 7257–7429 and 7540–52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. Conclusions. HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study.

BACKGROUND: Persistent infections with oncogenic human papillomavirus (HPV) types are causally related to cervical cancer. Little is known about the distribution of HPV types independent risk factors of incidence and persistence and patterns of persistence in sub-Saharan Africa. METHODS: A cohort of 2040 Zimbabwean women was enrolled in a randomized trial assessing the effect of diaphragm/gel provision on human immunodeficiency virus and HPV acquisition. Data from the study arms were pooled for this analysis because diaphragm/gel provision did not affect HPV acquisition and clearance. Clinicians collected cervical samples for HPV testing at enrollment 12 months and exit (median 21 months). RESULTS: HPV prevalence was 24.5% for any HPV type and 16.1% for oncogenic types. HPV incidence at 12 months was 23.3% for any HPV type and 11.4% for oncogenic types. HPV58 had the highest baseline prevalence (5.0%) and incidence (2.4%). Type-specific persistence was 29.8% among all HPV infections over a median of 21 months of follow-up. Baseline predictors of incident HPV infection were younger age having more than 1 lifetime sexual partner infrequent condom use herpes simplex virus-2 positive serology and having a sexually transmissible infection or a different HPV type at enrollment. Baseline predictors of persistent HPV infection were younger age having more than 1 lifetime sexual partner and having a high-risk partner. CONCLUSIONS: The novel association between herpes simplex virus-2 seropositivity and incident HPV infection warrants further investigation. Having a high-risk partner is a potentially modifiable risk factor for persistent HPV infection. The relatively high prevalence of HPV58 has implications for vaccine development.

OBJECTIVE: To estimate the effect of providing women with a latex diaphragm lubricant gel and male condoms (intervention) compared with condoms alone (control) on human papillomavirus (HPV) incidence and clearance. METHODS: Participants were 2040 human immunodeficiency virus (HIV)-negative Zimbabwean women enrolled in a randomized trial estimating the effect of the intervention on HIV acquisition. Clinicians collected cervical samples for HPV testing at baseline 12 months and exit. L1 consensus polymerase chain reaction primers were used to determine HPV presence and type. RESULTS: We found no differences in the following outcomes: HPV prevalence at the time of the first postenrollment HPV test (intention-to-treat analysis relative risk [RR] 1.02 95% confidence interval [CI] 0.90-1.16); HPV incidence at 12 months among women HPV-negative at baseline (RR 0.95 95% CI 0.80-1.14); and HPV clearance at 12 months among women HPV-positive at baseline (RR 0.80 95% CI 0.61-1.05). Clearance of HPV type 58 was lower in the intervention group at 12 months (RR 0.67 95% CI 0.48-0.92) but not at exit (RR 0.93 95% CI 0.75-1.16); clearance of HPV type 18 was lower in the intervention group at exit (RR 0.55 95% CI 0.33-0.89) but not at 12 months (RR 0.55 95% CI 0.29-1.05). Women reporting diaphragm/gel use at 100% of prior sex acts had a lower likelihood of having one or more new HPV types detected at 12 months (RR 0.75 95% CI 0.58-0.96) and exit (RR 0.77 95% CI 0.59-0.99). CONCLUSION: Among women receiving risk reduction counseling and condoms in an HIV prevention program diaphragm plus lubricant gel provision did not affect HPV incidence or clearance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00211459 LEVEL OF EVIDENCE: I.