Josaphat Byamugisha

Hormonal Contraception and HIV Acquisition: Reanalysis using Marginal Structural Modeling

Hormonal contraceptives are used widely worldwide; their effect on HIV acquisition remains unresolved. We reanalyzed data from the Hormonal Contraception and HIV Study using marginal structural modeling to reduce selection bias due to time-dependent confounding. Replicating our original analysis closely, we found that depo-medroxyprogesterone acetate (DMPA) but not combined oral contraceptive (COC) was associated with increased HIV acquisition. Also, young (18–24 years) but not older women who used DMPA and COCs were at increased HIV risk.

A multicountry evaluation of careHPV testing, visual inspection with acetic acid, and papanicolaou testing for the detection of cervical cancer.

Objective This study evaluates the feasibility and performance of careHPV, a novel human papillomavirus (HPV) DNA test, when used for screening women for cervical cancer in low-resource settings. Methods and Materials Clinician-collected (cervical) and self-collected (vaginal) careHPV specimens, visual inspection with acetic acid (VIA), and Papanicolaou test were evaluated among 16,951 eligible women in India, Nicaragua, and Uganda. Women with positive screening results received colposcopy and histologic follow-up as indicated. The positivity of each screening method was calculated overall, by site, and age. In addition, the clinical performance of each screening test was determined for detection of cervical intraepithelial neoplasia (CIN) grade 2 (CIN2+) and CIN grade 3. Results Moderate or severe dysplasia or cancer (taken together as CIN2+) was diagnosed in 286 women. The positivity rate ranged between 2.4% to 19.6% for vaginal careHPV, 2.9% to 20.2% for cervical careHPV, 5.5% to 34.4% for VIA, and 2.8% to 51.8% for Papanicolaou test. Cervical careHPV was the most sensitive for CIN2+ (81.5%; 95% confidence interval [CI], 76.5–85.8) and CIN grade 3 (85.3%; 95% CI, 78.6–90.6) at all sites, followed by vaginal careHPV (69.6% and 71.3%, respectively). The sensitivity of VIA ranged from 21.9% to 73.6% and Papanicolaou test from 40.7% to 73.7%. The pooled specificities of cervical careHPV, vaginal careHPV, VIA, and Papanicolaou test were 91.6%, 90.6%, 84.2%, and 87.7%, respectively. Conclusions careHPV performed well in large multicountry demonstration studies conducted in resource-limited settings that have not previously been conducted this type of testing; its sensitivity using cervical samples or vaginal self-collected samples was better than VIA or Papanicolaou test. The feasibility of using careHPV in self-collected vaginal samples opens the possibility of increasing coverage and early detection in resource-constrained areas.Objective This study evaluates the feasibility and performance of careHPV, a novel human papillomavirus (HPV) DNA test, when used for screening women for cervical cancer in low-resource settings. Methods and Materials Clinician-collected (cervical) and self-collected (vaginal) careHPV specimens, visual inspection with acetic acid (VIA), and Papanicolaou test were evaluated among 16,951 eligible women in India, Nicaragua, and Uganda. Women with positive screening results received colposcopy and histologic follow-up as indicated. The positivity of each screening method was calculated overall, by site, and age. In addition, the clinical performance of each screening test was determined for detection of cervical intraepithelial neoplasia (CIN) grade 2 (CIN2+) and CIN grade 3. Results Moderate or severe dysplasia or cancer (taken together as CIN2+) was diagnosed in 286 women. The positivity rate ranged between 2.4% to 19.6% for vaginal careHPV, 2.9% to 20.2% for cervical careHPV, 5.5% to 34.4% for VIA, and 2.8% to 51.8% for Papanicolaou test. Cervical careHPV was the most sensitive for CIN2+ (81.5%; 95% confidence interval [CI], 76.5–85.8) and CIN grade 3 (85.3%; 95% CI, 78.6–90.6) at all sites, followed by vaginal careHPV (69.6% and 71.3%, respectively). The sensitivity of VIA ranged from 21.9% to 73.6% and Papanicolaou test from 40.7% to 73.7%. The pooled specificities of cervical careHPV, vaginal careHPV, VIA, and Papanicolaou test were 91.6%, 90.6%, 84.2%, and 87.7%, respectively. Conclusions careHPV performed well in large multicountry demonstration studies conducted in resource-limited settings that have not previously been conducted this type of testing; its sensitivity using cervical samples or vaginal self-collected samples was better than VIA or Papanicolaou test. The feasibility of using careHPV in self-collected vaginal samples opens the possibility of increasing coverage and early detection in resource-constrained areas.

Plasma and Cervical Viral Loads among Ugandan and Zimbabwean Women during Acute and Early HIV-1 Infection

Objectives:High levels of HIV-1 viremia exist in peripheral blood during acute and early infection; however, data on HIV-1 viral loads in female genital secretions during this period are sparse. Design:Prospective cohort of 188 African women with primary HIV-1 infection. Methods:HIV-uninfected and infected women were followed quarterly; we tested serial plasma specimens by HIV PCR to estimate infection dates. We used the Loess procedure to estimate the magnitude and timing of viral setpoints in plasma and cervical secretions and generalized estimating equations (GEE) to identify predictors of plasma and cervical viral setpoints. Results:We estimated the mean HIV-1 plasma setpoint to be 4.20 log10 HIV-1 RNA copies/ml [95% confidence interval (CI) 4.04–4.35] at 121 days (95% CI 91–137) from infection; an analogous mean cervical viral setpoint was 1.64 log10 HIV-1 RNA copies/swab (95% CI 1.46–1.82) at 174 days (95% CI 145–194) from infection. Cervical loads were significantly higher (0.7–1.1 log10 copies/swab) during acute infection than subsequently. Subtype D infection, pregnancy, breastfeeding, and older age at the time of infection were associated with higher plasma viral setpoint. Subtype C infection, nonviral sexually transmitted infections, having a partner spending nights away from home, recent unprotected sex, and shorter time since infection were associated with higher cervical HIV-1 loads. Hormonal contraception was not associated with either the HIV-1 plasma setpoint or cervical loads during early infection. Conclusion:Cervical HIV-1 viral loads were highest during acute infection and then declined up to 6 months following infection, when a ‘setpoint’ was attained. The prognostic value of a cervical ‘setpoint’ on future transmission risk remains unclear.

A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.

Significance Pre-eclampsia is especially common in women of African ancestry and a major cause of maternal death. The killer-cell immunoglobulin-like receptor (KIR) genes that we analyzed are expressed by natural killer cells—immune cells that populate the uterus and are essential for successful pregnancy. KIR proteins bind HLA ligands on the implanting placental trophoblast cells. African and European women share similar risk associations for pre-eclampsia, but protection is associated with different KIR genes. African women are protected by a combination of KIR B haplotype genes that is present almost exclusively in Africans. This study emphasizes the importance of studying diseases in Africans, where the KIR/HLA genetic system is at its most diverse and maternal mortality rates are the highest in the world. In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.

Audit of severe maternal morbidity in Uganda – implications for quality of obstetric care

Background. For every maternal death, there are probably 100 or more morbidities, but the quality of health care for these women who survive has rarely been an issue. The purpose of this study is to explore audit of severe obstetric morbidity and the concept of near miss in four referral hospitals in Uganda. Methods. This was an exploratory systematic enquiry into the care of a subset of women with severe morbidity designated as near miss cases by organ failure or dysfunction. Patient factors and environmental factors were also explored. Data were abstracted from clinical records and from interviews with patients, relatives, and health workers. Results. Records of 685 women with severe maternal morbidity were examined and 229 cases fulfilled the criteria for near miss cases. Obstetric hemorrhage, rupture of the uterus, puerperal sepsis, and abortion complications were the major conditions leading to the near miss state in more than three quarters of the patients. Nearly half the cases were at home when the events occurred. More than half the cases delayed to seek care, because the patients were unwilling, or relatives were not helpful. Similar proportion also experienced substandard care in the hospitals. Conclusions. A systemic analysis found substandard care and records, and patient‐related factors in more than half the cases of severe maternal morbidity. Audit of near miss cases might offer a non‐threatening stimulus for improving the quality of obstetric care.

Results of a community-based cervical cancer screening pilot project using human papillomavirus self-sampling in Kampala, Uganda

To examine the feasibility of a community‐based screening program using human papillomavirus (HPV) self‐sampling in a low‐income country with a high burden of cervical cancer.

The impact of maternal highly active antiretroviral therapy and short-course combination antiretrovirals for prevention of mother-to-child transmission on early infant infection rates at the mulago national referral hospital in Kampala, Uganda, january 2007 to may 2009

Background:Early HIV infant diagnosis and treatment have been shown to dramatically improve survival in infants. Despite these findings, infants accessing HIV diagnosis and treatment remain low in Uganda. We describe the antiretroviral (ARV) drugs given in the Mulago Hospital prevention of mother-to-child transmission (PMTCT) program from January 2007 to May 2009 and its impact on early infant HIV infection rates. Methods:Pregnant women identified as HIV infected in the Mulago antenatal clinics received one of the following regimens: short-course ARV prophylaxis plus single-dose nevirapine (sdNVP) in labor, highly active antiretroviral therapy (HAART), or sdNVP if they presented in labor. Infants received sdNVP and zidovudine (ZDV) for 1 week. Infants HIV diagnosis was done from 6 weeks after delivery. Results:62.3% of HIV-infected women received combination ARVs, including HAART. Early infection rates were highest among infants with no maternal ARV [36.4; 95% confidence interval (CI): 17.2 to 59.3] or only sdNVP (11.2; 95% CI: 8.1 to 14.8). Similar rates were observed for the group that took short-course ARVs, ZDV/sdNVP (4.6; 95% CI: 3.2 to 6.4), and ZDV/lamivudine/sdNVP (4.9; 95% CI: 3.1 to 7.2) and lowest rates for those that took HAART (1.7: 95% CI: 0.8 to 2.8). Overall infection rate was 5.0% (95% CI: 4.1 to 5.9). Conclusions:Findings indicate low rates of infant infection for mothers receiving combination ARVs. These findings demonstrate that provision of combination ARV for PMTCT is feasible and effective in busy referral hospitals PMTCT programs in resource-limited settings.

Factors associated with high-risk HPV positivity in a low-resource setting in sub-Saharan Africa

OBJECTIVE We sought to determine demographic and behavioral factors associated with human papillomavirus (HPV) positivity in a community-based HPV self-collection cervical cancer screening pilot project. STUDY DESIGN HPV self-collected samples were obtained from 199 women aged 30-69 years in the impoverished urban Ugandan community of Kisenyi, during September through November 2011. Demographic and behavioral information was collected. Descriptive statistics and a logistic regression model were used to analyze factors associated with HPV positivity. RESULTS There was overwhelming acceptance of HPV self-collection in this community. High-risk HPV prevalence was found to be 17.6%. Lower levels of formal education (adjusted odds ratio [AOR], 0.40; 95% confidence interval [CI], 0.08-2.03) were associated with higher prevalence of HPV as was use of oral contraception (AOR, 2.01; 95% CI, 0.83-4.90) and human immunodeficiency virus status (AOR, 0.43; 95% CI, 0.14-1.37). CONCLUSION Screening should be targeted and prioritized for women with lower levels of education, oral contraceptive use, and human immunodeficiency virus positivity as they have the highest HPV prevalence in this low-resource population.

Consumption of alcoholic beverages among pregnant urban Ugandan women.

The World Health Organization estimated alcohol consumption in Uganda to be one of the highest in the world. We examined alcohol consumption among Ugandan women prior to and after learning of pregnancy. We developed a screening algorithm using factors that predicted alcohol consumption in this study. In 2006, we surveyed 610 women attending antenatal care at the national referral hospital in Kampala, Uganda about consumption of traditional and commercial alcoholic beverages before and after learning of pregnancy. Predictors of alcohol consumption during pregnancy were examined and a practical screening algorithm was developed for use in antenatal clinics. One hundred eighty women (30%) drank alcohol at least monthly before learning of their pregnancy. Among these women, almost one-third reported usual consumption of at least one beverage type at quantities that equal binging levels for women. Overall, 151 women (25%) consumed alcohol after learning of pregnancy. Commercial beverages, particularly beer, were consumed more often than traditional drinks. A two-stage screening algorithm asking women about their religion, male partner or friends’ drinking, and any lifetime drinking predicted self-reported consumption of alcohol during pregnancy with 97% sensitivity and 89% specificity. Alcohol consumption among pregnant Ugandan women attending antenatal care is high. A feasible screening algorithm can help providers target education and counseling to women who are likely drinking during pregnancy. Given the preference for commercial alcoholic beverages, it is recommended that labels be placed prominently on bottled alcoholic beverages warning of the adverse effects of consuming alcohol during pregnancy.

Discontinuation of oral contraceptives and depot medroxyprogesterone acetate among women with and without HIV in Uganda, Zimbabwe and Thailand

BACKGROUND We examined hormonal contraceptive (HC) discontinuation and factors associated with discontinuation among HIV-uninfected women and the effect of HIV diagnosis on subsequent contraceptive use. STUDY DESIGN We analyzed 4461 HIV-uninfected women from a prospective study of HC and HIV acquisition in Uganda, Zimbabwe and Thailand. Participants were ages 18-35 years, not pregnant, and using oral contraceptives (OCs) or injectable depot medroxyprogesterone acetate (DMPA) for at least 3 months before enrollment (median duration of OC and DMPA use before enrollment was 11.7 and 8.9 months, respectively). We compared the probability of OC and DMPA discontinuation using survival analysis and factors related to discontinuation using Cox regression. We also analyzed contraceptive patterns among 194 women who became infected with HIV. RESULTS Median duration of use after study enrollment was 15.6 months for OCs and 18.5 months for DMPA. Continuation rates for both methods were highest in Thailand. Factors associated with OC discontinuation included, nausea, breast tenderness, condom use, and no sex. Factors associated with DMPA discontinuation included young age, breast tenderness, nausea, irregular bleeding, high-risk sexual behaviors, partner risk, condom use, and no sex. Following an HIV diagnosis, 135 (98.5%) of 137 hormonal users continued HC and 14 (25%) of 57 nonusers began using HC. CONCLUSIONS Contraceptive continuation for OCs and DMPA was relatively high over 2 years. Young women, those reporting side effects, and those using condoms are more likely to discontinue and need ongoing contraceptive counseling. Many women receiving HIV-positive diagnoses desire effective contraception.