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Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug–drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; P < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; P < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; P = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ (P < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test–negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.

Objective HIV cure research urgently needs to identify pre-analytic treatment interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation. Design We profiled the circulating glycomes (plasma and bulk IgG) of two geographically distinct cohorts: Philadelphia Cohort - 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. Johannesburg Cohort - 23 HIV-infected, ART-suppressed individuals who had participated in a 2-week ATI. Methods Capillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses. Results Higher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratio = 0.12, P = 0.05). In addition to G2, we identified several predictive glycomic traits in plasma, for example, levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (hazard ratio = 0.023, P = 0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (hazard ratio = 24.1, P = 0.028). Additionally, pre-ATI plasma glycomic signatures associated with a lower viral setpoint, for example, T-antigen (Galβ1-3GalNAc) (r = 0.75, P = 0.0007), or a higher viral setpoint, for example, polylactosamine (r = -0.58, P = 0.01). These results were initially validated in the Johannesburg Cohort. Conclusion We describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically distinct cohorts.

Background Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)–naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. Methods PLWH with a CD4+ count Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. Results Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. Conclusions Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

Setting Ethiopia has a high prevalence of tuberculosis (TB) and is one of the countries with the highest burden of multidrug-resistant TB (MDR-TB). Objective To understand the costs that patients incur in obtaining diagnosis and treatment for MDR-TB. Design In March 2013, interviews were conducted with 169 MDR-TB patients at three hospitals in Ethiopia to identify the cost to patients and the impact on employment and family income. Results The average MDR-TB patient incurred a total cost of US$1378, which represented 25 months of a mid-treatment household income of US$54. The impact on the patient's employment and on overall patient and family income was generally catastrophic: 74% of all respondents reported losing their jobs, 66% of patients lost household income, and household income was reduced by 38%. To help cover the costs, 38% of patients sold some type of property, while 7% leased out property and 41% took out loans, any of which could jeopardize their future financial situation even further. Conclusion Despite services being officially free of charge, most patients incurred catastrophic costs and suffered significant income loss as a result of obtaining diagnosis and treatment for MDR-TB.

Background. Breast cancer is the most common cancer in women in many low- and middle-income countries, and often presents at an advanced stage that affects prognosis irrespective of the care available. Although patient-related delay is commonly cited, the reasons for delay and the relationship of delay to stage are still poorly documented, especially in Africa.Objectives. To identify where patient-related socioeconomic delays occur and how these relate to stage at presentation.Methods. Consecutive women with a new breast cancer diagnosis were prospectively invited to complete a questionnaire on their socioeconomic characteristics and ability to access care. Clinical stage at presentation was documented.Results. Over 14 months, 252 women completed the questionnaire (response rate 71.6%). Their median age was 55 years (interquartile range 44 - 65), with 26.5% aged

BACKGROUND With the advent of combined antiretroviral therapy (cART), HIV positive women are expected to live longer. The effect of chronic HIV infection and cART on cervical epithelial maturation has not been well studied in postmenopausal woman. The objective of this study was to determine whether HIV positive postmenopausal women on cART show expected atrophic changes in cervical Pap tests. METHODS The maturation index (MI) was performed on routine cervical smears from HIV-infected, postmenopausal women attending an HIV clinic in a tertiary hospital in Johannesburg, over a 4-year period from January 2009 to December 2012. RESULTS In Pap smears of 111 patients on cART, 58 (52%) showed an unexpected predominantly mature squamous epithelial pattern whereas 53 (48%) were predominantly immature or atrophic (P = .0001). There was no significant statistical difference in maturation according to cART use. CONCLUSION HIV-infected, postmenopausal women in this study had reduced rates of cervical atrophy than expected, irrespective of cART use and CD4 count. Initiation of cART before menopause was associated with greater cervical epithelium maturation than those women who started cART after menopause. Additional, larger studies are required to confirm this novel finding and to investigate the reason for this phenomenon.

Objectives: People living with HIV have increased Human Papillomavirus (HPV) related lesions and malignancies. We describe HPV DNA recovered from the cervix and anal canal, explore the effect of vaccination on HPV detection, and examine the durability of vaccine titers in women living with HIV-1 who were vaccinated with the quadrivalent HPV vaccine. Methods: AIDS Clinical Trials Group A5240 was a prospective study of the quadrivalent HPV (qHPV) vaccine in 315 HIV-1 infected women in three CD4 strata (A: >350, B; 201–350, C: ≤200 cells/mm3). Vaccine was administered at entry, week 8 and week 24. Cervical and anal HPV DNA specimens were collected at baseline, weeks 28 and 52; serum for antibody testing was obtained at baseline, weeks 28 and 72. Results: Vaccine antibody titers decreased across all four HPV types at week 72 compared to week 28. Lower proportions of sustained seropositivity were observed in women with lower CD4 counts for all four vaccine types, with the lowest titers for HPV 18. Despite the decrease, the geometric mean titer levels were above the seroconversion cut-off levels for all types except HPV 18 in the lowest CD4 stratum. Of the 174 participants who had a negative baseline HPV 16 antibody and developed antibody response at week 28, 95%, 88%, and 86% retained seropositivity at week 72 in strata A, B, and C respectively. Lower antibody retention was observed in women with CD4 350 (p = 0.016). Anal HPV detection was more prevalent compared to cervical detection at all visits. Among high risk types, type 52, 31, 16, 18 and 51 were the most common in the cervical compartment, while types 16, 35, 18, and 51 were the most prevalent in the anal canal at baseline (listed in the order of prevalence). Later detection of HPV not present at baseline was uncommon in either compartment. Serial recovery of HPV over time was more commonly observed in the anal canal. Conclusion: The qHPV vaccine elicits durable titer response above the seroconversion cut-off levels in HIV-infected women. However, the titer levels were substantially lower by Week 72, most noticeably in type 18. HPV DNA was detected more frequently in the anal canal. Detection of non-vaccine high risk HPV suggests a role for the nonavalent vaccine. Keywords: HPV, HIV, Anogenital, Quadrivalent HPV vaccine, Women, Immunogenicity

Background Women living with human immunodeficiency virus (HIV), especially in sub-Saharan Africa, are at high risk for cervical high-grade squamous intraepithelial lesions (HSIL) and cervical cancer. These women have high HSIL recurrence rates after loop electroexcision procedure (LEEP). Retrospective studies suggest that human papillomavirus (HPV) vaccination improves response to treatment of cervical HSIL. Methods We performed a double-blind, randomized clinical trial enrolling 180 women living with HIV in Johannesburg, South Africa, diagnosed with cervical HSIL by colposcopic biopsy. Women received quadrivalent HPV vaccine or placebo (1:1) at entry, week 4, and week 26. LEEP was performed at week 4. Colposcopic-directed biopsies and cervical cytology were performed at weeks 26 and 52. The primary endpoint, cervical HSIL by histology or cytology at either week 26 or 52, was compared between arms using χ 2 analysis. Results Participant characteristics included median age of 39 years and median CD4 count 489 cells/μL, and 94% had HIV suppression. One hundred seventy-four women completed the vaccine/placebo series and had evaluable results at week 26 or 52. The proportion experiencing the primary endpoint was similar in the vaccine and placebo groups (53% vs 45%; relative risk, 1.18 [95% confidence interval, .87–1.6]; P = .29). HSIL recurrence was associated with a LEEP biopsy result of HSIL and detection of HSIL at the margins of the LEEP sample. Conclusions This study did not support HPV vaccination to prevent recurrent HSIL after LEEP in women living with HIV. Recurrent HSIL was high despite virologic suppression. Improved treatments are needed for HSIL to reduce the burden of cervical cancer among women living with HIV. Clinical Trials Registration NCT01928225.

Identification of factors associated with human papillomavirus (HPV) cervical histopathology or recurrence/relapse following loop electrosurgical excision procedure (LEEP) would allow for better management of the disease. We investigated whether gene signatures could (i) associate with HPV cervical histopathology and (ii) identify women with post-LEEP disease recurrence/relapse. Gene array analysis was performed on paraffin-embedded cervical tissue-isolated RNA from two cross-sectional cohorts of antiretroviral therapy (ART)-suppressed HIV(+)HPV(+) coinfected women: (i) 55 women in South Africa recruited into three groups: high risk (HR) (−) (n = 16) and HR (+) (n = 15) HPV without cervical histopathology and HR (+) HPV with cervical intraepithelial neoplasia (CIN) grade 1/2/3 (n = 24), (ii) 28 women in Botswana with CIN2/3 treated with LEEP 12-month prior to recruitment and presenting with (n = 13) and without (n = 15) lesion recurrence/relapse (tissue was analyzed at first LEEP). Three distinct gene expression signatures identified were able to segregate: (i) HR(+) HPV and CIN1/2/3, (ii) HR HPV-free and cervical histopathology-free and (iii) HR(+) HPV and cervical histopathology-free. Immune activation and neoplasia-associated genes (n = 272 genes; e.g. IL-1A, IL-8, TCAM1, POU4F1, MCM2, SMC1B, CXCL6, MMP12) were a feature of cancer precursor dysplasia within HR HPV infection. No difference in LEEP tissue gene expression was detected between women with or without recurrence/relapse. In conclusion, distinctive gene signatures were associated with presence of cervical histopathology in tissues from ART-suppressed HIV(+)/HPV(+) coinfected women. Lack of detection of LEEP tissue gene signature able to segregate subsequent post-LEEP disease recurrence/relapse indicates additional factors independent of local gene expression as determinants of recurrence/relapse.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)–infected participants in resource-limited settings treated with 3 World Health Organization–recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/μL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.

Objective To estimate the provider costs of managing adverse drug reactions (ADRs) to standard long-course treatment for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) according to South African guidelines. Methods We parameterised a published Markov health state model for MDR/RR-TB with guidelines-based, bottom-up public-sector provider costing of ADR management. Frequency of ADR occurrence was extracted from the literature. Costs were estimated over 10 years, discounted 3% annually and tested using probabilistic sensitivity analysis. Results On average, guidelines-based costing of moderate ADRs weighted by the frequency of occurrence was US$135.76 (standard deviation [SD] US$17.18) and the cost of serious ADRs was US$521.29 (SD US$55.99). We estimated that the incremental costs of ADR management were US$380.17 annually per patient initiating MDR/RR-TB treatment. The incremental costs of ADR management for the public health sector in South Africa was US$4.76 million, 8.3% of the estimated cohort costs of MDR/RR-TB treatment ($57.55 million) for the 2015 cohort of 12 527 patients. Conclusions Management of multiple ADRs and serious ADRs, which are common during the first 6 months of standard, long-course MDR/RR-TB treatment, substantially increases provider treatment costs. These results need to be taken into account when comparing regimen costs, and highlight the urgent need to identify drug regimens with improved safety profiles.

Objectives This study investigated anal high-risk HPV (HR-HPV) prevalence in HIV-infected women using the Cepheid Xpert HPV assay and compares its performance with that of Hybrid Capture-2 (hc2). Methods A total of 199 HIV-infected women were recruited from Helen Joseph Hospital, Johannesburg. Stored ThinPrep anal swabs that had previously been tested using hc2 were tested for HPV using Xpert. Results The HR-HPV prevalence by Xpert was 40.8% and similar to hc2 (41.8%) with overall agreement of 86.7%; Cohen's kappa 0.73 (95% CI 0.63-0.82). High grade squamous intraepithelial lesions (HSIL) was associated with increasing number of multiple HPV infection (P < .001). Xpert and hc2 were similarly sensitive (77.4% and 77.4%, respectively) and specific (66.1% and 64.8% respectively) for HSIL detection. HPV16 (OR: 14.0, 95% CI: 3.9-48.0, P < .0001), HPV39/68/56/66 (OR: 4.1, 95% CI: 1.4-12, P = .01) and HPV51/59 (OR: 2.8, 95% CI: 1.1-7.6, P = .04) were independently associated with anal HSIL. Conclusions Xpert HPV typing is a promising anal screening test in HIV-infected women that performs similarly to hc2.

Objectives To estimate the prevalence of adverse drug reactions or events (ADR) during drug-resistant TB (DR-TB) treatment in the context of settings with high HIV prevalence (at least 20% of patients). Methods We conducted a systematic review and meta-analysis of articles in PubMed and Scopus. Pooled proportions of patients experiencing adverse events and relative risk with 95% CI were calculated. Results The search yielded 24 studies, all observational cohorts. Ten reported on the number of patients experiencing ADR and were included in the meta-analysis representing 2776 study participants of whom 1943 were known to be HIV infected (70.0%). An average of 83% (95% CI: 82%-84%) of patients experienced one or more ADR. Among the seven articles ( n = 664 study participants) with information on occurrence of severe ADR, 24% (95% CI: 21%-27%) of patients experienced at least one severe ADR during drug-resistant TB treatment. Sixteen of the 24 studies analysed the relative risk of ADR by HIV infection, nine of which found no statistically significant association between HIV infection and occurrence of drug-related ADR. There was insufficient information to disaggregate risk by concomitant treatment with HIV antiretrovirals or by immunosuppression (CD4 count). Conclusions No randomized clinical trials were found for WHO-recommended treatment of drug-resistant TB treatment where at least 20% of the cohort was coinfected with HIV. Nearly all patients (83%) experience ADR during DR-TB treatment. While no significant association between ADR and HIV coinfection was found, further research is needed to determine whether concomitant antiretrovirals or immunosuppression increases the risks for HIV-infected patients.

Objective Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Design Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. Methods HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Results Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). Conclusions HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

Background: Antiretrovirals, particularly efavirenz (EFV), have been shown to cause breast abnormalities in adults. Little is known about the prevalence of these adverse effects among adolescents receiving antiretroviral therapy (ART).Objectives: The aim of this article was to examine the extent of breast abnormalities in adolescents receiving ART and determine any clinical associations.Methods: A retrospective record review describing breast conditions in adolescents receiving ART at three facilities in Johannesburg was conducted. Patients aged 10–19 years, who presented from January to December 2014, were included in the study. Analyses were conducted to determine whether EFV was associated with increased breast conditions.Results: Of the 631 patient records reviewed, 37 (6%) had an abnormal breast event documented; with 24/37 (65%) being male patients. Patients with abnormal breast conditions were 1.5 years older than patients with normal breast development (p 0.0005). Forty-one abnormal breast events were observed in 37 patients, with 20 described as gynaecomastia or lipomastia (49%). Of the 37 patients, 44% (n = 19) had concurrent generalised lipodystrophy. Of those with an abnormal breast event, 71% of patients had CD4 counts 500 cells/µL and were virologically suppressed (n = 29). Those on EFV had a significantly higher prevalence of breast abnormalities compared to other regimens (p = 0.016).Conclusion: Of the studied patients, 6% had an abnormal breast condition. The use of EFV and increased age were associated with breast abnormalities in this population. Further research is needed to better understand the implications of this potential side effect.

Background Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. Methods This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration ( Results Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0–25.6%) had MPA Conclusions DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed. Clinical Trials Registration NCT02412436.

Background: In South Africa, cervical cancer remains among the most common cancers and a leading cause of cancer death. Co-infection with HIV increases the risk of developing cervical pre-cancer and cancer. We analysed National Health Laboratory Service cervical cytology data to investigate geographic variations of Pap smear coverage, quality, and high grade lesions. Methods: Facility-level data were extracted from the NHLS for April 2013–March 2014. We present results and choropleth maps detailing coverage, adequacy and high-grade Pap smear cytology abnormalities defined as Pap smears suspicious for invasive carcinoma, high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells: cannot exclude HSIL (ASC-H). Results: 4,562 facilities submitted 791,067 cytology slides. The interquartile range (IQR) for Pap smear coverage among HIV-infected women was 26–41%; similar to coverage in women aged 30 and older (IQR: 26–42%). 6/52 districts had adequacy rates above the national standard (70%) and 2/52 districts had adequacy rates below 35%. We observed marked variation in Pap smear abnormalities across the country, with the proportion of high-grade cytology abnormalities ≥0.3% in 17/52 districts.Conclusion: Using district-level choropleth maps, we are able to display variations in Pap smear coverage, quality, and results across South Africa. This approach may be used to improve resource allocation, achieving better equity in cervical cancer prevention.

Cervical cancer is one of the most common causes of cancer-related deaths in Southern Africa. Human papillomavirus vaccination offers a chance to markedly reduce this burden of disease although challenges with vaccine delivery need to be overcome.

Objectives The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). Results Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median age was 34 years. We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P = 0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P = 0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P = 0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P = 0.02, respectively. Conclusions Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

Background. The endocervical component of a Pap smear is an important indicator of sample quality – or ‘adequacy’. However, only 6 of 52 districts in South Africa (SA) meet the Department of Health (DoH) performance benchmark: a 70% adequacy rate. We implemented a quality-improvement (QI) intervention to address suboptimal Pap smear quality in Tshwane District, Gauteng Province, SA. Objectives. To determine whether training with the wooden Ayre spatula (step 1) or introduction of the cytobroom (step 2) resulted in greater improvements in Pap smear adequacy rates. Methods. Two Tshwane District health facilities participated in our QI project between May 2016 and February 2017. In step 1, staff received training on the Ayre spatula. In step 2, the spatula was replaced with the cytobroom. Pap smear volumes, adequacy rates and results are reported for the pre-intervention period and after each QI step. We compared adequacy rates using Fisher’s exact test, with a significance level of p =0.05. Results. In the pre-intervention period, 304 of 965 Pap smears were deemed adequate (32%; 95% confidence interval (CI) 29 - 35%). After step 1, the proportion increased to 109 of 191 (57%; 95% CI 50 - 64%; p

Background Adverse drug reactions (ADRs) are common during standard, long-course treatment for multidrug-resistant and rifampicin-resistant tuberculosis (MDR-/RR-TB). In particular, second-line injectables (SLIs) are associated with permanent hearing loss, acute renal injury and electrolyte imbalance. We adapted an established Markov model for ambulatory treatment to estimate the impact of the toxicity profile on the incremental cost-effectiveness ratio (ICER) for a proposed MDR-/RR-TB regimen replacing the SLI with bedaquiline (BDQ). Methods Treatment effectiveness was evaluated in disability-adjusted life-years (DALYs). Clinical outcomes and ingredient costs from a provider perspective were derived from the South African public-sector treatment program or extracted from the literature. Costs and effectiveness were discounted at 3% per year over 10 years. Results A BDQ-based MDR-/RR-TB regimen compared with the SLI regimen had a mean ICER of US$516 per DALY averted using the standard Markov model. Costs for both regimens increased and effectiveness decreased for the SLI regimen once adjusted for toxicity. The resulting ICER for the BDQ-based regimen was cost saving (US$96/patient) and more effective (0.96 DALYs averted) after adjusting for ADRs. Conclusion Decision-analysis models of treatment for MDR-/RR-TB, including new drug regimens, should consider the costs of managing ADRs and their sequelae.

Background: Due to the reduction in HIV transmission through male medical circumcisions (MMC), numerous clinics throughout South Africa offer a voluntary free service to boys from the age of ten years and above. An examination prior to the procedure may detect congenital abnormalities missed after birth. Objectives: The aim of this study was to measure the incidence of these abnormalities, determine the demographic and clinical characteristics of this group and determine what referral systems, interventions, and follow-up is available to them. Methods: The study was a descriptive, observational, retrospective analysis of de-identified medical records at a routine MMC service at a Johannesburg clinic in 2015. The participants were male patients between the ages of 10 – 49. Results: Out of 1548 participants, 91.0% (n=1409) had a normal genital examination while 3.7% (n=57) had an abnormal examination and 5.1% (n=79) had no examination recorded. Thirty five congenital anomalies were detected and only 2 patients (diagnosed with hypospadias) were seen at the urology out-patient’s department. Conclusion: The incidence of congenital genital abnormalities of males presenting for routine circumcision is low. Despite the low incidence the effect on fertility, sexuality, ability to urinate and on psychological wellbeing is significant. Referral services to the urology department should be restructured to improve all outcomes. Keywords: Congenital genital abnormalities, circumcision, South Africa.

Background. Cervical cancer remains the second most common cancer among women worldwide, with much of the global burden occurring in low- and middle-income countries. HIV-infected women are at increased risk of human papillomavirus infection, preinvasive cervical disease and invasive cervical cancer (ICC). Funded through the United States President’s Emergency Plan for AIDS Relief (PEPFAR) and working in collaboration with the South African (SA) Department of Health, our team supports cervical screening integrated within public sector HIV clinics in SA. Objectives. To estimate the burden of cervical disease among HIV-infected women accessing screening services supported through our programme. Methods. We constructed conditional probability models to estimate the burden of grade 1 and grades 2/3 cervical intraepithelial lesions (CIN1 and CIN2/3) and ICC among two cohorts: one consisting of 3 190 HIV-infected women for whom only cytology results were available for analysis, and another consisting of 75 358 HIV-infected women for whom neither cytology nor histology results were available. Parameter estimates for the models were derived from routinely collected programmatic data and published clinical trials. Results. Between January 2009 and November 2015, 75 358 HIV-infected women underwent Pap smear screening in public sector clinics supported by our cervical cancer prevention programme. Based on modelling analysis, we estimate that 46 123 cases of CIN1 (range 45 500 - 49 608), 13 598 cases of CIN2/3 (range 12 749 - 14 828), and 104 cases of ICC (range 61 - 186) occurred in this population. Conclusions. Our findings highlight the magnitude of cervical disease among HIV-infected women in SA.

Adverse outcomes from breast cancer disproportionately affect women in sub-Saharan Africa, with delay the most studied contribution to advanced stage at presentation. However, tumor molecular biology and its contribution to advanced stage are yet to be explored.Patients newly diagnosed with breast cancer in a South African tertiary breast center completed a questionnaire and file review concerning socioeconomics, delay to care, stage at presentation, and molecular characteristics. Logistic regression was done to determine the relative risk of advanced stage presentation.Advanced stage was present in 70.1% (n = 162) of the 231 participants, with 55.8% stage III (n = 129) and 32% (n = 72) having a T4 tumor. The median age was 56 y with 21.6% (n = 47) aged45 y. Most common subtype was luminal B (57.7%, n = 128) followed by luminal A (21.6%, n = 48), triple negative (13.9%, n = 31), and HER2 positive (6.7%, n = 15). Lobular cancer (incidence risk ratio [IRR], 1.29; 95% confidence interval [CI], 1.03-1.62), high grade and intermediate grade tumors (IRR, 1.90; 95% CI, 1.15-3.13 and IRR, 1.95; 95% CI, 1.18-3.22, respectively), high Ki67 proliferation index (IRR, 1.30; 95% CI, 1.02-1.66), and HER2 overexpression (IRR, 1.32; 95% CI, 1.12-1.55) were more likely to present with advanced disease, as were luminal B (HER2+) cancers (adjusted IRR [aIRR], 1.46; 95% CI, 1.10-1.95). Although on univariate analysis Black and young participants were both more likely to have advanced stage (IRR, 1.23; 95% CI, 1.01-1.49 and IRR, 1.25; 95% CI, 1.04-1.51, respectively), in multivariate analysis controlling for tumor biology and delay, these were no longer significant (aIRR, 1.12; 95% CI, 0.91-1.37 and aIRR, 1.17; 95% CI, 0.94-1.48, respectively).Tumor biology has a compelling role in the etiology of advanced-stage disease irrespective of socioeconomic factors. Accurate pathologic assessment is important in planning breast cancer care in Africa.

Background Cervical cancer incidence is significant in countries, such as South Africa, with high burdens of both HIV and human papillomavirus (HPV). Cervical cancer is largely preventable if dysplasia is diagnosed and treated early, but there is debate regarding the best approaches for screening and treatment, especially for low-resource settings. Currently South Africa provides Pap smears followed by colposcopic biopsy and LEEP if needed in its public health facilities. We estimated the costs and cost-effectiveness of two approaches for treating cervical intraepithelial neoplasia grade 2 or higher (CIN2+) among HIV-infected women, most of whom were taking antiretroviral treatment, at a public HIV treatment facility in Johannesburg, South Africa. Methods Method effectiveness was derived from an intention-to-treat analysis of data gathered in a clinical trial completed previously at the study facility. In the trial, women who were diagnosed with CIN2+ and eligible for cryotherapy were randomized to cryotherapy or LEEP. If women were CIN2+ at six months as determined via Pap smear and colposcopic biopsy, all women-regardless of their original treatment assignment-received LEEP. "Cure" was then defined as the absence of disease at 12 months based on Pap smear and colposcopic biopsy. Health service costs were estimated using micro-costing between June 2013 and April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered, and results from an as-treated analysis were considered in sensitivity analysis. Results In total, 166 women with CIN2+ were enrolled (86 had LEEP; 80 had cryotherapy). At 12 months, cumulative loss to follow-up was 12.8% (11/86) for the LEEP group and 13.8% (11/80) for cryotherapy. Based on the unadjusted intention-to-treat analysis conducted for this economic evaluation, there was no significant difference in efficacy. At 12 months, 83.8% (95% CI 73.8-91.1) of women with CIN2+ at baseline and randomized to cryotherapy were free of CIN2+ disease. In contrast, 76.7% (95% CI 66.4-85.2) of women assigned to LEEP were free from disease. On average, women initially treated with cryotherapy were less costly per patient randomized at US$ 118.00 (113.91-122.10), and per case "cured" at US$ 140.90 (136.01-145.79). Women in the LEEP group cost US$ 162.56 (157.90-167.22) per patient randomized and US$ 205.59 (199.70-211.49) per case cured. In the as-treated analysis, which was based on trial data, LEEP was more efficacious than cryotherapy; however, the difference was not significant. Cryotherapy remained more cost-effective than LEEP in all sensitivity and scenario analyses. Conclusions For this cost-effectiveness analysis, using an intention-to-treat approach and taking into consideration uncertainty in the clinical and cost outcomes, a strategy involving cryotherapy plus LEEP if needed at six months was dominant to LEEP plus LEEP again at six months if needed for retreatment. However, compared to other studies comparing LEEP and cryotherapy, the efficacy results were low in both treatment groups-possibly due to the HIV-positivity of the participants. Further research is needed, but at present choosing the "right" treatment option may be less important than ensuring access to treatment and providing careful monitoring of treatment outcomes.

Worldwide, 50% of human immunodeficiency virus (HIV)-infected people are women. This study was to evaluate whether the safety and efficacy outcomes of three initial antiretroviral regimens (ARVs) differed by sex.Antiretroviral regimen naive participants from nine countries in four continents were assigned to ARVs with efavirenz (EFV) plus lamivudine-zidovudine, atazanavir (ATV) plus didanosine (ddI)-EC/emtricitabine (FTC) or EFV plus FTC-tenofovir-DF. The primary objective was to estimate the sex difference on efficacy outcome of treatment failure defined as one of the following: 1. Time to 1st of confirmed virologic failure, 2. WHO Stage 4 progression or 3. death with hazard ratio (HR) and 95% confidence interval (CI) from adjusted Cox regression models.In all, 739 (47%) women and 832 (53%) men with HIV were evaluated. Women had higher pretreatment CD4+(182 vs 165 cells/mm(3); P 0.001) and lower HIV-1 RNA (4.9 log10 vs 5.2 log10 copies/ml; P 0.001) compared to men. Association of sex with time to regimen failure differed by treatment arm (P = 0.018). For atazanavir plus didanosine-EC plus emtricitabine, women had a longer time to treatment failure compared to men [adjusted HR (aHR) = 0.59; 95% CI 0.40-0.87]. Women were less likely to prematurely discontinue treatment prematurely (aHR = 0.74; 95% CI 0.56-0.98). Women assigned to efavirenz plus lamivudine-zidovudine were more likely to have a primary safety event compared to men (aHR = 1.49; 95% CI 1.18-1.88).Antiretroviral efficacy and safety differed by sex in this study. Consideration of potential effects of sex on antiretroviral outcomes is important for the design of future clinical trials and for HIV treatment guidelines.

Quality assurance with cervicography and specialist review significantly improved the sensitivity of visual inspection with acetic acid to detect cervical intraepithelial neoplasia grade 2 or worse., Objective To determine whether a quality assurance (QA) program using digital cervicography improved the performance of a visual inspection with acetic acid (VIA) to detect cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) in HIV-infected women in Johannesburg, South Africa. Materials and Methods Visual inspection with acetic acid was performed among HIV-infected women, aged 18 to 65 years, in Johannesburg, South Africa. Nurses received 2 weeks of training on the VIA procedure. The VIA interpretation was performed in real time. The VIA results were then photographed using a retail available digital camera. A gynecologist and medical officer reviewed the VIA digital images within 2 weeks of the procedure. Colposcopic biopsy was performed on all women with positive VIA and 25% negative VIA results. Sensitivity and specificity of VIA for the detection of CIN 2+ were compared between the nurses and physicians at the beginning and at the end of the study. Results Positive VIA results were found in 541 (45%) of the 1,202 participating women. The sensitivity of VIA to predict CIN 2+ was improved from 65% to 75% (p = .001) with the addition of digital cervicography and specialist review. There was no statistical difference in the sensitivity of the VIA readings when comparing the first 600 participants to the final 593 participants between the nurses (p = .613) and physicians (p = .624). Conclusions Quality assurance performed by specialists using digital cervicography improved the sensitivity of VIA. There was no difference in sensitivity in interpreting VIA between the beginning and the end of the study. Quality assurance should form a cornerstone of any VIA program to improve sensitivity in detecting CIN 2+ lesions.

Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain. Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen. We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012–2014) and after (2015–2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider’s perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%. For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1 years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted. Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

Objective To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. Design We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. Results Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naive patients (aHR 3.40, 95%CI 2.90-3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). Conclusion In EDRweb, mortality is highest in the first few weeks after MDR/RR-TB treatment initiation.

Background HIV-infected women are at an increased risk of cervical cancer, especially in resource-limited countries. Cervical cancer prevention strategies focus treating cervical high-grade squamous intraepithelial lesions (HSIL). The management of low-grade squamous intraepithelial lesions (LSIL) in HIV-infected women is unknown. Setting HIV treatment clinic in Johannesburg, South Africa. Methods We randomized HIV-infected women with histologic cervical LSIL to cervical cryotherapy vs. no treatment (standard of care). Cervical high-risk human papillomavirus testing (hrHPV) was performed at baseline. All women underwent cervical cytology and colposcopic biopsies 12 months after enrollment. The primary end point was HSIL on histology at month 12. Chi-square was used to compare arms. Results Overall, 220 HIV-infected women were randomized to cryotherapy (n = 112) or no treatment (n = 108). Median age was 38 years, 94% were receiving antiretroviral therapy; median CD4 was 499 cells per cubic millimeter, and 59% were hrHPV positive. Cryotherapy reduced progression to HSIL: 2/99 (2%) in the cryotherapy arm and 15/103 (15%) in the no treatment arm developed HSIL, 86% reduction (95% confidence interval: 41% to 97%; P = 0.002). Among 17 HSIL end points, 16 were hrHPV+ at baseline. When restricting the analysis to hrHPV+ women, HSIL occurred in 2/61 (3%) in the cryotherapy arm vs. 14/54 (26%) in the no treatment arm, 87% reduction (95% confidence interval: 47% to 97%; P = 0.0004). Participants in the cryotherapy arm experienced greater regression to normal histology and improved cytologic outcomes. Conclusions Treatment of cervical LSIL with cryotherapy decreased progression to HSIL among HIV-infected women especially if hrHPV positive. These results support treatment of LSIL in human papillomavirus test-and-treat approaches for cervical cancer prevention in resource-constrained settings.

Age and sex effects on antiretroviral therapy (ART) response are not well elucidated. Our pooled analysis of 40 randomized clinical trials measured the association of age and sex on CD4+ T cell count changes and virologic suppression using multivariable regression modeling. The average increase in CD4+ T cell count from baseline to week 48 was 17.3 cells/mm3 lower and clinically insignificant (95% confidence interval −30.8 to −3.8) among women ages ≥ 50 years (n = 573), compared to women ≤ 35 years (n = 3,939). Results were similar for men. Virologic suppression odds were 60% and 21% times greater among participants ≥50 years compared to ≤35 years, in women and men, respectively. In both sexes, larger increases in CD4+ T cell count changes were observed in younger, compared to older, participants; however, virologic suppression was higher in older, compared to younger, participants suggesting a non-sex-specific age effect response to ART.

Purpose Breast cancer is the most common cause of cancer in women in South Africa, and often patients present late. There is little understanding of the psychosocial stresses affecting women with breast cancer in Africa. Methods A questionnaire was distributed to 263 patients with breast cancer at two sites (one government and one private facility) in Johannesburg. Self-reported levels of fear were recorded on summative scales and their relationship to demographic variables assessed through univariable and multivariable modified Poisson regression. Results Fears related to treatments and prognosis, particularly radiation, loss of hair, and loss of breast, were far stronger than those related to socioeconomic barriers. Relative risk (RR) of most fears was higher in women younger than age 40 years, including treatment affordability (RR, 1.80; 95% CI, 1.26 to 2.56), hair loss (RR, 1.48; 95% CI, 1.12 to 2.95), and surgery (RR, 1.31; 95% CI, 1.02 to 1.68). Difficulty taking time off work predicted fear of job loss (RR, 2.59; 95% CI, 1.59 to 4.21) and missing appointments because of transport (RR, 2.46; 95% CI, 1.52 to 3.96) or family commitments (RR, 2.46; 95% CI, 1.52 to 3.96). Women with dependents and black women were more afraid of dying (RR, 1.73; 95% CI, 1.03 to 2.90; and RR, 1.79; 95% CI, 1.33 to 2.24, respectively); however, socioeconomic status in this sample was a strong confounder of race and explained most of the racial differences in levels of fear. Conclusion The most significant fears around breast cancer were related to treatment modalities and adverse effects rather than transport, financial, or work concerns. Young age and job insecurity were predictive of increased fears. Education about treatments has a key role to play in improving access to breast cancer care in South Africa.

Breast cancer is the most common cancer affecting women in South Africa. There is little knowledge of beliefs to help identify key areas to improve support and education in this demographically and culturally diverse population. Women with a variety of demographic and socioeconomic characteristics accessing care for breast cancer were asked their agreement to statements of knowledge and beliefs about breast cancer. Of the 259 participants, positive statements of medical cure (87.9%) and family support (90.5%) were most commonly believed. Beliefs in faith-based cure and alternative treatments were also present (79.5 and 24.9%, respectively). Negative beliefs were initially more likely in black patients (RR: 11.57, 95%CI: 1.37-97.69) as was belief of cancer as a punishment (RR: 6.85, 95%CI: 1.41-33.21). However, in multivariate analysis adjusting for age, education and access to information (by newspaper, Internet and confidence in reading and writing), there was no difference between racial groups or hospital attended. Reading a newspaper or accessing the Internet was the most protective against belief that cancer was a punishment or curse (Internet use: aRR: 0.12, 95%CI: 0.02-0.99), belief in alternative methods of cure (newspaper use: aRR: 0.51, 95%CI: 0.27-0.96) and the negative beliefs of death and disfigurement (Internet use: aRR: 0.00, 95%CI: 0.00-0.00). Positive expressions of cure and beating cancer were found equally in all women. Attitudes and beliefs about cancer showed little independent demographic or socioeconomic variance. Negative beliefs were mitigated by access to information and confidence in literacy.

Data on invasive cervical cancer (ICC) incidence in HIV-positive women and the effect of cervical cancer screening in sub-Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004 and 2011 and ii) the effect of a Pap-based screening program. We included 10,640 women; median age at ART initiation: 35 years [interquartile range (IQR) 30-42], median CD4 count at ART initiation: 113 cells/µL (IQR 46-184). During 27,257 person-years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys [95% confidence interval (CI) 428-598]. The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005 and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onward when the cervical cancer screening program and access to treatment of cervical lesions was expanded [adjusted hazard ratio (aHR) 0.42, 95% CI 0.20-0.87]. Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17-3.24) and middle age at ART initiation (36-45 versus 18-25 years, aHR 2.51, 95% CI 1.07-5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap-based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV-positive women in sub-Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.

Background Anal cancer is a relatively common cancer among HIV-infected populations. There are limited data on the prevalence of anal high-risk human papillomavirus (HR-HPV) infection and anal dysplasia in HIV-infected women from resource-constrained settings. Methods A cross-sectional study of HIV-infected women aged 25-65 years recruited from an HIV clinic in Johannesburg, South Africa. Cervical and anal swabs were taken for conventional cytology and HR-HPV testing. Women with abnormal anal cytology and 20% of women with negative cytology were seen for high-resolution anoscopy with biopsy of visible lesions. Results Two hundred women were enrolled. Anal HR-HPV was found in 43%. The anal cytology results were negative in 51 (26%); 97 (49%) had low-grade squamous intraepithelial lesions (SIL), 32 (16%) had atypical squamous cells of unknown significance, and 19 (9.5%) had high-grade SIL or atypical squamous cells suggestive of high-grade SIL. On high-resolution anoscopy, 71 (36%) had atypia or low-grade SIL on anal histology and 17 (8.5%) had high-grade SIL. Overall, 31 (17.5%) had high-grade SIL present on anal cytology or histology. Abnormal cervical cytology was found in 70% and cervical HR-HPV in 41%. Conclusions We found a significant burden of anal HR-HPV infection, abnormal anal cytology, and high-grade SIL in our cohort. This is the first study of the prevalence of anal dysplasia in HIV-infected women from sub-Saharan Africa. Additional studies are needed to define the epidemiology of these conditions, as well as the incidence of anal cancer, in this population.

Background. Cervical cancer is a major cause of cancer-related deaths, especially in the context of the HIV epidemic. Objective. To examine awareness, perceived risk and practices related to cervical cancer screening among HIV-positive women. Methods. Interviewer-administered structured questionnaires were administered to HIV-positive women (aged ≥18 years) enrolled in a cervical cancer screening study at the Themba Lethu Clinic, Johannesburg, South Africa, from November 2009 to December 2011. Modified Poisson regression with robust standard errors was used to identify factors at enrolment associated with awareness, perceived risk and adequate practice related to cervical screening. Adjusted relative risks (aRRs) with 95% confidence intervals (CIs) are presented. Results. Of the 1 202 women enrolled, 71.3% and 18.2% were aware of the Pap smear and HPV, respectively. Of the 1 192 participants with data evaluated, 76.5% were worried and 23.5% were not worried about cervical cancer; 28.6% of the women had adequate screening practice. Older age (40 - 49 years or ≥50 years v. 18 - 29 years) (aRR 1.63, 95% CI 1.12 - 2.37; aRR 2.22, 95% CI 1.44 - 3.41), higher education (tertiary v. less than grade 10) (aRR 1.39, 95% CI 1.00 - 1.93), initiation on combination antiretroviral therapy (aRR 1.36, 95% CI 1.00 - 1.85) and awareness of Pap smear screening (aRR 16.18, 95% CI 7.69 - 34.01) were associated with adequate screening practice. Conclusions. High levels of Pap smear awareness and low levels of Pap smear screening uptake were observed. However, Pap smear awareness was associated with adequate screening practice. More research into effective health education programmes to address these gaps is needed.

Mortality associated with cervical cancer is a public health concern for women, particularly in HIV-seropositive women in resource-limited countries. HIV-seropositive women are at a higher risk of high-grade cervical precancer, which can eventually progress to invasive carcinoma as compared to HIV-seronegative women. It is imperative to identify effective treatment methods for high-grade cervical precursors among HIV-seropositive women.Randomized controlled trial data are needed comparing cryotherapy vs loop electrosurgical excision procedure treatment efficacy in HIV-seropositive women. Our primary aim was to compare the difference in the efficacy of loop electrosurgical excision procedure vs cryotherapy for the treatment of high-grade cervical intraepithelial neoplasia (grade ≥2) among HIV-seropositive women by conducting a randomized clinical trial.HIV-seropositive women (n = 166) aged 18-65 years with histology-proven cervical intraepithelial neoplasia grade ≥2 were randomized (1:1) to cryotherapy or loop electrosurgical excision procedure treatment at a government hospital in Johannesburg. Treatment efficacy was compared using 6- and 12-month cumulative incidence posttreatment of: (1) cervical intraepithelial neoplasia grade ≥2; (2) secondary endpoints of histologic cervical intraepithelial neoplasia grade ≥3 and grade ≥1; and (3) high-grade and low-grade cervical cytology. The study was registered (ClinicalTrials.govNCT01723956).From January 2010 through August 2014, 166 participants were randomized (86 loop electrosurgical excision procedure; 80 cryotherapy). Cumulative cervical intraepithelial neoplasia grade ≥2 incidence was higher for cryotherapy (24.3%; 95% confidence interval, 16.1-35.8) than loop electrosurgical excision procedure at 6 months (10.8%; 95% confidence interval, 5.7-19.8) (P = .02), although by 12 months, the difference was not significant (27.2%; 95% confidence interval, 18.5-38.9 vs 18.5%; 95% confidence interval, 11.6-28.8, P = .21). Cumulative cervical intraepithelial neoplasia grade ≥1 incidence for cryotherapy (89.2%; 95% confidence interval, 80.9-94.9) did not differ from loop electrosurgical excision procedure (78.3%; 95% confidence interval, 68.9-86.4) at 6 months (P = .06); cumulative cervical intraepithelial neoplasia grade ≥1 incidence by 12 months was higher for cryotherapy (98.5%; 95% confidence interval, 92.7-99.8) than loop electrosurgical excision procedure (89.8%; 95% confidence interval, 82.1-95.2) (P = .02). Cumulative high-grade cytology incidence was higher for cryotherapy (41.9%) than loop electrosurgical excision procedure at 6 months (18.1%, P.01) and 12 months (44.8% vs 19.4%, P.001). Cumulative incidence of low-grade cytology or greater in cryotherapy (90.5%) did not differ from loop electrosurgical excision procedure at 6 months (80.7%, P = .08); by 12 months, cumulative incidence of low-grade cytology or greater was higher in cryotherapy (100%) than loop electrosurgical excision procedure (94.8%, P = .03). No serious adverse effects were recorded.Although rates of cumulative cervical intraepithelial neoplasia grade ≥2 were lower after loop electrosurgical excision procedure than cryotherapy treatment at 6 months, both treatments appeared effective in reducing cervical intraepithelial neoplasia grade ≥2 by70% by 12 months. The difference in cumulative cervical intraepithelial neoplasia grade ≥2 incidence between the 2 treatment methods by 12 months was not statistically significant. Relatively high cervical intraepithelial neoplasia grade ≥2 recurrence rates, indicating treatment failure, were observed in both treatment arms by 12 months. A different treatment protocol should be considered to optimally treat cervical intraepithelial neoplasia grade ≥2 in HIV-seropositive women.

Objectives: To evaluate an external quality assurance (EQA) program for the laboratory diagnosis of human papillomavirus (HPV) disease that was established to improve international research capability within the Division of AIDS at the National Institute of Allergy and Infectious Disease–supported Adult AIDS Clinical Trials Group network. Methods: A three-component EQA scheme was devised comprising assessments of diagnostic accuracy of cytotechnologists and pathologists using available EQA panels, review of quality and accuracy of clinical slides from local sites by an outside expert, and HPV DNA detection using a commercially available HPV test kit. Results: Seven laboratories and 17 pathologists in Africa, India, and South America participated. EQA scores were suboptimal for EQA proficiency testing panels in three of seven laboratories. There was good agreement between the local laboratory and the central reader 70% of the time (90% confidence interval, 42%-98%). Performance on the College of American Pathologists’ HPV DNA testing panel was successful in all laboratories tested. Conclusions: The prequalifying EQA round identified correctable issues that will improve the laboratory diagnosis of HPV-related cervical disease at the participating international study sites and will provide a mechanism for ongoing education and continuous quality improvement. Cervical cancer is the third most common cancer in women globally, and most of the burden occurs in resourcelimited settings. These areas have a disproportionate mortality: the age-specific mortality rates for women in resourcelimited countries are at least triple those of women in resource-rich environments. Human immunodeficiency virus (HIV)–infected women bear a greater burden of disease than uninfected women, and the high mortality rates from cervical cancer in the younger age groups in resource-limited countries

Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

In resource-limited settings, where genotypic drug resistance testing is rarely performed and poor adherence is the most common reason for treatment failure, programmatic approaches to handling treatment failure are essential. This study was performed to describe one such approach to adherence optimisation.This was a single-arm study of patients on second-line protease inhibitor (PI)-based antiretroviral therapy (ART) with a HIV-1 RNA ≥400 copies/ml in Johannesburg, South Africa, between 1 March 2012 and 1 December 2013. Patients underwent enhanced adherence counselling. Those with improved adherence and a repeat viral load of1000 copies/ml underwent HIV-1 drug resistance testing. We describe results using simple proportions and 95% confidence intervals.Of the 400 patients who underwent targeted adherence counselling after an elevated viral load on second-line ART, 388 (97%) underwent repeat viral load testing. Most of these (n = 249; 64%, 95% CI 59-69) resuppressed (400 copies/ml) on second line. By the end of follow-up (1 March 2014), among the 139 (36%, 95% CI: 31-41%), who did not initially resuppress after being targeted, 106 had a viral load400 copies/ml, 11 switched to third line, 5 were awaiting third line, 4 had died and 13 were lost to follow-up. Among the unsuppressed, 48 successfully underwent resistance testing with some resistance detected in most (41/48).Most (64%) second-line treatment failure in this clinic is related to adherence and can be overcome with careful adherence support. Controlled interventions are needed to determine what the optimal approach is to improving second-line outcomes and reducing the need for third-line ART.

Background The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation. Methods Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa. Results Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%. Conclusions In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

Background: Many women undergoing cervical screening as part of a national South African screening programme may be positive for HIV. The performance of liquid-based cytology (LBC) on samples from HIV-positive women needs to be determined. Objectives: The performance of the Cellslide ® automated LBC system was evaluated as a possible alternative to conventional cytology in a national cervical cancer screening programme. Methods: Split samples from 348 HIV-positive women attending an HIV treatment clinic in Johannesburg, South Africa were examined by conventional cytology and monolayer LBC methods. All samples were stained, examined and reported in the same manner. Cytotechnologists were blinded to the conventional smear diagnosis if the LBC smear was screened and vice versa. Results: The same percentage of inadequate smears (1.4%) was obtained by conventional cytology and LBC. Atypical squamous cells of undetermined significance were observed in 5.2% of conventional smears and 4.0% of LBC smears. Low-grade squamous intraepithelial lesions were found in 35.6% of conventional smears and 32.7% of LBC smears. Only one conventional smear was categorised as atypical squamous cells – cannot exclude a high-grade lesion, whereas five such cases were identified on LBC. High-grade squamous intraepithelial lesions were seen in 21.6% of conventional smears and 23.3% LBC smears. No invasive carcinoma was identified. Conclusion: The performance of the Cellslide ® LBC system was similar to that of conventional cytology in this population of high-risk HIV-positive women, indicating that it may be introduced successfully as part of a cervical cancer screening programme.

Background According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa. Methods We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment. Results Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm 3 and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30–5.84 and sHR: 3.07, 95 % CI: 1.46–6.46, respectively). Conclusion Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment.

OBJECTIVE: Recent studies have raised concerns about a change in rates of pregnancy among HIV-negative women exposed to tenofovir. Here our objective was to determine among HIV-positive women whether use of tenofovir at HAART initiation or thereafter is associated with subsequent changes in incidence of pregnancy. DESIGN: Analysis of prospectively collected clinical data. METHODS: We used Cox proportional hazards models and logistic regression to estimate hazard ratios and odds ratios for the association of baseline tenofovir use and first incident pregnancy. We used marginal structural Cox models to estimate hazard ratios for the association of current tenofovir use and time to first incident pregnancy. RESULTS: We studied 7275 women of whom 1199 were initiated on tenofovir-based HAART regimens and who experienced a total of 894 pregnancies in 17200 person-years of follow-up. Analyses showed slight reductions in hazards of pregnancy among women who used tenofovir but without sufficient precision to draw strong conclusions. Sensitivity analyses confirmed main results. CONCLUSIONS: Tenofovir may be associated with a lower hazard or rate of pregnancy in women receiving HAART. However conclusions are limited by low precision the observational nature of the data and possible uncontrolled confounding by temporal trends in contraception use and other factors.

BACKGROUND: Our objective was to test the hypothesis that treatment for trichomoniasis among HIV-infected women not taking antiretrovirals in South Africa would be associated with decreased HIV genital shedding. METHODS: HIV-infected women presenting for routine HIV care were screened for trichomoniasis using self-collected vaginal swabs with a rapid point-of-care immunochromatographic antigen test. Women testing positive were offered enrollment into a prospective cohort study if they had documented HIV infection were aged 18 to 50 years and were not receiving antiretroviral therapy. Recent use of postexposure prophylaxis or antibiotic therapy active genital ulcers or systemic illness were exclusion criteria. Cervical swabs were collected for gonococcal and chlamydial testing and those testing positive were excluded. Women were treated with directly observed oral therapy with 2 g of oral metronidazole. A follow-up visit was scheduled 1 month after therapy and partner letters were provided. Paired cervical wicks and plasma were collected for viral load measurement. RESULTS: In all 557 women were screened. Sixty tested positive for trichomoniasis 10 subsequently met exclusion criteria and 4 were lost to follow-up. Of 46 women evaluated at follow-up 37 (80.4%) were cured. Plasma viral load was not significantly different after therapy (P = 0.93). Genital tract viral load decreased by 0.5 log10 (P < 0.01). The mean genital tract viral load (log10) decreased from 4.66 (

Summary Objectives Hepatitis B virus (HBV) infection with undetectable hepatitis B surface antigen (HBsAg) has been reported in HIV patients, but the clinical significance is unknown. This study presents the prevalence of HBV DNA in HIV-positive patients negative for all HBV serological markers and a retrospective evaluation of the clinical course of mono- and co-infection. Methods Of 502 HIV-positive patients, 222 tested negative for HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). An in-house real-time PCR targeting the HBV S-region was used to quantify HBV DNA. HBV isolates were genotyped. Baseline demographic and clinical characteristics of HBV DNA-positive and HBV DNA-negative patients were described. Treatment outcomes of patients at 6, 12, and 24 months after initiation of antiretroviral therapy (ART) were summarized. Results HBV DNA was detected in 5.4% (12/222) of serologically negative patients. Mean HBV viral load was 5359.2 IU/ml (standard deviation (SD) ±12 768.27). Eleven HBV isolates belonged to genotype A and one to genotype C. There were no significant differences in baseline characteristics or clinical course between the HBV DNA-positive and HBV DNA-negative groups. Conclusions We found 5.4% of the HBV serologically-negative HIV-positive patients had low levels of HBV DNA. There were no significant differences in clinical outcome between the mono- and co-infected groups.

Background Many resource limited settings (RLS) suffer from high rates of both cervical cancer and HIV. Limited HPV serology data are available from RLS; such data could help describe local patterns of HPV infection and predict vaccine efficacy. Objectives To determine seropositivity to HPV types 6, 11, 16 and 18 in HIV-infected women from South Africa (SA), Botswana and Brazil. Study design HPV serotyping for high-risk types 6, 11, 16 and 18 was performed on samples collected from HIV-infected women from 2003–2010 using competitive Luminex Immuno Assay (HPV-4cLIA). We examined the association between seropositivity to these HPV types and country of enrollment, CD4, HIV-1 RNA level, and Pap smear. Results HPV serology results were available for 487 HIV-infected women (157, 170 and 160 from SA, Botswana and Brazil respectively). Approximately 65% of women had serum antibodies to one of the 4 HPV types and less than 3% of women had antibodies all 4 serotypes. Approximately 30% women demonstrated antibodies to type 16 HPV. Rates of seropositivity to HPV 11, and HPV 16+18 varied significantly between countries. Statistical difference was also shown in women in different age categories in the different countries. There was no difference in serology results compared by CD4 count, HIV viral load or Pap smear results. Conclusions These data suggest that the quadrivalent vaccine may be effective in preventing HPV infection in these countries.