A Randomized Clinical Trial of Human Papillomavirus Test-and-Treat as Compared to Cytology-Based Screening for Prevention of Cervical Cancer Among Women With Human Immunodeficiency Virus: AIDS Clinical Trials Group Protocol A5282.

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

A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug-Drug Interactions With Antiretroviral and Antituberculosis Treatment.

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 (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

Human Papillomavirus Vaccination Prior to Loop Electroexcision Procedure Does Not Prevent Recurrent Cervical High-grade Squamous Intraepithelial Lesions in Women Living With Human Immunodeficiency Virus: A Randomized, Double-blind, Placebo-controlled Trial.

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.

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus-positive and -Negative Cervical Precancers.

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.

Plasma and antibody glycomic biomarkers of time to HIV rebound and viral setpoint.

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 (Galß1-3GalNAc) (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.

Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency.

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 (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. 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 <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. 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.

Breast abnormalities in adolescents receiving antiretroviral therapy.

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.

Unraveling the South African Breast Cancer Story: The Relationship of Patients, Delay to Diagnosis, and Tumor Biology With Stage at Presentation in an Urban Setting.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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) aged <45 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). CONCLUSIONS: 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.

Gene expression profiling informs HPV cervical histopathology but not recurrence/relapse after LEEP in ART-suppressed HIV+HPV+ women.

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.

The relationship between menopausal women infected with the human immunodeficiency virus and cervical atrophy: A cytologic study.

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.

Anogenital human papillomavirus virus DNA and sustained response to the quadrivalent HPV vaccine in women living with HIV-1.

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 < 200 compared to 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.

Cost-Effectiveness of Cervical Cancer Screening in Women Living With HIV in South Africa: A Mathematical Modeling Study.

BACKGROUND: Women with HIV face an increased risk of human papillomavirus (HPV) acquisition and persistence, cervical intraepithelial neoplasia, and invasive cervical cancer. Our objective was to determine the cost-effectiveness of different cervical cancer screening strategies among women with HIV in South Africa. METHODS: We modified a mathematical model of HPV infection and cervical disease to reflect coinfection with HIV. The model was calibrated to epidemiologic data from HIV-infected women in South Africa. Clinical and economic data were drawn from in-country data sources. The model was used to project reductions in the lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs) of Pap and HPV DNA screening and management algorithms beginning at HIV diagnosis, at 1-, 2-, or 3-year intervals. Strategies with an ICER below South Africa's 2016 per capita gross domestic product (US$5270) were considered "cost-effective." RESULTS: HPV testing followed by treatment (test-and-treat) at 2-year intervals was the most effective strategy that was also cost-effective, reducing lifetime cancer risk by 56.6% with an ICER of US$3010 per year of life saved. Other cost-effective strategies included Pap (referral threshold: HSIL+) at 1-, 2-, and 3-year intervals, and HPV test-and-treat at 3-year intervals. Pap (ASCUS+), HPV testing with 16/18 genotyping, and HPV testing with Pap or visual triage of HPV-positive women were less effective and more costly than alternatives. CONCLUSIONS: Considering per capita gross domestic product as the benchmark for cost-effectiveness, HPV test-and-treat is optimal in South Africa. At lower cost-effectiveness benchmarks, Pap (HSIL+) would be optimal.

Age Differences by Sex in Antiretroviral-Naïve Participants: Pooled Analysis from Randomized Clinical Trials.

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.

Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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%. RESULTS: 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. CONCLUSION: 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.

The Effect of Access to Information on Beliefs Surrounding Breast Cancer 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.

Cryotherapy Reduces Progression of Cervical Intraepithelial Neoplasia Grade 1 in South African HIV-Infected Women: A Randomized, Controlled Trial.

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.

Prevalence of Anal Human Papillomavirus (HPV) and Performance of Cepheid Xpert and Hybrid Capture 2 (hc2) HPV Assays in South African HIV-Infected Women.

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.

Impact of Larger Sputum Volume on Xpert® MTB/RIF Assay Detection of Mycobacterium tuberculosis in Smear-Negative Individuals with Suspected Tuberculosis.

As a strategy to improve the sensitivity of nucleic acid-based testing in acid-fast bacilli (AFB) negative samples, larger volumes of sputum (5-10 mL) were tested with Xpert® MTB/RIF from 176 individuals with smear-negative sputum undergoing tuberculosis evaluation. Despite larger volumes, this strategy had a suboptimal sensitivity of 50% (4/8).

Fear of Treatments Surpasses Demographic and Socioeconomic Factors in Affecting Patients With Breast Cancer in Urban South Africa.

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.