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1.  Tuberculosis and Hepatic Steatosis Are Prevalent Liver Pathology Findings among HIV-Infected Patients in South Africa 
PLoS ONE  2015;10(2):e0117813.
Liver disease epidemiology in sub-Saharan Africa has shifted as a result of HIV and the increased use of antiretroviral therapy leading to a need for updated data on common causes of liver disease. We retrospectively reviewed records from all hospitalized patients who had liver biopsy at a single hospital in South Africa from 2001 to 2009 and compared diagnosis by HIV status. During the period of study 262 patients had liver biopsy, 108 (41%) were HIV-infected, 25 (10%) were HIV-sero-negative, and 129 (49%) had unknown or unrecorded HIV status. Overall 81% of biopsies provided additional diagnostic data. Malignancy was the most common finding reported on 56 (21%) biopsies followed by granuloma or TB, hepatic steatosis, and fibrosis or cirrhosis. HIV-infected patients were more likely to have granulomas and steatosis. Half of patients with granulomas were already on TB treatment, suggesting paradoxical reactions or drug induced liver injury may have been important causes of liver inflammation among these patients. We note that TB, paradoxical reactions during TB treatment, possible drug induced liver injury, and hepatic steatosis are important causes of liver pathology among HIV-infected hospitalized patients with unclear etiology of liver disease after initial assessment. Among HIV sero-negative patients, malignancy was the major cause of liver disease. Our findings re-enforce the importance of TB as a diagnosis among HIV-infected individuals.
doi:10.1371/journal.pone.0117813
PMCID: PMC4323253  PMID: 25668620
2.  Assessing cost and technical efficiency of HIV prevention interventions in sub-Saharan Africa: the ORPHEA study design and methods 
Background
Scaling up services to achieve HIV targets will require that countries optimize the use of available funding. Robust unit cost estimates are essential for the better use of resources, and information on the heterogeneity in the unit cost of delivering HIV services across facilities – both within and across countries – is critical to identifying and addressing inefficiencies. There is limited information on the unit cost of HIV prevention services in sub-Saharan Africa and information on the heterogeneity within and across countries and determinants of this variation is even more scarce. The “Optimizing the Response in Prevention: HIV Efficiency in Africa” (ORPHEA) study aims to add to the empirical body of knowledge on the cost and technical efficiency of HIV prevention services that decision makers can use to inform policy and planning.
Methods/Design
ORPHEA is a cross-sectional observational study conducted in 304 service delivery sites in Kenya, Rwanda, South Africa, and Zambia to assess the cost, cost structure, cost variability, and the determinants of efficiency for four HIV interventions: HIV testing and counselling (HTC), prevention of mother-to-child transmission (PMTCT), voluntary medical male circumcision (VMMC), and HIV prevention for sex workers. ORPHEA collected information at three levels (district, facility, and individual) on inputs to HIV prevention service production and their prices, outputs produced along the cascade of services, facility-level characteristics and contextual factors, district-level factors likely to influence the performance of facilities as well as the demand for HIV prevention services, and information on process quality for HTC, PMTCT, and VMMC services.
Discussion
ORPHEA is one of the most comprehensive studies on the cost and technical efficiency of HIV prevention interventions to date. The study applied a robust methodological design to collect comparable information to estimate the cost of HTC, PMTCT, VMMC, and sex worker prevention services in Kenya, Rwanda, South Africa, and Zambia, the level of efficiency in the current delivery of these services, and the key determinants of efficiency. The results of the study will be important to decision makers in the study countries as well as those in countries facing similar circumstances and contexts.
doi:10.1186/s12913-014-0599-9
PMCID: PMC4260235
Cost; Economic evaluation; Technical efficiency; HIV; AIDS; Prevention; Testing; Male circumcision; PMTCT; Sex workers
3.  Factors associated with mortality in HIV-infected people in rural and urban South Africa 
Global Health Action  2014;7:10.3402/gha.v7.25488.
Background
Factors associated with mortality in HIV-infected people in sub-Saharan Africa are widely reported. However rural–urban disparities and their association with all-cause mortality remain unclear. Furthermore, commonly used classical Cox regression ignores unmeasured variables and frailty.
Objective
To incorporate frailty in assessing factors associated with mortality in HIV-infected people in rural and urban South Africa.
Design
Using data from a prospective cohort following 6,690 HIV-infected participants from Soweto (urban) and Mpumalanga (rural) enrolled from 2003 to 2010; covariates of mortality were assessed by the integrated nested Laplace approximation method.
Results
We enrolled 2,221 (33%) rural and 4,469 (67%) urban participants of whom 1,555 (70%) and 3,480 (78%) were females respectively. Median age (IQR) was 36.4 (31.0–44.1) in rural and 32.7 (28.2–38.1) in the urban participants. The mortality rate per 100 person-years was 11 (9.7–12.5) and 4 (3.6–4.5) in the rural and urban participants, respectively. Compared to those not on HAART, rural participants had a reduced risk of mortality if on HAART for 6–12 (HR: 0.20, 95% CI: 0.10–0.39) and >12 months (HR: 0.10, 95% CI: 0.05–0.18). Relative to those not on HAART, urban participants had a lower risk if on HAART >12 months (HR: 0.35, 95% CI: 0.27–0.46).
The frailty variance was significant and >1 in rural participants indicating more heterogeneity. Similarly it was significant but <1 in the urban participants indicating less heterogeneity.
Conclusion
The frailty model findings suggest an elevated risk of mortality in rural participants relative to the urban participants potentially due to unmeasured variables that could be biological, socio–economic, or healthcare related. Use of robust methods that optimise data and account for unmeasured variables could be helpful in assessing the effect of unknown risk factors thus improving patient management and care in South Africa and elsewhere.
doi:10.3402/gha.v7.25488
PMCID: PMC4185089  PMID: 25280741
HIV; Mortality; Rural; Urban; Frailty; HAART
4.  Maternal hepatitis B and infant infection among pregnant women living with HIV in South Africa 
Introduction
Globally, hepatitis B virus (HBV) infection is the leading cause of liver-related mortality. Newborn vaccination, maternal antiviral therapy and administering hepatitis B immune globulin shortly after birth can greatly reduce the risk of perinatal and infant infection. However, evidence-based policy regarding these interventions in Africa is hampered by gaps in knowledge of HBV epidemiology. We describe maternal chronic hepatitis B (CHB) prevalence and infant infection during the first year of life within a cohort of women living with HIV.
Methods
We recruited and prospectively followed pregnant women living with HIV and their infants from prenatal clinics in an urban area of South Africa. Hepatitis B surface antigen, anti-hepatitis B surface antibodies and HBV DNA were assessed in all women. Hepatitis B testing was also performed at 6 and 52 weeks for all infants born to mothers with either positive surface antigen or detectable HBV DNA.
Results
We enrolled 189 women with a median age of 29 years and median CD4 count of 348 cells/mm3. Fourteen had a positive surface antigen (7.4%), of which six were positive for “e” antigen. An additional three had detectable HBV DNA without positive surface antigen. One infant developed CHB and three others had evidence of transmission based on positive HBV DNA assays. HBV vaccinations were delivered at six weeks of life to all infants.
Conclusions
Our findings highlight the risk of peripartum HBV transmission in this setting. Approaches to reducing this transmission should be considered.
doi:10.7448/IAS.17.1.18871
PMCID: PMC4032505  PMID: 24855985
HIV; HBV; peripartum; transmission; vaccination; Africa; occult HBV
5.  CD4 and Viral Load Dynamics in Antiretroviral-Naïve HIV-Infected Adults from Soweto, South Africa: A Prospective Cohort 
PLoS ONE  2014;9(5):e96369.
Background
CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates.
Methods
HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored.
Results
1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm3 (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm3 per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml.
Conclusions
Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART.
doi:10.1371/journal.pone.0096369
PMCID: PMC4022663  PMID: 24831447
6.  A comparative assessment of the price, brands and pack characteristics of illicitly traded cigarettes in five cities and towns in South Africa 
BMJ Open  2014;4(5):e004562.
Objective
The prevalence of illicitly traded cigarettes in South Africa has been reported to be 40–50%. However, these estimates do not account for the more nuanced characteristics of the illicit cigarette trade. With the goal of better understanding contraband cigarettes in South Africa, this study piloted three methods for assessing the price, brands, pack features and smoker's views about illicit cigarettes in five cities/towns. Data were collected in June and July 2012.
Setting
A convenience sample of three South African cities (Johannesburg, Durban and Nelspruit) and two smaller towns (Musina and Ficksburg) were chosen for this study.
Outcome measures
Three cross-sectional approaches were used to assess the characteristics of contraband cigarettes: (1) a dummy purchase of cigarettes from informal retailers, (2) the collection of discarded cigarette packs and (3) a survey of tobacco smokers.
Participants
For the purposes of the survey, 40 self-reported smokers were recruited at taxi ranks in each downtown site. Adults who were over the age of 18 were asked to verbally consent to participate in the study and answer a questionnaire administered by a researcher.
Results
The leading reason for labelling a pack as illicit in each city/town was the absence of an excise stamp (28.6% overall), and the least common reason was an illegal tar or nicotine level (11.1% overall). The overall proportion of informal vendors who sold illicit cigarettes was 41%. Singles and packs of 20 were consistently cheaper at informal vendors. Survey participants’ responses reflected varied perspectives on illicit cigarettes and purchasing preferences.
Conclusions
Each approach generated an interesting insight into physical aspects of illicit cigarettes. While this pilot study cannot be used to generate generalisable statistics on illicit cigarettes, more systematic surveys of this nature could inform researchers’ and practitioners’ initiatives to combat illicit and legal cigarette sales and usage.
doi:10.1136/bmjopen-2013-004562
PMCID: PMC4025410  PMID: 24812192
Health Economics; Public Health; Qualitative Research; Statistics & Research Methods
7.  Mortality associated with delays between clinic entry and ART initiation in resource-limited-settings: results of a transition-state model 
Objective
Estimate the mortality impact of delay in antiretroviral therapy (ART) initiation from the time of entry-into-care.
Design
A state-transition Markov process model. This technique allows for assessing mortality before and after ART initiation associated with delays in ART initiation among a general population of ART eligible patients without conducting a randomized trial.
Methods
We used patient-level data from three South African cohorts to determine transition probabilities for pre-ART CD4 count changes and pre-ART and on-ART mortality. For each parameter we generated probabilities and distributions for Monte Carlo simulations with one week cycles to estimate mortality 52 weeks from clinic entry.
Results
We estimated an increase in mortality from 11.0% to 14.7% (relative increase of 34%) with a 10 week delay in ART for patients entering care with our pre-ART cohort CD4 distribution. When we examined low CD4 ranges, the relative increase in mortality delays remained similar; however, the absolute increase in mortality rose. For example, among patients entering with CD4 count 50–99 cells/mm3, 12 month mortality increased from 13.3% with no delay compared to 17.0% with a 10 week delay and 22.9% with a 6 month delay.
Conclusions
Delays in ART initiation, common in routine HIV programs, can lead to important increases in mortality. Prompt ART initiation for patients entering clinical care and eligible for ART, especially those with lower CD4 counts, could be a relatively low cost approach with a potential marked impact on mortality.
doi:10.1097/QAI.0b013e3182893fb4
PMCID: PMC3647455  PMID: 23392457
ART delay; Africa; CD4 count; mortality; state-transition model
8.  Incidence of TB and HIV in Prospectively Followed Household Contacts of TB Index Patients in South Africa 
PLoS ONE  2014;9(4):e95372.
Objective
To report the incidence rates of TB and HIV in household contacts of index patients diagnosed with TB.
Design
A prospective cohort study in the Matlosana sub-district of North West Province, South Africa.
Methods
Contacts of index TB patients received TB and HIV testing after counseling at their first household visit and were then followed up a year later, in 2010. TB or HIV diagnoses that occurred during the period were determined.
Results
For 2,377 household contacts, the overall observed TB incidence rate was 1.3 per 100 person years (95% CI 0.9–1.9/100py) and TB incidence for individuals who were HIV-infected and HIV seronegative at baseline was 5.4/100py (95% CI 2.9–9.0/100py) and 0.7/100py (95% CI 0.3–1.4/100py), respectively. The overall HIV incidence rate was 2.2/100py (95% CI 1.3–8.4/100py).
Conclusions
In the year following a household case finding visit when household contacts were tested for TB and HIV, the incidence rate of both active TB and HIV infection was found to be extremely high. Clearly, implementing proven strategies to prevent HIV acquisition and preventing TB transmission and progression to disease remains a priority in settings such as South Africa.
doi:10.1371/journal.pone.0095372
PMCID: PMC3997400  PMID: 24759741
9.  CD4 Counts and Viral Loads of Newly Diagnosed HIV-Infected Individuals: Implications for Treatment as Prevention 
PLoS ONE  2014;9(3):e90754.
Objective
To report the viral load and CD4 count in HIV-infected, antiretroviral naïve, first -time HIV-testers, not immediately eligible for treatment initiation by current South Africa treatment guidelines.
Design
This was a cross-sectional study in a high-volume, free-of-charge HIV testing centre in Soweto, South Africa.
Methods
We enrolled first time HIV testers and collected demographic and risk-behaviour data and measured CD4 count and viral load.
Results
Between March and October 2011, a total of 4793 adults attended VCT and 1062 (22%) tested positive. Of the 1062, 799 (75%) were ART naïve and 348/799 (44%) were first-time HIV testers. Of this group of 348, 225 (65%) were female. Overall their median age, CD4 count and viral load was 34 years (IQR: 28-41), 364 (IQR: 238-542) cells/mm3 and 13,000 (IQR: 2050-98171) copies/ml, respectively. Female first time HIV testers had higher CD4 counts (419 IQR: 262-582 vs. 303 IQR: 199-418 cells/mm3) and lower viral loads (9,100 vs. 34,000 copies/ml) compared to males. Of 183 participants with CD4 count >350 cells/mm3, 62 (34%) had viral loads > 10,000 copies/ml.
Conclusions
A large proportion of HIV infected adults not qualifying for immediate ART at the CD4 count threshold of 350 cells/mm3 have high viral loads. HIV-infected men at their first HIV diagnosis are more likely to have lower CD4 counts and higher viral loads than women.
doi:10.1371/journal.pone.0090754
PMCID: PMC3942485  PMID: 24595317
10.  Rates and cost of hospitalisation before and after initiation of antiretroviral therapy in urban and rural settings in South Africa 
Few studies have compared hospitalisations before and after antiretroviral therapy (ART) initiation in the same patients. We analysed the cost of hospitalisations among 3,906 adult patients in two South African hospitals, 30% of whom initiated ART. Hospitalisations were 50% and 40% more frequent and 1.5 and 2.6 times more costly at a CD4 cell count <100 cells/mm3 when compared to 200–350 cells/mm3 in the pre-ART and ART period, respectively. Mean inpatient cost per patient year was USD 117 (95% confidence interval, CI, 85–158) for patients on ART and USD 72 (95% CI, 56–89) for pre-ART patients. Raising ART eligibility thresholds could avoid the high cost of hospitalisation before and immediately after ART initiation.
doi:10.1097/QAI.0b013e31827e8785
PMCID: PMC3625673  PMID: 23187948
hospitalisation; in-patient; admission; resource-limited setting; pre-ART
11.  The Clinical and Economic Impact of Genotype Testing at First-line Antiretroviral Therapy Failure for HIV-Infected Patients in South Africa 
Using a computer simulation of human immunodeficiency virus infection we project that genotype resistance testing at first-line antiretroviral therapy failure is very cost-effective in South Africa. The cost-effectiveness will depend on prevalence of wild-type virus and timely response to genotype results.
Background. In resource-limited settings, genotype testing at virologic failure on first-line antiretroviral therapy (ART) may identify patients with wild-type (WT) virus. After adherence counseling, these patients may safely and effectively continue first-line ART, thereby delaying more expensive second-line ART.
Methods. We used the Cost-Effectiveness of Preventing AIDS Complications International model of human immunodeficiency virus (HIV) disease to simulate a South African cohort of HIV-infected adults at first-line ART failure. Two strategies were examined: no genotype vs genotype, assuming availability of protease inhibitor–based second-line ART. Model inputs at first-line ART failure were mean age 38 years, mean CD4 173/µL, and WT virus prevalence 20%; genotype cost was $300 per test and delay to results, 3 months. Outcomes included life expectancy, per-person costs (2010 US dollars), and incremental cost-effectiveness ratios (dollars per years of life saved [YLS]).
Results. No genotype had a projected life expectancy of 106.1 months, which with genotype increased to 108.3 months. Per-person discounted lifetime costs were $16 360 and $16 540, respectively. Compared to no genotype, genotype was very cost-effective, by international guidance, at $900/YLS. The cost-effectiveness of genotype was sensitive to prevalence of WT virus (very cost-effective when prevalence ≥12%), CD4 at first-line ART failure, and ART efficacy. Genotype-associated delays in care ≥5 months decreased survival and made no genotype the preferred strategy. When the test cost was <$100, genotype became cost-saving.
Conclusions. Genotype resistance testing at first-line ART failure is very cost-effective in South Africa. The cost-effectiveness of this strategy will depend on prevalence of WT virus and timely response to genotype results.
doi:10.1093/cid/cis887
PMCID: PMC3552524  PMID: 23087386
HIV; resistance testing; antiretroviral treatment failure; resource-limited settings
12.  A Review of the Study Designs and Statistical Methods Used in the Determination of Predictors of All-Cause Mortality in HIV-Infected Cohorts: 2002–2011 
PLoS ONE  2014;9(2):e87356.
Background
Research in the predictors of all-cause mortality in HIV-infected people has widely been reported in literature. Making an informed decision requires understanding the methods used.
Objectives
We present a review on study designs, statistical methods and their appropriateness in original articles reporting on predictors of all-cause mortality in HIV-infected people between January 2002 and December 2011. Statistical methods were compared between 2002–2006 and 2007–2011. Time-to-event analysis techniques were considered appropriate.
Data Sources
Pubmed/Medline.
Study Eligibility Criteria
Original English-language articles were abstracted. Letters to the editor, editorials, reviews, systematic reviews, meta-analysis, case reports and any other ineligible articles were excluded.
Results
A total of 189 studies were identified (n = 91 in 2002–2006 and n = 98 in 2007–2011) out of which 130 (69%) were prospective and 56 (30%) were retrospective. One hundred and eighty-two (96%) studies described their sample using descriptive statistics while 32 (17%) made comparisons using t-tests. Kaplan-Meier methods for time-to-event analysis were commonly used in the earlier period (n = 69, 76% vs. n = 53, 54%, p = 0.002). Predictors of mortality in the two periods were commonly determined using Cox regression analysis (n = 67, 75% vs. n = 63, 64%, p = 0.12). Only 7 (4%) used advanced survival analysis methods of Cox regression analysis with frailty in which 6 (3%) were used in the later period. Thirty-two (17%) used logistic regression while 8 (4%) used other methods. There were significantly more articles from the first period using appropriate methods compared to the second (n = 80, 88% vs. n = 69, 70%, p-value = 0.003).
Conclusion
Descriptive statistics and survival analysis techniques remain the most common methods of analysis in publications on predictors of all-cause mortality in HIV-infected cohorts while prospective research designs are favoured. Sophisticated techniques of time-dependent Cox regression and Cox regression with frailty are scarce. This motivates for more training in the use of advanced time-to-event methods.
doi:10.1371/journal.pone.0087356
PMCID: PMC3911971  PMID: 24498313
13.  Cotrimoxazole Prophylaxis and Tuberculosis Risk among People Living with HIV 
PLoS ONE  2014;9(1):e83750.
Objectives
Many randomized and cohort studies have reported a survival benefit with cotrimoxazole prophylaxis without detecting a difference in tuberculosis (TB) incidence by cotrimoxazole status. However, several in vitro studies have reported that cotrimoxazole possesses anti-TB activity. We sought to compare TB incidence and TB diagnostic yield by cotrimoxazole use among participants in a well characterized cohort of HIV-infected adults living in a high TB prevalence region.
Methods
We analyzed prospective data from a long-term longitudinal cohort of adults receiving HIV care and TB investigations in Soweto, South Africa. Using longitudinal analysis, we compared total and laboratory confirmed TB incidence by cotrimoxazole status as well as all-cause mortality. In addition, we compared TB culture results by cotrimoxazole status.
Results
In a multivariable analysis, adjusted for sex, body mass index, WHO clinical stage, time-updated CD4 count, and antiretroviral therapy status, we observed an association between cotrimoxazole and an increase in TB incidence (hazard ratio 1.7, 95% CI: 1.2, 2.2). However, when restricted to laboratory-confirmed TB, there was no association between cotrimoxazole and TB incidence (hazard ratio: 0.97, 95% CI: 0.39, 2.4). In TB cases, we found no difference in the proportion of positive sputum cultures or days to culture positivity by cotrimoxazole status. Cotrimoxazole was associated with a reduction in mortality.
Conclusions
In this cohort with a mortality benefit from cotrimoxazole, we found an increased risk of all TB among individuals using cotrimoxazole, likely a result of residual confounding, but no association between use of cotrimoxazole and laboratory-confirmed TB. Cotrimoxazole did not compromise TB diagnosis.
doi:10.1371/journal.pone.0083750
PMCID: PMC3885446  PMID: 24421903
14.  Sexual Behavior and Reproductive Health Among HIV-Infected Patients in Urban and Rural South Africa 
Journal of acquired immune deficiency syndromes (1999)  2008;47(4):10.1097/QAI.0b013e3181648de8.
Background
With the rollout of antiretroviral therapy in South Africa and its potential to prolong the lives of HIV-infected individuals, understanding the sexual behavior of HIV-positive people is essential to curbing secondary HIV transmission.
Methods
We surveyed 3819 HIV-positive patients during their first visit to an urban wellness clinic and a rural wellness clinic.
Results
Urban residents were more likely than rural residents to have current regular sex partners (75.1% vs. 46.0%; χ2 odds ratio [OR] = 3.531; P < 0.001), to have any current sexual partners (75.3% vs. 51.2%; χ2 OR = 2.908; P < 0.001), and to report consistent condom use with regular partners (78.4% vs. 48.3%; χ2 OR = 3.886; P < 0.001) and with casual partners (68.6% vs. 48.3%; χ2 OR = 2.337; P < 0.001). In multivariate analysis, independent predictors of consistent condom use with regular partners included across gender, urban residence, and higher education levels; for women, disclosure and younger age; and for men only, no history of alcohol consumption. Male and female participants with a casual sexual partner were less likely to use a condom consistently with regular partners. Additionally, urban residence and a CD4 count greater than 200 cells/mm3 as well as (for women only) a higher household income and a history of alcohol consumption were predictors of having a regular sexual partner.
Conclusions
HIV prevention programs in South Africa that emphasize the importance of condom use and disclosure and are tailored to the needs of their attending populations are critical given the potential for HIV-infected individuals to resume risky sexual behavior with improving health.
doi:10.1097/QAI.0b013e3181648de8
PMCID: PMC3811008  PMID: 18209685
condom use; HIV prevention; positive prevention; sexual behavior; South Africa; urban-rural
15.  Prevalence and Associations with Hepatitis B and Hepatitis C infection Amongst HIV-infected Adults in South Africa 
International journal of STD & AIDS  2012;23(10):e10-e13.
We assessed prevalence and factors associated with hepatitis B in a cross-section of HIV-infected primary care and anti-natal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years, and median CD4 count was 354 cells/mm3. HBsAg ELISA, anti-hepatitis B core (HBc) antibodies, and hepatitis C virus antibody were positive among 4.2%, 37%, and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines, and higher CD4. HBsAg positivity was associated with lower CD4. Compared to the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found subjects with HBsAg positivity had lower CD4 counts.
doi:10.1258/ijsa.2009.009340
PMCID: PMC3724418  PMID: 23104758
HIV/AIDS; HBV; HBsAg; HCV; rapid test; Africa
16.  Increased regression and decreased incidence of human papillomavirus-related cervical lesions among HIV-infected women on HAART 
AIDS (London, England)  2012;26(13):1645-1652.
Objective
To determine the impact of HAART on incidence, regression, and progression of cytopathological abnormalities in HIV-infected women.
Design
Prospective cohort.
Methods
HIV-infected women (N=1123) from Soweto, South Africa underwent serial cervical smears that were analyzed and reported using the Bethesda System. The results of HAART and non-HAART users were compared using two statistical approaches: a survival analysis assessing risk of incident smear abnormality among women with baseline normal smear results; and analysis with marginal models assessing for an association between HAART use and likelihood of regression/progression in consecutive smears.
Results
After multivariate survival analysis, women using HAART with a normal baseline smear were 38% less likely to have an incident smear abnormality during follow-up than nonusers [confidence interval (CI) 0.42–0.91; P=0.01]. Multivariate marginal models analysis identified a significantly increased likelihood (odds ratio 2.61; CI 1.75–3.89; P< 0.0001) of regression of cervical lesions among women on HAART.
Conclusion
Our large prospective cohort study adds significant weight to the side of the balance of clinical research supporting the positive impact of HAART on the natural history of human papillomavirus-related cervical disease in HIV-infected women.
doi:10.1097/QAD.0b013e32835536a3
PMCID: PMC3709565  PMID: 22555167
cervical cancer; disease progression; disease regression; HAART; Papanicolaou smear
17.  High Prevalence of Pulmonary Tuberculosis but Low Sensitivity of Symptom Screening among HIV-Infected Pregnant Women in South Africa 
PLoS ONE  2013;8(4):e62211.
Symptom screening is a recommended component of intensified case-finding (ICF) for pulmonary tuberculosis (TB) among HIV-infected individuals. Symptomatic individuals are further investigated to either exclude or diagnose pulmonary TB, thus reducing the number of individuals requiring costly laboratory investigation. Those with laboratory evaluations negative for pulmonary TB or who lack symptoms may be eligible for antiretroviral therapy (ART) and/or TB isoniazid preventive therapy (IPT). A four-part symptom screen has been recommended by the World Health Organization (WHO) for identifying TB suspects and those unlikely to have TB. A meta-analysis of studies among HIV-infected individuals calculated a sensitivity of 90.1% for the four-part symptoms screen - of any of cough, fever, night sweats, or weight loss - among patients in clinical care, making it an effective tool for identifying most patients with TB. An important population for intensified case-finding not included in that meta-analysis was HIV-infected pregnant women. We undertook a cross-sectional survey among HIV-infected pregnant women receiving prenatal care at community clinics in South Africa. We obtained a four-symptom review and sputum smear microscopy and mycobacterial culture on all participants. Among 1415 women, 226 (16%) had a positive symptom screen, and 35 (2.5%) were newly diagnosed with culture-positive TB. Twelve were on TB treatment at the time of screening, yielding 47 (3.3%) women with prevalent TB. Symptom screening among women without known TB had a sensitivity of 28% and specificity of 84%. The poor performance of symptom screening to identify women with TB suggests that other approaches may be needed for intensified case-finding to be effective for this population.
doi:10.1371/journal.pone.0062211
PMCID: PMC3629105  PMID: 23614037
18.  Sexual Risk Behaviors Among HIV-Infected South African Men and Women with Their Partners in a Primary Care Program: Implications for Couples-Based Prevention 
AIDS and Behavior  2012;16(1):139-150.
We studied 1163 sexually-active HIV-infected South African men and women in an urban primary care program to understand patterns of sexual behaviors and whether these behaviors differed by partner HIV status. Overall, 40% reported a HIV-positive partner and 60% a HIV-negative or status unknown partner; and 17.5% reported >2 sex acts in the last 2 weeks, 16.4% unprotected sex in the last 6 months, and 3.7% >1 sex partner in the last 6 months. Antiretroviral therapy (ART) was consistently associated with decreased sexual risk behaviors, as well as with reporting a HIV-negative or status unknown partner. The odds of sexual risk behaviors differed by sex; and were generally higher among participants reporting a HIV-positive partner, but continued among those with a HIV-negative or status unknown partner. These data support ART as a means of HIV prevention. Engaging in sexual risk behaviors primarily with HIV-positive partners was not widely practiced in this setting, emphasizing the need for couples-based prevention.
doi:10.1007/s10461-011-9941-y
PMCID: PMC3184366  PMID: 21476005
HIV; AIDS; South Africa; Sexual risk behavior; ART
19.  Concordant Oral-Genital HPV Infection in South Africa Couples: Evidence for Transmission 
Frontiers in Oncology  2013;3:303.
Objective: Cervical cancer is a leading cause of cancer mortality in South Africa. However, little is known about oral human papillomavirus (HPV) infection in high human immunodeficiency virus (HIV) seroprevalence settings.
Method: Thirty-four adult heterosexual couples attending an HIV testing center in Soweto, South Africa were enrolled. Each participant provided an oral rinse sample and genital swab, which were tested for 37 types of HPV DNA, and completed a risk behavior survey.
Results: Median age was 31 years and 9% (3/34) of men and 29% (10/34) of women enrolled tested HIV-positive; median CD4 count was 437 cells/mm3. Oral HPV prevalence was similar in women and men (12 vs. 18%, p = 0.48), and was non-significantly higher in HIV-infected vs. HIV-uninfected (23 vs. 13%, p = 0.34) subjects. Most men (82%) and women (84%) reported ever performing oral sex. Median number of lifetime sexual partners was “2–5” while median number of lifetime oral sex partners was 1. Oncogenic HPV subtypes were detected in 4% of oral, 26% of penile, and 74% of vaginal samples, including HPV16 in 1, 12, and 21% of these samples respectively. Genital HPV prevalence was significantly higher than oral HPV prevalence (75 vs. 15%, p ≤ 0.001). Thirty-five percent of couples (12/34) had at least one type-specific concordant vaginal-penile HPV infection but only one of nine couples with oral HPV had concordant oral–oral infection. However, 67% (4/6) of men and 25% (1/4) of women with oral HPV infection had partners with concordant genital HPV infection.
Implications and Impact: Oral–oral HPV concordance between couples is low, but oral-genital and genital–genital HPV concordance is higher, including concordance of male oral HPV infection with their partners’ vaginal HPV infection. This data is consistent with possible transmission of vaginal HPV infection to the oral cavity of sexual partners performing oral sex.
doi:10.3389/fonc.2013.00303
PMCID: PMC3860183  PMID: 24377087
HIV; oral sex; South Africa; HPV; oral; genital; concordance; transmission
20.  Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa 
PLoS ONE  2012;7(10):e47542.
Background
Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.
Methods
HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.
Results
Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.
Conclusions
Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.
doi:10.1371/journal.pone.0047542
PMCID: PMC3472995  PMID: 23094059
21.  Hepatitis B Virus Infection in Human Immunodeficiency Virus Infected Southern African Adults: Occult or Overt – That Is the Question 
PLoS ONE  2012;7(10):e45750.
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) share transmission routes and are endemic in sub-Saharan Africa. The objective of the present study was to use the Taormina definition of occult HBV infection, together with stringent amplification conditions, to determine the prevalence and characteristics of HBV infection in antiretroviral treatment (ART)-naïve HIV+ve adults in a rural cohort in South Africa. The presence of HBV serological markers was determined by enzyme linked immunoassay (ELISA) tests. HBV DNA-positivity was determined by polymerase chain reaction (PCR) of at least two of three different regions of the HBV genome. HBV viral loads were determined by real-time PCR. Liver fibrosis was determined using the aspartate aminotransferase-to-platelet ratio index. Of the 298 participants, 231 (77.5%) showed at least one HBV marker, with 53.7% HBV DNA−ve (resolved) and 23.8% HBV DNA+ve (current) [8.7% HBsAg+ve: 15.1% HBsAg−ve]. Only the total number of sexual partners distinguished HBV DNA+ve and HBV DNA−ve participants, implicating sexual transmission of HBV and/or HIV. It is plausible that sexual transmission of HBV and/or HIV may result in a new HBV infection, superinfection and re-activation as a consequence of immunesuppression. Three HBsAg−ve HBV DNA+ve participants had HBV viral loads <200 IU/ml and were therefore true occult HBV infections. The majority of HBsAg−ve HBV DNA+ve participants did not differ from HBsAg+ve HBV DNA+ve (overt) participants in terms of HBV viral loads, ALT levels or frequency of liver fibrosis. Close to a quarter of HIV+ve participants were HBV DNA+ve, of which the majority were HBsAg−ve and were only detected using nucleic acid testing. Detection of HBsAg−ve HBV DNA+ve subjects is advisable considering they were clinically indistinguishable from HBsAg+ve HBV DNA+ve individuals and should not be overlooked, especially if lamivudine is included in the ART.
doi:10.1371/journal.pone.0045750
PMCID: PMC3462206  PMID: 23049685
22.  Active Tuberculosis Case-Finding among Pregnant Women Presenting to Antenatal Clinics in Soweto, South Africa 
Background
Human immunodeficiency virus (HIV) and tuberculosis (TB) are among the leading causes of death among women of reproductive age worldwide. TB is a significant cause of maternal morbidity. Detection of TB during pregnancy could provide substantial benefits to women and their offspring.
Methods
This was a cross-sectional implementation research study of integrating active TB case-finding with delivery of antenatal and prevention of mother-to-child transmission (PMTCT) services in six clinics in Soweto, South Africa. All pregnant women ≥18 years of age presenting for routine care to these public clinics were screened for symptoms of active TB, cough ≥2 weeks, sputum production, fevers, night sweats or weight loss, regardless of their HIV status. Participants with any symptom of active TB were asked to provide a sputum specimen for smear microscopy, mycobacterial culture and drug-susceptibility testing.
Results
Between December 2008 and July 2009, 3,963 pregnant women were enrolled and screened for TB, of whom 1,454 (36.7%) were HIV-seropositive. Any symptom of TB was reported by 23.1% of HIV-seropositive and 13.8% of HIV-seronegative women (p<0.01). Active pulmonary TB was diagnosed in 10/1,454 HIV-seropositve women (688 per 100,000) and 5/2,483 HIV-seronegative women (201 per 100,000, p = 0.03). The median CD4+ T-cell count among HIV-seropositive women with TB was similar to that of HIV-seropositive women without TB (352 versus 333 cells/μL, p=0.85).
Conclusions
There is a high burden of active TB among HIV-seropositive pregnant women. TB screening and provision of isoniazid preventive therapy and antiretroviral therapy should be integrated with PMTCT services.
doi:10.1097/QAI.0b013e31821ac9c1
PMCID: PMC3159850  PMID: 21436710
tuberculosis; HIV; pregnancy; epidemiology; screening
23.  New Regimens to Prevent Tuberculosis in Adults with HIV Infection 
BACKGROUND
Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.
METHODS
We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.
RESULTS
The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.
CONCLUSIONS
On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid.
doi:10.1056/NEJMoa1005136
PMCID: PMC3407678  PMID: 21732833
24.  Parametric Variable Selection in Generalized Partially Linear Models with an Application to Assess Condom Use by HIV-infected Patients 
Statistics in medicine  2011;30(16):2015-2027.
To study significant predictors of condom use in HIV-infected adults, we propose the use of generalized partially linear models and develop a variable selection procedure incorporating a least squares approximation. Local polynomial regression and spline smoothing techniques are used to estimate the baseline nonparametric function. The asymptotic normality of the resulting estimate is established. We further demonstrate that, with the proper choice of the penalty functions and the regularization parameter, the resulting estimate performs as well as an oracle procedure. Finite sample performance of the proposed inference procedure is assessed by Monte Carlo simulation studies. An application to assess condom use by HIV-infected patients gains some interesting results, which can not be obtained when an ordinary logistic model is used.
doi:10.1002/sim.4233
PMCID: PMC3116080  PMID: 21465515
AIDS; Condom use; LASSO; Least squares approximation; Local linear regression; Profile likelihood; Quasilikelihood; SCAD; Sexual behavior; Spline smoothing

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