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1.  Mother-to-child transmission of HIV in a community-based antiretroviral clinic in South Africa 
Objective
To examine the uptake of ART among pregnant women referred to an ART service and the associated rates and risk factors for vertical HIV transmission.
Method
Retrospective analysis of an observational cohort at a community ART clinic in Cape Town.
Results
Between 2002 and 2008, 367 treatment-naïve pregnant women accessed the clinic. The median age was 27.5 years, and median gestation at presentation was 28 weeks. The median baseline CD4 count and viral load were 134 cells/µl and 28 282 copies/ml. Two hundred and sixty-five women (72%) commenced ART before giving birth, 73 women (20%) were referred for prevention of mother-to-child transmission therapy (PMTCT), and 29 (8%) received no intervention. Among ART-eligible women, 13% were lost to follow-up. Of those starting ART, median duration of therapy prior to birth was 7.6 weeks (interquartile range (IQR) 4 – 11.9). The HIV transmission rate was 5.1% (95% confidence interval (CI) 2.8 – 9.0%). Factors associated with transmission were advanced maternal WHO disease stage (odds ratio (OR) 9.57, p=0.02), and follow-up viral load above 50 copies/ml (OR 3.64, p=0.03). Each additional week on ART reduced transmission by 20% (p=0.05). There was no HIV transmission among women who received more than 8 weeks’ therapy.
Conclusions
The rate of HIV transmission in this study was higher than reported in high-income countries. Prevention of vertical transmission with ART was hindered by women presenting late in pregnancy and with advanced stage of HIV disease. Interventions that facilitate earlier ART commencement and improve programmatic retention of pregnant women are required.
PMCID: PMC3954611  PMID: 21414276
2.  Resolution of anaemia in a cohort of HIV-infected patients with a high prevalence and incidence of tuberculosis receiving antiretroviral therapy in South Africa 
BMC Infectious Diseases  2014;14(1):3860.
Background
Anaemia is frequently associated with both HIV-infection and HIV-related tuberculosis (TB) in antiretroviral therapy (ART)-naïve patients in sub-Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa.
Methods
Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12 months of ART.
Results
Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12 months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12 months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12 months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors.
Conclusions
Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions.
doi:10.1186/s12879-014-0702-1
PMCID: PMC4300078  PMID: 25528467
HIV; Tuberculosis; Africa; Anaemia; Haemoglobin; Antiretroviral
3.  Undiagnosed Tuberculosis in a Community with High HIV Prevalence 
Background: Although failure of tuberculosis (TB) control in sub-Saharan Africa is attributed to the HIV epidemic, it is unclear why the directly observed therapy short-course (DOTS) strategy is insufficient in this setting. We conducted a cross-sectional survey of pulmonary TB (PTB) and HIV infection in a community of 13,000 with high HIV prevalence and high TB notification rate and a well-functioning DOTS TB control program.
Methods: Active case finding for PTB was performed in 762 adults using sputum microscopy and Mycobacterium tuberculosis culture, testing for HIV, and a symptom and risk factor questionnaire. Survey findings were correlated with notification data extracted from the TB treatment register.
Results: Of those surveyed, 174 (23%) tested HIV positive, 11 (7 HIV positive) were receiving TB therapy, 6 (5 HIV positive) had previously undiagnosed smear-positive PTB, and 6 (4 HIV positive) had smear-negative/culture-positive PTB. Symptoms were not a useful screen for PTB. Among HIV-positive and -negative individuals, prevalence of notified smear-positive PTB was 1,563/100,000 and 352/100,000, undiagnosed smear-positive PTB prevalence was 2,837/100,000 and 175/100,000, and case-finding proportions were 37 and 67%, respectively. Estimated duration of infectiousness was similar for HIV-positive and HIV-negative individuals. However, 87% of total person-years of undiagnosed smear-positive TB in the community were among HIV-infected individuals.
Conclusions: PTB was identified in 9% of HIV-infected individuals, with 5% being previously undiagnosed. Lack of symptoms suggestive of PTB may contribute to low case-finding rates. DOTS strategy based on passive case finding should be supplemented by active case finding targeting HIV-infected individuals.
doi:10.1164/rccm.200606-759OC
PMCID: PMC1899262  PMID: 16973982
African community; case finding; HIV infection; incidence and prevalence; pulmonary tuberculosis
4.  Sibanye Methods for Prevention Packages Program Project Protocol: Pilot Study of HIV Prevention Interventions for Men Who Have Sex With Men in South Africa 
JMIR Research Protocols  2014;3(4):e55.
Background
Human immunodeficiency virus (HIV) prevention intervention programs and related research for men who have sex with men (MSM) in the southern African region remain limited, despite the emergence of a severe epidemic among this group. With a lack of understanding of their social and sexual lives and HIV risks, and with MSM being a hidden and stigmatized group in the region, optimized HIV prevention packages for southern African MSM are an urgent public health and research priority.
Objective
The objective of the Sibanye Health Project is to develop and evaluate a combination package of biomedical, behavioral, and community-level HIV prevention interventions and services for MSM in South Africa.
Methods
The project consists of three phases: (1) a comprehensive literature review and summary of current HIV prevention interventions (Phase I), (2) agent-based mathematical modeling of HIV transmission in southern African MSM (Phase II), and (3) formative and stigma-related qualitative research, community engagement, training on providing health care to MSM, and the pilot study (Phase III). The pilot study is a prospective one-year study of 200 men in Cape Town and Port Elizabeth, South Africa. The study will assess a package of HIV prevention services, including condom and condom-compatible lubricant choices, risk-reduction counseling, couples HIV testing and counseling, pre-exposure prophylaxis (PrEP) for eligible men, and non-occupational post-exposure prophylaxis for men with a high risk exposure. The pilot study will begin in October 2014.
Results
Preliminary results from all components but the pilot study are available. We developed a literature review database with meta-data extracted from 3800 documents from 67 countries. Modeling results indicate that regular HIV testing and promotion of condom use can significantly impact new HIV infections among South African MSM, even in the context of high coverage of early treatment of HIV-positive men and high coverage of PrEP for at-risk HIV-negative men. Formative qualitative research consisted of 79 in-depth interviews, and six focus group discussions in Cape Town and Port Elizabeth. Analysis of these data has informed pilot study protocol development and has been documented in peer-reviewed manuscripts. Qualitative work regarding stigma faced by South African MSM resulted in finalized scales for use in the pilot study questionnaire. A total of 37 health care providers completed training designed to facilitate clinically and culturally competent care for MSM in the Eastern Cape.
Conclusions
The design of a future, larger study of the HIV prevention package will be conducted at the end of the pilot study, powered to detect efficacy of the prevention package. Data from the updated mathematical model, results of the pilot study, acceptability data, and advancements in HIV prevention sciences will be considered in developing the final proposed package and study design.
Trial Registration
ClinicalTrials.gov NCT02043015; http://clinicaltrials.gov/show/NCT02043015 (Archived by WebCite at http://www.webcitation.org/6THvp7rAj).
doi:10.2196/resprot.3737
PMCID: PMC4210958  PMID: 25325296
HIV; prevention & control; South Africa; Truvada
5.  Behavioral and Biomedical Combination Strategies for HIV Prevention 
Around 2.5 million people become infected with HIV each year. This extraordinary toll on human life and public health worldwide will only be reversed with effective prevention. What’s more, in the next few years, it is likely at least, that no single prevention strategy will be sufficient to contain the spread of the disease. There is a need for combination prevention as there is for combination treatment, including biomedical, behavioral, and structural interventions. Expanded HIV prevention must be grounded in a systematic analysis of the epidemic’s dynamics in local contexts. Although 85% of HIV is transmitted sexually, effective combinations of prevention have been shown for people who inject drugs. Combination prevention should be based on scientifically derived evidence, with input and engagement from local communities that fosters the successful integration of care and treatment.
Each year, 2.5 million people are infected with HIV. Although multiple prevention strategies exist, they must be effective, affordable, and population-specific.
doi:10.1101/cshperspect.a007435
PMCID: PMC3405825  PMID: 22908192
6.  Decreasing household contribution to TB transmission with age: a retrospective geographic analysis of young people in a South African township 
BMC Infectious Diseases  2014;14:221.
Background
Tuberculosis (TB) transmission rates are exceptionally high in endemic TB settings. Adolescence represents a period of increasing TB infection and disease but little is known as to where adolescents acquire TB infection. We explored the relationship between residential exposure to adult TB cases and infection in children and adolescents in a South African community with high burdens of TB and HIV.
Methods
TB infection data were obtained from community, school-based tuberculin skin test (TST) surveys performed in 2006, 2007 and 2009. A subset of 2007 participants received a repeat TST in 2009, among which incident TB infections were identified. Using residential address, all adult TB cases notified by the community clinic between 1996 and 2009 were cross-referenced with childhood and adolescent TST results. Demographic and clinic data including HIV status were abstracted for TB cases. Multivariate logistic regression models examined the association of adult TB exposure with childhood and adolescent prevalent and incident TB infection.
Results
Of 1,100 children and adolescents included in the prevalent TB infection analysis, 480 (44%) were TST positive and 651 (59%) were exposed to an adult TB case on their residential plot. Prevalent TB infection in children aged 5–9 and 10–14 years was positively associated with residential exposure to an adult TB case (odds ratio [OR]:2.0; 95% confidence interval [CI]: 1.1-3.6 and OR:1.5; 95% CI: 1.0-2.3 respectively), but no association was found in adolescents ≥15 years (OR:1.4; 95% CI: 0.9-2.0). HIV status of adult TB cases was not associated with TB infection (p = 0.62). Of 67 previously TST negative children, 16 (24%) converted to a positive TST in 2009. These incident infections were not associated with residential exposure to an adult TB case (OR: 1.9; 95% CI: 0.5-7.3).
Conclusions
TB infection among young children was strongly associated with residential exposure to an adult TB case, but prevalent and incident TB infection in adolescents was not associated with residential exposure. The HIV-status of adult TB cases was not a risk factor for transmission. The high rates of TB infection and disease among adolescents underscore the importance of identifying where infection occurs in this age group.
doi:10.1186/1471-2334-14-221
PMCID: PMC4012060  PMID: 24758715
Tuberculosis; Infection; Transmission; Adolescents
7.  The HVTN503/Phambili HIV vaccine trial: a comparison of younger and older participants 
By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January-September, 2007. Motivations for trial enrollment, social harms, adverse events, and loss to follow-up were compared between younger (18-20 years old) and older participants (21-35 years old). Both younger (n=238) and older participants (n=563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p=0.005), while younger males were more likely to enroll because the vaccine may provide protection from HIV-acquisition (p<0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years-old, 18-20-year-old females were less likely to experience adverse events (OR=0.1, CI 0.01-0.80) and no more likely to be lost to follow up (OR=0.7, CI 0.39-1.25), while 18-20-year-old males were no more likely to experience adverse events (OR=1.3, CI 0.58-2.83) or loss to follow-up (OR=0.8, CI 0.51-1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.
doi:10.1177/0956462413506892
PMCID: PMC3968181  PMID: 24104693
HIV; vaccine trials; clinical trials; youth; South Africa
8.  Mobile phone text messaging for promoting adherence to anti-tuberculosis treatment: a systematic review 
BMC Infectious Diseases  2013;13:566.
Background
Mobile phone text messaging (SMS) has the potential to promote adherence to tuberculosis treatment. This systematic review aims to synthesize current evidence on the effectiveness of SMS interventions in improving patients’ adherence to tuberculosis treatment.
Methods
We searched electronic databases (PubMed, EMBASE, Science Citation Index), reference lists of relevant articles, conference proceedings, and selected websites for eligible studies available by 15 February 2013; regardless of language or publication status. Two authors independently screened selected eligible studies, and assessed risk of bias in included studies; resolving discrepancies by discussion and consensus.
Results
We identified four studies that compared the outcomes of the SMS intervention group with controls. Only one of the four studies was a randomized controlled trial. This was conducted in Argentina and the SMS intervention did not significantly improve adherence to tuberculosis treatment compared to self-administration of tuberculosis treatment (risk ratio [RR] 1.49, 95% confidence intervals [CI] 0.90 to 2.42). One of the non-randomized studies, conducted in South Africa, which compared SMS reminders to directly observed therapy short course (DOTS) reported similar rates of tuberculosis cure (62.35% vs. 66.4%) and treatment success (72.94% vs. 69.4%). A second study from South Africa, utilized SMS reminders when patients delayed in opening their pill bottles and reported increased tuberculosis cure (RR 2.32, 95% CI 1.60 to 3.36) and smear conversion (RR 1.62, 95% CI 1.09 to 2.42) rates compared to DOTS. In the third non-randomized study, conducted in Kenya, use of SMS reminders increased rates of clinic attendance on scheduled days compared to standard care (RR 1.56, 95% CI 1.06 to 2.29). Using the GRADE approach, we rate the quality of the evidence as low, mainly because of the high risk of bias and heterogeneity of effects across studies.
Conclusions
This systematic review indicates that there is a paucity of high-quality data on the effectiveness of SMS interventions for improving patients’ adherence to tuberculosis treatment. The low quality of the current evidence implies that further studies (in particular randomized trials) on the subject are needed. In the interim, if the intervention is implemented outside research settings an impact evaluation is warranted.
doi:10.1186/1471-2334-13-566
PMCID: PMC4219402  PMID: 24295439
Mobile phone; Text messages; Tuberculosis treatment; Anti-tubercular agents; Adherence; Compliance
9.  Mobile phone text messaging for promoting adherence to anti-tuberculosis treatment: a systematic review protocol 
Systematic Reviews  2013;2:6.
Background
In 2010, there were approximately 8.8 million incident cases of tuberculosis (TB) worldwide. The treatment of TB is at least six months long and may be complicated by a high pill burden. In addition, TB patients often do not take their medication on schedule simply because they forget. Mobile phone text messaging has the potential to help promote TB treatment adherence. We, therefore, propose to conduct a review of current best evidence for the use of mobile phone text messaging to promote patient adherence to TB treatment.
Methods
This is a systematic review of the literature. We will preferably include randomized controlled trials (RCTs). However, non-randomized studies (NRS) will be considered if there is an inadequate number of RCTs.
We will search PubMed, EMBASE, CINAHL, CENTRAL, Science Citation Index, Africa-Wide Information, and WHOLIS electronic databases for eligible studies available by 30 November 2012 regardless of language or publication status. We will also check reference lists for additional studies, identify abstracts from conference proceedings and communicate with authors for any relevant material.
At least two authors will independently screen search outputs, select studies, extract data and assess the risk of bias (using separate criteria for RCTs and NRS); resolving discrepancies by discussion and consensus. We will assess clinical heterogeneity by examining the types of participants, interventions and outcomes in each study and pool studies judged to be clinically homogenous. We will also assess statistical heterogeneity using the chi-square test of homogeneity and quantify it using the I-square statistic. If study results are found to be statistically homogeneous (that is heterogeneity P > 0.1), we will pool them using the fixed-effect meta-analysis. Otherwise, we will use random-effects meta-analysis. We will calculate risk ratios and their corresponding 95% confidence intervals for dichotomous outcomes, and mean differences for continuous outcomes. For other outcomes without quantitative data, a descriptive analysis will be used.
Discussion
Our results can be used by researchers and policy-makers to help inform them of the efficacy of mobile phone text messaging interventions to promote patient adherence to TB treatment.
doi:10.1186/2046-4053-2-6
PMCID: PMC3564775  PMID: 23324135
Mobile phone; Text messages; Tuberculosis treatment; Anti-tubercular agents; Adherence; Compliance
10.  Systemic delays in the initiation of antiretroviral therapy during pregnancy do not improve outcomes of HIV-positive mothers: a cohort study 
Background
Antiretroviral therapy (ART) initiation in eligible HIV-infected pregnant women is an important intervention to promote maternal and child health. Increasing the duration of ART received before delivery plays a major role in preventing vertical HIV transmission, but pregnant women across Africa experience significant delays in starting ART, partly due the perceived need to deliver ART counseling and patient education before ART initiation. We examined whether delaying ART to provide pre-ART counseling was associated with improved outcomes among HIV-infected women in Cape Town, South Africa.
Methods
We undertook a retrospective cohort study of 490 HIV-infected pregnant women referred to initiate treatment at an urban ART clinic. At this clinic all patients including pregnant women are screened by a clinician and then undergo three sessions of counseling and patient education prior to starting treatment, commonly introducing delays of 2–4 weeks before ART initiation. Data on viral suppression and retention in care after ART initiation were taken from routine clinic records.
Results
A total of 382 women initiated ART before delivery (78%); ART initiation before delivery was associated with earlier gestational age at presentation to the ART service (p < 0.001). The median delay between screening and ART initiation was 21 days (IQR, 14–29 days). Overall, 84.7%, 79.6% and 75.0% of women who were pregnant at the time of ART initiation were retained in care at 4, 8 and 12 months after ART initiation, respectively. Among those retained, 91% were virally suppressed at each follow-up visit. However the delay from screening to ART initiation was not associated with retention in care and/or viral suppression throughout the first year on ART in unadjusted or adjusted analyses.
Conclusions
A substantial proportion of eligible pregnant women referred for ART do not begin treatment before delivery in this setting. Among women who do initiate ART, delaying initiation for patient preparation is not associated with improved maternal outcomes. Given the need to maximize the duration of ART before delivery for prevention of mother-to-child HIV transmission, there is an urgent need for new strategies to help expedite ART initiation in eligible pregnant women.
doi:10.1186/1471-2393-12-94
PMCID: PMC3490939  PMID: 22963318
Antiretroviral therapy; Pregnancy; Patient preparation; Prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa
11.  Lipoarabinomannan in urine during tuberculosis treatment: association with host and pathogen factors and mycobacteriuria 
Background
Detection of lipoarabinomannan (LAM), a Mycobacterium tuberculosis (Mtb) cell wall antigen, is a potentially attractive diagnostic. However, the LAM-ELISA assay has demonstrated variable sensitivity in diagnosing TB in diverse clinical populations. We therefore explored pathogen and host factors potentially impacting LAM detection.
Methods
LAM-ELISA assay testing, sputum smear and culture status, HIV status, CD4 cell count, proteinuria and TB outcomes were prospectively determined in adults diagnosed with TB and commencing TB treatment at a South African township TB clinic. Sputum TB isolates were characterised by IS61110-based restriction fragment length polymorphism (RFLP) and urines were tested for mycobacteriuria by Xpert® MTB/RIF assay.
Results
32/199 (16.1%) of patients tested LAM-ELISA positive. Median optical density and proportion testing LAM positive remained unchanged during 2 weeks of treatment and then declined over 24 weeks. LAM was associated with positive sputum smear and culture status, HIV infection and low CD4 cell counts but not proteinuria, RFLP strain or TB treatment outcome. The sensitivity of LAM for TB in HIV-infected patients with CD4 counts of ≥ 200, 100-199, 50-99, and < 50 cells/μl, was 15.2%, 32%, 42.9%, and 69.2% respectively. Mycobacteriuria was found in 15/32 (46.9%) of LAM positive patients and in none of the LAM negative controls.
Conclusions
Urinary LAM was related to host immune factors, was unrelated to Mtb strain and declined steadily after an initial 2 weeks of TB treatment. The strong association of urine LAM with mycobacteriuria is a new finding, indicating frequent TB involvement of the renal tract in advanced HIV infection.
doi:10.1186/1471-2334-12-47
PMCID: PMC3349560  PMID: 22369353
12.  Treatment outcomes in HIV-infected adolescents attending a community-based antiretroviral therapy clinic in South Africa 
Background
Very few data are available on treatment outcomes of adolescents living with HIV infection (whether perinatally acquired or sexually acquired) in sub-Saharan Africa. The present study therefore compared the treatment outcomes in adolescents with those of young adults at a public sector community-based ART programme in Cape Town, South Africa.
Methods
Treatment outcomes of adolescents (9-19 years) were compared with those of young adults (20-28 years), enrolled in a prospective cohort between September 2002 and June 2009. Kaplan-Meier estimates and Cox proportional hazard models were used to assess outcomes and determine associations with age, while adjusting for potential confounders. The treatment outcomes were mortality, loss to follow-up (LTFU), immunological response, virological suppression and virological failure.
Results
883 patients, including 65 adolescents (47 perinatally infected and 17 sexually infected) and 818 young adults, received ART. There was no difference in median baseline CD4 cell count between adolescents and young adults (133.5 vs 116 cells/μL; p = 0.31). Overall mortality rates in adolescents and young adults were 1.2 (0.3-4.8) and 3.1 (2.4-3.9) deaths per 100 person-years, respectively. Adolescents had lower rates of virological suppression (< 400 copies/mL) at 48 weeks (27.3% vs 63.1%; p < 0.001). Despite this, however, the median change in CD4 count from baseline at 48 weeks of ART was significantly greater for adolescents than young adults (373 vs 187 cells/μL; p = 0.0001). Treatment failure rates were 8.2 (4.6-14.4) and 5.0 (4.1-6.1) per 100 person-years in the two groups. In multivariate analyses, there was no significant difference in LTFU and mortality between age groups but increased risk in virological failure [AHR 2.06 (95% CI 1.11-3.81; p = 0.002)] in adolescents.
Conclusions
Despite lower virological suppression rates and higher rates of virological failure, immunological responses were nevertheless greater in adolescents than young adults whereas rates of mortality and LTFU were similar. Further studies to determine the reasons for poorer virological outcomes are needed.
doi:10.1186/1471-2334-12-21
PMCID: PMC3295677  PMID: 22273267
antiretroviral; adolescents; outcomes; mortality; virological failure; Africa
13.  Burden of New and Recurrent Tuberculosis in a Major South African City Stratified by Age and HIV-Status 
PLoS ONE  2011;6(10):e25098.
Aim
To describe the burden of tuberculosis (TB) in Cape Town by calculating TB incidence rates stratified by age and HIV-status, assessing the contribution of retreatment disease and estimating the cumulative lifetime TB risk in HIV-negative individuals.
Methods
Details of TB cases were abstracted from the 2009 electronic TB register. Population denominators were estimated from census data and actuarial estimates of HIV prevalence, allowing calculation of age-specific and HIV-stratified TB notification rates.
Results
The 2009 mid-year population was 3,443,010 (3,241,508 HIV-negative and 201,502 HIV-positive individuals). There were 29,478 newly notified TB cases of which 56% were laboratory confirmed. HIV status was recorded for 87% of cases and of those with known HIV-status 49% were HIV-negative and 51% were positive. Discrete peaks in the incidence of non-HIV-associated TB occurred at three ages: 511/100,000 at 0–4 years of age, 553/100,000 at 20–24 years and 628/100,000 at 45–49 years with 1.5%, 19% and 45% being due to retreatment TB, respectively. Only 15.5% of recurrent cases had a history of TB treatment failure or default. The cumulative lifetime risks in the HIV-negative population of all new TB episodes and new smear-positive TB episodes were 24% and 12%, respectively; the lifetime risk of retreatment disease was 9%. The HIV-positive notification rate was 6,567/100,000 (HIV-associated TB rate ratio = 17). Although retreatment cases comprised 30% of the HIV-associated TB burden, 88% of these patients had no history of prior treatment failure or default.
Conclusions
The annual burden of TB in this city is huge. TB in the HIV-negative population contributed almost half of the overall disease burden and cumulative lifetime risks were similar to those reported in the pre-chemotherapy era. Retreatment TB contributed significantly to both HIV-associated and non-HIV-associated TB but infrequently followed prior inadequate treatment. This likely reflects ongoing TB transmission to both HIV-negative and positive individuals.
doi:10.1371/journal.pone.0025098
PMCID: PMC3189963  PMID: 22016763
14.  HIV Risk and Associations of HIV Infection among men who have sex with men in Peri-Urban Cape Town, South Africa 
BMC Public Health  2011;11:766.
Background
The HIV epidemic in Sub Saharan Africa has been traditionally assumed to be driven by high risk heterosexual and vertical transmission. However, there is an increasing body of data highlighting the disproportionate burden of HIV infection among MSM in the generalized HIV epidemics across of Southern Africa. In South Africa specifically, there has been an increase in attention focused on the risk status and preventive needs of MSM both in urban centers and peri-urban townships. The study presented here represents the first evaluation of HIV prevalence and associations of HIV infection among MSM in the peri-urban townships of Cape Town.
Methods
The study consisted of an anonymous probe of 200 men, reporting ever having had sex with another man, recruited through venue-base sampling from January to February, 2009.
Results
Overall, HIV prevalence was 25.5% (n = 51/200). Of these prevalent HIV infections, only 6% of HIV-1 infected MSM were aware of their HIV status (3/50). 0% of men reported always having safe sex as defined by always wearing condoms during sex and using water-based lubricants. Independent associations with HIV infection included inconsistent condom use with male partners (aOR 2.3, 95% CI 1.0-5.4), having been blackmailed (aOR 4.4, 95% CI 1.6-20.2), age over 26 years (aOR 4.2, 95% CI 1.6-10.6), being unemployed (aOR 3.7, 95% CI 1.5-9.3), and rural origin (aOR 6.0, 95% CI 2.2-16.7). Bisexual activity was reported by 17.1% (34/199), and a total of 8% (16/200) reported having a regular female partner. Human rights violations were common with 10.5% (n = 21/200) reporting having been blackmailed and 21.0% (n = 42/200) reporting being afraid to seek health care.
Conclusions
The conclusions from this study include that a there is a high risk and underserved population of MSM in the townships surrounding Cape Town. The high HIV prevalence and high risk sexual practices suggest that prevalence will continue to increase among these men in the context of an otherwise slowing epidemic. These data further highlight the need to better characterize risk factors for HIV prevention and appropriate targeted combination packages of HIV interventions including biomedical, behavioural, and structural approaches to mitigate HIV risk among these men.
doi:10.1186/1471-2458-11-766
PMCID: PMC3196714  PMID: 21975248
15.  Force of tuberculosis infection among adolescents in a high HIV and TB prevalence community: a cross-sectional observation study 
BMC Infectious Diseases  2011;11:156.
Background
Understanding of the transmission dynamics of tuberculosis (TB) in high TB and HIV prevalent settings is required in order to develop effective intervention strategies for TB control. However, there are little data assessing incidence of TB infection in adolescents in these settings.
Methods
We performed a tuberculin skin test (TST) and HIV survey among secondary school learners in a high HIV and TB prevalence community. TST responses to purified protein derivative RT23 were read after 3 days. HIV-infection was assessed using Orasure® collection device and ELISA testing. The results of the HIV-uninfected participants were combined with those from previous surveys among primary school learners in the same community, and force of TB infection was calculated by age.
Results
The age of 820 secondary school participants ranged from 13 to 22 years. 159 participants had participated in the primary school surveys. At a 10 mm cut-off, prevalence of TB infection among HIV-uninfected and first time participants, was 54% (n = 334/620). HIV prevalence was 5% (n = 40/816). HIV infection was not significantly associated with TST positivity (p = 0.07). In the combined survey dataset, TB prevalence was 45% (n = 645/1451), and was associated with increasing age and male gender. Force of infection increased with age, from 3% to 7.3% in adolescents ≥20 years of age.
Conclusions
We show a high force of infection among adolescents, positively associated with increasing age. We postulate this is due to increased social contact with infectious TB cases. Control of the TB epidemic in this setting will require reducing the force of infection.
doi:10.1186/1471-2334-11-156
PMCID: PMC3130671  PMID: 21631918
16.  Caseation of Human Tuberculosis Granulomas Correlates with Elevated Host Lipid Metabolism 
EMBO molecular medicine  2010;2(7):258-274.
The progression of human tuberculosis to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome-wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous tuberculosis granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl-CoA synthetase long-chain family member 1, and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols, and lactosylceramide, which implicated low-density lipoprotein-derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human tuberculosis granuloma to caseation correlates with pathogen-mediated dysregulation of host lipid metabolism.
doi:10.1002/emmm.201000079
PMCID: PMC2913288  PMID: 20597103
17.  Identification of losses to follow-up in a community-based antiretroviral therapy clinic in South Africa using a computerized pharmacy tracking system 
BMC Infectious Diseases  2010;10:329.
Background
High rates of loss to follow-up (LTFU) are undermining rapidly expanding antiretroviral treatment (ART) services in sub-Saharan Africa. The intelligent dispensing of ART (iDART) is an open-source electronic pharmacy system that provides an efficient means of generating lists of patients who have failed to pick-up medication. We determined the duration of pharmacy delay that optimally identified true LTFU.
Methods
We conducted a retrospective cross-sectional study of a community-based ART cohort in Cape Town, South Africa. We used iDART to identify groups of patients known to be still enrolled in the cohort on the 1st of April 2008 that had failed to pick-up medication for periods of ≥ 6, ≥ 12, ≥ 18 and ≥ 24 weeks. We defined true LTFU as confirmed failure to pick up medication for 3 months since last attendance. We then assessed short-term and long-term outcomes using a prospectively maintained database and patient records.
Results
On the date of the survey, 2548 patients were registered as receiving ART but of these 85 patients (3.3%) were found to be true LTFU. The numbers of individuals (proportion of the cohort) identified by iDART as having failed to collect medication for periods of ≥6, ≥12, ≥18 and ≥24 weeks were 560 (22%), 194 (8%), 117 (5%) and 80 (3%), respectively. The sensitivities of these pharmacy delays for detecting true LTFU were 100%, 100%, 62.4% and 47.1%, respectively. The corresponding specificities were 80.7%, 95.6%, 97.4% and 98.4%. Thus, the optimal delay was ≥12 weeks since last attendance at this clinic (equivalent to 8 weeks since medication ran out). Pharmacy delays were also found to be significantly associated with LTFU and death one year later.
Conclusions
The iDART electronic pharmacy system can be used to detect patients potentially LTFU and who require recall. Using a short a cut-off period was too non-specific for LTFU and would require the tracing of very large numbers of patients. Conversely prolonged delays were too insensitive. Of the periods assessed, a ≥12 weeks delay appeared optimal. This system requires prospective evaluation to further refine its utility.
doi:10.1186/1471-2334-10-329
PMCID: PMC3000400  PMID: 21078148
18.  Utility of interferon-γ ELISPOT assay responses in highly tuberculosis-exposed patients with advanced HIV infection in South Africa 
Background
Interferon-gamma (IFN-γ) ELISPOT assays incorporating Mycobacterium tuberculosis-specific antigens are useful in the diagnosis of tuberculosis (TB) or latent infection. However, their utility in patients with advanced HIV is unknown. We studied determinants of ELISPOT responses among patients with advanced HIV infection (but without active TB) living in a South African community with very high TB notification rates.
Methods
IFN-γ responses to ESAT-6 and CFP-10 in overnight ELISPOT assays and in 7-day whole blood assays (WBA) were compared in HIV-infected patients (HIV+, n = 40) and healthy HIV-negative controls (HIV-, n = 30) without active TB. Tuberculin skin tests (TSTs) were also done.
Results
ELISPOTs, WBAs and TSTs were each positive in >70% of HIV- controls, reflecting very high community exposure to M. tuberculosis. Among HIV+ patients, quantitative WBA responses and TSTs (but not the proportion of positive ELISPOT responses) were significantly impaired in those with CD4 cell counts <100 cells/μl compared to those with higher counts. In contrast, ELISPOT responses (but not WBA or TST) were strongly related to history of TB treatment; a much lower proportion of HIV+ patients who had recently completed treatment for TB (n = 19) had positive responses compared to those who had not been treated (11% versus 62%, respectively; P < 0.001). Multivariate analysis confirmed that ELISPOT responses had a strong inverse association with a history of recent TB treatment (adjusted OR = 0.06, 95%CI = 0.10–0.40, P < 0.01) and that they were independent of CD4 cell count and viral load. Among HIV+ individuals who had not received TB treatment both the magnitude and proportion of positive ELISPOT responses (but not TST or WBA) were similar to those of HIV-negative controls.
Conclusion
The proportion of positive ELISPOT responses in patients with advanced HIV infection was independent of CD4 cell count but had a strong inverse association with history of TB treatment. This concurs with the previously documented low TB risk among patients in this cohort with a history of recent treatment for TB. These data suggest ELISPOT assays may be useful for patient assessment and as an immuno-epidemiological research tool among patients with advanced HIV and warrant larger scale prospective evaluation.
doi:10.1186/1471-2334-7-99
PMCID: PMC2031899  PMID: 17725839
19.  CD4 cell count recovery among HIV-infected patients with very advanced immunodeficiency commencing antiretroviral treatment in sub-Saharan Africa 
Background
Patients accessing antiretroviral treatment (ART) programmes in sub-Saharan Africa frequently have very advanced immunodeficiency. Previous data suggest that such patients may have diminished capacity for CD4 cell count recovery.
Methods
Rates of CD4 cell increase were determined over 48 weeks among ART-naïve individuals (n = 596) commencing ART in a South African community-based ART programme.
Results
The CD4 cell count increased from a median of 97 cells/μl at baseline to 261 cells/μl at 48 weeks and the proportion of patients with a CD4 cell count <100 cells/μl decreased from 51% at baseline to just 4% at 48 weeks. A rapid first phase of recovery (0–16 weeks, median rate = 25.5 cells/μl/month) was followed by a slower second phase (16–48 weeks, median rate = 7.7 cells/μl/month). Compared to patients with higher baseline counts, multivariate analysis showed that those with baseline CD4 counts <50 cells/μl had similar rates of phase 1 CD4 cell recovery (P = 0.42), greater rates of phase 2 recovery (P = 0.007) and a lower risk of immunological non-response (P = 0.016). Among those that achieved a CD4 cell count >500 cells/μl at 48 weeks, 19% had baseline CD4 cell counts <50 cells/μl. However, the proportion of these patients that attained a CD4 count 200 cells/μl at 48 weeks was lower than those with higher baseline CD4 cell counts.
Conclusion
Patients in this cohort with baseline CD4 cell counts <50 cells/μl have equivalent or greater capacity for immunological recovery during 48 weeks of ART compared to those with higher baseline CD4 cell counts. However, their CD4 counts remain <200 cells/μl for a longer period, potentially increasing their risk of morbidity and mortality in the first year of ART.
doi:10.1186/1471-2334-6-59
PMCID: PMC1435908  PMID: 16551345
20.  Creating an African HIV Clinical Research and Prevention Trials Network: HIV Prevalence, Incidence and Transmission 
PLoS ONE  2015;10(1):e0116100.
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.
doi:10.1371/journal.pone.0116100
PMCID: PMC4300215  PMID: 25602351
21.  Community viral load and CD4 count distribution among people living with HIV in a South African township: implications for treatment as prevention 
Introduction
The goals of scale-up of antiretroviral therapy (ART) have expanded from prevention of morbidity and death to include prevention of transmission. Morbidity and mortality risk are associated with CD4 counts; transmission risk depends on plasma viral load (VL). This study aimed to describe CD4 count and VL distributions among HIV-infected individuals in a South African township to gain insights into the potential impact of ART scale-up on community HIV transmission risk.
Methods
A random sample of 10% of the adult population was invited to attend an HIV testing service. Study procedures included a questionnaire, HIV testing, CD4 count and VL testing.
Results
1144 (88.0%) of 1300 randomly selected individuals participated in the study. 260 tested positive, giving an HIV prevalence of 22.7% (95%CI:20.3-25.3). A third of all HIV-infected individuals (33.5%, 95%CI:27.8-39.6) reported taking ART. The median CD4 count was 417 cells/μl (IQR:285-627); 33 (12.7%, 95%CI:8.9-17.4) had a CD4 count of ≤200 cells/μL. VL measurements were available for 219 (84.2%) individuals and were undetectable in 72 (33.9%), >1500 copies/ml in 127 (58.0%) and >10,000 copies/ml in 96 (43.8%). Of those reporting they were receiving ART, 30.4% had a VL>1500 copies/ml compared to 58.0% of those reporting they were not receiving ART.
Conclusion
A small proportion of those living with HIV in this community had a CD4 count <200 cells/μl; more than half had a VL high enough to be associated with considerable transmission risk. A substantial proportion of HIV-infected individuals remained at risk of transmitting HIV even after starting ART.
doi:10.1097/QAI.0b013e318293ae48
PMCID: PMC4233323  PMID: 23572010
22.  Combination HIV Prevention among MSM in South Africa: Results from Agent-based Modeling 
PLoS ONE  2014;9(11):e112668.
HIV prevention trials have demonstrated the effectiveness of a number of behavioral and biomedical interventions. HIV prevention packages are combinations of interventions and offer potential to significantly increase the effectiveness of any single intervention. Estimates of the effectiveness of prevention packages are important for guiding the development of prevention strategies and for characterizing effect sizes before embarking on large scale trials. Unfortunately, most research to date has focused on testing single interventions rather than HIV prevention packages. Here we report the results from agent-based modeling of the effectiveness of HIV prevention packages for men who have sex with men (MSM) in South Africa. We consider packages consisting of four components: antiretroviral therapy for HIV infected persons with CD4 count <350; PrEP for high risk uninfected persons; behavioral interventions to reduce rates of unprotected anal intercourse (UAI); and campaigns to increase HIV testing. We considered 163 HIV prevention packages corresponding to different intensity levels of the four components. We performed 2252 simulation runs of our agent-based model to evaluate those packages. We found that a four component package consisting of a 15% reduction in the rate of UAI, 50% PrEP coverage of high risk uninfected persons, 50% reduction in persons who never test for HIV, and 50% ART coverage over and above persons already receiving ART at baseline, could prevent 33.9% of infections over 5 years (95% confidence interval, 31.5, 36.3). The package components with the largest incremental prevention effects were UAI reduction and PrEP coverage. The impact of increased HIV testing was magnified in the presence of PrEP. We find that HIV prevention packages that include both behavioral and biomedical components can in combination prevent significant numbers of infections with levels of coverage, acceptance and adherence that are potentially achievable among MSM in South Africa.
doi:10.1371/journal.pone.0112668
PMCID: PMC4232469  PMID: 25398143
23.  Cervical Dysplasia and High-Risk Human Papillomavirus Infections among HIV-Infected and HIV-Uninfected Adolescent Females in South Africa 
Background. HIV-infected adolescents may be at higher risk for high-grade cervical lesions than HIV-uninfected adolescents. The purpose of this study was to compare the prevalence of high-risk HPV (HR-HPV) infections and Pap smear abnormalities between these two groups. Methods. In this cross-sectional study, we compared the HPV DNA and Pap smear results between 35 HIV-infected and 50 HIV-uninfected adolescents in order to determine the prevalence of HR-HPV genotypes and cervical cytological abnormalities. Comparisons were made using Pearson χ2 and independent-samples t-tests analyses, and associations between demographic and behavioral characteristics and HPV infections were examined. Results. HIV-infected participants were more likely to be infected with any HPV (88.6% versus 48.0%; P < 0.001) and with at least one HR-HPV (60.0% versus 24.0%; P = 0.001), and to have multiple concurrent HPV infections (68.6% versus 22.0%; P < 0.001). HPV 16 and 18 were relatively underrepresented among HR-HPV infections. Abnormal Pap test results were more common among HIV-infected participants (28.8% versus 12.0%; P = 0.054). A history of smoking was associated with HR-HPV infection. Conclusions. HIV-infected adolescents have an increased risk of infection with HR-HPV and of Pap test abnormalities. The majority of HR-HPV infections among our participants would not be prevented by the currently available vaccinations against HPV.
doi:10.1155/2014/498048
PMCID: PMC4217359  PMID: 25389377
24.  High Rate of Multiple Concurrent Human Papillomavirus Infections among HIV-Uninfected South African Adolescents 
Background
The epidemiology and impact of multiple concurrent Human papillomavirus (HPV) infections on the natural history of cervical disease is uncertain, but could have significant implications for cervical cancer prevention and HPV vaccination strategies.
Methods
A cross-sectional prevalence study was conducted to determine the overall prevalence of HPV and the rate of multiple concurrent HPV infections, in a cohort of sexually active HIV-uninfected South African adolescents. HPV genotyping was performed using the polymerase chain reaction.
Results
Overall prevalence of HPV was 64.1%. Multiple concurrent HPV infections were found in 43.6% of participants and 68% of HPV-infected participants. Non-vaccine high-risk HPV (HR-HPV) genotypes were found much more often than vaccine types (HPV16 and HPV18).
Conclusions
Our cohort of young South African females was found to have a high overall prevalence of HPV and multiple concurrent HPV infections. Most HR-HPV infections found were genotypes other than HPV16 or HPV18.
PMCID: PMC4201846  PMID: 25333073
Human papillomavirus; Multiple concurrent infections; Adolescent; South Africa
25.  Disengagement of HIV-positive pregnant and postpartum women from antiretroviral therapy services: a cohort study 
Introduction
Recent international guidelines call for expanded access to triple-drug antiretroviral therapy (ART) in HIV-positive women during pregnancy and postpartum. However, high levels of non-adherence and/or disengagement from care may attenuate the benefits of ART for HIV transmission and maternal health. We examined the frequency and predictors of disengagement from care among women initiating ART during pregnancy in Cape Town, South Africa.
Methods
We used routine medical records to follow-up pregnant women initiating ART within prevention of mother-to-child transmission of HIV services in Cape Town, South Africa. Outcomes assessed through six months postpartum were (1) disengagement (no attendance within 56 days of a scheduled visit) and (2) missed visits (returning to care 14–56 days late for a scheduled visit).
Results
A total of 358 women (median age, 28 years; median gestational age, 26 weeks) initiated ART during pregnancy. By six months postpartum, 24% of women (n=86) had missed at least one visit and an additional 32% (n=115) had disengaged from care; together, 49% of women had either missed a visit or had disengaged by six months postpartum. Disengagement was more than twice as frequent postpartum compared to in the antenatal period (6.2 vs. 2.4 per 100 woman-months, respectively; p<0.0001). In a proportional hazards model, later gestational age at initiation (HR: 1.04; 95% CI: 1.00–1.07; p=0.030) and being newly diagnosed with HIV (HR: 1.57; 95% CI: 1.07–2.33; p=0.022) were significant predictors of disengagement after adjusting for patient age, starting CD4 cell count and site of ART initiation.
Conclusions
These results demonstrate that missed visits and disengagement from care occur frequently, particularly post-delivery, among HIV-positive women initiating ART during pregnancy. Women who are newly diagnosed with HIV may be particularly vulnerable and there is an urgent need for interventions both to promote retention overall, as well as targeting women newly diagnosed with HIV during pregnancy.
doi:10.7448/IAS.17.1.19242
PMCID: PMC4192834  PMID: 25301494
antiretroviral therapy; pregnancy; postpartum; retention; prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa

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