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.

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.

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.

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.

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.

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.

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.

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.

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.

Background

Patients with prevalent or incident tuberculosis (TB) in antiretroviral treatment (ART) programmes in sub-Saharan Africa have high mortality risk. However, published data are contradictory as to whether TB is a risk factor for mortality that is independent of CD4 cell counts and other patient characteristics.

Methods/Findings

This observational ART cohort study was based in Cape Town, South Africa. Deaths from all causes were ascertained among patients receiving ART for up to 8 years. TB diagnoses and 4-monthly CD4 cell counts were recorded. Mortality rates were calculated and Poisson regression models were used to calculate incidence rate ratios (IRR) and identify risk factors for mortality. Of 1544 patients starting ART, 464 patients had prevalent TB at baseline and 424 developed incident TB during a median of 5.0 years follow-up. Most TB diagnoses (73.6%) were culture-confirmed. A total of 208 (13.5%) patients died during ART and mortality rates were 8.84 deaths/100 person-years during the first year of ART and decreased to 1.14 deaths/100 person-years after 5 years. In multivariate analyses adjusted for baseline and time-updated risk factors, both prevalent and incident TB were independent risk factors for mortality (IRR 1.7 [95% CI, 1.2–2.3] and 2.7 [95% CI, 1.9–3.8], respectively). Adjusted mortality risks were higher in the first 6 months of ART for those with prevalent TB at baseline (IRR 2.33; 95% CI, 1.5–3.5) and within the 6 months following diagnoses of incident TB (IRR 3.8; 95% CI, 2.6–5.7).

Conclusions

Prevalent TB at baseline and incident TB during ART were strongly associated with increased mortality risk. This effect was time-dependent, suggesting that TB and mortality are likely to be causally related and that TB is not simply an epiphenomenon among highly immunocompromised patients. Strategies to rapidly diagnose, treat and prevent TB prior to and during ART urgently need to be implemented.

A prospective survey of social mixing patterns relevant to respiratory disease transmission by large droplets (e.g., influenza) or small droplet nuclei (e.g., tuberculosis) was performed in a South African township in 2010. A total of 571 randomly selected participants recorded the numbers, times, and locations of close contacts (physical/nonphysical) and indoor casual contacts met daily. The median number of physical contacts was 12 (interquartile range (IQR), 7–18), the median number of close contacts was 20 (IQR, 13–29), and the total number of indoor contacts was 30 (IQR, 12–54). Physical and close contacts were most frequent and age-associative in youths aged 5–19 years. Numbers of close contacts were 40% higher than in corresponding populations in industrialized countries (P < 0.001). This may put township communities at higher risk for epidemics of acute respiratory illnesses. Simulations of an acute influenza epidemic predominantly involved adolescents and young adults, indicating that control strategies should be directed toward these age groups. Of all contacts, 86.2% occurred indoors with potential exposure to respiratory droplet nuclei, of which 27.2%, 20.1%, 20.0%, and 8.0% were in transport, own household, crèche/school, and work locations, respectively. Indoor contact time was long in households and short during transport. High numbers of indoor contacts and intergenerational mixing in households and transport may contribute to exceptionally high rates of tuberculosis transmission reported in the community.

Abstract

Pediatric antiretroviral adherence is difficult to assess, and subjective measures are affected by reporting bias, which in turn may depend on psychosocial factors such as alcohol use and depression. We enrolled 56 child–caregiver dyads from Cape Town, South Africa and followed their adherence over 1 month via various methods. The Alcohol Use Disorder Inventory Tool and Beck Depression Inventory 1 were used to assess these factors and their affect on pediatric adherence. The median age of the children was 4 years, and median time on antiretrovirals was 20 months. Increased time on ART was associated with poorer adherence via 3-day recall (3DR; p=0.03). Ethanol use was inversely associated with adherence by both subjective measures, 3DR and visual analogue scale (VAS) (both p<0.01), and with Medication Event Monitoring System (MEMS) adherence as a continuous variable. In a multivariate analysis predicting MEMS adherence greater than 95%, including variables that were associated with adherence in univariate analyses, having a mother as a caregiver and shorter time on highly active antiretroviral therapy (HAART) were significantly associated with adherence (odds ratio [OR] 19.2; 95% confidence interval [CI] 1.1–327 and 0.9; 95% CI 0.9–0.99). Pediatric adherence is affected by caregiver alcohol use, but caregiver relationship to the child is most important. This small study suggests that interventions should aim to keep mothers healthy and alive, as well as alcohol-free.

The provision of appropriate HIV prevention, treatment, and care services for most-at-risk populations (MARP) will challenge many health care systems. For people who sell sex (SW) or inject drugs (IDU) and for men who have sex with men (MSM), stigma, discrimination, and criminalization can limit access to care, inhibit service uptake, and reduce the disclosure of risks. Several models for provision of HIV services to MARP may address these issues. We discuss integrated models, stand-alone services, and hybrid models, which may be appropriate for some MARP in some settings. Both public health and human rights frameworks concur that those at greatest risk should have expanded access to services.

Recombinant adenovirus serotype 5 (rAd5) vaccine vectors for HIV-1 and other pathogens have been shown to be limited by high titers of Ad5 neutralizing antibodies (NAbs) in the developing world. Alternative serotype rAd vectors have therefore been constructed. Here we report Ad5, Ad26, Ad35, and Ad48 NAb titers in 4,381 individuals from North America, South America, sub-Saharan Africa, and Southeast Asia. As expected, Ad5 NAb titers were both frequent and high magnitude in sub-Saharan Africa and Southeast Asia. In contrast, Ad35 NAb titers proved infrequent and low in all regions studied, and Ad48 NAbs were rare in all regions except East Africa. Ad26 NAbs were moderately common in adults in sub-Saharan Africa and Southeast Asia, but Ad26 NAb titers proved markedly lower than Ad5 NAb titers in all regions, and these relatively low Ad26 NAb titers did not detectably suppress the immunogenicity of 4×1010 vp of a rAd26-Gag/Pol/Env/Nef vaccine in rhesus monkeys. These data inform the clinical development of alternative serotype rAd vaccine vectors in the developing world.

Purpose

Adolescents are at high risk for HIV infection, yet have not been included in HIV vaccine trials.

Methods

In preparation for their enrollment in HIV vaccine trials, 100 HIV-negative 14 to 17 year olds from Cape Town were recruited into a cohort. HIV, syphilis, pregnancy testing, and sexual risk questionnaires were performed at varying intervals for one year.

Results

The mean age of the participants was 15 years, and 70% were female. Recruitment was completed in three months. Retention was 82% at 1 year. The main reasons for dropout were relocation to other communities, phlebotomy, and visit frequency. In a Cox proportional hazards model, only female gender was significantly associated with retention. No change in reported sexual risk occurred, but the proportion knowing their partners’ HIV status was significantly higher (17% at baseline, 83% at one year; p<0.001). There were five pregnancies during follow-up.

Conclusions

To our knowledge, this is the first prospective adolescent HIV prevention cohort in Southern Africa. Despite reports of risky sex and high pregnancy rates, HIV seroconversions did not occur in the retained cohort. HIV prevention trials with high-risk adolescents will require rigorous efforts to prevent pregnancy, and may require risk eligibility criteria. Retention may improve with transport provision, incentivizing visits, and efforts to retain males.

Background

We hypothesized that in South Africa, with a generalized tuberculosis (TB) epidemic, TB infection is predominantly acquired indoors and transmission potential is determined by the number and duration of social contacts made in locations that are conducive to TB transmission. We therefore quantified time spent and contacts met in indoor locations and public transport by residents of a South African township with a very high TB burden.

Methods

A diary-based community social mixing survey was performed in 2010. Randomly selected participants (n = 571) prospectively recorded numbers of contacts and time spent in specified locations over 24-hour periods. To better characterize age-related social networks, participants were stratified into ten 5-year age strata and locations were classified into 11 types.

Results

Five location types (own-household, other-households, transport, crèche/school, and work) contributed 97.2% of total indoor time and 80.4% of total indoor contacts. Median time spent indoors was 19.1 hours/day (IQR:14.3–22.7), which was consistent across age strata. Median daily contacts increased from 16 (IQR:9–40) in 0–4 year-olds to 40 (IQR:18–60) in 15–19 year-olds and declined to 18 (IQR:10–41) in ≥45 year-olds. Mean daily own-household contacts was 8.8 (95%CI:8.2–9.4), which decreased with increasing age. Mean crèche/school contacts increased from 6.2/day (95%CI:2.7–9.7) in 0–4 year-olds to 28.1/day (95%CI:8.1–48.1) in 15–19 year-olds. Mean transport contacts increased from 4.9/day (95%CI:1.6–8.2) in 0–4 year-olds to 25.5/day (95%CI:12.1–38.9) in 25–29 year-olds.

Conclusions

A limited number of location types contributed the majority of indoor social contacts in this community. Increasing numbers of social contacts occurred throughout childhood, adolescence, and young adulthood, predominantly in school and public transport. This rapid increase in non-home socialization parallels the increasing TB infection rates during childhood and young adulthood reported in this community. Further studies of the environmental conditions in schools and public transport, as potentially important locations for ongoing TB infection, are indicated.

Objective. To assess awareness of and interest in intrauterine contraceptive device (IUCD) use among HIV-positive women in Cape Town, South Africa. Design. Cross-sectional survey. Methods. HIV-positive women aged 18 through 45 years presenting for care at a primary health care clinic in Cape Town, South Africa participated in this study. Consented participants completed a staff-administered questionnaire in a private setting. Descriptive statistics were generated. Comparisons between demographic and reproductive health-related variables and IUCD awareness and interest were performed with multiple logistic regression. Analyses for IUCD interest excluded women with prior surgical sterilization. Results. Of 277 HIV-positive women, 37% were aware of the IUCD; awareness was independently associated with greater age (adjusted odds ratio (AOR) = 1.15, 95%; confidence interval (CI): 1.10–1.20) and not switching contraceptive methods in the last year (AOR = 2.45, 95% CI: 1.03–5.83). Following an IUCD information session, 86% of women (n = 206/240) were interested in IUCD use. IUCD interest was inversely associated with age (AOR = 0.91, 95% CI: 0.86–0.97) and marginally positively associated with current menstrual bleeding pattern complaints (AOR = 2.14, 95% CI: 0.98–4.68). Conclusions. Despite low levels of method awareness, HIV-positive women in this setting are frequently interested in IUCD use, indicating need for programming to expand method access.

Background

Although antiretroviral therapy (ART) is known to be associated with time-dependent reductions in tuberculosis (TB) incidence, the long-term impact of ART on incidence remains imprecisely defined due to limited duration of follow-up and incomplete CD4 cell count recovery in existing studies. We determined TB incidence in a South African ART cohort with up to 8 years of follow-up and stratified rates according to CD4 cell count recovery. We compared these rates with those of HIV-uninfected individuals living in the same community.

Methodology/Principal Findings

Prospectively collected clinical data on patients receiving ART in a community-based cohort in Cape Town were analysed. 1544 patients with a median follow-up of 5.0 years (IQR 2.4–5.8) were included in the analysis. 484 episodes of incident TB (73.6% culture-confirmed) were diagnosed in 424 patients during 6506 person-years (PYs) of follow-up. The TB incidence rate during the first year of ART was 12.4 (95% CI 10.8–14.4) cases/100PYs and decreased to 4.92 (95% CI 3.64–8.62) cases/100PYs between 5 and 8 years of ART. During person-time accrued within CD4 cell strata 0–100, 101–200, 201–300, 301–400, 401–500, 501–700 and ≥700 cells/µL, TB incidence rates (95% CI) were 25.5 (21.6–30.3), 11.2 (9.4–13.5), 7.9 (6.4–9.7), 5.0 (3.9–6.6), 5.1 (3.8–6.8), 4.1 (3.1–5.4) and 2.7 (1.7–4.5) cases/100PYs, respectively. Overall, 75% (95% CI 70.9–78.8) of TB episodes were recurrent cases. Updated CD4 cell count and viral load measurements were independently associated with long-term TB risk. TB rates during person-time accrued in the highest CD4 cell count stratum (>700 cells/µL) were 4.4-fold higher that the rate in HIV uninfected individuals living in the same community (2.7 versus 0.62 cases/100PYs; 95%CI 0.58–0.65).

Conclusions/Significance

TB rates during long-term ART remained substantially greater than rates in the local HIV uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/µL.

Abstract

To characterize WHO-defined transmitted HIV drug resistance mutation (TDRM) data from recently HIV-infected African volunteers, we sequenced HIV (pol) and evaluated for TDRM the earliest available specimens from ARV-naive volunteers diagnosed within 1 year of their estimated date of infection at eight research centers in sub-Saharan Africa. TDRMs were detected in 19/408 (5%) volunteers. The prevalence of TDRMs varied by research center, from 5/26 (19%) in Entebbe, 6/78 (8%) in Kigali, 2/49 (4%) in Kilifi, to 3/106 (3%) in Lusaka. One of five volunteers from Cape Town (20%) had TDRMs. Despite small numbers, our data suggest an increase in DRMs by year of infection in Zambia (p = 0.004). The prevalence observed in Entebbe was high across the entire study. ARV history data from 12 (63%) HIV-infected sexual partners were available; 3 reported ARV use prior to transmission. Among four partners with sequence data available, transmission linkage was confirmed and two had the same TDRMs as the newly infected volunteer (both K103N). As ARV therapy continues to increase in availability throughout Africa, monitoring incident virus strains for the presence of TDRMs should be a priority. Early HIV infection cohorts provide an excellent and important platform to monitor the development of TDRMs to inform treatment guidelines, drug choices, and strategies for secondary prevention of TDRM transmission.

Rationale: In 2005, we reported high prevalence of untreated pulmonary tuberculosis (TB) in a South African community. Prevalent untreated TB is the main source of transmission. In settings with large burdens of human immunodeficiency virus (HIV) and TB, highly active antiretroviral therapy (HAART) may contribute to TB control.

Objectives: To assess the community-level impact of HAART on TB prevalence, we repeated a community-based TB prevalence cross-sectional survey in 2008 following HAART roll-out.

Methods: A random 10% adult population sample was identified from the community. Participants provided two sputum specimens for acid-fast bacilli microscopy and TB culture. Oral transudate specimen was collected for anonymous HIV testing, linked to TB diagnosis. An interviewer-administered, structured questionnaire identified TB and HIV history and risk factors.

Measurements and Main Results: In the 2008 survey, 1,250 adults participated (90% response rate); 306 (25%) tested HIV positive, of which 60 (20%) were receiving HAART. A total of 20 TB cases were identified (12 receiving TB treatment), representing a significant decline in prevalence from 3.2 to 1.6% (P = 0.02) between the surveys. TB prevalence in participants not infected with HIV was unchanged (P = 0.90). The decline occurred among participants not infected with HIV, decreasing from 9.2 to 3.6% in 2005 to 2008, respectively (P = 0.003). In participants infected with HIV, prevalence of treated TB declined from 4 to 2.3% (P = 0.06), and untreated TB prevalence from 5.2 to 1.3% (P = 0.02). The proportion of untreated TB in patients receiving HAART decreased significantly, from 22 to 0% (P < 0.001).

Conclusions: Prevalence of undiagnosed TB declined significantly over a period of increasing HAART availability. The decline was predominantly in individuals infected with HIV receiving HAART.

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.

Introduction

Tuberculosis (TB) transmission is determined by contact between infectious and susceptible individuals. A recent study reported a 4% annual risk of child TB infection (ARTI) in a Southern African township. A model was used to explore the interactions between prevalence of adult TB infection, adult-to-child contacts and household ventilation which could result in such a high ARTI.

Methods

Number of residents per household and TB incidence were derived from a household census and community TB registers. Using the “Wells-Riley” equation and probability analyses of contact between TB infectious adults and pre-school children, we estimated the ARTI within and outside of the home.

Results

There was a mean of 2.2 adults per child-household with a 1.35% annual adult smear-positive TB notification rate. The maximal household ARTI was 3% which was primarily determined by the number of resident adults. Transmission risk outside the home increased with numbers of households visited. Transmission probabilities were sensitive to exposure time, ventilation and period of adult infectivity. The benefits of increased ventilation were greatest when the period of infectivity was reduced. Similar reductions in household transmission could be achieved by increasing ventilation from 2 to 6 air changes/hour or separating child and adult sleeping areas.

Conclusions

The ARTI of pre-school children predominantly results from infectious residents in the home. However, even with limited social interactions, a substantial proportion of transmission may occur from non-resident adults. The benefits of increased ventilation are maximized when the period of infectivity is reduced by prompt treatment of source cases.

In a prospective study, Stephen Lawn and colleagues find that pre-ART screening with Xpert MTB/RIF increased tuberculosis case detection by 45% compared to smear microscopy in HIV-positive patients at high risk of TB risk. AE competing interests must also pull through to the proof. “The Academic Editor, Madhukar Pai, declares that he consults for the Bill & Melinda Gates Foundation (BMGF). The BMGF supported FIND which was involved in the development of the Xpert MTB/RIF assay. He also co-chairs the Stop TB Partnership's New Diagnostics Working Group that was involved in the WHO endorsement of the Xpert assay.” Linked: Scott pmed.1001061; Evans pmed.1001064; Dowdy pmed.1001063

Background

The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral therapy (ART) services is unknown.

Methods and Findings

Consecutive adult HIV-infected patients with no current TB diagnosis enrolling in an ART clinic in a South African township were recruited regardless of symptoms. They were clinically characterised and invited to provide two sputum samples at a single visit. The accuracy of the Xpert MTB/RIF assay for diagnosing TB and drug resistance was assessed in comparison with other tests, including fluorescence smear microscopy and automated liquid culture (gold standard) and drug susceptibility testing. Of 515 patients enrolled, 468 patients (median CD4 cell count, 171 cells/µl; interquartile range, 102–236) produced at least one sputum sample, yielding complete sets of results from 839 samples. Mycobacterium tuberculosis was cultured from 81 patients (TB prevalence, 17.3%). The overall sensitivity of the Xpert MTB/RIF assay for culture-positive TB was 73.3% (specificity, 99.2%) compared to 28.0% (specificity, 100%) using smear microscopy. All smear-positive, culture-positive disease was detected by Xpert MTB/RIF from a single sample (sensitivity, 100%), whereas the sensitivity for smear-negative, culture-positive TB was 43.4% from one sputum sample and 62.3% from two samples. Xpert correctly identified rifampicin resistance in all four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was confirmed to be drug sensitive by gene sequencing (specificity, 94.1%; positive predictive value, 57%).

Conclusions

In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug-resistant TB was sub-optimal.

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Tuberculosis (TB)—a contagious bacterial infection that mainly affects the lungs—is a leading cause of illness and death among people who are infected with HIV, the virus that causes AIDS by destroying the immune system, which leaves infected individuals susceptible to other infections. TB is caused by Mycobacterium tuberculosis, which is spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, weight loss, and night sweats. Diagnostic tests for TB include chest X-rays, sputum smear analysis (microscopic examination of mucus coughed up from the lungs for M. tuberculosis bacilli), and mycobacterial liquid culture (the growth of M. tuberculosis from sputum and determination of its drug sensitivity). TB can be cured by taking several drugs daily for six months, although the recent emergence of multidrug-resistant TB (MDR-TB) is making the disease increasingly hard to treat.

Why Was This Study Done?

TB is a major problem in clinics that provide antiretroviral therapy (ART) for HIV-positive people in resource-limited settings. Not only is it a major cause of sickness and mortality in those affected by it, but TB (especially MDR-TB) can also spread to other patients attending the same clinic for health services. Rapid diagnosis and appropriate treatment are very important to reduce these risks. Unfortunately, sputum smear analysis—the mainstay of TB diagnosis in resource-limited settings—only detects about a fifth of TB cases when used as a screening tool before initiating ART. Chest X-rays are costly and don't always detect TB, and liquid culture—the gold standard method for TB diagnosis—is costly, technically difficult, and slow. Consequently, the World Health Organization (WHO) recently endorsed a new test for the investigation of patients suspected of having TB, especially in regions where HIV infection and MDR-TB are common. Xpert MTB/RIF is an automated DNA test that detects M. tuberculosis and DNA differences that make the bacteria resistant to the drug rifampicin (an indicator of MDR-TB) within 2 hours. In this study, the researchers investigate whether Xpert MTB/RIF could be used as a routine screening test to increase TB detection among HIV-positive people initiating ART.

What Did the Researchers Do and Find?

The researchers collected sputum from HIV-infected adults with no current TB diagnosis enrolling at an ART clinic in a South African township where HIV infection and TB are both common. They then compared the diagnostic accuracy of Xpert MTB/RIF (performed at a centralized laboratory) with that of several other tests, including liquid culture (the reference test). Nearly a fifth of the patients had culture-positive TB. Xpert MTB/RIF identified three-quarters of these patients (a sensitivity of 73.3%). By contrast, the sensitivity of smear microscopy was 28%. The new test's specificity (the proportion of patients with a negative Xpert MTB/RIF result among patients without TB) was 99.2%. That is, Xpert MTB/RIF had a low false-positive rate. Notably, Xpert MTB/RIF detected all cases of smear-positive, culture-positive TB but only 43.4% of smear-negative, culture-positive cases from a single sputum sample; it detected 62.3% of such cases when two sputum samples were analyzed. Finally, Xpert MTB/RIF correctly identified rifampicin resistance in all four patients who had MDR-TB but incorrectly identified resistance in three patients with drug-sensitive TB.

What Do These Findings Mean?

In this population of HIV-positive patients with a high TB risk, pre-ART screening with Xpert MTB/RIF increased case detection by 45% compared to smear microscopy, a finding that needs confirming in other settings. Importantly, Xpert MTB/RIF reduced the delay in diagnosis of TB from more than 20 days to two days. This delay would be reduced further by doing the assay at ART clinics rather than at a centralized testing facility, but the diagnostic accuracy of point-of-care testing needs evaluating. Overall, these findings (and those of an accompanying article by Scott et al. that examines the performance of Xpert MTB/RIF in an area where HIV infection is common) support the replacement of smear microscopy with Xpert MTB/RIF for pre-ART TB screening (provided misdiagnosis of rifampicin resistance can be reduced). These findings also suggest that routine screening with Xpert MTB/RIF could reduce the risk of MDR-TB outbreaks in HIV care and treatment settings and improve outcomes for HIV-positive patients with MDR-TB who currently often die before a diagnosis of TB can be made.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001056.

This study is further discussed in a PLoS Medicine Perspective by Carlton Evans; a related PLoS Medicine Research Article by Scott et al. is also available

WHO provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the Xpert MTB/RIF test; further information about WHO's endorsement of Xpert MTB/RIF is included in a recent Strategic and Technical Advisory Group for Tuberculosis report

WHO also provides information about tuberculosis and HIV

The US National Institute of Allergy and Infectious Diseases has detailed information on tuberculosis and HIV/AIDS

The US Centers for Disease Control and Prevention also has information about tuberculosis, including information on the diagnosis of and on tuberculosis and HIV co-infection

Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on HIV-related tuberculosis (in English and Spanish)

Preventing HIV infection in adolescents and young adults will require a multimodal, targeted approach including individual-directed behavioral risk reduction, community-level structural change, and biomedical interventions to prevent sexual transmission. Trials testing biomedical interventions to prevent HIV transmission will require special attention in this population due to the unique psychosocial as well as physiologic characteristics that differentiate them from older populations. For example, microbicide research will need to consider acceptability, dosing requirements, and co-infection rates that are unique to this population. Pre-exposure prophylaxis studies also will need to consider potential unique psychosocial issues such as sexual disinhibition and acceptability as well as unique pharmacokinetic parameters of antiretroviral agents. Vaccine trials also face unique issues with this population, including attitudes towards vaccines, risks related to false-positive HIV tests related to vaccine, and different immune responses based on more robust immunity. In this paper, we will discuss issues around implementing each of these biomedical prevention modalities in trials among adolescents and young adults to help to guide future successful research targeting this population.

Background. We have previously shown that 75% of individuals on antiretroviral therapy (ART) in a resource-limited setting who experienced virological breakthrough to >1000 copies/mL were resuppressed after an intensive adherence intervention. This study examines the long-term outcomes of this group in order to understand the impact of the adherence intervention over time. Methods. ART-naïve adults commencing ART between September 2002 and December 2009 were reviewed. Those who achieved suppression (<50 copies/mL) were categorised by subsequent viral load: any >1000 copies/mL (virological breakthrough) or not. Those with breakthrough were sub-categorised by following viral load into failed (VL > 1000 copies/mL) or resuppressed (VL < 1000 copies/mL). Their outcome (lost-to follow-up, death, in care on first-line therapy or in care on second-line therapy) was determined as of the 13th April 2010. Findings. 4047 ART-naïve adults commenced ART. 3086 had >2 viral loads and were included in the analysis. 2959 achieved virological suppression (96%). Thereafter 2109 (71%) remained suppressed and 850 (29%) experienced breakthrough (n = 283 (33%) failed and n = 567 (67%) resuppressed). Individuals with breakthrough were younger (P < .001), had lower CD4 counts (P < .001), and higher viral loads (P < .001) than those who remained suppressed. By 7 years the risk of breakthrough was 42% and of failure 15%. Fewer adults with breakthrough remain in care over time (P < .001). Loss to care is similar whether the individuals failed or resuppressed. Interpretation. While 67% of those who experience initial virological breakthrough resuppress after an adherence intervention, these individuals are significantly less likely be retained in care than those who remain virologically suppressed throughout.