Drug-Resistant Tuberculosis among HIV-Infected Patients Starting Antiretroviral Therapy in Durban, South Africa

Objective

To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa.

Design

Cross-sectional cohort study.

Methods

Consecutive HIV-infected adults (≥18y/o) initiating HIV care were enrolled from May 2007–May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed.

Results

1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42–150/µl). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0–12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9–30.5) compared to 5.2% (95% CI 2.1–8.9) among those with no prior TB. 5.1% (95% CI 2.4–9.5) had rifampin or rifampin plus INH resistance.

Conclusions

The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.     

Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa

Background

Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients.

Methods

HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death.

Results

Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death.

Conclusions

Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.     

Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa

Objective

This study aims to describe the virological, immunological and clinical efficacy of protease inhibitor (PI)-based second-line antiretroviral therapy (ART) in rural South Africa.

Methods

An observational cohort study was performed on 210 patients (including 39 children) who initiated PI-based second-line therapy at least 12 months prior to data collection. Biannual clinical, immunological and virological monitoring was performed. Primary endpoints were adequate virological response (plasma HIV-1 RNA<400 copies/ml), full virological suppression (plasma HIV-1 RNA<50 copies/ml) and treatment failure (virological failure (plasma HIV-1 RNA>1000 after initial virological response) or on-going viremia (plasma HIV-1 RNA never<400 copies/ml for more than six months)). Data were analyzed by an on-treatment (OT) and intention-to-treat (ITT) approach. Analyses were primarily performed on the group of patients who switched following first-line virological failure.

Results

Median duration of follow-up after switch to second-line treatment was 20 months [IQR 11–35]. 191 patients had switched to second-line ART due to first-line virological failure. 139/191 of them (72.8%, ITT) were in care and on treatment at the end of follow-up and 11/191 (5.8%, ITT) had died. After twelve months, an adequate virological response was seen in 92/128 patients (71.9%, OT), of which 78/128 (60.9%, OT) experienced full virological suppression. Virological response remained stable after 24 months. Virological efficacy was similar amongst adult and pediatric patients. As in first-line ART, we observed a lack of correlation between virological failure and WHO-defined immunological failure.

Conclusions

Good virological outcomes following first-line failure can be achieved with PI-based, second-line antiretroviral therapy in both adult and pediatric patients in rural South Africa. Retention rates were high and virological outcomes were sustainable during the two-year follow-up period, although persisting low-level viremia occurred in a subset of patients. The observed viro-immunological dissociation emphasizes the need for virological monitoring.     

Antiretroviral therapy and demand for HIV testing: Evidence from Zambia

This paper examines the effects of antiretroviral therapy (ART) on demand for HIV testing and of ART-induced testing on demand for risky sexual behavior. I provide a model of sexual behavior decision-making under uncertainty and estimate the structural parameters of the model using nationally representative survey data from Zambia on HIV testing decisions before and after the introduction of ART. The empirical results indicate that although the introduction of ART appears to have increased HIV testing rates by upwards of 50 percent, the ART allocation process may have limited the prevention benefit of ART-induced testing. Simulation results show that eliminating this prevention inefficiency while holding the supply of ART constant would increase the prevention impact of ART-induced testing more than four-fold. More generally, the analysis indicates that existing studies which examine “universal” testing or quasi-experimental testing programs understate the efficacy of standard voluntary counseling and testing programs.     

Gender Differences in Survival among Adult Patients Starting Antiretroviral Therapy in South Africa: A Multicentre Cohort Study

Background

Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART.

Methods and Findings

Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population.Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22–1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12–1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86–1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located.

Conclusions

HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors'' Summary.     

Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study

Background

Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study''s finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.

Methods and Findings

We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study''s major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.

Conclusions

Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors'' Summary     

Temporal Trends in the Characteristics of Children at Antiretroviral Therapy Initiation in Southern Africa: The IeDEA-SA Collaboration

Background

Since 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration.

Methodology/Principal Findings

Data from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick''s test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<−3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines.

Conclusions/Significance

Between 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children.     

Increasing Transfers-Out from an Antiretroviral Treatment Service in South Africa: Patient Characteristics and Rates of Virological Non-Suppression

Objectives

To determine the proportion, characteristics and outcomes of patients who transfer-out from an antiretroviral therapy (ART) service in a South African township.

Methods

This retrospective cohort study included all patients aged ≥15 years who enrolled between September 2002 and December 2009. Follow-up data were censored in December 2010. Kaplan-Meier survival analysis was used to describe time to transfer-out and cox proportional hazard analysis was used to determine associated risk factors.

Results

4511 patients (4003 ART-naïve and 508 non-naïve at baseline) received ART during the study period. Overall, 597 (13.2%) transferred out. The probability of transferring out by one year of ART steadily increased from 1.4% in 2002/2004 cohort to 8.9% for the 2009 cohort. Independent risk factors for transfer-out were more recent calendar year of enrolment, younger age (≤25 years) and being ART non-naïve at baseline (i.e., having previously transferred into this clinic from another facility). The proportions of patients transferred out who had a CD4 cell count <200 cells/µL and/or a viral load ≥1000 copies/mL were 19% and 20%, respectively.

Conclusions

With scale-up of ART over time, an increasing proportion of patients are transferring between ART services and information systems are needed to track patients. Approximately one-fifth of these have viral loads >1000 copies/mL around the time of transfer, suggesting the need for careful adherence counseling and assessment of medication supplies among those planning transfer.     

Antiretroviral therapy outcomes in HIV-infected children after adjusting protease inhibitor dosing during tuberculosis treatment

Background

Modification of ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy is required for HIV-infected children co-treated for tuberculosis (TB). We aimed to determine virologic and toxicity outcomes among TB/HIV co-treated children with the following modifications to their antiretroviral therapy (ART): (1) super-boosted LPV/r, (2) double-dose LPV/r or (3) ritonavir.

Methods and Findings

A medical record review was conducted at two clinical sites in Johannesburg, South Africa. The records of children 6–24 months of age initiating LPV/r-based therapy were reviewed. Children co-treated for TB were categorized based on the modifications made to their ART regimen and were compared to children of the same age at each site not treated for TB.Included are 526 children, 294 (56%) co-treated for TB. All co-treated children had more severe HIV disease, including lower CD4 percents and worse growth indicators, than comparisons.Children in the super-boosted group (n = 156) were as likely to be virally suppressed (<400 copies/ml) at 6 months as comparisons (69.2% vs. 74.8%, p = 0.36). Children in the double-dose (n = 47) and ritonavir groups (n = 91) were significantly less likely to be virally suppressed at 6 months (53.1% and 49.3%) than comparisons (74.8% and 82.1%; p = 0.02 and p<0.0001, respectively). At 12 months only children in the ritonavir group still had lower rates of virological suppression relative to comparisons (63.9% vs 83.3% p<0.05). Grade 1 or greater ALT elevations were more common in the super-boosted (75%) than double-dose (54.6%) or ritonavir (33.9%) groups (p = 0.09 and p<0.0001) but grade 3/4 elevations were observed in 3 (13.6%) of the super-boosted, 7 (15.9%) of the double-dose and 5 (8.9%) of the ritonavir group (p = 0.81 and p = 0.29).

Conclusion

Good short-term virologic outcomes were achieved in children co-treated for TB and HIV who received super-boosted LPV/r. Treatment limiting toxicity was rare. Strategies for increased dosing of LPV/r with TB treatment warrant further investigation.     

Impact of Antiretroviral Therapy on Incidence of Pregnancy among HIV-Infected Women in Sub-Saharan Africa: A Cohort Study

Background

With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates.

Methods and Findings

We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19–2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts.

Conclusions

ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services. Please see later in the article for the Editors'' Summary