Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial.

BACKGROUND: Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. METHODS: In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. FINDINGS: 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. INTERPRETATION: Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. FUNDING: US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.

Polymorphisms in KSHV-encoded microRNA sequences affect levels of mature viral microRNA in Kaposi Sarcoma lesions.

Background: We previously reported Kaposi sarcoma-associated herpesvirus (KSHV) microRNA sequence variants in clinical samples correlated with increased risk of multicentric Castleman's disease (MCD). We then demonstrated that microRNAs with variant sequence have different maturation and mature microRNA expression in vitro. Here, we illustrate the association between microRNA sequence and changes in mature microRNA levels within Kaposi sarcoma (KS) lesions. Methods: KSHV microRNA sequences were determined from 20 KS lesions and 4 control skin biopsies from individuals evaluated for KS. Levels of mature KSHV microRNAs were measured with 21 custom small RNA qRT-PCR assays using RNA RNU6B as endogenous control. Results: The levels of 13 KSHV-encoded microRNAs were elevated in KS lesions compared to control biopsies. MicroRNA 9-5p was strongly down regulated in South African vs. US biopsies. Low levels of K12-9-5p were associated with single nucleotide polymorphisms (SNPs) in miR-K12-9-5p, 4-5p, 5-3p, 7-3p and pri-miR-K12-3. One SNP in pri-miR-K12-3 resulted in down regulation of miR-K12-6-3p, 8-3p, 10-3p, 12-5p and the upregulation of 5-5p, illustrating sequence variants outside pre-microRNAs were also associated with changes in mature microRNA levels. Conclusions: The levels of mature KSHV-encoded microRNAs in KS lesions correlate with sequence variation reflecting changes in secondary and tertiary RNA structure.

Effect of smoking on acute phase reactants, stress hormone responses and vitamin C in pulmonary tuberculosis.

BACKGROUND: Chronic inflammation, possibly exacerbated by cigarette smoking, is considered to be the primary cause of pulmonary damage in patients with tuberculosis (TB). However, the mechanisms which underpin these harmful inflammatory responses, have not been well documented. OBJECTIVES: The current study was undertaken to determine possible associations between systemic biomarkers of inflammation (acute phase reactants, stress hormones, leukocyte vitamin C) and smoking status in patients (n=71, 20 smokers) with newly-diagnosed pulmonary TB presenting at a tertiary hospital, Johannesburg, South Africa. METHODS: Plasma concentrations of C-reactive protein (CRP), ferritin, cortisol, epinephrine, norepinephrine, dopamine and leukocyte vitamin C were measured using a combination of immunonephelometric, radioimmunoassay, immunochromatographic and spectrophotometric procedures. Demographic, clinical and laboratory data was captured and analysed by parametric and non-parametric analyses where appropriate. RESULTS: Smokers were predominantly males (P<0.0001), of older age (P<0.0003) with a significantly lower body mass index (P<0.03). Plasma levels of CRP, ferritin and dopamine were higher in the group of smokers in the setting of lower levels of epinephrine, and leukocyte vitamin C, with CRP and vitamin C attaining statistical significance (P<0.04 and P<0.02 respectively). Those of cortisol and norepinephrine were comparable to those of non-smokers, as were radiographic changes and clinical indices of disease activity. CONCLUSION: Cigarette smoking is associated with an exaggerated systemic inflammatory response in pulmonary TB in the setting of decreased concentrations of leukocyte vitamin C. Although no significant associations with radiographic changes and most clinical indices of disease activity were evident on presentation, these pro-inflammatory interactions may have prognostic significance.

Cohort profile: the Right to Care Clinical HIV Cohort, South Africa.

PURPOSE: The research objectives of the Right to Care Clinical HIV Cohort analyses are to: (1) monitor treatment outcomes (including death, loss to follow-up, viral suppression and CD4 count gain among others) for patients on antiretroviral therapy (ART); (2) evaluate the impact of changes in the national treatment guidelines around when to initiate ART on HIV treatment outcomes; (3) evaluate the impact of changes in the national treatment guidelines around what ART regimens to initiate on drug switches; (4) evaluate the cost and cost-effectiveness of HIV treatment delivery models; (5) evaluate the need for and outcomes on second-line and third-line ART; (6) evaluate the impact of comorbidity with non-communicable diseases on HIV treatment outcomes and (7) evaluate the impact of the switch to initiating all patients onto ART regardless of CD4 count. PARTICIPANTS: The Right to Care Clinical HIV Cohort is an open cohort of data from 10 clinics in two provinces within South Africa. All clinics include data from 2004 onwards. The cohort currently has data on over 115 000 patients initiated on HIV treatment and patients are followed up every 3-6 months for clinical and laboratory monitoring. FINDINGS TO DATE: Cohort data includes information on demographics, clinical visit, laboratory data, medication history and clinical diagnoses. The data have been used to identify rates and predictors of first-line failure, to identify predictors of mortality for patients on second-line (eg, low CD4 counts) and to show that adolescents and young adults are at increased risk of unsuppressed viral loads compared with adults. FUTURE PLANS: Future analyses will inform national models of HIV care and treatment to improve HIV care policy in South Africa.

Prevalence of common vitamin D receptor gene polymorphisms in HIV-infected and uninfected South Africans.

BACKGROUND: Host genetic factors may a play role in susceptibility to infection. Vitamin-D is an immunomodulator that may play a role in HIV infection. Vitamin-D action is mediated by the vitamin-D receptor. We establish prevalence of ApaI, BsmI, FokI and TaqI polymorphisms (VDRPs) amongst a black southern African HIV+ve population and investigate polymorphic differences between HIV+ve and -ve people. METHODS: Seventy-nine sex and age-group matched HIV+ve patients of African origin initiating antiretroviral therapy (ART) and 79 HIV-ve participants, also of African origin, were recruited from a public sector HIV testing and treatment clinic and investigated for the 4 polymorphisms. The genotype frequencies were compared, odds ratios and 95% confidence intervals of the association of HIV status and each genotype were calculated. Both dominant, co-dominant, recessive and allele models were tested. RESULTS: We found no evidence of difference in distribution and association between HIV infection and the genotypes of the BsmI, FokI and TaqI VDR polymorphisms. The genotype distributions were consistent with Hardy-Weinberg equilibrium for these genotypes. The ApaI genotype showed differences in distribution by HIV status in the dominant and co-dominant models. However this finding is cautiously stated as the ApaI genotype violated the Hardy-Weinberg equilibrium and frequency of the minor variant was unexpectedly low in this population. CONCLUSION: We do not show convincing differences in distribution of the VDR genotypes among HIV+ve and HIV-ve black southern African persons. Future studies need to be replicated in larger study populations as understanding polymorphic differences and similarities may offer insights into the different susceptibility and progression of HIV in southern African populations.

CD4 criteria improves the sensitivity of a clinical algorithm developed to identify viral failure in HIV-positive patients on antiretroviral therapy.

INTRODUCTION: Several studies from resource-limited settings have demonstrated that clinical and immunologic criteria are poor predictors of virologic failure, confirming the need for viral load monitoring or at least an algorithm to target viral load testing. We used data from an electronic patient management system to develop an algorithm to identify patients at risk of viral failure using a combination of accessible and inexpensive markers. METHODS: We analyzed data from HIV-positive adults initiated on antiretroviral therapy (ART) in Johannesburg, South Africa, between April 2004 and February 2010. Viral failure was defined as ≥ 2 consecutive HIV-RNA viral loads >400 copies/ml following suppression ≤ 400 copies/ml. We used Cox-proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Weights for each predictor associated with virologic failure were created as the sum of the natural logarithm of the adjusted HR and dichotomized with the optimal cut-off at the point with the highest sensitivity and specificity (i.e. ≤ 4 vs. >4). We assessed the diagnostic accuracy of predictor scores cut-offs, with and without CD4 criteria (CD4 <100 cells/mm(3); CD4 < baseline; >30% drop in CD4), by calculating the proportion with the outcome and the observed sensitivity, specificity, positive and negative predictive value of the predictor score compared to the gold standard of virologic failure. RESULTS: We matched 919 patients with virologic failure (1:3) to 2756 patients without. Our predictor score included variables at ART initiation (i.e. gender, age, CD4 count <100 cells/mm(3), WHO stage III/IV and albumin) and laboratory and clinical follow-up data (drop in haemoglobin, mean cell volume (MCV) <100 fl, CD4 count <200 cells/mm(3), new or recurrent WHO stage III/IV condition, diagnosis of new condition or symptom and regimen change). Overall, 51.4% had a score 51.4% had a score ≥ 4 and 48.6% had a score <4. A predictor score including CD4 criteria performed better than a score without CD4 criteria and better than WHO clinico-immunological criteria or WHO clinical staging to predict virologic failure (sensitivity 57.1% vs. 40.9%, 25.2% and 20.9%, respectively). CONCLUSIONS: Predictor scores or risk categories, with CD4 criteria, could be used to identify patients at risk of virologic failure in resource-limited settings so that these patients may be targeted for focused interventions to improve HIV treatment outcomes.

Treatment response and mortality among patients starting antiretroviral therapy with and without Kaposi sarcoma: a cohort study.

BACKGROUND: Improved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART. METHODS: We analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment. RESULTS: Between January 2001-January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm³) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71-4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95-5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08-4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7-52cells/mm³) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99-2.06) within the first 6-months of treatment. CONCLUSIONS: HIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS.

Treatment outcomes after 7 years of public-sector HIV treatment.

OBJECTIVES: To assess outcomes over the first 7 years of antiretroviral therapy (ART) at Themba Lethu Clinic, Johannesburg, South Africa. DESIGN: Observational cohort study. METHODS: Patients are managed according to South African National Treatment Guidelines. Mortality is ascertained through linkage with the national vital registration system. Loss to follow-up is defined as at least 3 months late for the last scheduled appointment. RESULTS: Between April 2004 and March 2010, 13 227 patients initiated ART, increasing from 1794 in the year 2004/2005 to 2481 in 2009/2010. Median CD4 cell count at ART initiation increased 39% between 2004 and 2009 (82 vs. 114 cells/ml). The proportion who died within 1 year on ART was below 11% at all time points, whereas the proportion lost by 1 year increased from 8.5% in 2004 to 12.1% in 2009 [risk ratio (RR) 1.42, 95% confidence interval (CI) 1.18­1.71]. We followed the 1794 patients initiated in April 2004 and March 2005 through August 2011 for 8172 person-years. We estimated 25% of patients were lost and 16% died. The overall mortality rate was 3.59 per 100 person-years (95% CI 3.20­4.02). Of the 1577 who completed at least 6 months of follow-up, 213 (13.5%) failed first-line treatment in a median (interquartile range) of 25.9 (15.8­41.4) months on treatment. Of those who failed, 141 (66.2%) switched to second-line for a rate of 48.5 per 100 person-years (95% CI 41.1­57.2). CONCLUSION: Despite some improvements over 7 years, more intervention is needed in the first year on treatment to reduce overall attrition.

Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment.

OBJECTIVE: To compare clinical, immunologic and virologic outcomes among stable HIV-positive patients down-referred to a nurse-managed primary healthcare clinic (PHC) for treatment maintenance to those who remained at a doctor-managed treatment-initiation site. DESIGN: We conducted a matched cohort analysis among stable HIV patients at the Themba Lethu Clinic in Johannesburg, South Africa. Eligible patients met the criteria for down-referral [undetectable viral load <10 months, antiretroviral therapy (ART) >11 months, CD4 cell count ≥200 cells/µl, stable weight and no opportunistic infections], regardless of whether they were down-referred to a PHC for treatment maintenance between February 2008 and January 2009. Patients were matched 1 : 3 (down-referred : treatment-initiation) using propensity scores. METHODS: We calculated rates and hazard ratios (HRs) for the effect of down-referral on loss to follow-up (LTFU) and mortality and the relative risk of down-referral on viral rebound by 12 months of follow-up. RESULTS: Six hundred and ninety-three down-referred patients were matched to 2079 treatment-initiation patients. Two (0.3%) down-referred and 32 (1.5%) treatment-initiation patients died, 10 (1.4%) down-referred and 87 (4.2%) treatment-initiation patients were lost, and 22 (3.3%) down-referred and 100 (5.6%) treatment-initiation patients experienced viral rebound by 12 months of follow-up. After adjustment, patients down-referred were less likely to die [hazard ratio (HR) 0.2, 95% confidence interval (CI) 0.04-0.8], become LTFU (HR 0.3, 95% CI 0.2-0.6) or experience viral rebound (relative risk 0.6, 95% CI 0.4-0.9) than treatment-initiation patients during follow-up. CONCLUSION: The utilization of nurse-managed PHCs for treatment maintenance of stable patients could decrease the burden on specialized doctor-managed ART clinics. Patient outcomes for down-referred patients at PHCs appear equal, if not better, than those achieved at ART clinics among stable patients.

Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa.

BACKGROUND: The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. METHODS AND FINDINGS: We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. CONCLUSIONS: The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up.

Kaposi's Sarcoma Associated-Herpes Virus (KSHV) Seroprevalence in Pregnant Women in South Africa.

BACKGROUND: Factors previously associated with Kaposi's sarcoma-associated herpesvirus (KSHV) transmission in Africa include sexual, familial, and proximity to river water. We measured the seroprevalence of KSHV in relation to HIV, syphilis, and demographic factors among pregnant women attending public antenatal clinics in the Gauteng province of South Africa. METHODS: We tested for antibodies to KSHV lytic K8.1 and latent Orf73 antigens in 1740 pregnant women attending antenatal clinics who contributed blood to the "National HIV and Syphilis Sero-Prevalence Survey - South Africa, 2001". Information on HIV and syphilis serology, age, education, residential area, gravidity, and parity was anonymously linked to evaluate risk factors for KSHV seropositivity. Clinics were grouped by municipality regions and their proximity to the two main river catchments defined. RESULTS: KSHV seropositivity (reactive to either lytic K8.1 and latent Orf73) was nearly twice that of HIV (44.6% vs. 23.1%). HIV and syphilis seropositivity was 12.7% and 14.9% in women without KSHV, and 36.1% and 19.9% respectively in those with KSHV. Women who are KSHV seropositive were 4 times more likely to be HIV positive than those who were KSHV seronegative (AOR 4.1 95%CI: 3.4 - 5.7). Although, women with HIV infection were more likely to be syphilis seropositive (AOR 1.8 95%CI: 1.3 - 2.4), no association between KSHV and syphilis seropositivity was observed. Those with higher levels of education had lower levels of KSHV seropositivity compared to those with lower education levels. KSHV seropositivity showed a heterogeneous pattern of prevalence in some localities. CONCLUSIONS: The association between KSHV and HIV seropositivity and a lack of common association with syphilis, suggests that KSHV transmission may involve geographical and cultural factors other than sexual transmission.

Using vital registration data to update mortality among patients lost to follow-up from ART programmes: evidence from the Themba Lethu Clinic, South Africa.

OBJECTIVE: To estimate the rates of mortality in patients lost to follow-up (LTFU) from a large urban public sector HIV clinic in South Africa. METHODS: We compared vital status using the clinic's database to vital status verified against the Vital Registration system at the South African Department of Home Affairs. We compared rates of mortality before and after updating mortality data. Predictors of mortality were estimated using Kaplan-Meier curves and proportional hazard regression. RESULTS: Of the 7097 total patients who initiated highly active antiretroviral therapy at Themba Lethu Clinic by October 1st, 2008 and had an ID number, 6205 were included. 2453 patients (21%) were LTFU, of whom 1037 (42.3%) could be included in the analysis. After matching to the vital registration system, mortality more than doubled from 4.2% (258/6205) to 10.9% (676/6205). Overall 37% of those LTFU died by life-table analysis the probability of survival amongst those LTFU was 69% (95% CI: 66-72%), 64% (95% CI: 61-67%) and 59% (95% CI: 55-62%) by years 1, 2 and 3 since being lost, respectively. Those at highest risk of death after being lost were patients with a history of tuberculosis, CD4 count < 100 cells/microl, BMI < 17.5, haemoglobin < 10 and on <6 months of treatment. CONCLUSION: Mortality was substantially underestimated among patients lost from a South African HIV treatment programme despite limited active tracing. Linking to vital registration systems can provide more accurate assessments of programme effectiveness and target lost patients most at risk for mortality.

Mortality after failure of antiretroviral therapy in sub-Saharan Africa.

OBJECTIVE: To assess the outcome of patients who experienced treatment failure with antiretrovirals in sub-Saharan Africa. METHODS: Analysis of 11 antiretroviral therapy (ART) programmes in sub-Saharan Africa. World Health Organization (WHO) criteria were used to define treatment failure. All ART-naive patients aged >or=16 who started with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen and had at least 6 months of follow-up were eligible. For each patient who switched to a second-line regimen, 10 matched patients who remained on a non-failing first-line regimen were selected. Time was measured from the time of switching, from the corresponding time in matched patients, or from the time of treatment failure in patients who remained on a failing regimen. Mortality was analysed using Kaplan-Meier curves and random-effects Cox models. RESULTS: Of 16 591 adult patients starting ART, 382 patients (2.3%) switched to a second-line regimen. Another 323 patients (1.9%) did not switch despite developing immunological or virological failure. Cumulative mortality at 1 year was 4.2% (95% CI 2.2-7.8%) in patients who switched to a second-line regimen and 11.7% (7.3%-18.5%) in patients who remained on a failing first-line regimen, compared to 2.2% (1.6-3.0%) in patients on a non-failing first-line regimen (P < 0.0001). Differences in mortality were not explained by nadir CD4 cell count, age or differential loss to follow up. CONCLUSIONS: Many patients who meet criteria for treatment failure do not switch to a second-line regimen and die. There is an urgent need to clarify the reasons why in sub-Saharan Africa many patients remain on failing first-line ART.

Accuracy of WHO CD4 cell count criteria for virological failure of antiretroviral therapy.

OBJECTIVES: To examine the accuracy of the World Health Organization immunological criteria for virological failure of antiretroviral treatment. METHODS: Analysis of 10 treatment programmes in Africa and South America that monitor both CD4 cell counts and HIV-1 viral load. Adult patients with at least two CD4 counts and viral load measurements between month 6 and 18 after starting a non-nucleoside reverse transcriptase inhibitor-based regimen were included. WHO immunological criteria include CD4 counts persistently <100 cells/microl, a fall below the baseline CD4 count, or a fall of >50% from the peak value. Virological failure was defined as two measurements > or =10 0000 copies/ml (higher threshold) or > or =500 copies/ml (lower threshold). Measures of accuracy with exact binomial 95% confidence intervals (CI) were calculated. RESULTS: A total of 2009 patients were included. During 1856 person-years of follow up 63 patients met the immunological criteria and 35 patients (higher threshold) and 95 patients (lower threshold) met the virological criteria. Sensitivity [95% confidence interval (CI)] was 17.1% (6.6-33.6%) for the higher and 12.6% (6.7-21.0%) for the lower threshold. Corresponding results for specificity were 97.1% (96.3-97.8%) and 97.3% (96.5-98.0%), for positive predictive value 9.5% (3.6-19.6%) and 19.0% (10.2-30.9%) and for negative predictive value 98.5% (97.9-99.0%) and 95.7% (94.7-96.6%). CONCLUSIONS: The positive predictive value of the WHO immunological criteria for virological failure of antiretroviral treatment in resource-limited settings is poor, but the negative predictive value is high. Immunological criteria are more appropriate for ruling out than for ruling in virological failure in resource-limited settings.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

BACKGROUND: In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. DESIGN AND METHODS: Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. RESULTS: A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1-26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0-21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/microl (IQR 77-265) in programmes with viral load monitoring and 102 cells/microl (44-181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7-18 after starting ART (aHR 1.38; 95% CI 0.97-1.98), similar during months 19-30 (aHR 0.97; 95% CI 0.58-1.60) and less common during months 31-42 (aHR 0.29; 95% CI 0.11-0.79). CONCLUSION: In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy.

BACKGROUND: Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART. METHODS: We evaluated a cohort of 7066 patients who initiated HAART from April 2004 through March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation, concurrent initiation of TB treatment and HAART, and incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks. RESULTS: Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dosage. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI], 1.82-5.56) in the first 2 months of HAART, 2.51 (95% CI, 1.77-3.54) in months 3-6, and 1.19 (95% CI, 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI, 3.03-14.37) in the first 2 months, 1.88 (95% CI, 0.87-4.09) in months 3-6, and 1.07 (95% CI, 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk. CONCLUSIONS: Risk of stavudine substitution was increased among patients who received TB treatment and was especially elevated during the period soon after HAART initiation. In settings in which alternative antiretroviral drugs are available, initiation of stavudine therapy in patients receiving TB treatment may need to be reconsidered.

Effect of pulmonary tuberculosis on mortality in patients receiving HAART.

OBJECTIVE: To estimate the effect of ongoing treatment for pulmonary tuberculosis (PTB) at time of initiation of HAART on subsequent risk of death. DESIGN: Evaluation of an open cohort of 7512 patients who initiated HAART between April 2004 and March 2007 in the Themba Lethu Clinic in Johannesburg, South Africa. METHODS: Mortality hazard ratios were estimated using marginal structural Cox proportional hazards models to control for bias due to both confounding and loss to follow-up. Extensive sensitivity and secondary analyses were performed. RESULTS: Although the crude hazard ratio for mortality in HAART-treated patients comparing those with and without treated PTB was 1.71 (95% confidence interval 1.31-2.23), the adjusted hazard ratio was 1.06 (95% confidence interval 0.75-1.49), indicating no difference in mortality risk. Similar effects were found when we considered different durations of time between initiation of PTB treatment and HAART, and sensitivity analysis confirmed main results. Secondary analysis suggested that individuals with PTB and other risk factors for death might be at particularly high risk of death during HAART treatment. CONCLUSION: The increase in death that we observed among individuals with PTB at the time of HAART initiation appears not to be due to the to the presence of PTB, but instead to confounding factors such as low CD4 cell count, low BMI, and WHO stage IV disease. These results further demonstrate that initiation of HAART soon after initiation of PTB treatment is not likely to put patients at higher risk of death.

Monitoring the South African National Antiretroviral Treatment Programme, 2003-2007: the IeDEA Southern Africa collaboration.

OBJECTIVES: To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. DESIGN AND SETTING: Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. SUBJECTS: Adults and children (<16 years old) who initiated ART with > or =3 antiretroviral drugs before 2008. RESULTS: Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p<0.001) and for those in stage IV (39-89 cells/microl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001). CONCLUSIONS: IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting.

Occult hepatitis B virus infection in patients with isolated core antibody and HIV co-infection in an urban clinic in Johannesburg, South Africa.

BACKGROUND: The prevalence of HIV/hepatitis B virus (HBV) co-infection in South Africa ranges from 4.8% to 17% using the standard marker surface antigen (hepatitis B surface antigen, HBsAg) for chronic active HBV infection. However, sensitive molecular techniques for detecting HBV DNA in serum can detect occult HBV infection. We report the first observational prospective study of occult HBV infection in HIV-positive people in South Africa. METHODS: Five hundred and two patients attending an urban hospital were screened for HBV using serological testing for HBsAg, core antibody (anti-HBc), and surface antibody (anti-HBs). DNA was analyzed using real-time quantitative PCR to determine the HBV viral load. RESULTS: Of the 502 participants, 24 (4.8%) were HBsAg-positive and 53 (10.6%) were positive for anti-HBc alone. Of these 53, screening for occult disease was carried out in 43, of whom 38 (88.4%) were positive. The mean HBV viral load was 2.8 x 10(4) copies/ml (range 1 x 10(2) to 1 x 10(6) copies/ml). CONCLUSIONS: Combining the participants with positive HBsAg and occult HBV DNA results, the prevalence of HBV increases from 4.8% (HBsAg alone) to 12.4%. While the clinical impact of occult HBV infection is unclear, consideration should be given to changing the guidelines to recommend dual HBV therapy for the treatment of co-infected patients in the developing world.

The prevalence of hepatitis B co-infection in a South African urban government HIV clinic.

OBJECTIVE: There are an estimated 350 million hepatitis B carriers worldwide. In South Africa the prevalence of mono-infection with hepatitis B has been estimated to range from 1% in urban areas to approximately 10% in rural areas. The exact prevalence of hepatitis B in the HIV-infected population has not been well established. Hepatitis B screening is not standard practice in government HIV clinics. Co-infection with hepatitis B and HIV can influence antiretroviral treatment and prognosis of both diseases. The purpose of this study was to evaluate the prevalence of hepatitis B/HIV coinfection. DESIGN: This is believed to be the first prospective observational report on the prevalence of hepatitis B/HIV co-infection in South Africa. Patients on whom hepatitis B serological tests could not have been done previously were recruited from an HIV clinic in a regional hospital in Johannesburg. Standard hepatitis B serological tests were performed. RESULTS: Five hundred and two participants were screened. The cohort's average age was 37 +/- 9 years and the average CD4 count was 128 cells/pi. Twenty-four (4.80%) were hepatitis B surface antigen positive. Nearly half (47%) of the participants showed some evidence of hepatitis B exposure. The risk of hepatitis B co-infection was not significantly different when analysed in terms of sex, race, CD4 count or age. Liver function tests were not a good predictor of hepatitis B infection. CONCLUSION: The rate of hepatitis B infection, as defined by hepatitis B surface antigen positivity in HIV-infected individuals in urban South Africa was 5 times the rate in people who were not HIV-infected. A 5% rate of hepatitis B/HIV co-infection is a reason to increase the accessibility of tenofovir/emtricitabine (Truvada) for first-line treatment for this population.