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Background: The emergence of complex HIV-1 drug resistance mutations has been linked to the duration of time patients are on a failing antiretroviral drug regimen. This study reports on resistance profiles in a closely monitored subtype C infected cohort., Methods: A total of 812 participants were enrolled into the CIPRA-SA 'safeguard the household' study, viral loads were determined at 12-weekly intervals for 96 weeks. Virological failure was defined as either a <1.5 log decrease in viral load at week 12 or two consecutive viral load measurements of >1,000 RNA copies/ml after week 24. Regimens prescribed were in line with the South African roll-out programme (stavudine, lamivudine, efavirenz or nevirapine). Viral RNA was extracted from patients with virological failure, and pol reverse-transcriptase PCR and sequence analysis were performed to determine drug-resistant mutations., Results: Virological failure was observed in 83 participants on the first-line regimen during the study period, of which 61 (73%) had HIV-1 drug-resistant mutations. The M184V mutation was the most frequent (n=46; 65%), followed by K103N (46%) and Y181C (21%). Thymidine analogue mutations were infrequent (1%) and Q151M was not observed., Conclusions: Drug resistance profiles were less complex than has been previously reported in South Africa using the same antiretroviral drug regimens. These data suggest that frequent viral load monitoring limits the level and complexity of resistance observed in HIV-1 subtype C, preserving susceptibility to second-line options.

Background: With increased access to antiretroviral treatment (ART), immune reconstitution inflammatory syndrome (IRIS) in Mycobacterium tuberculosis (MTB)-infected populations remains a clinical challenge. We studied a cross-sectional cohort of HIV-infected subjects in Johannesburg (South Africa) to help define the immune correlates that best distinguish IRIS from ongoing MTB cases., Methods: We studied HIV+ subjects developing MTB-related unmasking tuberculosis-related immune reconstitution inflammatory syndrome (uTB-IRIS) after ART initiation; control groups were subjects with HIV and HIV/tuberculosis-coinfected subjects with comparable ART treatment. Testing was conducted with whole blood-based 4-color flow cytometry and plasma-based Luminex cytokine assessment., Results: Natural killer cell activation, C-reactive protein, and interleukin 8 serum concentration were significantly higher in uTB-IRIS subjects compared with both control groups. In addition, all MTB-coinfected subjects, independent of clinical presentation, had higher neutrophils and T-cell activation, together with lower lymphocytes, CD4⁺ T-cell, and myeloid dendritic cell counts. Using conditional inference tree analysis, we show that elevated natural killer cell activation in combination with lymphocyte count characterizes the immunological profile of uTB-IRIS., Conclusion: Our results support a role for innate immune effectors in the immunopathogenesis of unmasking MTB-related IRIS and identify new immune parameters defining this pathology.

Background: There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance., Methods: We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients., Findings: 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62-204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6-6.7), ranging from 1.1% (two of 176; 0.0-2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5-17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9-14.2), compared with 3.5% (73 of 1866; 2.5-4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8-3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5-4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8-1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7-1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13-1.68; p=0.001)., Interpretation: The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up., Funding: Ministry of Foreign Affairs of the Netherlands., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine., Methods: We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/μl); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US$), and incremental cost-effectiveness ratios., Results: With no ART, projected life expectancy was 1.6 years and per-person cost was $2980. First-line nevirapine increased life expectancy (15.2 years) and cost ($13 990; cost-effectiveness ratio: $810/year of life saved versus no ART). First-line lopinavir/ritonavir further increased life expectancy to 16.3 years and cost to $15 630 (cost-effectiveness ratio: $1520/year of life saved versus first-line nevirapine). First-line lopinavir/ritonavir cost-effectiveness was sensitive to prevalence of nevirapine-resistant virus at ART initiation, time from single-dose nevirapine exposure to ART initiation (6-12, 12-24, or >24 months), second-line ART efficacies, and outcomes after 24 weeks on ART., Conclusions: First-line lopinavir/ritonavir-based ART is very cost-effective in single-dose nevirapine-exposed, South African women similar to OCTANE participants. Lopinavir/ritonavir should be initiated in women with known nevirapine resistance or single-dose nevirapine exposure less than 12 months prior, or in whom such information is unknown.

Background: Increasing efavirenz (EFV) dose from 600 mg to 800 mg daily has been suggested with concomitant rifampicin (RFN), as induction of cytochrome P450 isoenzymes may reduce EFV plasma concentrations., Methods: Individuals from the CIPRA-South Africa cohort taking EFV-based antiretroviral therapy with concomitant tuberculosis (TB) were dosed with either increased (800 mg) or standard (600 mg) dose EFV during TB treatment. After TB therapy, all individuals took 600 mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and ≥4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed-rank test., Results: Paired samples were collected from 72 individuals. Overall, 45 (63%) were women and median weight was 59 kg (IQR 52-67). At antiretroviral therapy start, median CD4(+) T-cell count was 114 cells/mm(3) (IQR 37-165), median viral load was 5.5 log (IQR 5.1-5.9). A total of 38 (53%) individuals took 800 mg EFV during TB treatment and 34 (47%) took 600 mg. EFV concentrations in the 800 mg group were higher with RFN (2.9 mg/l [IQR 1.8-5.6]) than without (2.1 mg/l [IQR 1.4-3.0]; P=0.0003). There was no significant difference in EFV concentrations with RFN (2.4 mg/l [IQR 1.2-5.1]) or without (2.2 mg/l [IQR 1.4-3.7]) in the 600 mg group. There was no increase in EFV-linked adverse effects in either group. The proportion of virologically suppressed individuals at 48 weeks was similar in both groups., Conclusions: EFV concentrations were significantly increased in the EFV 800 mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600 mg group. Dose escalation of EFV 600 mg to 800 mg is not required during concomitant TB therapy in South Africa.

Objectives: To compare treatment outcomes by starting CD4 cell counts using data from the Comprehensive International Program of Research on AIDS-South Africa trial., Design: An observational cohort study., Methods: Patients presenting to primary care clinics with CD4 cell counts below 350 cells/microl were randomized to either doctor or nurse-managed HIV care and followed for at least 2 years after antiretroviral therapy (ART) initiation. Clinical and laboratory outcomes were compared by baseline CD4 cell counts., Results: Eight hundred and twelve patients were followed for a median of 27.5 months and 36% initiated ART with a CD4 cell count above 200 cells/microl. Although 10% of patients failed virologically, the risk was nearly double among those with a CD4 cell count of 200 cells/microl or less vs. above 200 cells/microl (12.2 vs. 6.8%). Twenty-one deaths occurred, with a five-fold increased risk for the low CD4 cell count group (3.7 vs. 0.7%). After adjustment, those with a CD4 cell count of 200 cells/microl had twice the risk of death/virologic failure [hazard ratio 1.9; 95% confidence interval (CI), 1.1-3.3] and twice the risk of incident tuberculosis (hazard ratio 1.90; 95% CI, 0.89-4.04) as those above 200 cells/microl. Those with either a CD4 cell count of 200 cells/microl or less (hazard ratio 2.1; 95% CI, 1.2-3.8) or a WHO IV condition (hazard ratio 2.9; 95% CI, 0.93-8.8) alone had a two-to-three-fold increased risk of death/virologic failure vs. those with neither, but those with both conditions had a four-fold increased risk (hazard ratio 3.9; 95% CI, 1.9-8.1). We observed some decreased loss to follow-up among those initiating ART at less than 200 cells/microl (hazard ratio 0.79; 95% CI, 0.50-1.25)., Conclusion: Patients initiating ART with higher CD4 cell counts had reduced mortality, tuberculosis and less virologic failure than those initiated at lower CD4 cell counts. Our data support increasing CD4 cell count eligibility criteria for ART initiation.

Background: Expanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients., Methods: This randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per microL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1.40. This study is registered with ClinicalTrials.gov, number NCT00255840., Findings: 408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1.09 (95% CI 0.89-1.33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60-144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively., Interpretation: Nurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART., Funding: National Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases., (Copyright 2010 Elsevier Ltd. All rights reserved.)

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.

Background: Antenatal clinics are a key entry point into HIV treatment and care, together with interventions to reduce mother-to-child transmission (MTCT). Further evaluation is needed of interventions linking antenatal with antiretroviral (ARV) treatment services and effectiveness of triple-ARV regimens for reducing MTCT in resource-constrained settings., Methods: Data were gathered from HIV-infected women attending antenatal care from June 2004 to July 2005 at Coronation Women and Children Hospital, South Africa. After a patient record review, interventions were implemented to strengthen service linkages and integrate ARV treatment within antenatal care. Laboratory investigations were streamlined, including CD4 cell count testing at the first antenatal visit. MTCT risk for women initiating ARV treatment is compared with that of women-infant pairs receiving single-dose nevirapine (sd-NVP)., Results: In total, 164 pregnant women initiated ARV treatment and 863 received sd-NVP. After changes to service delivery, time-to-treatment initiation was reduced from a median of 56 days to 37 days (P = 0.041). The risk of MTCT for women receiving ARV treatment (5 [4.3%] of 116 women) was lower than for those given sd-NVP (74 [10.7%] of 692 women; P = 0.032)., Conclusions: Strengthening linkages and integrating key components of ARV treatment within antenatal care reduces time-to-treatment initiation. In this setting, among women with a high MTCT risk, triple-ARV regimens are effective in reducing HIV infection in infants.

One hundred and eleven children under 5 years of age admitted with a diagnosis of paraffin ingestion, constituting 9.1% of total ward admissions in this age group, were studied prospectively. The majority were between 13 and 36 months old. One-fifth of the children were in the care of another child at the same time of ingestion. Fourteen families had a past history of paraffin ingestion. Only 22% of households normally stored in paraffin above ground level and in only 15% of cases was paraffin stored in a container specified for that purpose. Emesis was attempted using home remedies in 72% of cases and was associated with a significant increase in vomiting. Vomiting had an impact on the exacerbation of the clinical features of paraffin poisoning, particularly fever. Clinical criteria laid down for suspected superadded bacterial lung infection resulted in half of the study group having blood cultures performed on day 1 and another 17 on day 4. Only two yielded isolates which possibly could have been indicative of bacteremia secondary to infective pneumonia. No child in the suspected group was treated with antibiotics and all recovered uneventfully. Admission chest X-rays contributed little to the management of the illness. Paraffin ingestion remains a serious contributor to child morbidity in rural South Africa and there appears to be room for further preventive education at community level. Specific measures could include storage of paraffin in designated containers above ground level and emphasis on adult supervision of children. Superadded bacterial pneumonia is uncommon and antibiotics in the management of suspected cases are not routinely indicated.