Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial.

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.

Low rates of nucleoside reverse transcriptase inhibitor resistance in a well-monitored cohort in South Africa on antiretroviral therapy.

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.

Vicriviroc plus optimized background therapy for treatment-experienced subjects with CCR5 HIV-1 infection: final results of two randomized phase III trials.

BACKGROUND: Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS: Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS: Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/µL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS: The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).

Efavirenz and rifampicin in the South African context: is there a need to dose-increase efavirenz with concurrent rifampicin therapy?

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.

Treatment interruption in a primary care antiretroviral therapy program in South Africa: cohort analysis of trends and risk factors.

OBJECTIVE: To investigate antiretroviral treatment (ART) interruption in a long-term treatment cohort in South Africa. METHODS: All adults accessing ART between 2004 and 2009 were included in this analysis. Defaulting was defined as having stopped all ART drugs for more than 30 days. Treatment interrupters were patients who defaulted and returned to care during the study, whereas loss to follow-up was defined as defaulting and not returning to care. Kaplan-Meier estimates and Poisson regression models were used to analyze rates and determinants of defaulting therapy and of treatment resumption. RESULTS: Overall rate of defaulting treatment was 12.8 per 100 person-years (95% confidence interval: 11.4 to 14.4). Risk factors for defaulting were male gender, high baseline CD4 count, recency of ART initiation, and time on ART. The probability of resuming therapy within 3 years of defaulting therapy was 42% (event rate = 21.4 per 100 person-years). Factors associated with restarting treatment were female gender, older age, and time since defaulting. CONCLUSIONS: Defaulting treatment need not be an irreversible event. Interventions to increase retention in care should target men, less immunocompromised patients, and patients during the first 6 months of treatment. Resumption of treatment is most likely within the first year of interrupting therapy.

Linkage to HIV care and antiretroviral therapy in Cape Town, South Africa.

BACKGROUND: Antiretroviral therapy (ART) has been scaled-up rapidly in Africa. Programme reports typically focus on loss to follow-up and mortality among patients receiving ART. However, little is known about linkage and retention in care of individuals prior to starting ART. METHODOLOGY: Data on adult residents from a periurban community in Cape Town were collected at a primary care clinic and hospital. HIV testing registers, CD4 count results provided by the National Health Laboratory System and ART registers were linked. A random sample (n = 885) was drawn from adults testing HIV positive through antenatal care, sexual transmitted disease and voluntary testing and counseling services between January 2004 and March 2009. All adults (n = 103) testing HIV positive through TB services during the same time period were also included in the study. Linkage to HIV care was defined as attending for a CD4 count measurement within 6 months of HIV diagnosis. Linkage to ART care was defined as initiating ART within 6 months of HIV diagnosis in individuals with a CD4 count ≤200 cells/µl taken within 6 months of HIV diagnosis. FINDINGS: Only 62.6% of individuals attended for a CD4 count measurement within 6 months of testing HIV positive. Individuals testing through sexually transmitted infection services had the best (84.1%) and individuals testing on their own initiative (53.5%) the worst linkage to HIV care. One third of individuals with timely CD4 counts were eligible for ART and 66.7% of those were successfully linked to ART care. Linkage to ART care was highest among antenatal care clients. Among individuals not yet eligible for ART only 46.3% had a repeat CD4 count. Linkage to HIV care improved in patients tested in more recent calendar period. CONCLUSION: Linkage to HIV and ART care was low in this poor peri-urban community despite free services available within close proximity. More efforts are needed to link VCT scale-up to subsequent care.

Initiating patients on antiretroviral therapy at CD4 cell counts above 200 cells/microl is associated with improved treatment outcomes 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.