Prudence Ive

Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

BACKGROUND Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. METHODS We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. RESULTS A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38). CONCLUSIONS Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.).

Maraviroc versus Efavirenz, Both in Combination with Zidovudine-Lamivudine, for the Treatment of Antiretroviral-Naive Subjects with CCR5-tropic HIV-1 Infection

BACKGROUND The MERIT (Maraviroc versus Efavirenz in Treatment-Naive Patients) study compared maraviroc and efavirenz, both with zidovudine-lamivudine, in antiretroviral-naive patients with R5 human immunodeficiency virus type 1 (HIV-1) infection. METHODS Patients screened for R5 HIV-1 were randomized to receive efavirenz (600 mg once daily) or maraviroc (300 mg once or twice daily) with zidovudine-lamivudine. Coprimary end points were proportions of patients with a viral load <400 and <50 copies/mL at week 48; the noninferiority of maraviroc was assessed. RESULTS The once-daily maraviroc arm was discontinued for not meeting prespecified noninferiority criteria. In the primary 48-week analysis (n = 721), maraviroc was noninferior for <400 copies/mL (70.6% for maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%) at a threshold of -10%. More maraviroc patients discontinued for lack of efficacy (11.9% vs 4.2%), but fewer discontinued for adverse events (4.2% vs 13.6%). In a post hoc reanalysis excluding 107 patients (15%) with non-R5 screening virus by the current, more sensitive tropism assay, the lower bound of the 1-sided 97.5% confidence interval for the difference between treatment groups was above -10% for each end point. CONCLUSIONS Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

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.

Unnecessary Antiretroviral Treatment Switches and Accumulation of HIV Resistance Mutations; Two Arguments for Viral Load Monitoring in Africa

Objectives:This study aimed to investigate the consequences of using clinicoimmunological criteria to detect antiretroviral treatment (ART) failure and guide regimen switches in HIV-infected adults in sub-Saharan Africa. Frequencies of unnecessary switches, patterns of HIV drug resistance, and risk factors for the accumulation of nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations were evaluated. Methods:Cross-sectional analysis of adults switching ART regimens at 13 clinical sites in 6 African countries was performed. Two types of failure identification were compared: diagnosis of clinicoimmunological failure without viral load testing (CIF only) or CIF with local targeted viral load testing (targeted VL). After study enrollment, reference HIV RNA and genotype were determined retrospectively. Logistic regression assessed factors associated with multiple thymidine analogue mutations (TAMs) and NRTI cross-resistance (≥2 TAMs or Q151M or K65R/K70E). Results:Of 250 patients with CIF switching to second-line ART, targeted VL was performed in 186. Unnecessary switch at reference HIV RNA <1000 copies per milliliter occurred in 46.9% of CIF only patients versus 12.4% of patients with targeted VL (P < 0.001). NRTI cross-resistance was observed in 48.0% of 183 specimens available for genotypic analysis, comprising ≥2 TAMs (37.7%), K65R (7.1%), K70E (3.3%), or Q151M (3.3%). The presence of NRTI cross-resistance was associated with the duration of ART exposure and zidovudine use. Conclusions:Clinicoimmunological monitoring without viral load testing resulted in frequent unnecessary regimen switches. Prolonged treatment failure was indicated by extensive NRTI cross-resistance. Access to virological monitoring should be expanded to prevent inappropriate switches, enable early failure detection and preserve second-line treatment options in Africa.

Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis

BACKGROUND New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment. METHODS We did this phase 2b study of bactericidal activity--defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419. FINDINGS Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen. INTERPRETATION The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment. FUNDING Global Alliance for TB Drug Development.

Patterns of HIV-1 Drug Resistance After First-Line Antiretroviral Therapy (ART) Failure in 6 Sub-Saharan African Countries: Implications for Second-Line ART Strategies

BACKGROUND Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility. METHODS A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was >1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility. RESULTS HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried ≥1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with ≥1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine. CONCLUSIONS Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority.

Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

BACKGROUND The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. METHODS HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. FINDINGS Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p<0·0001) and acquired drug-resistance (2·30, 1·55-3·40; p<0·0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART. CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per μL difference after 12 months; 95% CI 13-58; p=0·002). INTERPRETATION At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. FUNDING The Netherlands Ministry of Foreign Affairs.

Initiating patients on antiretroviral therapy at CD4 cell counts above 200 cells/μl 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/μl 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/μl. Although 10% of patients failed virologically, the risk was nearly double among those with a CD4 cell count of 200 cells/μl or less vs. above 200 cells/μl (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/μl 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/μl. Those with either a CD4 cell count of 200 cells/μl 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/μl (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.

High rates of survival, immune reconstitution, and virologic suppression on second-line antiretroviral therapy in South Africa.

To determine rates of survival, viral suppression, and immunologic change after 1 year on second-line antiretroviral therapy, we conducted a cohort study among 328 patients initiated on zidovudine, didanosine, and lopinavir/ritonavir. All patients who switched to standard second-line therapy at a large urban public-sector clinic in Johannesburg, South Africa, were included. A year after initiating second-line therapy 243/313 [78%; 95% confidence interval (CI) 73%-82%], subjects were alive and in care. Further, 203/262 (77%; 95% CI: 72%-82%) had a suppressed viral load by 1 year. Mean CD4 gain by 12 months was 133 cells/μL (95% CI: 106-160). Patients on second-line therapy had a small decreased likelihood of being alive and in care by 1 year [hazard ratio (HR) 0.84; 95% CI: 0.73-0.97] as time-matched comparisons on first-line antiretroviral therapy (ART). Patients switched before 2 viral loads >1000 (HR 1.68; 95% CI: 1.08-2.61), and those switched for reasons not related to noncompliance with first-line (HR 1.83; 95% CI: 1.14-2.93) were more likely to achieve virologic suppression by 1 year on second-line ART. As rates of treatment failure over the first year on second-line therapy were low, provision of second-line treatment to patients who fail their first-line ART should be considered a high priority in resource-poor settings.

Relationship between renal dysfunction, nephrotoxicity and death among HIV adults on tenofovir.

Objective:In April 2010, the South African government added tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality. Design:Cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa, between April 2004 and September 2009. Methods:We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated onto tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding. Results:Of 890 patients initiated onto tenofovir, 573 (64.4%) had normal renal function (≥90 ml/min), 271 (30.4%) had mild renal dysfunction (60–89 ml/min) and 46 (5.2%) had moderate renal dysfunction (30–59 ml/min). A total of 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48 months of follow-up. Patients with mild [hazard ratio 4.8; 95% confidence interval (CI) 1.5–15.2] or moderate (hazard ratio 15.0; 95% CI 3.4–66.5) renal dysfunction were at greatest risk of nephrotoxicity, whereas those with mild (hazard ratio 1.2; 95% CI 0.7–2.3) or moderate (hazard ratio 3.2; 95% CI 1.3–7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48 months. Conclusion:Much of the incident renal dysfunction in tenofovir patients is likely related to preexisting renal disorder, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.