Francesca Conradie

HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study

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.

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.

Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P=0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National Institute of Allergy and Infectious Diseases and the National Research Center; ClinicalTrials.gov number, NCT00089505.).

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline. Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline. Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively. Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB. Bedaquiline safety data in a broad patient population treated for drug-resistant TB including XDR-TB (C209 study) http://ow.ly/TcZBh

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.

Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis.

BACKGROUND South Africa has a large burden of extensively drug-resistant tuberculosis (XDR-TB); only 15% of XDR-TB patients have successful outcomes. OBJECTIVE To describe the safety and effectiveness of bedaquiline (BDQ) in the South African BDQ Clinical Access Programme. DESIGN An interim cohort analysis. RESULTS Of the first 91 patients enrolled between March 2013 and July 2014 (with follow-up until August 2014), 54 (59%) were human immunodeficiency virus (HIV) infected. The median CD4 count was 239 cells/μl, and all patients were on antiretroviral therapy (ART) at initiation of BDQ; 33 had XDR-TB, 41 were pre-XDR-TB with fluoroquinolone resistance and 17 were pre-XDR-TB with resistance to an injectable. Of the 91 patients, 58 (64%) had completed 24 weeks of BDQ, 28 were still on BDQ, 3 were lost to follow-up, 1 had died and 1 had BDQ withdrawn following atrial fibrillation. Of the 63 patients with 6 months follow-up, 48 (76%) had either culture-converted or remained culture-negative after initiation of BDQ. QTcF was monitored monthly and exceeded 500 ms in three participants; this resolved in all three. CONCLUSION Interim safety and culture conversion outcomes for patients accessing BDQ in South Africa, including HIV-infected patients on ART and patients with pre-XDR- and XDR-TB, suggest that BDQ may be both efficacious and safe.

Cohort profile: The PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring studies to evaluate resistance-HIV drug resistance in sub-Saharan Africa and the Asia-Pacific

This article discusses two multi-centre prospective cohort studies in Africa that assess the prevalence and incidence of HIV in people using the first-line ART treatment. Participants are enrolled in the study for approximately 18 months after which new participants are recruited. The HIV positive people in the study are evaluated during their regular clinic visits. Researchers are collecting information about various HIV subtypes in the affected population incidence of duel infections and disease progression and response to treatment. Due to the various clinics involved in the study the study benefits from a large number of patients with very different backgrounds and disease characteristics.

Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient

The protease inhibitor (PI) lopinavir–ritonavir (Kaletra) combination is a potent antiretroviral drug with a high resistance barrier. Primary failure as a result of PI resistance has not previously been described in an antiretroviral-naive patient. A 25-year-old black female South African patient was enrolled onto the Early Access Programme 6 November 2000. The patient had no history of international travel. Her baseline CD4 cell count was 282 cells/ml and her viral load was 325 000 copies/ml. (Roche Amplicor 1.5). She received 2 weeks of stavudine didanosine and hydroxyurea in June 2000 but the treatment was stopped after the patient developed eosinophilic folliculitis that was reported as a possible drug reaction by a dermatologist. She was given dual therapy because of the cost constraints at the time. (excerpt)

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.

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.