Case report: Emergence of dolutegravir resistance in a patient on second-line antiretroviral therapy.

INTRODUCTION: The integrase strand transfer inhibitor dolutegravir (DTG) has a high genetic barrier to resistance. Only rare cases of resistance to DTG have been reported when it is used as a component of antiretroviral therapy regimens in treatment-experienced patients unless there was prior use of a first-generation integrase inhibitor. PATIENT PRESENTATION: A 38-year-old woman diagnosed with tuberculosis was switched to a second-line antiretroviral regimen of zidovudine, lamivudine and dolutegravir 50 mg 12-hourly together with rifampicin-based TB treatment. Based on treatment history and a previous resistance test there was resistance to lamivudine but full susceptibility to zidovudine. The patient did not suppress her viral load on this regimen and later admitted to only taking dolutegravir 50 mg in the morning because of insomnia. MANAGEMENT AND OUTCOME: A second resistance test was performed which showed intermediate level of resistance to dolutegravir. Her regimen was changed to tenofovir, emtricitabine and ritonavir-boosted atazanavir with rifabutin replacing rifampicin for the remainder of her TB treatment. She achieved viral suppression on this regimen. CONCLUSION: To our knowledge this is the first case report from South Africa of emergent dolutegravir resistance in a treatment-experienced, integrase inhibitor-naïve patient. Factors that may have contributed to resistance emergence in this patient were that there was only one fully active nucleoside reverse transcriptase inhibitor in the regimen and lower exposure to dolutegravir because of the reduced dosing frequency while on rifampicin.

A Clinical Prediction Rule for Protease Inhibitor Resistance in Patients Failing Second-Line Antiretroviral Therapy.

BACKGROUND: Most adults with virological failure on second-line antiretroviral therapy (ART) in resource-limited settings have no major protease inhibitor (PI) resistance mutations. Therefore, empiric switches to third-line ART would waste resources. Genotypic antiretroviral resistance testing (GART) is expensive and has limited availability. A clinical prediction rule (CPR) for PI resistance could rationalize access to GART. SETTING: A private sector ART cohort, South Africa. METHODS: We identified adults with virologic failure on ritonavir-boosted lopinavir/atazanavir-based ART and GART. We constructed a multivariate logistic regression model including age, sex, PI duration, short-term adherence (using pharmacy claims), concomitant CYP3A4-inducing drugs, and viral load at time of GART. We selected variables for the CPR using a stepwise approach and internally validated the model by bootstrapping. RESULTS: 148/339 (44%) patients had PI resistance (defined as ≥ 1 major resistance mutation to current PI). The median age was 42 years (interquartile range 36-48), 212 (63%) were females, 308 (91%) were on lopinavir/ritonavir, and median PI duration was 2.6 years (interquartile range 1.6-4.7). Variables associated with PI resistance and included in the CPR were age {adjusted odds ratio (aOR) 1.96 (95% confidence interval [CI]: 1.42 to 2.70) for 10-year increase}, PI duration (aOR 1.14 [95% CI: 1.03 to 1.26] per year), and adherence (aOR 1.22 [95% CI: 1.12 to 1.33] per 10% increase). The CPR model had a c-statistic of 0.738 (95% CI: 0.686 to 0.791). CONCLUSIONS: Older patients with high adherence and prolonged PI exposure are most likely to benefit from GART to guide selection of a third-line ART regimen. Our CPR to select patients for GART requires external validation before implementation.

Third-line antiretroviral therapy in Africa: effectiveness in a Southern African retrospective cohort study.

BACKGROUND: An increasing number of patients in Africa are experiencing virologic failure on second-line antiretroviral therapy (ART) and those who develop resistance to protease inhibitors (PI) will require third-line ART, but no data on the outcomes of third-line are available from the region. We assessed the virologic outcomes and survival of patients started on salvage ART in a Southern African private sector disease management programme. METHODS: Retrospective observational cohort study with linkage to the national death register. Adults (≥18 years) who started salvage ART between July 2007 and December 2011 were included. Salvage ART was defined by inclusion of darunavir or tipranavir in an ART regimen after having failed another PI. For Kaplan-Meier (KM) analysis, patients were followed up until event, or censored at death (only for virologic outcomes), leaving the programme, or April 2014. RESULTS: 152 patients were included. Subtype was known for 113 patients: 111 (98 %) were infected with subtype C. All 152 had a genotype resistance test demonstrating major PI resistance mutations. Salvage drugs included were: darunavir/ritonavir (n = 149), tipranavir/ritonavir (n = 3), raltegravir (n = 58), and etravirine (n = 8). Median follow-up was 2.5 years (IQR = 1.5-3.3). 82.9 % achieved a viral load ≤400 copies/ml and 71.1 % ≤50 copies/ml. By the end of the study 17 (11.2 %) of the patients had died. The KM estimate of cumulative survival was 87.2 % at 2000 days. CONCLUSIONS: Virologic suppression was comparable to that demonstrated in clinical trials and observational studies of salvage ART drugs conducted in other regions. Few deaths occurred during short term follow-up. Third-line regimens for patients with multidrug resistant subtype C HIV in Africa are virologically and clinically effective.