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

Abstract

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.

HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: A systematic review and meta-analysis

“…Of note, the only study reporting immune recovery (from 408 to 569 cells/mm 3 ) was a non-randomized trial carried among HIV-2 infected patients exposed to EVG for 12 months [29]. Two other case reports revealed a slight increase of CD4 cells count in patients infected by HIV-1 subtype C but without prior history of immunological failure in these patients (from 540 to 670 cells/ mm 3 after subsequent failure to RAL and DTG within a 9 years' timeframe for the first case and from 966 to 1,008 cells/mm 3 after 7 months of exposure to DTG for the second) [30,43]. Four other studies also reported a slight increase of CD4 cells count but without immune recovery among patients exposed to DTG and/or RAL [27,40,49,50].…”

“…Some studies (6/26) reported adverse events related to DTG-uptake within their settings [26,30,32,37,47,48]. The majority of these studies (5/6) involved only female participants at various stages of pregnancy, with summary estimates that were later used for meta-analysis.…”

“…Summary estimates of INSTI-DRMs were limited, underscoring the low-level of DTG major drug resistance within SSA. Nonetheless, some INSTI-DRMs reported are G118R in southern Africa [25,30] and R263K in East Africa [31,41]. Of note, if G118R has previously been described as DTG-resistance pathway in non-B (and especially HIV-1 subtype C viruses prevailing in southern Africa [4,64]), R263K -known as DTG-resistance signature in B-subtype viruses [4,[65][66][67][68]-is being reported in East Africa, a region with a prevailing HIV-1 subtype D infection.…”

Real‐world use and outcomes of dolutegravir‐containing antiretroviral therapy in HIV and tuberculosis co‐infection: a site survey and cohort study in sub‐Saharan Africa

“…The necessity of dolutegravir 50 mg twice daily for all patients receiving concomitant rifampicin remains unresolved [ 27 , 32 , 33 ]; however, further evidence is anticipated from an ongoing randomized trial [ 34 ]. Genotypic resistance testing would have allowed an assessment of resistance among patients with viral non‐suppression on dolutegravir, as emergent dolutegravir resistance in the context of the drug–drug interaction with rifampicin has been described [ 35 , 36 ]. We also did not have data about safety or tolerability, precluding an assessment of risks versus benefits.…”

Primary resistance against integrase strand transfer inhibitors in integrase strand transfer inhibitor-naive patients failing first- and second-line ART in Tanzania

“…These possibilities have also been described in some case reports in South Africa, Botswana and Uganda. 34 , 37 , 38 The inevitability of some emergent drug resistance against dolutegravir has also been explained by mutations outside the integrase gene, arising in patients receiving dolutegravir-containing regimens with no mutations in the integrase gene, 39 as well as by the role of natural polymorphisms. 33 , 40 …”