The World Health Organization has recommended the inclusion of the integrase strand transferase inhibitor (InSTI), dolutegravir (DTG), as part of first-, second- and third-line antiretroviral treatment (ART) regimens. Dolutegravir is co-formulated with other antiretroviral medicines, well tolerated, has a high genetic barrier to resistance and is available in generic formulations. To date, few cases of emergent DTG resistance in integrase-naïve patients have been reported,¹ but it is anticipated that with increasing use across treatment regimens, more cases will emerge, particularly in highly treatment experienced patients.

We describe two cases of highly treatment experienced, InSTI-naïve people living with HIV from Newlands Clinic, Harare, Zimbabwe, who developed InSTI drug-resistance mutations (DRMs) within 14 months of InSTI initiation.

Written informed consent was obtained from the patient described in this case report. The patient gave his consent to have his clinical and demographic data to be used as well as his images.

Ethical approval to conduct a case report on these patients was obtained from the Medical Research Council of Zimbabwe. Clearance number: E/316.

Following the genotypic resistance test, the patient was switched to TDF/3TC/boosted darunavir and adherence support was reinforced. Eight weeks after the switch, the VL was 400 copies/mL and at 24 weeks, the viral load was undetectable. He continues this regimen with 3-monthly VL monitoring and adherence support.

The patient was retreated for tuberculosis with adherence monitoring and the clinical response was good with weight gain and symptom resolution. On completion of six months of tuberculosis therapy, her integrase resistance data was available, but the initial sequencing of reverse transcriptase and protease had failed and was being repeated. Due to the long history of poor adherence, it was assumed that backbone NRTI resistance was likely; therefore, a third-line regimen consisting of TDF/3TC, darunavir in addition to twice daily DTG was considered the most robust regimen. After receiving weekly enhanced adherence support her VL at week 12 was 98 copies/mL and at week 24 was 71 copies/mL.

We report two cases of treatment experienced, InSTI-naïve patients who developed InSTI resistance within 14 months of starting DTG. The first patient had significant NRTI resistance prior to switching to TDF/3TC/DTG and suboptimal adherence post treatment switch. The second patient also reported suboptimal adherence and may have had sub-therapeutic drug levels of DTG due to a drug interaction between DTG and rifampicin. Known risk factors for incident drug resistance include suboptimal medication adherence, drug interactions, a high baseline VL and active opportunistic infections.¹ A similar case from South Africa has been described, of a treatment experienced patient who developed resistance to DTG after taking DTG 50 mg once a day with rifampicin, instead of the recommended twice daily dosing. Rifampicin is an inducer of the UGT1A1 and CYP3A4 pathways by which DTG is metabolised, resulting in reduced serum DTG concentrations. The current World Health Organization recommendation is to dose DTG at 50 mg 12-hourly for patients taking both medications concurrently.

Integrase strand transferase inhibitor resistance in those with previous exposure to first-generation InSTI has been well described; however, the development of InSTI resistance in patients taking DTG is rare in ART-naïve patients. In a systematic review, Cevik et al. report 15 cases of emergent InSTI resistance in patients on DTG: 5 cases in ART-naïve patients and 10 cases in ART experienced patients.¹ As increasing numbers of cases of DTG resistance are reported, the question arises as to whether patients who are treatment experienced may be at higher risk of InSTI resistance. The use of DTG in patients with compromised NRTI backbones has raised concerns regarding the efficacy and durability of these regimens.² However, emerging evidence from the NADIA, VISEND and DAWNING trials appears reassuring that viral suppression despite the presence of NRTI mutations is achievable.^3,4,5 Despite the good virological suppression rates achieved in these trials, it is of concern that a small percentage of participants developed treatment emergent DTG resistance; 4.0% of NADIA partcipants at week 96 and 0.6% of DAWNING participants. Although the risk of InSTI resistance was modest in these clinical trials, it is likely to be increased in real-world settings particularly those with failing health systems.