AIDS Research and Human Retroviruses, April 2020
The last few years have witnessed increased interest in treating HIV with two instead of three active drugs. In particular, the two-drug combination of dolutegravir plus lamivudine (3TC) garnered a lot of interest after two large clinical trials (GEMINI 1 and 2) showed it was effective among people who were new to treatment through 96 weeks. It was against this backdrop that a review article in the journal AIDS and Human Retroviruses commented on the strengths of dolutegravir plus 3TC and highlighted the regimen’s high barrier against resistance. Specifically, they noted the lack of resistance to either dolutegravir or 3TC in the large clinical trials through 96 weeks and in other studies.
In order to provide additional information on how well the combination of dolutegravir plus 3TC can be expected to fend off resistance during treatment, we shared our experience from A5303 in a Letter to the Editor of AIDS and Human Retroviruses. In the letter, we described the three (out of 120) participants who experienced virologic failure in A5303 and the additional probes we undertook (deep sequencing and phenotyping) to better understand our observations in the study. We reminded readers of our earlier report that one of the three participants with virologic failure in A5303 developed resistance mutations to both 3TC (M184V) and dolutegravir (R263R/K). We noted that deeper probes did not reveal evidence that the resistance mutations were present before taking the drugs (concluding that resistance developed in relation to treatment). Resistance to 3TC is well known to make the drug inactive, whereas the resistance mutation to dolutegravir did not seem to affect the activity of the drug or others in the integrase inhibitor class in a clinically meaningful manner. The patient who developed resistance was not consistently adherent, which we speculated led to the resistance.
Editor’s Clinical Impact Statement: From this study, resistance to 3TC and dolutegravir is rare but can occur.
Taiwo, B. O., Quiñones-Mateu, M. E., Smith, K., Zheng, L., Gulick, R., Nyaku, A. N., Sax, P. E., Ha, B., Kumwenda, J., Olefsky, M., Godfrey, C., & Wallis, C. (2020). Prior Case of Resistance on Dolutegravir Plus Lamivudine Dual Therapy. AIDS Research and Human Retroviruses, 36(4), 254–255. https://doi.org/10.1089/AID.2019.0253