The dogma for HIV treatment in the early 2000s was that three active drugs were needed. Period. If a patient had an M184V mutation, lamivudine (3TC) was often continued to reduce viral fitness but not considered an “active” medication. In 2007, raltegravir became the first integrase inhibitor approved by the Food and Drug Administration. Others followed, and they are now a cornerstone of HIV treatment today, with many of them studied as two-drug regimens. Dolutegravir was a part of the first two two-drug regimens approved by FDA (DTG/rilpivirine and DTG/3TC) and continues to be studied in this sphere.
Two recent trials, ART-PRO and SOLAR-3D, have looked at switching virologically suppressed patients with M184V to DTG/3TC, and both showed that DTG/3TC holds up. However, sample sizes were small, which may have made the average HIV clinician reluctant to recommend the change to their patients.
In a study published in Clinical Infectious Diseases, the ART-PRO authors set out to make believers of us skeptics by enrolling 121 patients with genotype M184V (n = 114) or suspected M184V due to prior failure (n = 7). Patients were virologically suppressed for an average of nine years. The primary outcome was virologic suppression at 48 weeks. They did DNA sequencing to identify lamivudine resistance mutations. Interestingly, less than 20% of patients had M184V in next-generation sequencing ≥ 5% threshold, perhaps related to the fact that the average number of years since the last M184V genotype was about 15.
Overall, failure rates were low, occurring in only 1.7% of patients. Reassuringly, no integrase resistance was seen in any patient at the end of the study. Because past studies with DTG monotherapy have shown a 7% failure rate with almost 50% integrase resistance, the authors hypothesize that the 3TC is working, even if it’s not supposed to. One reason might be that these patients did not recently acquire M184V, so this switch might be best for those with a history of M184V.
This is another study showing that DTG/3TC has good efficacy for patients with a remote history of M184V. We’ve seen it. Now, will we believe it?