Discussion
virological failure, tuberculosis, insomnia, treatment-emergent resistance mutations, HIV-associated tuberculosis
EVENTS, TUBERCULOSIS
In participants receiving treatment for both tuberculosis and HIV, we found acceptable virological suppression in the placebo arm and the supplemental dolutegravir arm at week 24. No participants developed treatment-emergent resistance mutations to integrase strand transfer inhibitors by week 48. Dolutegravir was generally well tolerated in both arms. Our findings suggest that supplemental dolutegravir dosing might not be necessary in patients on rifampicin-based antituberculosis therapy.Virological suppression decreased from week 24 to week 48, which was probably a result of reduced adherence (supported by a higher proportion of participants with low tenofovir diphosphate). At week 24 participants were issued a 6-month supply of ART without follow-up visits between weeks 24 and 48 as per local guidelines, to reduce clinic burden during the COVID-19 epidemic, which could have accounted for reduced adherence.Our finding that standard-dose dolutegravir is as effective as double-dose dolutegravir in people living with HIV on rifampicin-based antituberculosis therapy is consistent with findings of two other studies. A small trial in Thailand, which randomly assigned people with HIV with tuberculosis to dolutegravir once daily or twice daily, reported virological suppression in 18 of 20 patients in both groups.A key question is whether a phase 3 trial is necessary to confirm our findings. The probable delay in policy change that running a phase 3 trial would entail is illustrated by the experience of researchers exploring different dosing strategies for the first-generation integrase strand transfer inhibitor raltegravir in people with HIV on rifampicin-based antituberculosis therapy. Plasma concentrations of raltegravir are substantially reduced by rifampicin and double dosing is recommended.None of our participants with study-defined virological failure developed treatment-emergent resistance mutations to dolutegravir. Our findings are in keeping with the INSPIRING study, in which no acquired resistance mutations occurred in the dolutegravir arm.In our study, solicited and self-reported insomnia events occurred earlier and more frequently in the supplemental dolutegravir arm than in the placebo arm, but these differences were not statistically significant. Dolutegravir treatment is associated with an increased risk of insomniaOur study has limitations. First, the study was not powered to make efficacy comparisons between arms. Second, our findings might not be generalisable to people on dolutegravir-based second-line ART or to people with CD4 counts below 100 cells per μL. Third, we only enrolled participants who were ART-naive or had interrupted first-line ART without virological failure. Our findings might not be generalisable to people with dolutegravir in second-line ART. Fourth, we did not detect treatment-emergent dolutegravir resistance in the placebo arm, but larger sample sizes will be needed to determine the risk of resistance. Fifth, more participants in the placebo arm had dolutegravir trough concentrations below the lower limit of quantitation at weeks 4 and 24. However, as we did not observe the previous dose, we cannot be sure that the plasma sample was taken in the specified time window. Sixth, our study was done at a clinical research trial site; virological outcomes might be worse in real-world settings.In conclusion, we found similar rates of virological suppression in the supplemental dolutegravir and placebo arms when prescribed with rifampicin-based antituberculosis therapy, and there were no treatment-emergent integrase strand transfer inhibitor resistance mutations among participants with study-defined virological failure. Our findings suggest that twice-daily dolutegravir dosing might be unnecessary in people with HIV-associated tuberculosis. More evidence, from cohort studies or possibly a phase 3 trial, might be necessary to change policy on the need for a supplemental dolutegravir dose with rifampicin-based antituberculosis therapy.