Study suggests twice-daily dolutegravir dosing may not be required
A study from Botswana published in the October issue of the Journal of Acquired Immune Deficiency Syndromes provides important scientific evidence, but not strong enough data for a policy change, on the use of a dolutegravir-based antiretroviral therapy (ART) regimen along with a rifampicin-based anti-TB regimen, for people living with HIV and TB co-infection.
The study results establish the efficacy and safety of a dolutegravir-based regimen for people living with HIV and TB who are being treated using a rifampicin-based TB regimen. People treated with a dolutegravir-based regimen for HIV had slightly better TB treatment outcomes than those on non-dolutegravir based ART. Also, this study found that a single daily dose of dolutegravir produced slightly superior outcomes than a double daily dose of dolutegravir. This is important because the World Health Organization (WHO) currently recommends a double daily dose for people also taking rifampicin.
Dolutegravir has been recently recommended by WHO as part of preferred first- and second-line regimens for people living with HIV as it is more effective, has fewer side effects and a higher genetic barrier to developing drug resistance.
But, for people living with HIV who have co-infection with TB there are concerns, based on earlier scientific studies, of a possible drug-drug interaction between dolutegravir and rifampicin. This may result in decreased concentrations of dolutegravir, raising worries about safety and the development of HIV resistance due to low levels of dolutegravir. That is why WHO guidelines recommend dose adjustment by offering 50mg of dolutegravir twice a day (instead of a single daily dose of 50mg) in such cases.
Dr Chawangwa Modongo and colleagues conducted a retrospective cohort study in Botswana from 2016 to 2018 to evaluate the TB and HIV treatment outcomes of people with TB/HIV co-infection concomitantly receiving a rifampicin-based TB regimen and a dolutegravir-based ART regimen under programmatic conditions. Successful treatment outcomes were defined as TB cure or sputum/culture negative report within five months of anti-TB therapy and HIV viral load suppression (below 400).
The study included 1225 people with TB/HIV co-infection treated in 97 healthcare facilities in Botswana. Data were obtained from the combined national registry for TB and HIV and from medical records at the facilities. Out of the 1225 study participants, 739 received a rifampicin-based TB regimen and a dolutegravir-based ART regimen, and 486 received a rifampicin-based TB regimen and non-dolutegravir ART regimen.
Dolutegravir-based ART (with tenofovir disoproxil fumarate and emtricitabine) has been used as first-line therapy in Botswana since 2016, as well as being offered to those changing regimen due to treatment failure or side effects. There were a significant number of people in the study who were on non-dolutegravir-based ART regimens (efavirenz or lopinavir together with emtricitabine and tenofovir disoproxil fumarate), because they had been on ART before Botswana began using dolutegravir and did not need to change regimen.
Amongst those who received dolutegravir, 52.8% received the recommended twice-daily dose and 43.6% received a once-daily dose of dolutegravir. Contrary to WHO and Botswana guidelines for dolutegravir dose adjustment with rifampicin, a significant number of people received a once-daily dose of dolutegravir in this study. This was perhaps due to some clinicians not following these guidelines.
Among the people on dolutegravir and non-dolutegravir regimens, 90.9% and 88.3% achieved favourable TB treatment outcomes, respectively. Thus a dolutegravir-based regimen showed slightly better TB treatment outcomes than non-dolutegravir-based regimens (adjusted odds ratio = 1.56; 95% confidence interval = 1.06-2.31).
Both the once-daily and twice-daily doses of dolutegravir resulted in favourable TB treatment outcomes. However, a slightly stronger association was observed between a once-daily dose of dolutegravir and favourable TB treatment outcomes (adjusted odds ratio = 1.93; 95% confidence interval = 1.16-3.23), as compared to a twice-daily dose of dolutegravir and favourable TB treatment outcomes (adjusted odds ratio = 1.42; 95% confidence interval = 0.91-2.23).
High rates (more than 92%) of viral load suppression were found across all ART regimen categories. Also, similarly high rates of HIV viral suppression were found between those on once-daily and twice-daily dolutegravir regimens.
Study provides important evidence but also raises some questions
Earlier scientific studies indicated a possible drug-drug interaction between dolutegravir and rifampicin, resulting in decreased concentrations of dolutegravir. That is why WHO guidelines recommend the twice-daily dose (instead of single daily dose) of dolutegravir to people with TB/HIV co-infection who are on rifampicin-based anti-TB therapy.
However, as mentioned above, the results of this study indicate that there were slightly better treatment outcomes in people who were on a single rather than double daily dose of dolutegravir. So, we need more research on whether the dolutegravir dose adjustment is needed.
We also need longer follow-up of this cohort to ensure that there is no drug resistance or adverse HIV treatment outcome if a single-dose dolutegravir is used.
Of note, WHO guidelines recommend drug susceptibility testing when a person with presumptive TB has a TB test. For those who are found positive for active TB disease, treatment should be based on drugs that work for the specific individual. However, Botswana’s guidelines only recommend drug susceptibility testing for children, patients with sputum-negative TB diagnosis and those at risk of drug resistance.
This study instils confidence in using dolutegravir-based ART and rifampicin-based anti-TB therapy in people with HIV and TB co-infection. The results of the study also indicate the need for further research regarding dolutegravir dose adjustment.
“While our results provide a significant degree of confidence to clinicians and public health officials worldwide over the safety of once a day dolutegravir regimens, our results are not yet conclusive due to the intrinsic limitations of an observational study,” comment the authors. “Future pharmacokinetic/pharmacodynamic studies and controlled trials are required to confirm our results.”
References
Modongo C et al. Clinical and Virological Outcomes of TB/HIV Coinfected Patients Treated With Dolutegravir-Based HIV Antiretroviral Regimens: Programmatic Experience From Botswana. Journal of Acquired Immune Deficiency Syndromes 82: 111–115, 2019. doi: 10.1097/QAI.0000000000002126
