Dolutegravir-based ART in combination with rifampicin-based TB treatment is safe in a small cohort of co-infected patients

29 November 2016. Related: Conference reports, PK and drug interactions, TB coinfection, HIV 13 Glasgow 2016.

Polly Clayden, HIV i-Base

Twice daily dolutegravir in combination with rifampicin was well tolerated and produced good outcomes in a small retrospective study presented at HIV Drug Therapy Glasgow 2016. [1]

A rifampicin-based regimen is first-line TB treatment worldwide and co-administration of HIV and TB treatment is now standard of care. But there are significant drug interactions with ART as rifampicin is a potent inducer of cytochrome p450 and UGT.

Dolutegravir is a substrate of UGT1A1 and CYP3A4 so co-administration with rifampicin decreases dolutegravir plasma concentrations.

A previous phase 1 study showed 50 mg dolutegravir twice daily taken with rifampicin gave dolutegravir concentrations similar to those with 50 mg once daily. [2]

Muge Cevik and colleagues from Leeds Teaching Hospitals presented data from a retrospective case note review of TB/HIV co-infected patients who received rifampicin-based TB treatment with dolutegravir based ART. In this cohort, dolutegravir is used in co-infected patients who experience side effects with efavirenz or where efavirenz is contraindicated.

The investigators identified seven people (six women) who received a dolutegravir-based regimen in combination with rifampicin. Their median age was 41 years (range 27 to 48) and all were of black African origin. Five were ART naive. Three received dolutegravir with abacavir and 3TC and four FTC/TDF.

Median baseline CD4 count was 90 copies/mL (range: 3 to 365). Five people had very low CD4 count at baseline (<100 cells/mm3), four had viral load >100,000 copies/mL and only one was undetectable. At six months from starting ART, median CD4 count was 230 cells/mm3 (range: 104 to 625) and all but one had undetectable viral load.

One ART-experienced patient had viral load of 240,000 copies/mL at baseline. This was someone with transmitted antiretroviral resistance mutations to NRTIs (T69 deletion) and NNRTIs (Y181C and G190A). She had well documented poor adherence and had stopped her HIV treatment completely before re-starting ART with FTC/TDF plus dolutegravir (twice-daily) two weeks after starting TB treatment. At six months her viral load was 3,100 copies/mL. A month later she was undetectable but resistance testing showed a new M184 mutation and her regimen was changed.

All participants completed TB treatment and none experienced grade 3/4 side effects or TB-IRIS.

Comment

Alongside that in pregnant women, lack of data in people receiving concomitant TB treatment was one of the main reasons for WHO to recommend dolutegravir-based first-line ART as an alternative rather than preferred regimen. [3]

So far the evidence for using dolutegravir 50 mg twice daily in the presence of rifampicin comes from the PK study in HIV negative volunteers (fasted) mentioned above. Robust clinical data are urgently needed to demonstrate the efficacy, safety and tolerability of twice daily dolutegravir in combination with rifampicin.

The originator company ViiV Healthcare is sponsoring an open-label phase 3 study of dolutegravir (DTG) vs efavirenz with rifampicin co-treatment with an estimated primary completion date of December 2017.

In the meantime, there are probably a few small “real life” studies or reports of such co-treatment emerging – like this example from Glasgow. These smaller studies will need careful evaluation, to see how rigorous the methodology is. But in the absence of better data – but expected increased use of dolutegravir, including in low-income settings [5] – it might be possible to add these to the interim data from the main clinical trial when the time comes to look at the evidence for the next iteration of the guidelines in 2017.

References:

1. Cevik M et al. Use of dolutegravir in combination with rifampicin based TB therapy in HIV/TB co-infected patients. HIV Drug Therapy Glasgow, 23-26 Oct 2016. Poster abstract P147..
   http://jiasociety.org/index.php/jias/issue/view/1485
2. Dooley K et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7
3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach – Second edition. June 2016.
   http://www.who.int/hiv/pub/arv/arv-2016/en/
4. Open-label study of dolutegravir (DTG) or efavirenz (EFV) for human immunodeficiency virus (HIV) – tuberculosis (TB) co-infection
   https://clinicaltrials.gov/ct2/show/NCT02178592
5. ViiV press release. ViiV Healthcare announces public tender agreement with Botswana Ministry of Health for dolutegravir. 3 June 2016.
   http://www.gsk.com/en-gb/media/press-releases/2016/viiv-healthcare-announces-public-tender-agreement-with-botswana-ministry-of-health-for-dolutegravir