Dolutegravir 50 mg twice daily is effective and well-tolerated in adults with HIV/TB receiving rifampicin-based TB treatment. This is based on 24 weeks interim results from the INSPIRING study presented at CROI 2018.1
Treating TB and HIV is complicated by drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). Dolutegravir (DTG) is poised to become a massively-used antiretroviral worldwide -- including in settings were TB is common.
In healthy volunteers, rifampicin (RIF) reduced DTG concentrations considerably but this is likely overcome by giving DTG 50 mg twice daily.2
The INSPIRING study is being conducted to look at safety and efficacy of DTG in ART naive adults with HIV/TB. It is a phase 3b, non-comparative, active control, randomised, open-label study in HIV positive adults with at least 50 CD4 cells/mm3 and drug-sensitive TB.
Related: Dual Therapy Can Reduce TB Prophylaxis From Nine Months to One: Fewer Side Effects and More People Complete Treatment
Participants receiving rifampicin-based TB treatment for up to eight weeks were randomised (3:2) to receive DTG (50mg twice daily during and for two weeks after finishing TB treatment, followed by 50mg once daily) or efavirenz (EFV 600mg once daily), with two investigator-selected NRTIs for 52 weeks.
For the 24-week interim analysis, the investigators evaluated the proportion of participants with viral load <50 copies/mL using the modified FDA Snapshot algorithm in the intent to treat exposed population. They also assessed safety in all participants who received study drug. An independent adjudication committee looked at IRIS events. The study was not powered for non-inferiority. Kelly Dooley from Johns Hopkins University, Baltimore presented the results on behalf of the investigators.
INSPIRING enrolled 113 participants, across 37 sites in seven countries. The majority were from South Africa (n=65), other participating countries were: Peru, Brazil, Mexico, Russia, Argentina and Thailand. The study started in January 2015 and took about 21 months to fully enrol.
The participants were median age of 33 years and about 60% were male (TB is more common in men so this reflects incidence). Approximately 55-60% had a viral load >100,000 copies/mL and 20-30% CD4 <100 cells/mm3. They received TB treatment for about 30 days before starting ART. The most common ART backbone was TDF/XTC.
There were 69 and 44 participants randomised to the DTG and EFV arms respectively. Virological suppression <50 copies/mL was achieved in 56 (81% [95% CI 79 to 98]) and 39 (89% [95% CI 72 to 90]) participants in the respective arms.
There were 7 (10%) and 3 (7%) virological non-responders in the DTG and EFV arms respectively. Dr Dooley noted that among 5 participants who were not suppressed to <50 copies/mL in the DTG arm, 4 were between 50 and 400 copies/mL and 3 achieved suppression at later visits. Five (7%) of non-responders in the DTG arm were due to discontinuations for non-treatment reasons (mainly lost to follow up while suppressed).
Pharmacokinetics in INSPIRING are shown in Table 1.
|Table 1: INSPIRING Pharmacokinetic Data|
|Time||n||DTG concentration (ng/mL) GM (90%)|
|Pre-dose concentration: DTG 50 mg twice daily + RIF|
|Week 8||41||852 (208 to 2340) 118|
|Week 24||22||942 (19 to 3380) 276|
|Pre-dose concentration: DTG 50 mg once daily (post TB treatment)|
|Week 36||16||1143 (80 to 4370) 151|
|Week 48||12||591 (19 to 3310) 359|
Median CD4 cell increases at week 24 were 146 cells/mm3 (IQR 71-214) for DTG and 93 cells/mm3 (IQR 47-178) for EFV.
Adverse events were common, occurring in 72% in the DTG arm and 91% of participants in the EFV arm. There were only two serious adverse events, both TB IRIS, one in each arm.
Of participants with events sent to IRIS adjudication committee 6% in the DTG arm and 9% in the EFV arm met the criteria for TB-associated IRIS. No one permanently discontinued their treatment due to IRIS.
Two participants had grade 3 liver toxicity; there was one in each arm and neither had to discontinue.
One participant met viral withdrawal criteria and no DTG resistance was detected.
Interim week 24 results from this ongoing study suggest that DTG 50 mg twice daily seems effective and well-tolerated in HIV/TB co-infected adults receiving RIF-based TB therapy. The investigators concluded that these data support the use of a DTG based regimen in HIV/TB co-infection.
The DTG label already recommends twice-daily dosing in the presence of RIF based on the previous drug-drug interaction study in HIV negative participants. This study was not powered to make a comparison with EFV but conducted to obtain some data in people with HIV/TB.
New antiretroviral options for people with HIV/TB are very welcome, as are all new data to support the imminent widespread use of DTG across populations.
For large scale programmes such as South Africa, the logistical issues involved in procuring and dispensing DTG single tablets in addition to DTG-based fixed-dose combinations (which are less vulnerable to stock outs etc), might prove too complex. Another strategy could be to switch to an EFV-based fixed-dose combination during TB treatment and back to DTG after this is completed. How countries approach HIV/TB co-treatment is likely to vary according to the size and capacity of the programme.
- Dooley K et al. Safety and efficacy of dolutegravir-based ART in TB/HIV coinfected adults at week 24. 25th CROI. Boston. 4-7 March 2018.
Oral abstract 33.
- 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.
[Note from TheBodyPRO: This article was originally published by HIV i-Base on March 7, 2018. We have cross-posted it with their permission.]