October 27, 2017
Two oral presentations and numerous posters included new data on using dolutegravir-based dual ART (many with 3TC) as a switch option for people currently on stable three-drug ART.
Esteban Martinez from University of Barcelona presented 24-week results from the first phase of the open-label DOLAM study that randomised 91 participants (1:1:1) to dolutegravir plus 3TC, dolutegravir monotherapy or to a control group continuing on standard three-drug ART.1
Entry criteria included having an undetectable viral load (< 50 copies/mL) for ≥12 months, CD4 nadir >200 cells/mm3, no history of viral failure or resistance mutations to 3TC/FTC or integrase inhibitors and HBsAg negative.
Baseline characteristics included means age 46 years, 86% men, mean CD4 count 739 (+/- 303),
There were three discontinuations due to viral failure (one on dual therapy and two on monotherapy) and the monotherapy arm of this study was discontinued early following a recommendation by the DSMB due to higher rates for viral rebound. Importantly, both participants in the monotherapy arm developed integrase associated drug resistance.
The participant who discontinued in the dual arm due to low level viral rebound had no resistance and an additional participant in this arm also report low level viral blip (resuppressed without change or treatment).
Enrolment into the two remaining arms of the DOLAM study will expand to 129 participants in each arm. This will be powered for 8% margin for non-inferiority (rather than new FDA definition of 4% for studies looking for new licensing indication).
The second study was a meta-analysis presented by Buzzi and colleagues from University Hospital Geneva, reported low rates of virological failure in participants switched to dolutegravir-based dual therapy. From six studies, only 3/835 participants reported virological failure at 48 weeks (0.4%, 95% CI: 0.1-1.3). Of these, 1/3 reported emergent NNRTI drug resistance treated with rilpivirine plus dolutegravir.
The same study reported that dolutegravir monotherapy was associated with significantly higher risk of viral rebound. In 221 participants from six monotherapy switch studies, the rate of viral rebound was 3.3% (95%CI: 1.6 to 6.8) at 24 weeks and 8.9% (95%CI: 4.7 to 16.2) at 48 weeks. Emergent drug resistance developed in 7 (3%) participants on DTG-monotherapy.
The authors reported dolutegravir-based dual therapy is a promising simplification strategy for people with stable HIV suppression on ART and that large trials are already ongoing.
Additionally, numerous poster presented result from the dual combination of dolutegravir plus 3TC.5-10
Babafemi Toawo and colleagues from Northwestern University, Chicago, randomised 89 participants on stable ART to switch to dolutegravir plu 3TC (n= 44) or remain on current ART (n=45). The primary endpoint of viral suppression <50 copies/mL at week 24 was maintained in 93% (41/44) vs 91% (41/45) in the dual vs control groups (difference 2%; 95%CI: -11% to 15%) at week 24. This was maintained to 91% versus 89% at week 48 showing dual therapy to be non-inferior.5
Véronique Joly and colleagues from the French ANRS 167 LAMIDOL study reported on 110 participants in an open-label, single-arm, multicenter trial that switch people on stable ART (<50 copies/mL for >2 years, with no drug resistance). For the first eight weeks the third component of ART was switched to dolutegravir, changing to using only 3TC as background NRTI (if there very no earlier complications).
Six participants did not enter the second phase (n=3 due to dolutegravir side effects and n=3 due to viral load >50 copies/mL). At week 48, viral suppression was maintained by 101/104 participants with three therapeutic failures due to 1 x lost to follow-up, 1 x interruption of strategy, and 1 x virologic failure (rebound to 77copies/mL at week 4).6
A small study presented by Luba Tau and colleagues from Tel Aviv compared outcomes of 72 participants swthced to dolutegravir plus 3TC to historical cohort of 86 patients on non-dolutegravir containing ART. After 96 weeks, viral load <50 copies/mL was reported for approximately 97% in each group, with higher rates of blips >200 copies/mL in the control group (n=1 vs 6, p=0.08 NS).7
A larger prospective Italian cohort of 203 participants on stable ART (> 6 months) switched to dolutegravir plus 3TC was presented by Franco Maggiolo and colleagues.8
At switch, participants had been on ART for a median of 10.3 years (IQR: 5.5 to 17.6) and had been virally suppressed for a median of 72 (IQR: 33 to 121) months. No cases of viral failure were reported over 295 patient years of follow up. The 12 discontinuations (5.9%) were dues to death (n=3; 2 x neoplastic disease and 1 x cirrhosis), intolerance (n=5: 2 x muscle pain/stiffness, 1 x headache, 1 x dizziness and 1 x increased AST/ALT) or patient decision (n=2) and lost to follow-up (n=2).
From Spain, Carmen Hidalgo-Tenorio and colleague presented retrospective results on 105 participants in a multicentre observational cohort on ART (96% with viral load <50 copies/mL) who switched to dolutegravir plus 3TC for simplification (39%) or toxicity (45%). In 84 patients with viral load results after switch (after a median of 23 weeks of follow up), 97% (82/84) maintainded viral load <50 copies/mL. Two results were >50 copies, both pending confirmation, to 55 and 239 copies/mL.9
Finally, Alberto Borghetti presented retrospective results from a single centre in Rome of 494 treatment experienced patients switching to investigator choice of one of three simplified dual combinations of 3TC with dolutegravir (n=183), darunavir/r (n=170) or atazanavir/r (n=141).10
Viral failure occurred in 3, 6 and 4 cases with dolutegravir, darunavir/r and atazanavir/r respectively. The percentages of people remaining on switch treatment at weeks 48 and 96 were: 88.2% and 82.6% with dolutegravir, 79.8% and 48.3% with darunavir/r, and 87.0% and 70.9% with atazanavir/r (p< 0.001).
Although viral responses were similar between arms, dolutegravir/3TC had few discontinuations due to tolerability.
Both the above studies rightly emphasised that dolutegravir monotherapy should no longer be used due to the unpredictable risk of viral rebound with integrase inhibitor due resistance.
Two posters presented detailed case reports of viral rebound with dolutegravir monotherapy.3,4
Many other posters reported the use of dolutegravir/3TC dual therapy (detailed reports to follow).
Although the numerous poster studies are broadly encouraging, the results from larger randomised studies that are currently ongoing will clearly be important.
[Note from TheBodyPROD.com: This article was originally published by HIV i-Base on Oct. 26, 2017. We have cross-posted it with their permission.]
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