Dolutegravir-based dual therapy as switch option in multiple studies
Simon Collins, HIV i-Base
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. 
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 mean age 46 years, 86% men, 76% MSM, and mean CD4 count 739 cells/mm3 (SD +/- 303).
By week 24, there were three discontinuations due to viral failure (one on dual therapy at week 12 and two on monotherapy at week 24) and the monotherapy arm 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 oral study was a meta-analysis presented by Marta Buzzi and colleagues from University Hospital Geneva, and reported low rates of viral 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 to 1.3). Of these, only one developed drug resistance: a person using rilpivirine plus dolutegravir developed NNRTI drug resistance (K101K/E).
The same study reported that dolutegravir monotherapy was associated with significantly higher risk of viral rebound. In 212 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. However, 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.
Posters using dolutegravir/3TC dual therapy
Additionally, numerous poster presented result from the dual combination of dolutegravir plus 3TC, some of which had been included in the above meta-analysis by Buzzi et al described above. [5, 6, 7, 8, 9, 10]
Babafemi Taiwo and colleagues from Northwestern University, Chicago, randomised 89 participants on stable ART to switch to dolutegravir plus 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. At week 48, this was extended to 91% versus 89%, showing dual therapy to be non-inferior. 
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 were 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 viral failure (rebound to 77 copies/mL at week 4). 
A small study presented by Luba Tau and colleagues from Tel Aviv compared outcomes of 72 participants switched to dolutegravir plus 3TC compared to a 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). 
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. 
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 due 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) maintained viral load <50 copies/mL. Two results were >50 copies/mL, both pending confirmation, of 55 and 239 copies/mL. 
Again from Italy, 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). 
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% and 82% with dolutegravir, 80% and 48% with darunavir/r, and 87% and 71% with atazanavir/r (p< 0.001).
Although viral responses were similar between arms, dolutegravir/3TC had fewer discontinuations due to tolerability.
Dolutegravir-based dual therapy with darunavir/b
Finally, one small study paired dolutegravir with darunavir/r QD. 
A retrospective analysis from Navarro and colleagues reported on 27 highly treatment-experienced patients who were switched to dual therapy using dolutegravir with once-daily boosted darunavir. Median time with undetectable viral load before the switch was 44 months (IQR: 18 to 104) but treatment history included a median of 8 (IQR: 4 to 11) ART combinations with a median of 5 (IQR: 2 to 8) viral failures. Historical genotype primary mutations included: 96% (n=27) to NRTIs, 78% (n=21) to NNRTIs and 41% (n=11) to PI, of whom 6 had DRV-associated mutations. Importantly no participants had integrase mutations.
At week 48, viral load was <50 copies/mL in 93% (n=25) participants. There was one viral rebound without resistance emergence and one patient died due to bacterial peritonitis.
|Blanco JL et al.||RCT: DTG + 3TC vs mono vs 3-drug ART.||n=91.||Monotherapy stopped with 2 viral failures at week 24 (vs 1 in dual arm). Dual vs triple arms continue with expanded enrolment.|||
|Buzzi M et al.||Meta analysis and reanalysis of six studies with DTG + 3TC.||n=835 on DTG-based dual.||1/835 report viral failure at week 48 (using dolutegravir + rilpivirine). VF with NNRTI resistance.|||
|Taiwo BO et al.||RCT: switch to DTG + 3TC vs current ART.||n=89.||VL <50 in 93% vs 91% in dual vs control at week 24 and 91% vs 89% at week 48.|||
|Joly V et al.||Single-arm, prospective, open-label ANRS167 switch to DTG + 3TC.||n=104.||101/104 <50 copies/mL at week 48. Only one case of viral rebound (to 67 copies/mL).|||
|Tau L et al.||Prospective open-label switch to DTG + 3TC compared to historical control.||n=72 dual vs 86 control.||At 96 weeks, viral load <50 copies/mL in 97% of each group. higher numbers of blips > 200 copies/mL in the control group (n=1 vs 6, NS).|||
|Maggiolo F et al.||Single-arm, prospective, open-label switch study to DTG + 3TC.||n=203.||No viral failures during 295 patient-years of follow-up. 12 discontinuations were due to intolerance, clinical complications or loss to follow-up.|||
|Hidalgo-Tenorio C et al.||Retrospective results in people switched to DTG + 3TC.||n=105,||82/84 pts with results had viral load <50 copies/mL after median 23 weeks. Two rebound results of 55 and 239 copies/mL.|||
|Borghetti A et al.||Retrospective results after switch to 3TC dual with DTG, darunavir or atazanavir.||n=494;
(DTG: 183, DRV: 170, ATZ: 141).
|Viral failure in 3 (DTG) vs 6 (DRV) vs 4 (ATV).
At weeks 48/96: 88%/82% with DTG, 80%/48% with darunavir/r and 87%/70% with atazanavir/r were still on switch drugs.
|Navarro J et al.||Single-arm, open-label switch to DTG + darunavir/b QD in experienced pts.||n=27.||VL <50 c/mL in 25/27 (93%) at week 48. Only one viral failure – with no resistance.|||
Both the above studies rightly emphasised that dolutegravir monotherapy should no longer used due to the unpredictable risk of viral rebound with integrase inhibitor 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. The Gemini 1 and 2 studies that compare dolutegravir/3TC to dolutegravir plus TDF/FTC are already enrolled with results due in mid-2018.
Unless stated otherwise, references are to the programme and abstracts of the 16th European AIDS Conference (EACS 2017), 25–27 October 2017, Milan. Abstracts are available from the online conference planner:
- Blanco JL et al. Planned 24-week analysis of two dolutegravir (DTG)-based simplification strategies. 16th EACS, 25–27 October 2017, Milan. Oral abstract PS1/3.
- Buzzi M et al. Dolutegravir-based maintenance therapy in HIV-infected patients: systematic review and meta-analysis. 16th EACS, 25-27 October 2017, Milan. Oral abstract PS1/2.
- Wijting EA et al. Dynamics of viral rebound and development of resistance associated mutations in the DOlutegravir Maintenance MONOtherapy (DOMONO) study. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE6/16.
- Lungu C et al. Changes outside integrase in a patient failing on dolutegravir maintenance monotherapy points to a new resistance mechanism. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE6/17.
- Taiwo BO et al. Dolutegravir plus lamivudine maintains HIV-1 suppression through week 48 in a pilot randomized trial. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE8/5.
- Joly V et al. Promising results of dolutegravir + lamivudine maintenance in ANRS167 LAMIDOL trial. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/11.
- Tau L et al. Switch to dolutegravir in HIV patients responding to a first line antiretroviral treatment- 96 weeks of experience. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/26.
- Maggiolo F et al. Durability of dolutegravir + lamivudine as simplification cART in patients with suppressed HIV-RNA. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/49.
- Hidalgo-Tenorio C et al. Multicenter study of the effectiveness and safety of a dual therapy with dolutegravir plus lamivudine in treatment-experienced HIV patients. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/68.
- Borghetti A et al. Efficacy and tolerability of lamivudine plus dolutegravir compared with lamivudine plus boosted PIs in HIV-positive, virologically-suppressed individuals from the clinical practice. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/76.
- Navarro J et al. Efficacy of once-daily dolutegravir plus boosted-darunavir as a switch strategy in HIV-infected heavily-treated patients. 16th EACS, 25-27 October 2017, Milan. Poster abstract PE9/93.