Dolutegravir/lamivudine as dual ART
Simon Collins, HIV i-Base
The option to use dolutegravir/lamivudine (DTG/3TC) for both first-line ART and as switch option was a common topic at EACS, especially when compared to use of three-drug ART.
Numerous oral presentations and posters covered various clinical aspects of this dual ART that now included as a preferred combination for starting ART in the 2019 EACS guidelines
DTG/3TC has the potential to limit drug toxicity and also involve less expensive treatment but as with every combination it is important to define the best population who can benefit. This was also the basis of commercial rivalry between companies in the exhibition hall and related advertising throughout the conference.
Low level viraemia on DTG/3TC
Several studies presented new data on low-level viraemia on DTG/3TC, where any signal of suboptimal efficacy would be expected to be seen, but these studies continued to show no difference compared to triple-drug ART.
An oral presentation from the combined GEMINI 1 and 2 phase 3 studies analysed undetectable level viral load based on whether target was detected (TD) or not detected (TND) when less than 40 copies/mL. The 48-week analysis was presented as a poster at CROI in March 2019, showing no differences between groups. [2, 3]
The study at EACS 2019 included additional sub group analyses by baseline viral load (above and below 100,000 copies/mL) and CD4 count (above and below 200 cells/mm3).
Regardless of baseline viral load or CD4 count, similar proportions or participants in each group had TND results overall at week 96, although this was slightly lower in both groups for those starting >100,000 copies/mL (approximately 52% vs 70% for those <100.000).
In a poster presentation, Wang and colleagues presented an updated analysis from the phase 3 TANGO study, that randomised 741 participants on stable ART to either switch to DTG/3TC or continue on their current ART.  This poster was an update of week 48 results that were previously reported at IAS 2019. [5, 6]
This analysis looked at various categories of low-level viraemia overall and in a subset of people with archived NRTI drug resistance (M184I/V and K65R) at baseline.
Again, there were no significant differences in patterns of blips between the two groups, though there were numerically more cases of low level viraemia in the triple therapy group. See Table 1.
Retrospective analysis of baseline samples only detected M184I/V in 1% (7/626) and K65R in <1% (1/626) of samples that could be amplified. Irrespective of treatment group, none of these people experienced viral load > 50 copies/mL.
Table 1: Low level viraemia in TANGO study
|DTG/3TC (n=369)||Triple ART (n=372)|
|1. VL 50–200 c/mL (but always < 200)||11 (3%)||22 (6%)|
|1a. VL blips – single result 50 -200 c/mL||9 (2%)||18 (5%)|
|1b. >2 VL 50-200 c/mL||2 (<1%)||4 (1%)|
|2. VL >200 c/mL||3 (<1%)||3 (<1%)|
|2a. Single >200 c/mL without 50-200||3 (<1%)||1 (<1%)|
|2b. 2 x > 50 c/mL and at least 1 x >200 c/mL||0||2 (<1%)|
|Total||14 (4%)||25 (7%)|
Dual ART using dolutegravir + emtricitabine (FTC)
Results from a small open-label, multicentre Swiss study were presented by Delphine Sculier that randomimised 188 people on stable ART to either DTG + FTC or continuing triple therapy. 
Unlike phase 3 studies using DTG/3TC, there were no CD4, viral load or M184I/V exclusion criteria and the study additionally looked at reduced monitoring – with viral load monitored annually compared to every three months. Integrase inhibitor resistance was an exclusion criteria.
Baseline demographics included 17% women, 80% Caucasian and 9% HCV coinfection. Although median CD4 counts was about 660 cells/mm3(IQR: 500 to 900), many participants had a history of advanced HIV with approximate median CD4 nadir 250 cells/mm3 (IQR: 103 to 367) and viral load 100,000 c/mL (IQR: 30,000 to 326,000).
Baseline ART included integrase inhibitors in approximately 60% with 41 participants newly starting DTG in the dual therapy arm.
At week 48, by the standard endpoint of viral suppression <50 copies/mL by snapshot analysis, 90.3% vs 91.5% in the dual vs triple arms respectively (difference –1.1%; 95%CI: –9.3 to +7.1%).
However, the primary endpoint defined for this study used a higher cut-off of <100 copies/mL with viral failure defined as two consecutive viral load results >100 copies/mL. Results in this analysis were 93.5% vs 94.7% in the dual vs triple arms respectively (difference: –1.2%; 95% CI: –7.8 to +5.6%).
Although this met criteria for non-inferiorityusing predefined margin –12.0%, non-inferiority wouldn’t be met by the more stringent –4% margin now recommended for HIV switch studies. This is a factor of the small size of this study.
In either analysis, there were very few cases of virological failure, with the single confirmed viral rebound to >100 copies/mL occurring in the triple arm.
However, there were also no significant differences in side effects between the two groups, other than reduced creatinine clearance in the dual therapy arm (–2.4 vs +1.1: difference: 4.3, p=0.006).
Dolutegravir/lamivudine with historical M184I/V or K65R/E/N mutations
The question of whether historical/archived drug resistance to lamivudine (M184I/V mutation) could limit the option to use dolutegriavr/lamivudine as a switch option is important.
Although preexisting drug resistance has been an exclusion criterion for most studies, this has been based on limitations of population-based genotype results that can miss minority variants.
A small Spanish pilot study reported cases of successful viral suppression on dual therapy despite retrospectively discovered presence of either M184I/V or K65R/E/N at low levels by single probe next generation sequencing (NGS). 
This study include 41 INSTI-naive adults who were switched to DTG/3TC after having been <50 copies/mL on current combination for at least a year. Presence of M184I/V or K65R/E/N at baseline by routine genotype testing was an exclusion criteria. However, retrospective NGS testing later identified low levels of M184I/V or K65R/E/N in 21 participants including >5% 3TC mutations (combined M184I/VI and K65R/E/N) in 15/21.
At week 48, 92.7% of participants (38/41) remained with VL <50 copies/mL. There were no cases of virological failure however. The three premature discussions (all with historical 3TC resistance) included tow protocol violations (who discontinued with VL < 50 copies/mL) and one discontinuation due to insomnia (at week 8).
One participant with historical M184I rebounded to 1120 copies/mL at week 36 but resuppressed without changing treatment, and without developing 3TC or integrase resistance,
The conclusion noted that fully powered and long term studies were needed to confirm these results and the current study will run for 144 weeks.
Retrospective reviews of dual DTG/3TC in clinical practice
Several studies also reported on retrospective analysis of dual vs triple therapy.
Santoro and colleagues presented interim result of a 96-week superiority study that randomised 50 participants to either remain on their stable dolutegravir/lamivudine therapy or switch to elvitegravir/cobicistat/FTC/TAF (E/C/F/TAF). 
This was another way to look at whether low levels of viral activity that would not be picked up by routine viral load monitoring, could be detected between the 2-drug and 3-drug groups.
In 40/50 participants with results out to week-48 the study found no differences in levels of total HIV-DNA or in a panel of immune responses between the two groups, either at baseline or at week 48.
HIV DNA did increase in some participants, but this was similar between groups: 8/19 for DTG//3TC and 7/21 for E/C/F/TAF, p=0.745). Although the abstract commented on included two individuals in the dual therapy arm with a >4-fold increase in HIV DNA, these results were all well within the overall variability of the study overall.
However, a retrospective analysis of the large Spanish VACH cohort, was more controversial for reported shorter time to treatment failure with dual therapy (DTG/3TC or DTG/rilpivirine – roughly 2:1) compared to using an integrase inhibitor plus two NRTIs (roughly 50% E/C/F/TAF 40% DTG/ABC/3TC). 
The study, also funded by Gilead, included 5664 participants who either switched to dual (n=617) or triple (n=5047) integrase inhibitor-based ART between May 2016 (when TAF FDCs became available) to May 2019.
Importantly, baseline characteristics were significantly different for some important factors including that people in the two-drug arm were more likely to be older, women, people who injected drugs, to have had a longer treatment history, using more combinations and having more treatment failures (mostly p <0.001) although also better viral control (90% vs 80%).
Over 756 and 8617 patient years of follow-up (in dual and triple groups respectively), discontinuations due to side effects were low and overlapping throughout the three years.
However, after controlling for baseline characteristics, participants using dual therapy had a higher risk of treatment failure in Kaplan-Meyer analysis (aHR 2.3. 95% CI: 1.3 to 4.1, p=0.003). Although this difference seemed to develop after two years, there were very few participants with data at these endpoints (n=130 at 24 months, 62 at 30 months and only 10 at 36 months on dual therapy). These results were similar in a subanalyses in participants who had undetectable viral load at the time of the switch and in those who just had viral failure.
Analysis of preexisting drug resistance in those with virological failure was not yet available, nor were clinical data on their management after viral failure.
The presentation included a lively discussion after the talk, that also pointed out that while relative risk was significant the absolute risk in this study was small, only affecting a few patients.
Dolutegravir/lamivudine in transplant recipients
The potential to use dolutegravir/lamivudine in people who have undergone solid organ transplant was included in a poster presented by Castelli et al from University of Barcelona. 
Results from a retrospective case note review of six HIV positive recipients of solid organ transplants (five men, one women; three kidney, two liver and one heart) who were limited from using tenofovir or abacavir due to chronic renal and/or liver toxicity and who all switched to dolutegravir/lamivudine. Five people were receiving TDF/xTC plus either raltegravir (n=4) or rilpiviriine (n=1) and one was already taking dolutegravir/lamivudine before the transplant.
Exclusion criteria included previous ART failure, resistance to lamivudine or raltegravir and HBV infection.
Viral load remained undetectable (<50 copies/mL) during available follow-up (four to 36 months, one to 24 months and one to 6 months). Renal function (creatinine, glomerular filtration) stabilised or improved in all cases. Doses of immune suppressants (n=5 tacrolimus, 1 = cyclosporin) were not significantly changed and there were no cases of organ rejection.
However, one casewith positive anti-core HBV antibodies (indicating previous infection) but negative HBsAg, HBeAg and plasma DNA-HBV, developed acute HBV two years after simplification. This person reestablished after restarting TDF, and HBsAg and DNA returned to undetectable.
These studies continue to broadly support the safety of dolutegravir/lamivudine dual therapy in many settings.
The Spanish cohort study reporting higher relative risk of treatment failure by Teira and colleagues will keep a focus on long-term outcomes.
Randomised data will become available from large phase 3 TANGO study that continues both arms until 148 weeks, with further follow-up to week 200. 
Unless stated otherwise, references are to the Programme and Abstracts of the 17th European AIDS Clinical Society (17th EACS), 16–18 October 2019, Basel.
- Underwood M et al. Assessments of very low level HIV replication for dolutegravir+lamivudine (DTG+3TC) vs dolutegravir+tenofovir disoproxil/emtricitabine (DTG+TDF/FTC) in the GEMINI 1&2 studies through week 96. 17th EACS, 16–18 October 2019, Basel. Oral abstract PS8/2.
- Collins S. Dolutegravir/3TC dual ART is as effective at lowest viral load cut-off as triple therapy in GEMINI studies. HTB 28 March 20919.
- Underwood M et al. HIV replication at <40 c/mL for DTG+3TC vs DTG+TDF/FTC in the GEMINI 1 & 2 studies. CROI, 4-7 March 2019, Poster abstract 490.
- Wang R et al. Switching from a 3-drug tenofovir alafenamide (TAF)-based regimen (TBR) to a 2-drug dolutegravir/lamivudine (2DR, DTG/3TC FDC) was not associated with a higher frequency of intermittent viremia in suppressed patients in the TANGO study. 17th EACS, 16–18 October 2019, Basel. PE3/15.
- Collins S et al. Switching to dolutegravir/lamivudine dual therapy is non-inferior to TAF-based triple therapy at week-48 in TANGO study. HTB 24 July 2019.
- van Wyk J et al. Switching to DTG+3TC fixed dose combination (FDC) is non-inferior to continuing a TAF-based regimen (TBR) in maintaining virologic suppression through 24 weeks (TANGO Study). 10th IAS Conference on HIV Science (IAS 2019), 21-24 July 2019, Mexico City. Late-breaker oral abstract WEAB0403LB.
- Sculier D et al. Dolutegravir/emtricitabine dual therapy is non-inferior to standard combination antiretroviral therapy in maintaining HIV suppression throughout 48 weeks (SIMPL’HIV study). 17th EACS, 16–18 October 2019, Basel.Oral abstract PS8/3.
- De Miguel Buckley R et al. Dolutegravir and lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a pilot clinical trial (ART-PRO). 17th EACS, 16–18 October 2019, Basel. Oral abstract PS7/5.
- Santoro MM et al. Evaluation of total HIV-DNA changes in HIV-1 infected patients who continue a 2-drug regimen with dolutegravir plus one reverse transcriptase inhibitor or switch to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide enrolled in the Be-One Study. 17th EACS, 16–18 October 2019, Basel. Poster abstract PE3/3.
- Teira R et al. Shorter time to treatment failure in PLHIV switched to dolutegravir plus either rilpivirine or lamivudine compared to integrase inhibitor-based triple therapy in a large Spanish cohort – VACH. 17th EACS, 16–18 October 2019, Basel. PS8/5.
- Castelli A et al. Simplification to dual (2D) antiretroviral therapy (ART) with lamivudine and dolutegravir in HIV-infected patients with solid organ transplantation (SOT): a preliminary single-center experience. Poster abstract PE 2/35.
- clinicaltrials.gov. Switch study to evaluate dolutegravir plus lamivudine in virologically suppressed HIV-1 positive adults (TANGO).