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Infectious Disease and “Fight against AIDS and Infectious Diseases Foundation”
Hospital Universitari Germans Trias i Pujol
Josep M. Llibre, MD, PhD, has disclosed that he has received funds for research support from Gilead Sciences; consulting fees from Gilead Sciences, Janssen Cilag, and ViiV Healtchare; and fees for non-CME/CE services from Gilead Sciences, Thera Technologies, and ViiV Healthcare.
One of the most intriguing studies presented at the IAS 2021 Conference that is of particular relevance to Western Europe is the SALSA study, the second randomized, open-label, multinational phase III study demonstrating noninferior virologic efficacy of switching to dolutegravir/lamivudine instead of continuing various 3-drug or 4-drug antiretroviral therapy (ART) regimens through 48 weeks. The primary endpoint, the adjusted treatment difference between both arms, was -0.8%, well below the prespecified noninferiority margin of 5%. Efficacy rates were high at 94% in the dolutegravir/lamivudine arm and 93% in the control arm. The sensitivity analyses and a per protocol analysis also showed noninferiority.
The SALSA study recruited 493 participants with characteristics that differed from those in the previous TANGO study, adding important new information on baseline regimens, women, older patients, and non-White patients. Unlike in TANGO, SALSA recruited participants being treated with any 3-drug regimen, not just tenofovir alafenamide–based regimens. Also, in the dolutegravir/lamivudine arm in SALSA, nearly one half of participants were women (44%), much higher than in previous ART randomized trials (7% in TANGO). In addition, 40% of participants were 50 years of age or older, twice the percentage seen in the TANGO study. Finally, there was a wider variety of racial representation (39% non-White race), twice the percentage seen in the TANGO study.
Resistance and Safety
In the SALSA study, there were no confirmed virologic withdrawals and no cases of selection for resistance. Also, no patient discontinued dolutegravir/lamivudine in SALSA due to lack of efficacy (vs 2 participants in the control arm). Together with the TANGO study, we now have data from 615 participants in controlled studies of switching to dolutegravir/lamivudine, with 1-year and 3-year follow-up in the SALSA and TANGO studies, respectively. The zero resistance selection observed in both studies confirms the outstanding barrier against resistance selection of this regimen after switch. Thus, I believe the results of the SALSA study demonstrate that the regimen was well tolerated and, therefore, is a favorable choice for ART simplification. Regarding safety, the rates of overall or grade 2-5 adverse events leading to withdrawal or any serious adverse events were similar between arms. There were no drug-related serious adverse events. As commonly seen in open-label switch studies that recruit participants who are already tolerating a given regimen, the rates of low-grade drug-related adverse events were higher with the new regimen vs continuing with the previous one (20% vs 6%, respectively).
There was a greater weight increase (2.1 vs 0.6 kg) and BMI increase (0.7 vs 0.2 kg/m2) in the dolutegravir/lamivudine arm vs the control arm. This weight gain was higher than that observed in the TANGO study, where the median weight increase with dolutegravir/lamivudine at 48 weeks was 0.8 kg. Although SALSA recruited higher rates of women and Black participants, which are populations associated with greater weight gain, these groups were evenly distributed between arms, so this is unlikely to explain the greater weight increase. Rather, these data suggest that the weight gain may be influenced more by the drugs that are being withdrawn at switch than by the addition of dolutegravir itself. For example, efavirenz and tenofovir disoproxil, used by 32% and 44% of participants, respectively, are known to reduce or attenuate weight increase. Perhaps the switch from efavirenz and tenofovir disoproxil had more of an impact than the switch to dolutegravir/lamivudine. A complete analysis is underway and will be reported soon.
Considerations for ART Switch in Western Europe
The message that “no one should receive more medicines than they need” is extremely relevant to this second confirmatory switch study for the lifelong treatment of HIV. Although we do not yet have specific data for regional (European) participants in SALSA, 5 Western European countries (Spain, Germany, Italy, France, and the United Kingdom) were involved in the study recruitment. Overall, I believe we now have sufficient data confirming the efficacy and safety of this switch strategy for patients with no previous virologic failure and no nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor resistance. Dolutegravir/lamivudine is a recommended switch strategy in the EACS guidelines, which includes one bullet for 2-drug regimens. The main reasons acknowledged for switching ART are prevention or resolution of toxicity, mitigation of the effects of ageing/comorbidities, or simplification.
Of importance, dolutegravir/lamivudine is a dominant strategy in pharmaco-economy because it has the same safety and efficacy as 3-drug or 4-drug regimens but at a lower cost in Europe. In Western and Northern Europe and in the United Kingdom, cost-efficacy considerations have an increasing importance in ART selection. In properly selected patients, maybe we will have to change our scientific minds and reconsider why we would prescribe a third antiretroviral drug if there is no need to do so. Those physicians who still required a second confirmatory switch study with dolutegravir/lamivudine—with long-term follow-up, including data on ultravirologic suppression below 50 copies/mL of HIV-1 RNA (target not detected, blips, viral load decay in treatment-naive patients)—can be reassured with the addition of the SALSA study findings.
There are ongoing metabolic subanalyses that will add a new piece into this scientific puzzle. In addition, data on long-term toxicity or comorbidity avoidance with this 2-drug regimen are the main focus of analyses in Western Europe. So far, the only large, international cohort analysis (RESPOND Euro-Australian Collaboration) assessing clinical outcomes has found that the short-term incidence of severe clinical events is similar between 2-drug and 3-drug regimens.
Do you anticipate integration of 2-drug regimens in your practice? Join the discussion by posting a comment. For more details on this and other key issues from IAS 2021, review more CCO Conference Coverage including Capsule summary slidesets, video recaps with expert faculty, and ClinicalThought commentaries highlighting global perspectives.