Results From Systematic Review and Meta-analysis of the Efficacy and Safety of Two-drug Versus Three-drug (Tenofovir/Lamivudine/Dolutegravir; TLD) Regimens for HIV Treatment
Year: 2024
Type: review
Abstract: To the Editor—We thank the authors for their insightful response to our review. The authors argue primarily for safety reasons that dolutegravir/lamivudine (DTG/3TC), not tenofovir-disoproxil/lamivudine/dolutegravir (TLD), should be future first-line antiretroviral therapy. To answer this question, we conducted a meta-analysis of efficacy and safety of 6 randomized controlled trials (RCTs) that compared combinations of tenofovir, 3TC (or FTC) and DTG versus DTC/3TC (or DTG and FTC): GEMINI-1, GEMINI-2, DOLAM, TANGO, SALSA and PASO-DOBLE [1–5]. We included the 48-week data from each RCT for this analysis, with random-effects models. Summary results are shown in Table 1. In this meta-analysis of 6 RCTs in 3485 people with human immunodeficiency virus (HIV, PWH), there was no significant difference between DTG/3TC and DTG-based triple therapy for human immunodeficiency virus type 1 (HIV-1) suppression <50 copies/mL, or elevations in HIV RNA >50 copies/mL. There was also no significant difference in Grade 1–4 adverse events (AEs), serious AEs, or AEs leading to treatment discontinuation. It cannot be assumed a priori that 2-drug regimens are safer than 3: for instance, increasing evidence suggests TDF confers off-target metabolic benefits, leading to smaller rises in body weight and lower risk of lipid elevations when used [11]. Summary of Metanalysis Results Comparing Efficacy and Adverse Events Leading to Treatment Discontinuation for DTG/3TC and Three-drug Regimens (3DR) [1, 2, 6–10] Abbreviations: AE, adverse event; CI, confidence interval; Diff., difference; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; 3TC, lamivudine; SAE, severe adverse event; XTC, lamivudine or emtricitabine. Summary of Metanalysis Results Comparing Efficacy and Adverse Events Leading to Treatment Discontinuation for DTG/3TC and Three-drug Regimens (3DR) [1, 2, 6–10] Abbreviations: AE, adverse event; CI, confidence interval; Diff., difference; DTG, dolutegravir; HIV-1, human immunodeficiency virus type 1; 3TC, lamivudine; SAE, severe adverse event; XTC, lamivudine or emtricitabine. In our article we described 8 benchmarks against which novel antiretroviral regimens should be assessed to compete with generic TLD for widespread use. Through our meta-analysis we found DTG/3TC does not show superior efficacy or safety compared with TLD. Whether DTG/3TC is safe in pregnancy including effectively preventing perinatal transmission is unknown: pregnant women were excluded from the 6 RCTs. Safety and efficacy data are lacking for people taking DTG/3TC while coinfected with human immunodeficiency virus type 2 (HIV-2) [12] hepatitis B virus (HBV), or taking treatment for tuberculosis (TB) coinfection: these patients were all excluded from the 6 RCTs. This is particularly concerning given the high prevalence but low testing for HBV globally [13] and potential risks of treatment-emergent HBV resistance with DTG/3TC [14] and HBV flare-up after discontinuation of tenofovir [15]. Furthermore, all 6 trials excluded people with known major nucleoside reverse transcriptase inhibitor or DTG resistance, limiting widespread DTG/3TC use in regions without robust resistance capacities. With DTG patents expiring imminently in Europe and North America, fully generic TLD becomes an attractive possibility worldwide. Generic TLD currently costs $42 per person-year, whereas branded DTC/3TC costs over $10 000 per person-year in Europe. If it does not offer safety or efficacy benefits does DTG/3TC offer other benefits over TLD? We absolutely agree with the importance of the “fourth 90” and choice, and some PWH may prefer to take 2 drugs rather than 3. However, unfortunately substantial resources are required to ensure that this is safe for an individual. Meanwhile, another crucial programmatic advantage of TLD is its safety across the population including in settings without sophisticated diagnostic testing capacities. Furthermore, for many PWH long-acting injectable formulations are preferable to daily oral antiretrovirals, and neither TLD nor DTG/3TC yet offers this option (our eighth benchmark). In conclusion, we find no safety or efficacy benefits to justify introduction of DTG/3TC on a programmatic level, and instead identify several disadvantages compared to TLD. Financial support. No funding was received for this response.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/ciae490
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,001
OpenAlex ID: W4402995248