Dolutegravir–lamivudine as initial therapy in HIV‐1 infected, ARV‐naive patients, 48‐week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study

Abstract

Introduction: A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients.Methods: PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm).Results: Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients.Conclusions: This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients.ClinicalTrials.gov Identifier: NCT02211482.

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

“…While preliminary analyses of a Dutch DTG monotherapy simplification trial seemed encouraging at 24 weeks, rates of virological failures increased significantly by week 48, suggesting a sub-optimal potency of this regimen 8 . On the other hand, several studies evaluating DTG-based dual therapy with either 3TC or rilpivirine (RPV), showed a high virological efficacy 9– 12 . However, most reports were from small, observational cohort studies, with the exception of one DTG-RPV industry-sponsored randomized controlled trial (RCT) 11 .…”

Bioequivalence and Food Effect Assessment of 2 Fixed‐Dose Combination Formulations of Dolutegravir and Lamivudine

“…21 In particular, lamivudine is eliminated by filtration and active renal tubular secretion. 24,25 The GEMINI studies compared once-daily coadministration of 50 mg dolutegravir plus 300 mg lamivudine to a standard of care, once-daily, 3-drug regimen consisting of a 50-mg dolutegravir tablet plus a 2-drug, fixed-dose tablet containing 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine. In peripheral blood mononuclear cells, lamivudine is anabolized by phosphorylation to lamivudine triphosphate, the molecule required for antiviral activity.…”

“…19 Metabolism is a minor route of elimination, with only 5% to 10% of the parent drug metabolized to an inactive transsulfoxide metabolite that is excreted in the urine. 24,25 To pursue new fixed-dose tablet formulations, development was initiated for a 2-drug single tablet containing 50 mg dolutegravir and 300 mg lamivudine. 18 Lamivudine has demonstrated few interactions with cytochrome P450 enzymes, although drugs that are also renally excreted have the potential for interactions with lamivudine.…”

Comparison of 48‐week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor‐sparing regimens: a systematic review and network meta‐analysis

“…Currently, numerous recent trials have evaluated the use of two‐drug regimens to reduce toxicities, both in treatment‐naïve and in pretreated patients. The benefits of switching to an NRTI‐sparing regimen from E/C/F/TAF must be balanced against potential detriments: disruption of the single‐tablet regimen and increases in the number of pills and drug intake , changes in lipid parameters that may necessitate additional monitoring or treatment, persistence of viral replication in reservoir sites such as the central nervous system (CNS) , and absence of activity against hepatitis B virus (HBV). Only randomized clinical trials can definitively assess safety and efficacy differences between E/C/F/TAF and NRTI‐sparing regimens.…”