abacavir--lamivudine-drug-combination and Acquired-Immunodeficiency-Syndrome

The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults.. The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole.. As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation.. These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adolescent; Adult; Aged; Anti-HIV Agents; Biological Availability; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Middle Aged; Oxazines; Piperazines; Pyridones; Tablets; Young Adult

A week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials.. Treatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE).. A total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-of-virological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups.. Overall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black or African American; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Female; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Male; Nitriles; Organophosphonates; Pyrimidines; Rilpivirine; Sex Factors; Tenofovir; Treatment Outcome; Viral Load; Zidovudine

The effect of specific antiretrovirals on inflammation is unclear.. A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r.. Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Δ = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89).. Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

Topics: Acquired Immunodeficiency Syndrome; Adenine; Adult; Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Biomarkers; C-Reactive Protein; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV-1; Humans; Inflammation; Interleukin-6; Lamivudine; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Tumor Necrosis Factor-alpha

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Deoxycytidine; Dideoxynucleosides; Drug Approval; Drug Combinations; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Humans; Lamivudine; Organophosphorus Compounds; United States; United States Food and Drug Administration