Dolutegravir-based Antiretroviral Therapy Research Articles

Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy.

Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)-based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/μL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial.

The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis. International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1-infected antiretroviral therapy-naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65-86%) for DTG and 82% (36/44, 95% CI 70-93%) for EFV. The DTG nonresponses were driven by non-treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS. Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated. NCT02178592.

Dolutegravir-based anti-retroviral therapy is effective and safe in HIV\u2013infected paediatric patients

BackgroundTreatment of HIV infection in adolescents is challenging due to long duration of therapy and poor adherence. Recently, the integrase strand transfer inhibitor dolutegravir (DTG) has been approved for the use in adolescents with HIV, but evidence in clinical practice is very limited.MethodsWe describe six cases of HIV-infected children/adolescents successfully treated with DTG-based regimen. Data relative to children/adolescents managed at the Referral Center for Pediatric HIV/AIDS of the University of Naples were reviewed. Patients were tested before introduction of DTG, after 1 month and every 3 months in the first 2 years to assess virologic and immunological response, tolerance and development of side effects. Families were asked to report any suspected adverse events.ResultsSix patients (2 male, median age 17 years, range 12–18) were started on DTG-based anti-retroviral regimen due to low adherence to anti-retroviral treatment (ART), multiple drug resistance mutations, or development of ART-related side effects. Within 4–8 weeks after DTG treatment onset, a complete viral suppression and a concomitant increase of CD4+ cell count was observed. Four patients showed a persistent suppression after 2 years of follow-up, and 2 patients at about 1 year. One month after the introduction of DTG, the patient enrolled because of severe dyslipidaemia and hyper-transaminasemia showed a complete normalization of laboratory values. During follow-up (median 24 months, range 9–24) no adverse events were reported and most patients demonstrated a good adherence to treatment.ConclusionsDTG-based treatments demonstrated efficacy and good safety profile in adolescents. All patients demonstrated a rapid virologic and immunological response within 4–8 weeks, with good adherence and absence of side effects.

Dolutegravir-Based Antiretroviral Therapy for the Treatment of Patients Co-Infected with Tuberculosis and HIV: A Multicenter, Phase 3B, Noncomparative, Open-Label, Randomized Trial

Background: Concurrent treatment of tuberculosis and HIV is challenging owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir were assessed in adults with HIV and drug-susceptible tuberculosis. Methods: INSPIRING (NCT02178592) is a Phase 3b, non-comparative, active-control, randomised, open-label study in HIV-1-infected ARTcells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomised (3:2) to receive dolutegravir (50mg twice-daily during and 2 weeks post-tuberculosis therapy, then 50mg once-daily) or efavirenz (600mg once-daily), with two NRTI for 52 weeks. The primary endpoint was the proportion of dolutegravir-arm participants with plasma HIV-1-RNA <50c/mL (responders) by FDA Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. Findings: For dolutegravir (N=69), Baseline HIV-1-RNA was >100,000 c/mL in 64%, with median CD4 208 c/µL; for efavirenz (N=44), 55% had HIV-1-RNA >100,000 c/mL, median CD4 count was 202 c/µL. Week 48 response rate was 75% (52/69) (95%CI: 65%, 86%) for dolutegravir and 82% (36/44) (70%, 93%) for efavirenz. Dolutegravir non-response was driven by non-treatmentrelated discontinuations, mostly loss-to-follow-up following initial virologic suppression. There were no deaths or study drug switches in either arm; there were two discontinuations for toxicity (efavirenz).There were three protocol-defined virological failures (2 dolutegravir with no emergence of resistance, 1 efavirenz with NRTI and NNRTI emergent resistance detected). Tuberculosis treatment success was high. TBassociated IRIS was uncommon, with no discontinuations for IRIS. Interpretation: Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily dolutegravir was effective and well-tolerated. Clinical Trial Number: NCT02178592 Funding Statement: This study was funded by ViiV Healthcare. Declaration of Interests: MAK, MA, RS, CLT, KA, AT, DB and MRK are employed by and own shares in GSK. KED received salary support through her university for research effort devoted to this study. Ethics Approval Statement: The trial was approved by local ethics committees at each site, and participants gave written informed consent.

Clinical experience with dolutegravir/abacavir/lamivudine in HIV–HCV co-infected patients treated with a sofosbuvir-based regimen—safety and efficacy

Background: There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination.Methods: Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy.Results: Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21–59.78 years). The mean age was 59 years (95% CI: 58.21–59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6–100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events.Conclusion: Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

Dolutegravir-based antiretroviral therapy in a severely overweight child with a multidrug-resistant human immunodeficiency virus infection. Acase report and review.

The management of multidrug-resistant human immunodeficiency virus (MDR HIV) infections in children is particularly challenging due to the lack of experience with new drugs. Dolutegravir, combined with an optimized antiretroviral background therapy, is promising for the treatment of MDR HIV and has been approved recently for adults and adolescents. Data for children are extremely limited. We describe the efficacy, safety and plasmatic levels of a dolutegravir-based, complex active antiretroviral treatment regimen in a severely overweight 11-year-old child infected with an MDR HIV strain.