A Pilot Study of Abacavir/Lamivudine and Raltegravir in Antiretroviral-Naïve HIV-1–Infected Patients: 48-Week Results of the SHIELD Trial

Abstract

Purpose: To evaluate raltegravir plus abacavir/lamivudine in antiretroviral-naïve, HIV-1–infected patients. Methods: SHIELD is an ongoing 96-week pilot study of abacavir/lamivudine 600 mg/300 mg once daily with raltegravir 400 mg twice daily among HLA-B*5701-negative adults with screening viral load (VL) >1,000 copies/mL. HBsAg+ patients were excluded, as were patients with key mutation(s) to any study drug. Virologic failure (VF) was defined as either VL >400 copies/mL at week 24 or confirmed virologic rebound. Results: Thirty-five patients enrolled (mean age 38.7 years). Most were white males, but 26% self-identified as Hispanic/Latino. At baseline, 34% had VL ≥100,000 copies/mL (median, 4.8 log₁₀ copies/mL) and 20% had CD4 cell counts <200 cells/mm³ (median, 301). One patient discontinued due to adverse events (AEs); one patient experienced VF. At week 48, 91% (32/35) had VL <50 and <400 copies/mL by missing/discontinuation equals failure analysis. Median CD4 cell count change from baseline was +247 cells/mm³. Five patients (14%) had treatment-related grade 2–4 AEs; no treatment–related serious AEs were reported. Over 48 weeks, median fasting lipids increased for total (+17%), LDL (+9%), and HDL (+6%) cholesterol but remained stable for triglycerides (–1%) and total:HDL cholesterol ratio (0%). Conclusions: In this pilot study, abacavir/lamivudine plus raltegravir was effective and generally well-tolerated over 48 weeks with modest changes in fasting lipids.     

96-Week Results of a Pilot Study of Abacavir/Lamivudine and Raltegravir in Antiretroviral-Naïve HIV-1–Infected Patients: The SHIELD Trial

Abstract

We compared 4 years of antiretroviral therapy with tenofovir/emtricitabine and either raltegravir or efavirenz from the ongoing STARTMRK study of treatment-naïve HIV-infected patients. Through 192 weeks, raltegravir produced durable and consistent viral suppression and immune restoration compared with efavirenz irrespective of baseline demographic and prognostic factors, including in patients with high viral loads.     

Once-Daily Abacavir/Lamivudine/Zidovudine plus Tenofovir for the Treatment of HIV-1 Infection in Antiretroviral-NaïveSubjects: A 48-Week Pilot Study

Abstract

Purpose: To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA ?30,000 copies/mL at 48 weeks. Method: All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy. Results: Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm³. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (–9 mg/dL), HDL (+1 mg/dL), LDL (–9 mg/dL), and triglycerides (–4 mg/dL). Conclusion: A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.     

Once-Daily Abacavir/Lamivudine and Ritonavir-Boosted Atazanavir for the Treatment of HIV-1 Infection in Antiretroviral-Naïve Patients: A 48-Week Pilot Study

Abstract

Purpose: To assess the efficacy and safety of a once-daily (QD) regimen consisting of the co-formulation of abacavir/lamivudine (ABC/3TC) and atazanavir plus ritonavir (ATV-RTV) in antiretroviral (ART)-naïve patients with plasma HIV-1 RNA >5,000 copies/mL. Method: This open-label, multicenter study conducted between September 2004 and June 2006 included 112 patients who received ABC 600 mg/3TC 300 mg and ATV 300 mg-RTV 100 mg QD. Drug switches were permitted for ABC hypersensitivity and ATV-related hyperbilirubinemia. Primary endpoints were proportion of patients achieving HIV-1 RNA <50 copies/mL at Week 48 and treatment discontinuation due to study drugs. Results: A total of 111 patients were treated. At Week 48, the proportion of patients achieving HIV-1 RNA <50 copies/mL was 77% (85/111) by intent-to-treat (ITT) missing=failure, switch included response rate. Drug substitutions occurred in 8 (7%) patients for suspected ABC hypersensitivity reaction (HSR) and in 6 (5%) patients for ATV-related toxicities; only 1 patient discontinued study due to ABC HSR. Four patients met confirmed virologic nonresponse (HIV RNA ?400 copies/mL). Treatment-emergent drug resistance was rare, and no patient had virus that developed reduced susceptibility to ATV. Median change from baseline (95% confidence interval) in fasting lipids at Week 48 was 39 (26–66) mg/dL for triglycerides, 28 (22–38) mg/dL for total cholesterol (C), 14 (10.5–16) mg/dL for HDL-C, and 8 (2–16.5) mg/dL for LDL-C. Conclusion: ABC/3TC and ATV-RTV QD is an effective and well-tolerated regimen in ART-naïve patients through 48 weeks, with a modest impact on fasting lipids.     

Fosamprenavir Clinical Study Meta-Analysis in ART-Naïve Subjects: Rare Occurrence of Virologic Failure and Selection of Protease-Associated Mutations

Abstract

Background:In recent ritonavir-boosted protease inhibitor (PI) studies, high efficacy rates have been observed, with few PI mutations detected. Method: To better understand the types of mutations observed and their phenotypic impact and the likelihood of virologic failure (VF) on a regimen that includes either a ritonavir-boosted or unboostedPI, fosamprenavir, a meta-analysis of three studies (NEAT, SOLO, and KLEAN) of 922 ART-naïve participants receiving boosted (FPV/r) or unboosted fosamprenavir (FPV) plus abacavir/lamivudine was performed. 70% of participants by the missing and discontinuation equals failure analysis and 95% by the observed analysis had HIV-RNA <400 copies/mL through 48 weeks. Paired genotypes (baseline and follow-up) were obtained for 74/85 participants meeting VF analysis criteria. Results: FPV-associated resistance mutations were detected in 5/74 patients with VF, with 4/5 receiving unboosted FPV; in four patients viruses developed I54L or M andone developed the V32I+I47V combination. No virus from patients with VF receiving FPV/r had reduced FPV susceptibility (RS), whereasvirus from 3/4 of participants with VF who received unboosted FPV and who acquired FPV mutations had FPV RS. Little PI cross-resistance was detected in the VF virus; RS was observed for lopinavir, saquinavir, nelfinavir, atazanavir, and indinavir in 0, 0, 2, 0, and 1 of 5 subjects, respectively. Conclusion: These data suggest that inclusion of FPV as part of an initial HIV-treatment regimen is associated with low rates of VF. Selection of FPV resistance-associated mutations is unlikely, especially for FPV/r-containing regimens. If selection of FPV-associated mutations does occur, a second-line PI-containing regimen can be easily constructed.     

Long-Term Safety Study of Fosamprenavir-Containing Regimens in HIV-1–Infected Patients

Abstract

Background: Safety and efficacy of the protease inhibitor fosamprenavir (FPV) ± ritonavir (r) was evaluated in 3 pivotal 48-week phase III studies. A follow-on study provides long-term data on FPV-based regimens. Methods: International, multicenter, uncontrolled open-label study APV30005 provided FPV as part of combination therapy to HIV-1–infected patients aged ≥13 years who had participated in previous FPV and amprenavir studies. Regimens included FPV/r 1400/200 mg once daily, FPV/r 700/100 mg twice daily, or FPV 1400 mg twice daily. Safety and efficacy were evaluated every 12 weeks, including incidence and frequency of adverse events and laboratory abnormalities, plasma HIV-1 RNA levels, CD4+ cell counts, and frequency of HIV disease progression. Because this was a nonrandomized, observational study, no significance testing was performed. Results: Overall, 753 patients were enrolled. The most common reasons for premature discontinuation were lost to follow-up (88 [12%]) and insufficient viral load response (69 [9%]). The majority of patients had >192 weeks exposure to FPV, with 53 patients exposed for more than 8 years. Drug-related grade 2-4 adverse events were reported for 250 patients (33%), with the majority reported in the first 48 weeks of the study. Most commonly reported grade 3/4 laboratory parameters were increased lipase, triglycerides, and elevated liver enzymes. The observed proportions of patients with plasma HIV-1 RNA levels <50 copies/mL remained >70% from week 48 onwards. Conclusions: Extended treatment of up to 8 years with FPV-containing regimens revealed no new safety concerns and was associated with sustained antiviral responses.     

Simplicity and Efficacy of a Once-Daily Antiretroviral Regimen with Didanosine,Lamivudine, and Efavirenz in Naïve Patients: The VESD Study

Abstract

Purpose: Our aim was to analyze the efficacy and safety of didanosine-lamivudine-efavirenz in a cohort of HIV patients starting antiretroviral therapy between January and September 2003. Method: We undertook a prospective, open-label, observational, multicenter study. Results: 163 patients were enrolled. Over a 48-week period, plasma HIV RNA levels declined sharply, with a median decrease at the end of the observation time of >4.62 log copies/mL. The proportion of patients achieving a plasma HIV RNA level below 50 copies/mL was 62.9% (intention-to-treat analysis) at the end of the study period. The mean CD4 cell count increased steadily over time by 199 cells/mL. Antiviral efficacy was similar in patients with a baseline HIV RNA level above or below 100,000 copies/mL. Overall, 57 (34.1%) patients interrupted therapy; 9 due to lack of treatment response, 18 due to adverse side-effects, and 30 patients lost to follow-up or who withdrew their consent. Adherence was very high (90%-95%) and quality of life was good or very good in 69%. Conclusion: The once-daily combination of didanosine-lamivudine-efavirenz resulted in sustained viral suppression and was well-accepted by patients under real-life conditions, even immunosuppressed patients and those with a high viral load. Associated adverse events and virological failures were few.     

Compact Quadruple Therapy with the Lamivudine/Zidovudine Combination Tablet Plus Abacavir and Efavirenz,Followed by the Lamivudine/Zidovudine/Abacavir Triple Nucleoside Tablet Plus Efavirenz in Treatment-Naïve HIV-Infected Adults

Abstract

Purpose: To assess efficacy, safety, and adherence with compact quadruple therapy comprising one lamivudine 150-mg/zidovudine 300-mg tablet (COM) twice daily + one abacavir (ABC) 300-mg tablet twice daily + three efavirenz (EFV) 200-mg capsules at bedtime for 24 weeks, followed by one lamivudine 150-mg/zidovudine 300-mg/ABC 300-mg triple nucleoside tablet (TZV) twice daily + three EFV 200-mg capsules at bedtime for 24 weeks. Method: A pilot 48-week, prospective, open-label trial in which 38 antiretroviral-naïve HIV-infected adults (baseline median HIV-1 RNA 5.1 log₁₀ copies/mL, CD4+ cell count 285/μL) received the above treatment and were monitored regularly with respect to plasma HIV-1 RNA levels, CD4+ cell counts, T-cell receptor excision circles (TRECs), adherence, and adverse events. Results: At Week 48, intent-to-treat, switch-included analysis showed plasma HIV-1 RNA levels <400 copies/mL in 100% (29/29) of patients and <50 copies/mL in 93% (27/29); 59% of patients who achieved <50 copies/mL had <3 copies/mL (16/27). Similar virologic suppression was observed in patients with baseline HIV-1 RNA above or below 100,000 copies/mL. HIV-1 RNA and CD4+ cell counts changed from baseline by a median of –3.4 log₁₀ copies/mL and +172 cells/μL, respectively. One virologic failure occurred at Week 16. Median TRECs/100,000 peripheral blood lymphocytes increased 6-fold between baseline and Week 48. Median adherence rates were consistently 100% by self-report and 94% by pill count. Grade 2-4 treatment-related adverse events included dreams (16%), nausea (13%), decreased white cells (8%), dizziness (8%), sleep disorders (8%), and malaise and fatigue (8%). A suspected ABC hypersensitivity reaction occurred in 8% (3/38) of patients. Conclusion: COM/ABC/EFV or TZV/EFV produced potent, durable virologic suppression and immunologic benefits, was associated with high adherence rates, and was generally well tolerated.     

Switching From Twice-Daily Raltegravir Plus Tenofovir Disoproxil Fumarate/Emtricitabine to Once-Daily Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed,HIV-1–Infected Subjects: 48 Weeks Data

Background: Pill burden, dosing frequency, and concerns about safety and toler-ability are important obstacles to maintaining adequate medication adherence. Ralte-gravir (RAL) is indicated for twice-daily dosing and when taken with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), it becomes a twice-daily multiple-tablet regimen. Elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF, STB, is the first approved once-a-day integrase strand transfer inhibitor (INSTI) containing single-tablet regimen that combines EVG, an INSTI, and COBI, a novel pharmacoenhancer, with the preferred nucleos(t)ide backbone of FTC/TDF. Methods: This was a 48-week prospective, single-arm open-label study of the switch to STB in virologically sup-pressed HIV-1–infected adult patients on FTC/TDF and twice-daily RAL for at least 6 months. Objectives were to evaluate the tolerability and safety of a regimen simpli-fication to once-a-day STB, while maintaining viral suppression through 48 weeks. Results: Forty-eight individuals in the United States were enrolled. The median age was 44 years, 96% were male, and 83% were White. The median time on RAL + FTC/TDF treatment prior to enrollment was 34 months. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At base-line, the median CD4 count was 714 cell/µL and estimated glomerular filtration rate (eGFR) was 105 mL/min. At week 48, all assessed study participants remained viro-logically suppressed to the lower limit of quantification (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min). STB was well tolerated with no discontinuations, no study drug–related serious adverse events, and no study drug–related grade 3/4 adverse events. Conclusions: All participants switching to 1 tablet once-a-day STB from a twice-daily RAL + FTC/TDF regimen remained virologically suppressed. STB was well tolerated. Switching to STB may be a viable option for virologically suppressed patients wanting to simplify from a twice-daily RAL-containing regimen.     

Pharmacokinetics,Efficacy, and Safety of Darunavir/Ritonavir 800/100 mg Once-Daily in Treatment-Naïve and -Experienced Patients

Abstract

Darunavir is a new protease inhibitor (PI) with in vitro activity against wild-type and PI-resistant HIV; it is used with the pharmacokinetic booster ritonavir. The currently approved dose of darunavir/ritonavir is 600/100 mg twice-daily, licensed for treatment-experienced patients. However, during the clinical development of darunavir, a range of once-daily and twice-daily doses of darunavir/ritonavir were evaluated. The relatively long terminal elimination plasma half-life of darunavir (15 hours) supports once-daily dosing. In treatment-naïve patients, the ARTEMIS trial has shown high rates of HIV RNA suppression for darunavir-ritonavir at the 800/100 mg once-daily dose (84% with HIV RNA <50 copies/mL at Week 48) versus a control arm of lopinavir/ritonavir (78% with HIV RNA <50 copies/mL). In a population pharmacokinetic substudy, darunavir 24-hour minimum plasma concentration levels remained above the predefined EC₅₀ of 55 ng/mL for all 335 patients evaluated in the ARTEMIS trial. Once-daily darunavir/ritonavir has also been evaluated in treatment-experienced patients in the TMC114-C207 proof-of-principle trial and the POWER 1 and 2 trials. For the overall POWER trial population, with significant baseline resistance to PIs, the rates of HIV RNA suppression <50 copies/mL at Week 24 for darunavir/ritonavir 800/100 mg once-daily were lower than for the 600/100 mg twice-daily dosage (31% vs. 47%, respectively). However, for patients with no genotypic darunavir resistance-associated mutations at baseline, rates of HIV RNA suppression were 62% and 67% for the 800/100 mg once-daily and 600/100 mg twice-daily doses. The current evidence from clinical trials of darunavir/ritonavir supports the efficacy of the 800/100 mg once-daily dose for treatment-naïve patients and further evaluation for treatment-experienced patients with no genotypic resistance to darunavir.     

Characteristics of Treatment-naïve HBV-Infected Individuals with HIV-1 Coinfection: A Cross-sectional Study from South India

Purpose: Human immunodeficiency virus-1 (HIV-1) and hepatitis B virus (HBV) coinfection has become a major health problem across the globe. The increased life expectancy of HIV-1 patients due to antiretroviral therapy has led to the emergence of liver disease as a major mortality factor among them. The purpose of the study was to examine the baseline characteristics of HBV in treatment-naïve HBV/HIV coinfection from southern India compared to monoinfected individuals. Materials and Methods: The study was cross sectional in design, and samples were examined from 80 HIV-1, 70 HBV and 35 HBV/HIV-coinfected individuals using chemiluminescent microparticle immunoassay, real-time polymerase chain reaction and flow cytometry assays. Results: There was a significant increase in HBV DNA (P = 0.0001), higher hepatitis B e antigen percentage difference (P = 0.027) and lower CD4 counts (P = 0.01) among the HBV/HIV-coinfected individuals, but no difference in the HIV-1 viral load compared to HIV-1-monoinfected individuals. Also, the aspartate aminotransferase levels, prothrombin time and the international normalised ratio were significantly high among coinfected individuals. Conclusion: These findings conclude that HIV-1 coinfection can have serious implications on the outcome of HBV-related liver disease. To the contrary, HBV infection had no consequence on the progression of HIV-1 disease but distinctly lowered CD4+ T-cells.     

Pharmacokinetics and pharmacodynamics of the nucleoside sparing dual regimen containing rilpivirine plus darunavir/ritonavir in treatment-naïve HIV-1-infected individuals

Background: We aimed at investigating the antiviral activity and the pharmacokinetics of the dual antiretroviral (ARV) combination of rilpivirine plus darunavir/ritonavir 25/800/100 mg once-daily in naïve HIV-1-infected individuals (NHII) with different baseline viral loads.

Settings: Pharmacokinetic/pharmacodynamics study in ARV-naïve HIV-infected individuals.

Methods: The primary endpoint was the number of NHII with HIV-RNA < 40 copies/mL at week 48. Secondary endpoints included rilpivirine/darunavir/ritonavir pharmacokinetics, HIV-RNA decay, and changes in ECG QT interval.

Results: Thirty-six individuals were enrolled, 18 with a baseline viral load < 100,000 copies/mL (group A) and 18 with a baseline viral load > 100,000 copies/mL (group B). All but 1 (HIV-RNA = 63 copies/mL) subjects achieved viral load < 50 copies/mL by week 36, and all at week 48. Median (range) HIV-RNA reduction (Log10 copies/mL) was 1.3 (0.6–1.9) over the first week, with no differences between groups A and B. Geometric mean and 95%CI rilpivirine C_max, C_trough, AUC were 183 (165–239), 114 (104–109) ng/mL, 2966 (2704–3820) ng h/mL. No QTcF interval changes were recorded.

Conclusions: rilpivirine/darunavir/ritonavir could be efficacious, with limited short-term toxicity in ARV-naïve patients. Although rilpivirine was co-administered with ritonavir, its exposure was within ranges measured during phase III trials.