Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen with high antiviral potency, favourable safety and tolerability, and low propensity for resistance. We report week 48 results from a phase 3 trial evaluating switch from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·75 mg). METHODS: This phase 3, multicentre, randomised, active-controlled, open-label, non-inferiority trial was conducted at 77 research, community, and hospital-based clinics in 15 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation schedule to switch to doravirine (100 mg) and islatravir (0·75 mg) or to continue their baseline ART regimen. Block randomisation was based on a block size of four, and randomisation was stratified by baseline regimen (ie, protease inhibitor, integrase inhibitor, or other). Participants in the doravirine and islatravir group were instructed to take one tablet at approximately the same time each day, and participants in the baseline ART group continued to take the medication according to the locally approved label. HIV-1 RNA and safety evaluations were done at baseline and weeks 4, 12, 24, 36, and 48. CD4 cell counts were measured at baseline, week 24, and week 48. The primary endpoint was proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug) using the US Food and Drug Administration snapshot approach and prespecified non-inferiority margin of 4%. This study is registered with ClinicalTrials.gov (NCT04223778) and is completed. FINDINGS: Between Feb 18 and Oct 2, 2020, 740 individuals were screened for eligibility, of whom 672 (90·8%) participants (249 [37·1%] women and 423 [62·9%] men; median CD4 count of 678 cells per µL [IQR 496-868]) were randomly assigned to doravirine (100 mg) and islatravir (0·75 mg; n=336) or to continue baseline ART (n=336). The last follow-up visit occurred on Sept 8, 2021. At week 48, zero of 336 participants in the doravirine and islatravir group versus five (1·5%) of 336 participants in the baseline ART group had greater than or equal to 50 HIV-1 RNA copies per mL (difference -1·5, 95% CI -3·4 to -0·3). The per-protocol analysis showed consistent results. Headache was the most common adverse event in both groups (35 [10·4%] of 336 participants in the doravirine and islatravir group, 16 [4·8%] of 336 in the baseline ART group), infection rates were similar (113 [33·6%] in both groups), and discontinuations due to adverse events were low (seven [2·1%] vs one [0·3%]). 66 (19·6%) of 336 participants had treatment-related adverse events in the doravirine and islatravir group compared with 30 (8·9%) of 336 in the baseline ART group. In the islatravir and doravirine group, CD4 cell counts (mean change -30·3 cells per µL) and total lymphocyte counts (mean change -0·26 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to single-tablet doravirine (100 mg) and islatravir (0·75 mg) maintained viral suppression up to week 48 and was non-inferior to antiretroviral combinations used in clinical practice for adults with HIV-1; however, decreases in CD4 cell and total lymphocyte counts do not support further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1. METHODS: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791. FINDINGS: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per µL) and total lymphocyte counts (mean change -0·20 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine.

BACKGROUND: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). METHODS: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. RESULTS: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. CONCLUSIONS: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.

Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial.

BACKGROUND: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. METHODS: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347. FINDINGS: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. INTERPRETATION: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. FUNDING: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.

Safety and Efficacy of Atazanavir Powder and Ritonavir in HIV-1-Infected Infants and Children From 3 Months to <11 Years of Age: The PRINCE-2 Study.

BACKGROUND: Novel antiretroviral formulations that are palatable, safe, and effective are needed for infants and children. METHODS: PRINCE-2 is an ongoing clinical trial assessing safety, efficacy, and palatability of once-daily atazanavir powder formulation boosted with ritonavir (ATV + RTV) plus optimized dual nucleos(t)ide reverse transcriptase inhibitors therapy in antiretroviral-naïve/experienced children with screening HIV-1 RNA ≥1000 copies/mL. Children 3 months to <11 years received ATV + RTV by 5 baseline weight bands: 5 to <10 kg = 150/80 mg; 5 to <10 kg = 200/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg; and 25 to <35 kg = 300/100 mg. RESULTS: Of 99 treated children, 83.8% and 59.6% remained on ATV powder until 24 and 48 weeks, respectively. Through 48 weeks, the most common adverse events were upper respiratory tract infections (33.3%), gastroenteritis (28.3%), vomiting (21.2%) and hyperbilirubinemia (18.2%; none leading to treatment discontinuation). Serious adverse events occurred in 20.2% of patients. Laboratory grade 3-4 hyperbilirubinemia occurred in 9.2% and elevated total/pancreatic amylase in 33.7%/3.1%. At week 24, proportions with virologic suppression (HIV-1 RNA <50 copies/mL; intention-to-treat analysis) across weight bands were 10/23 (43.5%), 2/12 (16.5%), 10/21 (47.6%), 19/35 (54.3%) and 5/8 (62.5%), respectively. Virologic suppression was similar in antiretroviral-naïve/experienced patients and lowest in the 5 to <10 kg = 200/80 mg group, likely because of higher baseline HIV-1 RNA and discontinuation (66.7%). Overall, virologic suppression at weeks 24 (46.5%) and 48 (43.0%) was comparable. At week 48, 83.3% and 74.1% of caregivers reported no trouble giving ATV powder and RTV, respectively. CONCLUSIONS: ATV powder palatability, efficacy and lack of unexpected safety findings support its use for HIV-1-infected children ≥3 months to <11 years.

Pharmacokinetics and Pharmacodynamics of Atazanavir in HIV-1-Infected Children Treated With Atazanavir Powder and Ritonavir: Combined Analysis of the PRINCE-1 and -2 Studies.

BACKGROUND: Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor background therapy plus once-daily atazanavir (ATV) powder formulation boosted with ritonavir (ATV + RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies. METHODS: Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration-time curve in one dosing interval) in 5 ATV + RTV baseline weight-band dosing categories, with historic data in adults receiving ATV + RTV 300/100 mg capsules. Repeated ATV Ctrough measurements over 48 weeks explored relationships between ATV composite Ctrough quartiles (CCQs) with virologic efficacy and key safety parameters. RESULTS: Of 146 children included in this combined analysis, 49.3% were male, 56.8% were Black/African American and 62.3% were antiretroviral experienced. Proportions with HIV-1 RNA <50 copies/mL at week 48 were 13/32, 24/32, 19/32 and 13/28 in the lowest through highest ATV CCQs, respectively. Mean changes from baseline in total bilirubin at week 48 were +0.3, +0.5, +0.6 and +1.0 mg/dL in the lowest through highest ATV CCQs, respectively. Corresponding proportions with adverse events of hyperbilirubinemia by week 48 were 1/36, 4/36, 5/36 and 13/35, respectively. Changes from baseline in total amylase or electrocardiogram parameters and adverse events of diarrhea did not vary by ATV CCQs. CONCLUSIONS: Weight-band dosing of ATV + RTV plus optimized dual nucleos(t)ide reverse transcriptase inhibitors in young HIV-1-infected children achieved similar ATV exposure to that in adults; no unexpected safety findings occurred, and with the exception of lower virologic suppression in the lowest ATV CCQ, there was no apparent trend in virologic suppression across ATV CCQs.

PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years.

INTRODUCTION: PRINCE-1 is an ongoing prospective, international, multicentre, nonrandomized, two-stage clinical trial assessing safety and efficacy of once-daily atazanavir (ATV) powder boosted with ritonavir (RTV) liquid plus optimized dual nucleoside reverse-transcriptase inhibitor (NRTI) background therapy in antiretroviral (ARV)-naïve and -experienced children with HIV-1 infection aged ≥3 months to <6 years. METHODS: Children with HIV-1 infection without prior ATV exposure and with a screening HIV-1 RNA ≥1000 copies/mL were enrolled. The dosing of ATV powder, boosted with 80 mg RTV liquid, was based on three baseline weight bands (5 to <10 kg=150 mg, 10 to <15 kg=200 mg and 15 to <25 kg=250 mg). RESULTS: Of the 56 treated patients, 46 completed 48 weeks of therapy, 67.9% were from Africa and 60.7% were ART-naïve. Median ages at baseline were 6, 35 and 55 months, and proportions with HIV-1 RNA >100,000 were 85.7, 52.6 and 25% in the three baseline weight bands, respectively. No unexpected safety events occurred and no deaths were reported. Over 48 weeks, upper respiratory tract infections, diarrhoea, vomiting and Grade 3 to 4 hyperbilirubinaemia occurred in 35.7, 35.7, 28.6, and 9.4% of patients, respectively; five patients (8.9%) discontinued due to adverse events (AEs); and 11 patients (19.6%) experienced serious adverse events. At Week 48, using a modified intent-to-treat analysis (two patients were excluded because they switched to ATV capsules before Week 48), 61.1 and 74.1% of patients overall had an HIV-1 RNA level <50 copies/mL and <400 copies/mL, respectively. Virologic suppression rates increased across the lowest to highest baseline weight bands (47.6, 68.4 and 71.4% had HIV-1 RNA <50 copies/mL, and 66.7, 73.7 and 85.7% had HIV-RNA <400 copies/mL, respectively) but did not differ meaningfully between ARV-naïve and -experienced patients. Overall, the median change from baseline in CD4 cell count was +363 cells/mm(3), and the median change from baseline in CD4 percent was +7.5%. CONCLUSIONS: ATV powder boosted with RTV liquid once daily plus optimized dual NRTI background therapy was effective and well tolerated in this ART-naïve or -experienced paediatric population aged ≥3 months to <6 years. No unexpected safety findings compared with those from previous ATV paediatric and adult studies were identified.

Cost-effectiveness of the once-daily efavirenz/emtricitabine/tenofovir tablet compared with the once-daily elvitegravir/cobicistat/emtricitabine/tenofovir tablet as first-line antiretroviral therapy in HIV-infected adults in the US.

BACKGROUND: February 2013 US treatment guidelines recommend the once-daily tablet of efavirenz/emtricitabine/tenofovir (Atripla®) as a preferred regimen and the once-daily tablet of elvitegravir/cobicistat/emtricitabine/tenofovir (Stribild™) as an alternative regimen for first-line treatment of human immunodeficiency virus (HIV). This study assessed the clinical and economic trade-offs involved in using Atripla compared with Stribild as first-line antiretroviral therapy in HIV-infected US adults. METHODS: A Markov cohort model was developed to project lifetime health-related outcomes, costs, quality-adjusted life years (QALYs), and cost-effectiveness of Stribild compared with Atripla as first-line antiretroviral therapy in HIV-1-infected US patients. Patients progressed in 12-week cycles through second-line, third-line, and nonsuppressive therapies, acquired immune deficiency syndrome, and death. Baseline characteristics and first-line virologic suppression, change in CD4 count, and adverse effects (lipid, central nervous system, rash, renal) were based on 48-week clinical trial results. These results demonstrated equivalent virologic suppression between the two regimens. Point estimates for virologic suppression (favoring Stribild) were used in the base case, and equivalency was used in the scenario analysis. Published sources and expert opinion were used to estimate costs, utilities, risk of acquired immune deficiency syndrome, mortality, subsequent-line CD4 count, clinical efficacy, and adverse events. Costs were reported in 2012 US dollars. Sensitivity analyses were conducted to assess robustness of results. RESULTS: Compared with patients initiating Atripla, patients initiating Stribild were estimated to have higher lifetime costs. Stribild added 0.041 QALYs over a lifetime at an additional cost of $6,886, producing an incremental cost-effectiveness ratio of $166,287/QALY gained. Results were most sensitive to first-line response rates, product costs, and likelihood of renal adverse events. When equivalent efficacy was assumed, Atripla dominated Stribild with lower costs and greater QALYs. CONCLUSION: At a societal willingness to pay of $100,000/QALY, Stribild was not cost-effective in the base case compared with Atripla for first-line HIV treatment.

Cost-effectiveness of efavirenz vs rilpivirine in HIV patients initiating first-line combination antiretroviral therapy.

OBJECTIVE: In US treatment guidelines, efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) for first-line HIV treatment. In the ECHO and THRIVE trials comparing EFV with another NNRTI, rilpivirine (RPV), both medications had similar virologic suppression rates at 96-weeks; however, RPV had higher rates of virologic failure and drug resistance and lower rates of discontinuation due to adverse events. This study compared the cost-effectiveness of EFV to RPV in first-line HIV treatment in the US. METHODS: A Markov model with 14 health states was constructed to estimate 10-year costs and clinical outcomes from a US payer perspective for antiretroviral naïve HIV patients initiating EFV or RPV. First-line efficacy data came from 96-week results of the ECHO and THRIVE trials, which compared EFV and RPV, both in combination with two nucleos(t)ide reverse transcriptase inhibitors. Other clinical inputs, mortality rates, and costs (2011 US$) came from published sources. Subsequent therapy lines (second, third, non-suppressive) were based on US treatment guidelines and common to both treatment arms. Robustness of study results was assessed in sensitivity analyses varying model inputs by ±25%. Potential limitations of the model center on the ability of any model to capture the clinical complexity of HIV treatment. RESULTS: In the base case, 10-year costs were lower for EFV compared to RPV ($214,031 vs $222,090). Life expectancy (8.44 years) and years without AIDS (8.40 years) were equal; years in virologic suppression were similar (EFV = 7.87 years, RPV = 7.86 years). EFV had modest cost savings compared to RPV in terms of incremental cost-effectiveness per life-year gained, life-year gained in viral suppression, and life-year gained without AIDS. In sensitivity analyses, EFV remained cost-saving compared to RPV in over 90% of scenarios, demonstrating the robustness of study results. CONCLUSIONS: EFV was predicted to be modestly cost-saving compared with RPV over 10 years in US patients initiating first-line HIV treatment. Sensitivity analyses suggest that results may hold across multiple settings.

Effect of persistency of first-line HIV antiretroviral therapy on clinical outcomes.

Persistency is the time from initiation to discontinuation of therapy. Previous research has described factors that affect the persistency of initial antiretroviral therapy (ART); however, the impact of persistency on clinical outcomes is unknown. A retrospective study was conducted of treatment-naive HIV patients initiating ART between January 1, 2000 and December 31, 2010 at an academic medical center. Descriptive statistics and Cox proportional hazards regression models with persistency as a time-varying covariate were fit for (1) immunologic failure (subsequent CD4 lower than initial CD4); (2) development of an opportunistic infection (OI) or malignancy; and (3) mortality. Analyses were repeated with an interaction term of persistency (per 180 days) and time (before and after 1 year of ART). Among 879 patients who started ART, the mean age was 38 years (±10) and most patients were racial/ethnic minority (59%), males (80%), and with baseline CD4 <200 cells/mm(3) (52%). There were 100 deaths, 94 OIs/malignancy, and 183 immunologic failures; the mean persistency=723 days. In multivariable modeling, increased persistency decreased the overall and long-term hazard for immunologic failure (0.84 per 180 additional days; 0.70-1.00; 0.045). Increased persistency exhibited a potential trend toward decreased hazard for the occurrence of OI/malignancy (0.91; 0.80-1.03; 0.124) overall and after 1 year. Persistency exhibited a trend toward less risk of mortality in the first year of ART (0.42; 0.17-1.06; 0.067). In this study of the relationship between initial ART persistency and clinical outcomes, increased persistency was associated with a decreased hazard for the development of immunologic failure, a trend toward a decreased hazard for OI/malignancy, and a trend toward a decreased risk of first year mortality. Given these findings, the relationship between persistency and clinical outcomes merits further study.

Adherence and persistence with non-nucleoside reverse transcriptase inhibitor-based antiretroviral regimens.

OBJECTIVE: The objective of this study was to examine adherence and persistency in HIV patients initiating first-line combination antiretroviral therapy (cART) with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. METHODS: Using US health insurance records, the authors identified all persons aged ≥ 18 years with HIV, who began NNRTI-based cART between 1 January 2003 and 30 September 2009. They examined adherence using proportion of days covered (PDC), and non-persistency based on evidence of discontinuation, switching or augmentation. Differences in non-adherence (1 - PC) and non-persistency were compared over 12 months, between three treatment groups: i) efavirenz, emtricitabine and tenofovir as a fixed-dose combination ('EFV/FTC/TDF'); ii) EFV-based regimens other than EFV/TDF/FTC, with ≥ 2 NRTIs ('EFV + ≥ 2 NRTIs'); and iii) nevirapine-based regimens with ≥ 2 NRTIs (NVP + ≥ 2 NRTIs). RESULTS: There were 1874 patients receiving EFV/FTC/TDF, 893 receiving EFV + ≥ 2 NRTIs and 207 receiving NVP + ≥ 2 NRTIs. Adherence was lower for both EFV + ≥ 2 NRTIs and NVP + ≥ 2 NRTIs than for EFV/FTC/TDF (rate ratio (RR) = 1.57 and 2.01, respectively; both p < 0.01), while non-persistency was higher (hazard ratio (HR) = 1.56, p < 0.01 and 1.70, p < 0.01, respectively). CONCLUSION: Adherence and persistency may differ between NNRTI-based regimens; additional analyses are needed to understand the reasons for these differences.

Frequency of HIV-related medication errors and associated risk factors in hospitalized patients.

BACKGROUND: Retrospective studies of hospitalized HIV-infected patients have noted a high occurrence of drug-related errors, ranging from 5% to 30%. OBJECTIVE: To prospectively evaluate errors in antiretroviral (ARV) prescribing in the inpatient setting of a hospital tertiary care center and the association of risk factors with the occurrence of errors. METHODS: HIV-infected patients who received care and continued their ARVs for HIV infection on admission to a large academic teaching hospital between January and April 2006 were included in this study. The care and assessment of these patients was conducted on a daily basis by an infectious diseases/HIV specialized clinical pharmacist. All errors were documented and classified based on a severity scale. RESULTS: Among the 68 patients who met the study's eligibility criteria, at least one error in the initial HIV regimen occurred in 72% of patients, and in 56% of patients, the error had the potential to cause moderate-to-severe discomfort or clinical deterioration. Patients on atazanavir-based therapy had a statistically significant increased occurrence of errors throughout their hospitalization (RR = 1.69; 95% CI 1.03 to 2.78; p = 0.02). Receiving nonformulary (combination) HIV medications increased patients' risk of having more than one error occur in their ARV regimen on admission and during hospitalization (RR = 1.95; 95% CI 1.25 to 3.04; p = 0.02). The clinical pharmacist recommendations had 100% acceptance. CONCLUSIONS: The alarmingly high frequency of potentially harmful errors uncovered in this study necessitates further investigation using larger sample sizes. Interventions to reduce and prevent these errors must be sought to eliminate the unintended harm associated with hospitalization.

Integrase inhibitors: a new treatment option for patients with human immunodeficiency virus infection.

The emergence of antiretroviral drug resistance in patients infected by the human immunodeficiency virus (HIV) has prompted efforts to develop new antiretrovirals that differ from existing agents with regard to mechanism of action and resistance profiles. We evaluated the literature regarding a new class of antiretrovirals, the integrase inhibitors. A MEDLINE search (January 1996-May 2007) was performed to identify relevant clinical trials and review articles; abstracts from HIV conferences were also searched. Raltegravir (MK-0518) and elvitegravir (GS-9137) are the two integrase inhibitors in late-phase development. These agents prevent viral DNA integration into the CD4(+) cell chromosome. Both drugs showed potent antiviral activity in large clinical trials that were performed in treatment-experienced, multidrug-resistant patients. Promising results have also been seen in an initial dose-ranging study with raltegravir in treatment-naïve patients. Preliminary data describe integrase inhibitor resistance profiles, but more data are needed in this area. Both agents were well tolerated in clinical trials, with favorable pharmaco-kinetic profiles for once- or twice-daily dosing. Raltegravir and elvitegravir differ in their metabolism, resulting in distinct drug-interaction profiles for each agent. Based on available data, this new class of antiretrovirals will soon be widely used in antiretroviral-experienced patients infected with HIV. In the future, this class of drugs may become a reasonable treatment option for antiretroviral-naïve patients, but more data are needed in that patient population.