Daniel Seekins

Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial

Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING 57 sites in the United States and Puerto Rico. PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION The trial was open-label, and ritonavir was not provided. CONCLUSION Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases.

Prevalence and Clinical Significance of HIV Drug Resistance Mutations by Ultra-Deep Sequencing in Antiretroviral-Naive Subjects in the CASTLE Study

Background CASTLE compared the efficacy of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from 5 continents. Objectives Determine the baseline rate and clinical significance of TDR mutations using ultra-deep sequencing (UDS) in ARV-naïve subjects in CASTLE. Methods A case control study was performed on baseline samples for all 53 subjects with virologic failures (VF) at Week 48 and 95 subjects with virologic successes (VS) randomly selected and matched by CD4 count and viral load. UDS was performed using 454 Life Sciences/Roche technology. Results Of 148 samples, 141 had successful UDS (86 subtype B, 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the rate of TDRs by B (30.2%) or non-B subtypes (30.9%). VF (51) and VS (90) had similar rates of any TDRs (25.5% vs. 33.3%), NNRTI TDRs (11.1% vs.11.8%) and NRTI TDRs (24.4% vs. 25.5%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced VF. 16 (11.3%) subjects had multiple TAMs, and 7 experienced VF. 3 (2.1%) subjects had both multiple TAMs+M184V, and all experienced VF. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels): only 1 experienced virologic failure. The majority of PI TDRs were found in isolation (e.g. 46I) at <20% levels, and had low resistance algorithm scores. Conclusion Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virologic response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virologic failure.

Simplification of antiretroviral therapy to a single-tablet regimen consisting of efavirenz, emtricitabine, and tenofovir disoproxil fumarate versus unmodified antiretroviral therapy in virologically suppressed HIV-1-infected patients.

Objective:To evaluate a simplification strategy for HIV-1-infected patients virologically suppressed on antiretroviral therapy (ART) by switching to a single-tablet regimen consisting of efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Design:Prospective, randomized, controlled, open-label, multicenter study. Methods:Patients on stable ART with HIV-1 RNA <200 copies per milliliter for ≥3 months were stratified by prior nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based therapy and randomized (2:1) to simplify treatment to EFV/FTC/TDF or to stay on their baseline regimen (SBR). Efficacy and safety assessments were performed at baseline and at weeks 4, 12, 24, 36, and 48. Additional patient-reported outcomes included the following: adherence by visual analog scale, quality of life by SF-36 (v2) survey, HIV Symptom Index, and the Preference of Medication and Perceived Ease of the Regimen for Condition questionnaires. Results:Three hundred patients (EFV/FTC/TDF 203, SBR 97) were evaluated (prior protease inhibitor-based ART, 53%; nonnucleoside reverse transcriptase inhibitor-based ART, 47%). The arms were well balanced at baseline with 88% males, 29% blacks, and a mean age of 43 years; CD4 was 540 cells per cubic millimeter, 96% had HIV-1 RNA <50 copies per milliliter, and 88% were on their first ART regimen. Through 48 weeks, 89% vs. 88% in the EFV/FTC/TDF vs. SBR arms, respectively, maintained HIV-1 RNA <200 copies per milliliter by time to loss of virologic response algorithm (intent to treat, noncompleters = failures) with the difference (95% confidence interval) between arms of 1.1% (−6.7% to 8.8%), indicating noninferiority of EFV/FTC/TDF vs. SBR. Similarly, maintenance of HIV-1 RNA <50 copies per milliliter by time to loss of virologic response algorithm was 87% vs. 85% for EFV/FTC/TDF vs. SBR, respectively [difference (95% confidence interval) 2.6% (−5.9% to 11.1%)]. Discontinuation rates were similar (EFV/FTC/TDF 11%, SBR 12%); more discontinuations for adverse events occurred in the EFV/FTC/TDF arm vs. SBR (5% vs. 1%), most commonly for nervous system symptoms. More patients withdrew consent in the SBR arm vs. EFV/FTC/TDF (7% vs. 2%). Estimated glomerular filtration rate (by Modification of Diet in Renal Disease) remained unchanged over 48 weeks in both arms (median change <1 mL·min−1·1.73 m−2). A decrease in fasting triglycerides was observed at 48 weeks in the EFV/FTC/TDF vs. SBR arm (−20 vs. −3.0 mg/dL; P = 0.035). Adherence of ≥96% was reported by visual analog scale in both arms at baseline and at all study visits. Conclusion:Simplification to EFV/FTC/TDF maintained high and comparable rates of virologic suppression vs. SBR through 48 weeks.

Randomization to once-daily stavudine extended release/lamivudine/efavirenz versus a more frequent regimen improves adherence while maintaining viral suppression.

Abstract Background: In antiretroviral (ARV) therapy, pill burden, dosing frequency, and regimen complexity adversely affect adherence. We sought to evaluate the effect of regimen simplification on maintenance of virologic suppression and treatment adherence. Method: In this 48-week, open-label, randomized study, 320 HIV-1—infected adult patients with a viral load of <50 copies/mL on a twice-daily or more frequent ARV regimen were either switched to a once-daily regimen of efavirenz, extended-release stavudine, and lamivudine (QD arm) or continued on existing therapy (BID+ arm). Medication Event Monitoring System (MEMS) caps, AIDS Clinical Trials Group (ACTG)-validated questionnaire, and pill counts were used to evaluate adherence. Treatment satisfaction and preference were also evaluated. Results: The QD arm was noninferior to the BID+ arm in the primary efficacy measure (proportion of patients who maintained virologic suppression at Week 48; QD arm, 80.0% vs. BID+ arm, 75.8%). Adherence and treatment satisfaction significantly favored the QD arm, in which 91.0% of patients preferred the simpler regimen. Overall, the majority of adverse events were mild to moderate in severity and resulted in a low rate of treatment discontinuations. Conclusions: Simplifying twice-daily or more frequent ARV therapy to a once-daily efavirenz-containing regimen in virologically suppressed HIV-1—infected patients maintains virologic suppression while improving adherence and patient satisfaction.

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

Background It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects. Objective To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen. Methods/Results Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r. Conclusion Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping.

Therapy with Efavirenz plus Indinavir in Patients with Extensive Prior Nucleoside Reverse-Transcriptase Inhibitor Experience: A Randomized, Double-Blind, Placebo-Controlled Trial

A randomized, double-blind, placebo-controlled trial compared efavirenz (600 mg every 24 h) plus indinavir (1000 mg every 8 h) with placebo (every 24 h) plus indinavir (800 mg every 8 h) among 327 nucleoside analogue reverse-transcriptase inhibitor (NRTI)-experienced human immunodeficiency virus (HIV)-infected adults. Patients received </=2 concomitant NRTIs. Eligible patients had CD4 cell counts >50 cells/mm(3), >10,000 plasma HIV-1 RNA copies/mL, and no prior protease inhibitor or non-NRTI therapy. Patients had a mean of 2.8 years of prior NRTI therapy. At 24 weeks, plasma HIV-1 RNA level was <400 copies/mL in 68.2% of efavirenz versus 52.4% of placebo recipients (P=.004). CD4 cell count increases were 104+/-9 cells/mm(3) and 77+/-10 cells/mm(3) in efavirenz and placebo recipients, respectively (P=.023). Responses in efavirenz recipients were sustained at 48 weeks. Thus, efavirenz plus indinavir with concomitant NRTIs is effective therapy for NRTI-experienced patients.

No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database.

To assess the potential association of selected antiretrovirals (ARVs), including efavirenz, with suicidality.

Virologic suppression, treatment adherence, and improved quality of life on a once-daily efavirenz-based regimen in treatment-Naïve HIV-1-infected patients over 96 weeks.

Abstract Purpose: This study evaluated the long-term efficacy, safety, adherence, and quality of life (QoL) of a once-daily efavirenz-based antiretroviral regimen in two 96-week prospective open-label single-arm studies of treatment-naïve HIV-1–infected patients. Methods: Patients received once-daily efavirenz 600 mg and lamivudine 300 mg with either enteric-coated didanosine 400 mg (Daily Antiretroviral Therapy trial [DART] I) or extended-release stavudine 100 mg (DART II). The primary efficacy outcome measure was HIV RNA <400 copies/mL at Week 48. Results: In an intent-to-treat (ITT) analysis, HIV RNA level <400 (<50) copies/mL was reached by 82%(80%) and 74% (72%) of patients at Week 48 in DART I and II. At Week 96, the corresponding values were 74% (68%) and 55% (54%), respectively. Both regimens were well tolerated. There were no discontinuations for virologic failure. Medication adherence assessed by pill counts was above 80% in 90% of the patients in DART I and more than 80% of patients in DART II. Treatment produced a significant improvement in overall QoL. Conclusion: Once-daily efavirenz-based antiretroviral therapy was effective, durable, and well tolerated. In this study, a high level of adherence was achieved with improvement in overall QoL.

Phenotypic Susceptibility to Didanosine Is Associated with Antiviral Activity in Treatment-Experienced Patients with HIV-1 Infection

OBJECTIVE We investigated the relationship between human immunodeficiency virus (HIV) phenotypic susceptibility to didanosine and the antiviral activity of didanosine (ddI) in the JAGUAR study. METHODS Baseline plasma HIV phenotypic susceptibility to ddI was assessed using a phenotype assay of patients randomized to receive ddI or placebo for 4 weeks in addition to their current regimen. Phenotypic susceptibility scores (PSSs) were then calculated for each sample. Associations between PSS and week 4 reductions in plasma HIV-1 RNA load or virologic response were assessed using linear regression and Jonckherres test and the Wilcoxon and Cochran-Armitage tests, respectively. RESULTS In the ddI arm, a significant association between reduction in viral load and continuous PSS was observed (P<.0001). Using distinct categories, an increasing fold change (FC) in susceptibility to ddI was strongly associated with smaller reductions in plasma HIV-1 RNA load (P<.0001). The proportion of virologic responders was 83% (15/18) for patients with a ddI FC < or =1.3, 50% (33/66) for patients with an FC of 1.3-2.2, and 29% (4/14) for patients with an FC > or =2.2 (P=.0008). After we determined these findings, 3 ddI FC categories were defined using 1.3 and 2.2 as thresholds. CONCLUSIONS The relationship between phenotypic susceptibility to ddI and reduction in plasma HIV-1 RNA load describes a continuum. The establishment of a lower clinical cutoff at 1.3 and an upper clinical cutoff at 2.2 are clinically relevant.

Impact of health care payer type on HIV stage of illness at time of initiation of antiretroviral therapy in the USA

There is evidence that earlier initiation of HIV antiretroviral therapy (ART) is associated with better outcomes, including lower morbidity and mortality. Based on recent studies indicating that Medicaid enrollees are more likely to have suboptimal access to medical care, we hypothesized that HIV severity at time of ART initiation is worse for Medicaid patients than patients with other health care coverage. We conducted a US retrospective analysis of GE Centricity Outpatient Electronic Medical Records spanning 1 January 1997 through 30 September 2009. Subjects included all adult HIV patients initiating first-line ART who had CD4+ results within 90 days pre-initiation. HIV stage was defined using CD4 ranges: >500 (n=520), 351–500 (n=379), 201–350 (n=580), or ≤200 (n=406) cells/mm3, with lower CD4 count being indicative of increased disease severity. Payer type was defined as the patients primary payer: Medicaid, Medicare, commercial insurance, self-pay or other/unknown. After controlling for demographic and clinical covariates, cumulative logit models assessed the effect of payer type on HIV stage at ART initiation. The study included 1885 subjects with the primary payer being Medicaid (n=218), Medicare (n=330), commercial insurance (n=538), self-pay (n=159) or other/unknown (n=640). Final logit models demonstrated that, compared to patients on Medicaid, the odds of initiating ART at a higher CD4 range were significantly greater for those commercially insured (odds ratio [OR]=1.53; P=0.005), self-paying (OR=1.56; P=0.023) and other/unknown (OR=1.79; P<0.001) and similar for patients enrolled in Medicare (OR=1.11; P=0.521). Medicaid patients initiated ART at a more advanced stage of HIV than patients who were commercially insured, self-paying, or had other/unknown coverage. With HIV treatment guidelines now supporting ART initiation in patients with higher CD4 counts, these findings underscore the need for mitigating barriers, particularly in the Medicaid population, that may delay treatment initiation.