Steven Schnittman

Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects.

Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (−2.57 to −2.33 log10 copies/mL), the proportion of subjects with HIV RNA <400 copies/mL (56%–64%) and <50 copies/mL (28%–42%), and mean increases in CD4 cell count (185–221 cells/mm3) were comparable across treatment groups. Diarrhea was two to three times more common in the nelfinavir group (61% of subjects) than in the atazanavir groups (23%–30% of subjects, p < .0001 versus nelfinavir), and jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) (p < .03 for all atazanavir regimens vs. nelfinavir). Mean percent change from baseline in fasting low-density lipoprotein (LDL) cholesterol was significantly less in the atazanavir groups (−7% to 4%) than in the nelfinavir group (31%) (p < .0001). In conclusion, once-daily atazanavir is a potent, safe, and well tolerated PI that rapidly and durably suppresses HIV RNA and durably increases CD4 cell count in antiretroviral-naive subjects. Through 48 weeks, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglycerides. In comparison, nelfinavir was associated with prompt, marked, and sustained elevations in these parameters of a magnitude that suggests they are clinically relevant.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial

BACKGROUND Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING Bristol-Myers Squibb.

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.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study

Objective To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. Design In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients. Results Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups. Conclusions The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4. Trial registration number NCT01125189.

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression

BackgroundVirologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DesignMulticenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. MethodsSubjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 × 106 cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. ResultsTreatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. ConclusionsSwitching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Zidovudine Treatment in Patients with Primary (Acute) Human Immunodeficiency Virus Type 1 Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

A multicenter, double-blind, placebo-controlled trial randomized 28 patients with primary (acute) human immunodeficiency virus (HIV)-1 infection (PHI) to receive zidovudine, 1000 mg daily, or placebo for 24 weeks. At week 48, compared with placebo patients, zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) and lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) but no difference in plasma RNA (zidovudine, 3.93 log copies/mL; placebo, 4.00; P = .83). Serious adverse events and minor clinical events were infrequent and comparable in both arms. There were two deaths: 1 patient died of sepsis and renal disease (zidovudine arm), and 1 patient died of sepsis and tension pneumothorax (placebo arm). Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. Further studies with more potent antiretroviral combination therapies are warranted.

Hollow-Fiber Unit Evaluation of a New Human Immunodeficiency Virus Type 1 Protease Inhibitor, BMS-232632, for Determination of the Linked Pharmacodynamic Variable

BMS-232632 is a potent human immunodeficiency type 1 (HIV-1) protease inhibitor with a half-life that allows for once-daily dosing. A concentration of 4 times the viral 50% effective concentration (EC(50) [i.e., approximately EC(95)]) administered as a continuous infusion in vitro provides virtually complete suppression of viral replication. This exposure, modeled in vitro as once-daily administration with oral absorption, allows ongoing viral replication. An exposure 4 times as large was calculated to be necessary to provide virus suppression equivalent to the continuous-infusion exposure. These experiments demonstrated that concentration above a threshold (time > 4xEC50) is the pharmacodynamically linked variable for this HIV-1 protease inhibitor. Protein-binding experiments demonstrated that the EC(50) was increased 13.4 times by the addition of human binding proteins. Monte Carlo simulation of protein binding-adjusted pharmacokinetic data from volunteers demonstrated that 64%-70% of a simulated population (n = 3000) would achieve virus suppression with 400-600 mg of BMS-232632 given once daily, if the viral EC(50) were < or = 1 nM.

T cells containing T cell receptor excision circles are inversely related to HIV replication and are selectively and rapidly released into circulation with antiretroviral treatment

Objective: To examine baseline predictors of T-cell receptor rearrangement excision circle (TREC) levels and their changes during treatment with combined antiretroviral therapy. Methods: Peripheral blood and lymph node lymphocytes were examined for the presence of TREC by real-time polymerase chain reaction and circulating lymphocyte phenotypes were examined by flow cytometry. Correlates for CD4 and CD8 cell TREC levels at baseline were identified among CD4 and CD8 immunophenotypes, viral load and patient demographics; the significance of TREC changes after initiation of antiretroviral therapy was assessed. Results: Circulating TREC levels correlated inversely with age, with HIV RNA levels, with activation markers on circulating T cells and with naive CD4 but not CD8 cell frequencies. With initiation of antiretroviral therapy, TREC and naive T cell frequencies increased in peripheral blood during the first 2 weeks of treatment and these changes correlated negatively with TREC frequencies in lymph node aspirates, particularly among CD8 T cells. Conclusions: These findings suggest that recent thymic emigrants are sequestered in lymphoid tissue during uncontrolled HIV replication and are selectively released into circulation rapidly after initiation of antiretroviral therapies.

Antiviral activity of nucleoside analogues during short-course monotherapy or dual therapy: its role in preventing HIV infection in infants.

Background: This is the first report on the preliminary efficacy of 4 different short-course nucleoside analogue regimens (stavudine [d4T], didanosine [ddI], d4T+ddI, and zidovudine [ZDV]) for the prevention of mother-to-child transmission of HIV-1 (MTCT) in a resource-limited setting. Design: This prospective open-label, randomized 4-arm study (May 1999 to May 2000) conducted in South Africa enrolled 373 women from 34 weeks of gestation; medication was continued through delivery and for 6 weeks to infants. MTCT rates were ascertained at birth, 6, 12, and 24 weeks of age. Results: Mean maternal HIV-1 RNA levels decreased rapidly on treatment in all groups. At week 4, the mean decrease was 1.91 log10 copies/mL (c/mL) in the d4T+ddI group, 1.33 log10 c/mL in the ddI group, 1.12 log10 c/mL in the d4T group, and 0.76 log10 c/mL in the ZDV group. Among the 362 evaluable mother-infant pairs, 11 infants in the d4T group, 10 in the ddI group, 5 in the ZDV group, and 4 in the d4T+ddI group were infected by 24 weeks of age. Eleven infections occurred in utero. Treatment with d4T and ddI was not associated with lactic acidosis or hepatic steatosis. Conclusions: The abbreviated use of nucleoside analogues for the prevention of MTCT appears safe and effective.

Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents

Objective:To describe the pharmacokinetics of atazanavir (ATV) and ritonavir-boosted ATV (ATV/r) in children aged 91 days to 21 years. Design:A phase I/II, open-label, multicenter study of once-daily ATV and ATV/r as part of combination antiretroviral treatment in HIV-infected treatment-experienced and treatment-naive children. Setting:Sites in the United States and South Africa. Participants:One hundred and ninety-five children enrolled; 172 had evaluable ATV pharmacokinetics on day 7. Intervention:Children were entered in age, dose, and formulation (powder or capsule) cohorts. Intensive pharmacokinetic sampling occurred 7 days after starting ATV. ATV doses were increased or decreased if the 24-h area under the concentration time curves (AUC0–24hr) were less than 30 or more than 90 &mgr;g × h/ml, respectively. Main outcomes:Cohorts satisfied protocol-defined pharmacokinetic criteria if the median ATV AUC0–24hr was 60 &mgr;g × h/ml or less, and AUC0–24hr and ATV concentrations 24-h postdose (C24) were more than 30 &mgr;g × h/ml and at least 60 ng/ml, respectively, in at least 80% of the children, with no individual AUC0–24hr less than 15 &mgr;g × h/ml. Results:Unboosted ATV capsules satisfied pharmacokinetic criteria at a dose of 520 mg/m2 for those aged more than 2 to 13 years or less and 620 mg/m2 for those aged more than 13 to 21 years or less. ATV/r capsules satisfied criteria at a dose of 205 mg/m2 for those aged more than 2 to 21 years or less. ATV/r powder satisfied criteria at a dose of 310 mg/m2 for those aged more than 2 to 13 years or less, but pharmacokinetics in those aged 2 years or less were highly variable. Conclusion:Body surface area-determined doses of ATV capsules and of ATV/r powder and capsules provide ATV exposures in children of more than 2 years that approximate concentrations in adults receiving ATV/r.