Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Changes in Manufacturing Processes of Biologic Therapies Can Alter the Immunogenicity Profile of the Product.

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs.

Clinically meaningful visual improvements and predictors of early vision gains with ranibizumab for diabetic macular oedema.

OBJECTIVE: To determine the time to first clinically meaningful improvement in best-corrected visual acuity (BCVA) in patients treated with ranibizumab for diabetic macular oedema (DME) and identify predictors of early visual improvement. METHODS AND ANALYSIS: We retrospectively analysed the phase III RIDE (NCT00473382) and RISE (NCT00473330) trials, in which 759 patients with DME were randomised to monthly intravitreal ranibizumab 0.3 mg (n=250), ranibizumab 0.5 mg (n=252) or sham treatment (n=257). After month 24, 191 sham-treated patients crossed over to monthly ranibizumab 0.5 mg through month 36, while ranibizumab-treated patients continued treatment. Kaplan-Meier analyses assessed time to achieve ≥15 or ≥10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter gains from baseline or ≥20/40 Snellen equivalent BCVA in each treatment arm. Baseline predictors of ≥15 ETDRS letter gains at month 6 were identified by logistic regression. RESULTS: Median time to first ≥15 ETDRS letter gain was significantly shorter in patients who received ranibizumab (0.3 mg, 11.1 months; 0.5 mg, 10.9 months) than sham-treated patients who crossed over to ranibizumab 0.5 mg at month 24 (35.7 months; both p<0.0001). Half of ranibizumab-treated patients achieved ≥20/40 BCVA within 2.3 (0.3 mg) and 1.9 months (0.5 mg). Baseline predictors of early vision improvement among ranibizumab-treated patients were BCVA ≤55 ETDRS letters, younger age and presence of subretinal fluid. CONCLUSION: Prompt ranibizumab therapy for DME was associated with rapid, clinically meaningful vision gains that were maintained over 36 months of treatment. Lower BCVA, younger age and presence of subretinal fluid were predictive of early vision improvement.

MAVERICC, a Randomized, Biomarker-stratified, Phase II Study of mFOLFOX6-Bevacizumab versus FOLFIRI-Bevacizumab as First-line Chemotherapy in Metastatic Colorectal Cancer.

PURPOSE: MAVERICC compared the efficacy and safety of modified leucovorin/5-fluorouracil/oxaliplatin plus bevacizumab (mFOLFOX6-BV) with leucovorin/5-fluorouracil/irinotecan plus bevacizumab (FOLFIRI-BV) in patients with previously untreated metastatic colorectal cancer (mCRC).Patients and Methods: MAVERICC was a global, randomized, open-label, phase II study. Primary objectives were to assess associations between (i) excision repair cross-complementing 1 (ERCC1) expression with progression-free survival (PFS), and (ii) plasma VEGF A (VEGF-A) with PFS in patients with previously untreated mCRC receiving mFOLFOX6-BV or FOLFIRI-BV. Before randomization, patients were stratified by tumoral ERCC1/ß-actin mRNA expression level and region. RESULTS: Of 376 enrolled patients, 188 each received mFOLFOX6-BV and FOLFIRI-BV. PFS and overall survival (OS) were comparable between FOLFIRI-BV and mFOLFOX6-BV, with numerically higher PFS [HR = 0.79; 95% CI (confidence interval): 0.61-1.01; P = 0.06] and OS (HR = 0.76; 95% CI: 0.56-1.04; P = 0.09) observed for FOLFIRI-BV. In the high ERCC1 subgroup, PFS and OS were comparable between treatment groups (PFS, HR = 0.84; 95% CI: 0.56-1.26; P = 0.40; OS, HR = 0.80; 95% CI: 0.51-1.26; P = 0.33). Across treatment groups, high plasma VEGF-A levels (>5.1 pg/mL) were observed with shorter PFS (HR = 1.19; 95% CI: 0.93-1.53; P = 0.17) and significantly shorter OS (HR = 1.64; 95% CI: 1.20-2.24; P < 0.01) versus low levels (≤5.1 pg/mL). Safety findings for FOLFIRI-BV or mFOLFOX6-BV were comparable with those reported previously. CONCLUSIONS: First-line FOLFIRI-BV and mFOLFOX6-BV had comparable PFS and OS, similar to results in patients with high baseline tumor ERCC1 levels. There were no new safety signals with these bevacizumab-containing regimens.

Primary tumor location as a prognostic factor in metastatic colorectal cancer.

BACKGROUND: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.

Collateral vessel presence in branch and central retinal vein occlusions and their impact on visual acuity and anatomical gains: a retrospective analysis.

PURPOSE: To evaluate the incidence of collateral vessel formation and to determine their impact on best-corrected visual acuity and central foveal thickness in patients with branch or central retinal vein occlusion (BRVO, CRVO) receiving 0.3 mg or 0.5 mg of ranibizumab, or sham. METHODS: This retrospective analysis was performed in patients with macular edema secondary to retinal vein occlusion who received 6 monthly intravitreal injections of ranibizumab (0.3 mg or 0.5 mg), or sham, followed by 6 months of as-needed treatment. Collateral vessel presence, change from baseline best-corrected visual acuity, and change from baseline central foveal thickness were assessed at baseline and months 3, 6, 9, and 12. RESULTS: At month 12, 19.6% of BRVO patients receiving sham/0.5 mg and 16.7% receiving ranibizumab (0.3 mg and 0.5 mg pooled) manifested collaterals at the disk, whereas 48.2% and 47.2% displayed collaterals within the retina, respectively. In CRVO patients, 57.9% and 59.2% of all groups manifested collaterals on the disk, respectively, whereas 12.1% and 15.1% displayed collaterals within the retina. Mean best-corrected visual acuity gain in ranibizumab-treated BRVO and CRVO patients was similar, irrespective of collaterals within the retina ( BRVO: P > 0.05; CRVO: P > 0.05). CONCLUSION: The location of collaterals differed between retinal vein occlusion subtypes and ranibizumab treatment did not affect collateral vessel incidence. The presence of collaterals did not seem to impact best-corrected visual acuity gains at month 12 in both BRVO and CRVO patients receiving ranibizumab, whereas generally greater central foveal thickness reductions were observed with presence of collaterals in BRVO patients.

Monthly versus as-needed ranibizumab injections in patients with retinal vein occlusion: the SHORE study.

OBJECTIVE: To compare pro re nata (PRN) and monthly injections of 0.5 mg ranibizumab in retinal vein occlusion (RVO) patients stabilized by monthly injections. DESIGN: Randomized, open-label, vision-examiner masked, 15-month study. PARTICIPANTS: Subjects with macular edema secondary to branch or central RVO. METHODS: Subjects received monthly injections of 0.5 mg ranibizumab for 7 months and those meeting stability criteria between months 7 and 14 were randomized (1:1) to PRN injections versus continued monthly injections. Non-randomized (NR) subjects (never met stability criteria) received monthly injections. MAIN OUTCOME MEASURES: The primary endpoint was the slope of change in best-corrected visual acuity (BCVA) between months 7 and 15. RESULTS: There was no significant difference in the slope of change in BCVA between months 7 and 15 in patients treated PRN versus those treated with monthly injections (P = 0.509). Mean (± standard deviation) change from baseline BCVA in Early Treatment Diabetic Retinopathy Study letter score at month 15 was 21.0 ± 14.1 in the PRN group (n = 82) versus 18.7 ± 14.1 in the monthly group (n = 80) and 14.5 ± 14.7 in NR subjects (n = 13). The percentage of subjects who achieved BCVA ≥ 20/40 at month 15 was 76.8% in the PRN group, 71.3% in the monthly group, and 46.2% in NR subjects. The mean (± standard deviation) change from baseline central subfield thickness was -247.8 ± 207.5 µm in the PRN group, -289.9 ± 177.2 µm in the monthly group, and -93.2 ± 225.2 µm in NR subjects. There were no significant differences in mean BCVA gains or central subfield thickness reductions at month 15 between the PRN and monthly injection groups (all > 0.05). CONCLUSIONS: After edema resolution from 7 or more monthly ranibizumab injections in RVO subjects, visual outcomes at month 15 were excellent and not significantly different in subjects treated PRN versus those who continued monthly injections.

Time to clinically significant visual acuity gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials.

PURPOSE: To assess time to first achievement of clinically significant visual acuity (VA) gains from baseline in patients with retinal vein occlusion (RVO) receiving ranibizumab versus sham treatment. DESIGN: Post hoc analyses of 2 phase 3 clinical trials assessing efficacy and safety of ranibizumab in patients with branch RVO (Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety [BRAVO] study; NCT00061594) and central RVO (Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety [CRUISE]; NCT00056836) over 12 months. PARTICIPANTS: Seven hundred eighty-nine patients (BRAVO, n = 397; CRUISE, n = 392). INTERVENTION: Randomization to monthly intraocular ranibizumab injections (0.3 mg/0.5 mg) or sham. After 6 monthly injections (treatment period), patients meeting prespecified criteria received as-needed (pro re nata [PRN]) ranibizumab at their assigned dose (sham patients, ranibizumab 0.5 mg) through month 12 (observation period). BRAVO patients meeting specific eligibility criteria could receive rescue laser treatment once during the treatment and once during the observation periods. MAIN OUTCOME MEASURES: Time to first gain of 15 letters or more from baseline, analyzed using Kaplan-Meier methods. To evaluate the effect of delaying ranibizumab treatment, sham patients' VA data also were analyzed, with month 6 considered as baseline to assess vision gains during the 6 months of receiving ranibizumab PRN. RESULTS: Median time to first 15-letter or more gain from baseline was 12.0 (sham), 4.8 (ranibizumab 0.3 mg), and 4.0 months (ranibizumab 0.5 mg) in BRAVO and 12.2, 5.9, and 5.2 months, respectively, in CRUISE. The cumulative proportion of patients who had ever gained 15 letters or more from baseline by month 12 was 50% (sham), 68% (ranibizumab 0.3 mg), and 71% (ranibizumab 0.5 mg) in BRAVO and 42%, 61%, and 66%, respectively, in CRUISE. After 6 months of ranibizumab PRN treatment, a cumulative 10.8% (BRAVO) and 26.2% (CRUISE) of initially sham-treated patients ever gained 15 letters or more. CONCLUSIONS: This retrospective analysis shows that more than 50% of patients treated with monthly ranibizumab achieved clinically significant vision gains during the initial 6 months of treatment, which largely were maintained using PRN treatment to 12 months. In comparison, less than 50% of patients initially randomized to sham (and later receiving ranibizumab 0.5 mg PRN treatment) ever achieved clinically significant vision gains. These results suggest that initiating treatment immediately after diagnosis may provide the greatest vision gains. The potential benefits of early treatment should be evaluated further in prospective clinical studies.

Ranibizumab for macular edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial.

PURPOSE: To assess long-term safety and efficacy of intraocular ranibizumab injections in patients with macular edema after retinal vein occlusion (RVO). DESIGN: Open-label extension trial of the 12-month Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) and Central Retinal Vein Occlusion Study: Evaluation of Efficacy and Safety (CRUISE) trials. PARTICIPANTS: We included 304 patients who completed BRAVO and 304 patients who completed CRUISE. METHODS: Patients were seen at least every 3 months and given an intraocular injection of 0.5 mg ranibizumab if they met prespecified retreatment criteria. MAIN OUTCOME MEASURES: Primary outcomes were incidence and severity of ocular and nonocular adverse events (AEs). Key efficacy outcomes included mean change from baseline best-corrected visual acuity (BCVA) letter score by Early Treatment Diabetic Retinopathy Study protocol and central foveal thickness. RESULTS: In patients who completed month 12, the mean number of injections (excluding month 12 injection) in the sham/0.5-, 0.3/0.5-, and 0.5-mg groups was 2.0, 2.4, and 2.1 (branch RVO) and 2.9, 3.8, and 3.5 (central RVO), respectively. The incidence of study eye ocular serious AEs (SAEs) and SAEs potentially related to systemic vascular endothelial growth factor inhibition across treatment arms was 2% to 9% and 1% to 6%, respectively. The mean change from baseline BCVA letter score at month 12 in branch RVO patients was 0.9 (sham/0.5 mg), -2.3 (0.3/0.5 mg), and -0.7 (0.5 mg), respectively. The mean change from baseline BCVA at month 12 in central RVO patients was -4.2 (sham/0.5 mg), -5.2 (0.3/0.5 mg), and -4.1 (0.5 mg), respectively. CONCLUSIONS: No new safety events were identified with long-term use of ranibizumab; rates of SAEs potentially related to treatment were consistent with prior ranibizumab trials. Reduced follow-up and fewer ranibizumab injections in the second year of treatment were associated with a decline in vision in central RVO patients, but vision in branch RVO patients remained stable. Results suggest that during the second year of ranibizumab treatment of RVO patients, follow-up and injections should be individualized and, on average, central RVO patients may require more frequent follow-up than every 3 months.

Impact of comorbidities and drug therapy on development of renal impairment in a predominantly African American and Hispanic HIV clinic population.

PURPOSE: Renal impairment in human immunodeficiency virus (HIV)-infected patients could potentially be caused by many factors. HIV-related renal impairment risks have been little studied in African Americans and Hispanics. We investigated the impact of HIV itself, highly active antiretroviral therapy (HAART), comorbidities, and non-HIV-related drug treatment on glomerular filtration rate in a predominantly African American/Hispanic HIV-infected population who had received HAART for at least one year. This study was a retrospective electronic medical record database evaluation of renal impairment risks in a largely African American/Hispanic HIV population obtaining medical care at an HIV clinic in Dallas, Texas. METHODS: Proportional hazards models were used to investigate an association between an estimated glomerular filtration rate decrease >25% from baseline (ie, renal impairment) and demographics, antiretroviral/nonantiretroviral medications, comorbidities (hypertension, diabetes mellitus, hepatitis C virus [HCV] infection, hepatitis B virus [HBV] infection), CD4+ counts, viral load, and duration patients were monitored at the clinic (time on study). RESULTS: In total, 323 patients were evaluated: 82% males; 61% African American/12% Hispanic/19% Caucasian; mean age 37.9 years (standard deviation [SD] 8.5); 6% HBV-positive; 34% HCV-positive; 29% hypertensive; 3% diabetic; 52% tenofovir-treated; mean weight 75.4 kg (SD, 15.4); mean estimated glomerular filtration 114.5 mL/min/1.73 m(2) (SD, 36.7) using the Modification of Diet in Renal Disease (MDRD) calculation method; mean creatinine clearance (from which estimated glomerular filtration was extrapolated) by the Cockcroft-Gault calculation method 120.6 mL/min/1.73 m(2) (SD, 41.2); mean time on study 2.7 years (SD, 1.0 year). An estimated glomerular filtration rate decrease of >25% from baseline was significantly associated with time on study (P = 0.0017; hazards ratio [HR] = 0.999) and hypertension (HR = 1.706; P = 0.0158) by the MDRD method, and with age (HR = 1.039; P = 0.0077), weight (HR = 0.987; P = 0.0023), and time on study (HR = 0.999; P = 0.0043) by extrapolation of Cockcroft-Gault creatinine clearance calculation. No specific HAART agent was associated with significant renal impairment risk by the definition used in this study. CONCLUSION: This retrospective database study showed time on study, hypertension, weight, and age to be the only significant predictors of an estimated glomerular filtration rate decrease >25% from baseline.

A pilot study of abacavir/lamivudine and raltegravir in antiretroviral-naïve HIV-1-infected patients: 48-week results of the SHIELD trial.

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.

Similar virologic and immunologic efficacy with fosamprenavir boosted with 100 mg or 200 mg of ritonavir in HIV-infected patients: results of the LESS trial.

PURPOSE: ritonavir (RTV) effectively boosts most protease inhibitors but is associated with significant dose-dependent adverse events (AEs). In an effort to better manage toxicities through a reduced dose of RTV, this study compared fosamprenavir (FPV) boosted with RTV 100 mg (FPV/r100) or with RTV 200 mg (FPV/r200) daily. METHODS: this 24-week, open-label study enrolled patients taking a FPV/r 200-containing regimen who had HIV RNA <400 copies/mL and randomized them 1:2 to continue that regimen or simplify to FPV/r100 once daily. Other medications were not altered. The primary endpoint was the percentage of patients without suspected or confirmed virologic failure (HIV RNA ≥ 400 copies/mL) through week 24 by a missing/discontinuation equals failure (M/D=F) analysis. Noninferiority criteria were demonstrated if the lower bound of the 95% confidence interval (CI) for the difference in the primary endpoint rates between groups was greater than -12. RESULTS: the 2 regimens met prespecified noninferiority criteria (FPV/r100, 92%; FPV/r 200, 94%; 95% CI, -9.36 to 5.12). At week 24, the percentage of patients with HIV RNA <50 copies/mL by M/ D=F was 83% in the FPV/r100 group and 85% in the FPV/r 200 group. Drug-related grade 2-4 AEs were uncommon (FPV/r100, 4%; FPV/r 200, 7%). Median changes in lipids were similar in both groups, with the exception of triglycerides (FPV/r100, -21 mg/dL; FPV/r 200, -2 mg/dL). CONCLUSIONS: this 24-week study demonstrated that among previously suppressed patients, once-daily FPV/r100 was similar to FPV/r 200 in virologic and immunologic effects but was associated with greater decreases from baseline in triglyceride levels.

Modulation of K65R selection by zidovudine inclusion: analysis of HIV resistance selection in subjects with virologic failure receiving once-daily abacavir/lamivudine/zidovudine and tenofovir DF (study COL40263).

COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNA > or = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNA > or = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNA > or = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment.

BACKGROUND: Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients. METHODS: Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. RESULTS: At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. CONCLUSION: Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Once-daily abacavir/lamivudine and ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-naïve patients: a 48-week pilot study.

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 >or= 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.

The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial.

BACKGROUND: Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients. METHODS: This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943. FINDINGS: At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir. INTERPRETATION: Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Once-daily abacavir/lamivudine/zidovudine plus tenofovir for the treatment of HIV-1 infection in antiretroviral-naïve subjects: a 48-week pilot study.

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.

Asymptomatic hyperlactataemia: predictive value, natural history and correlates.

BACKGROUND: The significance of asymptomatic hyperlactataemia is unknown. METHODS: We measured serial lactate levels in a group of HIV-infected subjects. Objectives were to identify covariates associated with hyperlactataemia, and to explore the natural history of hyperlactataemia. RESULTS: Overall, 1487 lactate measurements were performed on 396 subjects; 299 subjects had serial lactate testing, with a median of four performed per patient (range: 2-16). At study entry, lactate was >2.4 mmol/l in 6% of subjects and >3.6 mmol/l in 1%. A multiple logistic regression analysis revealed that cholesterol and current stavudine were the only predictors of hyperlactataemia. Lactate levels were highly reproducible both for short-term (within 3 months) and long-term (>1 year) follow-up. During the study period, 16 subjects were identified with sustained hyperlactataemia; 12/16 remained asymptomatic after a median of 210 days (30-585), and four developed symptoms suggestive of lactic acidosis syndrome. In three of the four, asymptomatic hyperlactataemia had preceded the onset of symptoms by 18-122 days. A longitudinal model showed a rapid rise of lactate levels from 0 to 12 months on nucleoside reverse transcriptase inhibitor (NRTI) and then stabilization. Lactate levels did not correlate with baseline or on-study development of lipoatrophy. CONCLUSIONS: Even when optimal methods of collection are used, asymptomatic hyperlactataemia does exist and could be sustained in a subset of NRTI-treated subjects for as long as 585 days. A subset of these subjects became symptomatic, after as long as 122 days of asymptomatic hyperlactataemia. Asymptomatic hyperlactataemia is not predictive of lipoatrophy.