Changes over time in creatinine clearance and comparison of emergent adverse events for HIV-positive adults receiving standard doses (300 mg/day) of lamivudine-containing antiretroviral therapy with baseline creatinine clearance of 30-49 vs ≥50 mL/min.

A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ≥50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr≥50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ≥50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ≥50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ≥50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min.

Abacavir Hypersensitivity Reaction Reporting Rates During a Decade of HLA-B*5701 Screening as a Risk-Mitigation Measure.

INTRODUCTION: Human leukocyte antigen (HLA)-B*5701 screening identifies patients at increased risk for abacavir (ABC) hypersensitivity reaction (HSR). Screening was adopted in GlaxoSmithKline and ViiV Healthcare clinical trials in 2007 and human immunodeficiency virus treatment guidelines in 2008. Company meta-analyses of trials pre-HLA-B*5701 screening reported HSR rates of 4-8%. We analyzed the effectiveness of HLA-B*5701 screening on reducing HSR rates using clinical trial, Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and spontaneous reporting data. METHODS: A meta-analysis examined 12 trials in 3063 HLA-B*5701-negative patients receiving an ABC-containing regimen from April 9, 2007, to September 22, 2015. Potential cases were identified using prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (drug hypersensitivity, hypersensitivity, anaphylactic reaction, anaphylaxis) and adjudicated against a Company ABC HSR case definition. Investigator-diagnosed cases were identified and rates were calculated. In the OPERA cohort, 9619 patients initiating their first ABC-containing regimen from January 1, 1999, to January 1, 2016, were identified. Patients were observed from regimen start until the earliest-following censoring event: ABC discontinuation, loss to follow-up, death, or study end (July 31, 2016). OPERA physicians evaluated events against OPERA definitions for definite/probable cases of ABC HSR; rates were calculated pre- and post-2008. The Company case definition was used to identify spontaneously reported cases for four marketed ABC-containing products; reporting rates were calculated using estimated exposure from sales data, through December 31, 2016. RESULTS: Suspected ABC HSR rates were 1.3% or less in the meta-analysis. In the OPERA cohort, the rate was 0.4% among patients initiating ABC post-2008 versus 1.3% pre-2008 (p<0.0001). Spontaneous reporting rates were low post-2008 (54 to 22 cases per 100,000 patient-years exposure [PYE]) versus pre-2008 (618 to 55 cases per 100,000 PYE). CONCLUSIONS: Clinically suspected ABC HSR rates were 1.3% or less in HLA-B*5701-negative patients. Recognizing their limitations, data from the OPERA cohort and spontaneous reporting indicate that HLA-B*5701 screening has reduced reporting rates of suspected HSR in clinical practice. Where screening for HLA-B*5701 is standard care, patients should be confirmed negative for this allele before starting ABC treatment.

Abacavir Use and Risk for Myocardial Infarction and Cardiovascular Events: Pooled Analysis of Data From Clinical Trials.

BACKGROUND: Some observational studies and randomized controlled trials (RCTs) have suggested an association between abacavir (ABC) use and myocardial infarction (MI), whereas others have not. METHODS: This pooled analysis of 66 phase II-IV RCTs estimates exposure-adjusted incidence rates (IRs) and relative rates (RRs) of MI and cardiovascular events (CVEs) in participants receiving ABC- and non-ABC-containing combination antiretroviral therapy (cART). The primary analysis of MI included ABC-randomized trials with ≥48-week follow-up. Sensitivity analyses of MI and CVEs included non-ABC-randomized and <48-week follow-up trials. RESULTS: In 66 clinical trials, 13 119 adults (75% male, aged 18-85 years) were on ABC-containing cART and 7350 were not. Exposure-adjusted IR for MI was 1.5 per 1000 person-years (PY; 95% confidence interval [CI], 0.67-3.34) in the ABC-exposed group and 2.18 per 1000 PY (95% CI, 1.09-4.40) in the unexposed group. The IR for CVEs was 2.9 per 1000 PY (95% CI, 2.09-4.02) in the exposed group and 4.69 per 1000 PY (95% CI, 3.40-6.47) in the unexposed group with studies of ≥48 weeks of follow-up, with an RR of 0.62 (95% CI, 0.39-0.98). The inclusion of nonrandomized and shorter-duration trials did not significantly change the RR for MI or coronary artery disease. CONCLUSIONS: This pooled analysis found comparable IRs for MI and CVEs among ABC-exposed and -unexposed participants, suggesting no increased risk for MI or CVEs following ABC exposure in a clinical trial population. Modifiable risk factors for MI and CVEs should be addressed when prescribing ART.

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open-Label, Randomized Study.

In children aged ≤4 years, the relative bioavailability of lamivudine oral solution was 37% lower than that of a tablet formulation. An open-label, four-way crossover study was conducted in healthy adults to evaluate the effect of sorbitol, a common liquid excipient, on the pharmacokinetics of lamivudine oral solution (ClinicalTrials.gov identifier, NCT02634073). Sixteen subjects were randomized to one of four sequences consisting of four doses of lamivudine 300 mg (10 mg/mL) alone or with sorbitol 3.2, 10.2, or 13.4 g. Sorbitol 3.2, 10.2, and 13.4 g decreased lamivudine maximum concentration (Cmax ) by 28%, 52%, and 55% and area under the concentration-time curve from time 0 to 24 h (AUC0-24 ) by 20%, 39%, and 44%, respectively. Three subjects (19%) reported five nonserious adverse events (one drug-related). The dose-dependent effects of sorbitol on lamivudine Cmax and AUC0-24 reveal an absorption-based interaction that may decrease lamivudine exposure in patients coadministered sorbitol-containing medicines.

Pharmacokinetics, safety and antiviral activity of fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 2 years-48-week study data.

BACKGROUND: Pharmacokinetics, safety and antiviral activity of fosamprenavir (FPV) with ritonavir (RTV) twice daily were evaluated in HIV-1-infected infants and children 4 weeks to <2 years over 48 weeks. METHODS: Results from intensive pharmacokinetic sampling of subjects enrolled in single dose visits was used to determine individualized dosing for the first 6-10 subjects in each of 2 cohorts (4 weeks to <6 months, 6 months to <2 years); steady state pharmacokinetic data were then used to select the dosage regimen for the remaining subjects recruited to the cohort. Intensive pharmacokinetic sampling was performed at week 2 or 8; predose samples were collected every 4-12 weeks thereafter. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks. RESULTS: Fifty-nine subjects received study medication. FPV 45 mg/kg boosted with RTV 7 to 10 mg/kg BID achieved average plasma amprenavir area under curve(0-τ) values 26% to 28% lower and Cmax similar to historical adult data for FPV/RTV 700/100 mg BID; amprenavir Cτ values were lower in the subjects <6 months of age. At week 48, 35 of 54 (65%) subjects had achieved plasma HIV-1 RNA <400 copies/mL and 33 of 54 (61%) had plasma HIV-1 RNA values <50 copies/mL. The most common adverse events were diarrhea, upper respiratory tract infection, gastroenteritis and otitis media. CONCLUSIONS: Final FPV/RTV dosing regimens achieved plasma amprenavir exposures comparable with those from regimens approved in adults, with the exception of trough exposures in the <6-month-old infants. The FPV/RTV regimens led to viral suppression in 61% of patients and were generally well tolerated.

Pharmacokinetics and 48-week safety and antiviral activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old children.

BACKGROUND: Pharmacokinetics, safety and antiviral activity of twice-daily fosamprenavir with or without ritonavir were evaluated in 2- to 18-year-old protease inhibitor-naïve and -experienced HIV-1-infected children. METHODS: Serial pharmacokinetic samples were collected at week 2 and predose samples every 4-12 weeks. Safety and plasma HIV-1 RNA were monitored every 4-12 weeks. RESULTS: Twenty protease inhibitor-naïve 2- to <6-year-old subjects received antiretroviral treatment including unboosted fosamprenavir twice-daily, whereas 89 protease inhibitor-naïve and -experienced 2- to 18-year-old subjects received fosamprenavir/ritonavir-containing therapy twice-daily. Median fosamprenavir exposure was 891 days (range 15-1805 days), with 88% exposed >48 weeks. Twice-daily doses of fosamprenavir/ritonavir 23/3 mg/kg in 2- to <6-year olds, 18/3 mg/kg in ≥6-year olds and 700/100 mg in adolescents achieved plasma amprenavir exposures comparable with or higher than 700/100 mg twice-daily in adults while fosamprenavir 30 mg/kg twice-daily in 2- to <6-year olds led to exposures higher than 1400 mg twice-daily in adults. The proportion of subjects with HIV-1 RNA <400 copies/mL at week 48 was 60% for fosamprenavir and 53-74% for fosamprenavir/ritonavir (intent-to-treat [exposed], snapshot analysis). Median increases in absolute and relative (percentage) CD4 counts from baseline to week 48 occurred in both the fosamprenavir (340 cells/mm; 8%) and fosamprenavir/ritonavir group (190 cells/mm; 8%). The most common adverse events were vomiting, cough, and diarrhea; 18 subjects experienced serious adverse events, including 9 with suspected abacavir hypersensitivity. CONCLUSIONS: Fosamprenavir regimens administered to HIV-1-infected children aged 2-18 years were generally well-tolerated and provided sustained antiviral activity over 48 weeks, with plasma amprenavir exposures comparable with or higher than adults.