Advancing Research and Development of Anti-infectives for Children: A Clinical Development Perspective.

The HIV treatment landscape for adults has progressed dramatically in recent decades; however, paediatric populations continue to experience delayed and limited access to effective and safe antiretroviral therapy options. Despite current incentive programs, formulation research and development and approved drug dosing for children have been limited, particularly for neonates (aged <4 weeks). Regulatory approval of drug formulations and dosing in children may lag behind adult approvals by years. Formulation and trial design adjustments complicate paediatric drug development, all of which are vital to accommodate for physiological differences, organ maturation, and rapid weight gain, which are most significant in the youngest children. To facilitate more rapid anti-infective drug development for paediatric populations, regulatory agencies provide guidelines that include extrapolating efficacy and safety data from relevant populations; using pharmacokinetic (PK) bridging and modelling to reduce sample sizes and limit the number of PK studies needed before efficacy analyses; and enrolling age- or weight-based cohorts in parallel rather than sequentially for clinical trials. Ensuring access to approved drugs poses an additional challenge, as uncertainty in demand leads to manufacturing and supply complexity with potentially higher costs that can be a barrier to uptake. Here we summarize challenges in drug development for children living with HIV, which are not unique to antiretrovirals. We aim to propose strategies for how model-based approaches and global partnerships can overcome some of these barriers to accelerate paediatric drug development, with particular reference to HIV, and how lessons learnt from HIV could be extended to other anti-infectives.

Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children.

BACKGROUND: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS: The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS: As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS: These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.

Benchmarking the Study Initiation Process.

The study start-up phase of a trial is an area that pharmaceutical and biotechnology companies are focusing on in order to reduce delays and improve efficiency. To better understand and examine metrics within study start-up, the Tufts Center for the Study of Drug Development, in collaboration with 11 pharmaceutical and biotechnology companies, examined a comprehensive set of metrics and analyzed study data from 105 global clinical trials. The results indicate that the early stages of the site initiation process are areas that accounted for the majority of cycle time. An examination of cycle time to the first patient in by therapeutic area also reveals variation. Variations in cycle time to the first patient occur by site type as well as by region. Academic institutions and government-funded sites were longest to the first patient in, while physician practices were fastest.

Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.

BACKGROUND: Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. METHODS: In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per µL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. FINDINGS: 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. INTERPRETATION: Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials.

Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects.

BACKGROUND: Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy [relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001]. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged. METHODS: We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years). FINDINGS: Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed [n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years)] or not [n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years)] to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years). INTERPRETATIONS: In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.

High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.

BACKGROUND: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis. METHODS: White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants. RESULTS: Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%. CONCLUSIONS: Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.

PREDICT-1 (CNA106030): the first powered, prospective trial of pharmacogenetic screening to reduce drug adverse events.

Pharmacogenetics (PGx) - the study of DNA variation in the human genome and the way this impacts the efficacy and safety of medicines - is becoming an increasingly important research tool as physicians, patients, regulatory authorities and payers look for innovative ways to improve the risk:benefit ratio of medicines. While scientific knowledge about PGx is rapidly increasing, implementation of PGx findings to patient care has yet to be fully achieved. One area where significant progress has been made is in the identification of PGx markers associated with variable response to antiretroviral medicines. For example, the major histocompatibility complex HLA-B*5701 allele has been associated with hypersensitivity to abacavir (ABC) by several independent researchers. While PGx associations have been identified largely through retrospective examination, the clinical utility of these PGx markers in patient care has not been prospectively determined in a randomized study. This paper outlines the design of a study to evaluate the utility of prospective screening for HLA-B*5701 to reduce the incidence of ABC hypersensitivity in an ABC-naïve population of HIV-infected subjects. This represents the first fully powered, randomized, blinded, prospective study to determine the clinical utility of PGx screening to reduce drug-associated adverse events in any patient population. This type of trial design may have utility for other important medicines which have treatment-limiting side effects.

Long-term safety and tolerability of the lamivudine/abacavir combination as components of highly active antiretroviral therapy.

BACKGROUND: Numerous large, long-term clinical trials have assessed the safety and efficacy of the two antiretroviral nucleoside analogs lamivudine and abacavir as components of highly active antiretroviral therapy for the treatment of patients with HIV-1 infection. This analysis pools the safety data on multi-drug regimens containing lamivudine/abacavir in combination with a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or nucleoside reverse transcriptase inhibitor. METHODS: Data are presented from 2279 treatment-naive HIV-1-infected patients who were enrolled in one of five clinical trials that assessed the safety and tolerability of lamivudine/abacavir in combination with a third antiretroviral agent. The well characterised combination of lamivudine/zidovudine plus efavirenz was used as the comparator arm. All available safety data (including data beyond 48 weeks) were used in all analyses, which included calculation of treatment emergent laboratory values, adverse events (AEs), serious AEs, fatalities, drug discontinuations and any summaries by study week of safety data. RESULTS: In the total lamivudine/abacavir group, 1585 of 2229 (71%) patients experienced at least one drug-related AE during the study compared with 247 of 325 (76%) patients in the lamivudine/zidovudine/efavirenz treatment group. The most common drug-related AEs reported during the study were diarrhoea (19%), nausea (18%) and dizziness (12%) in patients treated with lamivudine/abacavir plus a third agent, and nausea (31%), dizziness (27%) and headache (16%) in the comparator group. Overall, in the total lamivudine/abacavir group there were only three severe (Division of AIDS 1992 toxicity table grade 3 or 4) AEs that were reported in >1% of subjects: drug hypersensitivity, elevated ALT levels and elevated AST levels. In the lamivudine/zidovudine/efavirenz group, six severe AEs that occurred in >1% of the safety population were reported. The abacavir hypersensitivity reaction rate reported in these five studies was comparable with the previously reported rate. In addition, there were no patient fatalities attributed by investigators to the study drugs. CONCLUSION: This analysis indicates that the combination of lamivudine/abacavir is generally safe for the majority of patients when used as part of combination therapy.