Could Less Be More? Accounting for Fractional-Dose Regimens and Different Number of Vaccine Doses When Measuring the Impact of the RTS,S/AS01E Malaria Vaccine.

BACKGROUND: The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya. METHODS: In total, 1500 children aged 5-17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32). RESULTS: At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%-49%) to 53% (R012-14-26; 95% CI: 42%-62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32). CONCLUSIONS: Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply. CLINICAL TRIALS REGISTRATION: NCT03276962 (ClinicalTrials.gov).

Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial.

BACKGROUND: Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings. METHODS: This open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5-17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01E at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962. FINDINGS: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01E group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was -21% (95% CI -57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed. INTERPRETATION: The Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01E regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up. FUNDING: GlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative.

Risk of deaths, AIDS-defining and non-AIDS defining events among Ghanaians on long-term combination antiretroviral therapy.

Combination antiretroviral therapy (cART) has been widely available in Ghana since 2004. The aim of this cohort study was to assess the incidences of death, AIDS-defining events and non-AIDS defining events and associated risk factors amongst patients initiating cART in a large treatment centre. Clinical and laboratory data were extracted from clinic and hospital case notes for patients initiating cART between 2004 and 2010 and clinical events graded according to recognised definitions for AIDS, non-AIDS events (NADE) and death, with additional events not included in such definitions such as malaria also included. The cumulative incidence of events was calculated using Kaplan Meier analysis, and association of risk factors with events by Cox proportional hazards regression. Data were closed for analysis on 31st December, 2011 after a median follow-up of 30 months (range, 0-90 months). Amongst 4,039 patients starting cART at a median CD4 count of 133 cells/mm3, there were 324 (8%) confirmed deaths, with an event rate of 28.83 (95% CI 25.78-32.15) deaths per 1000-person follow-up years; the commonest established causes were pulmonary TB and gastroenteritis. There were 681 AIDS-defining events (60.60 [56.14-65.33] per 1000 person years) with pulmonary TB and chronic diarrhoea being the most frequent causes. Forty-one NADEs were recorded (3.64 [2.61-4.95] per 1000 person years), of which hepatic and cardiovascular events were most common. Other common events recorded outside these definitions included malaria (746 events) and respiratory tract infections (666 events). Overall 24% of patients were lost-to-follow-up. Alongside expected risk factors, stavudine use was associated with AIDS [adjusted HR of 1.08 (0.90-1.30)] and death (adjusted HR of 1.60 [1.21-2.11]). Whilst frequency of AIDS and deaths in this cohort were similar to those described in other sub-Saharan African cohorts, rates of NADEs were lower and far exceeded by events such as malaria and respiratory tract infections.

Incidence and determinants of nevirapine and efavirenz-related skin rashes in West Africans: nevirapine's epitaph?

Non-nucleoside reverse transcriptase inhibitor (NNRTI) associated rash is common and frequently leads to discontinuation of NNRTIs. This study assessed the risk of developing rashes and discontinuing NNRTIs and associated factors in a large clinic in central Ghana. In this retrospective cohort study, clinical data were obtained in patients starting efavirenz or nevirapine between 2004-2010. Factors associated with rashes were explored using a multivariate Cox proportional hazards regression model. Of 3,999 patients who started NNRTI-based ART, 281 (7.0%) experienced at least one episode of NNRTI-related rash with an incidence of 2.63 events/100 person-years, occurring in 10.2% and 5.6% of patients taking nevirapine and efavirenz respectively. Most rashes (94%) were grade 1 or 2 and were reported a median of 2 months following initiation of ART. In multivariate analysis developing a rash was associated with nevirapine use (aHR 1.67, 95% CI 1.28-2.10), female gender (aHR of 1.39, 95% CI 1.01-1.92) and lower baseline CD4 counts (aHR 0.88, 95% CI 0.82-0.95 per 50 cells/mm³ increment). Patients with nevirapine-associated rash were 11 times more likely to discontinue treatment as patients with efavirenz-associated rash. In contrast to findings in other studies, NNRTI-associated rashes in Ghanaians appear more common in patients with lower baseline CD4 counts. Given the increased frequency of rashes with nevirapine and subsequent discontinuations in many patients, along with other treatment-limiting toxicities, this provides further impetus for the replacement of nevirapine by efavirenz as the first-line NNRTI treatment of choice in Africa.

Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients.

OBJECTIVES: Efavirenz is widely used in first-line antiretroviral therapy in sub-Saharan Africa. However, exposure to efavirenz shows marked interindividual variability that is genetically mediated with potential for important pharmacodynamic consequences. The aims of this study were to assess the frequencies of CYP2B6, CYP2A6, UGT2B7 and CAR single nucleotide polymorphisms (SNPs) and their impact on plasma efavirenz concentration and clinical/immunological responses in Ghanaian patients. METHODS: Genomic DNA from 800 HIV-infected patients was genotyped for selected SNPs by real-time PCR-based allelic discrimination. Mid-dose plasma efavirenz concentrations were measured for 521 patients using HPLC with UV detection. Clinical outcomes in 299 patients on efavirenz were retrospectively assessed. Univariate and multivariate linear regression were performed using best subset selection. Time-to-event outcomes were analysed using a Cox proportional hazards regression model. RESULTS: The variant allele frequencies for CYP2B6 516G>T (rs3745274), CYP2B6 983T>C (rs28399499), CYP2A6 -48T>G (CYP2B6*9B; rs28399433), UGT2B7 802C>T (UGT2B7*2; rs7439366), UGT2B7 735A>G (UGT2B7*1c; rs28365062) and CAR 540C>T (rs2307424) were 48%, 4%, 3%, 23%, 15% and 7%, respectively. CYP2B6 516G>T, CYP2B6 983T>C and CYP2A6 -48T>G were associated with significantly elevated efavirenz concentrations. A trend towards association between plasma efavirenz concentration and CAR 540C>T was observed. CYP2B6 516G homozygosity was associated with immunological failure [adjusted hazards ratio compared with T homozygosity, 1.70 (1.04-2.76); P = 0.03]. CONCLUSIONS: CYP2B6 and CYP2A6 SNPs were associated with higher plasma efavirenz concentrations due to reduction in major and minor phase I routes of elimination, respectively. Further prospective studies are needed to validate the pharmacodynamic correlates of these polymorphisms in this population.

Long-term effectiveness of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in Ghana.

OBJECTIVES: Information on the long-term effectiveness and tolerability of efavirenz- or nevirapine-based antiretroviral therapy (ART) in Africa is lacking. The primary objective of this retrospective observational study was to compare the long-term clinical and immunological outcomes of efavirenz- versus nevirapine-based first-line ART in a large government clinic in Ghana. PATIENTS AND METHODS: The main outcomes were AIDS, death, ART-related toxicity, discontinuation of ART and a composite endpoint of death, AIDS or ART discontinuation. These time-to-event outcomes were compared using a Cox proportional hazards regression model. CD4 counts on ART were compared using a mixed-effects model. RESULTS: A total of 3990 patients started non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART between 2004 and 2010, of which 2369 (59%) were on efavirenz. No significant differences were apparent between each NNRTI for subsequent risk of AIDS, death or the composite of treatment failure; however, stavudine use was independently associated with an increased risk of death [adjusted hazard ratio (HR) 1.60 (95% CI: 1.21-2.11)]. There was an increased risk of early toxicity with nevirapine leading to discontinuation [adjusted HR 1.53 (95% CI: 1.23-1.97)], mostly due to excess skin rashes in the first 2 months of treatment; however, overall discontinuation rates were low. CONCLUSIONS: There was no difference in the long-term effectiveness of efavirenz- and nevirapine-based ART in this population; however, patients initiating nevirapine were more likely to develop early toxicity and discontinue this drug. The excess mortality observed in patients taking stavudine is of concern and should prompt increased efforts to replace it with alternative antiretroviral drugs in developing countries.