Page 267 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 3 of 10 Original Research

electrocardiogram (ECG) to be eligible. Patients co-infected percentage of patients with plasma HIV-1 RNA levels
with Mycobacterium tuberculosis, who were likely to require < 400 copies/mL after 48 weeks (non-inferiority margin of
rifampicin-based treatment during the study, were excluded. 10%) using a modified Food and Drug Administration (FDA)
31
Written informed consent was obtained from each patient Snapshot method. Patients were classified as virologic
prior to the screening procedures. responders if their HIV-1 RNA was < 400 copies/mL within
the time window of the week 48 visit (between week 42 and
Treatment week 58), or if a single HIV-1 RNA value ≥ 400 copies/mL
within the time window was not confirmed by a second
At baseline, patients were randomly assigned (1:1) to receive measurement – the definition of virologic suppression
an STR of either TDF (300 mg)/FTC (200 mg)/RPV (25 mg) selected was < 400 copies/mL, to reflect the real-life practice
or TDF (300 mg)/FTC (200 mg)/EFV (600 mg). Both products in LMICs where a viral load of < 1000 copies/mL should be
were supplied by the sponsor and given in accordance with taken as evidence as suppression. Patients with no HIV-1
37
the product labels at the recommended dose of one tablet per RNA measurement within the time window of the week 48
day. Patients randomised to TDF/FTC/RPV were advised to visit were considered non-responders.
take the medication with food, whereas patients randomised
to TDF/FTC/EFV were advised to take it on an empty Secondary endpoints were non-inferiority in the percentage of
stomach at bedtime. To assess adherence, patients were asked patients with plasma HIV-1 RNA levels < 50 copies/mL after
to bring the study drug containers, whether empty or not, to 48 weeks (modified FDA Snapshot method), rates of virologic
each study visit. failure during the 48 weeks of treatment with HIV-1 RNA
levels ≥ 400 or ≥ 50 copies/mL (non-virologic failure-censored
Assessments analysis excluding patients who discontinued the study with
HIV-1 RNA < 400 or < 50 copies/mL), change in CD4+ cell
Blood samples were collected at screening, baseline, weeks 4, count, loss of treatment options, as defined by treatment-
12, 24, 36 and 48, and every 24 weeks up to study end or until emergent drug resistance, and adherence to study treatment
discontinuation and then at post-treatment follow-up. HIV-1 based on tablet count at each study visit up to week 48.
RNA was measured at a central laboratory, using the Abbott
RealTime HIV-1 RNA assay with a lower limit of quantification
of 40 copies/mL. Patients with a plasma HIV-1 RNA level Assuming response rates of 90% at 48 weeks for both treatment
≥ 50 copies/mL were counselled on treatment adherence, arms, 192 patients were required per arm to establish non-
inferiority of TDF/FTC/RPV versus TDF/FTC/EFV, with a
and had blood samples collected for re-testing at the central
laboratory at up to 8-week intervals until the plasma HIV-1 maximum allowable difference of 10%, a one-sided significance
RNA was < 50 copies/mL or the plasma HIV-1 RNA level level of 2.5%, and 90% power. To account for a maximum of up
was confirmed by two consecutive tests to be ≥ 400 copies/ to 10% major protocol deviations that would result in exclusion
mL. Patients with a confirmed plasma HIV-1 RNA level ≥ 400 of patients from the per protocol (PP) analysis, 213 patients
copies/mL measured at the central laboratory were classified were planned to be recruited in each treatment arm, resulting
as virologic failures. The confirmatory viral load sample was in 426 randomised patients in total.
tested for genotypic drug resistance at the central laboratory.
The primary efficacy analysis was conducted on the intent-
CD4+ cell counts were determined at a central laboratory at to-treat (ITT) population (all randomised patients who had
screening, baseline, every 24 weeks up to study end or until taken at least one dose of study drug, regardless of their
discontinuation and then at post-treatment follow-up. compliance with the protocol). This analysis was repeated for
the PP population (a subset of the ITT population that
excluded patients with major protocol deviations). As pre-
Safety specified in the statistical analysis plan (SAP), treatment arms
Safety monitoring (adverse events [AEs], including HIV-related were compared using the Cochran–Mantel–Haenszel
events, clinical laboratory analyses, vital signs and physical method, adjusted for the stratification variable (use of EFV
examination) was performed throughout the treatment phase vs. NVP at the screening visit). TDF/FTC/RPV was
until study end. Electrocardiograms were recorded at screening, considered non-inferior to TDF/FTC/EFV if the lower limit
weeks 24 and 48, or at treatment discontinuation if earlier. The of the 95% CI of the difference in efficacy was ≥ 10%. Analysis
following AE classes of interest were investigated based on of the percentages of patients with HIV-1 RNA levels
previous data from the RPV pivotal studies: rashes, < 50 copies/mL, a secondary efficacy outcome, used the
neuropsychiatric events, potential QT prolongation-related same statistical methods as the primary analysis.
events, hepatic events and endocrinological events. In addition,
hyperglycaemia and new onset diabetes were analysed based Subgroup analyses of the virologic response were performed
on reported AEs during the study. in the ITT population for the following pre-defined groups:
NNRTI taken at screening (as stratified), baseline CD4+ count
category, sex, country and treatment adherence. The ITT
Statistical analysis and endpoints
population was used for all safety analyses; as pre-specified
The primary objective was to demonstrate non-inferiority of in the SAP, there was no formal statistical testing of safety
a TDF/FTC/RPV STR versus TDF/FTC/EFV STR in the parameters in the study.

http://www.sajhivmed.org.za 260 Open Access