Included Studies

The evidence for this review was drawn from two phase 3 multi-centre, double-blind (DB), double-dummy, active-controlled, non-inferiority trials (Study 104, n = 872; Study 111, n = 872), one phase 3 multi-centre, open-label, active-controlled, non-inferiority trial (Study 109, n = 1,443), and two multi-centre, open-label, single-group cohort studies (Study 112, n = 252; Study 106, n = 48). The primary efficacy outcome for all studies was the percentage of patients with HIV-1 ribonucleic acid (RNA) < 50 copies/mL at week 48 (Studies 104, 111, and 109) or week 24 (Studies 112 and 106) using the FDA-defined snapshot algorithm. The non-inferiority margin in Studies 104, 111, and 109 was 12%, which is accepted by the FDA.

Studies 104 and 111 exclusively enrolled treatment-naive adults, whereas Study 109 enrolled only virologically suppressed adults who had been on an ARV regimen consisting of FTC/TDF + a third drug. No major methodological limitations with these studies were identified. There were no direct comparative data available against dolutegravir/abacavir/lamivudine (DTG/ABC/3TC), which is another US Department of Health and Human Services (DHHS)-preferred initial regimen available in Canada. Studies 112 and 106 evaluated the efficacy and safety of EVG/COBI/FTC/TAF in HIV-infected adults with mild to moderate renal impairment and treatment-naive adolescents, respectively. Due to the lack of a comparator group, however, the results could not demonstrate the relative efficacy and safety of EVG/COBI/FTC/TAF in the study populations. In addition, given the small sample sizes, the results were insufficient to draw robust conclusions about the efficacy and safety of EVG/COBI/FTC/TAF in these populations.

Efficacy

In Studies 104 and 111, EVG/COBI/FTC/TAF was statistically non-inferior to EVG/COBI/FTC/TDF with respect to the primary efficacy outcome (Table 1). In Study 109, results from the primary analyses demonstrated that significantly more patients who switched to EVG/COBI/FTC/TAF versus those who stayed on their pre-existing FTC/TDF + a third drug regimen achieved VL < 50 copies/mL at week 48. In Study 112, the primary analysis demonstrated that the virologic success rates at 24 weeks were 95.0% and 83.3% among adults who switched to EVG/COBI/FTC/TAF from their existing ARV regimen and treatment-naive adults who received EVG/COBI/FTC/TAF, respectively (Table 2). In Study 106, the virologic success rate at 24 weeks was 91.3% for 23 antiretroviral therapy (ART)-naive adolescents receiving EVG/COBI/FTC/TAF.

Table 1

Summary of Results — Treatment-naive or Virologically Suppressed Adults.

Table 2

Summary of Results — Special Populations.

Across the three randomized controlled trials (RCTs), there were very few patients who developed primary genotypic resistance through week 48. In Studies 112 and 106, through week 48, no patients receiving EVG/COBI/FTC/TAF developed new resistance or mutations that were not already present at baseline. Further, there were no differences in health-related quality of life (HRQoL) among patients receiving EVG/COBI/FTC/TAF or a comparator.

Harms

Across all five studies, at least 80% of patients in each trial experienced at least one treatment-emergent adverse event (AE). Diarrhea, nausea, upper respiratory tract infections (URTIs), and headache appeared to be the most common AEs reported by patients receiving EVG/COBI/FTC/TAF. The percentage of patients who experienced a serious adverse event (SAE) while receiving EVG/COBI/FTC/TAF varied. Across the three RCTs, fewer patients receiving EVG/COBI/FTC/TAF withdrew due to AEs than those receiving a comparator. There were two deaths reported in Study 104 (one in the EVG/COBI/FTC/TAF group) and three in Study 111 (one in the EVG/COBI/FTC/TAF group). In Study 109, four patients who switched to EVG/COBI/FTC/TAF from a pre-existing regimen of FTC/TDF + a third drug died, although none of those deaths were considered treatment-related; no patients died in the comparator group. There were no deaths in Studies 112 and 106.

Exposure to TDF as part of a combination ART regimen has been shown to increase kidney damage and reduce kidney function in patients with HIV, although these changes rarely warrant discontinuation of therapy according to the clinical expert consulted for this review. EVG/COBI/FTC/TAF decreased the effect on kidney function (median estimated glomerular filtration rate [eGFR]) from baseline to week 48 in treatment-naive patients relative to EVG/COBI/FTC/TDF in Studies 104 and 111. In Study 109, median eGFR increased slightly from baseline among patients who switched to EVG/COBI/FTC/TAF from a pre-existing regimen of FTC/TDF + a third drug but decreased among those who stayed on their pre-existing regimen, resulting in a significant difference between groups. In Study 112, among virologically suppressed adults, overall kidney function appeared to decrease at 24 weeks, although the effect seemed to differ by severity of kidney impairment at baseline. Among treatment-naive patients in the same study, there was minimal change in median eGFR from baseline. In Study 106, there appeared to be a larger decrease compared with the adult studies in overall median eGFR from baseline to week 24 among treatment-naive adolescents receiving EVG/COBI/FTC/TAF. In all, the consulting clinical expert highlighted that the magnitude of the changes and differences between treatments across studies were not likely to be clinically meaningful in clinical practice, but may be important to track in the long term.

HIV-infected individuals experience accelerated bone loss compared with the general population, especially with TDF exposure, although the risk of fracture is low according to the consulting clinical expert. In the three RCTs, treatment with EVG/COBI/FTC/TAF appeared to decrease harmful effects on the bone system, as measured by changes in mean bone mineral density (BMD) at the hip and spine from baseline to week 48. In Study 112, the overall mean BMD at the hip and spine increased in the patients who switched to EVG/COBI/FTC/TAF from their existing ARV regimen, but decreased among treatment-naive patients at week 24. In Study 106, the overall mean spine and total body less head (TBLH) BMD increased among treatment-naive adolescents from baseline to week 24. The consulting clinical expert highlighted that the magnitude of the changes (across all studies) in BMD were not likely to be clinically meaningful in clinical practice, but may be important to track in the long term.