Efficacy

Even though the comparators chosen in the treatment-naive trials, DRV/r and EFV, are available in Canada, they are not the preferred choice of drugs for treatment initiation according to the clinical expert consulted for this review. The DHHS guidelines⁴ widely recognized for the management and treatment of HIV recommend the following treatment combinations in treatment-naive patients: BIC/TAF/FTC, DTG/ABC/3TC, DTG/TDF/FTC, raltegravir/TDF/FTC; with 3TC as an alternative to FTC and tenofovir used with consideration of bone and renal toxicities and lipid levels.⁴ The clinical expert agreed that the aforementioned regimens, in addition to FTC/EVG/cobicistat/TAF (Genvoya), are the most relevant comparators from a Canadian perspective. Notably, the DHHS guidelines recommend DOR/TDF/3TC and DOR plus TAF/FTC as initial regimens in certain clinical situations, including patients with a high cardiac risk and hyperlipidemia.⁴

For treatment-experienced patients with viral suppression, the DHHS guidelines do not provide a list of recommended therapies. Instead, selecting a new ART regimen should be based on patients’ previous ART history, including virologic responses, past ART-associated toxicities and intolerances, resistance-test results, drug-drug interactions, and pill burden, in addition to other non-clinical considerations.⁴ The baseline regimens for the treatment-switch patients in DRIVE-SHIFT, namely boosted PI, boosted EVG, and NNRTI, are relevant comparators in this setting.

The trials in treatment-naive patients (DRIVE-FORWARD and DRIVE-AHEAD) were conducted with sufficient methodological rigour, with appropriate statistical analyses plans, selection of trial population and outcomes, and adequate follow-up. A number of design features and methodological issues limited the validity and interpretability of the switch trial (DRIVE-SHIFT). The primary outcome for treatment-naive trials was consistent with the FDA snapshot algorithm for virologic suppression, i.e., HIV-1 RNA < 50 copies/mL at week 48. However, the switch trial also used the above end point as the primary outcome, as opposed to the FDA-recommended outcome of virologic failure, i.e., HIV-1 RNA ≥ 50 copies/mL at week 48.³⁴ Although the proportional difference in HIV-1 RNA ≥ 50 copies/mL between the treatment arms was compared statistically, adjustment for multiple comparisons was not made. The reported result for the primary efficacy outcome showed the 8% NIM was met. However, the FDA snapshot algorithm to account for missing data (missing data = failure) was not followed properly. Instead, some patients with missing data at week 48 had their blood samples reanalyzed from other sources and the data were added to the analyses dataset post hoc. Following this modification, the NIM was met for the primary efficacy outcome. However, noninferiority was not demonstrated with the true snapshot approach. Finally, testing of primary and secondary end points in the statistical hierarchy was based on different periods of exposure for the two treatment arms. Patients in the ISG arm received DOR/3TC/TDF for 48 weeks whereas those in the DSG arm received their baseline regimens for weeks 0 to 24 and DOR/3TC/TDF for weeks 24 to 48. Statistical comparisons were not made between the treatment arms at week 24 for most end points (including the primary efficacy end point), or were not controlled for multiplicity. Instead, results for the ISG arm at week 48 were compared with the DSG arm at week 24.

All trials met the a priori defined NIM (10% for treatment-naive and 8% for treatment-switch trials) for the primary efficacy outcome, i.e., virologic success. The virologic success rates across trials were approximately 80% in treatment-naive patients and > 90% in treatment-switch patients by week 48. The higher response rate among treatment-switch patients was expected because they achieved virologic suppression on a stable baseline regimen of ART at baseline. Among treatment-naive patients, the rate of discontinuation ranged between 13% and 19% at week 48, and between 18% and 29% at week 96 across trials. The primary causes for study discontinuation were AEs, lack of efficacy, lost to follow-up, and patient withdrawal. Two reasons were provided by the manufacturer to explain the increased dropout rates and the subsequent decreased virologic success rate, in particular from week 48 to week 96. First, the pill burden in the trials was high (e.g., four pills/day in DRIVE-FORWARD). Second, patients who met the stringent PDVF criteria had to discontinue the study. Under this rule, patients who experienced a viral rebound (i.e., confirmed HIV-1 RNA ≥ 50 copies/mL after having been suppressed to < 50 copies/mL) during the study were required to discontinue. Other recent clinical trials used a higher threshold for PDVF: 200 to 400 copies/mL HIV-1 RNA. Additionally, the majority of the patients who met the PDVF criteria had < 200 copies/mL HIV RNA between the viral failure visit and the viral failure confirmation visit. It is possible that several patients could have been re-suppressed to < 50 copies/mL had they been allowed to continue in the trial. Results using the OF approach, which excluded patients who discontinued for non-efficacy–related reasons and therefore can be considered more reflective of viral efficacy, confirmed the findings and showed a higher response rate in both arms within the trials.

Despite the relatively lower virologic success rates among treatment-naive patients overall, patients receiving DOR in both trials had a numerically greater success rate at both time points. Likewise, a smaller proportion of patients receiving DOR had no virologic data available. These differences can partially be attributed to the lower discontinuation rate among the DOR recipients, resulting from lost to follow-up, non-compliance with study drug, and withdrawal by patient, as described above.

Notably, the proportions of patients with HIV-1 RNA ≥ 50 copies/mL were higher than expected according to the clinical expert, ranging between 10% and 14% at week 48, and between 12% and 21% at week 96. Between-treatment differences were largely similar. It is unclear if all of the patients were classified appropriately according to the FDA snapshot algorithm for the included studies, as patients lacking virologic data were not included as failures (assumption of HIV-1 RNA ≥ 50 copies/mL). The impact this would have had on the results is uncertain.

Among other efficacy end points, resistance to the study medications, i.e., background NRTI or the third ARV agent, occurred infrequently. Adherence to treatment was generally high, with most patients (> 85%) reporting an adherence of 90% or more. However, overall adherence among all participants was likely much lower owing to the discontinuation rate, which occurred in part due to high pill burden. Results from the subgroup analyses indicated that the virologic success rate was lower in patients with baseline plasma HIV-1 RNA > 100,000 copies/mL. Patients consulted for this review indicated that the stigma and stress associated with HIV are important outcomes for them, yet none of the trials assessed such outcomes. One HRQoL measure, EQ-5D-5L, was assessed in DRIVE-SHIFT. However, only the self-reported VAS component was reported, and no index score was generated which includes a domain assessing anxiety.

Harms

The overall frequency of AEs among treatment-naive patients increased only slightly between week 48 and week 96 (overall incidence 78% to 91% at week 48 and 82% to 94% at week 96). Treatment-naive patients experienced more AEs (range 78% to 91%, data not presented) than treatment-switch patients (range 52% to 81%) by week 48. Patients in the ISG arm of DRIVE-SHIFT had an increased rate of AEs at week 24 compared with the baseline regimen at week 24 for the DSG arm; a pattern consistent with the notion that patients switching therapies are likely to experience more AEs versus those remaining on their baseline therapy. Common AEs across trials included diarrhea, headache, URTI, nausea, nasopharyngitis, pharyngitis, fatigue, back pain, bronchitis, cough, syphilis, upper abdominal pain, insomnia, dizziness, somnolence, abnormal dreams, and rash-related events. The frequency of SAEs was generally low among treatment-naive patients (5% to 9%), and even lower among treatment-switch patients (1% to 5%). Likewise, the frequency of WDAEs was low (1% to 8%), with a lower rate reported for treatment-switch patients. A total of 13 deaths was reported across the trials, of which one incidence in DRIVE-SHIFT was considered to be related to the study drug (primary cause of death: myocardial infarction), although no confirmatory diagnosis (diagnosis by a medical professional or autopsy) was done.

DOR showed an improvement in lipid profile compared with DRV/r and EFV (among treatment-naive patients) and ritonavir or cobicistat-boosted PI, cobicistat-boosted InSTI, or NNRTI (among switch patients) at all time points. DOR was also associated with a lower incidence of neuropsychiatric AEs. However, the benefits were largely in comparison with EFV, which is commonly associated with neuropsychiatric side effects. The effects of DOR on hepatic enzymes, cardiovascular disease, renal and bone-related toxicity, and skin disorders are less clear.

Indirect Comparisons

The manufacturer-submitted network meta-analysis (NMA)³⁵ suggests that, with respect to virologic success (HIV-1 RNA < 50 copies/mL) ▬ ▬ ▬ ▬ ▬ The NMA did not provide adequate information on the statistical analyses plan to assess the validity of the results and NMA assumptions. The missing information, coupled with the small network size, and the lack of assessing NMA assumptions, and the differences in trial design and the definition used for PDVF to determine virologic response, translate to a high degree of uncertainty in the presented efficacy and safety results. Other limitations include the limited scope of the manufacturer-submitted indirect comparison (IDC), in which only interventions that are relevant to the economic model in treatment-naive patients were analyzed, without assessing relevant comparators such as ▬ ▬ ▬ ▬ ▬

Potential Place in Therapy^b

As an NNRTI, DOR has some positive attributes compared with its predecessors in the class, including the lack of neuropsychiatric side effects (compared with EFV), lack of requirement to be taken with food and with normal gastric acidity (unlike rilpivirine) and once-daily dosing (unlike etravirine).

Its role will be limited by its late entry into the market. As a single daily-dose “third component” of an antiretroviral combination, it has been preceded to market by rilpivirine, DTG, and boosted DRV, among others. As a co-formulated STR, Delstrigo (DOR/3TC/TDF) is one of almost a dozen available single-tablet options, including Atripla (and generics), Complera, Odefsey, Stribild, Genvoya, Triumeq, Biktarvy, Symtuza and Juluca.

The most commonly prescribed antivirals for treatment-naive patients, or those switching for reasons of convenience or tolerance, are the STRs, in particular Genvoya and Triumeq. Although they come with their own idiosyncracies, most are well tolerated, convenient, and effective. Use of the DOR STR would be infrequent, as the tenofovir component of this Delstrigo STR is the TDF formulation, which is associated with renal and bone toxicities. The newer TAF, found in Biktarvy and Genvoya, is not associated with these side effects and is generally preferred by prescribing physicians.

As a single component of a regimen, DOR (Pifeltro) would be a reasonable treatment consideration if an STR is not available or an option for the individual patient. Most likely, it would be used where a tenofovir-containing regimen is not considered ideal, and where side effects of Triumeq have occurred. It would most likely be used with Kivexa (or its generic counterpart). Its use is anticipated to be infrequent.