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Patient-Reported Symptoms Over 48 Weeks Among Participants in Randomized, Double-Blind, Phase III Non-inferiority Trials of Adults with HIV on Co-formulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide versus Co-formulated Abacavir, Dolutegravir, and Lamivudine
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The Patient - Patient-Centered Outcomes Research June 29 2018 - David Wohl1 ⋅ Amanda Clarke2 ⋅ Franco Maggiolo3 ⋅ Will Garner4 ⋅ Marianne Laouri4 ⋅ Hal Martin4 ⋅ Erin Quirk4

Integrase strand transfer inhibitors (INSTIs) are recommended for first-line antiretroviral therapy in combination with two nucleos(t)ide reverse transcriptase inhibitors. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF), a novel, INSTI-based regimen, is currently approved in the US and EU for the treatment of HIV-1 infection and recommended as first-line treatment in current guidelines. In our current analysis, we aimed to determine changes in patient-reported symptoms over time among HIV-1-infected adults who initiated or switched to B/F/TAF versus another INSTI-based regimen, co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC).
A planned secondary analysis of patient-reported outcomes was conducted for two double-blind, randomized, phase III studies in HIV-1-infected adults comparing B/F/TAF with ABC/DTG/3TC: one in treatment-naïve individuals (GS-US-380-1489, ClinicalTrials.gov NCT02607930) and the other in virologically suppressed participants (GS-US-380-1844, ClinicalTrials.gov NCT02603120). In both studies, the HIV symptoms distress module (HIV-SI) was administered at baseline (BL) and weeks 4, 12, and 48. Responses to each of the 20 items were dichotomized as bothersome or not bothersome. Treatment differences were assessed using unadjusted and adjusted logistic regression models (adjusted for BL HIV-SI count, age, sex, BL Veterans Aging Cohort Study [VACS] Index, medical history of serious mental illness, BL Short Form [SF]-36 Physical Component Summary [PCS], BL SF-36 Mental Component Summary [MCS], and, for virologically suppressed participants only, years since HIV diagnosis). We conducted longitudinal modeling of bothersome symptoms using a generalized mixed model including treatment, time, time-by-treatment, and additional covariates from the adjusted logistic regression model as described above. The Pittsburgh Sleep Quality Index (PSQI) was administered at the same frequency as the HIV-SI, and the total score was dichotomized as good or poor sleep quality. Similar models to those used for HIV-SI were applied, using BL sleep quality and BL SF-36 MCS as covariates. Statistical significance was assessed using p < 0.05.
Across both studies, bothersome symptoms were reported by fewer participants on B/F/TAF than those on ABC/DTG/3TC. In treatment-naïve adults, fatigue/loss of energy, nausea/vomiting, dizzy/lightheadedness, and difficulty sleeping were reported significantly less with B/F/TAF at two or more time points. Fatigue and nausea were also significantly less common for those receiving B/F/TAF in longitudinal models. In virologically suppressed participants, nausea/vomiting, sad/down/depressed, nervous/anxious, and poor sleep quality (from the PSQI) were reported significantly less with B/F/TAF at two or more time points, as well as in longitudinal models.
B/F/TAF was associated with lower prevalence of bothersome symptoms than ABC/DTG/3TC in both treatment-naïve and virologically suppressed adults.
Key points for decision makers
As the efficacy of triple-therapy antiretroviral regimens remains consistently high, patient well-being (e.g., patient-reported outcomes [PROs]) has become an important differentiator between regimens.
We evaluated PROs in two studies comparing co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) with co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC), where treatment differences were noted if prevalence was statistically significantly different at two or more time points in the adjusted logistic regression model or at one time point in the adjusted logistic regression model and in the longitudinal model.
Among treatment-naïve participants, initiating B/F/TAF was associated with lower prevalence of fatigue/loss of energy, dizzy/lightheadedness, nausea/vomiting, difficulty sleeping, and loss of appetite compared with ABC/DTG/3TC.
For virologically suppressed participants, switching to B/F/TAF was associated with lower prevalence of dizzy/lightheadedness, nausea/vomiting, sad/down/depressed, nervous/anxious, difficulty sleeping, and loss of appetite compared with remaining on ABC/DTG/3TC. In both patient populations, no symptom had a greater prevalence with B/F/TAF compared with ABC/DTG/3TC.
Over the past decade, antiretroviral treatments for HIV infection have demonstrated high potency, yielding viral suppression rates above 90%. Integrase strand inhibitors (INSTIs; e.g., bictegravir, dolutegravir, elvitegravir, and raltegravir) in combination with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are currently recommended as initial treatment for HIV in many international guidelines [1, 2, 3]. As the success of antiretroviral therapy largely depends on patient adherence, fixed-dose combinations (FDCs) have emerged as preferred treatment regimens and are associated with less treatment failure [4]. The impact of FDCs on an individual's overall health, including sense of wellbeing, has also become an important consideration for clinicians when prescribing HIV treatment.
Bictegravir (BIC, B) and dolutegravir (DTG) are INSTIs that do not require the co-administration of a pharmaco-enhancer (i.e., cobicistat or ritonavir) [5]. Both have been co-formulated with NRTIs as FDCs: BIC with emtricitabine (FTC, F) and tenofovir alafenamide (TAF) as B/F/TAF and DTG with abacavir (ABC) and lamivudine (3TC) as ABC/DTG/3TC. ABC/DTG/3TC is currently recommended as first-line antiretroviral therapy (ART) [1, 2, 3] and represents a logical, standard-of-care comparator for new INSTI-based FDCs. ABC requires HLA B*5701 testing prior to use, and the ABC/DTG/3TC co-formulation does not provide adequate treatment for hepatitis B in individuals co-infected with HIV [1, 3]. The US AIDS Clinical Trials Group (ACTG) 5202 study found a significantly shorter time to treatment modification and a greater incidence of nausea with the ABC/3TC NRTI backbone than with FTC/tenofovir disoproxil fumarate [6]. Furthermore, some reports have emerged showing associations between DTG and neuropsychiatric adverse events, while others have not [7, 8, 9, 10, 11, 12, 13].
BIC has a high barrier to resistance and a low potential for drug-drug interactions [14]. In four studies reported to date (two in treatment-naïve adults and two in virologically suppressed participants), the B/F/TAF FDC has shown similar high efficacy and tolerability to standard-of-care comparators, with no treatment-emergent resistance [15, 16, 17, 18]. The primary outcome of all studies demonstrated non-inferiority of B/F/TAF to either ABC/DTG/3TC, DTG + F/TAF, or boosted protease-inhibitor (PI) regimens. Switching to B/F/TAF from ABC/DTG/3TC specifically has the potential to maintain high rates of suppression while avoiding limitations of ABC, such as potential cardiovascular risk [19, 20, 21], as well as central nervous system adverse effects and discontinuations that have been reported more frequently with DTG in clinical practice and cohort studies than in published results of clinical trials [9, 22, 23]. B/F/TAF also provides two NtRTIs with hepatitis B activity and the tablet is less than half the size of co-formulated ABC/DTG/3TC, which may improve acceptability amongst individuals and ability to use in pediatric populations [24, 25, 26, data on file]. B/F/TAF has been approved in the US and EU for treatment of HIV-1 infection in adults and adolescents and is now also recommended as first-line ART in current treatment guidelines [3].
Health-related quality-of-life (HRQL) outcomes have long been regarded as important in the evaluation and differentiation of treatment strategies [27]. To better understand the two FDCs of B/F/TAF and ABC/DTG/3TC, patient-reported outcomes (PROs), including one specifically designed for HIV-1-infected participants, were measured in both treatment-naïve and HIV-1-suppressed adults using previously validated questionnaires in comparative trials of these regimens. For treatment-naïve individuals, characterization of PROs provided the opportunity to assess the two regimens directly after initiating treatment. Comparison of the treatments in virologically suppressed individuals who were presumably tolerating their baseline regimen of ABC/DTG/3TC provided further delineation of how changes to medication may alter quality-of-life outcomes. We aimed to achieve a better understanding of the relationship between these treatments and bothersome HIV symptoms and/or adverse events that impact adherence and persistence.

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