Low Incidence and Brief Duration of Gastrointestinal Adverse Events with Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Over 96 Weeks: Post hoc Analyses of AMBER and EMERALD

Abstract

Gastrointestinal intolerance has been associated with ritonavir-boosted protease inhibitors. This post hoc analysis evaluated gastrointestinal adverse events of interest (AEOIs; diarrhea, nausea, abdominal discomfort, flatulence [MedDRAv21]) through Wk96 among patients enrolled in the phase 3 AMBER (treatment-naïve) and EMERALD (virologically suppressed) studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. 362 and 763 patients initiated D/C/F/TAF in AMBER and EMERALD, respectively. All D/C/F/TAF-related gastrointestinal AEOIs were grade 1/2 in severity; none were serious. Across studies, incidence of D/C/F/TAF-related diarrhea and nausea were each ≤5% in Wk1 (≤1% post-Wk2); prevalence of each decreased to <5% post-Wk2. In each study, there was 1 case of D/C/F/TAF-related abdominal discomfort during Wk1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was <1% throughout. Median duration of D/C/F/TAF-related gastrointestinal AEOIs was 16.5 (AMBER) and 8.5 (EMERALD) days. In conclusion, in treatment-naïve and virologically suppressed patients, incidences and prevalences of D/C/F/TAF-related gastrointestinal AEOIs were low and tended to present early.

Keywords

darunavir/cobicistat/emtricitabine/tenofovir alafenamide gastrointestinal adverse events tolerability HIV-1

Introduction

Gastrointestinal (GI) intolerance in people with human immunodeficiency virus (HIV)–1 has been associated with ritonavir-boosted protease inhibitors (PIs).^1–3 Ritonavir was originally developed as a standalone PI at high doses but has primarily been used as a low-dose pharmacokinetic booster for other PIs since its approval to improve side effect profiles and decrease pill burden.^1,3 Despite being used at lower doses, GI-associated symptoms remained a challenge with ritonavir.^3–6

GI tolerability varies across boosted PI–based regimens, with relatively better tolerability with once-daily darunavir/ritonavir and once-daily atazanavir/ritonavir versus lopinavir/ritonavir,^2,4–6 possibly attributed to lower daily doses of ritonavir with darunavir and atazanavir. In one study of treatment-naïve patients initiating once-daily darunavir/ritonavir 800/100 mg or lopinavir/ritonavir 800/200 mg (total daily dose), patients receiving darunavir/ritonavir had a lower incidence of treatment-related grade 2–4 diarrhea (4% vs 10%) and nausea (2% vs 3%) than patients receiving lopinavir/ritonavir at Week 48.⁷ These observations suggest consideration of specific boosted PI–based regimens is important, particularly as they have evolved over time. In 2015, the requirement for ritonavir was obviated with the approval of a fixed-dose combination of once-daily darunavir/cobicistat 800/150 mg.⁸

Cobicistat is a selective, potent cytochrome P450 3A inhibitor without anti-HIV activity but with a chemical profile that allows for coformulation with other agents.⁹ Most recently, in 2018, the once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was approved.¹⁰ As this combination includes a different chemical agent than ritonavir, the resulting tolerability profile of cobicistat combined with darunavir is unique from that observed when boosting with ritonavir. Accordingly, as the most commonly used PI-based regimen today, D/C/F/TAF was studied in this post hoc analysis of the AMBER and EMERALD trials to evaluate the GI tolerability of this formulation in both treatment-naïve and treatment-experienced, virologically suppressed patients over 96 weeks.^11–14

Methods

Study Designs

In the phase 3 AMBER study (ClinicalTrials.gov Identifier: NCT02431247), treatment-naïve adults with HIV-1 infection were randomized (1:1) to initiate either D/C/F/TAF or darunavir/cobicistat 800/150 mg + emtricitabine/tenofovir disoproxil fumarate (TDF) 200/300 mg (control regimen) for 48 weeks. In the phase 3 EMERALD study (NCT02269917), treatment-experienced, virologically suppressed adults with HIV-1 infection were randomized (2:1) to switch to D/C/F/TAF or continue their boosted PI (atazanavir and ritonavir, atazanavir and cobicistat, darunavir and ritonavir, darunavir and cobicistat, or lopinavir and ritonavir) + emtricitabine/TDF regimen for 48 weeks. In both AMBER and EMERALD, all patients received D/C/F/TAF in an extension phase through Week 96. Detailed methods have been published.^11–14

Analyses

The primary objective of this post hoc analysis was to assess the incidence, prevalence, and duration of GI adverse events (AEs), as well as the percentage of patients receiving a concomitant medication for treatment of GI AEs, through 48 and 96 weeks from baseline for patients enrolled in AMBER and EMERALD. For both studies, analyses were performed in the intent-to-treat population, and D/C/F/TAF arm data were evaluated through Week 96 while control arm data were evaluated through Week 48. Diarrhea, nausea, abdominal discomfort, and flatulence were identified as GI AEs of interest (AEOIs) based on the most common GI AEs observed with previous darunavir-based regimens¹⁵ and defined using Medical Dictionary for Regulatory Activities v21 preferred terms. Related GI AEOIs were those evaluated by the investigator to be very likely, probably, or possibly related to study drug. Incidence and prevalence were assessed at weekly intervals during the first month and every month thereafter. Duration was reported for D/C/F/TAF-related GI AEOIs for patients whose AEs had start and stop dates through Week 96.

Ethical Approval and Informed Consent

AMBER and EMERALD were conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocols and amendments were approved by local or central institutional review boards or independent ethics committees, and all participants provided written informed consent prior to enrollment in the studies.

Results

Incidence, Prevalence, and Severity of Study Drug–Related GI AEOIs Over Time

In AMBER, 362 patients were randomized to initiate D/C/F/TAF and 363 patients were randomized to initiate darunavir/cobicistat + emtricitabine/TDF in the control arm. Through Week 48, 14% of patients receiving D/C/F/TAF and 19% of patients in the control arm experienced a study drug–related GI AEOI. In both the D/C/F/TAF arm (through Week 96) and the control arm (through Week 48), all study drug–related GI AEOIs were grade 1 or 2 in severity and no serious events were reported.

During Week 1 in AMBER, the incidence of D/C/F/TAF-related diarrhea and nausea was each 5% and decreased to ≤1% after Week 2 (Figure 1A). The prevalence of D/C/F/TAF-related diarrhea decreased to <5% starting at Week 2, and the prevalence of D/C/F/TAF-related nausea decreased to <3% starting at Week 2 and to <1% by Week 5. Only 1 case of D/C/F/TAF-related abdominal discomfort was reported and it was during Week 1. The incidence of D/C/F/TAF-related flatulence was <1% from Week 1 through Week 96. The incidence and prevalence of each study drug–related GI AEOI in the control arm through Week 48 were comparable to those in the D/C/F/TAF arm.

Figure 1.

Incidence of D/C/F/TAF-related diarrhea and nausea over time.

In EMERALD, 763 patients were randomized to switch to D/C/F/TAF and 378 patients were randomized to continue their boosted PI + emtricitabine/TDF regimen in the control arm. Through Week 48, 3% of patients receiving D/C/F/TAF and 1% of patients in the control arm experienced a study drug–related GI AEOI. In both the D/C/F/TAF arm (through Week 96) and the control arm (through Week 48), all study drug–related GI AEOIs were grade 1 or 2 in severity and no serious events were reported.

During Week 1 in EMERALD, the incidence of D/C/F/TAF-related diarrhea and nausea was 2% and <1%, respectively, and decreased to ≤0.1% after Week 2 (Figure 1B). Starting at Week 2, the prevalence of D/C/F/TAF-related diarrhea and nausea was each <1%. There was 1 case of D/C/F/TAF-related abdominal discomfort reported during Week 1 and none thereafter. The incidence of D/C/F/TAF-related flatulence was 0.4% at Week 1 and remained <0.1% from Week 2 through Week 96. No new cases of flatulence were reported after Week 3. The incidence and prevalence of each study drug–related GI AEOI in the control arm through Week 48 were comparable to those in the D/C/F/TAF arm.

Treatment and Discontinuation due to D/C/F/TAF-Related GI AEOIs

In AMBER through Week 96, 10 (3%) patients required treatment with a concomitant medication for a D/C/F/TAF-related GI AEOI; 2 patients discontinued before Week 96 due to D/C/F/TAF-related diarrhea (1 patient with grade 2 and 1 patient with grade 1). In EMERALD through Week 96, 6 (1%) patients required treatment with a concomitant medication for a D/C/F/TAF-related GI AEOI; 1 patient discontinued due to D/C/F/TAF-related diarrhea, and 1 patient discontinued due to D/C/F/TAF-related abdominal pain. Across both studies, the most common concomitant medications required were antipropulsives.

Duration of D/C/F/TAF-Related GI AEOIs

Through Week 96, there were 62 events in AMBER for which duration could be calculated (out of 76 events in total) and 28 events in EMERALD for which the duration could be calculated (out of 32 events in total); the median duration of a D/C/F/TAF-related GI AEOI was 16.5 (Figure 2A and B) and 8.5 (Figure 2C and D) days, respectively. In both studies, the results were skewed towards shorter durations.

Figure 2.

Distribution of duration of D/C/F/TAF-related GI AEOIs.

Discussion

In this post hoc analysis of the AMBER and EMERALD studies of the most recent darunavir formulation, a favorable GI tolerability profile was observed for D/C/F/TAF. GI tolerability can be a factor when considering an appropriate antiretroviral therapy (ART) regimen across patient populations. Additionally, when selecting an ART regimen, the US Department of Health and Human Services recommends a regimen with a high genetic barrier to resistance, such as a darunavir-based regimen, when suboptimal adherence is suspected or resistance testing is pending or unavailable.¹ Thus, for treatment-naïve patients concerned about potential GI side effects when initiating therapy, D/C/F/TAF may be an appropriate option, as shown in the current report.

Treatment-experienced, virologically suppressed patients may consider switching regimens due to poor tolerability on their current regimen. Tolerability concerns regarding weight gain and neuropsychiatric AEs, mainly with integrase inhibitors, have recently been recognized.^1,16–20 Given the favorable GI tolerability profile of D/C/F/TAF and the low risk of weight gain and neuropsychiatric AEs^14,21–23 with its use, D/C/F/TAF may serve as an important option for patients experiencing these AEs and considering switching to a new regimen. Moreover, for both treatment-experienced, virologically suppressed and treatment-naïve patients, the GI tolerability of D/C/F/TAF is generally consistent with that of commonly used integrase inhibitor–based regimens.^18,24–28 For example, Stellbrink et al reported GI AEs in 9% and 14% of treatment-naïve patients receiving bictegravir or dolutegravir regimens, respectively.¹⁸

Overall, findings from the current analysis suggest prompt resolution of D/C/F/TAF-related GI AEOIs among the few treatment-naïve and virologically suppressed patients who experienced such an event. The perception of GI intolerance as a barrier to this regimen, largely based on older formulations and dosing schema, may not be in proportion to the reality of actual patient experience.

Footnotes

Acknowledgments

Medical writing support was provided by Melanie Chen, PharmD, and Caryn Gordon, PharmD, of Cello Health Communications/MedErgy, and was funded by Janssen Scientific Affairs, LLC.

Data Availability

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at .

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J. Campbell, S. Seyedkazemi, and D. Anderson are employees of Janssen Scientific Affairs, LLC. K. Dunn and N. Bejou are former employees of Janssen Scientific Affairs, LLC. B. Baugh and D. Luo are employees of Janssen Research & Development, LLC. All authors may be stockholders of Johnson & Johnson.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Janssen Scientific Affairs, LLC.

ORCID iD

David Anderson

References

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services; 2019. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Accessed June 29, 2021.

Kim

Chang

, et al. Comparison of antiretroviral regimens: adverse effects and tolerability failure that cause regimen switching. Infect Chemother. 2015;47(4):231–238.

Hill

Balkin

. Risk factors for gastrointestinal adverse events in HIV treated and untreated patients. AIDS Rev. 2009;11(1):30–38.

Orkin

DeJesus

Khanlou

, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2013;14(1):49–59.

Molina

Andrade-Villanueva

Echevarria

, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53(3):323–332.

Malan

Mancini

, et al. Gastrointestinal tolerability and quality of life in antiretroviral-naive HIV-1-infected patients: data from the CASTLE study. AIDS Care. 2010;22(6):677–686.

Ortiz

DeJesus

Khanlou

, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008;22(12):1389–1397.

Janssen Therapeutics. PREZCOBIX^® (Darunavir and Cobicistat) (Package Insert). Janssen Therapeutics; June 2018.

Liu

Murray

, et al. Cobicistat (GS-9350): a potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer. ACS Med Chem Lett. 2010;1(5):209–213.

10.

Janssen Therapeutics. SYMTUZA™ (Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide) (Package Insert). Janssen Therapeutics; July 2018.

11.

Eron

Orkin

Gallant

, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):1431–1442.

12.

Orkin

Molina

J-M

Negredo

, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23–e34.

13.

Orkin

Eron

Rockstroh

, et al. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020;34(5):707–718.

14.

Eron

Orkin

Cunningham

, et al. Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1. Antiviral Res. 2019;170:104543.

15.

Janssen Therapeutics. PREZISTA^® (Darunavir) (Package Insert). Janssen Therapeutics; May 2019.

16.

Penafiel

de Lazzari

Padilla

, et al. Tolerability of integrase inhibitors in a real-life setting. J Antimicrob Chemother. 2017;72(6):1752–1759.

17.

Walmsley

Antela

Clumeck

, et al. Dolutegravir plus Abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–1818.

18.

Stellbrink

Arribas

Stephens

, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e364–e372.

19.

Hill

Venter

Delaporte

, et al. Progressive rises in weight and clinical obesity for TAF/FTC + DTG and TDF/FTC + DTG versus TDF/FTC/EFV: ADVANCE and NAMSAL trials. Presented at: 10th International Antiviral Society (IAS) Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico. Abstract 47722019.

20.

NAMSAL ANRS 12313 Study Group, Kouanfack

Mpoudi-Etame

, Omgba Bassega P, et al. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1. N Engl J Med. 2019;381(9):816–826.

21.

Huhn

Crofoot

Ramgopal

, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a rapid initiation model of care for HIV-1 infection: primary analysis of the DIAMOND study. Clin Infect Dis. 2020;71(12):3110–3117.

22.

Dunn

Simonson

Luo

, et al. Use of D/C/F/TAF with neurologic/psychiatric comorbidities: AMBER subgroup analysis. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8–11, 2020; Boston, MA, USA.

23.

Bushen

Luo

Simonson

, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-naïve (AMBER) and virologically suppressed (EMERALD) patients with neurologic and/or psychiatric comorbidities: week 96 subgroup analysis. Poster presented at: 23rd International AIDS Conference (AIDS 2020); July 6–10, 2020; Virtual.

24.

Gallant

Lazzarin

Mills

, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, Abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–2072.

25.

Wohl

Yazdanpanah

Baumgarten

, et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, Abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e355–e363.

26.

Cahn

Madero

Arribas

, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143–155.

27.

van Wyk

Ajana

Bisshop

, et al. Efficacy and safety of switching to dolutegravir/lamivudine fixed-dose 2-drug regimen vs continuing a tenofovir alafenamide-based 3- or 4-drug regimen for maintenance of virologic suppression in adults living with human immunodeficiency virus type 1: phase 3, randomized, noninferiority TANGO study. Clin Infect Dis. 2020;71(8):1920–1929.

28.

Molina

Ward

Brar

, et al. Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus Abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e357–e365.