Simplification from Twice-Daily to Once-Daily Darunavir/Ritonavir in a Randomized Trial among HIV-Infected Persons with HIV-1 RNA Suppression on Antiretroviral Therapy

Abstract

Background

DRIVESHAFT is a randomized, open-label, 48-week clinical trial that examined virological outcomes and safety of antiretroviral simplification among virologically suppressed, treatment-experienced HIV-infected patients switching from darunavir/ritonavir (DRV/r) twice-daily-based regimens to a once-daily DRV/r component.

Methods

HIV-infected adults with a stable antiretroviral regimen including DRV/r 600/100 mg twice daily plus a minimum of two other antiretrovirals, <2 historical DRV-associated mutations and HIV RNA<40 copies/ml for at least 12 weeks prior to entry were eligible. Participants were randomized 1:1 to switch DRV/r to 800/100 mg once daily or maintain their current regimen. The primary end point was HIV-1 RNA<40 copies/ml at week 48 using the Snapshot algorithm.

Results

Demographics and baseline characteristics were similar between arms. Virological suppression was greater in the DRV/r once-daily (n=30) versus twice-daily (n=30) arm at week 48 (90.0% versus 83.3%; 95% CI: -11.5, 24.8). Three subjects discontinued the once-daily arm, with four discontinuations and one virological failure in the twice-daily arm. No discontinuations were related to adverse events. Reduction in LDL was significantly greater in the once-daily arm at week 24 (-8.0 mg/dl versus 3.3 mg/dl; P=0.04). There was a trend towards suboptimal adherence <90% to antiretrovirals among subjects taking twice-daily versus once-daily DRV/r by week 48 (12.0% versus 0.0%; P=0.06).

Conclusions

Switching from twice-daily to once-daily DRV/r in virologically suppressed patients maintains viro-logical control, with greater reduction in LDL cholesterol by 24 weeks. This study provides pilot data that could be used to design a non-inferiority study to definitively answer the question of whether switching from twice-daily to once-daily DRV/r maintains viral suppression. ClinicalTrials.gov number: NCT01423812.

References

US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. (Updated 1 May 2014. Accessed 28 September 2014.) Available from http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0/.

Thompson

M.A.

, Mugavero

M.J.

, Amico

K.R.

Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: evidence-based recommendations from an International Association of Physicians in AIDS Care panel.

Ann Intern Med 2012; 156: 817–833.

European AIDS Clinical Society. EACS guidelines version 7.02 (Updated June 2014. Accessed 28 September 2014.) Available from http://eacsociety.org/Portals/0/140601_EACS%20EN7.02.pdf.

Hull

, Cescon

, Raboud

Switching from first antiretroviral therapy regimen while virologically suppressed is associated with increased risk of subsequent virologic failure. 20th International AIDS Conference. 20–25 July 2014, Melbourne, Australia. Abstract TUAB0103.

Ortiz

, Dejesus

, Khanlor

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48.

AIDS 2008; 22: 1389–1397.

Cahn

, Fourie

, Grinsztejn

Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients.

AIDS 2011; 25: 929–939.

US Department of Health and Human Services. Guidance for industry. Antiretroviral drugs using plasma HIV RNA measurements – clinical considerations for accelerated and traditional approval. (Updated October 2002. Accessed 28 September 2014.) Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070968.pdf.

Walsh

J.C.

, Mandalia

, Gazzard

B.G.

Responses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome.

AIDS 2002; 16: 269–277.

Paterson

D.L.

, Swindells

, Mohr

Adherence to protease inhibitor therapy and outcomes in patients with HIV infection.

Ann Intern Med 2000; 133: 21–30.

10.

Moltó

, Valle

, Santos

J.R.

Treatment simplification to once daily darunavir/ritonavir guided by the darunavir inhibitory quotient in heavily pretreated HIV-infected patients.

Antivir Ther 2010; 15: 219–225.

11.

Ghosn

, Slama

, Chermak

Switching to darunavir/ ritonavir 800/100 mg once-daily containing regimen maintains virological control in fully suppressed pre-treated patients infected with HIV-1.

J Med Virol 2013; 85: 8–15.

12.

Möbius

, Lubach-Ruitman

, Castro-Frenzel

Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia.

J Acquir Immune Defic Syndr 2005; 39: 174–180.

13.

Gatell

, Salmon-Ceron

, Lazzarin

Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN study (AI424-097) 48-week result.

Clin Infect Dis 2007; 44: 1484–1492.

14.

Soriano

, García-Gasco

, Vispo

Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viremia: final results of the SLOAT trial.

J Antimicrob Chemother 2008; 61: 200–205.

15.

Mallolas

, Podzamczer

, Milinkovic

Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virologic suppression receiving a LPV/r-containing HAART: the ATAZIP study.

J Acquir Immune Defic Syndr 2009; 51: 29–36.

16.

Data Collection on Adverse Events of Anti-HIV Drugs Study Group.

Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction.

Clin Infect Dis 2008; 46: 1101–1110.

17.

Dubé

M.P.

, Stein

J.H.

, Aberg

J.A.

Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group.

Clin Infect Dis 2003; 37: 613–627.

18.

Lundgren

J.D.

, Battegay

, Behrens

European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV.

HIV Med 2008; 9: 72–81.

19.

Mills

, Ortiz

, Crofoot

Jr. 48 Week study of the first PI-based single tablet-regimen (STR) darunavir/ cobicistat/emtricitabine/tenofovir alafenamide versus cobicistat-boosted darunavir and emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. 5–9 September 2014, Washington, DC, USA. Abstract H-647c.

20.

Curran

, Gutirerrez

, Deig

Efficacy, safety and pharmacokinetics of 900/100 mg of darunavir/ritonavir once daily in treatment-experienced patients.

J Antimicrob Chemother 2010; 65: 2195–2203.