DRV/r + RPV QD: Efficacy and Toxicity Reduction

Human Immunodeficiency Virus Clinical Trial

Official title:

Strategic Study of Dual-therapy With Darunavir/Ritonavir and Rilpivirine QD Versus Triple-therapy in Patients With Suppressed Viral Load: Virological Efficacy and Evaluation of Non-HIV Related Morbidity.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01792570
• Other study ID #: HLS03/2012
• Status: Completed
• Phase: Phase 3
• Start date: September 30, 2014
• Est. completion date: December 31, 2018

Study information

• Verified date: March 2020
• Source: ASST Fatebenefratelli Sacco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Clinical approach to HIV infection treatment is based on the use of highly active antiretroviral therapies (HAART) and recent national and international guidelines for guiding HIV therapy recommend the use of triple-combination therapy using antiretrovirals with 2 nucleos(t)ide inhibitors [N(n)RTI] as backbone plus a third drug to be chosen among a boosted protease inhibitor (PI/r), a nonnucleoside inhibitor (NNRTI) or an integrase inhibitor (II).

In spite of evident efficacy of HAART, as demonstrated by survival increasing, long term side effects, as for example the impact on renal function, remain principal problem.

In patient with risk factor for renal disease, a reduction of eGRF (estimated Glomerular Filtration Rate) between 90 and 60 mL/min/1,73 m2 could be already considered as a risk condition [1,2].

Efficacy of HAART, with increase of media survival and the parallel decrease of mortality, has underlined the necessity to reflect on long term HAART effects [3].

There are many evidences of HAART-related toxicity that, in spite of the necessity of a life-saving therapy, focus on the additional costs of this situation, in terms of health as well as in terms of economic costs.

Particular attention has been focused on the impact of some drugs on renal function, as tenofovir, especially on tubule, without forgetting the modification of lipid and bone metabolisms.

According to further studies which have evidenced the potential of some recently introduced molecules [4,5], the investigators had the need to realize a study to deepen the feasibility of a dual-therapy that permit to exclude NRTIs from the backbone, with the aim to prevent NRTIs-related long-term toxicity.

The investigators have designed a prospective randomized controlled trial, open-label, with a duration of 96 weeks, to compare the efficacy of a dual-therapy based on rilpivirine 25mg plus darunavir 800mg/ritonavir 100mg QD, in HIV-positive subjects with suppressed viremia from at least 3 months. In fact, there are a few data about association of these drugs, which it has been shown to be safe, well tolerated, and with a strong pharmacological synergy, without nucleos(t)idic backbone, while the necessity to minimize the costs toxicity-related is becoming increasingly compelling.

According to clinical experience and literature data, the investigators hope this study shows positive results in term of immune-virological efficacy, as well as in term of decrease of VACS index - a complex parameter which has the purpose to quantify general organic decay - and markers of lipid and bone metabolism, in group which receives dual-therapy versus the group with standard therapy.

Description:

Pilot, phase III prospective, randomized, open-label, multicentric controlled study, which will offer a novel dual-therapy regimen including RPV 25mg + DRV 800mg/rtv 100mg QD to HIV+ subjects with suppressed viremia.

132 HIV+ subjects will be randomized, 1:1, to switch to RPV+DRV/r versus continue triple-drug therapy. Subjects will be switched from any PI/r-containing regimen.

The duration of the study is 96 weeks and patients will be stratified according to their HCV serostatus (Ab positive or negative), age (> or < 50 years), and immunological status (CD4<200/µL; CD4=200-500/µL; CD4>500/µL). It is planned to enroll at least 30% of female subjects.

Follow-up visits will be performed at 4, 8, 12, 24, 36, 48, 60, 72, and 96 weeks (laboratory and physical examination).

Effectiveness will be measured by determination of HIV-RNA, safety will be evaluated by determination of AST, ALT, creatinine, plasmatic and urinary phosphate, albuminuria, total cholesterol, HDL and LDL cholesterol, triglycerides at the follow-up visits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: December 31, 2018
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult HIV+ subjects (>18 years old), giving and signing an informed consent;

• Any HAART treatment for at least 12 months;

• Current treatment with a PI/r-containing regimen initiated at least 6 months earlier;

• HIV-RNA <50 cp/mL for at least 3 months, without viral blip due to virologic failure at any time;

• Any nadir CD4 lymphocytes;

• Current CD4 count > 100 cell/uL;

• eGFRs >60 mL/min/1.73 m2.

Exclusion Criteria:

• Previous drug resistance genotypic test showing the presence of any RPV (RT: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, Y188L, H221Y, F227C, M230I/L) or DRV (protease: V11I, V32I, L33F, I47V, I50V, I54M/L, T74P, L76V, I84V, L89V) resistance associated mutation (RAM), according to the November 2011 IAS-USA list;

• Child-Pugh C or grade 3-4 AST or ALT values;

• Acute cardiovascular event within 6 months;

• AIDS event within 6 months;

• Current IVDU;

• HBsAg +;

• Pregnancy or lactation.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus

Intervention

Drug:
• RPV + DRV/r
Switch to dual HAART
• continue the PI/r-containing HAART.
Continue the on-going triple drug HAART.

Locations

Country	Name	City	State
Italy	Clinica delle Malattie Infettive, Policlinico Universitario	Bari	BA
Italy	Divisione di Malattie Infettive, Ospedale S. Maria Annunziata, Antella	Firenze	FI
Italy	Clinica delle Malattie Infettive, Ospedale San Martino, Università degli Studi	Genova	GE
Italy	Divisione Clinicizzata di Malattie Infettive dell'Università degli Studi, Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco"	Milano	MI
Italy	I e II Divisione Malattie Infettive, Azienda Ospedaliera-Polo Universitario "Luigi Sacco"	Milano	MI
Italy	Clinica Malattie Infettive, Policlinico Universitario	Modena	MO
Italy	Divisione di Malattie Infettive, Ospedale San Gerardo	Monza	MB
Italy	U.O. Malattie Infettive, Policlinico S. Matteo	Pavia	PV
Italy	Clinica delle Malattie Infettive, Policlinico "Tor Vergata"	Roma	RM
Italy	Istituto di Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore	Roma	RM
Italy	U.O. Malattie Infettive, Azienda Policlinico Umberto I, Università degli Studi "La Sapienza"	Roma	RM
Italy	Clinica delle Malattie Infettive, Ospedale Amedeo di Savoia, Università degli Studi	Torino	TO

Sponsors (4)

Lead Sponsor	Collaborator
ASST Fatebenefratelli Sacco	Elisa Colella, M.D., Massimo Galli, M.D., Valentina Di Cristo, M.D.

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Broder S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 2010 Jan;85(1):1-18. doi: 10.1016/j.antiviral.2009.10.002. Epub 2009 Dec 16. Review. — View Citation

Burgos J, Crespo M, Falcó V, Curran A, Imaz A, Domingo P, Podzamczer D, Mateo MG, Van den Eynde E, Villar S, Ribera E. Dual therapy based on a ritonavir-boosted protease inhibitor as a novel salvage strategy for HIV-1-infected patients on a failing antiretroviral regimen. J Antimicrob Chemother. 2012 Jun;67(6):1453-8. doi: 10.1093/jac/dks057. Epub 2012 Feb 29. — View Citation

Clumeck N, Cahn P, Molina JM, Mills A, Nijs S, Vingerhoets J, Witek J. Virological response with fully active etravirine: pooled results from the DUET-1 and DUET-2 trials. Int J STD AIDS. 2010 Nov;21(11):738-40. doi: 10.1258/ijsa.2010.010139. — View Citation

Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med. 2012 Jun 5;156(11):785-95, W-270, W-271, W-272, W-273, W-274, W-275, W-276, W-277, W-278. doi: 10.7326/0003-4819-156-6-201203200-00391. Epub 2012 Feb 6. Review. — View Citation

Maggi P, Bartolozzi D, Bonfanti P, Calza L, Cherubini C, Di Biagio A, Marcotullio S, Montella F, Montinaro V, Mussini C, Narciso P, Rusconi S, Vescini F. Renal complications in HIV disease: between present and future. AIDS Rev. 2012 Jan-Mar;14(1):37-53. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HIV-RNA < 50 cp/mL	Responders: HIV+ subjects with HIV-RNA < 50 cp/mL at week 48 according to the intention-to-treat (ITT-TLOVR) approach.	Week 48
Secondary	ACTG grade III and IV events.	Safety will be assessed through the number of ACTG grade III and IV in the specified safety parameters.	over 96 weeks.