DRV/r + RPV QD: Efficacy and Toxicity Reduction

• ClinicalTrials.gov Identifier: NCT01792570
• Recruitment Status: Completed
• Last Update Posted: April 2, 2020
• Sponsor: ASST Fatebenefratelli Sacco
• Collaborators: Elisa Colella, M.D.; Valentina Di Cristo, M.D.; Massimo Galli, M.D.
• Information provided by (Responsible Party): Stefano Rusconi, ASST Fatebenefratelli Sacco

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus	Drug: RPV + DRV/r; Drug: continue the PI/r-containing HAART.	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: September 30, 2014
• Actual Primary Completion Date: December 31, 2018
• Actual Study Completion Date: December 31, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: RPV + DRV/r; switch to RPV + DRV/r	Drug: RPV + DRV/r; Switch to dual HAART; Other Names: RVP: rilpivirine; brand name: EdurantTM.; DRV: darunavir; brand name: PrezistaTM.
Active Comparator: continue the PI/r-containing HAART.; continue the PI/r-containing HAART	Drug: continue the PI/r-containing HAART.; Continue the on-going triple drug HAART.; Other Name: the drugs will depend on the successful regimen.

Outcome Measures

Primary Outcome Measures :

1. HIV-RNA < 50 cp/mL [ Time Frame: Week 48 ]
   Responders: HIV+ subjects with HIV-RNA < 50 cp/mL at week 48 according to the intention-to-treat (ITT-TLOVR) approach.

Secondary Outcome Measures :

1. ACTG grade III and IV events. [ Time Frame: over 96 weeks. ]
   Safety will be assessed through the number of ACTG grade III and IV in the specified safety parameters.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

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 di Malattie Infettive, Ospedale San Gerardo

Monza, MB, Italy

Divisione Clinicizzata di Malattie Infettive dell'Università degli Studi, Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco"

Milano, MI, Italy, 20157

I e II Divisione Malattie Infettive, Azienda Ospedaliera-Polo Universitario "Luigi Sacco"

Milano, MI, Italy, 20157

Clinica Malattie Infettive, Policlinico Universitario

Modena, MO, 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, Italy

Sponsors and Collaborators

ASST Fatebenefratelli Sacco

Elisa Colella, M.D.

Valentina Di Cristo, M.D.

Massimo Galli, M.D.

Investigators

• Principal Investigator: Stefano Rusconi, M.D.; DIBIC "Luigi Sacco", Università degli Studi di Milano, Italy

More Information

Publications:

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.

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. doi: 10.7326/0003-4819-156-6-201203200-00391. Epub 2012 Feb 6.

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.

Burgos J, Crespo M, Falco 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.

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.

• Responsible Party: Stefano Rusconi, Associate professor in infectious diseases, ASST Fatebenefratelli Sacco
• ClinicalTrials.gov Identifier: NCT01792570
• Other Study ID Numbers: HLS03/2012
• First Posted: February 15, 2013
• Last Update Posted: April 2, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Keywords provided by Stefano Rusconi, ASST Fatebenefratelli Sacco:

HIV-1; darunavir; rilpivirine; strategic study

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome; HIV Infections; HIV Protease Inhibitors; Anti-HIV Agents; Immunologic Deficiency Syndromes; Immune System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Darunavir; Rilpivirine; Viral Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors