DRV/r + RPV QD: Efficacy and Toxicity Reduction

Sponsor

ASST Fatebenefratelli Sacco (Other)

Overall Status

Completed

CT.gov ID

NCT01792570

Collaborator

Elisa Colella, M.D. (Other), Valentina Di Cristo, M.D. (Other), Massimo Galli, M.D. (Other)

Enrollment

Locations

Arms

Actual Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

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 :

Sep 30, 2014

Actual Primary Completion Date :

Dec 31, 2018

Actual Study Completion Date :

Dec 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 Names: the drugs will depend on the successful regimen.

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 Names:

the drugs will depend on the successful regimen.

Outcome Measures

Primary Outcome Measures

HIV-RNA < 50 cp/mL [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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Clinica delle Malattie Infettive, Policlinico Universitario	Bari	BA	Italy
2	Divisione di Malattie Infettive, Ospedale S. Maria Annunziata, Antella	Firenze	FI	Italy
3	Clinica delle Malattie Infettive, Ospedale San Martino, Università degli Studi	Genova	GE	Italy
4	Divisione di Malattie Infettive, Ospedale San Gerardo	Monza	MB	Italy
5	Divisione Clinicizzata di Malattie Infettive dell'Università degli Studi, Dipartimento di Scienze Biomediche e Cliniche "Luigi Sacco"	Milano	MI	Italy	20157
6	I e II Divisione Malattie Infettive, Azienda Ospedaliera-Polo Universitario "Luigi Sacco"	Milano	MI	Italy	20157
7	Clinica Malattie Infettive, Policlinico Universitario	Modena	MO	Italy
8	U.O. Malattie Infettive, Policlinico S. Matteo	Pavia	PV	Italy
9	Clinica delle Malattie Infettive, Policlinico "Tor Vergata"	Roma	RM	Italy
10	Istituto di Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore	Roma	RM	Italy
11	U.O. Malattie Infettive, Azienda Policlinico Umberto I, Università degli Studi "La Sapienza"	Roma	RM	Italy
12	Clinica delle Malattie Infettive, Ospedale Amedeo di Savoia, Università degli Studi	Torino	TO	Italy