Evaluation of Third-line cART Regimen in Cambodia (3DICAM)

Dolutegravir, Darunavir/Ritonavir and Optimized NRTI Recycling as a Third-line Antiretroviral Regimen in Cambodia

The study aims to evaluate the virological effectiveness of a third-line regimen combining dolutegravir (DTG), ritonavir-boosted darunavir (DRV/r) and optimized NRTI in Cambodian HIV-infected adults, who failed a protease inhibitors (PI)-based second-line regimen despite 3 months of boosted adherence counseling (BAC).

Study Overview

• Status: Recruiting
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: Dolutegravir + Darunavir/ritonavir + optimized NRTI

Detailed Description

Each patient will be informed of the objectives and the total duration of the study as well as the benefits and risks to participate. After signature of consent form, Genotyping Resistance Test (GRT) and pre-inclusion samples will be done for all patients with HIV RNA > 1000 copies/mL after 3 months of boosted adherence counselling (BAC). After receiving results of the GRT and the pre-inclusion sample, the technical working group (TWG) of HIV national program will decide to switch the patient to third-line regimen or to continue second-line regimen with new BAC.

PI-based second-line regimen will be continue if 1/ GRT shows sensitivity to ATV 2/ GRT shows sensitivity to at least one of the 3 NRTI recommended in Cambodia (AZT, ABC and TDF). In that case, adherence counselling will be boosted according to the new national guidance and the patient will not be enrolled in the study.

In case of intermediate or fully resistance to ATV/r OR sensitivity to ATV but both resistances to AZT, ABC and TDF and after confirmation of eligibility criteria, patient could be enrolled in the study. A third-line regimen will be started including DRV/r 600/100 twice daily + DTG 50 mg once daily + 3TC 300 mg once daily +/- one fully or intermediate sensitive NRTI among TDF, ABC and AZT. The choice of the last NRTI will be discussed and decided by the TWG according to the HBsAg status, to the result of the GRT and to the medical history of the patient.

At 6 months, plasma HIV-1 RNA will be measured:

• HIV1-RNA < 40 copies/mL and no resistance to DRV at inclusion: a switch to DRV/r 800/100mg once daily will be done and adherence counseling provided to confirm the new dosing with the patient
• HIV1-RNA > 40 copies/mL and/or intermediate or fully resistance to DRV at inclusion: the same regimen will be continued and adherence counseling provided

For all patients, a new virological assessment will be done at 9 and 12 months.

DRV and DTG exposure and pharmacokinetic parameters (Cmax, Cmin and AUC) will be estimated for the 20 first enrolled patients, allowing an intra-patient comparison of the 2 dosing regimens of DRV/r for at least 15 patients.

• Study Type: Interventional
• Enrollment (Anticipated): 54
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Phearavin Pheng; Phone Number: +85512578726; Email: phearavinpheng@uhs.edu.kh
• Study Contact Backup: Name: Olivier Segeral; Phone Number: +85512479313; Email: oliseg@hotmail.com

Study Locations

• Cambodia
  • Phnom Penh, Cambodia
    • Recruiting
    • NCHADS
    • Contact: Sun Ly Penh, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Documented HIV-1 infection
• Failing a NNRTI-based first-line regimen
• Failing a PI-based second-line regimen after 3 months of adherence boosting (HIV RNA > 1000 copies/mL)
• HIV strain intermediate or fully resistant to ATV/r OR sensitive to ATV but both resistant to AZT, ABC and TDF
• For women of childbearing age: acceptance to use effective contraceptive methods
• Informed consent obtained with information sheet given and explained before the inclusion visit and the consent form signed by the participant and the parents or legal guardians for adolescents at the latest the day of the inclusion

Exclusion Criteria:

• History of antiretroviral treatment including darunavir and integrase inhibitor
• Active pregnancy < 12 weeks of amenorrhea and desire of pregnancy during the duration of the study
• Opportunistic infection in acute phase at inclusion including tuberculosis treated since less than one month and/or with no stable clinical condition
• Advanced cirrhosis (Child-Pugh score B or C)
• Creatinine clearance < 50 ml/mn
• Any concomitant medical condition that, according to the clinical site investigator would contraindicate participation in the study
• Concurrent participation in any other clinical study without written agreement of the two study teams

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dolutegravir + Darunavir/ritonavir + optimized NRTI; All patients will receive ART regimen every day including: Dolutegravir 50mg once daily Darunavir/ritonavir 600/100 twice daily Optimized NRTI recycling with lamivudine and one other NRTI (zidovudine or tenofovir or abacavir)	Drug: Dolutegravir + Darunavir/ritonavir + optimized NRTI; Dolutegravir 50mg once daily Darunavir/ritonavir 600/100 twice daily Optimized NRTI recycling with lamivudine and one other NRTI (zidovudine or tenofovir or abacavir)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological effectiveness at 6 months	Proportion of patients with plasma HIV-1 RNA < 40 copies/mL by FDA Snapshot analysis	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological effectiveness at 12 months	Proportion of patients with plasma HIV-1 RNA < 40 copies/mL by FDA Snapshot analysis at 12 months	Month 12
Incidence of adverse events (safety)	Incidence of grade 3-4 adverse events (ANRS grading table)	Month 12
Tolerance	Proportion of patients with permanent study treatment discontinuation during the first year	Month 12
Adherence to treatment strategy	Proportion of patients with adherence > 90%	Month 12
Plasmatic drug concentrations	Plasmatic dolutegravir concentrations	Month 1
Plasmatic drug concentrations	Plasmatic darunavir concentrations	Month 1

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2018
• Primary Completion (Anticipated): April 11, 2022
• Study Completion (Anticipated): April 11, 2022

Study Registration Dates

• First Submitted: July 6, 2018
• First Submitted That Met QC Criteria: July 18, 2018
• First Posted (Actual): July 27, 2018

Study Record Updates

• Last Update Posted (Actual): August 26, 2021
• Last Update Submitted That Met QC Criteria: August 25, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Dolutegravir; Darunavir; Cambodia; Third-line regimen
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Darunavir; Dolutegravir
• Other Study ID Numbers: ANRS 12374 3DICAM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No