Efficacy and Safety Study of Darunavir for the Treatment of HIV/AIDS (MANET)

Monotherapy in Africa: Evaluation of New Therapy

The aim of this pilot study is to assess the feasibility, efficacy and safety of Darunavir/ritonavir 800/100 mg once daily (DRV/r) monotherapy as a switch-maintenance strategy for patients receiving second-line ART at Yaoundé Central Hospital in Cameroon. HIV-infected adults receiving second-line antiretroviral therapy (ART) for ≥3 months with 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) will undergo plasma HIV-1 RNA ("viral") load testing. Those with a viral load below 50 copies/ml (<50 cps/ml) will undergo a repeat test ideally 4-6 weeks later (allowed up to 12 weeks); if the viral load is confirmed as <50 cps/ml the patient will be invited to join the randomised phase of the study. Patients (n=150) will be randomised 1:2 to either continue the current triple ART regimen (n=50) or switch to DRV/r monotherapy (n=100). The primary end-point will be viral load suppression <400 cps/ml at week 24; secondary end-points will be viral load suppression <50 cps/ml at week 12 and week 24, safety, tolerability, and emergence of protease inhibitor (PI) drug-resistance. Patients will continue observational follow-up depending on the treatment arm they are randomized to. After week 48, patients will return to local standard of care. Pharmacokinetics (PK) and pharmacogenomics sub-study to correlate plasma concentrations of DRV to outcomes, HIV-1 drug resistance testing sub study to detect mutants archived at the time of first-line ART failure and measuring HIV DNA load will be performed, as well as a cost-effectiveness analysis will test the hypothesis that savings can be achieved by switching to DRV/r monotherapy without affecting quality of care. The primary virological objective is to evaluate efficacy in terms of the percentage of subjects who have plasma HIV-1 RNA levels <400 cps/ml after 24 weeks of follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing 2 NRTIs + LPV/r (or ATV/r) (FDA Snapshot method).

Study hypothesis:

we propose that maintenance therapy with DRV/r monotherapy is a feasible, effective and safe treatment option for patients receiving second-line ART in Yaoundé.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: ART with 2 NRTIs plus LPV/r (or ATV/r); Drug: Darunavir

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Cameroon
  • Centre
    • Yaounde, Centre, Cameroon, 5777
      • Yaoundé Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects with documented HIV-1 infection.
2. Male or female aged > 21 years old.
3. Subjects receiving ART with 2 NRTIs + LPV/r (or ATV/r) for at least 3 months at the time of Screening 1.
4. Nadir T lymphocyte cluster of differentiation 4 (CD4) >100 cells/mm3
5. Plasma HIV-1 RNA <50 copies/ml at Screening 1 confirmed ideally 4-6 weeks later at Screening 2 (two results must be documented; a first result obtained up to 12 weeks earlier will be accepted).
6. Subjects can comply with the protocol requirements. In particular, subjects should be willing to be followed up at least until week 24 (discontinuation prior to week 24) and for the DRV/r arm up to week 48 (discontinuation after week 24) even if they discontinue randomized treatment.
7. Subjects who have voluntarily signed and dated the consent form.

Exclusion Criteria:

1. Clinical or laboratory evidence of significantly decreased hepatic function or decompensation, irrespective of liver enzyme levels (liver insufficiency).
2. Co-infection with hepatitis B (HBsAg positive).

3. Grade 3 or 4 laboratory abnormality as defined by AIDS, including haemoglobin ≤8mg/dL; platelets ≤50 000/mm3; estimated creatinine clearance ≤60ml/ minute, aspartate aminotransferase; alanine aminotransferase and alkaline phosphatase >3 times the upper limit of normal; and total bilirubin >2.5 times the upper limit of normal; with the following exceptions unless clinical assessment foresees an immediate health risk to the subject:

   • Pre-existing diabetes or asymptomatic glucose grade 3 or 4 elevations.
   • Asymptomatic triglyceride or cholesterol elevations of grade 3 or 4.

4. Presence of any currently active AIDS defining illness (Category C conditions according to the Centers for Disease Control Classification System for HIV Infection 1993) with the following exceptions:

   • Stable cutaneous Kaposi's Sarcoma (i.e., no internal organ involvement other than oral lesions) that is unlikely to require any form of systemic therapy during the study.
   • Wasting syndrome due to HIV infection. Note: An AIDS defining illness that is not clinically stabilized for at least 30 days will be considered as currently active.
5. Pregnant or breastfeeding women.
6. Active substance abuse, including alcohol or recreational drugs.
7. Any clinically significant disease (e.g., tuberculosis, cardiac dysfunction, pancreatitis, acute viral infections) or life threatening disease in the previous 14 days, or findings during screening of medical history or physical examination that, in the investigator's opinion, would compromise the subject's safety or outcome of the study.
8. Any medical or psychiatric condition which, in the opinion of the investigator, could compromise the subject's safety or adherence to the trial protocol.

9. Previously demonstrated clinically allergy or hypersensitivity to any of the excipients of the investigational medication (DRV).

   Note: DRV is a sulfonamide. Subjects who have previously experienced a sulfonamide allergy will be allowed to enter the trial. To date, no potential for cross sensitivity between drugs in the sulfonamide class and DRV has been identified in subjects participating in phase II trials.

10. Participation in any other clinical trials that involve administration of antiretrovirals or other drugs within the last 4 weeks and during the participation in this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: ART with 2 NRTIs plus LPV/r (or ATV/r); 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r).	Drug: ART with 2 NRTIs plus LPV/r (or ATV/r); Patients on second line antiretroviral therapy take 2 NRTIs and either protease inhibitor lopinavir/ritonavir or atazanavir/ritonavir.; Other Names: NRTI, lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r)
EXPERIMENTAL: Darunavir; Dosage form: Darunavir (PREZISTA) is a film coated, oval shaped, light orange 19.1mm tablet, debossed with "400 mg" on one side and TMC on the other side.	Drug: Darunavir; Darunavir (PREZISTA) is a film coated, oval shaped, light orange 19.1mm tablet, debossed with 400 mg on one side and TMC on the other side.; Other Names: PREZISTA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA Viral Load	Percentage of subjects who have plasma HIV-1 RNA levels <400 cps/ml after 24 weeks of follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing 2 NRTIs + LPV/r (or ATV/r) (FDA Snapshot method). The FDA 'Snapshot' algorithm evaluates HIV RNA response using only the results at the week 24 time-point which also means that rebound at earlier time-points are not classified as treatment failure, unless it lead to discontinuation prior to the week 48.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA Viral Load	Percentage of subjects who have plasma HIV-1 RNA levels <50 cps/ml after 12 weeks of follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing 2 NRTIs + LPV/r (or ATV/r), using the FDA "Time to Loss of Virologic Response" method. The FDA 'Snapshot' algorithm evaluates HIV RNA response using only the results at the week 12 time-point which also means that rebound at earlier time-points are not classified as treatment failure, unless it lead to discontinuation prior to the week 48.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA Viral Load	Percentage of subjects who have plasma HIV-1 RNA levels <50 cps/ml after 24 weeks of follow-up following a switch to DRV/r monotherapy versus continuing triple therapy containing 2 NRTIs + LPV/r (or ATV/r), using the FDA "Time to Loss of Virologic Response" method. The FDA 'Snapshot' algorithm evaluates HIV RNA response using only the results at the week 24 time-point which also means that rebound at earlier time-points are not classified as treatment failure, unless it lead to discontinuation prior to the week 48.	24 weeks

Collaborators and Investigators

• Sponsor: University of Liverpool
• Collaborators: Janssen Pharmaceutica; Yaounde Central Hospital; Chantal Biya International Reference Centre for Research on Prevention and Management of HIV/AIDS
• Investigators: Principal Investigator: Anna Maria Geretti, MD, PhD, University of Liverpool

Publications and helpful links

General Publications

• Geretti AM, Abdullahi A, Mafotsing Fopoussi O, Bonnett L, Defo VF, Moudourou S, Fokam J, Kouanfack C, Torimiro J. An apparent paradox: resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy. J Antimicrob Chemother. 2019 Oct 1;74(10):3011-3015. doi: 10.1093/jac/dkz264.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (ACTUAL): June 1, 2016
• Study Completion (ACTUAL): July 1, 2016

Study Registration Dates

• First Submitted: June 2, 2014
• First Submitted That Met QC Criteria: June 2, 2014
• First Posted (ESTIMATE): June 4, 2014

Study Record Updates

• Last Update Posted (ACTUAL): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 30, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Darunavir; Cameroon; HIV-1 RNA level
• 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 Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir; Darunavir; Atazanavir Sulfate
• Other Study ID Numbers: ChantalIRCB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED