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

• Sponsor: University of Liverpool (Other)
• Overall Status: Completed
• CT.gov ID: NCT02155101
• Collaborator: Janssen Pharmaceutica (Industry), Chantal Biya International Reference Centre for Research on Prevention and Management of HIV/AIDS (Other), Yaounde Central Hospital (Other)
• Enrollment: 120
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 4.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HIV/AIDS	Drug: Darunavir; Drug: ART with 2 NRTIs plus LPV/r (or ATV/r)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Monotherapy in Africa: Evaluation of New Therapy
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jul 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. HIV-1 RNA Viral Load [24 weeks]

   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.

Secondary Outcome Measures

1. HIV-1 RNA Viral Load [12 weeks]

   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.

Other Outcome Measures

1. HIV-1 RNA Viral Load [24 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Presence of any currently active AIDS defining illness (Category C conditions according to the Centers for Disease Control Classification System for HIV Infection

1. 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.

1. Pregnant or breastfeeding women.

2. Active substance abuse, including alcohol or recreational drugs.

3. 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.

4. Any medical or psychiatric condition which, in the opinion of the investigator, could compromise the subject's safety or adherence to the trial protocol.

5. 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.

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yaounde Central Hospital	Yaounde	Centre	Cameroon	5777

Sponsors and Collaborators

• University of Liverpool
• Janssen Pharmaceutica
• Chantal Biya International Reference Centre for Research on Prevention and Management of HIV/AIDS
• Yaounde Central Hospital

Investigators

• Principal Investigator: Anna Maria Geretti, MD, PhD, University of Liverpool

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anna Maria Geretti, Principal Investigator, University of Liverpool
• ClinicalTrials.gov Identifier: NCT02155101
• Other Study ID Numbers: ChantalIRCB
• First Posted: Jun 4, 2014
• Last Update Posted: Sep 4, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Anna Maria Geretti, Principal Investigator, University of Liverpool: Efficacy; Safety; Darunavir; HIV-1 RNA level; Cameroon
• Additional relevant MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections; Ritonavir; Lopinavir; Atazanavir Sulfate; Darunavir

Study Results

Participant Flow

Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)	Darunavir
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.	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. 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.
Period Title: Overall Study
STARTED	39	81
COMPLETED	39	80
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)	Darunavir	Total
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.	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. 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.	Total of all reporting groups
Overall Participants	39	81	120
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	45	45	45
Sex: Female, Male (Count of Participants)
Female	30 76.9%	61 75.3%	91 75.8%
Male	9 23.1%	20 24.7%	29 24.2%
Region of Enrollment (participants) [Number]
Cameroon	39 100%	81 100%	120 100%
Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	26.0	25.4	25.5
Haemoglobin (g/dl) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [g/dl]	12.4	12.3	12.3
Estimated glomerular filtration rate >90 (Count of Participants)
Count of Participants [Participants]	35 89.7%	67 82.7%	102 85%
Time since HIV diagnosis (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	8.0	8.8	8.5
CD4 cell count (cells/mm3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm3]	536	466	467
History of previous AIDS defining diagnosis (Count of Participants)
Count of Participants [Participants]	4 10.3%	12 14.8%	16 13.3%
HIV-1 DNA (log10 copies/106 PBMC) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/106 PBMC]	2.7	2.9	2.9
Duration on antiretroviral therapy(ART) (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	6.9	7.6	7.5
Duration on protease inhibitor based ART (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	3.1	3.2	3.1
ART regimen at baseline (Count of Participants)
Tenofovir/lamivudine + lopinavir/ritonavir	37 94.9%	69 85.2%	106 88.3%
Abacavir + didanosine + lopinavir/ritonavir	1 2.6%	5 6.2%	6 5%
Zidovudine/lamivudine + lopinavir/ritonavir	1 2.6%	4 4.9%	5 4.2%
Tenofovir/lamivudine + atazanavir/ritonavir	0 0%	2 2.5%	2 1.7%
Tenofovir + abacavir + lopinavir/ritonavir	0 0%	1 1.2%	1 0.8%

Outcome Measures

1. Primary Outcome

Title	HIV-1 RNA Viral Load
Description	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.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)	Darunavir
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.	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. 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.
Measure Participants	39	81
Count of Participants [Participants]	37 94.9%	72 88.9%

2. Secondary Outcome

Title	HIV-1 RNA Viral Load
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)	Darunavir
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.	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. 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.
Measure Participants	39	81
Count of Participants [Participants]	35 89.7%	73 90.1%

3. Other Pre-specified Outcome

Title	HIV-1 RNA Viral Load
Description	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.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)	Darunavir
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.	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. 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.
Measure Participants	39	81
Count of Participants [Participants]	36 92.3%	62 76.5%

Adverse Events

Time Frame	Adverse event data was collected over the 48 week study period
Arm/Group Title	ART With 2 NRTIs Plus LPV/r (or ATV/r)		Darunavir
Arm/Group Description	2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus either lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r). 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.		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. 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.
All Cause Mortality
	ART With 2 NRTIs Plus LPV/r (or ATV/r)		Darunavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		1/81 (1.2%)
Serious Adverse Events
	ART With 2 NRTIs Plus LPV/r (or ATV/r)		Darunavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/39 (0%)		3/81 (3.7%)
General disorders
acute anxiety, hospitalisation, resolved	/39 (NaN)		1/81 (1.2%)	1
Infections and infestations
malaria, progressive anaemia, hospitalisation, transfusion reaction, death	/39 (NaN)		1/81 (1.2%)	1
Social circumstances
Car accident, hospitalisation, resolved;	/39 (NaN)		1/81 (1.2%)	1
Other (Not Including Serious) Adverse Events
	ART With 2 NRTIs Plus LPV/r (or ATV/r)		Darunavir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/39 (5.1%)		3/81 (3.7%)
General disorders
Acute febrile illness	1/39 (2.6%)	1	0/81 (0%)	0
Hypertension	1/39 (2.6%)	1	1/81 (1.2%)	1
Infections and infestations
Acute hepatitis B	0/39 (0%)	0	1/81 (1.2%)	1
Pulmonary TB	0/39 (0%)	0	1/81 (1.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.