Evaluation of Three Strategies of Second-line Antiretroviral Treatment in Africa (Dakar - Bobo-Dioulasso - Yaoundé) (2LADY)

Multicentric, Non-inferiority, Randomized, Non-blinded Phase 3 Trial Comparing Virological Response at 48 Weeks of 3 Antiretroviral Treatment Regimens in HIV-1-infected Patients With Treatment Failure After 1st Line Antiretroviral Therapy (Cameroon, Burkina Faso, Senegal)

Since the first line antiretroviral (ARV) treatment is now largely accessible in the Sub-Saharian Africa countries, documentation of virological failure, drug resistance patterns and second line treatment evaluation are still to be consolidated in settings where viral load monitoring is not available and non-B HIV subtype is predominant.

This trial aims at evaluating the efficacy and tolerance of 3 different second line treatment strategies: two recommended by WHO combine two non-nucleoside reverse transcriptase inhibitor associated with a ritonavir boosted protease inhibitor (emtricitabine-tenofovir-lopinavir/ritonavir and abacavir-didanosine-lopinavir/ritonavir); the third strategy combines emtricitabine-tenofovir-darunavir/ritonavir and is not yet evaluated in Sub-Saharian Africa. Darunavir has a potentially superior antiviral efficacy, a better tolerance and its single daily administration may facilitate treatment adherence.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV
• Intervention / Treatment: Drug: emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line); Drug: abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line); Drug: emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)

• Study Type: Interventional
• Enrollment (Actual): 454
• Phase: Phase 3

Contacts and Locations

Study Locations

• Burkina Faso
  • Bobo Dioulasso, Burkina Faso
    • Day Hospital, CHU Sanou Souro
• Cameroon
  • Yaounde, Cameroon
    • Day Hospital, Central Hospital
• Senegal
  • Dakar, Senegal
    • Clinical Research and Training Center, Fann Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patient over the age of 18 years at pre-inclusion and monitored under outpatient conditions
• Documented HIV-1 infection regardless of clinical stage and CD4 lymphocyte count
• Patient with treatment failure after first-line antiretroviral treatment with a combination including a non-nucleoside reverse transcriptase inhibitor and two nucleoside reverse transcriptase inhibitors, failure being defined as 2 measurements (at 1 month interval) of plasma HIV RNA levels > 1000 copies/ml after at least 6 months of uninterrupted treatment
• Adherence (> 80%) to first- line antiretroviral treatment (questionnaire) at pre inclusion
• Patient agrees not to take any concomitant medication during the trial without informing the investigator
• Informed consent signed no later than D-15
• For women in childbearing age: negative pregnancy test at inclusion, with no plan of pregnancy in the coming 12 months and agreeing to use mechanical contraception (with or without hormonal contraception) during the study

Exclusion Criteria:

• Infection with HIV-2 or HIV-1 groups O or N or HIV1+2
• Deficiency of the patient, making it difficult, if not impossible, for him/her to take part in the trial or understand the information provided to him/her
• Participation in any other clinical trial
• Presence of an uncontrolled, ongoing opportunistic infection or of any severe or progressive disease
• First-line treatment with a protease inhibitor, abacavir, tenofovir or ddI
• Ongoing treatment with rifampicin
• Severe hepatic insufficiency (TP < 50%)
• ALAT > 3 x ULN
• Creatinine clearance calculated by Cockcroft formula < 50 ml/min
• Hb ≤ 8 g/dl
• Platelets < 50,000 cells/mm3
• Neutrophiles < 500 cells/ mm3
• Use of drugs prohibited in the context of this trial (drugs contraindicated by the SCP of the trial drugs) - in the event of tuberculosis or malaria during the trial, a list of authorized medicines and, if necessary, a dose adjustment of the antiretroviral medication will be provided
• Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A; emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line)	Drug: emtricitabine/tenofovir + lopinavir/ritonavir (WHO recommended second line); Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets in the morning and 2 tablets in the evening
Active Comparator: Arm B; abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line)	Drug: abacavir + didanosine + lopinavir/ritonavir (WHO recommended second line); Didanosine 1 entero-coated capsule/day in fasting conditions (dosage 250 mg if weight < 60 kg, 400 mg if weight > 60 kg) + abacavir 300 mg 1 tablet in the morning and in the evening + Lopinavir 200 mg/Ritonavir 50 mg 2 tablets morning and evening
Active Comparator: Arm C; emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation)	Drug: emtricitabine/tenofovir + darunavir + ritonavir (Second line strategy under evaluation); Emtricitabine 200 mg/tenofovir 300 mg 1 tablet/day with food + darunavir 400 mg 2 tablets + ritonavir 100 mg 1 capsule, in a single dose with food

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Patients With Plasma HIV RNA < 50 Copies/mL	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With WHO Stage 3 and 4 HIV Related Events	patients having a diagnosis of HIV related event classified as stage 3 or 4	between baseline and 48 weeks
Patients With Plasma HIV RNA < 200 Copies/ml	number of patients with plasma HIV RNA below 200 copies/ml	48 weeks
Gain in CD4 Cells Between Baseline and W48	median gain in circulating CD4 cells between baseline and W48	between baseline and 48 weeks
Number of Patients Discontinuing Study Treatment	number of patients discounting treatment because of adverse events	between baseline and W48
Tolerance: Gastrointestinal Complains	Gastrointestinal complaints (grade 1 to 4) between baseline and W48.	between baseline and 48 weeks
Tolerance: Neuropathies (Grade 1 to 4)	any symptom of peripheral neuropathy	between baseline and W48
Tolerance: Equal or Superior to a 25% Reduction in eGFR (Glomerular Filtration Rate)	evaluation of estimated glomerular filtration rate and number of participant with a decrease equal or superior to 25% of the baseline value	between baseline and W48
Adherence	number of patients in different categories of adherence as measured by questionnaire	between baseline and W48
Number of Patients With Resistance Mutations	number of patients with resistance mutations after second line treatment failure (HIV RNA> 1000 copies/ml)	between W12 and W48
Development of Metabolic Syndrome	number of patients developing metabolic syndrome over a period of 48 weeks	from baseline to week 48
Number of Patients With HIV Plasma Viral Load < 50 Copies/ml	Snapshot of patients with HIV viral load less then 50 copies/ml at week 24	Week 24
Number of Patients With HIV Plasma Viral Load < 200 Copies/ml	number of patients having a plasma viral load below 200 copies/ml at week 24	Week 24

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Gilead Sciences; Janssen Pharmaceutica
• Investigators: Principal Investigator: Sinata Koulla Shiro, PhD, Infectious diseases department, Central Hospital, Yaounde, Cameroon; Principal Investigator: Papa Salif Sow, PhD, Infectious Diseases Department, Fann Hospital, Dakar, Senegal; Principal Investigator: Adrien Sawadogo, MD, Day Hospital, CHU Sanou Souro, Bobo Dioulasso, Burkina Faso

Publications and helpful links

General Publications

• Boyer S, Nishimwe ML, Sagaon-Teyssier L, March L, Koulla-Shiro S, Bousmah MQ, Toby R, Mpoudi-Etame MP, Ngom Gueye NF, Sawadogo A, Kouanfack C, Ciaffi L, Spire B, Delaporte E; 2-Lady Group. Cost-Effectiveness of Three Alternative Boosted Protease Inhibitor-Based Second-Line Regimens in HIV-Infected Patients in West and Central Africa. Pharmacoecon Open. 2020 Mar;4(1):45-60. doi: 10.1007/s41669-019-0157-9.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: June 23, 2009
• First Submitted That Met QC Criteria: June 24, 2009
• First Posted (Estimate): June 25, 2009

Study Record Updates

• Last Update Posted (Actual): February 27, 2017
• Last Update Submitted That Met QC Criteria: January 12, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: HIV; Africa; treatment experienced; Treatment strategies; Second line treatment; WHO recommendations
• 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; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Tenofovir; Emtricitabine; Ritonavir; Lopinavir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Didanosine; Darunavir; Abacavir
• Other Study ID Numbers: ANRS12169 2LADY