Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST)

A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa

The trial aim is to ascertain what, if anything, needs to be combined with a boosted protease inhibitor (bPI) backbone in second-line therapy in order to maximize the chance of a good clinical outcome following WHO-defined failure on a first-line nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI-containing regimen with probable extensive NRTI and NNRTI resistance mutations.

Study Overview

• Status: Completed
• Conditions: HIV; Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Aluvia + 2NRTIs; Drug: Aluvia + raltegravir; Drug: Aluvia monotherapy

Detailed Description

The standard of care for second-line HIV therapy in patients who have failed a first-line NNRTI-based regimen is to combine a boosted protease inhibitor (bPI) with two (new) NRTIs. However, patients failing first-line therapy in roll-out programmes often have extensive NRTI resistance mutations that may compromise the efficacy of the NRTI drugs used in second-line therapy and it is likely that the virological potency of the second-line regimen is mostly due to the bPI. It is possible that the contribution of the NRTI drugs to efficacy may be outweighed by additional toxicity and cost. It is also possible that replacing the NRTI drugs with a new class of drug (integrase inhibitors) will improve outcome from second-line therapy, although if the boosted protease inhibitor alone is providing close to optimal response, incremental gains from adding a new class may be small.

The principal aims are to determine whether, in patients failing a first-line NRTI and NNRTI-containing regimen:

• The use of bPI plus raltegravir (an integrase inhibitor) is superior to standard of care (bPI plus 2 new NRTIs) in achieving good HIV disease control at 96 weeks after randomisation
• The use of bPI monotherapy, preceded by a 12-week induction period in combination with raltegravir, is non-inferior to standard of care in achieving good HIV disease control at 96 weeks after randomisation

• Study Type: Interventional
• Enrollment (Actual): 1277
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Eldoret, Kenya
    • AMPATH Centre at Moi Teaching Referral Hospital
• Malawi
  • Blantyre, Malawi
    • University of Malawi
  • Mzuzu, Malawi
    • Mzuzu Central Hospital
• Uganda
  • Fort Portal, Uganda
    • Joint Clinical Research Centre
  • Gulu, Uganda
    • JCRC
  • Kabale, Uganda
    • JCRC
  • Kakira, Uganda
    • JCRC
  • Kampala, Uganda
    • Infectious Diseases Institute
  • Kampala, Uganda
    • Joint Clinical Research Centre
  • Kampala, Uganda
    • San Raphael of St Francis Hospital Nsambya
  • Mbale, Uganda
    • Joint Clinical Research Centre
  • Mbarara, Uganda
    • Joint Clinical Research Centre
• Zambia
  • Lusaka, Zambia
    • University Teaching Hospital
• Zimbabwe
  • Harare, Zimbabwe
    • University of Zimbabwe Clinical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previously documented HIV infection on at least one standard antibody-based test
• Age 12 years and above
• Taking 2NRTI + NNRTI-based regimen continuously for at least 12 months
• Naive to protease inhibitor therapy
• Good adherence to ART in the 12 weeks prior to screening defined as missing medication on no more than 3 days in the prior month
• Clinically stable and receiving treatment for any known opportunistic infections
• HIV treatment failure defined by one or more of clinical, immunological or virological criteria defined in the protocol, including VL and CD4 at screening visit
• Willing and able to give informed consent
• Able to attend for regular study follow up visits

Exclusion Criteria:

• Any major clinical contra-indications to the use of bPI, the NRTIs that are available to be selected for a second-line regimen or raltegravir
• Known Hepatitis B carrier (Hepatitis B surface antigen positive if tested)
• Requires concomitant medication with known major interactions with study drugs for which drug substitutions or dose alterations are not available or acceptable
• Women who are currently pregnant or breastfeeding
• Current participation in another clinical trial involving a treatment intervention (may be permitted in some circumstances, but must be discussed with MRC CTU)
• Life expectancy of less than one month in the opinion of the treating physician

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: bPI + 2NRTIs	Drug: Aluvia + 2NRTIs; Aluvia (lopinavir/ritonavir 400mg/100mg), twice daily The choice of NRTIs will be at the discretion of the managing clinician and based on the local standard of care and drug availability, taking into account patient's previous drug exposure and side effects on first-line therapy.
Experimental: bPI + raltegravir	Drug: Aluvia + raltegravir; Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily
Experimental: bPI monotherapy	Drug: Aluvia monotherapy; Aluvia (lopinavir/ritonavir 400mg/100mg) twice daily raltegravir (400mg) twice daily for the first 12 weeks only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Good HIV disease control defined as a composite endpoint consisting of all of: - No new WHO stage 4 events - CD4 count >250 cells/mm3 - viral load <10,000 copies/ml or >10,000 copies/ml with no PI resistance mutations	week 96

Secondary Outcome Measures

Outcome Measure	Time Frame
Good HIV disease control	week 144
Proportion with CD4 cell count >250 cells/mm3	week 96 and week 144
Proportion with new or recurrent WHO stage 4 event	week 96 and week 144
Proportion of patients with plasma viral load <50 copies	week 48, week 96 and week 144
Adverse events	During trial
Quality of life change from randomisation	During trial
Neurocognitive function change from randomisation	during trial
Healthcare costs	During trial
Proportion with serious non-AIDS events	Week 96 and week 144

Collaborators and Investigators

• Sponsor: Justine Boles
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Study Director: Nicholas Paton, MD FRCP, MRC CTU

Publications and helpful links

General Publications

• Shi Y, Thompson J, Walker AS, Paton NI, Cheung YB; EARNEST Trial Team. Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3 L) utility index. Health Qual Life Outcomes. 2019 May 10;17(1):83. doi: 10.1186/s12955-019-1135-8.
• Thompson JA, Kityo C, Dunn D, Hoppe A, Ndashimye E, Hakim J, Kambugu A, van Oosterhout JJ, Arribas J, Mugyenyi P, Walker AS, Paton NI; Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial. Clin Infect Dis. 2019 Mar 19;68(7):1184-1192. doi: 10.1093/cid/ciy589.
• Paton NI, Kityo C, Thompson J, Nankya I, Bagenda L, Hoppe A, Hakim J, Kambugu A, van Oosterhout JJ, Kiconco M, Bertagnolio S, Easterbrook PJ, Mugyenyi P, Walker AS; Europe Africa Research Network for Evaluation of Second-line Therapy (EARNEST) Trial Team. Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial. Lancet HIV. 2017 Aug;4(8):e341-e348. doi: 10.1016/S2352-3018(17)30065-6. Epub 2017 May 8.
• Paton NI, Kityo C, Hoppe A, Reid A, Kambugu A, Lugemwa A, van Oosterhout JJ, Kiconco M, Siika A, Mwebaze R, Abwola M, Abongomera G, Mweemba A, Alima H, Atwongyeire D, Nyirenda R, Boles J, Thompson J, Tumukunde D, Chidziva E, Mambule I, Arribas JR, Easterbrook PJ, Hakim J, Walker AS, Mugyenyi P; EARNEST Trial Team. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014 Jul 17;371(3):234-47. doi: 10.1056/NEJMoa1311274.

Helpful Links

• EARNEST trial website

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: September 30, 2009
• First Submitted That Met QC Criteria: September 30, 2009
• First Posted (Estimate): October 1, 2009

Study Record Updates

• Last Update Posted (Estimate): April 4, 2014
• Last Update Submitted That Met QC Criteria: April 3, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; second line therapy; monotherapy; raltegravir; Human Immunodeficiency virus; aluvia; integrase inhibitor; protease inhibitor
• 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; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; 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; Raltegravir Potassium; Lopinavir
• Other Study ID Numbers: U.1228.03.004.00021.01; IP_2007_33011_003; ISRCTN37737787

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No