Clinical trial NCT00988039: Europe-Africa Research Network for Evaluation of Second-line Therapy
Official title: A Randomised Controlled Trial to Evaluate Options for Second-line Therapy in Patients Failing a First-line 2NRTI + NNRTI Regimen in Africa
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Human Immunodeficiency Virus
HIV
Keywords: Human Immunodeficiency virus
second line therapy
raltegravir
aluvia
monotherapy
integrase inhibitor
protease inhibitor
Randomized Controlled Trial
Lead sponsor: Medical Research Council
Sponsor class: OTHER_GOV
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2009-10-01
Enrollment: 1277
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: week 96
Secondary outcomes:
measure: Good HIV disease control
timeFrame: week 144
measure: Proportion with CD4 cell count >250 cells/mm3
timeFrame: week 96 and week 144
measure: Proportion with new or recurrent WHO stage 4 event
timeFrame: week 96 and week 144
measure: Proportion of patients with plasma viral load <50 copies
timeFrame: week 48, week 96 and week 144
measure: Adverse events
timeFrame: During trial
measure: Quality of life change from randomisation
timeFrame: During trial
measure: Neurocognitive function change from randomisation
timeFrame: during trial
measure: Healthcare costs
timeFrame: During trial
measure: Proportion with serious non-AIDS events
timeFrame: Week 96 and week 144
Other outcomes:
Locations:
city: Eldoret
country: Kenya
facility: AMPATH Centre at Moi Teaching Referral Hospital
city: Blantyre
country: Malawi
facility: University of Malawi
city: Mzuzu
country: Malawi
facility: Mzuzu Central Hospital
city: Fort Portal
country: Uganda
facility: Joint Clinical Research Centre
city: Gulu
country: Uganda
facility: JCRC
city: Kabale
country: Uganda
facility: JCRC
city: Kakira
country: Uganda
facility: JCRC
city: Kampala
country: Uganda
facility: Infectious Diseases Institute
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre
city: Kampala
country: Uganda
facility: San Raphael of St Francis Hospital Nsambya
city: Mbale
country: Uganda
facility: Joint Clinical Research Centre
city: Mbarara
country: Uganda
facility: Joint Clinical Research Centre
city: Lusaka
country: Zambia
facility: University Teaching Hospital
city: Harare
country: Zimbabwe
facility: University of Zimbabwe Clinical Research Centre
Study officials:
affiliation: MRC CTU
name: Nicholas Paton, MD FRCP
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.