Dolutegravir and Darunavir Evaluation in Adults Failing Therapy

NCT ID: NCT03017872

Last Updated: 2023-04-18

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 831 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-23
• Study Completion Date: 2023-10-31

Brief Summary

D²EFT is a randomised, open-label study in HIV-1 infected patients failing first-line antiretroviral therapy (ART). The study compares 2 regimens of second-line ART (dolutegravir and darunavir pharmaco-enhanced with ritonavir and dolutegravir and 2 prespecified NRTIs) with the WHO recommended regimen of 2NRTIs plus a ritonavir-boosted PI (Standard of Care (SOC)). 1,010 participants from 14 predominantly low-middle income countries will be followed for 96 weeks with the primary endpoint at week 48. The design is based on the hypothesis that one or both of the new regimens will be non-inferior to SOC in terms of virologic control while being easier to take, economically viable and affording simplification of treatment programs.

Detailed Description

Consenting participants will be screened and within 45 days randomly allocated to receive either dolutegravir and darunavir/ritonavir, dolutegravir and 2 prespecified NRTIs or the SOC regimen. Participants will be seen four weeks after their randomisation (week 0) visit and then at weeks 12, 24, 48 and 96. Consenting participants will have storage samples collected and cryopreserved at their week 0, 48 & 96 visits. This repository will be used in future for central baseline resistance testing, pharmacogenomic testing (separate consent required) and has inherent value for later studies of HIV pathogenesis. A 1-time PK sample will be collected at week four for future testing and any participants failing therapy at 24 weeks will have a plasma sample stored for future genotypic resistance testing.

A number of secondary outcomes will be considered in order to compare the performance of the two study treatment regimens. Secondary analyses will focus on virological, immunological, safety, antiretroviral treatment change and medication adherence. A comparison of costs and estimates of cost-effectiveness for the randomised comparison will be a critical component of this study. ART costs will be assessed across study arms. Health-care utilisation will be self-reported and then used to estimate costs. Safety data, viral loads and quality of life data will also be analysed.

The open label nature of the study allows routine care to be undertaken and the use of objective endpoints limit potential bias. The study has well defined and integrated clinical data collection and patient management systems that have been shown to be effective in a wide range of clinical settings.

The choice of NRTIs in the SoC regimen is based on clinical judgement and may be guided by resistance testing if locally available, while those used with dolutegravir are predetermined (tenofovir and lamivudine or emtricitabine). The NRTIs are not provided via the study. At the end of 96 weeks (completion of the protocol) study drug can be offered to all participants for a further 48 weeks as informed by the 48-week study results and clinical judgement. After 144 weeks study drug will no longer be available and composition of the participant's post-study regimen will be the clinician's decision.'

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care (SoC) arm

2 x NRTIs + darunavir/ritonavir 800mg/100mg po od

Group Type: ACTIVE_COMPARATOR

NRTIs

Intervention Type: DRUG

In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.

In D2N arm, NRTIs are predetermined.

Darunavir

Intervention Type: DRUG

800mg tablet by mouth once daily for 96 weeks.

Ritonavir

Intervention Type: DRUG

100mg tablet by mouth once daily for 96 weeks.

Dolutegravir arm

Dolutegravir 50mg + darunavir/ritonavir 800mg/100mg po od

Group Type: EXPERIMENTAL

Dolutegravir

Intervention Type: DRUG

50mg tablet by mouth once daily for 96 weeks.

Darunavir

Intervention Type: DRUG

800mg tablet by mouth once daily for 96 weeks.

Ritonavir

Intervention Type: DRUG

100mg tablet by mouth once daily for 96 weeks.

Dolutegravir 2NRTI arm (D2N)

Dolutegravir 50mg + 2 x NRTIs (tenofovir plus emtricitabine or lamivudine)

Group Type: EXPERIMENTAL

NRTIs

Intervention Type: DRUG

In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.

In D2N arm, NRTIs are predetermined.

Dolutegravir

Intervention Type: DRUG

50mg tablet by mouth once daily for 96 weeks.

Interventions

NRTIs

In SOC arm, choice of NRTIs determined by clinician, guided by either genotypic resistance testing or use of a protocol-specified algorithm for N(t)RTI selection.

In D2N arm, NRTIs are predetermined.

Intervention Type: DRUG

Dolutegravir

50mg tablet by mouth once daily for 96 weeks.

Intervention Type: DRUG

Darunavir

800mg tablet by mouth once daily for 96 weeks.

Intervention Type: DRUG

Ritonavir

100mg tablet by mouth once daily for 96 weeks.

Intervention Type: DRUG

Other Intervention Names

Nucleoside/Nucleotide Reverse Transcription Inhibitors; Tivicay; Prezista; Norvir

Eligibility Criteria

Inclusion Criteria

1. HIV-1 positive by licensed diagnostic test

2. Aged ≥16 years of age (or minimum age as determined by local regulations or as legal requirements dictate)

3. Failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) + 2N(t)RTI combination therapy according to virological criteria, defined as at least two consecutive (≥7 days apart) pVL results >500 copies/mL after a minimum period of exposure to continuous NNRTI + 2N(t)RTI first-line therapy of 24 weeks (only the second pVL result needs to be within 45 days of randomisation)

4. For women of child-bearing potential, willingness to use appropriate contraception

5. Able to provide written informed consent

Exclusion Criteria

1. The following laboratory variables:

1. absolute neutrophil count (ANC) <500 cells/µL

2. haemoglobin <7.0 g/dL

3. platelet count <50,000 cells/µL

4. AST and/or ALT ≥5xULN OR ALT ≥3xULN and bilirubin ≥1.5xULN (with >35% direct bilirubin)

2. Change in antiretroviral therapy within 12 weeks prior to randomisation

3. Prior exposure to HIV protease inhibitors and/or HIV integrase inhibitors

4. Patients with chronic viral hepatitis B infection defined by positive serum hepatitis B surface antigen

5. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy (INR >2.3), hypoalbuminemia (serum albumin <2.8g/dL), esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

6. Anticipated need for Hepatitis C virus (HCV) therapy during the study

7. Subject has creatinine clearance of <50 mL/min via CKD-EPI equation

8. Current use of rifabutin or rifampicin

9. Use of any contraindicated medications (as specified by product information sheets)

10. Intercurrent illness requiring hospitalization

11. An active opportunistic disease not under adequate control in the opinion of the investigator

12. Pregnant or nursing mothers

13. Patients with current alcohol or illicit substance use that in the opinion of the investigator might adversely affect participation in the study

14. Patients deemed unlikely by the investigator to be able to remain in follow-up for the protocol-defined period

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UNITAID

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

National Health and Medical Research Council, Australia

OTHER

Sponsor Role: collaborator

ViiV Healthcare

INDUSTRY

Sponsor Role: collaborator

Janssen Pharmaceutica

INDUSTRY

Sponsor Role: collaborator

Kirby Institute

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gail Matthews, MD

Role: PRINCIPAL_INVESTIGATOR

Kirby Institute

Locations

Hospital Dr Diego Paroissien

Isidro Casanova, Buenos Aires, Argentina

Hospital G de Agudos JM Ramos Mejia

Buenos Aires, Buenos Aires F.D., Argentina

CAICI

Rosario, Santa Fe Province, Argentina

Hospital Interzonal de Agudos San Juan de Dios

La Plata, , Argentina

Laboratório de Pesquisa Clinica Em Hiv/Aids - Instituto Nacional de Infectologia - Fiocruz

Rio de Janeiro, , Brazil

Hospital San Borja-Arriaran

Santiago, , Chile

ASISTENCIA Cientifica De Alta Complejidad S.A.S.

Bogotá, , Colombia

Centre de traitementambulatoire de Donka ( Hopital de jour)

Conakry, , Guinea

CART CRS, VHS Hospital

Chennai, Tamil Nadu, India

Dr. Cipto Mangunkusumo Hospital

Jakarta, , Indonesia

RSUP Dr. Wahidin Sudirohusodo

Makassar, , Indonesia

Dr. Soetomo Hospital

Surabaya, , Indonesia

Dr Sardjito Hospital

Yogyakarta, , Indonesia

Hospital Pulau Pinang

George Town, Pulau Pinang, Malaysia

University of Malaya Medical Centre

Kuala Lumpur, , Malaysia

University of Sciences, Techniques and Technologies of Mali, University Clinical Research Center (UCRC)

Bamako, , Mali

Morales Vargas Centro de Investigacion SC

León, Guanajuato, Mexico

Hospital Civil de Guadalajara

Guadalajara, Jalisco, Mexico

Instituto Nacional de Ciencias Medicas y Nutriciòn Salvador Zubiran

Mexico City, , Mexico

Institute of Human Virology, Nigeria (IHVN)

Abuja, , Nigeria

Desmond Tutu HIV Foundation

Cape Town, , South Africa

Clinical HIV Research Unit (CHRU), Wits Health Consotium (Pty) Ltd

Johannesburg, , South Africa

Perinatal HIV Research Unit (PHRU), Chris Hani Baragwanath Hospital

Soweto, , South Africa

HIV-NAT (The HIV Netherlands Australia Thailand Research Collaboration), Thai Red Cross AIDS Research Centre

Bangkok, , Thailand

Chiangrai Prachanukroh Hospital

Chiang Rai, , Thailand

Srinagarind Hospital, Khon Kaen University

Khon Kaen, , Thailand

Bamrasnaradura Infectious Diseases Institute

Nonthaburi, , Thailand

University of Zimbabwe Clinical Research Centre

Harare, , Zimbabwe

Countries

Argentina; Brazil; Chile; Colombia; Guinea; India; Indonesia; Malaysia; Mali; Mexico; Nigeria; South Africa; Thailand; Zimbabwe

References

D2EFT Study Group. Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial. Lancet HIV. 2024 Jul;11(7):e436-e448. doi: 10.1016/S2352-3018(24)00089-4. Epub 2024 May 21.

Reference Type: DERIVED

PMID: 38788744 (View on PubMed)

Nyein PP, Petoumenos K, Borok M, Eriobu N, Kumarasamy N, Avihingsanon A, Azwa I, Dao S, Cisse M, Dharan NJ, Hanson J, Matthews GV. Associations Between Antiretroviral Regimen and Changes in Blood Pressure: Results From the D2EFT Study. Clin Infect Dis. 2025 Feb 5;80(1):160-163. doi: 10.1093/cid/ciae256.

Reference Type: DERIVED

PMID: 38721980 (View on PubMed)

Other Identifiers

18Q065

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

19Q120

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

D2EFT

Identifier Type: -

Identifier Source: org_study_id