Resistance Testing to Improve Management of Virologic Failure in Sub-Saharan Africa

NCT02787499 | Completed Results

• 2 other identifiers: 2016P000589R01AI124718
• Study Type: interventional
• Target: 840
• Locations: 2 countries
• Sites: 2

Brief Summary

The study design is an open-label, randomized controlled trial. The study will be conducted at study sites in Uganda and South Africa. The study population will include HIV-infected patients on first-line antiretroviral therapy with a recent viral load \>1,000 copies/milliliter (or dried blood spot viral load \>1,000 copies/milliliter). Eligible participants will be randomized to the WHO-based standard of care for management of virologic failure or immediate resistance testing to guide ART regimen decisions. The primary outcome of interest will be viral suppression (\<200 copies/mL) at 9 months after study enrollment, and will be assessed using an intention to treat analysis, where missing or absent results will be considered failures. Secondary outcomes of interest will be viral suppression below the limit of assay detection, viral suppression on continuation of first-line (non-nucleoside reverse transcriptase inhibitor \[NNRTI\]-based) therapy, drug resistance at study conclusion, and mortality, among others. The overarching goal of this study is to determine whether addition of routine resistance testing, to guide management of virologic failure and sustain the successful completion of the HIV continuum of care, improves clinical outcomes and reduces costs for patients with virologic failure on first-line therapy in sub-Saharan Africa.

Conditions

HIV; AIDS

Keywords

Drug resistance; Standard of care; sub-saharan africa; antiretroviral therapy; diagnostics; implementation

Outcome Measures

Primary Outcomes (1)

• Number and Percentage of Patients Achieving Virologic Resuppression

  Number and percentage of participants achieving virologic suppression. Virologic resuppression defined as viral load \< 200 copies/mL

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

Secondary Outcomes (7)

• Number and Percentage of Patients With an Undetectable Viral Load (Below Limit of Detection) at Study Conclusion

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

• Number and Percentage of Patients With an Undetectable Viral Load on First-line (NNRTI-based) Therapy at Study Conclusion

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

• Number and Percentage of Patients With International AIDS Society-defined Drug Resistance Mutations to Their Current Regimen.

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

• Total Patient Care Costs, Including Diagnostic Testing and ART Costs for the Study Duration

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

• Number and Percentage of Patients Retained in HIV Clinical Care at Study Completion

  9 months (end point extended up to 15 months for participants affected by the COVID-19 epidemic)

Study Arms (2)

Standard of Care

NO INTERVENTION

Follows the 2013 World Health Organization (WHO) HIV treatment guidelines. Study participants will receive adherence support and return for a repeat viral load test in 3 months (or in 1 month for pregnant participants). Treatment failure will be defined by two consecutive viral load measurements greater than 1,000 copies/mL. Participants who meet this criteria will be switched to second-line therapy. Those with a viral load \<1,000 copies/mL at repeat testing will be retained on first-line therapy.

HIV-1 RNA Resistance Testing

EXPERIMENTAL

Participants will receive HIV-1 RNA drug resistance testing at study enrollment. ART treatment regimen decisions will be determined based on the results of resistance testing.

Procedure: HIV-1 RNA Resistance Testing

Interventions

HIV-1 RNA Resistance Testing PROCEDURE

Perform drug resistance on enrollment to guide management of virologic failure

HIV-1 RNA Resistance Testing

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In care at a public HIV clinic within a PEPFAR-focus sub-Saharan African country (South Africa or Uganda) and living within 100 kilometers of the clinic
• Age ≥ 18 years at the time of enrollment
• Currently prescribed first-line (non-nucleoside reverse transcriptase inhibitor \[NNRTI\]-based) ART for at least 5 months. Switches within first line regimens, including NNRTI and nucleos(t)ide backbone changes are allowed.
• Detectable plasma viral load \> 1,000 copies/mL or dried blood spot viral load \> 1,000 copies/mL within 90 days of enrollment

You may not qualify if:

• Known prior drug resistance
• Prior exposure to PI-based ART
• Current clinical indication to start PI-based ART
• Not planning to remain in the clinic catchment area for the next nine months

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Mbarara University of Science and Technology: collaborator
• University of KwaZulu: collaborator
• Emory University: collaborator
• University of Rochester: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

University of Kwa-Zulu Natal

Durban, South Africa

Location

Mbarara University of Science and Technology

Mbarara, Uganda

Location

Related Publications (5)

• Rautenberg TA, George G, Bwana MB, Moosa MS, Pillay S, McCluskey SM, Aturinda I, Ard K, Muyindike W, Moodley P, Brijkumar J, Johnson BA, Gandhi RT, Sunpath H, Marconi VC, Siedner MJ. Comparative analyses of published cost effectiveness models highlight critical considerations which are useful to inform development of new models. J Med Econ. 2020 Mar;23(3):221-227. doi: 10.1080/13696998.2019.1705314. Epub 2020 Jan 11.

  PMID: 31835974 BACKGROUND

• Siedner MJ, Bwana MB, Moosa MS, Paul M, Pillay S, McCluskey S, Aturinda I, Ard K, Muyindike W, Moodley P, Brijkumar J, Rautenberg T, George G, Johnson B, Gandhi RT, Sunpath H, Marconi VC. The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates. HIV Clin Trials. 2017 Jul;18(4):149-155. doi: 10.1080/15284336.2017.1349028. Epub 2017 Jul 18.

  PMID: 28720039 BACKGROUND

• Siedner MJ, Moosa MS, McCluskey S, Gilbert RF, Pillay S, Aturinda I, Ard K, Muyindike W, Musinguzi N, Masette G, Pillay M, Moodley P, Brijkumar J, Rautenberg T, George G, Gandhi RT, Johnson BA, Sunpath H, Bwana MB, Marconi VC. Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa : An Unblinded Randomized Controlled Trial. Ann Intern Med. 2021 Dec;174(12):1683-1692. doi: 10.7326/M21-2229. Epub 2021 Oct 26.

  PMID: 34698502 RESULT

• Reynolds Z, McCluskey SM, Moosa MYS, Gilbert RF, Pillay S, Aturinda I, Ard KL, Muyindike W, Musinguzi N, Masette G, Moodley P, Brijkumar J, Rautenberg T, George G, Johnson BA, Gandhi RT, Sunpath H, Marconi VC, Bwana MB, Siedner MJ. Who's slipping through the cracks? A comprehensive individual, clinical and health system characterization of people with virological failure on first-line HIV treatment in Uganda and South Africa. HIV Med. 2022 May;23(5):474-484. doi: 10.1111/hiv.13203. Epub 2021 Nov 9.

  PMID: 34755438 RESULT

• Rautenberg TA, Ng SK, George G, Moosa MS, McCluskey SM, Gilbert RF, Pillay S, Aturinda I, Ard KL, Muyindike WR, Musinguzi N, Masette G, Pillay M, Moodley P, Brijkumar J, Gandhi RT, Johnson B, Sunpath H, Bwana MB, Marconi VC, Siedner MJ. Determinants of health-related quality of life in people with Human Immunodeficiency Virus, failing first-line treatment in Africa. Health Qual Life Outcomes. 2023 Aug 21;21(1):94. doi: 10.1186/s12955-023-02179-x.

  PMID: 37605150 DERIVED

Related Links

• De-identified Participant Data Set

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

The study underwent a single major protocol change in 2020, when the study window was extended for participants who were actively enrolled in the trial but unable to return to the clinic for their outcome assessment while COVID-19 transportation restrictions were imposed in both countries (24 March 2020 in Uganda and 27 March 2020 in South Africa.

Results Point of Contact

• Title: Mark Siedner
• Organization: Massachusetts General Hospital/Harvard Medical School

msiedner@mgh.harvard.edu

6177264686

Study Officials

• Mwebesa Bwana, MBChB MPH

  Mbarara University of Science and Technology

  PRINCIPAL INVESTIGATOR

• Yunus Moosa, MBChB PhD

  University of KwaZulu

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: May 26, 2016
• First Posted: June 1, 2016
• Study Start: December 8, 2016
• Primary Completion: September 8, 2020
• Study Completion: September 8, 2020
• Last Updated: March 21, 2023
• Results First Posted: April 25, 2022

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: Data will become publicly available after study completion.
• Access Criteria: Publicly available

Locations

UG (1); ZA (1)