NNRTI Versus PI Containing Regimens for HIV Infected Women After They Have Taken Nevirapine to Prevent Mother-To-Child Transmission of HIV

Condition(s) targeted: HIV Infections

Intervention: Emtricitabine (Drug); Emtricitabine/Tenofovir disoproxil fumarate (Drug); Lopinavir/Ritonavir (Drug); Nevirapine (Drug); Tenofovir disoproxil fumarate (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Shahin Lockman, MD, MSc, Study Chair, Affiliation: Brigham and Women's Hospital and Infectious Diseases Division, Department of Immunology and Infectious Diseases, Harvard School of Public Health

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly included in anti-HIV drug regimens. However, HIV infected women who have previously taken the NNRTI nevirapine (NVP) for the prevention of mother-to-child transmission (MTCT) of HIV may not respond as well to NNRTIs as women who have never taken NVP. Another class of anti-HIV drugs, protease inhibitors (PIs), may be more effective for women who have previously taken NNRTIs. This study will compare the effectiveness of NNRTI- and PI-based regimens in women who have taken NVP for prevention of MTCT of HIV. This study will also compare regimens including an NNRTI with regimens including a PI in women who have never taken NVP.

Official title: Optimal Combination Therapy After Nevirapine Exposure

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: Time from randomization to virologic failure or death

Secondary outcome:

Drug-resistant plasma virus as determined by virologic failure by bulk sequencing

Tolerability and safety of drug regimens

CD4 count

Time from randomization to HIV-related disease progression or death

NVP-associated rash or hepatitis

Adherence to study drug regimens

Measures of resource utilization

Detailed description: NVP is the NNRTI of choice to prevent MTCT of HIV, especially in resource-limited settings. However, prolonged use of NVP may result in drug resistance, decreasing the efficacy of future anti-HIV regimens containing NVP. PIs are more expensive and cause different adverse effects than NNRTIs, but PI-containing regimens may be more effective than NNRTI-containing regimens in treating HIV infected women who previously took NVP for MTCT prophylaxis. This study will compare the efficacy of NNRTI- and PI-containing anti-HIV regimens in women who have previously taken NVP for MTCT of HIV and in women who have never taken NVP.

The study will last a minimum of 48 weeks. Participants will be grouped by previous NVP exposure: participants who have previously taken NVP as MTCT prophylaxis (Trial 1 participants), and participants who have never taken NVP (Trial 2 participants). Participants in each trial will be randomly assigned to one of two arms, A or B. At the start of the study, Arm A participants will receive emtricitabine (FTC) daily, tenofovir disoproxil fumarate (TDF) daily, and NVP daily for the first 14 days, then twice daily. Arm B participants will receive both FTC and TDF daily and lopinavir/ritonavir (LPV/RTV) twice daily. FTC and TDF may be replaced in either arm with the combination drug FTC/TDF.

If participants experience virologic failure, toxicity, or otherwise cannot tolerate their regimens, they will switch to a different regimen. Arm A participants will switch to a regimen of two or more nucleoside reverse transcriptase inhibitors (NRTIs) and LPV/RTV; Arm B participants will switch to a regimen of two or more NRTIs and NVP. Study visits will occur at entry and at Weeks 2, 4, 8, 12, 16, 24, 36, and 48. Visits will consist of a physical exam, medication assessment, and blood collection. Participants will be asked to complete adherence questionnaires at Weeks 4, 12, 24, and 28 and quality of life questionnaires at Weeks 24 and 48.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

Inclusion Criteria for All Participants:

- HIV infected

- CD4 count less than 200 cells/mm3

- Willing to use acceptable forms of contraception

- Parent or guardian willing to provide informed consent, if applicable

- Planning to remain in the same geographical area of residence and are willing to

attend study visits as required

Inclusion Criteria for Trial 1 Participants:

- Previously received NVP for prevention of MTCT of HIV

- Has documentation of all prior doses of NVP used for prevention of MTCT of HIV

- Last dose of NVP for prevention of MTCT of HIV taken at least 6 months prior to study

entry

Exclusion Criteria for All Participants:

- Previously received any antiretrovirals, excluding NVP for MTCT prophylaxis for Trial

1 participants. Participants who have received up to 10 weeks of zidovudine alone and completed this course at least 6 months prior to study entry are not excluded.

- Use of systemic cancer chemotherapy, systemic investigational agents,

immunomodulators, or rifampin within 30 days of study entry

- Known allergy or sensitivity to study drugs or their formulations

- Any condition, including drug or alcohol abuse, that, in the opinion of the

investigator, may interfere with adherence to study regimens

- Serious illness requiring systemic treatment or hospitalization. Participants who

complete therapy or are clinically stable on therapy for at least 30 days prior to study entry are not excluded.

- Tuberculosis (TB) treatment within 30 days prior to study entry

- Require certain medications

- Involuntary incarceration in a correctional facility, prison, or jail for legal

reasons or in a medical facility for treatment of either a psychiatric or physical illness

- Pregnant or breastfeeding

Molepolole BHP Study Clinic, Scottish Livingstone Hospital, Bontleng Gaborone, Botswana; Recruiting
Aida Asmelash, MD, MPH, Phone: (267) 393-0335, Email: aasmelash@bhp.org.bw

KMRI / Walter Reed Project Clinical Research Center, Kericho, Kenya; Recruiting
Hellen Ngeno, Phone: (254 52) 30686, Email: hngeno@wrp-kch.org

Moi University International Clnical Trials Unit, Eldoret 30100, Kenya; Recruiting
Kipruto Kirwa, Phone: 254-53-20-60850, Email: kkr380@yahoo.com

University of North Carolina Project (UNC Project), Lilongwe (265) 175-5056, Malawi; Recruiting
Cecelia Kanyama, MBBS, Phone: (265) 175-5056, Email: zayithway@yahoo.co.uk

Kamuzu Central Hospital, Tidziwe Centre, Lilongwe, Malawi; Recruiting
Cecelia Kanyama, MBBS, Phone: (265) 175-5056, Email: zayithway@yahoo.co.uk

University of Witwatersrand, Johannesburg, South Africa; Recruiting
Pauline S. Vunandlala, BSc, Phone: 27 11 717 2810, Email: idsyndicate@witshealth.co.za

Chris Hani Baragwanath Hospital, Johannesburg, Johannesburg, South Africa; Recruiting
Cornelia Steyn, Phone: 27 11 989 9709, Email: steync@hivsa.com

Joint Clinical Research Centre (JCRC), Kampala, Uganda; Recruiting
Sandra Rwambuya, Phone: (256) 413-42521, Email: dxr23@case.edu

Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia; Recruiting
Brad Fuller, BSN, MPH, Phone: 260-1-293-661, Ext: 159, Email: brad@cidrz.org

The Gaborone BHP Study Clinic, Bontleng, Gaborone, Botswana; Recruiting
Aida Asmelash, MD, MPH, Phone: (267) 393-0335, Email: aasmelash@bhp.org.bw

University of Zimbabwe, Avondale, Harare, Zimbabwe; Recruiting
Patricia Mutama, Phone: 263 91 418 436, Email: pmutama@uzcrc.co.zw

University of KwaZulu Natal, Durban, KZN 4013, South Africa; Recruiting
Fawzia Williamson, Phone: 27 31 260 4365, Email: amodf1@nu.ac.za

Click here for more information about emtricitabine

Click here for more information about emtricitabine/tenofovir disoproxil fumarate

Click here for more information about lopinavir/ritonavir

Click here for more information about nevirapine

Click here for tenofovir disoproxil fumarate

Click here for more information about nucleoside reverse transcriptase inhibitors

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Related publications:

Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63. Review.

Eshleman SH, Mracna M, Guay LA, Deseyve M, Cunningham S, Mirochnick M, Musoke P, Fleming T, Glenn Fowler M, Mofenson LM, Mmiro F, Jackson JB. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS. 2001 Oct 19;15(15):1951-7.

Harris M. Efficacy and durability of nevirapine in antiretroviral-experienced patients. J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S53-8. Review.

Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, Ariyadej S, Leenasirimakul P, Hammer S, Lallemant M; Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004 Jul 15;351(3):229-40. Epub 2004 Jul 09.

Nightingale S, Dabis F. Evidence behind the WHO guidelines: hospital care for children: what antiretroviral agents and regimens are effective in the prevention of mother-to-child transmission of HIV? J Trop Pediatr. 2006 Aug;52(4):235-8. Review. No abstract available.

Turner D, Wainberg MA. HIV transmission and primary drug resistance. AIDS Rev. 2006 Jan-Mar;8(1):17-23. Review.

Starting date: October 2005
Ending date: October 2009
Last updated: September 29, 2008