Clinical trial NCT00099632: Comparison of Three Anti-HIV Regimens to Prevent Nevirapine Resistance in Women Who Take Nevirapine During Pregnancy
Official title: Maintaining Options for Mothers Study (MOMS): A Phase II Randomized Comparison of Three Antiretroviral Strategies Administered for 7 or 21 Days to Reduce the Emergence of Nevirapine Resistant HIV-1 Following a Single Intrapartum Dose of Nevirapine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Treatment Naive
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2004-12-20
Enrollment: 484
Sex: FEMALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: HIV infected pregnant women may take single-dose nevirapine (SD NVP) prior to giving birth to prevent mother-to-child transmission (MTCT) of HIV. However, SD NVP may cause NVP resistance in the mother, potentially ruling out some treatment options in the future. The purpose of this study is to determine which of three anti-HIV drug regimens most effectively reduces the development of maternal NVP resistance in HIV infected pregnant women. The effectiveness of short-term (7 day therapy) versus long-term (21-day therapy) regimens will also be compared.

The study hypotheses are: 1) intrapartum SD NVP with a 21-day course of antiretroviral therapy (ART) results in less frequent selection of NVP-resistant HIV-1 variants than intrapartum SD NVP with a 7-day course of ART, and 2) a 7- or 21-day course of lamivudine/zidovudine (3TC/ZDV), emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), or lopinavir/ritonavir (LPV/r) following SD NVP will not select nucleoside reverse transcriptase inhibitor (NRTI)- or protease inhibitor (PI)- resistant HIV-1 variants.

Detailed description: A major disadvantage of giving SD NVP is the potential for maternal development of NVP resistance and additional resistance to other nonnucleoside reverse transcriptase inhibitors (NNRTI) in the mother; as a result, future treatment options may be limited for these HIV infected women. The purpose of the study is to determine which of three ART regimens most effectively deters the development of maternal NVP resistance in HIV infected pregnant women postpartum. This study also compared the effectiveness of short-term versus long-term ART in discouraging the development of maternal NVP resistance.

Some mothers in this study received ZDV monotherapy prior to SD NVP administration; initiation of ZDV monotherapy was at the discretion of the site investigator and was be provided by this study. Randomization was stratified by receipt of ZDV monotherapy during the pregnancy.

Prior to labor, mothers were randomly assigned to receive SD NVP at the onset of labor and one of three postpartum ART regimens: 3TC/ZDV, FTC/TDF, and LPV/r. In addition, participants were randomly assigned to receive 7 or 21 days of their assigned postpartum treatment.

Mothers were followed for 96 weeks following delivery; there were 11 study visits for mothers during the study. At the onset of labor, medical and medication history, a targeted physical exam, and an obstetrical exam occurred. Additional physical exams occurred on Day 1 and Weeks 1 and 3. Blood collection occurred at 8 study visits between Weeks 3 and 96. Infants were followed for up to 96 weeks after birth; there were 8 study visits for infants during the study. Infants who had ever been breastfed had study visits at Weeks 16, 24, 48, and 96, and at about 1 and 2 years of age. A physical exam, medication history, and blood collection occurred at each infant visit. Mothers and infants could be prescribed continuing ART, but such ART was be provided by this study.

Eligibility criteria: Inclusion Criteria for Mothers:

* HIV-1 infected
* CD4 count 250 cells/mm3 or greater within 30 days of study entry
* The following laboratory values obtained within 30 days prior to study entry: absolute neutropil count \>= 750/mm3; hemoglobin \>= 8.0 g/dL; platelet count \>= 50,000/mm3; calculated creatinine clearance (Cockcroft-Gault formula) \> 60 mL/min; AST(SGOT) and ALT(SGPT) \< 5 x ULN; total bilirubin \< 1.5 X ULN.
* Pregnant with a viable fetus at 28 to 38 weeks gestation at study entry.
* Willing to give birth to baby in a hospital or clinic
* Written informed consent from parent or guardian, if applicable

Exclusion Criteria for Mothers:

* Any ART, including single-dose NVP, prior to study entry. Mothers who receive ZDV monotherapy prior to labor under the supervision of the site investigator are not excluded.
* Known allergy or sensitivity to study drugs or their formulations
* Current drug or alcohol abuse that may interfere with the study
* Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 14 days prior to study entry are not excluded.
* Hepatitis B surface antigen positive within 180 days prior to study entry
* Active tuberculosis infection requiring treatment
* Prior enrollment in this study
* Expect to use ART, except ZDV monotherapy, prior to onset of labor
* Expect to use ART other than study medications from delivery to 9 weeks postpartum

Primary outcomes:
measure: Number of Participants With New Circulating Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)-Resistant Variants as Detected by Standard Composite (Bulk) Genotyping
timeFrame: 2 and 6 weeks after completion of treatment
Secondary outcomes:
measure: Number of Participants With New Circulating NRTI-resistant Variants Detected by Standard Composite (Bulk) Genotyping.
timeFrame: 2 and 6 weeks after completion of treatment
measure: Number of Participants With New PI-resistant Variants as Detected by Standard Composite (Bulk) Genotyping.
timeFrame: 2 and 6 weeks after completion of treatment
measure: Severe (Grade 3) and Higher Adverse Events and Any Grade Adverse Event That Leads to a Treatment Change From First Day of Study Treatment to Week 12
timeFrame: From first day of study treatment to week 12
measure: Number of Participants Who Discontinued Study Treatment Prematurely
timeFrame: From first day of study treatment to last day of study treatment (up to 21 days)
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Pune
country: India
facility: Byramjee Jeejeebhoy Government Medical College CRS
state: Maharashtra
city: Chennai
country: India
facility: Chennai Antiviral Research and Treatment (CART) CRS
state: Tamil Nadu
city: Blantyre
country: Malawi
facility: Blantyre CRS
city: Johannesburg
country: South Africa
facility: Wits Helen Joseph Hospital CRS (Wits HJH CRS)
state: Gauteng
city: Westville
country: South Africa
facility: Durban International CRS
state: KwaZulu-Natal
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical CRS
city: Kampala
country: Uganda
facility: Joint Clinical Research Center (JCRC)/Kampala CRS
Study officials:
affiliation: Department of Obstetrics/Gynecology, Perinatal Medicine, University of Washington Medical Center
name: Jane Hitti, MD, MPH
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh
name: Deborah McMahon, MD
role: STUDY_CHAIR
References:
citation: Cunningham CK, Chaix ML, Rekacewicz C, Britto P, Rouzioux C, Gelber RD, Dorenbaum A, Delfraissy JF, Bazin B, Mofenson L, Sullivan JL. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a substudy of pediatric AIDS clinical trials group protocol 316. J Infect Dis. 2002 Jul 15;186(2):181-8. doi: 10.1086/341300. Epub 2002 Jun 26.
citation: Eshleman SH, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Rev. 2002 Apr-Jun;4(2):59-63.
citation: 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. doi: 10.1056/NEJMoa041305. Epub 2004 Jul 9.
citation: Lyons FE, Coughlan S, Byrne CM, Hopkins SM, Hall WW, Mulcahy FM. Emergence of antiretroviral resistance in HIV-positive women receiving combination antiretroviral therapy in pregnancy. AIDS. 2005 Jan 3;19(1):63-7. doi: 10.1097/00002030-200501030-00007.
citation: Sullivan JL. Prevention of mother-to-child transmission of HIV--what next? J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S67-72. doi: 10.1097/00126334-200309011-00010.
citation: McMahon D, Noel F, Zheng L, Kabanda J, Halvas E, Taulo F, Kumarasamy N, Wallis C, Hughes M, Mellors J. Suppression of NVP Resistance with 7- vs 21-day ARV Regimens after Single-dose NVP: Results of A5207. Presented at 18th Conference on Retroviruses & Opportunistic Infections (CROI 11) on 03/01/2011 at Boston, MA
citation: Hong F, Halvas E, Chan E, Zheng L, Hughes M, Hitti J, McMahon D, Mellors J. Suppression of Minor NVP-Resistant Variants With 7- vs. 21-Day Antiretroviral Regimens After Single Dose Nevirapine. Presented at 20th Anniversary of the International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies on Jun 9, 2011, Los Cabos, Mexico
citation: McMahon DK, Zheng L, Hitti J, Chan ES, Halvas EK, Hong F, Kabanda J, Taulo F, Kumarasamy N, Bonhomme J, Wallis CL, Klingman KL, Hughes MD, Mellors JW. Greater suppression of nevirapine resistance with 21- vs 7-day antiretroviral regimens after intrapartum single-dose nevirapine for prevention of mother-to-child transmission of HIV. Clin Infect Dis. 2013 Apr;56(7):1044-51. doi: 10.1093/cid/cis1219. Epub 2013 Jan 8.