HIVNET 012
A Phase IIB Trial to Determine the Efficacy of Oral AZT and the Efficacy of Oral Nevirapine for the Prevention of Vertical Transmission of HIV-1 Infection in Pregnant Ugandan Women and Their Neonates
What is HIVNET 012?HIVNET 012 was a randomized clinical trial to evaluate the efficacy of two short course antiretroviral drug regimens for prevention of HIV transmission from infected mothers to their babies. The overall goal of the study was to identify a safe, effective means of preventing mother-to-infant HIV transmission that would be applicable and affordable in resource-limited settings. Enrollment in the study began in 1997 and was completed in 1999. Early results were released in 1999. Follow-up continued through July 2004.
This landmark study found that a short intrapartum/neonatal regimen of Nevirapine given to the mother at the onset of labor and to the infant within 72 hours of life reduced the risk of perinatal HIV transmission among breastfeeding women in Uganda by 47% at 14-16 weeks and by 41% at 18 months compared to a short intrapartum/neonatal regimen of AZT. This simple, safe regimen has been adopted as the standard of care in resource-limited countries worldwide and has been endorsed by UNAIDS and many other international health organizations. |
Protocol Status: Enrolling
Study Purpose: To determine the efficacy of oral AZT and the efficacy of oral nevirapine for the prevention of vertical transmission of HIV-1 infection from pregnant Ugandan women to their infants.
Study Design: This study was originally designed as a randomized, double-blind, three-arm placebo-controlled trial to determine the efficacy of a short course of Nevirapine and the efficacy of a short course of AZT for the prevention of mother to infant HIV transmission, with the goal of finding a safe, effective means of preventing mother-to-infant transmission that would be applicable and affordable in resource-limited countries. Soon after the study was initiated, results of another study were released which led to the placebo arm being dropped. Enrollment into the two active agent arms of the study (open-label Phase IIB component) was continued to provide preliminary screening data on the efficacy of the two antiretroviral regimens in an effort to select one of the two for inclusion in a re-designed efficacy trial comparing the selected regimen with an appropriate control.
Study Population: HIV-1 infected Ugandan women and their neonates
Study Size: The original study size was 1500 mother-infant pairs. 642 evaluable mother/infant pairs were enrolled in the interim (phase IIB) study.
Study Sites: Kampala, Uganda
Study Duration: Enrollment took place over 18 months. The original study design included 18 months of follow-up for infants and 6 weeks of follow-up for mothers; follow-up was later extended to five years.
Treatment Regimen: After the placebo arm was dropped, mother-infant pairs were randomized in a 1:1 ratio to one of two arms. In one arm mothers received a single oral 200 mg dose of NVP at onset of labor and their infants received a single oral 2 mg/kg dose of NVP within 72 hours or birth. In the other arm, mothers received a single oral 600 mg bolus dose of AZT at onset of labor, then 300 mg of AZT every 3 hours until delivery and their infants received an oral 4 mg/kg dose of AZT once a day for 7 days.
Primary Objectives: To determine the rate of HIV-1 infection in infants born to study participants in each arm of the study as determined by a positive qualitative plasma HIV-1 RNA result confirmed at the next visit by a positive culture or quantitative plasma RNA level on a different specimen for infants < 18 months of age. To determine the proportion of infants who are alive and free of HIV at 18 months. To evaluate the safety/tolerance of oral NVP and oral AZT given to pregnant Ugandan women during labor and their neonates during the first week of life.
Secondary Objectives: Rates of disease progression in the infected infants in each arm Infant survival in each arm (mortality, regardless of HIV infection) Relationship of maternal plasma RNA levels at delivery with risk of perinatal transmission The rate of infant death or HIV-1 infection
Study Purpose: Increase scientific knowledge through basic research on mechanisms of transmission, innate immunity, protective immune responses and host defense at the mucosal level to facilitate the development of vaccines to prevent and/or control mucosal HIV infection.
Study Design: Multi-site, prospective, observational, cohort study
Study Population: Participants with acute HIV-1 infection (AHI), and with established HIV infection as controls: Group 1:Acute HIV-1 infection: approximately 30 that fall into two sub-groups: Group 1a: Participants with AHI who are antiretroviral therapy (ART) naïve. Group 1b: Participants with AHI, on ART, with suppressed viremia. Group 2: Established HIV-1 infection: approximately 10.
Study Size: ~40
Study Sites:
Study Duration: Participants will be enrolled over the course of approximately a five year period. The number of study visits will be dictated by the procedure performed, and will range from up to 2 visits, to up to 4 or 5 visits.
Treatment Regimen:
Primary Objectives: To determine the host mucosal acquired and both systemic and mucosal innate immune responses that contribute to virus control and/or protection against infection with HIV-1 by: Determining the degree of CD4+ cell loss in GI mucosa in AHI patients. Measuring alterations in HIV-specific mucosal immunity. Analyzing innate immune functions in AHI. Studying the polyspecificity of IgG, IgA and IgM against transmitted HIV at mucosal sites. Measuring T and B cell responses in mucosal samples of AHI or control subjects.
Secondary Objectives: To measure viral replication, cellular viral burden, and persistent viral infection in the circulating and gut-associated lymphoid systems in acute HIV-1 infection by: Obtaining viral isolates from the GI tract in AHI participants Quantitating persistent, latent infection within resting T cells
SDMC Protocol Specialist: Lynda Marie Emel get info
Protocol Chair: J. Brooks Jackson get info
CORE Protocol Specialist: Marybeth McCauley get info
CORE Protocol Specialist: Missie Allen get info
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Makerere University- JHU Research Collaboration {MUJHU CARE LTD} CRS 30293 Kampala, Uganda |
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Duke Univ. Med. Ctr., Infectious Diseases Clinic CHAVI CRS
Durham, United States |
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Becker-Pergola G, Mellquist JL, Guay L, Mmiro F, Ndugwa C, Kataaha P, Jackson JB, Eshleman SH. Identification of diverse HIV type 1 subtypes and dual HIV type 1 infection in pregnant Ugandan women. AIDS Res Hum Retroviruses. 2000, 16: 1099-04 Cates W Jr, Allen M. Mother-to-child HIV-1 transmission. Lancet. 2000, 356: 945 Eshleman SH, Guay LA, Fleming T, Mwatha A, Mracna M, Becker-Pergola G, Musoke, Mmiro F, Jackson JB. Survival of Ugandan infants with subtype A and D HIV-1 infection (HIVNET 012). J Acquir Immune Defic Syndr. 2002, 31: 327-30 Eshleman SH, Guay LA, Mwatha A, Brown E, Musoke P, Mmiro F, Jackson JB. Comparison of mother-to-child transmission rates in Ugandan women with subtype A versus D HIV-1 who received single-dose nevirapine prophylaxis: HIV Network For Prevention Trials 012. J Acquir Immune Defic Syndr. 2005, 39: 593-97 Eshleman SH, Guay LA, Mwatha A, Brown ER, Cunningham SP, Musoke P, Mmiro F, Jackson JB. Characterization of nevirapine resistance mutations in women with subtype A vs. D HIV-1 6-8 weeks after single-dose nevirapine (HIVNET 012).. J Acquir Immune Defic Syndr. 2004, 35: 126-30 Eshleman SH, Guay LA, Mwatha A, Cunningham SP, Brown ER, Musoke P, Mmiro F, Jackson JB. Comparison of nevirapine (NVP) resistance in Ugandan women 7 days vs. 6-8 weeks after single-dose nvp prophylaxis: HIVNET 012. AIDS Res Hum Retroviruses. 2004, 20: 595-99 Eshleman SH, Guay LA, Wang J, Mwatha A, Brown ER, Musoke P, Mmiro F, Jackson JB. Distinct Patterns of Emergence and Fading of K103N and Y181C in Women With Subtype A vs. D After Single-Dose Nevirapine: HIVNET 012. J Acquir Immune Defic Syndr. 2005, 40: 24-9 Eshleman SH, Hoover DR, Chen S, Hudelson SE, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Jackson JB, Kumwenda N, Taha T. Nevirapine (NVP) resistance in women with HIV-1 subtype C, compared with subtypes A and D, after the administration of single-dose NVP. J Infect Dis. 2005, 192: 30-6 Eshleman SH, Hoover DR, Chen SH, Hudelson SH, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Jackson JB, Kumwenda N, and Taha T. Resistance after single dose nevirapine prophylaxis emerges in a high portion of Malawian newborns. AIDS. 2005, 19: 2167-68 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, 15: 1951-7 Eshleman SH, Wang J, Guay LA, Cunningham SP, Mwatha A, Brown ER, Musoke P, Mmiro F, Jackson JB. Distinct patterns of selection and fading of K103N and Y181C are seen in women with subtype A vs. D HIV-1 after single dose nevirapine: HIVNET 012. Antiviral Therapy. 2004, 9: S59 Flys T, Nissley DV, Claasen CW, Jones D, Shi C, Guay LA, Musoke P, Mmiro F, Strathern JN, Jackson JB, Eshleman JR, Eshleman SH. Sensitive drug-resistance assays reveal long-term persistence of HIV-1 variants with the K103N nevirapine (NVP) resistance mutation in some women and infants after the administration of single-dose NVP: HIVNET 012. J Infect Dis. 2005, 192: 24-9 Flys TS, Donnell D, Mwatha A, Nakabiito C, Musoke P, Mmiro F, Jackson JB, Guay LA, Eshleman SH. Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission. J Infect Dis. 2007, 195: 711-5 Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999, 354: 795-802 Jackson B, Mmiro F, HIVNET 012 Study Team. HIVNET 012 and Petra (authors' reply). Lancet. 2004, 363: 244 Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003, 362: 859-68 Jackson JB, Parsons T, Musoke P, Nakabiito C, Donnell D, Fleming T, Mirochnick M, Mofenson L, Fowler MG, Mmiro F, Guay L. Association of cord blood nevirapine concentration with reported timing of dose and HIV-1 transmission. AIDS. 2006, 20: 217-22 Jones D, Parkin N, Hudelson SE, Guay LA, Musoke P, Mmiro F, Jackson JB, Eshleman SH. Genetic linkage of nevirapine resistance mutations in HIV type 1 seven days after single-dose nevirapine. AIDS Res Hum Retroviruses. 2005, 21: 319-24 Marseille E, Kahn JG, Mmiro F, Guay L, Musoke P, Fowler MG, Jackson JB. Cost effectiveness of single-dose nevirapine regimen for mothers and babies to decrease vertical HIV-1 transmission in sub-Saharan Africa. Lancet. 1999, 354: 803-9 Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T, Elliott T, Horton S, Dransfield K, Pav JW, Murarka A, Allen M, Fowler MG, Mofenson L, Hom D, Mmiro F, Jackson JB. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS. 1999, 13: 479-86 |
