FacebookTwitterYouTube

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.

HIVNET 012 Protocol V2.0


Protocol Status: Concluded

Study Summary

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


HIVNET 012 Publications

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.

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.

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.

Jackson JB, Becker-Pergola G, Guay LA, Musoke P, Mracna M, Fowler MG, Mofenson LM, Mirochnick M, Mmiro F, Eshleman SH. Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS. 2000, 14: F111-5.

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, 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, Jackson JB. Nevirapine resistance after single dose prophylaxis. AIDS Reviews. 2002, 4: 59-63.

Jackson JB, Barnett S, Piwowar-Manning E, Apuzzo L, Raines, C, Hendrix C, Hamzeh F, Gallant J. A Phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1 transmission in uninfected subjects at high risk. AIDS. 2003, 17: 547-53.

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.

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.

Jackson B, Mmiro F, HIVNET 012 Study Team. HIVNET 012 and Petra (authors' reply). Lancet. 2004, 363: 244.

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, 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.

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.

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.

Church JD, Jones D, Flys T, Hoover D, Marlowe N, Chen S, Shi C, Eshleman JR, Guay LA, Jackson JB, Kumwenda N, Taha TE, Eshleman SH. Sensitivity of the ViroSeq HIV-1 genotyping system for detection of the K103N resistance mutation in HIV-1 subtypes A, C, and D. J Mol Diagn. 2006, 8: 430-2 PMCID: 1867617.

Eshleman SH, Church JD, Chen S, Guay LA, Mwatha A, Fiscus SA, Mmiro F, Musoke P, Kumwenda N, Jackson JB, Taha TE, Hoover DR. Comparison of HIV-1 mother-to-child transmission after single-dose nevirapine prophylaxis among African women with subtypes A, C, and D. J Acquir Immune Defic Syndr. 2006, 42: 518-21 PMID 16810119.

Eshleman SH, Hoover DR, Hudelson SE, Chen S, Fiscus SA, Piwowar-Manning E, Jackson JB, Kumwenda NI, Taha T. Development of nevirapine resistance is reduced by using infant-only nevirapine plus zidovudine post-exposure prophylaxis to prevent HIV-1 mother–to-child transmission. J Infect Dis. 2006, 193: 479-81 PMID:16425125.

Eshleman SH, Jones D, Galovich J, Paxinos EE, Petropoulos CJ, Jackson JB, Parkin N. Phenotypic Drug Resistance Patterns in Subtype A HIV-1 Clones with Nonnucleoside Reverse Transcriptase Resistance Mutations. AIDS Res Hum Retroviruses. 2006, 22: 289-93 PMID:16545016.

Flys TS, Chen S, Jones DC, Hoover DR, Church JD, Fiscus SA, Mwatha A, Guay LA, Mmiro F, Musoke P, Kumwenda N, Taha TE, Jackson JB, Eshleman SH. Quantitative analysis of HIV-1 variants with the K103N resistance mutation after single-dose nevirapine in women with HIV-1 subtypes A, C, and D. J Acquir Immune Defic Syndr. 2006, 42: 610-13 PMID 16773030.

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 PMID: 16511414.

Church JD, Hudelson SE, Guay LA, Chen S, Hoover DR, Parkin N, Fiscus SA, Mmiro F, Musoke P, Kumwenda N, Jackson JB, Taha TE, Eshleman SH. HIV type 1 variants with nevirapine resistance mutations are rarely detected in antiretroviral drug-naive African women with subtypes A, C, and D. AIDS Res Hum Retroviruses. 2007, 23: 764-68 PMID 17604538.

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 PMID 17262714.

Flys TS, Mwatha A, Guay LA, Nakabiito C, Donnell D, Musoke P, Mmiro F, Jackson JB, and Eshleman SH. Detection of K103N in Ugandan women after repeated exposure to single dose nevirapine. AIDS. 2007, 21: 2077-82 PMID 17885298.

Huang W, Eshleman SH, Toma J, Fransen S, Stawiski E, Paxinos EE, Whitcomb JM, Young AM, Donnell D, Mmiro F, Musoke P, Guay LA, Jackson JB, Parkin NT, Petropoulos CJ. Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations. J Virol. 2007, 81: 7885-93 PMCID: 1951291.

Church JD, Huang W, Mwatha A, Toma J, Stawiski E, Donnell D, Guay LA, Mmiro F, Musoke P, Jackson JB, Parkin N, Eshleman SH. HIV-1 tropism and survival in vertically infected Ugandan infants. J Infect Dis. 2008, 197: 1382-8 PMCID: 3075545.

Musoke PM, Young AM, Owor MA, Lubega IR, Brown ER, Mmiro FA, Mofenson LM, Jackson JB, Fowler MG, Guay LA. Total lymphocyte count: not a surrogate marker for risk of death in HIV-infected Ugandan children. J Acquir Immune Defic Syndr. 2008, 49: 171-8. PMCID:2721476.

Towler WI, Church JD, Eshleman JR, Fowler MG, Guay LA, Jackson JB, Eshleman SH. Analysis of nevirapine resistance mutations in cloned HIV type 1 variants from HIV-infected Ugandan infants using a single-step amplification-sequencing method (AmpliSeq). AIDS Res Hum Retroviruses. 2008, 24: 1209-13. PMCID:2562759.

Church JD, Mwatha A, Bagenda D, Omer SB, Donnell D, Musoke P, Nakabiito C, Eure C, Bakaki P, Matovu F, Thigpen MC, Guay LA, McConnell M, Fowler MG, Jackson JB, and Eshleman SH. In utero HIV infection is associated with an increased risk of nevirapine resistance in ugandan infants who were exposed to perinatal single dose nevirapine. AIDS Res Hum Retroviruses. 2009, 25: 673-7 PMCID: 2752753.

Huang W, Eshleman SH, Toma J, Stawiski E, Whitcomb JM, Jackson JB, Guay L, Musoke P, Parkin N, Petropoulos CJ. Vertical transmission of X4-tropic and dual-tropic HIV-1 in five Ugandan mother-infant pairs. AIDS. 2009, 23: 1903-8 PMCID: 2764460.

Mmiro FA, Aizire J, Mwatha AK, Eshleman SH, Donnell D, Fowler MG, Nakabiito C, Musoke P, Jackson JB, Guay LA. Predictors of early and late mother-to-child transmission of HIV in a breastfeeding population: HIV Network for Prevention Trials 012 experience, Kampala, Uganda. J Acquir Immune Defic Syndr. 2009, 52: 32-9 PMCID: 2767188.

Church JD, Huang W, Mwatha A, Musoke P, Jackson JB, Bagenda D, Omer SB, Donnell D, Nakabiito C, Eure C, Guay LA, Taylor A, Bakaki PM, Matovu F, McConnell M, Fowler MG, Eshleman SH. Analysis of HIV tropism in Ugandan infants. Curr HIV Res. 2010, 8: 498-503 PMCID: 3075545.

Laeyendecker O, Church JD, Oliver AE, Mwatha A, Owen SM, Donnell D, Brookmeyer R, Musoke P, Jackson JB, Guay L, Nakabiito C, Quinn TC, Eshleman SH. Pregnancy does not affect HIV incidence test results obtained using the BED capture enzyme immunoassay or an antibody avidity assay. PLoS One. 2010, 5: e 13259 PMCID: 2952593.

Onyango-Makumbi C, Bagenda D, Mwatha A, Omer SB, Musoke P, Mmiro F, Zwerski SL, Kateera BA, Musisi M, Fowler MG, Jackson JB, Guay LA. Early Weaning of HIV-Exposed Uninfected Infants and Risk of Serious Gastroenteritis: Findings from Two Perinatal HIV Prevention Trials in Kampala, Uganda. J Acquir Immune Defic Syndr. 2010, 53: 20-27 PMCID: 2888913.

Towler WI, James MM, Ray SC, Wang L, Donnell D, Mwatha A, Guay L, Nakabiito C, Musoke P, Jackson JB, Eshleman SH. Analysis of HIV diversity using a high-resolution melting assay. AIDS Res Hum Retroviruses. 2010, 26: 913-8 PMCID: 2920076.