2
Overview of HIVNET 012

HIVNET 012 initially was a randomized, double-blind, placebo-controlled Phase III clinical trial designed to compare the safety and efficacy of short-course oral nevirapine (NVP) and zidovudine (ZDV) for preventing mother-to-child transmission of HIV-1. The original target enrollment was 1,500 mother/infant pairs. Pregnant HIV-infected women were randomized to four treatment arms: oral ZDV (n=500), ZDV placebo (n=250), single-dose NVP (n=500), and NVP placebo (n=250) (Jackson et al., 1997). The study included placebo arms because the efficacy of short-course oral antiretroviral regimens for preventing mother-to-child transmission—whether of ZDV or NVP—for preventing mother-to-child transmission had not yet been proven. Enrollment in HIVNET 012 began in November 1997, under a protocol approved by institutional review boards in Uganda and the United States (Jackson et al., 2003).

In February 1998, a randomized, double-blind, placebo-controlled trial sponsored by the U.S. Centers for Disease Control and Prevention in Thailand of 393 mother/infant pairs showed that a short course of oral ZDV could reduce HIV-1 transmission by about 50% over a placebo—to an overall rate of 10%—in a non-breastfeeding population (CDC, UNAIDS, NIH, and NRS, 1998; Shaffer et al., 1999).1 As a result, HIVNET 012 researchers formally dropped the placebo arms in a letter of amendment

1  

The target sample size of 392 women had the ability to detect a 50% reduction in transmission risk—from 24% to 12%—with 80% power and a Type I error rate of 5% (Shaffer et al., 1999).



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Review of the HIVNET 012 Perinatal HIV Prevention Study 2 Overview of HIVNET 012 HIVNET 012 initially was a randomized, double-blind, placebo-controlled Phase III clinical trial designed to compare the safety and efficacy of short-course oral nevirapine (NVP) and zidovudine (ZDV) for preventing mother-to-child transmission of HIV-1. The original target enrollment was 1,500 mother/infant pairs. Pregnant HIV-infected women were randomized to four treatment arms: oral ZDV (n=500), ZDV placebo (n=250), single-dose NVP (n=500), and NVP placebo (n=250) (Jackson et al., 1997). The study included placebo arms because the efficacy of short-course oral antiretroviral regimens for preventing mother-to-child transmission—whether of ZDV or NVP—for preventing mother-to-child transmission had not yet been proven. Enrollment in HIVNET 012 began in November 1997, under a protocol approved by institutional review boards in Uganda and the United States (Jackson et al., 2003). In February 1998, a randomized, double-blind, placebo-controlled trial sponsored by the U.S. Centers for Disease Control and Prevention in Thailand of 393 mother/infant pairs showed that a short course of oral ZDV could reduce HIV-1 transmission by about 50% over a placebo—to an overall rate of 10%—in a non-breastfeeding population (CDC, UNAIDS, NIH, and NRS, 1998; Shaffer et al., 1999).1 As a result, HIVNET 012 researchers formally dropped the placebo arms in a letter of amendment 1   The target sample size of 392 women had the ability to detect a 50% reduction in transmission risk—from 24% to 12%—with 80% power and a Type I error rate of 5% (Shaffer et al., 1999).

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Review of the HIVNET 012 Perinatal HIV Prevention Study (known as Amendment I) to the protocol, and stopped enrollment on February 18, 1998. HIVNET 012 was redesigned and reopened on April 6, 1998—with approval of the Ugandan and U.S. institutional review boards—as a randomized, open-label, Phase IIB clinical trial.2 In this newly approved protocol, the target enrollment was 400 to 600 mother/infant pairs randomized in a 1:1 ratio. Women in the NVP arm of the trial would receive a single, oral 200-milligram dose of NVP at the onset of labor. Their infants would receive a single, oral 2-milligram-per-kilogram-of-body-weight dose of NVP suspension within 72 hours of birth. Women in the ZDV arm would receive 600 milligrams of oral ZDV at the onset of labor, followed by 300-milligram doses every 3 hours during labor. Their infants would receive oral 4-milligram-per-kilogram-of-body-weight doses of ZDV twice daily for the first 7 days of life. Boehringer Ingelheim Pharmaceuticals and GlaxoWellcome, respectively, donated the study drugs. The HIVNET 012 protocol specified follow-up of mothers for adverse events for 6 weeks after delivery. Infants were followed for adverse events until 6 weeks of age, and for serious adverse events until 18 months of age. Researchers graded such events based on toxicity tables from the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) for neonates, children, and adults, ranging from grade 1 (mild) to grade 4 (life-threatening). The 1997 Study Specific Procedures manual included the DAIDS toxicity tables, as well as a special grading system for adverse experiences related to skin rashes and dermatitis and hemoglobin in mothers (Jackson et al., 1997). As the medications were given for a week or less, the study did not modify drug doses for toxicity. The primary endpoints for evaluating the efficacy of the drug regimens were HIV infection and HIV-1-free survival (the absence of HIV-1 infection or death from any cause) of infants at 6–8 weeks, 14–16 weeks, and 18 months of age. Researchers used a qualitative RNA polymerase chain reaction (PCR) assay to determine the infants’ HIV-1 status. Positive test results were confirmed by a quantitative HIV-1 RNA PCR assay3 or HIV-1 culture on a second blood sample. For infants who tested positive for HIV-1, the quantitative HIV-1 RNA PCR assay was performed at each scheduled 2   A Phase IIb trial is sometimes viewed as an intermediate safety and efficacy trial. In this case the trial was designed to provide preliminary comparisons of the efficacy and safety of the two treatments. 3   Both quantitative and qualitative plasma HIV-1 RNA measurements were assessed with Roche AMPLICOR MONITOR (Roche Diagnostics, Indianapolis, IN) with 1.0 version kit with additional primers if tested prior to November 1998, and with the 1.5 version primers after that (Guay et al., 1999).

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Review of the HIVNET 012 Perinatal HIV Prevention Study blood draw, including at 12 and 18 months of age. Investigators used enzyme immunoassay to test for HIV-1 antibodies at 18 months of age. Positive test results were confirmed by an HIV-1 Western blot assay (Cambridge Biotech, Rockville, MD). Researchers amended the study protocol in February 2000 (Amendment II) in response to findings in other studies that some women could develop viral resistance to NVP, and that some children treated with various antiretroviral drugs in utero or perinatally could possibly experience mitochondrial toxicity. The modification entailed extending follow-up of women in the NVP arm and all children in the 18-month study to 5 years, with yearly evaluations for NVP resistance in women who had received NVP (HIVNET 012 Investigators, 2000). RESULTS HIVNET 012 enrolled 645 pregnant women between November 1997 and April 1999, when the study reached its target enrollment. The analysis of the study did not include 19 women randomized to placebo before February 18, 1998. The first of two papers, published in The Lancet in 1999, reported safety and efficacy data through 14–16 weeks of follow-up of the infants (Guay et al., 1999). This paper reported that the study had randomized 313 pregnant women to ZDV, 313 to NVP, and 19 to placebo. Of infants exposed to ZDV and NVP, 307 and 309, respectively, could be evaluated for HIV-1-free survival. The relative risk of HIV-1 infection was 0.53 in the NVP as compared to the ZDV arm (a 47% reduction) (see Table 2.1).4 The 1999 Lancet paper also analyzed adverse events and toxic effects based on the first 556 mother/infant pairs assigned to treatment with ZDV (279 pairs) and NVP (277 pairs). The authors reported that “the rates of maternal serious adverse events were similar in the two groups (4.4% in the ZDV group and 4.7% in the NVP group),” and that “the occurrence of clinical or laboratory abnormalities in mothers was similar in the two groups.” The authors also reported that for infants, “the rate of occurrence of serious adverse events in the two groups was similar up to the 18-month visit (19.8% in the ZDV group and 20.5% in the NVP group).” The “frequency and severity of laboratory-detected toxic effects … were similar in the two groups.” 4   The authors report the “efficacy” of NVP compared with ZDV as 47%, which is actually 100*(1-RR)—that is, the percentage reduction in risk. Standard relative risks are reported above.

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE 2.1 Numbers (percentages) of Infants with HIV-1 Infection and HIV-1 Infection or Death at Ages 1–3 Days, 6–8 Weeks, and 14–16 Weeks, by Study Arm   Zidovudine Arm (total number of infants=307) Nevirapine Arm (total number of infants=309)   HIV-1 Infection HIV-1 Infection P value Day 1–3 31 (10.4%) 25 (8.2%) 0.35 Week 6–8 59 (21.3%) 35 (11.9%) 0.0027 Week 14–16 65 (25.1%) 37 (13.1%) 0.0006   HIV-1 Infection or Death HIV-1 Infection or Death P value Day 1–3 37 (12.2%) 27 (8.8%) 0.17 Week 6–8 66 (23.1%) 38 (12.8%) 0.0012 Week 14–16 74 (27.6%) 41 (14.4%) 0.0002 SOURCE: Adapted from Guay et al. (1999). Used with permission from the authors and from Elsevier. NOTE: A “p value” represents the probability that an event as extreme or more extreme than the observed result would have occurred by chance if the specified null hypothesis is true.

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Review of the HIVNET 012 Perinatal HIV Prevention Study The second Lancet paper (Jackson et al., 2003), reported that infants assigned to the NVP arm continued to have a significantly lower rate of HIV-1 infection and a significantly greater likelihood of HIV-1-free survival through 18 months of age (Table 2.2). Specifically, the efficacy of NVP compared with ZDV was 41%. This paper analyzed adverse events and serious adverse events more completely, reporting that both types of events among mothers up to 56 days were balanced between the study arms. Three deaths occurred among women assigned to the ZDV arm, but all were judged related to complications of HIV-1 infection. Among infants, reported rates of serious adverse events during the first 56 days after birth and through 18 months of age were similarly balanced between the ZDV and NVP arms. However, all adverse events5 were significantly more frequent in infants in the ZDV arm versus the NVP arm during the first 56 days. Jaundice (18.4% versus 5.6%), skin infections (17.5% versus 9.7%) and pustular rash (4.5% versus 0.6%) all occurred more often among infants in the ZDV arm. Only one condition—dermal exfoliation—occurred more often among infants in the NVP arm (4.9% versus 8.4%). All cases of dermal exfoliation were graded mild or moderate. Researchers reported no cases of Stevens-Johnson syndrome.6 They further reported no significant differences between the treatment arms with respect to grade 3 or 4 laboratory toxicities7, and no grade 3 or 4 abnormalities in serum liver enzymes in either study arm (see Table 2-3). The infant death rates reported after 18-month follow-up (13.6% in the ZDV arm and 10.6% in the NVP arm) should be considered in the context of infant mortality for children under 5 years of age in Uganda, which in 1998 was 134 per 1,000 births (UNICEF, 2000). KEY EVENTS DURING HIVNET 012 The HIVNET 012 trial and its aftermath were marked by a complicated series of events involving the study sponsors (DAIDS, NIAID, NIH), various contract organizations, the U.S. Food and Drug Administration, study investigators, the pharmaceutical company Boehringer Ingelheim, and institutional review boards in Uganda and the United States. Table 2.4 outlines some of these events. 5   This refers to both serious and non-serious adverse events. 6   Stevens-Johnson syndrome is a rare disorder characterized by inflammation of the mucous membranes of the mouth, throat, anogenital region, intestinal tract, and membrane lining the eyelids (conjunctiva). 7   DAIDS pediatric and adult toxicity tables are available at: http://rcc.tech-res-intl.com/tox_tables.htm.

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE 2.2 Numbers (percentages) of Infants with HIV-1 Infection and HIV-1 Infection or Death at Ages 12 and 18 Months, by Study Arm   Zidovudine (total number of infants=302) Nevirapine (total number of infants=308)   HIV-1 Infection HIV-1 Infection P value Month 12 70 (23.9%) 46 (15.3%) 0.0083 Month 18 75 (25.8%) 47 (15.7%) 0.0023   HIV-1 Infection or Death HIV-1 Infection or Death P value Month 12 86 (28.6%) 59 (19.4%) 0.0076 Month 18 92 (30.7%) 63 (20.7%) 0.0048   SOURCE: Adapted from Jackson et al. (2003). Used with permission from the authors and from Elsevier.

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE 2.3 Numbers (percentages) of Women and Infants with Adverse Events, by Study Arm   Zidovudine Nevirapine P value Women   Total 302 306   First 8 weeks   All adverse events (AEs) 259 (85.8%) 263 (85.9%) 0.95 Rash 20 (6.6%) 21 (6.9%) 0.91 Hepatic related 5 (1.7%) 2 (0.7%) 0.25 Serious AEs 11 (3.6%) 15 (5.9%) 0.44 Deaths 3 (1.0%) 0 (0.0%) 0.08 Infants   Total 309 320   First 8 weeks   All adverse events 288 (93.2%) 260 (81.3%) < 0.0001 Infection 84 (27.2%) 83 (25.9%) 0.72 Rash 81 (26.2%) 59 (18.4%) 0.02 Conjunctivitis 54 (17.6%) 61 (19.1%) 0.61 Hepatic related 67 (21.7%) 30 (9.4%) < 0.0001 Skin infection 54 (17.5%) 31 (9.7%) 0.004 Oral thrush 37 (12.0%) 38 (11.9%) 0.97 Serious AEs 35 (11.3%) 29 (9.1%) 0.35 Deaths 3 (1.0%) 4 (1.3%) 0.09 18 months   Serious AEs 97 (31.4%) 109 (34.1%) 0.48 Deaths 42 (13.6%) 34 (10.6%) 0.25   SOURCE: Adapted from Jackson et al. (2003). Used with permission from the authors and from Elsevier.

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE 2.4 HIVNET 012 Timeline Date Event February 1996 Investigational new drug application #49,991 opened by DAIDS and later reviewed and accepted by FDA July 1997 Protocol approved by Johns Hopkins Joint Committee on Clinical Investigation (JCCI) and Ugandan AIDS Research Committee (ARC)   Data and Safety Monitoring Board (DSMB) meeting (July 1, 1997) August 1997 Protocol version 1.0 sent to FDA November 1997 HIVNET 012 enrollment begins February 1998 Enrollment stopped; placebo arms are dropped (Amendment I to Protocol Version 1.0) March 1998 Investigators ask JCCI and ARC to approve redesigned study April 1998 Enrollment begins into revised protocol May 1998 Enrollment stopped because of drug unavailability and drug packaging issue July 1998 Enrollment resumes into 2-arm trial DSMB meeting (July 16, 1998) April 1999 HIVNET 012 enrollment completed June 1999 DSMB meeting (June 24, 1999) July 1999 DSMB telephone conference (July 12, 1999) September 1999 Early results of HIVNET 012 published in The Lancet April 2000 Protocol amended to follow women and infants for 5 years (Amendment II to Protocol Version 1.0) June 2001 Boehringer Ingelheim (BI) submits supplemental new drug application (sNDA) for NVP to FDA January 2002 BI study site visit February 2002 Westat study site visit March 2002 BI withdraws NVP sNDA July to December 2002 DAIDS audit (remonitoring) of HIVNET 012 March 2003 DAIDS remonitoring report released September 2003 Second Lancet paper published September 2004 IOM committee convened

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Review of the HIVNET 012 Perinatal HIV Prevention Study REFERENCES CDC (Centers for Disease Control and Prevention), UNAIDS (Joint United Nations Programme on HIV/AIDS), NIH (National Institutes of Health), and ANRS (Agence Nationale de Recherche sur le SIDA). 1998. Joint Statement by the Centers for Disease Control and Prevention (CDC), the Joint United Nations Programme on HIV/AIDS (UNAIDS), the National Institutes of Health (NIH) and the Agence Nationale de Recherche sur le SIDA (ANRS), Following the Announcement by the Ministry of Public Health of Thailand and the CDC of Results from their Mother-to-Child Transmission Trial, February 18, 1998. 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. 1999. 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 354(9181): 795-802. HIVNET 012 Investigators. 2000. Protocol HIVNET 012. Amendment II. Extended Mother and Child Follow-Up. Jackson B, Mmiro F, Guay L, Musoke P, Fowler MG. 1997. Protocol HIVNET 012: A Phase III Placebo-Controlled 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. 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. 2003. 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 362(9387):859-868. Shaffer N, Chuachoowong R, Mock P, Bhadrakom C, Siriwasin W, Young N, Chotpitayasunondh T, Chearskul S, Roongpisuthipong A, Chinayon P, Karon J, Mastro T, Simonds R. 1999. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 353(9155):773-780. UNICEF (United Nations Children’s Fund). 2000. State of the World’s Children 2000. [Online] Available at http://www.unicef.org/sowc00/. Accessed February 27, 2005.