Trial of Three Neonatal Antiretroviral Regimens for Prevention of Intrapartum HIV Transmission

Study Overview
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Brief Summary
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Giving anti-HIV medications to babies born of HIV positive mothers right after birth can lower the babies' risk of contracting HIV. This study will assess the safety and efficacy of two different combinations of anti-HIV medications compared to a one drug standard regimen in preventing mother to baby transmission. The one drug standard treatment and two combinations to be studied are: 1) zidovudine, 2) zidovudine/nevirapine and 3) zidovudine/lamivudine/nelfinavir.

Detailed Description
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Despite the notable reductions in perinatal transmission of HIV-1 with antiretroviral therapy and other interventions, perinatal transmission continues to occur at rates of 20-30% among pregnant women who are not identified as HIV-1-infected and/or are not provided with antiretroviral therapy. The optimum treatment strategy for prevention of transmission of HIV-1 to infants born to these women is unknown. No trials have evaluated the efficacy of neonatal antiretroviral therapy alone but observational data suggest benefit from zidovudine (ZDV) therapy given to the infant beginning within 48 hours of birth and continued for six weeks. This protocol will compare the safety and efficacy of three antiretroviral regimens administered in the neonatal period: Arm A- ZDV, Arm B- ZDV plus nevirapine (NVP), and Arm C- ZDV plus nelfinavir (NFV) and lamivudine (3TC). Two regimens were selected based on expected antiretroviral activity, pharmacokinetic data, and toxicity profiles. Standard of care (6 weeks of ZDV) alone will be compared to the 6 weeks of ZDV plus either 3 doses of NVP or 2 weeks of 3TC and NFV. Arm B (ZDV + NVP) is the regimen expected to provide the best profile when factors of efficacy, safety, cost, acceptability and convenience are considered. The comparison of Arms B and C is also of considerable interest since the 2-drug Arm B is easier to implement and less expensive than the triple drug Arm C. Although triple drug therapies have been recommended for post-exposure prophylaxis for needle-stick injuries in high-risk circumstances, it is unknown whether the triple drug arm will provide better efficacy than the 2-drug arm for post-exposure prophylaxis of the infant. This open-label study is expected to accrue 1731 infants of women identified in labor as being HIV positive or who are HIV positive but have not received antiretroviral medication during the pregnancy. If eligible the infant will be randomized at birth to one of three aforementioned treatment arms. Medical history, social, demographic, physical exam, RNA and T- lymphocyte data are collected on the mother during the delivery visit. The infant will have a birth visit and then return for 1-week, 2-week, 4-week, 3-month and a final 6-month visit. Infant evaluations will include: a medical history and physical exam, DNA testing, CBC and liver function tests, cells for long-term storage and RNA/CD4/CD8 testing if HIV positive. The initial study drug doses will be given to the infant while in the hospital. Mothers will administer the infants' remaining treatment doses at home depending on ability.

Official Title
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Phase III Randomized Trial of the Safety and Efficacy of Three Neonatal Antiretroviral Regimens for Prevention of Intrapartum HIV-1 Transmission

Conditions
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Disease Transmission, Vertical, Vertical Human Immunodeficiency Virus Transmission, HIV Infections

Intervention / Treatment
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* Drug: Zidovudine
* Drug: Nevirapine (NVP)
* Drug: Epivir (3TC)
* Drug: Nelfinavir (NFV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants who meet all of the following criteria are eligible for the study: Mother known to be HIV-1-infected prior to labor or identified at the time of labor or <48 hours postpartum. HIV-1 infection for the purposes of enrollment into this study is defined as: (a) Single positive HIV-1 rapid test in mother or her infant; or (b) Historical documentation of a positive HIV-1 diagnostic test confirmed by repeat diagnostic testing for HIV-1 according to country guidelines in mother (written documentation of test results must be present in the medical record). Maternal written informed consent for study participation. Mother has not received any antiretroviral therapy during the current pregnancy prior to the onset of labor and delivery; women may have received intravenous or oral ZDV during labor. Women may have received any antiretroviral therapy in previous pregnancies for prevention of vertical HIV-1 transmission. Infant is <48 hours old. Infant may have received up to 48 hours of ZDV as standard care before study enrollment. Exclusion Criteria: Infants who meet any of the following criteria will be excluded from the study: Extreme prematurity (< 32 weeks of gestation). Birth weight <1500 grams. Presence of life-threatening conditions. Inability to take oral medication throughout the first 48 hours of life (must be able to receive oral medication by age 48 hours). Maternal inability to provide informed consent because of a lack of a conscious state, psychiatric conditions, or language barriers. Mother received any antiretroviral therapy during labor and delivery other than intravenous or oral ZDV.

Ages Eligible for Study
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Maximum Age: 2 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Standard of care ( Zidovudine only) | Drug: Zidovudine<br>* Given for 6 weeks. 12mg PO BID if birthweight (BW) > 2000 grams 8 mg PO BID if BW < 2000 grams<br>* Other names: Retrovir;|
| Experimental: B<br>Standard of care (Zidovudine) plus Nevirapine | Drug: Nevirapine (NVP)<br>* Standard of Care (Zidovudine) plus NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose : 12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams<br>* Other names: Viramune;|
| Experimental: C<br>Standard of Care (Zidovudine) plus 2 weeks of Epivir and Nelfinavir | Drug: Epivir (3TC)<br>* Stand of care (Zidovudine) plus 3TC, given for 2 weeks: 6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND NFV, given for 2 weeks: 200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 - 3000 grams 100 mg PO BID if BW < 2000 grams<br>* Other names: Lamivudine;Drug: Nelfinavir (NFV)<br>* 200 mg BID if birth weight (BW) > 3000 grams for 2 weeks;150 mg BID if BW > 2000-3000 grams for 2 weeks; 100 mg BID BW </= 2000 grams for 2 weeks<br>* Other names: Viracept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant HIV Infection Status | Intrapartum HIV infection at 3 Months | 3 months | 
| Participants With Serious Adverse Events | Serious Adverse Events by System Organ Class=Blood and lymphatic system disorders | through age 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant HIV-1 Infection Status | In utero HIV-1 infection rate | birth | 
| Participant Deaths |  | through age 6 months | 
| Clinical Covariates of HIV-1 Infection | Compare HIV-1 RNA levels; CD4+ lymphocyte counts; and rates of genotypic and phenotypic resistance among the three treatment regimens. | through age 3 months | 
| 3TC and NFV Pharmacokinetics | Descriptive study of 3TC and NFV pharmacokinetics during first two weeks of life using weight band dosing regimen in a subset of enrolled infants. | through age 14 days | 
| Risk Factors for Perinatal HIV-1 Transmission | Risk factors to be assessed include maternal HIV-1 RNA levels at delivery, maternal syphilis and other infections, obstetrical factors such as duration of membrane rupture, and adherence to neonatal medication. | through age 3 months | 
| NVP Pharmacokinetics | Descriptive study of NVP pharmacokinetics during first two weeks of life using weight band dosing in a subset of enrolled infants. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Perinatal, Prevention, Transmission, Nevirapine, Epivir, Zidovudine, Nelfinavir, ZDV, NVP, 3TC, NFV, Viracept, Viramune, HIV Seronegativity, Treatment Naive