Maternal/Infant Peripartum NVP, Versus Infant Only Peripartum NVP, or Maternal LPV/r in Addition to Standard ZDV Prophylaxis for the Prevention of Perinatal (PMTCT) HIV in Thailand

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the efficacy of two doses of nevirapine (NVP) given only to the infants or lopinavir/ritonavir (LPV/r) from 28 weeks gestation with single dose (SD) NVP given to the mothers plus two doses to the infants, in addition to zidovudine (ZDV) prophylaxis (from 28 weeks' gestation and for one week of ZDV in neonates) for the prevention of mother-to-child transmission of HIV-1.

Detailed Description
-----------------
Multicenter, placebo-controlled, double blind, clinical trial where non immunocompromised women receiving the ZDV prophylaxis regimen from 28 weeks gestation, as recommended in Thailand, will be randomized to one of two arms: Arm 1: NVP-NVP: In women, one NVP 200 mg tablet at onset of labor+; In neonates, NVP oral suspension 6 mg in the delivery room immediately after birth plus a second dose between 48 and 72 hours+++ Arm 2: PL-NVP: In women, one placebo tablet at onset of labor++; In neonates, NVP oral suspension 6 mg in the delivery room immediately after birth plus a second dose between 48 and 72 hours+++ Arm 3: LPV/r: In women, LPV/r 400/100 mg bid from 28 weeks' gestation until delivery women in Arm 1 will also receive 7-day ZDV 300mg bid plus 3TC 150mg bid from delivery. ++women in Arm 2 will also receive 7-day (ZDV+3TC) Placebo from delivery. +++If the new born weight less than 2500 g, nevirapine will be administered 2 mg./1 kg (As per Thai Guideline). All infants will receive ZDV for at least one week. Follow-up of women and infants is carried out on an outpatient basis except for delivery and the first three days after delivery. Mothers and infants are followed-up for 24 months after delivery. Note: The study was stopped and data unblinded upon DSMB recommendations in September 2010 because of changes in Thai PMTCT guidelines recommending use of HAART in all HIV infected pregnant women regardless of their CD4 count. At the time of unblinding 435 pregnant women had been enrolled and follow-up of these women and their children is continuing.

Official Title
-----------------
Maternal and Infant Peripartum Nevirapine, Versus Infant Only Peripartum Nevirapine, or Maternal Lopinavir/Ritonavir in Addition to Standard Zidovudine Prophylaxis for the Prevention of Perinatal HIV in Thailand.

Conditions
-----------------
HIV Infections, Pregnancy

Intervention / Treatment
-----------------
* Drug: Maternal and infant nevirapine
* Drug: Maternal placebo and infant nevirapine
* Drug: Maternal lopinavir+ritonavir
* Drug: zidovudine


Participation Criteria
=================
Eligibility Criteria
-----------------
Pre-Entry Criteria Evidence of HIV infection (documented by two HIV antibody tests on two different dates) Intend to be followed at a study site for the duration of the study At least 18 years old Written informed consent. Inclusion Criteria: Women are eligible for the study if they met all pre-entry criteria Evidence of HIV infection, as documented by two serology tests obtained at two different dates; between 28 and 36 weeks gestational age; antiretroviral naïve except for exposure to ZDV prophylaxis PMTCT; CD4 count above 250 cells/mm3 (within 4 months prior to randomization) agreement not to breastfeed; consent to participate and to be followed for the duration of the study; and the following laboratory values within 14 days prior to randomization: hemoglobin > 8.5 mg/dl; absolute neutrophil count > 750 cells/mm3; platelets > 50,000 cells/mm3; SGPT ≤ 5 times upper limit of normal; serum creatinine ≤ 1.5 times upper limit of normal (women with a serum creatinine > 1.5 times upper limit of normal must have a measured eight-hour urine creatinine clearance > 70 ml/min). Exclusion criteria: Evidence of pre-existing fetal anomalies incompatible with life; patients who meet the criteria of Classes III/IV of the WHO classification of HIV-associated clinical disease; known hypersensitivity to any benzodiazepine; active tuberculosis; concurrent participation to any other clinical trial; receipt of benzodiazepines or antiretroviral agent other than ZDV; uncontrolled hypertension; anticoagulant therapy or magnesium sulfate within 2 weeks of enrollment or the need for them during labor or at delivery. If any of these conditions occurs after randomization, the women will be excluded from study drug dosing. Women with CD4 count lower than 250 cells/mm3 will be excluded from the study and offered HAART in the context of the national program.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>NVP-NVP: In women, one NVP 200 mg tablet at onset of labor; In neonates, NVP oral suspension 6 mg in the delivery room immediately after birth plus a second dose between 48 and 72 hours | Drug: Maternal and infant nevirapine<br>* In women, one NVP 200 mg tablet at onset of labor; In neonates, NVP oral suspension 6 mg in the delivery room immediately<br>Drug: zidovudine<br>* In addition, all women and infants in the 3 arms will receive standard ZDV prophylaxis, as per Thai and WHO guidelines.<br>|
| Experimental: 2<br>PL-NVP: In women, one placebo tablet at onset of labor; In neonates, NVP oral suspension 6 mg in the delivery room immediately after birth plus a second dose between 48 and 72 hours | Drug: Maternal placebo and infant nevirapine<br>* In women, one placebo tablet at onset of labor; In neonates, NVP oral suspension 6 mg in the delivery room immediately after birth plus a second dose between 48 and 72 hours Comparison between Arms 1 and 2 is double-blinded.<br>Drug: zidovudine<br>* In addition, all women and infants in the 3 arms will receive standard ZDV prophylaxis, as per Thai and WHO guidelines.<br>|
| Experimental: 3<br>LPV/r: In women, LPV/r 400/100 mg bid from 28 weeks' gestation until delivery | Drug: Maternal lopinavir+ritonavir<br>* - In women, LPV/r 400/100 mg bid from 28 weeks' gestation until delivery<br>Drug: zidovudine<br>* In addition, all women and infants in the 3 arms will receive standard ZDV prophylaxis, as per Thai and WHO guidelines.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Definitive HIV infection in infants as assessed by positive HIV DNA PCR on two peripheral blood samples |  | At birth, 7-10 days, 1, 2, 4 and 6 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety for mothers and children of two NVP doses in neonates with and without maternal single dose NVP at onset of labor or LPV/r from 28 weeks gestation. |  | From randomization during pregnancy until 24 months after delivery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Thailand, Developing Countries, Prophylaxis, Mother-to-child transmission, HIV-1, HIV-1 infection, HIV Seronegativity