The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance

Study Overview
=================
Brief Summary
-----------------
The primary objective of this two-phase trial is as follows: To determine the elimination half-life of NVP in HIV positive pregnant women receiving it as a single dose in labour in addition to the ZDV and 3TC with or without seven days phenytoin (pilot PK phase) To determine NVP resistance in HIV positive pregnant women receiving it as a single dose in labour in addition to ZDV and 3TC with or without seven days phenytoin (main trial phase) The secondary objectives of this two-phase trial are as follows: To determine the safety of single dose nevirapine with seven days phenytoin as a part of ARV prophylaxis for PMTCT vs. single dose of nevirapine without phenytoin as a part of ARV prophylaxis for PMTCT To determine the HIV status of the infant To determine the safety of the ARV prophylaxis for PMTCT with seven days of phenytoin on the newborn Hypothesis: phenytoin reduces the elimination half life of SD NVP and thereby decreases development of resistance to NVP in HIV positive pregnant Tanzanian and Zambian women.

Detailed Description
-----------------
This trial (VITA2) will be done with phenytoin as enzyme inducer to decrease the elimination half-life of NVP as it has also shown a significant difference in the elimination half-life of NVP in the ENVI study and side effects were also transient and mild. The guidelines for ARV prophylaxis for PMTCT has been changed to a more complex regimen. Therefore addition of phenytoin OD for 7 days after delivery will not complicate the regimen for the mother. Tanzania and Zambia are among the countries in sub-Saharan Africa most affected by the HIV pandemic. In 2008, an estimated 85,000 children were living with HIV in Zambia and out of the 89,000 children born to HIV infected women, 28,000 are infected annually. In Tanzania, 140,000 children were living with HIV in 2007. Both countries use NVP alone or in combination with other drugs as ARV prophylaxis for PMTCT. Little data are available on the extent of NVP resistance in the Tanzanian, Zambian PMTCT setting. Moreover, there is no data available on the follow-up of mother-infant pair with particular focus on resistance to NVP and the infants HIV status. No studies have explored possibilities of reducing NVP resistance by use of an enzyme inducer. This study seeks to the effect of phenytoin on the pharmacokinetics of NVP and the development of NVP resistance on SD NVP as part of the ARV prophylaxis for PMTCT. This intervention will be part of the VITA2 trial to test the hypothesis that phenytoin reduces the elimination half life of SD NVP and thereby decreases development of resistance to NVP in HIV positive pregnant Tanzanian and Zambian women.

Official Title
-----------------
The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance After a Single Dose Nevirapine (VIramune®), Which is Part of ARV Prophylaxis for PMTCT in Moshi, TAnzania, and in Lusaka, Zambia (VITA2 Trial)

Conditions
-----------------
HIV-infection, Pregnancy, Mother to Child Transmission

Intervention / Treatment
-----------------
* Drug: phenytoin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV-infected as documented by positive HIV antibody test Antiretroviral naïve Starting ARV prophylaxis from 28th weeks of gestation or at least 4 weeks before delivery Not intending to relocate out of the area for the duration of study participation Willingness of subject to adhere to follow up schedule (note: this is more intensive for the pilot PK phase) Ability and willingness of subject to give written consent Pregnant women aged 18 years and above Willing and able to regularly attend the antenatal clinic Exclusion Criteria: Serious illness that requires systemic treatment or hospitalization Use of concomitant medication, which interferes with the ARV prophylaxis for PMTCT or phenytoin Any condition that in the opinion of the investigator would compromise the subjects' ability to participate in the study Previously treated for HIV infection with antiretroviral agents, including ARV prophylaxis for PMTCT Inability to understand the nature and extent of the trial and the procedures required CD4 count <350 cells/µl because such a patient is eligible for HAART

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

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 |
| --- | --- |
| No Intervention: Control<br>ARV prophylaxis for PMTCT follows national guidelines. | |
| Experimental: phenytoin interaction<br>ARV prophylaxis for PMTCT follows national guidelines + start phenytoin 184 mg (2 tablets of 92mg) OD at onset of labour and continue for seven days | Drug: phenytoin<br>* phenytoin 184 mg (2 tablets of 92mg) OD at onset of labour and continue for seven days<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| half-life time nevirapine | blood samples will be taken <30 min after delivery, 24 hours after delivery, at day 3, at day 5, at day 7 and at day 14 | untill two weeks after NVP dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NVP resistance | resistance testing at week 4 or week 6 after delivery (and NVP dosing). | week 4 / week 6 after delivery | 
| safety of co-administration phenytoin and NVP | Adverse events will be collected during the entire trial (for both mother and child). | entire trial | 
| HIV status of the newborn | HIV status of the newborn will be assessed at week 6 after birth. | week 6 after birth | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, pregnancy, phenytoin, ARV prophylaxis, nevirapine