Clinical trial NCT01187719: The Effect of Phenytoin on the Pharmacokinetics of Nevirapine and the Development of Nevirapine Resistance
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-infection
Pregnancy
Mother to Child Transmission
Keywords: HIV
pregnancy
phenytoin
ARV prophylaxis
nevirapine
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2010-08-24
Enrollment: 66
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: half-life time nevirapine
timeFrame: untill two weeks after NVP dosing
Secondary outcomes:
measure: NVP resistance
timeFrame: week 4 / week 6 after delivery
measure: safety of co-administration phenytoin and NVP
timeFrame: entire trial
measure: HIV status of the newborn
timeFrame: week 6 after birth
Other outcomes:
Locations:
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre
state: Kilimanjaro Region
city: Lusaka
country: Zambia
facility: University Teaching Hospital
Study officials:
affiliation: Kilimanjaro Christian Medical Centre
name: Elton Kisanga, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fillekes Q, Muro EP, Chunda C, Aitken S, Kisanga ER, Kankasa C, Thomason MJ, Gibb DM, Walker AS, Burger DM. Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial. J Antimicrob Chemother. 2013 Nov;68(11):2609-15. doi: 10.1093/jac/dkt246. Epub 2013 Jul 17.