Clinical trial NCT00142337: One Month Dual Antiretroviral Prophylaxis to Prevent Resistance Mutations in Mothers Exposed to Single Dose Nevirapine
Official title: A Phase 2, One Arm, Open Label, Feasibility Study Assessing One Month Zidovudine/Didanosine Postpartum Prophylaxis to Prevent Resistance Mutations in Mothers Exposed to Single Dose Nevirapine to Prevent Mother to Child Transmission of HIV
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: zidovudine
didanosine
Prevention of mother to child transmission of HIV
nevirapine
Thailand
Resistance
HIV
Postpartum period
Lead sponsor: Institut de Recherche pour le Developpement
Sponsor class: OTHER_GOV
First posted: 2005-09-02
Enrollment: 244
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to determine whether providing zidovudine (ZDV) and didanosine (ddI) during labor and for one month postpartum can reduce the selection of nevirapine (NVP) resistance mutations postpartum in women who received a single dose of nevirapine during labor and standard ZDV prophylaxis for the prevention of mother to child transmission of HIV.

Detailed description: A single nevirapine dose to the mother, with or without a dose to the child, in addition to oral ZDV prophylaxis starting from 28 weeks gestation has been proven to be highly effective in reducing further mother-to-child HIV transmission (PMTCT).

However, post exposure nevirapine resistance mutations are observed in the mother's viral population. These mutations detectable very early after exposure tend to disappear over time.

Nevertheless, they may be associated with decrease in efficacy of non-nucleoside reverse transcriptase inhibitor (NNRTI) containing regimens subsequently given to the women for their own health.

Therefore, there is a need for research to prevent selection of resistance in the first place or to overcome the resistance in subsequent treatment of the infected mother or infant.

Nevirapine plasma levels above IC50 have been detected in women exposed to a single 200 mg dose of nevirapine in a significant number of women during the third week postpartum.

We hypothesize that giving ZDV+ddI to women exposed to nevirapine for one month as soon as possible after exposure may prevent the selection of nevirapine resistance mutations.

Eligibility criteria: Inclusion Criteria:

* Meet all pre-entry criteria;
* Consent to participate and to be followed for the duration of the study;
* Present the following laboratory values within 14 days prior to inclusion:

  * Hemoglobin \> 8.0 mg/dl
  * Absolute neutrophil count \> 1000 cells/mm3
  * Platelets \> 100,000 cells/mm3
  * Serum creatinine \< 1.5 mg/dl (women with a serum creatinine \> 1.5 mg/dl must have a measured eight-hour urine creatinine clearance \> 70 ml/min)
  * SGPT less than 10 times the upper limit of normal
  * Amylase less than 150/L IU (this upper limit may change slightly depending on the normal range at the hospital laboratory).

Exclusion Criteria:

* Evidence of pre-existing fetal anomalies incompatible with life;
* Known hypersensitivity to any benzodiazepine or to NVP;
* Receipt of antiretroviral agent other than ZDV;
* Receipt of non-allowed concomitant treatment or contraindication to ddI
* Concurrent participation in another clinical trial;
* Women with a CD4 count \<200/µL or history of oral candidiasis if they are not receiving pneumocystis carinii pneumonia (PCP) prophylaxis
* Any other contra-indicated drugs during ZDV+ddI treatment for the mother as well as the child (Contra-indicated drugs such as gancyclovir, isoniazid, linezolid, ethambutol, rifabutin, cidofovir are not allowed during the ZDV ddI treatment after delivery in order to prevent pharmacological interactions or overlapping toxicities.)

Primary outcomes:
measure: Proportion of patients with viral NNRTI mutations detectable during the 4 month follow-up compared with the incidence observed in the PHPT-2 clinical trial, who received the same antiretroviral prophylaxis but no post-partum regimen
timeFrame: Within 4 months postpartum
Secondary outcomes:
Other outcomes:
Locations:
city: Muang
country: Thailand
facility: Chacheongsao Hospital
state: Chacheongsao
city: Muang
country: Thailand
facility: Prapokklao Hospital
state: Chantaburi
city: Mae Rim
country: Thailand
facility: Nakornping Hospital
state: Chiang Mai
city: Muang
country: Thailand
facility: Health Promotion Center Region 10
state: Chiang Mai
city: Munag
country: Thailand
facility: Lamphun Hospital
state: Chiang Mai
city: Mae Chan
country: Thailand
facility: Mae Chan Hospital
state: Chiang Rai
city: Mae Sai
country: Thailand
facility: Mae Sai Hospital
state: Chiang Rai
city: Phan
country: Thailand
facility: Phan Hospital
state: Chiang Rai
city: Muang
country: Thailand
facility: Chiangrai Prachanukroh Hospital
state: Chiangrai
city: Muang
country: Thailand
facility: Chonburi Hospital
state: Chonburi
city: Muang
country: Thailand
facility: Kalasin Hospital
state: Kalasin
city: Munag
country: Thailand
facility: Phaholpolphayuhasena Hospital
state: Kanjanaburi
city: Kranuan
country: Thailand
facility: Kranuan Crown Prince Hospital
state: Khon Kaen
city: Muang
country: Thailand
facility: Khon Kaen Hospital
state: Khon Kaen
city: Muang
country: Thailand
facility: Regional Health Promotion Centre 6, Khon Kaen
state: Khon Kaen
city: Muang
country: Thailand
facility: Srinagarind Hospital
state: Khon Kaen
city: Muang
country: Thailand
facility: Lampang Hospital
state: Lampang
city: Muang
country: Thailand
facility: Nakhonpathom Hospital
state: Nakhonpathom
city: Muang
country: Thailand
facility: Maharaj Nakornratchasrima Hospital
state: Nakornratchasrima
city: Muang
country: Thailand
facility: Nong Khai Hospital
state: Nong Kai
city: Muang
country: Thailand
facility: Pranangklao Hospital
state: Nonthaburi
city: Chiang Kham
country: Thailand
facility: Chiang Kham Hospital
state: Phayao
city: Muang
country: Thailand
facility: Buddhachinaraj Hospital
state: Pitsanuloke
city: Muang
country: Thailand
facility: Ratchaburi Hospital
state: Ratchaburi
city: Muang
country: Thailand
facility: Rayong Hospital
state: Rayong
city: Muang
country: Thailand
facility: Roi-et Hospital
state: Roi-et
city: Muang
country: Thailand
facility: Samutsakorn Hospital
state: Samutsakorn
city: Hat Yai
country: Thailand
facility: Hat Yai Hospital
state: Songkla
city: Bangkok
country: Thailand
facility: Bhumibol Adulyadej Hospital
city: Bangkok
country: Thailand
facility: Health Promotion Hospital Regional Center I
city: Chonburi
country: Thailand
facility: Somdej Pranangchao Sirikit Hospital
city: Samutprakarn
country: Thailand
facility: Samutprakarn Hospital
Study officials:
affiliation: Institut de Recherche pour le Developpement
name: Marc Lallemant, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lallemant M, Jourdain G, Le Coeur S, Mary JY, Ngo-Giang-Huong N, Koetsawang S, Kanshana S, McIntosh K, Thaineua V; Perinatal HIV Prevention Trial (Thailand) Investigators. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med. 2004 Jul 15;351(3):217-28. doi: 10.1056/NEJMoa033500. Epub 2004 Jul 9.
citation: Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, Ariyadej S, Leenasirimakul P, Hammer S, Lallemant M; Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004 Jul 15;351(3):229-40. doi: 10.1056/NEJMoa041305. Epub 2004 Jul 9.
citation: Cressey TR, Jourdain G, Lallemant MJ, Kunkeaw S, Jackson JB, Musoke P, Capparelli E, Mirochnick M. Persistence of nevirapine exposure during the postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-child transmission of HIV-1. J Acquir Immune Defic Syndr. 2005 Mar 1;38(3):283-8.
citation: Lallemant M, Ngo-Giang-Huong N, Jourdain G, Traisaithit P, Cressey TR, Collins IJ, Jarupanich T, Sukhumanant T, Achalapong J, Sabsanong P, Chotivanich N, Winiyakul N, Ariyadej S, Kanjanasing A, Ratanakosol J, Hemvuttiphan J, Kengsakul K, Wannapira W, Sittipiyasakul V, Pornkitprasarn W, Liampongsabuddhi P, McIntosh K, Van Dyke RB, Frenkel LM, Koetsawang S, Le Coeur S, Kanchana S; PHPT-4 Study Team. Efficacy and safety of 1-month postpartum zidovudine-didanosine to prevent HIV-resistance mutations after intrapartum single-dose nevirapine. Clin Infect Dis. 2010 Mar 15;50(6):898-908. doi: 10.1086/650745.