Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00193947
Status:
TERMINATED
Last Update Posted:
2011-08-03
First Post:
2005-09-15
Brief Title:
An Evaluation of the Development of Nevirapine Induced Mutations in HIV Patients Initiating or Discontinuing Combination Antiretroviral Therapy
Sponsor:
University Health Network Toronto
Organization:
University Health Network Toronto
Study Overview
Official Title:
An Evaluation of the Development of Nevirapine Induced Mutations in HIV Patients Initiating or Discontinuing Combination Antiretroviral Therapy
Status:
TERMINATED
Status Verified Date:
2007-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypothesis
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a consequence of use of an agent with a long t½ as monotherapy in individuals with high viral loads
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected patients when used as part of triple antiretroviral combination therapy between the initiation of treatment and suppression of HIV RNA to 1000 copiesml
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a consequence of use of an agent with a long t½ as monotherapy in individuals with high viral loads
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected patients when used as part of triple antiretroviral combination therapy between the initiation of treatment and suppression of HIV RNA to 1000 copiesml
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine
Detailed Description:
The HIVNET 012 clinical trial demonstrates a cost effective strategy to prevent maternal fetal transmission of HIV In this study a single 200 mg dose of Nevirapine was given to pregnant Ugandan women at the onset of labour and a single 2 mgkg dose to their infants within 72 hours of birth 1 Given the efficacy simplicity and low cost of this regime the World Health Organization recently recommended implementation of this regimen as one of several options for prevention of maternal fetal transmission of HIV in resource limited settings
Pharmacokinetic studies have demonstrated that 200 mg of Nevirapine given to the mother during labour results in concentrations 100 mgmL 10 times the in vitro IC50 in the newborn Nevirapine elimination is prolonged in both mothers and infants with median t½ of 368 to 657 hours Administration of 200 mg orally to the mother and a single 2 mgkg oral dose to the infant at 48-72 hours maintains serum concentration in the infants 100 mgml through 7 days of life 2 3
Early studies demonstrated that the use of Nevirapine monotherapy resulted in a rapid selection of Nevirapine resistant mutations 4 This was associated with loss of antiviral activity and return of the viral load to baseline within 12 weeks It appeared very soon that the non-nucleoside reverse transcriptase inhibitors were drugs with a low genetic barrier and that a single mutation in the reverse transcriptase gene induced a high level of phenotypic resistance 5 Similarly when Nevirapine was used in combination with a single nucleoside and there was incomplete suppression of viral replication resistance emerged to the non-nucleoside reverse transcriptase inhibitor 6
In contrast when used as part of triple antiretroviral combination and there was successful inhibition of viral replication to 50 copiesml the viral response was maintained in 50 of patients out to 48 weeks 7 8 9 10 However again when virologic control is lost resistance to Nevirapine emerges rapidly in 50-100 of patients 11 It is unclear whether or not these mutations developed during the initial suppression of viral load replication or during rebound of viremia with failure
Given the pharmacokinetics of Nevirapine in pregnant women and infants concern was raised that mother and child would be exposed to Nevirapine monotherapy for one to several days and that the selection of resistant mutants could arise limiting this strategy over the long term In fact a recent sub-analysis of the HIVNET 012 cohort found Nevirapine resistant mutations in 21111 19 of women tested at 6-8 weeks after delivery The K103N was the most common mutation Women with the highest baseline viral load developed the mutations more frequently Nevirapine resistant mutations were also detected in 1124 or 46 of infected infants at 6-8 weeks In contrast to the mothers the Y181C was the most commonly detected
Similarly the K103N resistance mutation was detected 6 weeks after Nevirapine administration in 315 20 women in the HIVNET006 phase III trial This had the same Nevirapine dosing schedule as HIVNET012 12
New information has become available based on recent post-marketing surveillance data clarifying risk factors for severe life threatening and fatal hepatotoxicity with nevirapine Women with CD4 counts 250 cellsmm3 at initiation of therapy including pregnant women receiving chronic treatment for HIV infection are at considerably higher risk 12-fold of hepatotoxicity which in some cases has been fatal The greatest risk of severe and potentially fatal hepatic events occurs in the first 6 weeks of therapy However the risk continues after this time and patients should be closely monitored for the first 18 weeks of therapy For this reason women with CD4 250mm3 will not be included in Objective 1 of this study
Hypothesis
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a consequence of use of an agent with a long t½ as monotherapy in individuals with high viral loads
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected patients when used as part of triple antiretroviral combination therapy between the initiation of treatment and suppression of HIV RNA to 1000 copiesml
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine
Pharmacokinetic studies have demonstrated that 200 mg of Nevirapine given to the mother during labour results in concentrations 100 mgmL 10 times the in vitro IC50 in the newborn Nevirapine elimination is prolonged in both mothers and infants with median t½ of 368 to 657 hours Administration of 200 mg orally to the mother and a single 2 mgkg oral dose to the infant at 48-72 hours maintains serum concentration in the infants 100 mgml through 7 days of life 2 3
Early studies demonstrated that the use of Nevirapine monotherapy resulted in a rapid selection of Nevirapine resistant mutations 4 This was associated with loss of antiviral activity and return of the viral load to baseline within 12 weeks It appeared very soon that the non-nucleoside reverse transcriptase inhibitors were drugs with a low genetic barrier and that a single mutation in the reverse transcriptase gene induced a high level of phenotypic resistance 5 Similarly when Nevirapine was used in combination with a single nucleoside and there was incomplete suppression of viral replication resistance emerged to the non-nucleoside reverse transcriptase inhibitor 6
In contrast when used as part of triple antiretroviral combination and there was successful inhibition of viral replication to 50 copiesml the viral response was maintained in 50 of patients out to 48 weeks 7 8 9 10 However again when virologic control is lost resistance to Nevirapine emerges rapidly in 50-100 of patients 11 It is unclear whether or not these mutations developed during the initial suppression of viral load replication or during rebound of viremia with failure
Given the pharmacokinetics of Nevirapine in pregnant women and infants concern was raised that mother and child would be exposed to Nevirapine monotherapy for one to several days and that the selection of resistant mutants could arise limiting this strategy over the long term In fact a recent sub-analysis of the HIVNET 012 cohort found Nevirapine resistant mutations in 21111 19 of women tested at 6-8 weeks after delivery The K103N was the most common mutation Women with the highest baseline viral load developed the mutations more frequently Nevirapine resistant mutations were also detected in 1124 or 46 of infected infants at 6-8 weeks In contrast to the mothers the Y181C was the most commonly detected
Similarly the K103N resistance mutation was detected 6 weeks after Nevirapine administration in 315 20 women in the HIVNET006 phase III trial This had the same Nevirapine dosing schedule as HIVNET012 12
New information has become available based on recent post-marketing surveillance data clarifying risk factors for severe life threatening and fatal hepatotoxicity with nevirapine Women with CD4 counts 250 cellsmm3 at initiation of therapy including pregnant women receiving chronic treatment for HIV infection are at considerably higher risk 12-fold of hepatotoxicity which in some cases has been fatal The greatest risk of severe and potentially fatal hepatic events occurs in the first 6 weeks of therapy However the risk continues after this time and patients should be closely monitored for the first 18 weeks of therapy For this reason women with CD4 250mm3 will not be included in Objective 1 of this study
Hypothesis
Nevirapine resistance developed in women and infants in the HIVNET 006 and 012 cohorts as a consequence of use of an agent with a long t½ as monotherapy in individuals with high viral loads
Objective 1 To demonstrate that Nevirapine resistance does not develop in HIV infected patients when used as part of triple antiretroviral combination therapy between the initiation of treatment and suppression of HIV RNA to 1000 copiesml
Objective 2 To demonstrate that resistance to nevirapine does not develop when patients with suppressed HIV RNA discontinue combination antiretroviral therapy which contains nevirapine
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None