NNRTI vs PI Regimens for HIV Infected Women After They Have Taken Nevirapine to Prevent Mother-To-Child HIV Transmission

Study Overview
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Brief Summary
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly included in anti-HIV drug regimens. However, HIV infected women who have previously taken the single dose NNRTI nevirapine (SD NVP) for the prevention of mother-to-child transmission (MTCT) of HIV may not respond as well to NNRTIs as women who have never taken NVP. Another class of anti-HIV drugs, protease inhibitors (PIs), may be more effective for women who have previously taken NNRTIs. This study will compare the effectiveness of NNRTI- and PI-based regimens in women who have taken NVP for prevention of MTCT of HIV. This study will also compare regimens including an NNRTI with regimens including a PI in women who have never taken NVP.

Detailed Description
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NVP is the NNRTI of choice to prevent MTCT of HIV, especially in resource-limited settings. However, prolonged use of NVP may result in drug resistance, decreasing the efficacy of future anti-HIV regimens containing NVP. PIs are more expensive and cause different adverse effects than NNRTIs, but PI-containing regimens may be more effective than NNRTI-containing regimens in treating HIV infected women who previously took NVP for MTCT prophylaxis. This study will compare the efficacy of NNRTI- and PI-containing anti-HIV regimens in women who have previously taken NVP for MTCT of HIV and in women who have never taken NVP. The study will last a minimum of 48 weeks. Participants will be grouped by previous NVP exposure: participants who have previously taken NVP as MTCT prophylaxis (Trial 1 participants), and participants who have never taken NVP (Trial 2 participants). Participants in each trial will be randomly assigned to one of two arms, NVP-containing arm(NVP/NVP for trial 1 participants and NoNVP/NVP for trial 2 participants) or PI-containing arm(NVP/LPV_r for Trial 1 participants and NoNVP/LPV_r for Trial 2 participants). At the start of the study, Arm NVP/NVP and NoNVP/NVP participants will receive emtricitabine (FTC) daily, tenofovir disoproxil fumarate (TDF) daily, and NVP daily for the first 14 days and then twice daily. Arm NVP/LPV_r and NoNVP/LPV_r participants will receive both FTC and TDF daily and lopinavir/ritonavir (LPV/RTV) twice daily. FTC and TDF may be replaced in either arm with the combination drug FTC/TDF. If participants experience virologic failure, toxicity, or otherwise cannot tolerate their regimens, they will switch to a different regimen. Arm NVP/NVP and NoNVP/NVP participants will switch to a regimen of two or more nucleoside reverse transcriptase inhibitors (NRTIs) and LPV/RTV; Arm NVP/LPV_r and NoNVP/LPV_r participants will switch to a regimen of two or more NRTIs and NVP. Study visits will occur at entry and at Weeks 2, 4, 8, 12, 16, 24, and then every 12 weeks thereafter. Visits will consist of a physical exam, medication assessment, and blood collection. Participants will be asked to complete adherence questionnaires at Weeks 4, 12, 24, and every 24 weeks thereafter, and quality of life questionnaires at Weeks 24 and ever 24 weeks thereafter. Study drugs will be provided for all participants through 48 weeks after the final participant is randomized. As per an amendment (dated April 13, 2009), participants will be asked to take part in an extension of this study. Enrollment in the extension is completely voluntary. The purpose of the extension is to monitor, in greater extent, the participants' health as they transition from study treatment to local, clinical care. During the study extension participants will not receive any medications through the study; it is expected that participants will receive their treatments through a local clinic. Participants enrolling in the extension will enter the extension at the same time as their last visit in the current study. For the extension, participants will be asked to come back to the clinic two times for study visits: at 12 and 72 weeks after entry into the extension. Because there will be a long time between these study visits, participants will also be contacted by phone (or through some other means) close to 48 weeks after entry into the extension. At each of these visits, participants will be asked about their health and medications, including current anti-HIV drugs. Participants will also be asked about any HIV care received outside of the study. As part of this study, investigators may need to review participants' non-study medical records and speak with their non-study care providers, to find out more about their HIV care and medical problems, and also to check results of lab tests. During the study extension period, participants will have blood drawn and also be tested for pregnancy.

Official Title
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Optimal Combination Therapy After Nevirapine Exposure

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Emtricitabine
* Drug: Emtricitabine/Tenofovir disoproxil fumarate
* Drug: Lopinavir/Ritonavir
* Drug: Nevirapine
* Drug: Tenofovir disoproxil fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for All Participants: HIV infected CD4 count less than 200 cells/mm^3 within 90 days prior to study entry Plasma HIV-1 RNA using standard Roche Amplicor HIV-1 Monitor Assay within 45 days prior to study entry the following laboratory values obtained within 45 days prior to study entry: absolute neutrophil count>=750/mm^3;Hemoglobin>=7.0g/dL;platelet count>=50000/mm^3;aspartate aminotransferase (AST),Alanine aminotransferase (ALT), and alkaline phosphatase <=2.5 x ULN; total bilirubin <=2.5 x ULN Normal renal function within 45 days prior to study entry Willing to use acceptable forms of contraception Karnofsky performance score >=70 on at least one occasion within 45 days prior to study entry Parent or guardian willing to provide informed consent, if applicable Planning to remain in the same geographical area of residence and are willing to attend study visits as required Inclusion Criteria for Trial 1 Participants: Previously received NVP for prevention of MTCT of HIV Has documentation of all prior doses of NVP used for prevention of MTCT of HIV Last dose of NVP for prevention of MTCT of HIV taken at least 6 months prior to study entry Exclusion Criteria for All Participants: Previously received any antiretrovirals, excluding NVP for MTCT prophylaxis for Trial 1 participants. Participants who have received up to 10 weeks of zidovudine alone and completed this course at least 6 months prior to study entry are not excluded. Use of systemic cancer chemotherapy, systemic investigational agents, immunomodulators, or rifampin within 30 days of study entry Pregnant or breastfeeding Known allergy or sensitivity to study drugs or their formulations Any condition, including drug or alcohol abuse, that, in the opinion of the investigator, may interfere with adherence to study regimens Serious illness requiring systemic treatment or hospitalization. Participants who complete therapy or are clinically stable on therapy for at least 30 days prior to study entry are not excluded. Tuberculosis (TB) treatment within 30 days prior to study entry Use of any prohibited medications within 30 days prior to study entry Involuntary incarceration in a correctional facility, prison, or jail for legal reasons or in a medical facility for treatment of either a psychiatric or physical illness

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NVP/NVP<br>For participants who had SD NVP exposure prior to study entry. FTC, TDF, and NVP daily the first 14 days, then twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive LPV/RTV twice daily plus two more NRTIs. | Drug: Emtricitabine<br>* 200 mg taken orally<br>* Other names: FTC;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200/300 mg taken orally<br>* Other names: FTC/TDF;Drug: Nevirapine<br>* 200 mg taken orally<br>* Other names: NVP;Drug: Tenofovir disoproxil fumarate<br>* 300 mg taken orally<br>* Other names: TDF;|
| Experimental: NVP/LPV_r<br>For participants who had SD NVP exposure prior to study entry. FTC and TDF daily and LPV/RTV twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP daily for 14 days before taking it twice daily. plus 2 more NRTIs. | Drug: Emtricitabine<br>* 200 mg taken orally<br>* Other names: FTC;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200/300 mg taken orally<br>* Other names: FTC/TDF;Drug: Lopinavir/Ritonavir<br>* 400/100 mg taken orally<br>* Other names: LPV/RTV;Drug: Tenofovir disoproxil fumarate<br>* 300 mg taken orally<br>* Other names: TDF;|
| Experimental: NoNVP/NVP<br>For participants who did NOT have SD NVP exposure prior to study entry.FTC, TDF, and NVP daily the first 14 days, then twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive LPV/RTV twice daily plus two more NRTIs. | Drug: Emtricitabine<br>* 200 mg taken orally<br>* Other names: FTC;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200/300 mg taken orally<br>* Other names: FTC/TDF;Drug: Nevirapine<br>* 200 mg taken orally<br>* Other names: NVP;Drug: Tenofovir disoproxil fumarate<br>* 300 mg taken orally<br>* Other names: TDF;|
| Experimental: NoNVP/LPV_r<br>For participants who did NOT have SD NVP exposure prior to study entry. FTC and TDF daily and LPV/RTV twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP daily for 14 days before taking it twice daily. plus 2 more NRTIs. | Drug: Emtricitabine<br>* 200 mg taken orally<br>* Other names: FTC;Drug: Emtricitabine/Tenofovir disoproxil fumarate<br>* 200/300 mg taken orally<br>* Other names: FTC/TDF;Drug: Lopinavir/Ritonavir<br>* 400/100 mg taken orally<br>* Other names: LPV/RTV;Drug: Tenofovir disoproxil fumarate<br>* 300 mg taken orally<br>* Other names: TDF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 5th and 10th Percentiles in weeks from randomization to virologic failure (VF) or death. VF is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is >=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF. | Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks. | 
| Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 5th and 10th Percentiles in weeks from randomization to virologic failure (VF) or death. VF is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is >=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF. | Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Virologic Failure or Died. | Virologic failure (VF) is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is >=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r. | 
| Percent of Participants Who Experienced Virologic Failure or Died | Results report cumulative percent of participants reaching virologic failure (VF) or death by week 48 and week 96 calculated using the Kaplan-Meier method. VF is defined as a plasma HIV-1 RNA level that is 1 log10 below baseline 12 weeks after treatment is initiated or as a plasma HIV-1 RNA level that is >=400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized treatment was being taken at the time of VF. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r arms. Throughout study for NoNVP/NVP and NoNVP/LPV_r arms. | 
| CD4 Count Change From Randomization | Change was calculated as the CD4 count at Week 48 (or at Week 96) minus the baseline CD4 count (last CD4 before/on treatment start date). For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r. Week 48 and 96. | 
| Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | The outcome is defined as treatment-related toxicity (as evaluated by sites), regardless of grade, that led to discontinuation of randomized regimen. For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r. | 
| Number of Participants Who Experienced HIV-related Disease Progression or Death | Worsening to WHO stage III/IV (among subjects who had WHO stage I/II at baseline) and death were the composite secondary endpoint. WHO Disease Staging System for HIV Infection and Disease in Adults and Adolescents is an approach for use in resource limited settings in studies of progression to symptomatic HIV disease. There are 4 stages of disease staging, 1 being the least severe and 4 being the most severe disease stage based on the HIV related symptoms and diagnoses. Please refer to the following web page for detailed staging criteria: http://www.who.int/docstore/hiv/scaling/anex1.html | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r. Throughout study for NoNVP/NVP and NoNVP/LPV_r. | 
| Number of Participants Who Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality | Any grade of rash or grade 2+ liver lab abnormality events that were claimed to be NVP associated (definitely, probably, or possibly) by site investigators were evaluated. Grade 2+ liver lab abnormality is defined as aspartate aminotransferase (AST)>=2.6 x ULN or alanine aminotransferase (ALT)>=2.6 x ULN. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm. | 
| Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | Self-reported adherence at week 48 and 96 while participants remained on randomized regimen. Adherence interviews for each antiretroviral drug drug the participant is taking was performed by site personnel every 24 weeks. For NVP/NVP and NVP/LPV_r arms, data through DSMB review cutoff (October 6, 2008) were used to report the outcome. For NoNVP/NVP and NoNVP/LPV_r arms, since the follow-up continued as planned, data through overall study were used. | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP and NVP/LPV_r arms. Throughout study for NoNVP/NVP and NoNVP/LPV_r arms. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced, Treatment Naive, MTCT, HIV Seronegativity