HIV Infections
Conditions
Keywords
Treatment Experienced, Treatment Naive, MTCT, HIV Seronegativity
Brief summary
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
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.
Interventions
DRUGEmtricitabine
200 mg taken orally
DRUGEmtricitabine/Tenofovir disoproxil fumarate
200/300 mg taken orally
DRUGLopinavir/Ritonavir
400/100 mg taken orally
DRUGNevirapine
200 mg taken orally
DRUGTenofovir disoproxil fumarate
300 mg taken orally
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks. | 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. |
| Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD4 Count Change From Randomization | 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. | 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. |
| Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | 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. | 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. |
| Number of Participants Who Experienced Virologic Failure or Died. | 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. | 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. |
| Number of Participants Who Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality | Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm. | 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. |
| Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | 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. | 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. |
| Number of Participants Who Experienced HIV-related Disease Progression or Death | 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. | 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 |
| Percent of Participants Who Experienced Virologic Failure or Died | 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. | 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. |
Countries
Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, Zimbabwe
Participant flow
Recruitment details
Study participants were recruited at 10 sites from 7 African countries: 3 from South Africa, 2 from Kenya, and 1 each in Botswana, Malawi, Uganda, Zambia and Zimbabwe, between November 2006 to July 2008. The Botswana site enrolled participants from two locations.
Pre-assignment details
HIV-infected, treatment-naive women, at least 13 years of age with CD4+ count\<200 cells/mm\^3. Four participants were randomized but did not start treatment.
Participants by arm
| Arm | Count |
|---|---|
| NVP/NVP For participants had single dose Nevirapine (SD NVP) exposure prior to study entry, Emtricitabine capsules(FTC) 200mg (1 capsule orally), Tenofovir disproxil fumerate (TDF) 300mg (1 tablet orally), and NVP 200mg (1 tablet orally) once daily in the morning for the first 14 days, then twice daily after 14 days. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive Lopinovir/Ritonovir (LPV/RTV)400/100mg (3 capsules orally) twice daily plus two more Nucleoside reverse transcriptase inhibitors (NRTIs). Following the review on 6 October 2008, the Data Safety Monitoring Board(DSMB) recommended release of the results from this arm. | 121 |
| NVP/LPV_r For participants had SD NVP exposure prior to study entry, FTC 200mg (1 capsule orally) and TDF 300mg (1 tablet orally) daily and LPV/RTV 400/100mg (3 capsules orally) twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP 200mg (1 tablet orally) daily for 14 days before taking it twice daily. plus 2 more NRTIs. Following the review on 6 October 2008, the DSMB recommended release of the results from this arm. | 120 |
| NoNVP/NVP For participants had NO SD NVP exposure prior to study entry, FTC 200mg (1 capsule orally), TDF 300mg (1 tablet orally), and NVP 200mg (1 tablet orally) once daily for the first 14 days, then twice daily after 14 days. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue NVP will receive LPV/RTV 400/100mg (3 capsules orally) twice daily plus two more NRTIs. | 249 |
| NoNVP/LPV_r For participants had SD NVP exposure prior to study entry, FTC 200mg (1 capsule orally) and TDF 300mg (1 tablet orally) once daily and LPV/RTV 400/100mg (3 capsules orally) twice daily. FTC and TDF may be replaced by the combination drug FTC/TDF. Participants who discontinue LPV/RTV will receive NVP daily 200mg (1 tablet orally) for 14 days before taking it twice daily plus 2 more NRTIs. | 251 |
| Total | 741 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 4 | 1 | 5 | 8 |
| Overall Study | Lost to Follow-up | 1 | 1 | 9 | 7 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 6 | 6 |
Baseline characteristics
| Characteristic | Total | NoNVP/LPV_r | NVP/NVP | NoNVP/NVP | NVP/LPV_r |
|---|---|---|---|---|---|
| Age, Continuous | 33 years STANDARD_DEVIATION 7 | 35 years STANDARD_DEVIATION 8 | 30 years STANDARD_DEVIATION 5 | 35 years STANDARD_DEVIATION 7 | 31 years STANDARD_DEVIATION 5 |
| Age, Customized >=50 years | 20 participants | 12 participants | 1 participants | 7 participants | 0 participants |
| Age, Customized Between 13 and 19 years | 2 participants | 2 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 20 and 29 years | 232 participants | 64 participants | 56 participants | 63 participants | 49 participants |
| Age, Customized Between 30 and 39 years | 370 participants | 124 participants | 59 participants | 125 participants | 62 participants |
| Age, Customized Between 40 and 49 years | 117 participants | 49 participants | 5 participants | 54 participants | 9 participants |
| Baseline HIV-1 RNA Categorial >=750,000 copies/mL | 74 participants | 22 participants | 11 participants | 26 participants | 15 participants |
| Baseline HIV-1 RNA Categorial Between 100,000 and 749,999 copies/mL | 375 participants | 128 participants | 61 participants | 123 participants | 63 participants |
| Baseline HIV-1 RNA Categorial Between 10,000 and 99,999 copies/mL | 246 participants | 88 participants | 44 participants | 81 participants | 33 participants |
| Baseline HIV-1 RNA Categorial Between 1000 and 9,999 copies/mL | 42 participants | 11 participants | 5 participants | 18 participants | 8 participants |
| Baseline HIV-1 RNA Categorial Between 400 and 999 copies/mL | 4 participants | 2 participants | 0 participants | 1 participants | 1 participants |
| CD4 count Categorical >=350 cells/mm^3 | 4 participants | 2 participants | 0 participants | 2 participants | 0 participants |
| CD4 count Categorical <50 cells/mm^3 | 93 participants | 36 participants | 14 participants | 32 participants | 11 participants |
| CD4 count Categorical Between 100 to 149 cells/mm^3 | 216 participants | 78 participants | 35 participants | 65 participants | 38 participants |
| CD4 count Categorical Between 150 to 199 cells/mm^3 | 184 participants | 57 participants | 37 participants | 58 participants | 32 participants |
| CD4 count Categorical Between 200 to 249 cells/mm^3 | 64 participants | 19 participants | 15 participants | 18 participants | 12 participants |
| CD4 count Categorical Between 250 to 299 cells/mm^3 | 18 participants | 4 participants | 1 participants | 9 participants | 4 participants |
| CD4 count Categorical Between 300 to 349 cells/mm^3 | 5 participants | 2 participants | 1 participants | 2 participants | 0 participants |
| CD4 count Categorical Between 50 to 99 cells/mm^3 | 157 participants | 53 participants | 18 participants | 63 participants | 23 participants |
| CD4 count Continuous | 129 cell/mm^3 STANDARD_DEVIATION 67 | 125 cell/mm^3 STANDARD_DEVIATION 71 | 136 cell/mm^3 STANDARD_DEVIATION 60 | 126 cell/mm^3 STANDARD_DEVIATION 68 | 135 cell/mm^3 STANDARD_DEVIATION 61 |
| HIV-1 RNA Continuous | 5.2 log 10 copies/mL | 5.2 log 10 copies/mL | 5.2 log 10 copies/mL | 5.2 log 10 copies/mL | 5.1 log 10 copies/mL |
| Region of Enrollment Botswana | 88 participants | 30 participants | 13 participants | 33 participants | 12 participants |
| Region of Enrollment Kenya | 137 participants | 48 participants | 21 participants | 45 participants | 23 participants |
| Region of Enrollment Malawi | 68 participants | 22 participants | 14 participants | 22 participants | 10 participants |
| Region of Enrollment South Africa | 207 participants | 67 participants | 35 participants | 69 participants | 36 participants |
| Region of Enrollment Uganda | 60 participants | 21 participants | 8 participants | 22 participants | 9 participants |
| Region of Enrollment Zambia | 64 participants | 21 participants | 12 participants | 19 participants | 12 participants |
| Region of Enrollment Zimbabwe | 117 participants | 42 participants | 18 participants | 39 participants | 18 participants |
| Sex: Female, Male Female | 741 Participants | 251 Participants | 121 Participants | 249 Participants | 120 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO stage Clinical stage I | 290 participants | 93 participants | 44 participants | 97 participants | 56 participants |
| WHO stage Clinical stage II | 219 participants | 67 participants | 42 participants | 72 participants | 38 participants |
| WHO stage Clinical stage III | 208 participants | 80 participants | 30 participants | 73 participants | 25 participants |
| WHO stage Clinical stage IV | 24 participants | 11 participants | 5 participants | 7 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 110 / 121 | 105 / 120 | 225 / 249 | 227 / 251 |
| serious Total, serious adverse events | 9 / 121 | 6 / 120 | 26 / 249 | 19 / 251 |
Outcome results
Primary
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.
Time frame: Through database cutoff for DSMB review (by October 6, 2008) with median follow-up 72 weeks and range from 0 to 144 weeks.
Population: Numbers presented use the intent-to-treat approach (i.e. ignoring changes from randomized treatment).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 5th percentile | 12 weeks |
| NVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 10th percentile | 12 weeks |
| NVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 25th percentile | 60 weeks |
| NVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 5th percentile | 60 weeks |
| NVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 10th percentile | 84 weeks |
| NVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Who Had SD NVP Exposure Prior to Study Entry | 25th percentile | NA weeks |
p-value: <0.00195% CI: [1.79, 7.61]Regression, Cox
Primary
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.
Time frame: Throughout study with median follow-up 72 weeks and range from 0 to 180 weeks.
Population: The analysis was intent to treat per protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NoNVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 5th percentile | 24 weeks |
| NoNVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 10th percentile | 36 weeks |
| NoNVP/NVP | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 25th percentile | NA weeks |
| NoNVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 5th percentile | 12 weeks |
| NoNVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 10th percentile | 36 weeks |
| NoNVP/LPV_r | Time From Randomization to Virologic Failure or Death for Participants Without SD NVP Exposure Prior to Study Entry | 25th percentile | 132 weeks |
p-value: 0.4395% CI: [0.56, 1.29]Regression, Cox
Secondary
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.
Time frame: 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.
Population: Changes were calculated using the intent-to-treat approach (i.e. ignoring changes from randomized treatment) but no imputation was done for missing values.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| NVP/NVP | CD4 Count Change From Randomization | Week 48 CD4 count change from randomization | 191 cells/mm^3 |
| NVP/NVP | CD4 Count Change From Randomization | Week 96 CD4 count change from randomization | 291 cells/mm^3 |
| NVP/LPV_r | CD4 Count Change From Randomization | Week 96 CD4 count change from randomization | 278 cells/mm^3 |
| NVP/LPV_r | CD4 Count Change From Randomization | Week 48 CD4 count change from randomization | 201 cells/mm^3 |
| NoNVP/NVP | CD4 Count Change From Randomization | Week 48 CD4 count change from randomization | 172 cells/mm^3 |
| NoNVP/NVP | CD4 Count Change From Randomization | Week 96 CD4 count change from randomization | 223 cells/mm^3 |
| NoNVP/LPV_r | CD4 Count Change From Randomization | Week 48 CD4 count change from randomization | 172 cells/mm^3 |
| NoNVP/LPV_r | CD4 Count Change From Randomization | Week 96 CD4 count change from randomization | 256 cells/mm^3 |
Secondary
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
Time frame: 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.
Population: Numbers presented use the intent-to-treat approach (i.e. ignoring changes from randomized treatment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NVP/NVP | Number of Participants Who Experienced HIV-related Disease Progression or Death | 6 participants |
| NVP/LPV_r | Number of Participants Who Experienced HIV-related Disease Progression or Death | 4 participants |
| NoNVP/NVP | Number of Participants Who Experienced HIV-related Disease Progression or Death | 19 participants |
| NoNVP/LPV_r | Number of Participants Who Experienced HIV-related Disease Progression or Death | 26 participants |
Secondary
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.
Time frame: 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.
Population: Numbers presented use as-treated method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NVP/NVP | Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | 15 participants |
| NVP/LPV_r | Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | 0 participants |
| NoNVP/NVP | Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | 35 participants |
| NoNVP/LPV_r | Number of Participants Who Experienced Treatment-related Toxicity That Led to Discontinuation of Randomized Regimen. | 0 participants |
Secondary
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.
Time frame: 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.
Population: Numbers presented use the intent-to-treat approach (i.e. ignoring changes from randomized treatment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NVP/NVP | Number of Participants Who Experienced Virologic Failure or Died. | 32 participants |
| NVP/LPV_r | Number of Participants Who Experienced Virologic Failure or Died. | 10 participants |
| NoNVP/NVP | Number of Participants Who Experienced Virologic Failure or Died. | 42 participants |
| NoNVP/LPV_r | Number of Participants Who Experienced Virologic Failure or Died. | 50 participants |
Secondary
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.
Time frame: Through database cutoff for DSMB review (by October 6, 2008) for NVP/NVP arm. Throughout study for NoNVP/NVP arm.
Population: Numbers presented use the as-treated approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NVP/NVP | Number of Participants Who Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality | 20 participants |
| NoNVP/NVP | Number of Participants Who Received NVP-containing Regimens at Randomization and Experienced NVP-associated Rash or Grade 2+ Liver Lab Abnormality | 51 participants |
Secondary
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.
Time frame: 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.
Population: Numbers presented use the intent-to-treat approach (i.e. ignoring changes from randomized treatment).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVP/NVP | Percent of Participants Who Experienced Virologic Failure or Died | week 48 percent of virologic failure or death | 23 Percent of participants |
| NVP/NVP | Percent of Participants Who Experienced Virologic Failure or Died | week 96 percent of virologic failure or death | 31 Percent of participants |
| NVP/LPV_r | Percent of Participants Who Experienced Virologic Failure or Died | week 96 percent of virologic failure or death | 12 Percent of participants |
| NVP/LPV_r | Percent of Participants Who Experienced Virologic Failure or Died | week 48 percent of virologic failure or death | 4 Percent of participants |
| NoNVP/NVP | Percent of Participants Who Experienced Virologic Failure or Died | week 48 percent of virologic failure or death | 14 Percent of participants |
| NoNVP/NVP | Percent of Participants Who Experienced Virologic Failure or Died | week 96 percent of virologic failure or death | 17 Percent of participants |
| NoNVP/LPV_r | Percent of Participants Who Experienced Virologic Failure or Died | week 48 percent of virologic failure or death | 14 Percent of participants |
| NoNVP/LPV_r | Percent of Participants Who Experienced Virologic Failure or Died | week 96 percent of virologic failure or death | 20 Percent of participants |
Secondary
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.
Time frame: 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.
Population: Numbers presented use as-treated approach.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NVP/NVP | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 48 percent of full adherence in past month | 89 percent of participants |
| NVP/NVP | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 96 percent of full adherence in past month | 94 percent of participants |
| NVP/LPV_r | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 96 percent of full adherence in past month | 95 percent of participants |
| NVP/LPV_r | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 48 percent of full adherence in past month | 88 percent of participants |
| NoNVP/NVP | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 48 percent of full adherence in past month | 90 percent of participants |
| NoNVP/NVP | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 96 percent of full adherence in past month | 93 percent of participants |
| NoNVP/LPV_r | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 48 percent of full adherence in past month | 86 percent of participants |
| NoNVP/LPV_r | Percent of Participants Who Reported to Never Missed Any of the Study Drug Regimen in the Past Month | week 96 percent of full adherence in past month | 87 percent of participants |