HIV Infections
Conditions
Keywords
Treatment Experienced
Brief summary
Most anti-HIV regimens include a non-nucleoside reverse transcriptase inhibitor (NNRTI); however, some individuals fail on these regimens. The purpose of this study is to evaluate the safety and effectiveness of the protease inhibitor (PI) lopinavir/ritonavir (LPV/r) in HIV infected individuals who are failing an anti-HIV regimen that includes an NNRTI.
Detailed description
Standard effective antiretroviral therapy for HIV infected individuals includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a PI or an NNRTI. However, three-drug regimens may not be ideal in resource-limited settings, where viral load and resistance testing may not be readily available. The purpose of this study is to evaluate the safety and efficacy of the PI LPV/r alone in treatment-experienced, PI-naive HIV infected individuals who are experiencing virologic failure on three-drug regimens. This study will last 104 weeks. All participants will receive LPV/r twice daily for up to 104 weeks. Participants who experience virologic failure will receive emtricitabine/tenofovir disoproxil fumarate once daily in addition to LPV/r twice daily for the remainder of the study. There will be 16 study visits for participants on LPV/r monotherapy and 12 study visits for participants who have intensified LPV/r with emtricitabine/tenofovir disoproxil fumarate. Blood collection and clinical assessment will occur at all visits; urine collection and resistance testing will occur at selected visits.
Interventions
DRUGEmtricitabine/Tenofovir disoproxil fumarate
Once daily
DRUGLopinavir/Ritonavir
Twice daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Step 1 Participants: * HIV infected * Continuous treatment with a three-drug, NNRTI-containing regimen for at least 6 months prior to study entry * Viral load of 1,000 copies/ml or greater and less or equal to 200,000 copies/ml obtained within 30 days of study entry * Negative pregnancy test within 48 hours of study entry * Willing to use acceptable forms of contraception for the duration of the study * Laboratory values obtained within 30 days of study entry: * Hemoglobin greater or equal to 8.0 g/dL * Platelet count greater or equal to 50,000/mm3 * Estimated Creatinine Clearance greater or equal to 60 mL/min x ULN * AST (SGOT), ALT (SGPT) and alkaline phosphatase \< 3 x ULN * Total bilirubin less or equal to 2.5 x ULN * Ability and willingness of participant or legal guardian/representative to give informed consent Inclusion Criteria for Step 2 Participants: * Virologic failure on LPV/r monotherapy defined as viral load of 400 copies/ml or greater after 24 consecutive weeks on LPV/r monotherapy OR virologic failure after initial viral suppression on LPV/r monotherapy * Estimated creatinine clearance of 60 ml/min or greater * Negative pregnancy test within 48 hours of entry into Step 2 * Willing to use acceptable forms of contraception for the duration of the study
Exclusion criteria
for All Participants: * Breastfeeding * Known allergy or sensitivity to study drugs * Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with study adherence to study requirements * History of chronic hepatitis B infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy | From study entry to week 24 | Virologic success at week 24 on LPV/r monotherapy was defined as remaining on LPV/r monotherapy at week 24 without prior virologic failure. Virologic failure was met with either of these two conditions: (i) failure to suppress HIV-1 RNA to \< 400 copies/mL by week 24 or (ii) confirmed HIV-1 RNA \>= 400 copies/mL after confirmed HIV-1 RNA \< 400 copies/mL. |
| Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study. | From study entry to week 24 | Probability of Grade 3 or 4 sign or symptom, or laboratory toxicity over 24 weeks on study using Kaplan-Meier estimates of the cumulative probability of Grade 3 or 4 sign or symptom, or laboratory toxicity at week 24. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure. | Study entry to Week 104 | 25th percentile in weeks from study entry to treatment failure, defined as the first occurrence of death, disease progression, or virologic failure. Virologic failure was defined as HIV-1 \>= 400 copies/mL after week 24 or 2 consecutive HIV-1 RNA \>= 400 copies/mL after week 16 following suppression on LPV/r monotherapy. |
| Number of Participants With Study-targeted Diagnoses and Clinical Events | Study entry to week 104 | Cardiac disorders, Infections and infestations, Metabolism and nutrition disorders, Neoplasms benign, malignant and unspecified (including cysts and polyps), Pregnancy, puerperium and perinatal conditions, Vascular disorders, were specified a priori as study-targeted events by the study chair. |
| Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure. | At time of virologic failure | Number of subjects with at least one new PI-associated resistance mutation at time of virologic failure. Resistance interpretations used the May 6, 2009 Stanford algorithm. |
| Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | Study entry and weeks 2, 4, 8, 12, 16, 20, and 24 | The percentage of subjects reporting never missing medications in the last month. |
| Change in CD4+ Cell Counts From Study Entry to Week 104 | Study entry and week 104 | — |
| Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | At study entry and weeks 24 and 48 | Proportion of DBS samples with HIV-1 RNA level \<= 400 copies/mL, proportion of plasma samples with HIV-1 RNA level \<= 400 copies/mL and proportion of paired DBS and plasma samples that are concordant (both \<= 400 copies/mL or both \> 400 copies/mL). Results are pooled over 4 different storage temperature conditions (-80C, -20C, 4C and room temperature). |
| HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma | At study entry and virologic failure | HIV-1 viral sequencing as ascertained from paired DBS and plasma |
| Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104 | — |
| Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification | From LPV/r intensification to week 104 | 25th percentile in weeks from study entry to first new grade 3 or 4 sign or symptom or laboratory toxicity following LPV/r intensification. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004. |
| Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening. | Screening | Number of screened subjects with at least one NNRTI, or NRTI-associated resistance mutation. Resistance interpretations used the November 30, 2011 Stanford algorithm. |
Countries
India, Malawi, South Africa, Tanzania, Thailand
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LPV/r Monotherapy Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir (TDF) once a day will be added to their regimen. | 123 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Screening | Did not meet eligibility criteria | 84 |
| Weeks 0 to 24 | Death | 1 |
| Weeks 24 to 104 | Death | 3 |
| Weeks 24 to 104 | Not able to get to clinic | 2 |
Baseline characteristics
| Characteristic | LPV/r Monotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 123 Participants |
| Age, Continuous | 39.4 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment India | 12 participants |
| Region of Enrollment Malawi | 40 participants |
| Region of Enrollment South Africa | 22 participants |
| Region of Enrollment Tanzania | 25 participants |
| Region of Enrollment Thailand | 24 participants |
| Sex: Female, Male Female | 70 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 122 / 123 |
| serious Total, serious adverse events | 20 / 123 |
Outcome results
Primary
Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy
Virologic success at week 24 on LPV/r monotherapy was defined as remaining on LPV/r monotherapy at week 24 without prior virologic failure. Virologic failure was met with either of these two conditions: (i) failure to suppress HIV-1 RNA to \< 400 copies/mL by week 24 or (ii) confirmed HIV-1 RNA \>= 400 copies/mL after confirmed HIV-1 RNA \< 400 copies/mL.
Time frame: From study entry to week 24
Population: All enrolled individuals.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy | 87 percentage of enrolled subjects |
Comparison: The null hypothesis was that LPV/r monotherapy provides at least a 65% short-term virologic response. The target sample size was 120 subjects. Assuming an underlying true 24 week success rate of 76%, this sample size was chosen in order to provide at least 90% power to show that the true 24 week virologic success rate of LPV/r monotherapy in this population is greater than 65%.90% CI: [81, 92]confidence interval
Primary
Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study.
Probability of Grade 3 or 4 sign or symptom, or laboratory toxicity over 24 weeks on study using Kaplan-Meier estimates of the cumulative probability of Grade 3 or 4 sign or symptom, or laboratory toxicity at week 24. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
Time frame: From study entry to week 24
Population: All enrolled individuals.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study. | 0.23 cumulative probability of grade 3 or 4 |
Secondary
Change in CD4+ Cell Counts From Study Entry to Week 104
Time frame: Study entry and week 104
Population: All participants enrolled.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LPV/r Monotherapy | Change in CD4+ Cell Counts From Study Entry to Week 104 | 213 cells/mm^3 |
Secondary
HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma
HIV-1 viral sequencing as ascertained from paired DBS and plasma
Time frame: At study entry and virologic failure
Population: HIV-1 viral sequence testing in DBS was not performed
Secondary
Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma
Proportion of DBS samples with HIV-1 RNA level \<= 400 copies/mL, proportion of plasma samples with HIV-1 RNA level \<= 400 copies/mL and proportion of paired DBS and plasma samples that are concordant (both \<= 400 copies/mL or both \> 400 copies/mL). Results are pooled over 4 different storage temperature conditions (-80C, -20C, 4C and room temperature).
Time frame: At study entry and weeks 24 and 48
Population: Participants with DBS samples available at study entry, week 24 or 48, with corresponding plasma HIV-1 RNA levels.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | study entry DBS <= 400 cp/mL | 0.17 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | study entry plasma <= 400 cp/mL | 0.00 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | study entry DBS & plasma concordance | 0.83 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 24 DBS <= 400 cp/mL | 0.82 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 24 plasma <= 400 cp/mL | 0.80 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 24 DBS & plasma concordance | 0.80 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 48 DBS <= 400 cp/mL | 0.94 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 48 plasma <= 400 cp/mL | 0.91 proportion of samples |
| LPV/r Monotherapy | Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | week 48 DBS & plasma concordance | 0.97 proportion of samples |
Secondary
Number of Participants With Study-targeted Diagnoses and Clinical Events
Cardiac disorders, Infections and infestations, Metabolism and nutrition disorders, Neoplasms benign, malignant and unspecified (including cysts and polyps), Pregnancy, puerperium and perinatal conditions, Vascular disorders, were specified a priori as study-targeted events by the study chair.
Time frame: Study entry to week 104
Population: All participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Number of Participants With Study-targeted Diagnoses and Clinical Events | 39 participants |
Secondary
Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening.
Number of screened subjects with at least one NNRTI, or NRTI-associated resistance mutation. Resistance interpretations used the November 30, 2011 Stanford algorithm.
Time frame: Screening
Population: All screened individuals.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LPV/r Monotherapy | Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening. | At least one NNRTI-associated mutation | 201 number of screened subjects |
| LPV/r Monotherapy | Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening. | At least one NRTI-associated mutation | 197 number of screened subjects |
Secondary
Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure.
Number of subjects with at least one new PI-associated resistance mutation at time of virologic failure. Resistance interpretations used the May 6, 2009 Stanford algorithm.
Time frame: At time of virologic failure
Population: 16 subjects met the criteria for endpoint failure; 15 subjects were virologic failures and 1 subject intensified prior to virologic failure. Of the 15 subjects with virologic failure, 11 had sequence data, and sequencing failed for 4.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure. | 2 participants |
Secondary
Percentage of Subjects Reporting Not Skipping Medications in the Last Month.
The percentage of subjects reporting never missing medications in the last month.
Time frame: Study entry and weeks 2, 4, 8, 12, 16, 20, and 24
Population: All participants enrolled.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 20 (N=120) | 90.9 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 24 (N=122) | 89.4 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 2 (N=120) | 90 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 4 (N=121) | 86.8 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 8 (N=123) | 87.8 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 12 (N=123) | 86.2 percentage of subjects with data |
| LPV/r Monotherapy | Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | week 16 (N=122) | 86.1 percentage of subjects with data |
Secondary
Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104
Time frame: At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104
Population: All participants enrolled.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 0 (N=123) | 0.02 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 32 (N=121) | 0.83 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 40 (N=118) | 0.84 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 48 (N=118) | 0.87 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 56 (N=120) | 0.86 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 68 (N=116) | 0.91 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 80 (N=117) | 0.85 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 92 (N=116) | 0.87 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 104 (N=117) | 0.89 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 12 (N=122) | 0.75 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 16 (N=121) | 0.87 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 20 (N=115) | 0.84 proportion of participants |
| LPV/r Monotherapy | Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 | week 24 (N=122) | 0.84 proportion of participants |
Secondary
Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification
25th percentile in weeks from study entry to first new grade 3 or 4 sign or symptom or laboratory toxicity following LPV/r intensification. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.
Time frame: From LPV/r intensification to week 104
Population: All participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification | 26.0 weeks |
Secondary
Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure.
25th percentile in weeks from study entry to treatment failure, defined as the first occurrence of death, disease progression, or virologic failure. Virologic failure was defined as HIV-1 \>= 400 copies/mL after week 24 or 2 consecutive HIV-1 RNA \>= 400 copies/mL after week 16 following suppression on LPV/r monotherapy.
Time frame: Study entry to Week 104
Population: All participants enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/r Monotherapy | Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure. | 48.0 weeks |