Clinical trial NCT01352715
Conditions: HIV-1 Infection
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Start date: 2012-03-13; Completion date: 2014-10-29
Enrollment: 515 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was conducted on people who were taking their first anti-HIV drug regimen (including an Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), a type of anti-HIV drug) but the drugs in this regimen were not doing a good job of fighting their HIV infection.

The main purpose of this study was to compare two other anti-HIV drug regimens to see how well they fight HIV. The study also looked at how well participants tolerate the drug regimens and how safe they are.

The study was designed to determine whether taking the combination of lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) works as well as what is usually used for second-line therapy: LPV/r plus the best-available nucleoside (nucleotide) reverse transcriptase inhibitor (NRTI) combination. Testing a regimen that does not include any NRTIs was important because NRTIs may no longer work for patients who received them as part of their first treatment regimen.

Detailed description:
As more HIV-infected persons start antiretroviral therapy (ART) worldwide, the number needing second-line therapy is increasing. In many settings, an NNRTI-based regimen is the preferred first-line ART, whereas a protease inhibitor (PI)-based regimen is often reserved for second-line ART. Both of these types of regimens usually include two NRTIs.

As with initial ART, second-line regimens ideally should be composed of three fully active drugs that have potent anti-HIV activity to maximize the chances of durable viral suppression. However, such a goal may not be achieved with second-line PI-based regimens containing NRTIs because of resistance mutations from first-line therapy that reduce the activity of the NRTI class. The most significant of these mutations include M184V, thymidine analogue mutations (TAMs), Q151M complex, and K65R. The presence of K65R would result in resistance to most NRTIs (leaving only zidovudine (ZDV) and possibly abacavir (ABC) as active second-line options); the presence of multiple TAMs and/or Q151M alone or in complex with other mutations would also result in resistance to most NRTIs.

Recent data suggest that patients with isolated M184V-related NRTI resistance who subsequently switch to a boosted PI plus lamivudine (3TC)- or emtricitabine (FTC)-based regimen may achieve HIV-1 RNA suppression without the need to switch to more complex regimens \[1\]. Detection of an isolated M184V NRTI mutation is possible when resources allow for early diagnosis of virologic failure. However, in many resource-limited settings (RLS) early diagnosis of virologic failure is difficult because of infrequent monitoring of viral load or unavailability of viral load testing. This study intended to provide information applicable to the vast majority of RLS where resistance testing is not used routinely for selection of second-line regimens and PIs not needing refrigeration are preferred.

This was a phase III, dual-arm, open-label, randomized, non-inferiority study for participants who were on a failing NNRTI-containing first-line regimen. The study evaluated the difference in virologic failure rate between two treatment arms:

Arm A: LPV/r plus RAL Arm B: LPV/r plus best available NRTIs

Best available NRTI combinations were selected by the site investigator prior to randomization from a list of combinations approved by the study or in consultation with the A5273 Clinical Management Committee (CMC). The NRTIs provided by the study were FTC/TDF, ABC/3TC/ZDV, ABC/3TC, 3TC/ZDV, ABC, 3TC, and ZDV.

Participants took their assigned study therapy until 96 weeks of follow-up or 52 weeks after the last participant was enrolled (protocol amendment), whichever was earlier. This study originally planned to enroll 600 participants (300 per study arm), but the sample size was re-evaluated to 480 participants (240 per study arm), due to emergent data from other studies. Participants were assigned with equal probability to one of the two treatment regimens using permuted blocks. Randomization was stratified by three factors: screening HIV-1 RNA (≥100,000 versus \<100,000 copies/mL); screening CD4+ cell count (≥100 versus \<100 cells/mm3), and selection of ZDV in the NRTI regimen (yes/no). Furthermore, randomization was balanced by site.

During the study, participants were asked to return to the clinic at Weeks 4, 12, 24, and then every 12 weeks. Visits lasted about 30 minutes. At most visits, participants had a physical exam, had their arm, waist and hip circumference measured, and answered questions about their medical condition and any medications they were taking. At some visits, participants completed questionnaires to see how they were feeling, if they had been hospitalized recently, and how well they were taking their anti-HIV drugs, had their blood drawn and were asked to give urine samples. If the participant was female and able to become pregnant, a pregnancy test was taken at any visit that pregnancy was suspected.

Arms: arm 1: Participants were administered LPV/r plus RAL orally twice daily throughout follow-up. arm 2: Participants were administered LPV/r orally twice daily, plus NRTI options provided by the study, to include the best available NRTIs (listed below) throughout follow-up-

* FTC/TDF orally twice daily
* ABC/3TC/ZDV orally twice daily
* ABC/3TC orally once daily
* 3TC/ZDV orally twice daily
* ABC 300mg orally twice daily or 600 mg once daily
* 3TC orally twice daily
* ZDV orally twice daily
Interventions: intervention 1: Lopinavir/ritonavir intervention 2: Lopinavir/ritonavir intervention 3: Raltegravir intervention 4: Emtricitabine/tenofovir disoproxil fumarate intervention 5: Abacavir/lamivudine/zidovudine intervention 6: Abacavir/lamivudine intervention 7: Lamivudine/zidovudine intervention 8: Abacavir intervention 9: Zidovudine intervention 10: Lamivudine
Intervention descriptions: intervention 1: Lopinavir 400mg/ritonavir 100mg (given as two LPV 200mg/RTV 50mg fixed-dose combination tablets) orally twice daily, with or without food, throughout follow-up. intervention 2: Lopinavir 400mg/ritonavir 100mg (given as three LPV 133.3 mg/RTV 33.3 mg fixed-dose combination soft gelatin capsules) orally twice daily, with food, throughout follow-up. intervention 3: Raltegravir 400 mg tablet orally twice daily, with or without food, throughout follow-up. intervention 4: Emtricitabine 200 mg/tenofovir disoproxil fumarate 300mg fixed-dose combination tablet orally once daily, with or without food, throughout follow-up. intervention 5: Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, throughout follow-up. intervention 6: Abacavir 600 mg/lamivudine 300 mg fixed-dose combination tablet orally once daily, with or without food, throughout follow-up. intervention 7: Lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet orally twice daily, with or without food, throughout follow-up. intervention 8: Abacavir 300 mg tablet orally twice daily or 600 mg (given as two 300 mg tablets) once daily, with or without food, throughout follow-up. intervention 9: Zidovudine 300 mg tablet orally twice daily, with or without food, throughout follow-up. intervention 10: Lamivudine 150 mg tablet orally twice daily, with or without food, throughout follow-up.

Protocol documents: