Comparison of NRTI-, NNRTI, and PI-sparing Regimens for First-line Therapy

Researchers have explored so-called "class sparing" regimens to reduce the side effects associated with specific antiretroviral classes. The U.S. federal treatment guidelines list both the protease inhibitor (PI) lopinavir/ritonavir (Kaletra) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva), each combined with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), as preferred initial antiretroviral regimens.

At the XVI International AIDS Conference, held last week in Toronto, Sharon Riddler presented data from AIDS Clinical Trials Group (ACTG) study 5142, a randomized, open-label Phase III trial comparing NRTI-, NNRTI-, and PI-sparing regimens as first-line therapy for HIV infection.

A total of 753 participants with HIV RNA levels above 2000 copies/mL were randomly assigned to receive one of three regimens:

lopinavir/ritonavir 400/100 mg twice daily plus two NRTIs;
efavirenz 600 mg once daily plus two NRTIs;
lopinavir/ritonavir 533/133 mg twice daily plus efavirenz 600 mg once daily (no NRTIs).

NRTIs were selected before randomization, and included 3TC (Epivir) plus either AZT (Retrovir; 42%), d4T (Zerit; 24%), or tenofovir (Viread; 34%).

The primary endpoint was time to confirmed virological failure (HIV RNA > 200 after week 32) and regimen completion (toxicity-related discontinuation of any regimen component). An intent-to-treat (ITT) analysis was performed. The threshold for significance was set at 0.016.

Results

At baseline, the median viral load was 100,000 copies/mL and the median CD4 cell count was 182 cells/mm3.

After a median of 112 weeks, no statistically significant differences were observed between the treatment arms in terms of time to virological failure or regimen discontinuation (P > 0.016).

There was a non-significant trend toward shorter time to virological failure (P = 0.033) and regimen discontinuation (P = 0.065) with lopinavir/ritonavir plus NRTIs compared with efavirenz plus NRTIs.

Proportions of patients without virological failure by week 96 were:

- 67% in the lopinavir/ritonavir plus NRTIs arm;
- 73% in the lopinavir/ritonavir plus efavirenz arm;
- 76% in the efavirenz plus NRTIs arm.

Proportions of patients still on the assigned regimen at week 96 were:

- 54% in the lopinavir/ritonavir plus NRTIs arm;
- 60% in the efavirenz plus NRTIs arm;
- 61% in the lopinavir/ritonavir plus efavirenz arm.

At week 96, the percentages with HIV RNA below 50 copies/mL were:

- 77% in the lopinavir/ritonavir plus NRTIs arm;
- 83% in the lopinavir/ritonavir plus efavirenz arm;
- 89% in the efavirenz plus NRTIs arm (P = 0.003 lopinavir/ritonavir vs efavirenz).

The median 96-week increase in CD4 cells was significantly greater for the two arms containing lopinavir/ritonavir:

- 285 cells/mm3 in the lopinavir/ritonavir plus NRTIs arm;
- 268 cells/mm3 in the lopinavir/ritonavir plus efavirenz arm;
- 241 cells/mm3 in the efavirenz plus NRTIs arm (P = 0.01).

Treatment-limiting toxicities were similar in all arms, with 18%-20% experiencing any new grade 3-4 clinical or laboratory events.

There was a trend toward more NNRTI-resistance mutations in the lopinavir/ritonavir plus efavirenz arm than in the efavirenz plus NRTIs arm; resistance to two drug classes was more common in the efavirenz plus NRTIs arm, and major PI-resistance mutations were rare.

Conclusion

The authors concluded that, compared with a PI-sparing regimen of efavirenz plus two NRTIs, patients receiving the NNRTI-sparing regimen of lopinavir/ritonavir plus two NRTIs had a significantly shorter time to virological failure and tended to have a shorter time to regimen discontinuation. The NRTI-sparing regimen of lopinavir/ritonavir plus efavirenz had similar virological efficacy and time to treatment-limiting toxicity as efavirenz plus two NRTIs.

8/25/06

Reference
S A Riddler, R Haubrich, G DiRienzo, and others. A prospective, randomized, Phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection - ACTG 5142. XVI International AIDS Conference. Toronto, August 13-18, 2006. Abstract THLB0204.