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Nuke Sparing Regimen: Kaletra + 1000 mg Saquinavir
Reported by Jules Levin
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This 3 PI regimen sounds like a useful treatment option for individuals who have sensitivity to protease inhibitors but unable to take nukes due to resistance or toxicity. Actually, it's a 2 PI regimen (Kaletra & saquinavir), both being boosted by 100 mg of ritonavir. Perhaps Viread (Tenofovir) can still be effective despite nuke resistance. A resistance test can help evaluate if Tenofovir can be effective. Recently, Gilead Sciences, the manufacturer of Tenofovir, reported resistance research listing the resistance mutations that confer resistance to Tenofovir and the cut-off for phenotypic resistance to Tenofovir which was 4-fold resistance. Some doctors feel 5-6 fold Tenofovir resistance is a cut-off, but this has not been studied and established. Mike Miller, from Gilead Sciences, reported the presence of the M41L or L210W mutation plus 3 or more nuke mutations severely reduces Tenofovir effectiveness. But Tenofovir can still be effective even if 3 or 4 nuke mutations are present if the 41 or 210 mutations are not present. T-20, the new entry inhibitor, can help. T-20 is administered by twice daily subcutaneous injection, but is a potent anti-HIV drug even if a patient has resistance to the current classes of drugs. Roche, the manufacturer of T-20, is planning to offer an expanded access program this Fall for patients in desperate need. But T-20 is expected to be approved by the FDA in March 2003.
It was recently reported in a pilot preliminary study at the 3rd Pharmacology Wksp that Invirase achieves similar drug blood levels as Fortovase when both are boosted by 100 mg of ritonavir. And Invirase was more tolerable, less diarrhea and abdominal distress. At Barcelona, 1000mg saquinavir + 100 mg ritonavir twice daily was compared to indinavir 800 mg + 100 mg ritonavir twice daily (MaxCmin Study). The SQV/RTV regimen was found to be as potent but had less side effects and toxicity and was more tolerable. Roche is planning a study comparing 1000mg SQV+ 100 mg RTV to Kaletra. It's my understanding that Roche is developing 500 mg capsules of saquinavir to reduce pill count.
3rd Pharmacology Wksp Report (Invirase vs Fortovase Study)
www.natap.org/2002/3pharm/day1.htm
Tenofovir Resistance Reports
www.natap.org/2002/HIVDrugRes/day4.htm (genotypic resistance)
www.natap.org/2002/HIVDrugRes/day3.htm (phenotypic resistance)
T-20 Report from Barcelona
www.natap.org/2002/barcelona/day1.htm
Schlomo Staszewski reported on a pilot study evaluating the safety and efficacy of a twice daily boosted double PI regimen (Kaletra plus 1000 mg saquinavir) without nukes in patients who have limited nuke options available due to resistance or toxicity, but have PI-sensitive virus.. These preliminary pilot study results suggest that this regimen can be effective for patients with PI sensitivity noted with resistance testing.
63 patients in the Frankfurt HIV Cohort who were pre-treated and also experiencing therapy failure of their current regimen due to resistance or systemic toxicities were switched to a new regimen of Kaletra (lopinavir: LPV/r) and saquinavir (SQV). The authors reported on 33/63 patients who have either reached at least 24 weeks on therapy or have discontinued. In most cases, it was possible to perform genotype resistance testing prior to starting therapy. Patients were switched when genotype testing showed PI susceptibility and limited options for combining reverse transcriptase inhibitors based on resistance mutations and/or systemic toxicities. 21/33 patients first had a treatment interruption.
Jennifer King, PharmD, reported PK results for NATAP presented at the 3rd Pharmacology Wksp in April. Patients received SQV-sgc 1000mg BID in addition to LPV 400mg/RTV 100mg. Individual 24-hour PK drug levels were assessed in all 27 patients. SQV Cmin was 1250 ng/mL, which was within the expected range (authors state the suggested SQV Cmin is 216 ng/mL). LPV levels were not negatively affected by SQV co-administration. Staszewski reported that between 12 and 24 hours post-dose, the LPV level fell below the estimated IC50, suggesting that this regimen is not suited for once daily dosing. At week 17, 55% of patients had a plasma HIV RNA <50 copies/mL. At Barcelona, these German researchers reported results of comparing PK of RTV/SQV to Kaletra+1000mg SQV. The average SQV Cmin was no less and perhaps more for patients receiving Kaletra/SQV compared to patients receiving RTV/SQV.
The 33 patients who received Kaletra/SQV and who they reported on because they reached 24 weeks had much prior treatment experienced: average of 6 years of prior ART; 9 previous therapies; average viral load 164,000; CD4 157. 4 patients were PI-naive. 29 were PI experienced. 15/29 had PI-sparing regimen as their last regimen. 6 patients had previous Kaletra exposure, 6 had previous amprenavir exposure, and 3 had exposure to both.
11 patients had responded (<400 copies) to previous therapy but had to switch regimen due to toxicity/intolerance.
RESULTS
12 patients reached 36 weeks on study, 8 reached 48 weeks, and the average time on therapy was 29 weeks. 24/33 patients remained on therapy, and 7 discontinued due to virologic failure, 1 due to toxicity, and 1 due to non-HIV death.
The average viral load reduction was -3.5 log. The median viral load lowest point reached (nadir) was 49 copies. The average time to VL nadir was 14 weeks. Average CD4 increase was 159. 6/33 (18%) rebounded after reaching their viral load nadir. But at the 14 week nadir point 73% (24/33 achieved 2 log reduction or more; 82% (27/33) had <400 copies at 7 weeks, and 19/33 (56%) had <50 copies at 13 weeks.
The authors reported 5/8 patients with a shift from PI resistance to PI sensitivity following STI or PI-sparing regimen were responders (<400). Authors suggest patients with previous PI-resistance may benefit from this strategy after shift to wild-type in the PI mutations.
After 29 weeks 73% are still on study regimen.
When comparing responders to non-responders -- patients who responded had a baseline CD4 count 4 times greater than those who did not respond (206 vs 54); less prior exposure to Kaletra; less prior exposure to ART; less prior exposure to PI; less exposure to HIV drugs; less previous PI therapies (2 vs 5); and less viral load (100,000 vs 177,000). Authors reported large range of inter-individual drug levels.
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