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PATIENTS TREATED WITH RITONAVIR-BOOSTED SAQUINAVIR"
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.....No patients with VF acquired any major PI-resistance mutations....
Reported by Jules Levin
3rd IAS Conference
Rio de Janeiro, Brazil
24-27 July 24-27, 2005
Poster WePe4.4C12
Viral failure of ritonavir boosted protease inhibitors Kaletra (lopinavir/r) and fosamprenavir (Lexiva) have not been associated with protease inhibitor mutations. Here is a study presented at the IAS meeting in Rio that found similarly for the boosted PI therapy Invirase/r. Saquinavir boosted by low dose ritonavir has been the subject of several studies in the past few years showing good potency, and now Invirase boosted by low dose ritonavir is being developed by Roche and is being studied in comparison to Kaletra as well as to Reyataz/r.
Authors: Jintanat Ananworanich1, Kiat Ruxrungtham1,2, Sunee Sirivichayakul2, Sasiwimol Ubolyam1, Thidarat Jupimai1, Malte Schutz3,
Wendy Snowden3, David Cooper1,4, Bernard Hirschel5 and the Staccato Study Team
1The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand; 2Chulalongkorn University, Bangkok, Thailand;
3Roche, Welwyn, UK; 4NCHECR, University of New South Wales, Sydney, Australia; 5Geneva University Hospital, Geneva, Switzerland.
The study authors presented this background information:
--Boosting of protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) with ritonavir increases plasma exposure to the PI. Higher PI exposure has been associated with increased antiviral efficacy and a corresponding reduction in the incidence of PI-associated resistance mutations at subsequent virological failure (VF) in antiretroviral therapy (ART)-naive patients.1,2
--Boosted saquinavir (SQV) is a well-tolerated and potent PI, and in the QUAD study there was no evidence of SQV resistance at VF in ART-naive patients receiving boosted SQV soft capsules (Fortovase) twice daily with NRTIs.3
--The current larger study examined the potential for acquisition of resistance-associated mutations in Thai ART-naive patients with HIV subtype A/E failing a HAART regimen of boosted SQV mesylate (Invirase) once daily (1600/100) plus a nucleoside reverse transcriptase inhibitor (NRTI) backbone.
AUTHOR CONCLUSIONS:
There was a very low incidence of VF in ART-naive patients receiving SQV/r (10/258, 3.9%).
--Most patients (8/9 who were on treatment) with VF achieved VL < 50 copies/ml after increasing SQV/r dosing or switching to another regimen.
Of 258 patients, 10 had viral load over 500 copies/ml and had genotyping performed. Of these, none had detectable major PI mutations and 3 had detectable RT mutations.
--There was a very low incidence (< 1%) of selection of new natural/minor substitutions following treatment with SQV/r which is consistent with observations made for other boosted PIs in ART-naive patients.5
VF did not appear to be associated with low SQV Cmin.
These results support the use of SQV/r in first-line therapy and indicate that in these patients VF following SQV/r treatment occurs with relatively low frequency and may not compromise future regimen selection.
Invirase/r is the subject of large ongoing randomized studies in ART-naïve patients compared to Kaletra.
STUDY RESULTS
Baseline characteristics: mean age 34; 40% men; median CD$: 269; median HIV RNA: 4.7 log; CDC Class A: 90%; B: 20%.
Out of the 258 patients on SQV/r, only 10 (3.9%) patients had VF after a median of 29.6 weeks (range 19-48 weeks) and their median VL at VF was 1410 copies/ml.
--Two of these patients with VF (patients 7 and 10) switched NRTIs to TDF/3TC before genotyping at VF.
After VF, 4/10 patients increased dosing of SQV/r to 1000/100 mg bid, 5/10 patients switched to NNRTI-based HAART and one patient stopped treatment.
--All patients continuing on modified treatment subsequently achieved viral load
< 50 copies/ml, except patient 10 who was non-adherent.
Mutations in protease
No patients with VF acquired any major PI-resistance mutations.
At VF, the virus of seven patients carried other protease substitutions (L10I, K20R, M36I, L63V/P), all of which are natural polymorphisms/minor substitutions.4
- In 4/7 patients, the substitutions detected at VF were already present at baseline.
- Virus from two patients acquired a single polymorphism/minor substitution at VF that was not detected at baseline (M36I [patient 7] and K20R [patient 10]).
- The seventh patient had polymorphism L10I at VF, but baseline virus could not be amplified for comparison.
Conversely, natural polymorphisms/minor protease substitutions L10I, L33F, M36I and L63P that were present at baseline in virus from three patients with VF were no longer detectable at the time of VF.
Mutations in reverse transcriptase
RT mutations were detected in virus from 3/10 patients with VF (3/258, 1%).
- Patients 4 and 9 had virus with a single NRTI-resistance mutation
(MI84V and L210F, respectively).
- Patient 10 was non-compliant and had virus with three thymidine analogue mutations (D67N, K70R, M184V, G190A, K219E), Y188L and G190A, when genotyping was performed at week 96, 72 weeks after VF. Y188L and G190A are associated with resistance to NNRTIs, although there was no record of previous NNRTI use in this patient.
Therapeutic drug monitoring
8/10 patients with VF had therapeutic drug monitoring performed at or close to the time of VF.
5/8 patients with VF and TDM had SQV Cmin > 100 ng/ml - the target Cmin value for SQV.
--The three VF patients with SQV Cmin below the target value had: no polymorphism (patient 2); a single protease substitution but baseline virus could not be amplified for comparison (patient 5); and a single substitution in protease and in RT (patient 4).
METHODS
Two hundred and fifty-eight ART-naive Thai adults with baseline CD4 counts of 200-350 cells/mm3 were treated with saquinavir/ritonavir (SQV/r) 1600/100 mg once daily plus stavudine (d4T) and enteric-coated didanosine (ddI) for >6 months as part of the induction phase of the Staccato trial.
A subsequent protocol amendment permitted patients to change their nucleoside backbone to tenofovir (TDF) plus lamivudine (3TC) in case of toxicity to the original NRTIs.
Viral load (VL) and CD4 cell count were monitored routinely at 0, 8, 16 and 24 weeks. After 24 weeks, patients whose last two CD4 cell counts were > 350 cells/mm3, and whose last VL was < 50 copies/ml, were randomized to one of the two arms of the Staccato trial.
Following 24 weeks induction phase treatment, patients who could not be randomized to Staccato due to a VL > 50 copies/ml were permitted to continue in the induction phase study.
Genotypic analysis was performed on the protease (PRO) and reverse transcriptase (RT) genes of viral isolates from patients who experienced VF during treatment with their induction phase regimen. VF was defined as two consecutive VLs > 500 copies/ml after at least 12 weeks of therapy. Therapeutic drug monitoring was done in patients with VF. Patients with VF were given the
option of increasing the dosing of SQV/r to 1000/100 mg bid (twice daily), or switching to a non-nucleoside reverse transcriptase inhibitor
(NNRTI)-based regimen.
Statistical analyses were by intent-to-treat.
References
1. MacManus S, Yates PJ, Elston RC, et al. GW433908/ritonavir once daily in
antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks. AIDS 2004; 18:651-655.
2. Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a doubleblind study comparing lopinavir/ritonavir plus stavudine and lamivudine to
nelfinavir plus stavudine and lamivudine. J Infect Dis 2004; 189:51-60.
3. Staszewki S, Stark T, Knecht G, et al. The Quad study: a pilot study to
assess the efficacy and safety of Trizivir + RTV-boosted saquinavir
(TZV+SQVR) compared to combivir + RTV-boosted saquinavir (CBV+SQVR)
in ART-naive patients with high viral load (VL) and low CD4 cell count. 24
Week interim analysis. 9th European AIDS Conference. Warsaw, Poland,
25-29 October 2003; Abstract F1/1.
4. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance
mutations in HIV-1: 2005. Topics in HIV Med 2005; 13:51-57.
5. Kempf D, King M, Bauer E, et al. Analysis of the emergence of secondary
mutations with or without primary PI resistance in ARV-naïve subjects with
detectable viral load on nelfinavir or lopinavir/ritonavir therapy. XI International
HIV Drug Resistance Workshop. Seville, Spain, 2-5 July 2002; Abstract 145.
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