Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine.
BACKGROUND
Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3.


METHODS
In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48.


RESULTS
Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed.


CONCLUSIONS
Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.
Michelet
C
C
Clinique des Maladies Infectieuses, Unité de Pharmacologie Clinique, Hôpital Universitaire, Rennes, France. Christian.Michelet@univ-rennes1.fr
Bellissant
E
E
Ruffault
A
A
Arvieux
C
C
Delfraissy
J F
JF
Raffi
F
F
Bazin
C
C
Renard
I
I
Sébille
V
V
Chauvin
J P
JP
Dohin
E
E
Cartier
F
F
D000163:Acquired Immunodeficiency Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects / Q000235:genetics; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use*; D019258:Saquinavir / Q000009:adverse effects / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013997:Time Factors; D019562:Viral Load; D015215:Zidovudine / Q000009:adverse effects / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019258:Saquinavir; D019438:Ritonavir