Reductions in viral load and increases in T lymphocyte numbers in treatment-naive patients with advanced HIV-1 infection treated with ritonavir, zidovudine and zalcitabine triple therapy.
In order to test the hypothesis that a combination of protease inhibitors with nucleoside analogues-agents known to inhibit different steps of the human immunodeficiency virus (HIV) life cycle--is likely to prove more effective in reducing viral loads than either of those modalities alone, we performed a 60 week, open-label trial in 32 HIV-positive patients with depressed CD4 T lymphocyte cell counts but no active AIDS-defining illnesses. For the first 2 weeks, patients received 600 mg twice daily of liquid ritonavir, a protease inhibitor; then zidovudine 200 mg three times daily and zalcitabine 0.75 mg three times daily were added to the treatment regimen. Mononuclear blood cell fractions were analysed for infected cell levels, using a co-culture system. HIV-1 RNA in plasma was measured both by reverse transcriptase-polymerase chain reaction (RT-PCR) and reverse transcriptase quantitative PCR (QcRT-PCR); lymphocyte counts were determined by standard laboratory methods. In the 2 weeks of ritonavir therapy, both the mean count of infectious blood cells and plasma HIV RNA levels decreased dramatically. Mean CD4 cell counts increased from 173 cells/mm3 at baseline to 286 cells/mm3; CD8 cell counts rose from 951 cells/mm3 to 1,141 cells/mm3. With the introduction of the nucleoside analogues, infectious cell counts and plasma virus dropped another log unit to a nadir at 8 weeks, while CD4 T lymphocyte counts continued to rise slowly. By week 28, 12 patients had withdrawn due to adverse events, none of which were life-threatening. At week 36, infectious material could not be detected in the cells of 10 of the 17 remaining patients; by week 60, four of the seven patients with residual viraemia at week 24 had undergone viral relapse. After the introduction of a more palatable capsule formulation of ritonavir at week 52, infectious cells and plasma virus were undetectable in 50-60% of patients. The combination of protease inhibitors and nucleoside analogues significantly reduces HIV load, and in some patients may suppress viral activity for sustained periods.
Mathez
D
D
Unite d'Immunovirologie, H pital Raymond Poincaré, Paris, France.
Bagnarelli
P
P
Gorin
I
I
Katlama
C
C
Pialoux
G
G
Saimot
G
G
Tubiana
P
P
De Truchis
P
P
Chauvin
J P
JP
Mills
R
R
Rode
R
R
Clementi
M
M
Leibowitch
J
J
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000008:administration & dosage*; D016047:Zalcitabine / Q000008:administration & dosage*; D015215:Zidovudine / Q000008:administration & dosage*
D019380:Anti-HIV Agents; D012367:RNA, Viral; D015215:Zidovudine; D016047:Zalcitabine; D019438:Ritonavir