Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients [see comments]
Ann Intern Med. 1996 Jun 15;124(12):1039-50. Unique Identifier : AIDSLINE MED/96233412 Schapiro JM; Winters MA; Stewart F; Efron B; Norris J; Kozal MJ; Merigan TC; Division of Infectious Diseases, Stanford University School of; Medicine, CA 94305-5107, USA.
Abstract:
OBJECTIVE: To evaluate the efficacy and safety of high-dose therapy with the human immunodeficiency virus (HIV) protease inhibitor saquinavir and to establish the duration of the effect of this therapy. DESIGN: Open-label study. SETTING: Clinical research referral center. PATIENTS: 40 adults with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ T-cell counts of 200 to 500 cells/mm3. INTERVENTION: Monotherapy with 3600 mg or 7200 mg of saquinavir per day, in six divided doses, for 24 weeks. MEASUREMENTS: Patients were monitored for adverse events and were evaluated monthly for CD4+ T-cell count, HIV-1 viral load (as measured by reverse transcriptase polymerase chain reaction [PCR] for plasma HIV RNA levels), immune-complex-disassociated p24 antigen levels, peripheral blood mononuclear cell viral DNA levels (as measured by PCR), and resistance mutations to saquinavir. Quantitative peripheral blood mononuclear cell cultures were also done every 2 months. RESULTS: The low-dose saquinavir regimen (3600 mg/d) resulted in a maximal mean decrease in plasma HIV RNA levels of 1.06 log RNA copies/mL of plasma and a mean maximal increase in CD4 counts of 72 cells/mm3. At week 24, the plasma HIV RNA level remained 0.48 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 31 cells/mm3 higher than baseline (P = 0.165). The high-dose saquinavir regimen (7200 mg/d) produced a mean maximal decrease in the plasma HIV RNA level of 1.34 log RNA copies/mL of plasma and a mean maximal increase in CD4 count of 121 cells/mm3. At week 24, the plasma HIV RNA level remained 0.85 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 82 cells/mm3 higher than baseline (P = 0.002). The high-dose regimen produced a greater reduction in plasma HIV RNA level (P = 0.08), a greater reduction in peripheral blood mononuclear cell cultures (P = 0.008), and a greater increase in CD4 count (P = 0.002) than did the low-dose regimen. Higher plasma drug concentrations in individual patients correlated with greater reductions in plasma HIV RNA levels over the two doses. Nine patients receiving the low-dose regimen and four patients receiving the high-dose regimen developed key saquinavir resistance mutations. Adverse reactions, most commonly gastrointestinal problems and elevated serum aminotransferase levels, were more common in patients receiving the high-dose regimen, but most adverse events were mild and all were reversible. CONCLUSION: Saquinavir is a potent antiviral agent that has a favorable toxicity profile at high doses. Higher doses produce a greater and more durable suppression of viral load and elevation in CD4+ T-cell counts and may delay the development of resistance mutations. Therapy with high-dose saquinavir alone or in combination with other antiretroviral agents should be investigated further.
Keywords: Adult Base Sequence CD4 Lymphocyte Count/*DRUG EFFECTS Dose-Response Relationship, Drug DNA Primers Female Human HIV Core Protein p24/BLOOD HIV Infections/*DRUG THERAPY/IMMUNOLOGY/VIROLOGY HIV Protease/GENETICS HIV Protease Inhibitors/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ PHARMACOKINETICS HIV-1/GENETICS Isoquinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ PHARMACOKINETICS Male Middle Age Molecular Sequence Data Mutation Quinolines/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS/ PHARMACOKINETICS RNA, Viral/BLOOD Support, U.S. Gov't, P.H.S. Viremia/*DRUG THERAPY/IMMUNOLOGY JOURNAL ARTICLE Comment in: Ann Intern Med 1996 Jun 15;124(12):1086-8
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Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
