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The Effect of High-Dose Saquinavir on Viral Load and CD4+ T-Cell Counts in HIV-Infected Patients

Jonathan M. Schapiro, MD; Mark A. Winters, MSc; Fran Stewart, PhD; Bradley Efron, PhD; Jane Norris, PAC; Michael J. Kozal, MD; and Thomas C. Merigan, MD
[+] Article and Author Information

For author affiliations and current author addresses, see end of text. Acknowledgments: The authors thank Drs. Cheryl Karol, Richard Ginsberg, and Miklos Salgo (Roche Pharmaceuticals, Inc., Nutley, New Jersey) for their support, Patricia Cain for clinical assistance, and Shannon Crawford, Kathy Richmond, and Teri Banks for technical assistance. Grant Support: By Hoffmann-LaRoche and grant GCRC RR00070 from the National Institutes of Health. Roche Products had no influence on the gathering of the data, the interpretation of the data, or the reporting of the results, which were all the responsibility of the primary investigator, Dr. Merigan. Dr. Merigan has no financial interest in saquinavir or in Roche Products. Requests for Reprints: Thomas C. Merigan, MD, Center For AIDS Research, S-156 Grant Building, Stanford University, Stanford, CA 94305. Current Author Addresses: Dr. Schapiro: Division of Infectious Diseases, Room S-156, 300 Pasteur Drive, Stanford University School of Medicine, Stanford, CA 94305-5107.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(12):1039-1050. doi:10.7326/0003-4819-124-12-199606150-00003
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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.

Figures

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Figure 1.
CD4+ T-cell counts and plasma human immunodeficiency virus (HIV) RNA levels over time in patients receiving saquinavir, 3600 mg/d or 7200 mg/d. Top.Bottom.

Patients receiving 3600 mg/d. Open squares = CD4+ T-cell counts; open circles = plasma HIV-1 RNA levels. Patients receiving 7200 mg/d. Solid squares = CD4+ T-cell counts; solid circles = plasma HIV-1 RNA levels. Bars indicate 95% Cls.

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Figure 2.
Immune-complex-dissociated p24 antigen levels, quantitative peripheral blood mononuclear cell culture titers, and proviral DNA levels over time in patients receiving saquinavir, 3600 mg/d or 7200 mg/d. Top.Middle.Bottom.

Immune-complex–dissociated p24 antigen levels. Open circles = patients receiving 3600 mg/d; solid circles = patients receiving 7200 mg/d. Quantitative peripheral blood mononuclear cell culture titers. Open triangles = patients receiving 3600 mg/d; solid triangles = patients receiving 7200 mg/d. Proviral DNA levels. Open squares = patients receiving 3600 mg/d; solid squares = patients receiving 7200 mg/d. IUPM = infectious units per million peripheral blood mononuclear cells.

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Figure 3.
Mean plasma drug concentrations on day 28 after oral administration of saquinavir, 600 or 1200 mg, every 4 hours (total daily dose, 3600 or 7200 mg).

Bars indicate 95% Cls.

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Figure 4.
Drug levels at week 4 (area under the curve to 24 hours) plotted against the decrease in plasma human immunodeficiency virus (HIV) RNA levels at week 4 for each patient in whom pharmacokinetics were studied.r

The line represents best fit and was determined using the least-squares algorithm, = 0.801, expressed as the Pearson correlation coefficient. Open circles = patients receiving 3600 mg of saquinavir per day; solid circles = patients receiving 7200 mg of saquinavir per day.

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Figure 5.
Mutations at codons 48 or 90 of the protease gene over time in plasma samples from patients receiving saquinavir, 3600 mg/d or 7200 mg/d.

Open circles = plasma human immunodeficiency virus (HIV) RNA levels of patients receiving 3600 mg/d; solid circles = plasma HIV RNA levels of patients receiving 7200 mg/d; □s = percentage of patients receiving 3600 mg/d who had mutations; solid squares = percentage of patients receiving 7200 mg/d who had mutations. Bars indicate 95% Cls.

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