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Multiple Concurrent Reverse Transcriptase and Protease Mutations and Multidrug Resistance of HIV-1 Isolates from Heavily Treated Patients

Robert W. Shafer, MD; Mark A. Winters, MS; Sarah Palmer, PhD; and Thomas C. Merigan, MD
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From Stanford University Medical Center, Stanford, California. For current author addresses, see end of text. Acknowledgments: Patient 1 was enrolled in the National Institutes of Health AIDS Clinical Trials Group Protocol 019 between 1987 and 1990. The authors thank Darcy Levee (Stanford University) for assistance with DNA sequencing; Muoi Loi (Stanford University) for assistance with drug susceptibility testing; and Andy Zolopa, MD, for critical review of the manuscript. Grant Support: In part by National Institutes of Health grant AI27666 and a gift from the J.M. Kaplan Fund (New York, New York). Requests for Reprints: Robert W. Shafer, MD, Division of Infectious Diseases, Room S-156, Stanford University Medical Center, Stanford, CA 94305; e-mail, rshafer@cmgm.stanford.edu. Current Author Addresses: Drs. Shafer, Winters, Palmer, and Merigan: Division of Infectious Diseases, Stanford University Medical Center, Stanford, CA 94305.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(11):906-911. doi:10.7326/0003-4819-128-11-199806010-00008
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Background: Drug resistance of HIV-1 is an obstacle to the long-term efficacy of antiretroviral therapy.

Objective: To characterize reverse transcriptase and protease genes of multidrug-resistant HIV-1 isolates.

Design: Descriptive case series.

Setting: Academic medical center.

Patients: Four consecutive patients with HIV-1 infection were selected because they had previously received many antiretroviral drugs and had not achieved plasma HIV-1 RNA suppression despite treatment with several three-drug combinations.

Measurements: Reverse transcriptase sequencing, protease sequencing, and drug susceptibility testing of HIV-1.

Results: Isolates of HIV-1 from the four patients shared seven protease mutations and eight reverse transcriptase mutations. These mutations were present in biological clones and at three time points in three of the patients. Susceptibility testing showed high-level resistance (30-fold to >100-fold) to zidovudine, lamivudine, saquinavir, indinavir, and nelfinavir and lower-level resistance (3-fold to 5-fold) to didanosine, zalcitabine, and stavudine.

Conclusions: Simultaneous resistance to almost all available antiretroviral drugs may occur in HIV-1. The concordance and persistence of mutations in drug-resistant HIV-1 isolates suggest that some combinations of reverse transcriptase and protease mutations give the virus a selective advantage in the presence of various drug combinations.


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Figure 1.
Serial plasma HIV-1 RNA levels and CD4+ lymphocyte counts of four patients with multidrug-resistant HIV-1 isolates.10

The time course for each patient begins at the start of plasma HIV-1 RNA level monitoring. The drug regimens received by each patient are listed along the x-axis. Arrows indicate plasma HIV-1 isolates that were sequenced; dashed lines show the limit of detection of the plasma HIV-1 RNA assays used during the study (500 log copies/mL). Drugs were given at standard dosages with several exceptions. Patients 2 and 4 received periods of reduced-dose zidovudine (300 mg/d); patient 3 received saquinavir, 1200 mg/d, for 6 months; and patients 1, 3, and 4 received a combination of ritonavir (600 to 1200 mg/d) and saquinavir (600 to 1800 mg/d) for several months. Before HIV-1 RNA monitoring began, patient 1 received zidovudine from 1987 to 1990, zidovudine-didanosine and zidovudine-zalcitabine from 1990 to 1993, and zidovudine-lamivudine from 1994 to 1995. Patient 2 received zidovudine from 1989 to 1992, zidovudine-didanosine and zidovudine-zalcitabine from 1992 to 1993, and zalcitabine-saquinavir in 1994. Patient 3 received zidovudine from 1992 to 1993 and didanosine from 1993 to 1994. Patient 4 received zidovudine in 1990, zidovudine-zalcitabine in 1991, didanosine and zidovudine-didanosine in 1993, and stavudine in 1994. 3TC = lamivudine; AZT = zidovudine; d4T = stavudine; ddC = zalcitabine; ddi = didanosine; IND = indinavir; RIT = ritonavir; SQV = saquinavir.

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