Reduced antiretroviral drug susceptibility among patients with primary HIV infection

Susan J. Little, Eric S. Daar, Richard T. D'Aquila, Philip Keiser, Elizabeth Connick, Jeannette M. Whitcomb, Nicholas S. Hellmann, Christos J. Petropoulos, Lorraine Sutton, Jacqui A. Pitt, Eric S. Rosenberg, Richard A. Koup, Bruce D. Walker, Douglas D. Richman

Research output: Contribution to journalArticle

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Abstract

Context: The transmission of drug-resistant human immunodeficiency virus (I-IV) has been documented, but the prevalence of such transmission is unknown. Objective: To assess the spectrum and frequency of antiretroviral susceptibility among subjects with primary HIV infection. Design, Setting, and Patients: Retrospective analysis of 141 subjects identified from clinical research centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV seroconversion within the preceding 12 months and no more than 7 days' prior antiretroviral (ARV) therapy. Main Outcome Measures: Phenotypic and genotypic ARV susceptibility of HIV from plasma samples. Results: The transmission of drug-resistant HIV as assessed by a greater than 10-fold reduction in ARV susceptibility to 1 or more drugs was observed in 3 (2%)of 141 subjects, including to a nonnucleoside reverse transcriptase inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor and a protease inhibitor in 2 patients. Population-based sequence analysis of these 3 samples identified multidrug-resistance mutations in reverse transcriptase (M184V, T215Y, K219K/R) and protease (L101/V, K20R, M361, M461, G48V, L63P, A71T, V771, V82T, 184V, L90M) in the 2 latter patient samples, along with numerous polymorphisms. A reduction in susceptibility of greater than 2.5- to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients (26%). Sequence analysis of these 36 samples identified well-characterized drug resistance mutation in reverse transcriptase and protease in only 1 of these patients. Conclusions: Reductions in drug susceptibility of more than 10-fold were rare among this cohort of recently HIV-infected subjects and were distributed among each of the 3 major classes of ARV drugs tested. Reductions in susceptibility of more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance were highly prevalent among newly infected patients. Resistance testing may be warranted to monitor the frequency of drug resistance over time and to assess the potential for geographic variability.

Original languageEnglish (US)
Pages (from-to)1142-1149
Number of pages8
JournalJournal of the American Medical Association
Volume282
Issue number12
DOIs
StatePublished - Sep 22 1999
Externally publishedYes

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HIV Infections
Pharmaceutical Preparations
HIV
Reverse Transcriptase Inhibitors
RNA-Directed DNA Polymerase
Drug Resistance
Sequence Analysis
HIV Seropositivity
Mutation
Multiple Drug Resistance
Protease Inhibitors
Nucleosides
Peptide Hydrolases
Outcome Assessment (Health Care)
Research
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Little, S. J., Daar, E. S., D'Aquila, R. T., Keiser, P., Connick, E., Whitcomb, J. M., ... Richman, D. D. (1999). Reduced antiretroviral drug susceptibility among patients with primary HIV infection. Journal of the American Medical Association, 282(12), 1142-1149. https://doi.org/10.1001/jama.282.12.1142

Reduced antiretroviral drug susceptibility among patients with primary HIV infection. / Little, Susan J.; Daar, Eric S.; D'Aquila, Richard T.; Keiser, Philip; Connick, Elizabeth; Whitcomb, Jeannette M.; Hellmann, Nicholas S.; Petropoulos, Christos J.; Sutton, Lorraine; Pitt, Jacqui A.; Rosenberg, Eric S.; Koup, Richard A.; Walker, Bruce D.; Richman, Douglas D.

In: Journal of the American Medical Association, Vol. 282, No. 12, 22.09.1999, p. 1142-1149.

Research output: Contribution to journalArticle

Little, SJ, Daar, ES, D'Aquila, RT, Keiser, P, Connick, E, Whitcomb, JM, Hellmann, NS, Petropoulos, CJ, Sutton, L, Pitt, JA, Rosenberg, ES, Koup, RA, Walker, BD & Richman, DD 1999, 'Reduced antiretroviral drug susceptibility among patients with primary HIV infection', Journal of the American Medical Association, vol. 282, no. 12, pp. 1142-1149. https://doi.org/10.1001/jama.282.12.1142
Little, Susan J. ; Daar, Eric S. ; D'Aquila, Richard T. ; Keiser, Philip ; Connick, Elizabeth ; Whitcomb, Jeannette M. ; Hellmann, Nicholas S. ; Petropoulos, Christos J. ; Sutton, Lorraine ; Pitt, Jacqui A. ; Rosenberg, Eric S. ; Koup, Richard A. ; Walker, Bruce D. ; Richman, Douglas D. / Reduced antiretroviral drug susceptibility among patients with primary HIV infection. In: Journal of the American Medical Association. 1999 ; Vol. 282, No. 12. pp. 1142-1149.
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AU - Daar, Eric S.

AU - D'Aquila, Richard T.

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AU - Connick, Elizabeth

AU - Whitcomb, Jeannette M.

AU - Hellmann, Nicholas S.

AU - Petropoulos, Christos J.

AU - Sutton, Lorraine

AU - Pitt, Jacqui A.

AU - Rosenberg, Eric S.

AU - Koup, Richard A.

AU - Walker, Bruce D.

AU - Richman, Douglas D.

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N2 - Context: The transmission of drug-resistant human immunodeficiency virus (I-IV) has been documented, but the prevalence of such transmission is unknown. Objective: To assess the spectrum and frequency of antiretroviral susceptibility among subjects with primary HIV infection. Design, Setting, and Patients: Retrospective analysis of 141 subjects identified from clinical research centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV seroconversion within the preceding 12 months and no more than 7 days' prior antiretroviral (ARV) therapy. Main Outcome Measures: Phenotypic and genotypic ARV susceptibility of HIV from plasma samples. Results: The transmission of drug-resistant HIV as assessed by a greater than 10-fold reduction in ARV susceptibility to 1 or more drugs was observed in 3 (2%)of 141 subjects, including to a nonnucleoside reverse transcriptase inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor and a protease inhibitor in 2 patients. Population-based sequence analysis of these 3 samples identified multidrug-resistance mutations in reverse transcriptase (M184V, T215Y, K219K/R) and protease (L101/V, K20R, M361, M461, G48V, L63P, A71T, V771, V82T, 184V, L90M) in the 2 latter patient samples, along with numerous polymorphisms. A reduction in susceptibility of greater than 2.5- to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients (26%). Sequence analysis of these 36 samples identified well-characterized drug resistance mutation in reverse transcriptase and protease in only 1 of these patients. Conclusions: Reductions in drug susceptibility of more than 10-fold were rare among this cohort of recently HIV-infected subjects and were distributed among each of the 3 major classes of ARV drugs tested. Reductions in susceptibility of more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance were highly prevalent among newly infected patients. Resistance testing may be warranted to monitor the frequency of drug resistance over time and to assess the potential for geographic variability.

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