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Antimicrob Agents Chemother. 1994 February; 38(2): 307–314.
PMCID: PMC284445

Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group.


Human immunodeficiency virus type 1 (HIV-1) isolates resistant to zidovudine (ZDV) have previously been demonstrated to exhibit in vitro cross-resistance to other similar dideoxynucleoside agents which contain a 3'-azido group. However, cross-resistance to didanosine (ddI) or dideoxycytidine (ddC) has been less well documented. ZDV, ddI, and ddC susceptibility data have been collected from clinical HIV-1 isolates obtained by five clinical centers and their respective retrovirology laboratories. All subjects were treated only with ZDV. Clinical HIV-1 isolates were isolated, amplified, and assayed for drug susceptibility in standardized cultures of phytohemagglutinin-stimulated donor peripheral blood mononuclear cells obtained from healthy seronegative donors. All five cohorts showed a correlation between decreased in vitro susceptibility to ZDV and decreased susceptibility to ddI and ddC. For each 10-fold decrease in ZDV susceptibility, an average corresponding decrease of 2.2-fold in ddI susceptibility was observed (129 isolates studied; P < 0.001, Fisher's test of combined significance). Similarly, susceptibility to ddC decreased 2.0-fold for each 10-fold decrease in ZDV susceptibility (82 isolates studied; P < 0.001, Fisher's test of combined significance). These data indicate that a correlation exists between HIV-1 susceptibilities to ZDV and ddI or ddC for clinical HIV-1 isolates.

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  • Boucher CA, O'Sullivan E, Mulder JW, Ramautarsing C, Kellam P, Darby G, Lange JM, Goudsmit J, Larder BA. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. J Infect Dis. 1992 Jan;165(1):105–110. [PubMed]
  • Boucher CA, Tersmette M, Lange JM, Kellam P, de Goede RE, Mulder JW, Darby G, Goudsmit J, Larder BA. Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy. Lancet. 1990 Sep 8;336(8715):585–590. [PubMed]
  • Dimitrov DH, Hollinger FB, Baker CJ, Kline MW, Doyle M, Bremer JW, Shearer WT. Study of human immunodeficiency virus resistance to 2'-3'-dideoxyinosine and zidovudine in sequential isolates from pediatric patients on long-term therapy. J Infect Dis. 1993 Apr;167(4):818–823. [PubMed]
  • Fitzgibbon JE, Howell RM, Haberzettl CA, Sperber SJ, Gocke DJ, Dubin DT. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992 Jan;36(1):153–157. [PMC free article] [PubMed]
  • Fitzgibbon JE, Howell RM, Schwartzer TA, Gocke DJ, Dubin DT. In vivo prevalence of azidothymidine (AZT) resistance mutations in an AIDS patient before and after AZT therapy. AIDS Res Hum Retroviruses. 1991 Mar;7(3):265–269. [PubMed]
  • Gao Q, Gu ZX, Parniak MA, Li XG, Wainberg MA. In vitro selection of variants of human immunodeficiency virus type 1 resistant to 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine. J Virol. 1992 Jan;66(1):12–19. [PMC free article] [PubMed]
  • Gao WY, Shirasaka T, Johns DG, Broder S, Mitsuya H. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Clin Invest. 1993 May;91(5):2326–2333. [PMC free article] [PubMed]
  • Gu Z, Gao Q, Li X, Parniak MA, Wainberg MA. Novel mutation in the human immunodeficiency virus type 1 reverse transcriptase gene that encodes cross-resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. J Virol. 1992 Dec;66(12):7128–7135. [PMC free article] [PubMed]
  • Japour AJ, Chatis PA, Eigenrauch HA, Crumpacker CS. Detection of human immunodeficiency virus type 1 clinical isolates with reduced sensitivity to zidovudine and dideoxyinosine by RNA.RNA hybridization. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3092–3096. [PubMed]
  • Japour AJ, Mayers DL, Johnson VA, Kuritzkes DR, Beckett LA, Arduino JM, Lane J, Black RJ, Reichelderfer PS, D'Aquila RT, et al. Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group. Antimicrob Agents Chemother. 1993 May;37(5):1095–1101. [PMC free article] [PubMed]
  • Jung M, Agut H, Candotti D, Ingrand D, Katlama C, Huraux JM. Susceptibility of HIV-1 isolates to zidovudine: correlation between widely applicable culture test and PCR analysis. J Acquir Immune Defic Syndr. 1992;5(4):359–364. [PubMed]
  • Kahn JO, Lagakos SW, Richman DD, Cross A, Pettinelli C, Liou SH, Brown M, Volberding PA, Crumpacker CS, Beall G, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. The NIAID AIDS Clinical Trials Group. N Engl J Med. 1992 Aug 27;327(9):581–587. [PubMed]
  • Kellam P, Boucher CA, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1934–1938. [PubMed]
  • Kozal MJ, Shafer RW, Winters MA, Katzenstein DA, Merigan TC. A mutation in human immunodeficiency virus reverse transcriptase and decline in CD4 lymphocyte numbers in long-term zidovudine recipients. J Infect Dis. 1993 Mar;167(3):526–532. [PubMed]
  • Land S, Terloar G, McPhee D, Birch C, Doherty R, Cooper D, Gust I. Decreased in vitro susceptibility to zidovudine of HIV isolates obtained from patients with AIDS. J Infect Dis. 1990 Feb;161(2):326–329. [PubMed]
  • Larder BA, Chesebro B, Richman DD. Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrob Agents Chemother. 1990 Mar;34(3):436–441. [PMC free article] [PubMed]
  • Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. [PubMed]
  • Larder BA, Kellam P, Kemp SD. Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS. 1991 Feb;5(2):137–144. [PubMed]
  • Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science. 1989 Dec 1;246(4934):1155–1158. [PubMed]
  • Mayers DL, McCutchan FE, Sanders-Buell EE, Merritt LI, Dilworth S, Fowler AK, Marks CA, Ruiz NM, Richman DD, Roberts CR, et al. Characterization of HIV isolates arising after prolonged zidovudine therapy. J Acquir Immune Defic Syndr. 1992;5(8):749–759. [PubMed]
  • McLeod GX, McGrath JM, Ladd EA, Hammer SM. Didanosine and zidovudine resistance patterns in clinical isolates of human immunodeficiency virus type 1 as determined by a replication endpoint concentration assay. Antimicrob Agents Chemother. 1992 May;36(5):920–925. [PMC free article] [PubMed]
  • Montaner JS, Singer J, Schechter MT, Raboud JM, Tsoukas C, O'Shaughnessy M, Ruedy J, Nagai K, Salomon H, Spira B, et al. Clinical correlates of in vitro HIV-1 resistance ot zidovudine. Results of the Multicentre Canadian AZT Trial. AIDS. 1993 Feb;7(2):189–196. [PubMed]
  • Reichman RC, Tejani N, Lambert JL, Strussenberg J, Bonnez W, Blumberg B, Epstein L, Dolin R. Didanosine (ddI) and zidovudine (ZDV) susceptibilities of human immunodeficiency virus (HIV) isolates from long-term recipients of ddI. Antiviral Res. 1993 Apr;20(4):267–277. [PubMed]
  • Richman DD. Susceptibility to nucleoside analogues of zidovudine-resistant isolates of human immunodeficiency virus. Am J Med. 1990 May 21;88(5B):8S–10S. [PubMed]
  • Richman DD, Grimes JM, Lagakos SW. Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J Acquir Immune Defic Syndr. 1990;3(8):743–746. [PubMed]
  • Richman DD, Guatelli JC, Grimes J, Tsiatis A, Gingeras T. Detection of mutations associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction. J Infect Dis. 1991 Dec;164(6):1075–1081. [PubMed]
  • Rooke R, Tremblay M, Soudeyns H, DeStephano L, Yao XJ, Fanning M, Montaner JS, O'Shaughnessy M, Gelmon K, Tsoukas C, et al. Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS. 1989 Jul;3(7):411–415. [PubMed]
  • St Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, Kellam P, Kemp SD, Larder BA. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991 Sep 27;253(5027):1557–1559. [PubMed]
  • Tudor-Williams G, St Clair MH, McKinney RE, Maha M, Walter E, Santacroce S, Mintz M, O'Donnell K, Rudoll T, Vavro CL, et al. HIV-1 sensitivity to zidovudine and clinical outcome in children. Lancet. 1992 Jan 4;339(8784):15–19. [PubMed]
  • Wainberg MA, Tremblay M, Rooke R, Blain N, Soudeyns H, Parniak MA, Yao XJ, Li XG, Fanning M, Montaner JS, et al. Characterization of reverse transcriptase activity and susceptibility to other nucleosides of AZT-resistant variants of HIV-1. Results from the Canadian AZT Multicentre Study. Ann N Y Acad Sci. 1990;616:346–355. [PubMed]

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