Antiretroviral Drug Resistance: Mechanisms, Pathogenesis, Clinical Significance

  • Douglas D. Richman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 394)

Abstract

Since HIV drug resistance was first recognized, many studies have documented the emergence of isolates with reduced susceptibility under the selective pressure of drug therapy, both in vitro and in vivo. These resistant isolates have been identified for nucleosides, non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors. Resistant isolates have been characterized with regard to cross resistance to other drugs, enzymatic activity of the target protein, mutations in the target gene and protein, and the relationship of these mutations to the x-ray crystallographic structure of the enzyme. Many of these aspects of HIV drug resistance were reviewed in some detail in the preceding symposium proceedings.’ I shall briefly summarize the status of the in vitro data with reverse transcriptase inhibitors before concentrating upon more recent developments in the field relating to resistance to protease inhibitors, the interrelationships of pathogenesis and drug resistance, and the clinical significance of drug resistance.

Keywords

Human Immunodeficiency Virus Human Immunodeficiency Virus Type Resistance Mutation Antimicrob Agent Drug Resistance Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Richman DD. Drug resistance of HIV. In: Mills J, Corey L, eds. Antiviral Chemotherapy. 3rd ed. Englewood Cliffs, NJ: PTR Prentice Hall, 1993: 373–84.Google Scholar
  2. 2.
    Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Richman DD, Grimes JM, Lagakos SW. Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J AIDS 1990; 3: 743–6.Google Scholar
  4. 4.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992; 256: 1783–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Jacobo-Molina A, Clark AD, Jr., Williams RL, et al. Crystals of a ternary complex of human immunodeficiency virus type 1 reverse transcriptase with a monocloncal antibody Fab fragment and double-stranded DNA diffract x-rays to 3.5A resolution. Proc Natl Acad Sci USA 1993; 88: 10895–9.CrossRefGoogle Scholar
  6. 6.
    Carroll SS, Geib J, Olsen DB, Stahlhut M, Shafer JA, Kuo LC. Sensitivity of HIV-1 reverse transcriptase and its mutants to inhibition by azidothymidine triphosphate. Biochemistry 1994; 33; 2113–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Boyer PL, Tantillo C, Jacobo-Molina A, et al. Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not.. Proc Natl Acad Sci USA 1994; 91: 4882–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Nunberg JH. Schleif WA, Boots EJ, et al. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol 1991; 65: 4887–92.PubMedGoogle Scholar
  9. 9.
    Richman DD, Shih C-K, Lowy I, et al. HIV-1 mutants resistant to non-nucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 1991; 88: 11241–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Richman DD, Rosenthal AS, Skoog M, et al. BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother 1991; 35: 305–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989; 246: 1155–8.PubMedCrossRefGoogle Scholar
  12. 12.
    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 USA 1992; 89: 1934–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Richman DD, Guatelli JC, Grimes J, Tsiatis A. Gingeras TR. Detection of mutations associated with zidovudine resistance in human immunodeficiency virus utilizing the polymerase chain reaction. J Infect Dis 1991; 164: 1075–81.PubMedCrossRefGoogle Scholar
  14. 14.
    Sardana VV. Emini E, Gotlib L. et al. Functional Analysis of HIV-1 Reverse Transcriptase Amino Acids Involved in Resistance to Multiple Nonnucleoside Inhibitors. J Biol Chem 1992; 267: 17526–30.PubMedGoogle Scholar
  15. 15.
    Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of HIV-1 selected during therapy. J Virol 1994;68:1660–6_Google Scholar
  16. 16.
    Boucher CAB, O’Sullivan E, Mulder JW, et al. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. J Infect Dis 1992; 165: 105–10.PubMedCrossRefGoogle Scholar
  17. 17.
    St.Clair MH, Martin JL, Tudor-Williams G, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991; 253: 1557–9.CrossRefGoogle Scholar
  18. 18.
    Shafer RW, Kozal MJ, Winters MA, et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis 1994; 169: 722–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Larder BA. 3’-Azido-3’-Deoxthymidine Resistance Suppressed by a Mutation Conferring Human Immunodeficiency Virus Type 1 Resistance to Nonnucleoside Reverse transcriptase Inhibitors. Antimicrob Agents Chemother 1992; 36: 2664–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Dueweke TJ, Pushkarskaya T, Poppe SM, et al. A Novel Mutation in Bisheteroarylpiperazine-Resistant HIV-1 Reverse Transcriptase Confers Increased Sensitivity to Other Nonnucleoside Inhibitors. Proc Natl Acad Sci USA 1993; 90: 4713–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3’-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA 1993; 90: 5653–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Chow Y-K, Hirsch MS, Merrill DP, et al. Replication incompatible and replication compromising combinations of HIV-1 RT drug resistance mutations. Nature 1993; 361: 650–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Richman DD. Playing chess with reverse transcriptase. Nature 1993; 361: 588–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Larder BA, Kellam P, Kemp SD. Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature 1993; 365: 451–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Emini EA, Graham DJ, Gotlib L, Condra JH, Byrnes VW, Schleif WA. HIV and multidrug resistance. Nature 1993; 364: 679PubMedCrossRefGoogle Scholar
  26. 26.
    Coffin JM. Genetic diversity and evolution of retroviruses. Current Topics Microbiol Immunol 1992; 176: 143–64.CrossRefGoogle Scholar
  27. 27.
    Otto MJ, Garber S, Winslow DL, et al. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc Natl Acad Sci USA 1993; 90: 7543–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Ho DD, Toyoshima T, Mo H, et al. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol 1994; 68: 2016–20.PubMedGoogle Scholar
  29. 29.
    El-Farrash MA, Kuroda MJ, Kitazaki T, et al. Generation and characterization of a human immunodeficiency virus type 1 (HIV-1) mutant resistant to an HIV-1 protease inhibitor. J Virol 1994; 68: 233–9.PubMedGoogle Scholar
  30. 30.
    Kaplan AH, Michael SF, Wehbie RS, et al. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc Natl Acad Sci USA 1994; 91: 5597–601.PubMedCrossRefGoogle Scholar
  31. 31.
    Pillay D, Bryant M, Getman D, Richman DD. HIV-1 protease inhibitors: their development, mechanism of action and clinical potential. Rev Med Virol 1995; 5: 23–33.CrossRefGoogle Scholar
  32. 32.
    Pillay D, Smidt ML, Potts KE, Bryant ML, Richman DD. In vitro selection of protease inhibitor resistant human immunodeficiency virus type 1 (HIV-1) strains. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy 1994; Orlando, FL:October 4–7 (Abstract)Google Scholar
  33. 33.
    Ho DD, Moudgil T, Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Eng1J Med 1989; 321: 1621–5.CrossRefGoogle Scholar
  34. 34.
    Coombs RW, Collier AC, Allain J-P, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626–31.PubMedCrossRefGoogle Scholar
  35. 35.
    Nâjera I, Richman DD, Olivares I, et al. Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses 1994; 10: 1475–84.CrossRefGoogle Scholar
  36. 36.
    Luque F, Caruz A, Pineda JA, Torres Y, Larder B, Leal M. Provirus load changes in untreated and zidovudine-treated human immunodeficiency virus type-1 infected patients. J Infect Dis 1994; 169: 267–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Montaner JSG, Singer J, Schechter MT, et al. Clinical correlates of in vitro HIV-1 resistance to zidovudine. Results of the multicentre Canadian AZT trial. AIDS 1993; 7: 189–96.PubMedCrossRefGoogle Scholar
  38. 38.
    Kozal MJ, Kroodsma K, Winters MA, et al. Didanosine resistance in HIV-infected patients switched from zidovudine to didanosine monotherapy. Ann Intern Med 1994; 121: 263–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Hooper C, Welles S, D’Aquila R, et al. HIV-1 RNA level in plasma and association with disease progression, zidovudine sensitivity phenotype and genotype, syncytium-inducing phenotype, CD4+ cell count and clinical diagnosis of AIDS. HIV Drug Resistance Third International Workshop 1994; Kuaui, Hawaii:August 2–5.(Abstract)Google Scholar
  40. 40.
    Koot M Keet IPM, Vos AHV, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann Intern Med 1993;118:681–8.Google Scholar
  41. 41.
    Richman DD, Bozzette SA. The impact of syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 1994; 169: 968–74.PubMedCrossRefGoogle Scholar
  42. 42.
    D’Aquila RT, Johnson VA, Welles SL, et al. Zidovudine resistance and human immunodeficiency virus type 1 disease progression during antiretroviral therapy. Ann Intern Med 1995; 122: 401–408.PubMedCrossRefGoogle Scholar
  43. 43.
    Kozal MJ, Shafer RW, Winters MA, et al. HIV-1 syncytium-inducing phenotype, virus burden, codon 215 reverse transcriptase mutation and CD4 cell decline in zidovudine-treated patients. J AIDS 1994; 7: 832–8.Google Scholar
  44. 44.
    Karlsson A, Parsmyr K, Sandstrom E, Fenyö EM, Albert J. MT-2 cell tropism as prognostic marker for disease progression in human immunodeficiency virus type 1 infection. J Clin Microbial 1994; 32: 364–70.Google Scholar
  45. 45.
    Meyerhans A, Cheynier R, Albert J, et al. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell 1989; 58: 901–10.PubMedCrossRefGoogle Scholar
  46. 46.
    Goodenow M, Huet T, Saurin W, Kwok S, Sninsky J, Wain-Hobson S. HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. JAIDS 1989; 2: 344–52.Google Scholar
  47. 47.
    Hahn BH, Shaw GM, Taylor ME, et al. Genetic variation in HTLV-IIULAV over time in patients with AIDS or at risk for AIDS. Science 1986; 232: 1548–33.PubMedCrossRefGoogle Scholar
  48. 48.
    Saag MS, Hahn BH, Gibbons J, et al. Extensive variation of human immunodeficiency virus type-1 in vivo. Nature 1988; 334: 440–4.PubMedCrossRefGoogle Scholar
  49. 49.
    Ait-Khaled M, Emery VC. Phylogenetic relationship between human immunodeficiency virus type I (HIV-1) long terminal repeat natural variants present in the lymph node and peripheral blood of three HIV-1-infected individuals. J Gen Virol 1994; 75: 1615–21.PubMedCrossRefGoogle Scholar
  50. 50.
    Simmonds P, Zhang LQ, McOmish F, Balfe P, Ludlam CA, Leigh Brown AJ. Discontinuous sequence change of human immunodeficiency virus (HIV) type 1 env sequences in plasma viral and lymphocyte-associated proviral populations in vivo: implications for models of HIV pathogenesis. J Virol 1991; 65: 6266–76.PubMedGoogle Scholar
  51. 51.
    Delassus S, Cheynier R, Wain-Hobson S. Evolution of human immunodeficiency virus type 1 nef and long terminal repeat sequences over 4 years in vivo and in vitro. J Virol 1991; 65: 225–31.PubMedGoogle Scholar
  52. 52.
    Zhang LQ, MacKenzie P, Cleland A, Holmes EC. Leigh Brown AJ, Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virology 1993; 67: 3345–56.PubMedGoogle Scholar
  53. 53.
    Balfe P, Simmonds P, Ludlam CA, Bishop JO, Leigh Brown M. Concurrent evolution of human immunodeficiency virus type 1 in patients infected from the same source: rate of sequence change and low frequency of inactivating mutations. J Virology 1990; 64: 6221–33.PubMedGoogle Scholar
  54. 54.
    Wolinsky SM, Wike CM, Korber B, et al. Selective transmission of human immunodeficiency, virus type 1 variants from mothers to infants. Science 1992; 255: 1134–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Ball JK, Holmes EC, Whitwell H, Desselberger U. Genomic variation of human immunodeficiency virus type 1 (HIV-1): molecular analyses of HIV-I in sequential blood samples and various organs obtained at autopsy. J Gen Virol 1994; 75: 867–79.CrossRefGoogle Scholar
  56. 56.
    Delassus S, Cheynier R, Wain-Hobson S. Nonhomogeneous distribution of human immunodeficiency virus type 1 proviruses in the spleen. J Virol 1992; 66: 5642–5.PubMedGoogle Scholar
  57. 57.
    Korber BTM, Kunstman KJ, Patterson BK, et al. Genetic differences between blood-and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J Virol 1994; 68: 7467–81.PubMedGoogle Scholar
  58. 58.
    Haggerty S, Stevenson M. Predominance of distinct viral genotypes in brain and lymph node compartments of HIV-1-infected individuals. Viral Immunology 1991; 4. 123–31.PubMedCrossRefGoogle Scholar
  59. 59.
    Pang S, Vinters HV, Akashi T, O’Brien WA, Chen ISY. HIV-1 env sequence variation in brain tissue of patients with AIDS-related neurologic disease. JAIDS 1991; 4: 1082–92.Google Scholar
  60. 60.
    Epstein LG, Kuiken C, Blumberg BM. et al. HIV-1 V3 domain variation in brain and spleen of children with AIDS: Tissue-specific evolution within host-determined quasispecies. Virology 1991: 180: 583–90.PubMedCrossRefGoogle Scholar
  61. 61.
    Power C, McArthur JC, Johnson RT, et al. Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol 1994: 68: 4643–9.PubMedGoogle Scholar
  62. 62.
    Albert J, Wahlberg J, Lundeberg J, et al. Persistence of azidothymidine-resistant human immunodeficiency virus type 1 RNA genotypes in posttreatment sera. J Virol 1992; 66: 5627–30.PubMedGoogle Scholar
  63. 63.
    Mayers DL, McCutchan FE, Sanders-Buell EE, et al. Characterization of HIV isolates arising after prolonged zidovudine therapy. J AIDS 1992; 5: 749–59.Google Scholar
  64. 64.
    Wildemann B, Haas J. Ehrhart K, et al. In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1-infected patients. Neurol 1993; 43: 2659–63.CrossRefGoogle Scholar
  65. 65.
    Löpez-Galíndez C, Rojas JM, Nâjera R. Richman DD, Perucho M. Characterization of genetic variation and AZT resistance mutations of HIV by the RNase A mismatch cleavage method. Proc Natl Acad Sci USA 1991; 88: 4280–4.PubMedCrossRefGoogle Scholar
  66. 66.
    Smith MS, Koerber KL, Pagano JS. Zidovudine-resistant human immunodeficiency virus type 1 genomes detected in plasma distinct from viral genomes in peripheral blood mononuclear cells. J Infect Dis 1993; 167: 445–8.PubMedCrossRefGoogle Scholar
  67. 67.
    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; 167: 526–32.PubMedCrossRefGoogle Scholar
  68. 68.
    Wainberg MA, Beaulieu R, Tsoukas C, Thomas R. Detection of zidovudine-resistant variants of HIV-1 in genital fluids. AIDS 1993; 7: 433–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Wong JK, Fitch NJS, Torriani F, Havlir D, Richman DD. Discordance of RT sequences conferring ZDV resistance in proviral DNA from brain and spleen. HIV Drug Resistance Third International Workshop 1994; Kauai, Hawaii:August 2–5 (Abstract)Google Scholar
  70. 70.
    Land S, McGavin K, Lucas R, Birch C. Incidence of zidovudine-resistant human Immunodeficiency virus isolated from patients before, during, and after therapy. J Infect Dis 1992; 166: 113942.Google Scholar
  71. 71.
    Boucher CAB, van Leeuwen R, Kellam P, et al. Effects of discontinuation of zidovudine treatment on zidovudine sensitivity of human immunodeficiency virus type 1 isolates. Antimicrob Agents Chemother 1993; 37: 1525–30.PubMedCrossRefGoogle Scholar
  72. 72.
    Smith MS, Koerber KL, Pagano JS. Long-term persistence of zidovudine resistance mutations in plasma isolates of human immunodeficiency virus type 1 of dideoxyinosine-treated patients removed from zidovudine therapy. J Infect Dis 1994; 169: 184–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Piatak M, Jr., Saag MS, Yang LC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993; 259: 1749–54.PubMedCrossRefGoogle Scholar
  74. 74.
    Mulder J, McKinney N, Christopherson C, Sninsky J, Greenfield L, Kwok S. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 1994; 32: 292–300.PubMedGoogle Scholar
  75. 75.
    Holodniy M, Katzenstein DA, Sengupta S, et al. Detection and quantification of human immunodeficiency virus RNA in patient serum by use of the polymerase chain reaction. J Infect Dis 1991; 163: 862–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Urdea MS, Wilber JC, Yeghiazarian T, et al. Direct and quantitative detection of HIV-1 RNA in human plasma with a branched DNA signal amplification assay. AIDS 1994; 7 (Suppl 2): S11–4.Google Scholar
  77. 77.
    Cheeseman SH, Havlir D, McLaughlin MM, et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. JAIDS 1995; 8: 14 1151.Google Scholar
  78. 78.
    Havlir D, Cheeseman SH, McLaughlin M, et al. High dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis 1995; 171: 537–545.PubMedCrossRefGoogle Scholar
  79. 79.
    Schuurman R, Nijhuis M, van Leeuwen R, et al. Relationship between HIV-1 viral load and appearance of drug resistance mutations in patients initially treated with 3TC and subsequently with a combination of AZT and 3TC. HIV Drug Resistance Third International Workshop 1994; Kauai, Hawaii:August 2–5 (Abstract)Google Scholar
  80. 79a.
    Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in 111V-1 infection. Nature 1995; 373: 123–6.PubMedCrossRefGoogle Scholar
  81. 80.
    Angarano G, Monno L, Appice A, et al. Transmission of zidovudine-resistant HIV-1 through heterosexual contacts. AIDS 1994; 8: 1013–4.PubMedCrossRefGoogle Scholar
  82. 81.
    Conlon CP, Klenerman P, Edwards A, Larder BA, Phillips RE. Heterosexual transmission of human immunodeficiency virus type 1 variants associated with zidovudine resistance. J Infect Dis 1994; 169: 411–5.PubMedCrossRefGoogle Scholar
  83. 82.
    Wahlberg J, Fiore J, Angarano G, Uhlén M, Albert J. Apparent selection against transmission of zidovudine-resistant human immunodeficiency virus type 1 variants. J Infect Dis 1994; 169: 6114.CrossRefGoogle Scholar
  84. 83.
    Kuritzkes DR, Bell S, Bakhtiari M. Rapid CD4+ cell decline after sexual transmission of a zidovudine-resistant syncytium-inducing isolate of HIV-1. AIDS 1994; 8: 1017–8.PubMedCrossRefGoogle Scholar
  85. 84.
    Erice A, Mayers DL, Strike DG, et al. Brief Report: Primary Infection With Zidovudine-Resistant Human Immunodeficiency Virus Type 1. N Engl J Med 1993; 328: 1163–6.PubMedCrossRefGoogle Scholar
  86. 85.
    Hermans P, Sprecher S, Clumeck N. Primary infection with zidovudine-resistant HIV [letter]. NEJM 1993; 329: 1123PubMedCrossRefGoogle Scholar
  87. 86.
    Sönnerborg A, Johansson B, Ayehunie S, Inlander I. Transmission of zidovudine-resistant HIV-1. AIDS 1993; 7: 1684–5.CrossRefGoogle Scholar
  88. 87.
    Fitzgibbon JE, Gaur S, Frenkel LD, Laraque F, Edlin BR, Dubin DT. Transmission from one child to another of human immunodeficiency virus type 1 with a zidovudine-resistance mutation. N Engl J Med 1993; 329: 1835–41.PubMedCrossRefGoogle Scholar
  89. 88.
    Masquelier B, Lemoigne E, Pellegrin I, Douard D, Sandler B, Fleury HJA. Primary infection with zidovudine-resistant HIV [letter]. NEJM 1993: 329: 1123–4.PubMedCrossRefGoogle Scholar
  90. 89.
    Hirschei B, Kinloch S, Hoehn B, et al. Controlled trial of zidovudine (Z) in primary HIV infection (PHI). 34th Interscience Conference on Antimicrobial Agents and Chemotherapy 1994; Orlando, FL:October 4–7. (Abstract)Google Scholar
  91. 90.
    Richman DD. Resistance of clinical isolates of HIV to antiretroviral agents. Antimicrob Agents Chemother 1993; 37: 1207–13.PubMedCrossRefGoogle Scholar
  92. 91.
    Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 581–7.PubMedCrossRefGoogle Scholar
  93. 92.
    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; 34: 436–41.PubMedCrossRefGoogle Scholar
  94. 93.
    Japour AJ, Welles SL, D’Aquila RT, et al. Prevalence and clinical significance of zidovudine resistance mutations in human immunodeficiency virus isolated from patients following long-term zidovudine treatment. J Infect Dis 1995; 171: 1172–1179.PubMedCrossRefGoogle Scholar
  95. 94.
    Saag MS, Emini EA, Laskin OL, et al. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993; 329: 1065–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Douglas D. Richman

There are no affiliations available

Personalised recommendations