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1st International Workshop on HIV Drug Resistance & Treatment Strategies25-28 June 1997, St. Petersburg, Florida, USA |
DRUG SUSCEPTIBILITY AND SEQUENCE ANALYSIS OF NON-SUBTYPE B HIV-1 ISOLATES
Antiviral Therapy 1997;2 (Suppl 5):23 (abstract no. 36)
S Palmer1,2, R Shafer2, A Alaeus3, S Cox1, TC Merigan2, D Katzenstein2 and J Albert1
1Swedish Institute for Infectious Disease Control, Karolinska Institute, Stockholm, Sweden; 2Center for AIDS Research, Stanford University, Stanford, California, USA; and 3Department of Infectious Diseases, Karolinska Institute, Danderyds Hospital, Danderyd, Sweden
BACKGROUND: The global spread of HIV subtypes other than subtype B in developing and industralized countries highlights the need to assess the activity of anti-HIV drugs against non-subtype B viruses. Moreover, the genetic variablity of HIV-1 subtypes may promote naturally occurring resistance mutations in non-B subtypes that affect the susceptibility of these viral strains to anti-HIV agents.
METHODS: The susceptibility of subtypes A, B, C, D and E to zidovudine, lamivudine, didanosine, nevirapine, foscarnet and ritonavir was tested in peripheral blood mononuclear cells (PBMC). At least five different isolates for each subtype were studied. In addition, the sequence of the reverse transcriptase (RT) was determined for 12 subtype C isolates and a phylogenetic analysis of published non-B HIV-1 RT sequences was done. The sequences of the others are pending.
RESULTS:
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| GEOMETRIC MEAN IC50 (µM) | ||||||
| SUBTYPE | ZDV | 3TC | ddI | NVP | PFA | RNV |
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| A | 0.011 | 0.091 | 2.40 | 0.065 | 19.5 | 0.041 |
| B | 0.008 | 0.081 | 0.80 | 0.067 | 6.79 | 0.022 |
| C | 0.005 | 0.049 | 0.39 | 0.044 | 12.9 | 0.026 |
| D | 0.022 | 0.236 | 4.10 | 0.321 | 25.3 | 0.053 |
| E | 0.021 | 0.108 | 2.03 | 0.094 | 9.00 | 0.051 |
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| ZDV, zidovudine; 3TC, lamivudine; ddI, didanosine; NVP, nevirapine; PFA, foscarnet; RNV, ritonavir. | ||||||
In untreated patients, the mean IC50 values of each drug for subtypes A, C, D and E isolates were similar to the mean IC50 value for subtype B isolates. Of note, three of four non-B isolates (one C, one D and one E) from patients receiving zidovudine treatment were less susceptible to zidovudine compared to isolates from untreated patients. Phylogenetic analysis of HIV-1 RT sequences revealed sufficient intrasubtype nucleotide variation to differentiate subtype A, B, C and D, but inter-subtype RT comparisons were notable for high ratios of synonymous/non-synonymous differences.
CONCLUSIONS: Non-B subtype isolates of HIV-1 were similar in their drug susceptibility to RT inhibitors compared to subtype B isolates. Moreover, no drug-resistance mutations were observed in the RT genes of subtype A, C and D isolates from untreated patients. The reduced susceptibility to zidovudine of non-B subtype isolates from patients already receiving zidovudine may indicate development of zidovudine resistance mutations in these isolates. This study suggests that similar clinical benefits of anti-retroviral therapy might be anticipated in persons infected with subtypes of HIV-1 other than subtype B.
1997-06-25
36
Copyright © 1997 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.