Tenofovir (PMPA), defining cross-resistance profiles
Tenofovir (PMPA) is a nucleotide reverse transcriptase inhibitor with activity against both HIV-1 and HIV-2 which is being developed by Gilead Sciences. The oral prodrug of tenofovir, tenofovir DF, is currently in phase III clinical trials for treatment of HIV-1.
Adefovir, another Gilead nucleotide RT inhibitor, was withdrawn from development for the treatment of HIV after phase III trials failed to convince regulatory authorities of sufficient efficacy. Adefovir is being further explored for treatment of hepatitis B.
Michael Miller of Gilead Sciences presented data at this meeting further characterising the potential cross-resistance profile of tenofovir . Phenotypic susceptibility to tenofovir was determined using clinical samples derived from patients with evidence of genotypic resistance to a range of nucleoside analogue reverse transcriptase inhibitors (NRTIs).
Clinical samples were classified according to genotype associated with resistance
|Resistance type||No. of samples||Genotypic pattern|
|ZDV, high level||20||T215Y/F + other ZDV mutations (+/- M184V)|
|Multinucleoside resistance (A)||10||Q151M complex (+/- M184V)|
|Multinucleoside resistance (B)||15||T69S insertions (+/- M184V)|
|ddC resistance||8||K65R (+/- M184V)|
Results (by increasing loss of phenotypic sensitivity to tenofovir) are shown in Table 2.
|Resistance type||Phenotypic sensitivity to tenofovir (mean fold change from wild type)
||No. of samples|
|ddC resistance (+M184V)||1.5-fold||4|
|Multinucleoside A (+ M184V)||1.6-fold||5|
|Multinucleoside A (- M184V)||1.8-fold||5|
|ZDV high (+ M184V)||2.4-fold||10|
|ddC resistance (- M184V)||3.4-fold||4|
|ZDV high (- M184V)||3.7-fold||10|
|Mulinucleoside B (+ M184V)||6-old||10|
|Multinucleoside B (- M184V)||23-fold||5|
As can be seen, the M184V mutation increases susceptibility to tenofovir in multiple HIV genotypes, including the tenofovir in vitro selected K65R. Most HIV with high-level ZDV resistance remains susceptible to tenofovir with 3/20 isolates showing intermediate (4 to 10 – fold) susceptibility. Additionally, tenofovir appears to be retain activity against HIV with the multinucleoside Q151M resistance complex. However, HIV with the T69S double insertion mutation shows reduced susceptibility.
Despite small sample numbers these data would suggest that tenofovir should retain antiretroviral activity in NA experienced patients who have HIV with:
- M184V mutation
- High level ZDV resistance mutations (+/- M184V)
- Q151M multinucleoside resistance mutations
- K65R mutations (+/- M184V)
Maintaining the M184V mutation
The previous observation that maintaining the M184V mutation during exposure to tenofovir may be beneficial is supported by this study.
In tissue culture the M184V mutation can be selected under drug pressure from either 3TC, or ddI, or abacavir. The presence of this mutation confers high level resistance (>100 – fold) to 3TC, but only moderate resistance (2 to 10 – fold) to ddI and abacavir. The presence of the M184V mutation does not appear to influence virological response to regimens containing abacavir or ddI.
Data on maintaining the M184V mutation were presented at this meeting. Matthias Gotte of The McGill AIDS Centre, Montreal, performed in vitro studies looking at the outgrowth of wild-type virus in mixtures of wild-type HIV and HIV containing the mutant M184V . Various ratios of wild-type to mutant virus were used, and outgrowth under the influence of no drug, 3TC, abacavir, ddI or ZDV measured. The results revealed that, as expected, maintenance of the M184V mutation did not occur to any great extent in the absence of drug pressure. In contrast, 95 to 100% of HIV maintained the M184V mutation in the presence of abacavir and 100% in the presence of 3TC. The M184V mutation diminished somewhat in mixtures of viruses grown in the presence of ddI. ZDV appeared to facilitate the disappearance of the M184V mutants. The study concludes that ddI may not be able to exert selective pressure to maintain the 184V mutation as adequately as 3TC and abacavir.
Additionally the Havanna trial reported that in a subgroup of thirty five 3TC – experienced subjects who had experienced virological failure while receiving prior NA therapy the subsequent use of ddI was not associated with a significant prevalence of the M184V mutation .
- Miller MD, Margot NA, Hertogs K et al. Anti-HIV activity of tenofovir (PMPA) against a panel of nucleoside-resistant clinical samples.4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 4.
- Gotte M, Arion D, Parniak MA and Wainberg MA. Pressure to maintain the M184V mutation in tissue culture can more efficiently be exerted by lamivudine and abacavir than by didanosine. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 21.
- Ruiz L, Tural C, Holtzer C et al. Prevalence of zidovudine and lamivudine resistance-related mutation in the absence of active zidovudine or lamivudine use in a large, multi-centred, comparative trial of genotyping and standard of care – the Havanna Trial. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 59.