Report 8 -  4th International Workshop on HIV Drug Resistance and Treatment Strategies
Written by Jules Levin
Sitges, Spain, June 12-16 2000

PMPA: New Resistance Data

Tenofovir (PMPA) is a nucleotide RT (reverse transcriptase) inhibitor. Tenofovir DF (which is generally referred to as PMPA) is an oral prodrug of tenofovir and is currently in phase III human studies.

The goal of the study presented by Miller in Sitges was to further establish the potential cross-resistance profile of PMPA by assessing the PMPA susceptibility (resistance) of HIV from outpatient clinical blood samples with a wide range of RT resistance patterns.

As a brief introduction, Miller reported findings from in vitro experiments with patient blood samples showing:

Miller concluded that these in vitro (test tube) findings were consistent with the results of their studies in humans. This study reports findings of looking at patient blood samples in the laboratory. Although it's suggested this indicates the effects humans will see when using PMPA or any drug, the actual results of human experience is the final indicator.

Study 902 looked at highly NRTI experienced individuals receiving 300 mg once daily PMPA. The mean change in HIV RNA from baseline for patients receiving the 300 mg dose was -0.68 log10 copies/mL after 48 weeks of treatment (n=41). In that study the mean baseline viral load was 3.7 log (5000 copies/ml). In study 901 a 1.06 log reduction was seen in treatment experienced individuals, ansd in a 28 day monotherapy study og treatment-naÔve individuals a 1.5 log reduction in HIV RNA was reported. A full report on PMPA in study 902 is available on the NATAP web site.

So I think, Individuals naÔve to PMPA will receive the most antiviral activity for PMPA. This set of data reported by Miller at Sitges shows that some individuals with NRTI experience should receive antiviral activity from PMPA. I think the degree of response to PMPA by individuals with NRTI experience will depend on the amount of NRTI experience and posibly the types of mutations they've developed.

Miller selected blood samples from the Virco library of resistant viruses. 72 outpatient samples with the following genotypic resistance patterns were chosen according to pre-defined resistance genotypic patterns. Susceptibility to all approved NRTIs and PMPA were assessed using the Virco Antivirogram phenotypic test. The patterns were:

Phenotypic susceptibility to PMPA and all other nucleosides were reported as fold changes in IC50 compared to the wild-type (non-resistant ) virus. The Antivirogram calls phenotypic sensitivity when the IC50 fold change is < 4 fold; intermediate susceptibility is 4 to 10 fold; and, >10 fold reduced susceptibility is called resistant.

PMPA and AZT Susceptibility of HIV Samples with M184V or High Level AZT Resistance Mutations With & Without M184V 3TC Mutation

Again, they looked at three viruse types: one had the M184V mutation alone, the second had high level AZT resistance alone (mean 3.5 AZT mutations) and the third virus had high level AZT resistance with the M184V mutation. They evaluated PMPA and AZT resistance to these three viruses.

PMPA had a slight hypersensitivity (mean 0.7 EC50 fold change) to the set of viruses with M184V resistance alone. These viruses also showed a slight hypersensitivity to AZT (0.9 IC50 fold change).

PMPA had a mean 3.7 fold reduced susceptibility to the set of viruses with high level AZT resistance, and 3/10 of these viruses had intermediate susceptibility to PMPA (between 4-10 fold reduced susceptibility). These viruses had a mean 47 fold increase in IC50 (47 fold resistance) to AZT. 9/10 of these viruses had susceptibility reduced by >10 fold.

All the viruses with the 3TC M184V mutation added to high level AZT resistance had less than 4 fold resistance to PMPA with a mean fold change in IC50 of 2.4. When looking at AZT, these viruses showed only a 15 fold reduced susceptibility (resistance) to AZT; 7/10 of these viruses had >10 fold reduced susceptibility (10 fold increased IC50) to AZT, while 1 virus had 10 fold reduced susceptibility and 2 viruses had 4 fold or less reduced susceptibility. This data is in line with the concept that 3TC can reduce resistant for some people with AZT resistance but maybe not for everyone and maybe not enough to make AZT effective again.

DISCUSSION

This data suggests to me that PMPA should have antiviral activity for people with low level and high level AZT resistance accompanied by 3TC resistance. High level resistance was defined by a mean of 3.5 AZT mutations. So I think you can say that PMPA should have antiviral activity for some individuals with dual AZT/3TC resistance. The amount of antiviral activity may differ between individuals and may be related to how much AZT/3TC resistance a person has. Individuals with no AZT/3TC resistance should receive better antiviral activity from PMPA.

PMPA, AZT, and d4T Susceptibility To HIV Patient Blood Samples with the Q151M Complex Multi-Nucleoside Mutations with & without M184V Mutation

To both sets of viruses with the Q151M complex of mutations and the set with the M184V mutation added to this complex, PMPA displayed wild-type sensitivity (mean 1.7 fold increase in IC50; no resistance shown) to these viruses. However, AZT showed mean 43 fold and 46 fold reduced susceptibility (increase in IC50; resistance) to these two sets of viruses, respectively. One virus with only the Q151M complex showed only 10 fold reduced susceptibility . Both sets of viruses displayed a mean increase in IC50 above 10 fold. To the Q151M complex, although the mean increase in IC50 (reduced susceptibility or resistance) was 20 fold, a few viruses had between 4-10 fold or intermediate resistance.  D4T displayed a mean 11 fold resistance to the viruses with the Q151M complex and the M184V mutation added to it. One virus had <4 fold and a second virus had between 4-10 fold d4T resistance. So, several viruses from both sets retained sensitivity to d4T.

PMPA appeared to retain almost full antiviral activity (mean 1.7 fold increase in IC50) to viruses with the Q151M complex (multi-nucleoside resistance) and with the Q151M+M184V.

PMPA and AZT Susceptibility To HIV Patient Samples with the T69S Double Insertion Multi-Nucleoside Resistance Mutations with & without the M184V Mutation

For all the samples with the currently rare T69S double insertion mutation without the M184V mutation there was over 10 fold resistance was displayed to PMPA (mean 23 fold increased IC50 or resistance) and AZT (mean 101 fold increased IC50 or resistance).  However, when adding the M184V mutation the mean increased IC50 was 5 fold, and there were several viruses within <4 fold resistance. A mean 31 fold increased IC50 (reduced sensitivity) was displayed to AZT by viruses with the T69S and the M184V mutation. But, several viruses displayed sensitivity to AZT when the M184V was present with the T69S double insertion mutation.

DISCUSSION

It appears that PMPA is more effective in highly NRTI experienced individuals when the M184V mutation is also present. This suggests to me that when treating a person with PMPA you want to retain the presence of the M184V, so this suggests you need to combine PMPA with 3TC to retain the M184V mutation.

PMPA and Abacavir Susceptibility to HIV Patient Samples with the K65R Mutation with & without M184V

Viruses with the K65R, a mutation associated with ddC, ddI, and abacavir in vivo, and also with PMPA resistance in vitro, showed a 3.4 fold (increased IC50) reduced sensitivity (resistance) to PMPA, and only  1.5  fold reduced sensitivity when the M184V mutation was present. Two viruses displayed slight hypersensitivity to PMPA when the M184V was present with the K65R. To abacavir, there was a 7.3 mean fold increase in IC50 to viruses with the L65R and the IC50 increased further to a mean 13 fold increase in IC50 when the M184V was present with the K65R.

Again, adding the 3TC M184V mutation appeared to slightly decrease resistance to viruses with the K65R mutation.