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Mutation Score for Tenofovir: guidance in using tenofovir (Viread)
Reported by Jules Levin
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These researchers reported a mutation score that included mutations previously reported plus T69 and E44D. After the report from these authors I'll place this in context by reporting the resistance profile reported here by Mike Miller from Gilead Sciences. These reports give very helpful guidance in optimizing the use of tenofovir. This information should help in identifying how much tenofovir viral load response you can expect based on the genotypic resistance the patient has. This should help in selecting and optimizing a treatment regimen.
In order to understand better the drug resistance profile for tenofovir, a French research group (B Masquelier, ANRS AC11 Resistance Study Group) examined between March 2001 and February 2002 a large cohort (group) of patients with multiple treatment failure enrolled in the tenofovir (TDF) expanded access program. Genotypic resistance was tested in a subgroup of patients receiving a TDF 3-drug regimen for 3 months or more. This presentation was in an oral session along with other key oral presentations. Since TDF is a new drug for HIV resistance researchers and doctors want to learn more about the resistance to this drug. This will help in understanding when to use it and what responses to expect.
There were 191 patients in this subgroup. Viral load at the beginning of the study was 4.9 log (almost 100,000). The patients averaged a 0.9 log viral load reduction at 3 months on therapy. 27% (n=52) of patients had <400 copies/ml viral load at month 3 and 44% (n=84) had a decrease of at least 1 log of viral load at month 3. Here is a description of the mutations the patients had at the beginning of the study before they received TDF showing the patients had extensive nuke experience:
--74% of patients had 3 or more TAMs (thymidine analogue mutations, NRTI mutations: 41L, 67N, 70R, 210W, 215Y/F, 219Q/E).
--69% had at least 1 NNRTI mutation
--58% had at least 2 primary PI mutations
The study authors reported finding that the following mutations reduced the antiviral effect of TDF and appear to be key in reducing TDF antiviral activity:
M41L, D67N, L210W, T215Y/F are associated with the worst response to tenofovir. Three additional mutations are associated with a worse response: E44D, T69D/N/S, and V118I.
41, 210, 215, and 67 are key mutations for AZT resistance. The 69 mutation is one that is called a nuke multi-drug resistance mutation and uncommonly can emerge when a patient has extensive resistance to a number of nukes.
The important conclusion is that a TDF mutation score of less than 3 predicted the absence of resistance, 3 to 4 mutations possible absence of resistance, and more than 4 mutations resistance to TDF; and corresponded to viral load reductions of 1.3 log (=/- 1.1), 0.8 (+/- 1.1), and 0.4 (+/- 0.9 log), respectively. The authors reported this was found to be significant using bootstrap sampling (n=100).
A patient mutation profile including 4 TAMS plus a T69, E44, V118 or 4 TAMS plus a combination of these 3 increased the resistance to TDF.
New Gilead Mutation Score
Mike Miller from Gilead reported here additional information to that previously reported. In treatment-experienced study TDF has shown to reduce viral load on average 0.6 log and in small studies in treatment-naive patients 1.5 log. The following information was found in looking at 333 patients in TDF studies 902 and 907. Patients had extensive NRTI resistance (5 years of prior nuke experience). 71% of the patients had a TAM. And 30-50% had a key TAM. Miller previously reported:
--when no TAM or mutation was present average patient viral load reduction was 0.8 log
--when 1 or 2 TAMS were present viral load reduction was 0.7 log
--when 3 or more TAMS were present plus the M41L or the L210W the viral load reduction was only 0.25. So, the presence of the 41 or 210 with 3 TAMS severely reduces antiviral response to TDF.
--when 3 or more TAMS are present without the 41 or 210 the viral load reduction on average was 0.7
--a new finding by Miller is that the following mutations (NAMS) also appear to have an effect in reducing response to TDF: 39, 43, 208.
So, this TDF mutation score includes 8 mutations:
4 TAMS: 41, 67, 210, and 215 and
4 NAMS: 39, 43, 74, 208
--also, the presence of the K65R is an independent predictor of poor response to TDF although Gilead reports it has been found in only 2% of patients in studies.
--M184V, the 3TC mutation may marginally improve TDF response (about 0.1 log).
VIRAL RESPONSE USING NEW 8 MUTATION SCORE
Using the new mutation score when 0 mutations are present the viral load reduction is almost 1 log, when 1 mutation is present reduction is 0.65, 2 mutations 0.6, 3 mutations 0.3, 4, 5 or 6 mutations 0.2 log, and 7 mutations 0.1 log.
It appears to me that there are some subtle differences between the French finding and the two Miller scores. In one Miller report the 41 and 210 mutations are key and display graphically their effect. There appear to be additional subtle differences that I think will be addressed in time. But these reports should give guidance to doctors and patients in optimizing the use of TDF.
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