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Tenofovir Resistance in Treatment-Naive Individuals, FDA Approval
Report from 6th Glasgow Conference on HIV
Written for NATAP by Graeme Moyle, MD, Chelsea & Westminster Hospital, London,
UK and Jules Levin
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This report is excerpted from complete Glasgow Reporting by Dr Moyle and Mike
Youle, MD archived on the NATAP website in Conference Reports, Glasgow
Conference Reports.
Researchers reported at the Glasgow conference that tenofovir resistance was
detected in 24% (7/29) of the 29 treatment-naive patients receiving
tenofovir in this study who experienced virologic failure. Some of these
patients exhibited resistance to ddI, abacavir, and tenofovir when Virco
phenotypic resistance testing was performed. The Gilead 903 study is a 600
patients randomised placebo-controlled study comparing tenofovir 245 mg once
(300 mg pill) daily with d4T 40 mg twice daily (weight adjusted, immediate
release formulation) combined with efavirenz and lamivudine, which has thus
far completed 48 weeks of follow-up (in treatment-naive patients). By
intention to treat missing equals failure analysis 82 percent of tenofovir
recipients and 81 percent of d4T recipients had viral load is less than 50
copies/ml at week 48. CD4 benefits have also been similar in the two groups.
Individuals meeting definition for virological failure were described. In
the tenofovir group 29 individuals (9.7% of those randomised) and in the d4T
group 25 individuals (8.3%) were defined as virological failure. Mutations
associated with efavirenz resistance were found in 16 tenofovir failures and
12 d4T failures. The 3 TC signature mutations 184 V was found in 12
tenofovir failures and eight d4T failures. Wild type virus was detected in
10 tenofovir failures and 12 d4T failures. In vitro tenofovir is known to
select for the K65R mutation, a mutation which may be associated with reduced
viral fitness but when combined with other mutations may affect the activity
of 3 TC, abacavir and ddI. No patient in either group had the K65R mutation.
However, K65 was found in association with an efavirenz resistance mutation
alone in 2 tenofovir failures and one d4T failure, and in combination with
both an efavirenz resistance mutation and 184V in five tenofovir failures and
one d4T failure. Overall, this meant that seven individuals in the tenofovir
group of 29 (24%) with virological failure had the K65R mutation compared
with two of the 25 virological failures in the d4T group having K65R.
Assessment of the seven isolates from the tenofovir group using both the
Virco and ViroLogic phenotype assays was performed. Using the Virco assay,
three of the isolates with K65R were resistant to ddI, three resistant to
abacavir and four resistant to tenofovir. A number of the isolates showed
modest increases in susceptibility to AZT via both phenotypic assay.
Follow-up information on all seven individuals with K65R associated failure
in the tenofovir group were reported. All patients changed therapy, in
general to regimens that contained a thymidine analog and protease inhibitor
or ddI and a protease inhibitor. Five of these individuals had achieved
viral load is less than 50 copies/ml at last follow-up the other two
individuals had detectable virus below 2000 copies, with one individual lost
to follow-up and a second individual known to be incompletely adherence to
medication. These data would suggest that re-establishment of an optimal
virological response is achievable in individuals who experience viral
rebound associated with resistance mutations including the K65R mutation.
FDA Approval Process
Editorial note from Jules Levin: these study results are the first reporting
resistance data from this study comparing tenofovir to d4T in firstline
therapy for treatment-naive patients. As reported above, of 29 patients on
tenofovir who experienced virologic failure while receiving efavirenz
(Sustiva), tenofovir, and 3TC combination therapy 24% (7 of 29) had the
signature tenofovir resistance mutation (K65R). These data have implications
in making treatment decisions regarding choices for firstline therapy and
what drugs are saved for subsequent regimens. Tenofovir has demonstrated
effectiveness in patients who fail and develop resistance to other
nucleosides such as AZT, d4T, and 3TC. When making treatment decisions,
selecting drugs for a regimen, it is important to consider future strategies.
For example, if a patient fails a firstline or secondline regimen, what drugs
will be useful to suppress HIV. What drugs will the patient stil be sensitive
to and will they need these drugs to keep HIV suppressed. At the FDA hearing
for approval of tenofovir about one year ago, I opposed the recommendation to
grant approval for use of tenofovir for both firstline therapy and for
subsequent use in patients with resistance. There was opposition to this
position. But the committee vote was close. If I recall correctly the
committee voted 8-6 in favor of granting tenofovir approval only for patients
with resistance. But the FDA overrided this position and granted tenofovir
approval for firstline use. Why did the FDA override the committee
recommendation, which they usually do not do, and grant firstline approval?
Perhaps it was popular opinion which supported firstline approval although
the committee did not approve it. It is unusual for the FDA to not follow
committee recommendations. This FDA behavior is interesting in the light of
recent FDA positions in drug approval to require more of drug companies
before approving HIV drugs. In retrospect it might have been preferable to
require resistance data before granting an indication for a drug. It is
likely that eventually tenofovir would have received firstline approval but
it would have been better to have the resistance data in making firstline
treatment decisions for patients.
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