icon-folder.gif   Conference Reports for NATAP  
  6th Intl Congress on Drug Therapy in HIV Infection
Glasgow, Scotland Nov 17-20, 2002
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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
  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.