The manufacturer of the nucleotide analogue tenofovir (Viread) has written to doctors in the US warning them not to use the drug in combination with the NRTIs ddI and 3TC after a 24 week pilot study showed that patients using this combination experienced a high rate of virological failure and NRTI resistance.
The tenofovir/ddI/3TC combination is the latest triple NRTI, or tenofovir plus two NRTI combination, to be associated with high rates of virological failure and resistance.
A 24 week pilot study designed to evaluate the safety and efficacy of a combination of tenofovir, ddI and 3TC taken once daily found that 91% of patients experienced virological failure (defined as a failure to achieve a 2 log10 reduction in viral load by week 12). Resistance tests were performed on 21 individuals. Of these, 20 (95%) had the M1841V mutation associated with 3TC resistance, with ten patients also having the K65R mutation associated with moderate resistance to tenofovir. The K65R mutation has been shown previously to occur in 14% of patients failing regimens containing tenofovir and ddI together (Winston 2003).
Gilead is warning doctors that these results mean that the tenofovir/ddI/3TC combination should not be used in either treatment-naïve or experienced patients. If doctors have any patients currently taking this regimen then consideration should be given to switching to alternative anti-HIV therapies.
Earlier studies have shown that triple NRTI regimens consisting of abacavir/AZT/3TC and abacavir/ddI/d4T achieve suboptimal viral suppression. In the late summer of this year both the European and US regulatory authorities issued a warning about the use of the tenofovir/abacavir/3TC combination after studies showed a high failure rate. Data presented at the 43rd ICAAC in Chicago last month also showed a high rate of virological failure and resistance was associated with the tenofovir/abacavir/3TC combination.
It is recommended that patients taking tenofovir and ddI together are always closely monitored because tenofovir increases blood levels of ddI, which can increase the risk of serious side-effects such lactic acidosis and pancreatitis.
Further information on this website
Tenofovir - overview
EMEA issues warning against use of abacavir/lamivudine/tenofovir - news story
Major PI-sparing study closes Trizivir arm due to inferiority to efavirenz arms - news story
Winston A et al. Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase? XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, abstract 137, 2003.