July 14, 2003
FTC (emtricitabine, Emtriva) was recently approved for the treatment of HIV infection. This agent is a nucleoside reverse transcriptase inhibitor (NRTI) similar to 3TC (lamivudine, Epivir), but with a longer half-life. One of the known complications of NRTIs is elevated blood lactic acid levels; symptomatic hyperlactatemia (SH) is the most severe form of this complication. This study was done by researchers at Washington University School of Medicine in St. Louis (and sponsored by Gilead Sciences, the maker of FTC) to determine if FTC was associated with the development of SH.
Mitochondrial toxicity has been shown to be associated with the development of SH. Studies previously performed have suggested that FTC was less likely to produce mitochondrial toxicity than other NRTIs. This was based on in vitro studies involving the effect of FTC on human polymerase gamma. Human polymerase gamma is the enzyme responsible for mitochondrial DNA synthesis; FTC has been shown to have a lower rate of incorporation into polymerase gamma, which indicates a lower risk for mitochondrial toxicity and SH.
For this study, the FTC research database was searched for adverse effects, including elevated lactate levels and investigator reports of lactic acidosis and lactatemia. This database included 13 long-term studies of FTC for both HIV and hepatitis B virus treatment.
There were 2,227 patients identified with 3,013 total person-years of exposure. In this data set there were 22 cases of SH identified for a total case rate of 7.3 cases per 1,000 person years (7.3/1,000 PY). Notably, all of these cases of SH occurred in patients who had received d4T (stavudine, Zerit) together with FTC. Another important observation was the absence of SH reports when patients were on FTC monotherapy and when FTC was a component of dual-NRTI therapy with AZT (zidovudine, Retrovir) or didanosine (ddI, Videx). These data were consistent with a number of other studies that have implicated d4T as the major culprit in NRTI-associated SH.
One other issue presented in this poster was a comparison of the SH rates with regimens containing 3TC versus regimens containing FTC. Cross-study comparisons are not always reliable, but may highlight areas of interest for prospective studies. With that said, there was a lower rate of SH in otherwise similar regimens that contained FTC (7.6/1000 PY) compared to 3TC (16.9/1,000 PY).
The take-home message from this study was that FTC both represents a new NRTI for HIV combination therapy and has a low rate of SH. The rate of SH is certainly lower than d4T and possibly lower than 3TC.
FTC has just been approved by the FDA and is now available for clinical use. Since it is produced by the same company that makes tenofovir (TDF, Viread), we will likely see FTC used in combination with tenofovir in the future and will have the opportunity to follow rates of SH in a much larger population of patients.