triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir (Moyle et al 2006). However, in recent years conﬂicting data about the poten- tial risk of nephrotoxicity associated with a mild to moderate disturbance of renal function, as well as several cases of renal failure, on tenofovir have been published. At the end of study 903 no signiﬁcant differences in mean serum creatinine levels among 299 patients treated with tenofovir, efavirenz, and lamivudine and 303 patients treated with stavudine efa- virenz and lamivudine could be measured. Only 4 patients experienced a grade 1 creatinine elevation ( 0.5 mg/dL from baseline) in the tenofovir DF group, compared with 2 patients in the stavudine group (difference ns) (Izzedine et al 2005). Nevertheless other studies found that patients treated with a tenofovir DF-containing regimen had a small but signiﬁcantly greater decline in estimated creatinine clearance compared to individuals who received an alternative NRTI-containing regimen (–7.48 mL/min per 1.73 m2 versus –0.87 mL/min per 1.73 m2; p = 0.036) (Julg et al 2005; Gallant et al 2005). Gilead Sciences Inc., the manufacturer of tenofovir, has since recommended that patients with renal disease require dosing interval adjustments (300 mg 3 times per week) when the creatinine clearance is less than 50 mL/min and avoidance of tenofovir when the glomerular ﬁltration rate (GFR) is less than 30 mL/min. Nevertheless renal function in all patients on tenofovir-containing regimens should be monitored regularly. Another concern with tenofovir was raised by the obser- vation of Schmid and colleagues, who found a signiﬁcant association between the use of tenofovir and the presence of the enzyme variant “macroenzyme creatine kinase type 2” (Macro CK2). Electrophoresis and immunoblotting demon- strated that the Macro CK2 in TDF-treated patients consisted of the ubiquitous mitochondrial creative kinase (uMtCK) suggesting that the appearance of uMtCK in these patients might be a ﬁrst indicator of mitochondrial toxicity of TDF in the kidney (Schmid et al 2006). Study 903 at week 144 showed furthermore a signiﬁcantly greater mean percentage decrease from baseline in bone min- eral density (BMD) at the lumbar spine in patients receiving tenofovir + lamivudine + efavirenz (–2.2% ± 3.9%) compared with patients receiving stavudine + lamivudine + efavirenz (–1.0% ± 4.6%). In total, 28% of tenofovir-treated patients versus 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7% of BMD at the hip. One explanation could be an increased bone turnover, as a signiﬁcant increases in biochemical markers of bone metabolism such as alkaline phosphatase, serum osteocalcin, Therapeutics and Clinical Risk Management 2008:4(4) Atripla™ – HIV therapy in one pill and serum C-telopeptide could be observed in the group on a tenofovir-containing regimen compared with the stavudine group (Gallant et al 2004). In terms of drug resistance, which will be discussed later, the mutation K65R is selected by tenofovir and confers a 2- to 4-fold reduced susceptibility to this drug. However the inci- dence of K65R is low (3%) and has not been observed in clini- cal trials with the concomitant use of tenofovir and FTC. Emtricitabine (FTC) Another NRTI, FTC is a pyrimidine nucleoside analog. FTC is similar to lamivudine (3TC) but seems to be more effective in in vivo studies and has a longer half-life. Several phases 3 studies have demonstrated equal or superior activity of once- daily administration of FTC, when compared head-to-head with activity of stavudine and 3TC. In the FTC-301 study, FTC, didanosine, and efavirenz were compared with stavu- dine, didanosine, and efavirenz. Baseline characteristics were no different between the two groups. After 60 weeks, 76% of patients in the FTC arm had achieved and maintained HIV RNA loads of 50 copies/mL, compared with 54% in the stavudine arm (p 0.001) (Saag et al 2004). Because renal excretion of unchanged drug is the principal route of FTC elimination, the potential of FTC to cause metabolic drug interactions is low. No speciﬁc drug interactions have been reported in the literature. Development of drug resistance to FTC is comparable to that observed with 3TC. Used as mono- therapy, a single point mutation at position 184 of reverse transcriptase develops rapidly and confers cross-resistance to 3TC, but other nucleoside agents retain their activity (Sanne et al 2002; Rousseau et al 2003). Truvada® (tenofovir DF/emtricitabine) In 2005, a ﬁxed-dose combination of FTC (200 mg) and tenofovir (300 mg) was licensed and has been widely used since The combination of tenofovir + FTC (administered as separate tablets) plus efavirenz (n = 258 patients) was superior to zidovudine + 3TC (administered as a ﬁxed-dose combination with combivir), and efavirenz (n = 259 patients) in study 934. Results at 48 week revealed that 84% of the tenofovir-FTC group achieved HIV RNA loads of 400 copies/mL, compared with 73% of the zidovudine-3TC group (p = 0.002) (Gallant et al 2006). Continued follow-up through week 96 demonstrated that patients treated in the tenofovir DF/emtricitabine arm continued to have higher rates of viral suppression (75%), versus patients in the zidovu- dine/lamivudine arm (62%) in maintaining HIV RNA levels 400 copies/mL (Pozniak et al 2006). Patients treated with 575