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FTC+Efavirenz+ddI EC Once Daily; Tenofovir & mitochondrial DNA
Written by Graeme Moyle, MD, Chelsea & Westminster Hospital, London, UK
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The late breaker session today heard outcomes of two studies indicating high levels of efficacy for regimens involving new or recently approved antiretroviral agents.
Dr Michael Saag from UAB Alabama presented the outcome of a randomised, placebo controlled trial evaluating the safety and efficacy of a once daily regimen of emtricitabine (FTC) in combination with ddI EC and efavirenz compared with ddI and efavirenz dosed with twice daily d4T. This therefore represents the first randomised comparative study of once daily vs twice daily therapy in the setting of HIV infection. Study participants were antiretroviral therapy naive with viral loads > 5000 copies/Ml. The study randomised a total of 571 individuals, 285 to the d4T and 286 to be FTC arm. Baseline entry criteria included a median viral load of 4.9log and median CD4 cell count of 288/mm3. Due to differences in efficacy and regimen tolerability the study was prematurely discontinued by a data and safety monitoring board. At the time the study completion the median duration of follow-up was 42 weeks. Virological efficacy data to 24 weeks and safety outcomes to most recent follow-up were presented. In the FTC arm 4% as compared to 10% d4T patients experienced virologic failure. By intent to treat missing = failure analysis the proportion of participants with viral load <50copies/ml at week 24 were 81% for FTC and 70% for d4T patients, these differences were highly statistical different (p=0.002). Adverse events significantly more common in the d4T arm included nausea, diarrhoea, abnormal dreams, symptomatic hyperlactatemia or acidosis, hyperamylasemia and peripheral paraesthesiae. Only cough was more common in the FTC group.
The study indicates that a once a day regimen of FTC with ddI and efavirenz is an effective and well tolerated once a day treatment option. The reasons for the demonstrable efficacy superiority in the study may be related to several factors. Firstly, a once daily regimen is likely to lead to an incremental improvement in adherence to study medication, and fewer missed doses, relative to a twice daily regimen. Secondly, the comparator group in the study was a regimen that has recently (in ACTG 384) been demonstrated to not be the optimal standard of care nucleoside analog backbone. Indeed, physicians do not routinely now consider using a d4T /ddI backbone for reasons of tolerability particularly with regard to an increased risk of peripheral neuropathy, hyperlactatemia and lactic acidosis and in the longer term peripheral lipoatrophy. This being said, the proportion of patients achieving an optimal response at 24 weeks with the once daily regimen are comparable to 24 week results in other studies where excellent virological outcomes have been achieved and therefore it appears reasonable to consider that this is a robust treatment option were the of comparative evaluation against current standard of care therapies.
Tenofovir: mitochondrial DNA improvement
The second study to grace the late breaker session was the Gilead 903 study. Some 48 week safety and efficacy down from the study were recently presented at the world AIDS conference in Barcelona. The presentation at ICAAC focused on updating details of toxicity within the study. The Gilead 903 study is an ongoing randomised placebo-controlled comparative study of tenofovir or d4T in combination with 3TC and efavirenz in treatment naive individuals. The study has randomised 600 individuals, including 24 percent women, with baseline viral load of 4.9 log (almost 100,000 copies) and mean baseline CD4 of 279 cells/mm3. The virological efficacy in the study as determined by the proportion of patients at 48 weeks with viral load values below 50 copies/NL was not significantly different between the groups with 82 percent of tenofovir and 81 percent of d4T treated patients achieving this response. The majority of treatment failures in the study had been related to events other than virological failure. The increase in CD 4 cell count is also similar in the two groups rising 169 cells with tenofovir and 167 cells in the d4T group. The incidence of grades three and four adverse events was reported to be 19% for tenofovir and 17 percent for d4T treated individuals, with lab abnormalities of grade three or four in 28 percent of tenofovir and 31 percent of d4T treated patients. Rises in triglycerides and cholesterol were greater in the d4T group relative to the tenofovir group. Triglycerides levels increased by 74 milligrams per dl in the d4T group that were unchanged in the tenofovir group, and cholesterol increased by 53 milligrams per dl in the d4T group and only 25 milligrams per dl in the tenofovir group. Other adverse events that showed the trend to be more common with d4T included hyperlactatemia, peripheral neuropathy and investigator defined reports of lipodystrophy, whereas with tenofovir there was some what more neutropenia events. The study included a subset analysis involving 227 individuals in whom the PBMC mitochondrial DNA content was assayed at baseline and weeks 48. Relative to historic controlled data, both groups had mitochondrial DNA lower than would be expected in healthy individuals, consistent with the study by Cote et al recently reported in New England Journal of Medicine. During the course of the study there was an increase in mitochondrial DNA content in both groups, however this rise was only statistically significant in the group who received tenofovir. The changes in mitochondrial DNA content in the tenofovir group effectively lead to a correction in mitochondrial DNA content up to a level similar to healthy volunteers. The study which plans to continue for three years aims to investigate whether the measurement of mitochondrial DNA content in PBMCs in any way correlates with clinical adverse events.
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