July 25, 2007
Lipoatrophy and hyperlipidemia in HIV-infected individuals are thought to be preventable toxicities associated with prolonged therapy with thymidine analog nucleoside reverse transcriptase inhibitors (NRTIs). By contrast, the use of thymidine-sparing NRTI backbones is typically associated with fewer instances of lipoatrophy and hyperlipidemia, even over prolonged follow-up.
The most commonly prescribed thymidine-sparing NRTI backbones for initial antiretroviral therapy include two fixed-dose combinations: tenofovir/emtricitabine (TDF/FTC, Truvada) and abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa). Although both of these combinations have demonstrated impressive activity in treatment-naive, HIV-infected patients initiating therapy, no head-to-head comparisons of tenofovir/emtricitabine and abacavir/lamivudine have yet been performed to determine if one combination is superior to the other in terms of effectiveness, safety and tolerability. The Spanish BICOMBO study is a randomized trial designed to do just that.
The BICOMBO study1 evaluated 333 individuals on stable antiretroviral therapy consisting of a lamivudine (3TC, Epivir)-based regimen for at least six months (HIV-1 RNA less than 200 copies/mL). Patients were randomly assigned to switch to either tenofovir/emtricitabine (n = 166) or abacavir/lamivudine (n = 167) while continuing on the third agent in their regimen. Changes in virologic efficacy, CD4+ cell count, safety, and laboratory parameters were reported through 48 weeks of follow-up.
Participants were well matched for baseline characteristics. The median age of patients was 43 years, 77% to 78% were male, and the median CD4+ cell count was 508 to 520 cells/mm3. At baseline, 100 patients were receiving tenofovir (TDF, Viread) + lamivudine, 30 individuals were receiving abacavir (ABC, Ziagen) + lamivudine, 54 individuals were receiving didanosine (ddI, Videx) + lamivudine and 48 individuals were receiving stavudine (d4T, Zerit) + lamivudine. The most common NRTIs included in patients' regimens at baseline were zidovudine/lamivudine (AZT/3TC, Combivir), which was used by 117 individuals.
Thus, 34% of individuals in the tenofovir/emtricitabine arm simply switched lamivudine to emtricitabine, and 7% of individuals in the abacavir/lamivudine arm maintained the same antiretroviral agents and simply modified the formulation.
Treatment failure was defined as:
By week 48, treatment failure had occurred in 19% of abacavir/lamivudine recipients and 13% of tenofovir/emtricitabine recipients (estimated difference: 5.9%; 95% confidence interval [CI]: -2.0% to 14.0%). This difference was primarily attributed to a higher discontinuation rate in the abacavir/lamivudine group due to suspected abacavir hypersensitivity reactions (HSR).
The upper limit of the 95% CI for the difference in treatment failure rate between the abacavir/lamivudine and tenofovir/emtricitabine arms exceeded the predefined cutoff of 12.5%, thus indicating that abacavir/lamivudine is inferior to tenofovir/emtricitabine with regard to the prevention of treatment failure.
Although viral rebound above 200 copies/mL was observed in four individuals in the abacavir/lamivudine group (2.4%) but was not observed in any individuals in the tenofovir/emtricitabine group (0%), abacavir/lamivudine did meet the noninferiority criteria for virologic efficacy compared with tenofovir/emtricitabine based on the virologic failure rates between the two arms (estimated difference: 2.4%; 95% CI: 0.05% to 6.0%).
Changes in CD4+ cell count were +44 and -3 cells/mm3 for the abacavir/lamivudine and tenofovir/emtricitabine arms, respectively (P = .03).
Changes in lipid parameters from baseline to week 48 are summarized in the table below. Interestingly, significantly greater declines in all lipid parameters, including high-density lipoprotein (HDL) cholesterol, were observed with a switch to tenofovir/emtricitabine relative to abacavir/lamivudine. However, these changes were modest in nature.
|Lipid Parameter||ABC/3TC||TDF/FTC||P Value|
|n||Median Change, mg/dL (IQR)||n||Median Change, mg/dL (IQR)|
|Triglycerides||117||0 (-34 to 28)||124||-16 (-63 to 9)||.01|
|Total cholesterol||120||12 (-6 to 26)||126||-9 (-31 to 6)||.001|
|LDL cholesterol||104||7 (-6 to 24)||106||-4 (-25 to 8)||< .0001|
|HDL cholesterol||114||0 (-4 to 8)||118||-4 (-9 to 2)||< .0001|
IQR = interquartile range; LDL = low-density lipoprotein.
In a sub-study of 47 individuals who underwent dual energy X-ray absorptiometry scanning at baseline and week 48, the abacavir/lamivudine and tenofovir/emtricitabine treatment arms showed no significant differences in the observed changes in total fat (449 and 80 g), limb fat (132 and 164 g), and bone mineral density (0.0009 and -0.0061 mg/mL). Similarly, no differences were observed between the respective arms for changes in serum creatinine (-0.03 and -0.02 mg/dL) or estimated glomerular filtration rate (1.3 and -0.5 mL/minute) between baseline and week 48.
These data indicate that switching patients to a thymidine-sparing, fixed-dose combination of NRTIs is feasible and associated with no unexpected adverse events, including those affecting renal function and bone mineral density. Moreover, switching to either tenofovir/emtricitabine or abacavir/lamivudine may lead to increases in limb fat, while switching to tenofovir/emtricitabine as opposed to abacavir/lamivudine may lead to improved lipid profiles.
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