November 16, 2006
The long-term toxicity of zidovudine (AZT, Retrovir) remains an important obstacle for sustained therapy with this drug. Although the initial nausea associated with the commencement of zidovudine-containing therapy usually settles within a matter of weeks, anemia, neutropenia, dyslipidemia and peripheral lipoatrophy are all well-documented adverse events associated with long-term zidovudine use. Moreover, the initiation of zidovudine-containing regimens is sometimes associated with smaller increases in CD4+ cell counts than the initiation of alternative nucleoside reverse transcriptase inhibitors (NRTIs).
Limited data derived from a small subset of individuals who switched away from zidovudine in the RAVE (Randomized Abacavir Viread Evaluation) study suggested that replacing zidovudine with either abacavir (ABC, Ziagen) or tenofovir (TDF, Viread) could yield benefits in hemoglobin increases and body morphology.1-3 Moreover, a regimen consisting of tenofovir + emtricitabine (FTC, Emtriva) + efavirenz (EFV, Sustiva, Stocrin) has been shown to produce fewer side effects, leading to significantly fewer treatment discontinuations due to adverse events (9% versus 4%, P = .02), than a regimen consisting of zidovudine/lamivudine (AZT/3TC, Combivir) + efavirenz.4 As such, several ongoing randomized studies in Europe are comparing the consequences of remaining on the fixed-dose coformulation of zidovudine/lamivudine as opposed to switching to the tenofovir/emtricitabine (TDF/FTC, Truvada) coformulation. The final results of these studies are expected in 2007.
A U.S. cohort study known as COMET (Combination of Efavirenz and Truvada) has already evaluated, in a non-comparative way, the effects of switching from twice-daily zidovudine/lamivudine to once-daily tenofovir/emtricitabine in individuals receiving efavirenz as the third agent in a successful antiretroviral regimen.5 This prospective, multi-center, single-arm study included 402 individuals who received at least one dose of tenofovir/emtricitabine. All individuals had HIV-1 RNA below 400 copies/mL for at least eight weeks, zidovudine/lamivudine-associated adverse events or a desire to switch medications, and a creatinine clearance rate at or above 50 mL/min by the Cockcroft-Gault method. Participants had a median CD4+ cell count of 559 cells/mm3 and had received zidovudine/lamivudine for a median of 3.9 years. The most common single reason for entering the study was a desire for regimen simplification, reported by 84.3% of individuals.
After switching to tenofovir/emtricitabine, adverse events led to premature discontinuation in 10 individuals (2.5%), half of which were due to gastrointestinal symptoms. Only one individual in the study discontinued due to virologic failure, defined as two HIV-1 RNA values above 400 copies/mL more than four weeks apart. Other discontinuations were related to a loss to follow-up (n = 9), protocol violations (n = 4), pregnancy (n = 2) and other reasons (withdrew consent, moved; n = 4), making a total of 7% of individuals (n = 30) who did not complete the study.
A total of 81% of patients achieved a viral load below 50 copies/mL after 24 weeks of tenofovir/emtricitabine treatment according to intent-to-treat analysis, which was significantly better than the baseline value (P < .001).
A wide range of hematologic benefits was observed following the switch to tenofovir/emtricitabine based on changes in hematologic parameters at week 24. Notably, 31% of individuals experienced an increase in hemoglobin of 1 g/dL or greater.
|Parameter*||Baseline Value||Change From Baseline||P Value|
|CD4+ cell count (cells/mm3)||558 (381, 784)||12 (-55, 88)||.023|
|Hemoglobin (g/dL)||14.6 (13.6, 15.6)||0.6 (0.0, 1.2)||< .001|
|Absolute neutrophil count (cells/mm3)||2,789 (1,991, 3,784)||301 (-225, 1,042)||< .001|
|Mean corpuscular volume (fL)||113 (108, 118)||-18 (-21, -14)||< .001|
Lipid parameters also improved modestly, with significant differences between baseline and week 24 for declines in total cholesterol (P < .001), low-density lipoprotein cholesterol (P = .024), high-density lipoprotein cholesterol (P = .033) and triglycerides (P < .001). The clinical significance of these small changes is not clear.
Patient responses on treatment satisfaction questionnaires indicated significant improvements relative to baseline. The proportion of patients reporting general satisfaction with their treatment regimen, convenience/simplicity, tolerability and HIV control all significantly improved to rates exceeding 80% (all Ps < .001). Furthermore, the proportion of individuals reporting fatigue, bothersome side effects and nausea/vomiting significantly declined from baseline to week 24 (all Ps < .001). The proportion of individuals reporting 100% adherence to medication also increased significantly from baseline to week 24 (P = .002), with 87% of patients achieving at least 95% adherence to the study regimen.
No important safety issues were observed during the study. Treatment-emergent adverse events reported in more than 2% of patients included nausea (5%), diarrhea (5%), headache (3%) and insomnia (3%). Grade 3/4 laboratory abnormalities were very uncommon: only two individuals experienced neutropenia, one patient experienced thrombocytopenia and two patients experienced hypertriglyceridemia. The median creatinine clearance rate declined from 116 mL/min to 109 mL/min (P < .001).
In summary, this uncontrolled cohort study indicates that switching from zidovudine/lamivudine to tenofovir/emtricitabine maintains virologic suppression and is generally well tolerated, thereby leading to a number of improvements in hematologic and lipid parameters as well as patient satisfaction and adherence. A modest decline in the creatinine clearance rate was also observed following the switch.
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