July 14, 2004
Although tenofovir (TDF, Viread) was only approved on October 26, 2001, it quickly has become a widely-prescribed nucleoside reverse transcriptase inhibitor (NRTI). There were many presentations at this conference regarding tenofovir's efficacy, tolerability, toxicity and pharmacokinetics. This report will summarize 4 presentations on the long-term follow-up of Gilead Sciences study 903 (GS903), a pivotal study on tenofovir.
GS903 was the first large study of treatment-naive persons receiving tenofovir. The double-blinded, placebo-controlled study randomized 600 persons to receive either tenofovir or stavudine (d4T, Zerit) in combination with lamivudine (3TC, Epivir) and efavirenz (EFV, Sustiva, Stocrin). This landmark study is the largest, longest-term study of its kind.
Drs. Gallant (Johns Hopkins University School of Medicine, Baltimore) and De Ruiter (St. Thomas' Hospital, London) discussed the 144-week results of the GS903 study. Overall, the study showed that a high proportion of patients achieved HIV-RNA suppression in both study arms, with 73% and 69% of patients in the tenofovir and stavudine arms, respectively, with viral loads <50 copies/mL. CD4+ cell counts increased to about 270 cells/mm3 over the duration of the study in both groups. There were no apparent differences in response rates among persons who entered the study with either extremely high baseline viral loads or low CD4+ cell counts.
De Ruiter also reported on the gender differences between men and women in GS903, noting that there was no apparent difference in viral load response to treatment. There were subtle differences in CD4+ cell count changes, with women tending to have significantly greater increases in CD4+ cell counts than men.
Overall, the 144-week results of this study corroborate previous reports. There were no new safety or tolerability issues raised in the third year of observation of these study subjects.
Statistically, significantly more cases of peripheral neuropathy and investigator-defined lipodystrophy occurred among patients who received stavudine. After 144 weeks, 10% and 19% of stavudine patients had these 2 adverse effects, respectively, compared to 3% and 3% of tenofovir patients. In the third year of GS903, there were no new cases of peripheral neuropathy, while 2% of tenofovir and 6% of stavudine patients had new lipodystrophy. Additionally, the study confirmed differences in lipid profiles between stavudine and other nucleosides, with a greater rise in triglycerides and low-density lipoprotein (LDL) cholesterol among stavudine subjects, and more stavudine subjects receiving a lipid-lowering therapy. Women had lesser increases in triglycerides and LDL cholesterol than men. It is important to recall that the GS903 study was double-blinded and placebo-controlled, and neither study investigators nor patients knew which active antiretroviral medications were being taken, emphasizing the unbiased nature of these conclusions.
Decreases in bone mineral density (BMD) were observed in patients in GS903. In the first year of study, significant decreases in hip and spine density were seen, and lesser decreases were observed in the second and third years of the study. Statistically, significantly greater decreases in spine, but not hip, BMD were reported in tenofovir-receiving patients, but this was not associated with any increase in the rate of bone fractures.
An important consideration in the use of tenofovir is the potential for renal toxicity. There have been several reports of tenofovir-associated renal toxicity, occurring mostly in patients with pre-existing impairment of creatinine clearance (renal function). It is recommended that the dosing interval of tenofovir be increased in persons with significant decreases in renal function. GS903 excluded patients with pre-existing renal insufficiency, but nevertheless provides important insight into this large population of patients. Dr. Staszewski (University Hospital, J.W. Goethe-Universität, Frankfurt, Germany) reported on a detailed analysis of the renal safety profile of patients in GS903, confirming the 1- and 2-year analyses. He provided a detailed account of changes in laboratory measures of kidney function, showing that there was no difference in renal safety between tenofovir and stavudine subjects, and no cases of Fanconi's syndrome. No study subjects discontinued tenofovir therapy due to renal toxicity, even after 3 years of treatment.
Virologist Michael Miller (Gilead Sciences, Foster City, Calif.) reported the final drug resistance analysis for patients in GS903. Previously, the Gilead group reported that efavirenz and lamivudine resistance were the most commonly observed forms of treatment-emergent drug resistance in patients in either study arm. It may seem trivial, but it is important to note (as with any new drug) that no new or novel genotypic resistance patterns were observed.
The tenofovir-associated K65R reverse transcriptase mutation appeared infrequently, in 8 tenofovir subjects (7 in year one and 1 in year two) and 2 stavudine subjects. No new patients had virus with K65R in the third year of observation. Importantly, all viral isolates were subjected to population-based phenotypic testing using the ViroLogic Phenosense assay, which revealed tenofovir susceptibility with a mean fold change of 1.3. Furthermore, stavudine and zidovudine (AZT, Retrovir) susceptibility was preserved in all 8 subjects. Miller's current report also provided additional follow-up for the tenofovir patients who acquired K65R. Four of the 8 patients continued on second-line treatments (median follow-up, 155 weeks) with undetectable viral loads (<50 copies/mL). The remaining 4 subjects either discontinued treatment or were lost to follow-up.
GS903 has provided key information about the efficacy and safety of the use of tenofovir in treatment-naive persons. These 4 presentations provide important, if not entirely unexpected, results, confirming the excellent virologic response and tolerability of the tenofovir, lamivudine and efavirenz combination.
In our clinic and across the world, tenofovir is widely prescribed, particularly in combination with lamivudine and efavirenz. The anticipated approval of the tenofovir plus emtricitabine (FTC, Emtriva) fixed-dose combination tablet will no doubt be received warmly by clinicians. Renal toxicity has not been a significant issue, with the exception of patients with pre-existing renal disease. For these patients, careful monitoring and dose-interval change (when appropriate) should be performed. Because of the known increases in tenofovir drug exposure when given with either lopinavir/ritonavir (LPV/r, Kaletra) or atazanavir (ATV, Reyataz), it might be prudent to monitor renal disease patients who receive tenofovir with these protease inhibitors with extra care.
Lastly, while this topic did not receive its due attention at this meeting, the recent 37% reduction in the price of tenofovir for the developing world, as well as the announcement of the first cross-company collaboration (with Bristol-Myers Squibb and Merck) to make a fixed-dose combination pill (tenofovir, emtricitabine and efavirenz), are exemplary of overdue and innovative ways to address the many issues of access and cost of HIV health care. I hope and trust that others will follow suit.
Abstract: Long-Term Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF): A 144-Week Comparison Versus Stavudine (d4T) in Antiretroviral-Naive Patients
Abstract: Final 144 Week Resistance Analysis for Treatment-Naive Patients Taking Tenofovir DF (TDF) or Stavudine (d4T) in Combination With Lamivudine (3TC) and Efavirenz (EFV) (Poster WePeB5757)
Authored by: M D Miller, N A Margot, D J McColl, A K Cheng
Abstract: Three-Year Analysis of the Renal Safety of Tenofovir DF (TDF) Versus Stavudine (d4T) When Used in Combination With Lamivudine (3TC) and Efavirenz (EFV) in Antiretroviral-Naive Patients (Poster WePeB5917)
Authored by: S Staszewski, J E Gallant, A L Pozniak, K Yale, B Lu, J Enejosa, A K Cheng
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