Reports

Findings from RAVE

In a presentation of the RAVE (Randomized Abacavir Viread Evaluation) data by Dr. Jonathan Cartledge, Mortimer Market Centre and University College London, UK, switching patients from a thymidine analogue to either the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (TDF) or to the nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) was shown to improve lipoatrophy and exert a modestly beneficial effect on lipids.

A total of 105 patients with moderate to severe lipoatrophy on either zidovudine (ZDV) or stavudine (d4T) at baseline were switched to either once-daily TDF plus a NRTI plus a protease inhibitor (PI), a boosted PI with ritonavir (PI/r) or a non-NRTI (NNRTI) or to twice-daily ABC plus a NRTI plus a PI or PI/r or a NNRTI, with both arms receiving treatment for 48 weeks. At baseline, HIV disease was well controlled, with median CD4+ cell counts in the TDF arm at 522 cells/mm3 and 478 cells/mm3 in the ABC arm.

The median time on antiretroviral (ARV) therapy was 5.7 years for patients switched to TDF and 4.9 years for those switched to ABC. Some 77% of patients treated with TDF were on d4T at the time of the switch vs. 59% of those switched to ABC. The remainder had been on ZDV. At 48 weeks, intent-to-treat (ITT) analysis showed that 100% of patients who had switched to TDF had HIV RNA <50 copies/mL, according to a stringent, ITT missing-equals-failure analysis, as did 91% of those receiving ABC. Median CD4+ cell count increased by 44 cells/mm3 in the TDF arm and by 10 cells/mm3 in the ABC arm by week 48 as well.

At week 48, the median change in limb fat as measured by DEXA arm fat plus total leg fat increased by 393 g in the TDF arm and by 316 g in the ABC arm (P=0.97). In a facial substudy in which the mean volume of cheek fat was measured, the mean volume change from baseline to week 48 in TDF patients was 2812 mm3 compared with 2208 mm3 for the ABC arm (P=0.88).

In one multivariable model used to assess factors associated with absolute change in limb fat, age at randomization and ZDV use at baseline were both associated with a reduced likelihood of fat recovery at week 48. For every additional five years of age, “there were 103 fewer grams of fat recovery at week 48. Among those who were receiving ZDV at baseline, there was 419 grams less fat recovered at the same end point,” commented the investigators. Dyslipidemia at baseline was not striking, with median baseline triglyceride levels of 2.0 mmol/L in the TDF group vs. 1.7 mmol/L in the ABC group. Median baseline total cholesterol (TC) levels for TDF at 5.6 mmol/L and 5.2 mmol/L for ABC patients were also not significantly elevated, nor were baseline LDL-C levels at 3.3 mmol/L and 3.0 mmol/L for TDF and ABC, respectively.

By week 48, 35% of TDF patients and 34% of ABC patients had the same triglyceride levels, and there was a trend towards a slight benefit for TDF in terms of lower TC and LDL-C, but not significantly so. At baseline, 19% of patients in both groups had T-score-defined osteopenia and this rate increased to 27% at week 48 in TDF patients vs. a slight decrease to 16% in ABC patients.

Six per cent of patients on TDF discontinued treatment at a median of 36 weeks into the study while 15% of those switched to ABC also discontinued treatment, at a median of 19 weeks. “All discontinuations due to adverse events in ABC patients were due to a hypersensitivity reaction, while TDF-related discontinuations were secondarily related to diarrhea,” investigators stated.

They concluded, “TDF and ABC similarly allow restoration of limb fat over 48 weeks when switching from a thymidine analogue in patients with lipoatrophy. These data suggest that early modification of ARV away from thymidine analogue-based therapy should be considered.”

Expanded Access Program

Both the Viread Expanded Access Program (EAP) and post-marketing safety surveillance data demonstrate that TDF has a favourable safety profile and is well-tolerated. The EAP encompasses a total of 10,343 patients worldwide, some 1761 of them in the Canadian EAP. Median time to TDF exposure in Canada and Europe was 22 weeks. Serum creatinine data have been collected in over 1600 patients in the EAP. As presented by Dr. Sharon Walmsley, Associate Professor of Medicine, UHN- Toronto General Hospital and Assistant Director, Immunodeficiency Clinic, Toronto Hospital, the EAP showed that the incidence of worrisome adverse events is extremely low: 0.1% for bone abnormalities and lactic acidosis and less than 0.1% for mitochondrial toxicity and neuropathy, as was the incidence of pancreatitis at 0.5%. Rates of serious renal events were again low at 0.5% according to EAP data and 43.3/100,000 person-years based on EAP safety surveillance data. The EAP data place the incidence of renal failure at 0.3%. In a database consisting of 2821 patients in whom serum creatinine data were obtained, only three patients (0.01%) developed grade 4 abnormalities in serum creatinine (>6.0 mg/dL), none developed grade 3 abnormalities and only two patients developed grade 2 abnormalities while receiving TDF.

“The most common serious adverse events reported in the EAP database were typical of patients with advanced HIV disease and the incidence of all serious renal side effects was 0.5% among 10,343 patients in the EAP, with no new unexpected toxicities throughout the four years of post-marketing safety surveillance database,” Dr. Walmsley reported.

COMET Switch Study

In turn, Dr. Edwin DeJesus, Medical Director, Orlando Immunology Center, Florida, presented results from the COMET (Combination of Efavirenz and Truvada) study in which investigators evaluated the impact of switching virologically-controlled patients from a twice-daily regimen of fixed-dose ZDV/lamivudine (CBV) plus efavirenz (EFV) to a simplified, 2-pill, once-daily regimen of fixed-dose TDF plus emtricitabine (TVD) for 24 weeks. A total of 411 patients were switched from twice-daily CBV plus EFV to once-daily TVD plus EFV. “All patients had a viral load of <400 copies/mL at baseline,” investigators noted, while over 70% had a baseline viral load of <50 copies/mL.

After 24 weeks of once-daily TVD/EFV, 95% of patients based on the ITT missing-data-equals-excluded analysis had achieved HIV RNA <400 copies/mL, as did 87% of patients based on the ITT missing-data-equals-failure analysis. Some 81% of patients achieved an HIV RNA <50 copies/mL at 24 weeks on the missing-data-equals-excluded analysis, as did 74% on the ITT missing-data-equals-failure analysis. Triglycerides dropped by approximately 18 mg/dL (0.17 mmol/L) from baseline to week 24 following the switch (P<0.001), while TC dropped by approximately 10 mg/dL (0.26 mmol/L) from baseline to week 24 (P<0.001).

Perhaps most importantly, the percentage of patients who reported they were “very satisfied” with the new once-daily regimen improved from less than 60% at baseline to over 80% at week 24. At baseline, approximately 50% of patients said their twice-daily regimen was convenient and simplistic. By week 24, over 80% of patients stated the same opinion regarding the simplified once-daily regimen. Tolerability had also improved from baseline, where approximately 60% of patients indicated they were “very satisfied” with the tolerability of the b.i.d. regimen compared with over 80% at week 24 for the once-daily regimen.

Approximately 70% of participants also indicated they were very satisfied with the level of HIV control at baseline; by week 24, over 80% of study participants indicated they were very satisfied with the level of HIV control, differences between baseline ratings and those at study end point all being significant at P<0.001. Adherence also improved with the once-daily regimen, with 87% of patients achieving at least 95% adherence to the TVD/EFV regimen, and the percentage of patients who achieved full adherence (100%) on 95% or more days approached 85% by week 24. Only 2.5% of the study cohort discontinued the new regimen due to adverse events.