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Once Daily - d4T, AZT
Reported by Jules Levin
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Well, I'm finally on my way back from 2 weeks in Spain-one week in Seville at the 11th Resistance Workshop and a second week in Barcelona at the 14th World AIDS Conference. I'm anxious to get home. I missed the 4th of July celebration & the beach and barbeque. I'm in my 17th month of pegylated interferon plus ribavirin, and I'm tired. I will end the therapy after 18 months in August. I almost didn't go to Barcelona because of the fatigue, which is associated with the therapy.
I left Barcelona this morning for Madrid where I'm connecting tomorrow for NYC. It's hotter in Madrid than it was a few hours ago in Barcelona. And Madrid seems very empty-it's Sunday-compared to the crowded Barcelona. It seems pretty hot here. My reports from both conferences are I think a good comprehensive review of the important clinical information and new data reported at both conferences. These reports are posted and archived on the NATAP website in the Conference Reports section for you to reference. But additional reports will be posted by myself and David Margolis, MD, University of Texas, and David Wohl, MD, UNC. Dr Wohl will be covering lipodystrophy and metabolics at Barcelona.
This report will discuss the presentations at Barcelona on AZT and d4T taken once daily. As you know AZT is currently taken twice daily. At Barcelona, GlaxoSmithKline presented the first study in HIV-infected patients comparing once vs twice daily AZT. Bristol Myers Squibb reported a few studies on d4T once daily including the results of a 48-week study comparing d4T once daily to d4T twice daily in combination with 3TC and efavirenz. You may know that several weeks ago the FDA approved 3TC to be taken one tablet once daily. DDI is FDA approved one capsule taken once daily. Tenofovir is approved one pill once daily. It's expected that the FDA will be approving d4T once daily in the Fall 2002. This opens up the possibility for several once a day regimens. Once daily therapy may or may not be appropriate for you and your situation. Before seriously considering a once daily regimen you should talk to your doctor about this. You should ask him/her what is best for you and your situation. I expect there will be more research in the next few years about the pluses and minuses of once daily therapy. True once daily therapy is taking all your pills at the same time once a day. Due to food restrictions for some drugs, it may be necessary to space out the taking of pills timewise.
As well, several protease inhibitor regimens are being examined in research studies to be taken once a day. The once daily PI regimens use a small dose of ritonavir to boost the PI drug levels in blood allowing them to perhaps be once daily regimens. Atazanavir is however a once daily PI but is still in phase III study. New research on taking Kaletra once daily was reported at the conference and the report of this study is on the NATAP website. Nevirapine is still being studied as a once a day drug. FTC is a cousin of 3TC and is taken once daily but is cross-resistant with 3TC. It's still in studies & not yet FDA approved.
D4T ONCE DAILY
In poster TuPeB4555, Bristol Myers researchers reported on a study of d4T once daily extended release formulation in healthy volunteers. Investigators reported that d4T extended release (XR) can be given without regard to food. The total daily exposure (AUC), the amount of drug in the blood, for d4T XR was equivalent to that for d4T IR (immediate release, the current form). They concluded that the d4T XR was safe & well tolerated by all patients in the study, with mild abdominal pain or headache occurring infrequently.
BMS also reported (poster LbPe9014) on a study comparing in 700 HIV-infected patients the use of the new once daily d4T vs the twice daily d4T. This was a multinational, randomized, double-blind, placebo-controlled study evaluating the antiviral activity, safety and tolerability of once daily d4T extended release (XR) to the current twice daily formulation of d4T immediate release (IR). Both versions of d4T were used in a 3-drug combination with 3TC 150 mg twice daily plus efavrienz 600 mg once daily. In cases of EFV intolerance patients could switch to nelfinavir.
70% of study patients were male. 43% white, 23% black, and 22% hispanic. Viral load was on average 4.8 log, about 65,000 copies. And on average Cd4 count was 280.
Results
In terms of viral load response, CD4 count response, and the number of patient discontinuations after 48 weeks in the study, both d4T formulations performed about equally. 59% of patients receiving d4T XR had <50 copies and 57% receiving IR had <50 copies after 48 weeks. Both groups had a similar viral load reduction (-2.86 XR vs -2.83 IR). CD4 count increased by 202 in the XR group vs 182 in the IR group.
Safety and Adverse Events
There appeared to be little difference between the 2 D4Ts when looking at clinical adverse events including dizziness, rash, abnormal dreams, headache, insomnia. There were 3% cases of peripheral neuropathy in the XR group vs 5% in the IR group. This is pure speculation on my part, but the Cmax (peak drug level which occurs shortly after taking drug) was higher in the IR patients than the XR patients in the study looking at that presented at this conference (TuPeB4555): d4T IR fasted 694 ng/mL Cmax vs d4T XR fasted 339 ng/mL. It is thought that higher Cmax may be associated with certain side effects and toxicities. Perhaps, the higher Cmax is related to more incidence of neuropathy, but again this is speculative on my part. There were 3% in the XR group with insomnia or fatigue vs 1% with either in the IR group.
When looking at grade 3/4 lab abnormalities there was no difference between the 2 groups: hemoglobin, neutrophils, liver enzymes, bilirubin, lipase.
Over an average of 56 weeks the following safety observations were reported:
--pancreatitis occurred in 0 XR patients and 3 IR patients
--lactic acidosis syndrome or symptomatic hyperlactemia occurred in 2 XR patients and 6 IR patients
--lipodystrophy was reported in 3% of XR patients and 4% of IR patients.
AZT ONCE DAILY
Currently, AZT is taken 300 mg twice a day. COD 2002 was a phase II study comparing the antiviral efficacy and safety of 600 mg once daily AZT vs 300 mg twice daily AZT. This was a 14 day study of AZT monotherapy, no other anti-HIV drugs. Patients were required to return to the clinic every day to draw blood samples. The once daily AZT was administered at the same time every day (within a 3 hour window) and all dosing was observed in the clinic. For the twice daily AZT, one dose was observed in the clinic and the time of the second dose was recorded by the patient in a diary (3 hour window). 32 therapy naïve HIV-infected patients were randomized and completed the study. No patients withdrew from the study.
There were 16 patients in each group, average age 34, 94% male. 56% white, 30% black. 90% asymtomatic. 88% homosexual contact acquisition of HIV. Mean HIV viral load was 4.33 log (21,379 copies) in the once daily regimen patients vs 4.40 (25,118 copies) in the twice daily regimen group.
RESULTS
--The mean reduction in viral load was -0.585 log at day 14 in the once daily patients vs -0.849 at day 14 in the twice daily patients.
--14 patients in the once daily group had >0.5 log reduction in viral load and 15 achieved this in the twice daily group
--it appeared that the slope of decline in viral load in the first 4 days after starting therapy was more rapid for the patients taking the twice daily regimen. After this period of time the decline in viral load slope appeared about the same for both the once & twice daily groups. GSK is considering a follow-up study in which patients would receive AZT twice daily for a period of time, perhaps 2 weeks, and then switch to AZT once daily to address the more rapid viral load decline associated with the twice daily dose.
SAFETY, TOLERABILITY
No grade 3/4 adverse events were reported. 8 patients in the once daily group & 9 in the twice daily group reported at least 1 treatment-related adverse event.
Adverse Events with >10% Incidence
--Nausea: 19% (3) in once daily group, 38% (6) in twice daily group
--diarrhea: 13% (2) once daily, 6% (1) twice daily
--vomiting: 6% (1) once daily, 13% (2) twice daily
--dyspeptic symptoms (upset stomach): 0% once daily, 13% twice daily
--fatigue: 13% once daily, 19% twice daily
--headaches: 13% once daily, 0% twice daily
As you can see the 600 mg AZT once a day dose did not reduce viral load as well as the 300 mg AZT dose twice daily (-0.585 log vs -0.849 log). The twice daily dose had a more rapid decline in viral load in the first 4 days appears to be a reason for the better overall outcome. GSK is considering which follow-up studies to conduct in exploring the possibility that AZT might be able to be used once daily. At this point, considering the results of this study, further research is needed to examine whether AZT once daily has a benefit. In a 3-drug HAART regimen will the overall viral load reduction be equivalent if comparing once daily AZT vs twice daily AZT? Would the use of a lead-in induction dose of twice daily for 2 weeks followed by once daily be effective? These are questions to be answered in studies.
It's 7pm & I'm off to dinner now.
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