Reports for NATAP

1st International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment

July 7-11, 2001 Buenos Aires, Argentina

Abacavir and 3TC Once Daily

Researchers from Thailand reported at IAS in July (poster 004) on a preliminary pilot study looking at abacavir once daily dosing and 3TC once a day dosing. The study was a 3-arm randomized, open-label design in 159 treatment-naïve patients. The 48 week results from this preliminary study are encouraging and suggest equivalent antiviral activity. The preliminary safety data raised some questions about once daily dosing with abacavir and are discussed below, but may be related to data collection inconsistencies, the population studied, or the difficulties in combining twice daily and once daily drugs in one regimen. Further study of abacavir once daily can address these questions. Simpler, more tolerable, and easier to take treatment regimens are very welcome by patients and doctors, due to the complexity and side effects of current regimens. Considering efavirenz is once daily and the new BMS protease inhibitor is taken once daily, the prospect for once daily therapy options is improving. As well, the double PI regimens of RTV/SQV and RTV/amprenavir are being researched to be used once daily.

For background information, the study authors provided the rationale for using 3TC and abacavir (ABC) once daily. The active anabolite is 3TC-TP and intracellular half-life is 17 hours. 3TC-TP should remain at inhibitory concentrations over a 24-hour dosing period. Recent studies suggest that 3TC used once-daily as part of once daily regimens appear to be antivirally effective. The authors also said that in vitro pharmacodynamics experiments have suggested that once daily ABC dosing may be possible. The ABC intracellular half-life was not reported in this poster. But in communication with GSK they say intracellular t1/2 of carbovir TP in preliminary data suggest at least 12 hrs (Drusano, in vitro, hollow-fiber model, Biello, Clin Inf Dis, 1999. Kewn, 5th Intl Conf Drug Therapy HIV Infection. Montaner, 8th CROI).

There were 2 such preliminary 3TC clinical studies presented at the 8th Retrovirus Conference (Feb 2001; Sension abstract 317). The Sension study switched patients who were taking 3TC bid to taking 3TC once daily and found viral load remained equally well suppressed. Here is a link to a review of the 2nd of those studies using ddI and efavirenz in combination with 3TC all used once daily, and also suggesting good viral suppresion: FTC vs 3TC Once Daily

The study authors reported their objective was to demonstrate equivalence (non-inferiority) of 3TC and ABC once daily as a component of a combination regimn vs the same triple regimen administered twice daily. The secondary study objective was to explore the safety and tolerability of the regimens. The primary efficacy analysis was plasma HIV-1 RNA average area under the curve minus baseline (AAUCMB). The secondary analyses were proportion with HIV- RNA <400 copies/ml and time to <400 copies/ml.

The study compared a twice daily regimen of AZT, 3TC and ABC to two other regimens which had 3TC once daily in one regimen and ABC once daily in a 3rd regimen but the other drug components in regimens 2 and 3 were taken twice daily.

Three regimens:

• --Twice daily-- AZT (300 mg), 3TC (150 mg) and ABC (300 mg)
• --AZT (300 mg twice daily), 3TC (300 mg once daily), and ABC (300 mg twice daily)
• --AZT (300 mg twice daily), 3TC (150 mg twice daily), and ABC (600 mg once daily)

RESULTS

As you can see there were twice as many switches in the regimens with once daily (QD) drugs and these regimens had more discontinuations and adverse events. Half of the discontinuations in the QD-containing regimens were due to reasons other than adverse events. As you can see below 8% (4) in the BID regimen reported ABC hypersenstivity but only 1 discontinuation was reported due to an adverse event. The problems with taking 3TC or ABC once daily may be related to the patient group studied or to combining a once daily drug with twice daily drugs. 68% were female, 100% Asian, and weight was only 55kg so the patients had very low body weight. ABC and 3TC will need to be further evaluated in the US to get a better sense of safety and viral response.

GSK is enrolling two 600+ patient studies:

(1) ABC/3TC/EFV (all once daily) vs ABC (BID)/3TC (once daily)/ EFV (once daily);
(2) ABC/3TC (BID) + EFV (once daily) vs AZT/3TC (BID) + EFV (once daily).

There were no differences in viral load reduction between the 3 regimens as measured by the median plasma HIV-RNA average area under the curve minus baseline (AAUCMB), (ITT exposed).

There was no difference between the 3 arms at week 49 in terms of % <400 (about 85%) copies/ml and <50 copies/ml (about 75%) when using an as-treated analysis.

The change in CD4s (ITT exposed) due to study therapy was a rise of about 210 by week 48 for the patients in the twice daily regimen, compared to a rise of about 150 CD4s in both other regimens.