A combination of four reverse transcriptase inhibitors (the nucleotide analogue tenofovir [Viread], and the nucleoside analogues AZT [zidovudine], 3TC [lamivudine] and abacavir [Trizivir]) appears to be as effective and tolerable as the favoured two-class regimen (efavirenz [Sustiva], and the nucleoside analogues AZT and 3TC [Combivir]) in HIV-positive patients who have never taken antiretrovirals before, according to a presentation made to the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington.
Since 1996, recommended antiretroviral therapy has normally consisted of three drugs from at least two different classes of anti-HIV drugs. The current guidelines of the British HIV Association recommend that initial HIV therapy should include the non-nucleoside analogue efavirenz, plus two nucleoside analogues (NRTIs) or a boosted protease inhibitor and two NRTIs. Triple NRTI therapy is not normally recommended after studies showed it to be suboptimal compared to two-class therapy. There have been reservations about the use of tenofovir in antiretroviral regimens when only combined with NRTIs due to early failure of such regimens in a number of studies.
However, NRTI regimens remain attractive in first-line therapy because of a lack of drug interactions and because they spare both the protease inhibitor and non-nucleoside class of drugs for subsequent use, according to Dr Graeme Moyle of London's Chelsea and Westminster Hospital, who presented the results of TIMS - the Trizivir Induction / Maintenance Study - today.
TIMS was originally designed to evaluate the effect of starting treatment with an induction regimen that excluded both non-nucleosides and protease inhibitors, and then stepping down to a maintenance regimen of Trizivir at week 48. However the study design was modified after the ACTG 5095 study showed that Trizivir was less effective than an efavirenz-containing regimen.
Investigators wished to see if the use of a four drug combination comprising the nucleotide analogue tenofovir with the NRTIs AZT, 3TC and abacavir (available together in a single pill as Trizivir) was as effective and tolerable as a conventional two class regimen comprising efavirenz and the NRTIs AZT and 3TC (available in a combined pill, Combivir). Both regimens involve three pills a day, taken with or without food.
A randomised open label study was designed by investigators which enrolled a total of 113 patients who were equally divided between the tenofovir and efavirenz arms. Patients randomised between the two arms had comparable CD4 cell count (tenofovir 153 cells/mm3 vs. efavirenz 194 cells/mm3) and viral load (mean 180,000 vs. 130,000 copies/ml).
30% of patients in the Trizivir arm discontinued treatment by week 48, compared to 29% of the Combivir arm. Treatment discontinuations due to adverse events were more frequent in the Trizivir group (16 vs. 11%); this difference was driven by hypersensitivity reactions to abacavir. The loss to follow up rate was higher in the Combivir arm (11 vs. 6%).
Both regimens were equally well tolerated over 48 weeks, at which point on-treatment analysis showed that all the 39 patients still taking the efavirenz-based regimen had a viral load below 50 copies/ml. At week 48, 97% (39 of 40) of individuals in the tenofovir arm still on treatment also had a viral load below 50 copies/ml. The single virological failure in the Trizivir / tenofovir group may be explained by poor adherence following initial virological suppression, said Dr Moyle, since the patient's virus was successfully resuppressed with a regimen of tenofovir, ddI (didanosine, Videx) and lopinavir / ritonavir (Kaletra).
Results were also comparable when the investigators looked at the more rigorous intent-to-treat data. These showed that of the patients initially randomised to receive the tenofovir-containing regimen 67% had a viral load below 50 copies/ml compared to 68% of patients randomised to take the efavirenz-containing combination.
Increases in CD4 cell count were similar between the two arms of the study at week 48 (tenofovir 165 cells/mm3 vs. efavirenz 119 cells/mm3).
Total cholesterol increased by 1.1mM in patients taking the three drug regimen and fell by 0.1mM in patients taking tenofovir and Trizivir. Median triglycerides fell by 0.1mM in both arms of the study.
The investigators conclude that tenofovir and Trizivir had similar efficacy and potency to the two class regimen of efavirenz and Combivir and that tenofovir with Trizivir provides an effective first line option leaving open the use of other major classes of antiretrovirals in later regimens.
Moyle G et al. A randomised open label comparative study of Combivir and efavirenz (two class triple therapy) versus Trizivir and tenofovir (single class quadruple therapy) in initial therapy for HIV-1 infection. 44th Interscience Conference on Antimicrobial Aegnts and Chemotherapy, Washington, abstract H-1131, 2004.