Results of ACTG Study 306 were reported by Dr. Daniel Kuritzkes. This study compared various nucleoside-only containing regimens, including some monotherapy and 2-drug therapy regimens, to define the most potent and least toxic initial nucleoside(s).
299 therapy-naive patients with an average of 400 CD4 cells and an average viral load of about 10,000 copies were enrolled into one of six arms that included combinations of ddI, d4T, 3TC, and AZT. They found that all regimens were well-tolerated and that two of the two-drug combination, d4T-3TC and AZT-3TC, resulted in sustained 1 log suppression of viral load at 48 weeks. In addition, a ddI monotherapy arm, to which 3TC was added at 24 weeks, performed comparably.
The authors concluded that d4T-3TC is at least as active as AZT-3TC as an initial regimen.
Dr. Diane Havlir and colleagues presented results from 2 ACTG studies (ACTG 290 and ACTG 298). An important result from these studies was a definitive conclusion that AZT should never be used in combination with d4T. A controversy about this issue had existed for many years -- in vitro antagonism between the two drugs has been described by many. The two ACTG studies looked at both treatment-naive and AZT-experienced patients and randomized them to receive various mono- and 2-drug nucleoside regimens. Patients enrolled had moderate HIV disease (about 400 CD4 cells and 40,000 HIV RNA copies). Patients with AZT experience who received either d4T alone or AZT-d4T had no virologic response, compared to those who received ddI alone or with AZT. Furthermore, naive patients who received AZT-d4T had a more modest virologic effect than those receiving d4T alone or AZT-3TC.
The authors concluded that AZT and d4T should never be used in combination.
The scientific basis for the observation that AZT and d4T cannot be used together was addressed by Dr. J.P. Sommadossi and colleagues. They studied intracellular (between-cell) levels of the active metabolite (ingredient) of d4T in a very small group of patients from ACTG 290 (four patients receiving d4T alone and two receiving AZT-d4T). They found that those receiving d4T alone had 6.5 times more active metabolite than those on the combination of AZT-d4T. They concluded that the markedly lower levels of intracellular metabolite was directly associated with the inferior virologic effect.
During the first session the Retrovirus Conference in Chicago, Dr. John
Mellors of the University of Pittsburgh presented data from a Phase II
study of abacavir (also known as 1592), an experimental nucleoside
analogue being developed by Glaxo Wellcome. The study examined the safety and efficacy of abacavir (300 mg every 12 hours) in combination with five protease inhibitors in their standard dosages: indinavir, ritonavir, saquinivir soft gel, nelfinavir, and the investigational PI
amprenavir, also known as 141W94 or Vertex-478 (1200 mg every 12
78 treatment-naive patients -- with a median viral load of about 60,000
copies/ml and a median T-cell count of 349 -- participated. They were
randomized to one of the five possible treatment combinations and
monitored for 16 weeks. Data were presented on 57 of the 78 patients
who has completed 16 weeks of therapy, with results as follows:
||Median Log Drop
(under 400 copies/ml)
|Abacavir + indinavir
|Abacavir + ritonavir
|Abacavir + SGV softgel
|Abacavir + nelfinavir
|Abacavir + amprenavir
Because of the small study sample, none of the differences in treatment
arms were statistically significant except Dr. Mellors noted a trend
towards inferior performance in the saquinavir softgel (Fortovase) arm.
The major issue with this trial was safety. Four of the 78 patients
(nearly 5%) had a severe systemic hypersensitivity reaction, including
vomiting, nausea, rash, and malaise. Dr. Mellors cautioned that treatment
must be stopped immediately if this occurs, and that 'rechallenge,' or
trying to start drug again, is not recommended and could be
life-threatening. It remains to be seen whether the 5% number holds
steady in further trials and broader use.