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The Body Covers: The 8th Conference on Retroviruses and Opportunistic Infections

Clinical Trials of HIV-1 Reverse Transcriptase Inhibitors

Coverage provided by Richard Alan Elion, M.D.

February 6, 2001

Videx was the second NRTI agent brought to market in the early 1990s and has been associated with chalky large pills, bloating, gas, and potent antiviral activity. It was a sheep in wolf's clothing. Efforts to make it better were slow and incremental ranging from switching from chalk to mandarin orange flavor and eventually smaller tablets that still contained a buffer that was responsible for the upset stomachs. Meanwhile, Bristol-Meyers Squibb -- the company that first manufactured this medicine -- were trying to figure out how to make it more tolerable and palatable. They seemed to have fixed the problem. They studied the technology of time release capsules with little coated beadlets that release the medicine in the intestine thereby eliminating the need for the buffer and making a new drug out of an old, unpopular, but useful medicine.

Videx is a useful medicine because it is taken once daily. It is currently recommended to be taken one hour after eating and then to avoid food for two hours after administration, thus rendering it easy for night administration. It can be taken with other medicines, but not with food. The improved tolerability and once-daily administration make this a useful NRTI again and the first to be approved for once-daily use. Clinical applications (320, 321, 491) demonstrate the utility of once-daily regimens using ddI as a cornerstone with previously mentioned research providing other NRTI choices to be paired with NNRTIs as well.

These studies were designed to evaluate the enteric-coated ddI versus the old version of ddI tablets in two different study regimens.

Comparison of HIV RNA Suppression Produced by Triple Regimens Containing Either Didanosine Enteric-Coated or Didanosine Tablet Formulations Each Administered Once Daily (Poster 318)

Schrader et al. compared the antiviral safety and efficacy of ddI EC with ddI tablet with a backbone of d4T and nelfinavir in treatment-naive patients whose CD4 count was >100. The goal was to demonstrate equal efficacy as measured by antiviral suppression in this open label randomized naive trial with 138 patients studied for 48 weeks. This trial really compared the difference in tolerability between the two different ddI preparations, as well as the antiviral efficacy. The conclusion is both regimens showed similar safety and efficacy with similar magnitude of viral suppression in both arms with comparable immunologic improvement seen in both arms. The key difference is that there were significantly fewer discontinuation secondary to adverse events in the Videx EC arm compared to the tablets (7% vs. 20%; P=.04).

Comparison of a Triple Combination Regimen Containing an Enteric-Coated Formulation of Didanosine Administered Once Daily Versus a Regimen of Combivir Plus Nelfinavir (Poster 319)

Gathe compared antiviral activity as measured by the proportion of patients with HIV RNA of less than 400 copies at 48 weeks. The secondary objective was to evaluate the changes over time from baseline for both HIV RNA and CD4 levels. The trial compared a protease inhibitor -- nelfinavir (750 TID) with Videx EC and D4T (40mg BID) (as the NRTI backbone) to a different NRTI duo of AZT (300mg BID) and 3TC (150mg BID) and the same dose of nelfinavir.

Videx EC results in a lower Cmax, increased Tmax, and equivalent AUCs when compared to chewable ddI. The drug had a favorable profile in terms of ease of use and therefore was relevant to test in this three-drug combination to demonstrate equivalent efficacy to the combivir arm.

The results showed:

  1. Videx EC provided similar antiviral efficacy as well as safety across both trials compared to either the old ddI form or the Combivir regimen.

  2. Videx EC was better tolerated than its Videx cousin, as reflected in significantly fewer patients stopping the EC arm as compared to the tablet due to AES (7% vs. 20%).

  3. Similar and significant viral suppression and immune improvements were seen in all arms, so efficacy was similar between all approaches.

  4. The incidence of adverse events was different between ddI EC and Combivir, with more nausea experienced with Combivir (35% vs. 21%), more neuropathy with ddI EC (20% vs. 8%) though neither of these side effects resulted in drug cessation.

The improvements in palatability, with equal efficacy and once-daily administration reestablish Videx as an important antiviral agent. As more agents are available for once-daily usage, Videx EC may be used as a cornerstone of future simplified regimens.

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