Important note: Information in this article was accurate in January 2001. The state of the art may have changed since the publication date.
Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 15, Number 1, January 2001
The 8th Conference on Retroviruses and Opportunistic Infections is being held in Chicago, IL during the first week of February this year. As we went to press, a Monday morning session on antiretroviral chemotherapy offered an update on the progress of several "new generation" drugs in the development pipeline. Here's an overview:
Attachment, fusion, and entry inhibitors were hot topics at the conference with news about CCR5 inhibitors, a gp120-CD4 attachment inhibitor, a gp120-coreceptor inhibitor and the gp41 fusion inhibitors, T-20 and T-1249. Combinations of some of these agents in pre-clinical testing have been reported to have synergistic anti-HIV activity. Now a few are reporting results from early human testing.
T-1249 is a younger sibling to T-20 and is said to have a non-overlapping resistance profile. Both drugs are given as daily injections under the skin. Seventy-two drug-experienced patients were enrolled to receive T-1249 injections as their only therapy for 14 days. Doses ranged from 6.25 mg per day to 50 mg per day on a once or twice daily schedule. Median decreases of HIV RNA from baseline at the end of 14 days were correlated with dosage — down –1.40 copies/mL at the highest dose. An improvement over T-20, once-a-day injections of T-1249 seem to provide adequate blood levels. One case of hypersensitivity reaction and one case of severe (Grade 4) neutropenia were reported. As with T-20, mild pain at the site of injection occurred in nearly half of the participants.
T-20 and is said to have a non-overlapping resistance profile. Both drugs are given as daily injections under the skin. Seventy-two drug-experienced patients were enrolled to receive T-1249 injections as their only therapy for 14 days. Doses ranged from 6.25 mg per day to 50 mg per day on a once or twice daily schedule. Median decreases of HIV RNA from baseline at the end of 14 days were correlated with dosage — down –1.40 copies/mL at the highest dose. An improvement over T-20, once-a-day injections of T-1249 seem to provide adequate blood levels. One case of hypersensitivity reaction and one case of severe (Grade 4) neutropenia were reported. As with T-20, mild pain at the site of injection occurred in nearly half of the participants.
BMS-232632 is a new protease inhibitor that has efficacy in line with that of the competition but gets bonus points for once-a-day dosing. The quality that may distinguish this newcomer is a remarkable lack of blood lipid abnormalities compared to other protease inhibitors. Lest anyone rejoice that this is the first non-toxic HIV drug, blood lipid levels have not been definitively associated with certain treatment-related toxicities, such as lipodystrophy. BMS-232632 also has one striking peculiarity: Mild to moderate elevation of unconjugated bilirubin has been observed in nearly all patients to receive the drug. Although these bilirubin elevations have been asymptomatic and no other liver laboratory markers have been affected, larger Phase III trials lay ahead and long-term follow up will determine the drug's safety.
DPC 681 and DPC 684, billed as "second generation" protease inhibitors, have entered Phase I safety trials. Pre-clinical studies report inhibitory activity at attainable plasma levels against several subtypes of HIV-1 as well as clinical HIV-1 isolates with multiple mutations known to reduce susceptibility to current generation protease inhibitors.
And a pre-clinical report on what some will surely choose to call a "third generation" protease inhibitor, a drug yet to be tested in people, called TMC126 shows activity against multi-drug resistant viral isolates at extremely small concentrations and atypical mutation patterns when resistance does emerge.
TMC120 is a new orally available NNRTI from the Belgian laboratory bringing us TMC126. Its first use in people was reported at the conference. The drug is said to be active against HIV strains that are less susceptible to current generation NNRTI, such as efavirenz. In a Phase I study design similar to that reported for T-1249 above, 43 treatment-naive patients (34 men, 9 women) were randomized to receive either 50 mg or 100 mg of TMC120 or placebo, twice daily for 7 days as their only therapy. On the eighth day, median decreases in HIV RNA from baseline were correlated with dosage, with drops of –1.44 log copies/mL for the 50 mg dose; –1.51 log copies/mL for the 100 mg dose; and –0.17 log copies/mL for placebo. Mild sleep abnormalities were noted.
Treatment Issues will have more from the 8th Retrovirus Conference in our next issue.
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