Forty-three people with an average viral load of about 32,000 copies and CD4+ cell counts of about 600 participated in this study. Participants received 50mg of TMC-120 twice a day, 100mg of TMC-120 twice a day or placebo for seven days, after which everybody received three-drug therapy. There was essentially no difference in viral load or CD4+ cell count response between the two doses of TMC-120, with about a one and a half log (32 times) reduction in viral load. CD4+ cell increases of 120 were seen at the end of the seven days.
One of the primary concerns with the NNRTIs is the potential for rapid development of resistance, especially when used alone or part of a sub-optimal regimen. No resistance was found among any of the individuals at the end of this study.
Nevertheless, the true test for this drug will be in how effective it is for people who have developed resistance to the current NNRTIs. Only when those studies are conducted will we learn whether this drug is really different from what is currently available.
The future of the new NNRTI capravirine is up in the air. Laboratory studies suggesting long-term side effects in some animals have put future studies on temporary hold. Inflammation of the blood vessels (vasculitis) was seen in some animals receiving a high dose of the drug. This has not been observed in any of the human studies of capravirine.
Preliminary results were reported from a study of capravirine in people who were experiencing increases in viral load while on a NNRTI-based regimen. The 61 participants had an average viral load of about 10,000 copies HIV RNA and CD4+ cell count of about 300 at the start of the study. No one had previously used a protease inhibitor. All of the volunteers received nelfinavir (Viracept) + two new nucleoside drugs and 1,400mg or 2,100mg of capravirine twice a day or placebo. There was little difference in response rates after sixteen weeks among the three groups with 60-75% of participants having viral loads below 400 copies HIV RNA. However, people receiving capravirine experienced more side effects (diarrhea), especially those receiving the higher dose. Based on this small short-term study, it is difficult to determine exactly how much, if any, capravirine is contributing to the overall anti-HIV response.
The results of the three T-20 doses were pooled together and after 16 weeks of the study 71% of people receiving T-20 had viral loads below 400 copies HIV RNA compared to 58% for those not receiving the drug. The percentage of people with viral load below 50 copies HIV RNA was 48% for those receiving T-20 and 37% for those not receiving the drug. Additionally, volunteers receiving T-20 had about a 50 CD4+ cell count increase whereas there was no change in CD4+ cell counts for those not receiving the drug.
A small expanded access program for T-20 should open within the next few months for people needing the drug to construct a third line regimen. Watch for announcements about the program and when you hear it, call the Project Inform Hotline to get the details on how to apply.
A second generation fusion inhibitor is now being studied. In laboratory studies T-1249 remains sensitive to virus that have developed resistance to T-20. Preliminary results from a small study shows that the drug does have activity against HIV; however, there were also a large number of mild-to-moderate side effects.
Seventy-two people with an average viral load of about 100,000 copies HIV RNA and CD4+ cell counts of 100 participated in this study. Almost all of the participants had been on previous anti-HIV therapies. Six different doses were studied ranging from 6.25mg once a day to 25mg twice a day all dosed by subcutaneous injection. Volunteers receiving the highest dose had an average 1.3 log (20 times) reduction in viral load after 14 days on the drug. Side effects included injection site reaction (mostly pain or redness in the skin), headaches and dizziness. Two serious side effects were observed, a hypersensitivity reaction to the drug and neutropenia (a reduction in neutrophils, a type of white blood cell used to fight infections).
The study enrolled 420 people with an average viral load of 50,000 copies HIV RNA and CD4+ cell counts of about 350. None of the participants had previously received anti-HIV therapies. All the volunteers received d4T (stavudine, Zerit) + ddI (didanosine, Videx) and either 200mg, 400mg, 500mg of BMS-232632 once a day or 750mg of nelfinavir (Viracept) dosed three times a day. Results were similar for all four groups with 63-68% of the participants achieving viral loads under 400 copies HIV RNA after 24 weeks and about 100 cell increase in CD4+ cell counts. Participants receiving nelfinavir had increases in cholesterol and triglyceride levels whereas those receiving BMS-232632 had no changes in either of these markers. A number of people had to reduce from the 500mg to the 400mg dose primarily because of an increase in bilirubin levels, a measure of liver function. As a result of this, future studies will be using the 400mg once a day dose.
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