Anti-HIV Drug Update
There continues to be progress in the development of a number of new anti-HIV drugs. Additional research has focused on optimizing the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). This has resulted in studies of dual protease inhibitor combinations, protease inhibitor and NNRTI combinations and now dual NNRTI combinations.
Protease InhibitorsA study at Stanford looked at the effectiveness of adding ritonavir (Norvir) to an existing three-drug regimen including indinavir (Crixivan) for people who have detectable HIV levels. The purpose of this study was to determine if higher levels of indinavir in blood would result in greater anti-HIV activity. Previous studies have shown that ritonavir substantially increases and stabilizes indinavir levels in blood.
Thirty-five volunteers with a viral load of about 1,200 copies HIV RNA and CD4+ cell counts averaging around 420 participated. The dose of ritonavir and indinavir used was 400mg twice a day for each drug. For the first three weeks of the study, volunteers did not change their anti-HIV regimens but added ritonavir. After three weeks, people were allowed to change their nucleoside analogue drugs.
The addition of ritonavir increased the overall anti-HIV activity of the regimen with 48% of the volunteers reaching viral loads under 400 copies HIV RNA (up from 26%) and 28% under 50 copies HIV RNA (up from 0%) after three weeks. After sixteen weeks, 59% of the volunteers had HIV levels below 400 copies and 53% were below 50 copies. These preliminary short-term results suggest that this type of intensification strategy can further decrease viral levels in people with low but detectable virus.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Preliminary results from a study with capravirine (formerly known as AG1549, from Agouron Pharmaceuticals) show that the drug is quite potent. Laboratory studies suggest that this drug may be effective against NNRTI-resistant virus. Volunteers in this small ten-day study received varying dose levels of 700mg twice a day, 700mg three times a day, 1,400mg twice a day, 1,400mg three times a day or 2,100mg twice a day of capravirine.
HIV levels were reduced by 1.23 logs (17 times) on the lowest dose to 1.65 logs (45 times) on the highest dose. There was no real difference in anti-HIV activity between the twice and three-times daily dosing schedules. The most common side effects were headache, nausea and vomiting, which were all considered mild to moderate in severity.
One small study looked at the effect of combining two NNRTIs in people with increasing HIV levels while on protease inhibitors. Volunteers were started on 500mg twice a day of emivirine (Coactinon, an experimental NNRTI from Triangle Pharmaceuticals) for eight days and then the dose was increased to 750mg twice daily and 600mg once a day of efavirenz (Sustiva) was added to the regimen. There was a greater than expected interaction between the two drugs which apparently reduced the effectiveness of efavirenz. The doses were changed to 500mg of emivirine twice a day and 800mg of efavirenz once a day.
Volunteers experienced moderate-to-severe side effects including rash, nausea, decreased appetite and diarrhea. Preliminary results show that people who had the highest emivirine and efavirenz levels in blood had the greatest anti-HIV responses; however, they were also most likely to develop side effects.
This study shows that there is a big potential for drug interactions when combining NNRTIs as well as an increased risk for side effects. So far, though, there is no clear evidence of any gain in effectiveness. People should be carefully monitored if they are considering such combinations.
Once Daily Dosing?Preliminary results of a once-a-day regimen shows promising anti-HIV activity. This study followed forty people with a viral load of about 60,000 copies HIV RNA and CD4+ cell counts averaging around 400 who were taking anti-HIV therapies for the first time. Volunteers received the experimental NRTI emtricitabine (FTC, Coviracil, an experimental nucleoside analogue from Triangle Pharmaceuticals), ddI (didanosine, Videx) and efavirenz, all given once a day at bedtime.
After 24 weeks, 98% of the volunteers had HIV RNA levels below 400 copies and 93% were below 20 copies. The most common side effects were central nervous symptoms (dizziness, sleep disturbances, depression and headaches), diarrhea and rash, almost all of which were considered mild-to-moderate in severity.
CommentaryIt is becoming more likely that people starting anti-HIV therapy for the first time will be able to use a potent once daily regimen. However, there is still no standard-of-care for what to do after a first or second regimen fails. As a result many approaches are being studied and sometimes combined. These include structured treatment interruptions, resistance test utilization to select anti-HIV therapies and mega-HAART (using five to nine anti-HIV drugs).
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