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Project Inform - April, 1998
Preliminary results from a small study show no significant difference in antiviral activity between two triple-drug regimens. One hundred people with a mean viral load of about 35,000 copies of HIV RNA and a CD4+ cell count of 400 received either AZT + 3TC + indinavir (Crixivan©) or d4T + 3TC + indinavir. There were no differences in side effects between the two groups. The most commonly reported side effects included increases in bilirubin levels and elevated liver enzymes. After 24 weeks of the study, the results are shown in Table 1.
| Viral load drop | CD4+cell change | % below 500 copies HIV | |
|---|---|---|---|
| AZT + 3TC + IDV | 1.6 logs | +145 | 80% |
| d4T + 3TC + IDV | 1.9 logs | +170 | 85% |
| IDV = indinavir | |||
Another small study also shows no difference in antiviral activity between two triple-drug regimens. One hundred people with a mean viral load of about 30,000 copies of HIV RNA and a CD4+ cell count of about 450 received either AZT + 3TC + IDV or d4T + ddI + IDV. There were no differences in side effects between the two groups. The most commonly reported side effects were nausea and vomiting. After 24 weeks of the study, the results were as shown in Table 2.
| Viral load drop | CD4+cell change | % below 500 copies HIV RNA | |
|---|---|---|---|
| AZT + 3TC + IDV | 1.6 logs | +145 | 75% |
| d4T + ddI + IDV | 1.6 logs | +210 | 70% |
| IDV = indinavir | |||
The first encouraging data on a study involving delavirdine (Rescriptor©) shows that the drug, when used in an appropriate combination, can be quite potent. Three hundred and fifty-two people with CD4+ cell counts of about 350 and a viral load of 25,000 copies of HIV RNA received AZT + 3TC, AZT + delavirdine or AZT + 3TC + delavirdine. Results are similar to those seen with another NNRTI, nevirapine (Viramune©), when used in combination with AZT and ddI. After 32 weeks of the study the results are shown in Table 3.
| Viral load drop | CD4+cell change | % below 400 copies HIV RNA | % below 40 copies HIV RNA | |
|---|---|---|---|---|
| AZT + DLV | 0.5 logs | +25 | 5% | 0 |
| AZT + 3TC | 1.1 logs | +90 | 35% | 15% |
| AZT + 3TC + DLV | 1.5 logs | +130 | 65% | 50% |
| DLV = delavirdine | ||||
Preliminary data suggest that it may be possible to recycle drugs in order to put together a combination regimen. Twelve people who had failed regimens containing all the NARTIs and three protease inhibitors (hard gel (hgc) saquinavir (Invirase©), indinavir and ritonavir (Norvir©)) went on a 6- drug regimen consisting of d4T + 3TC + ddI + nevirapine + nelfinavir + hgc saquinavir. Only nelfinavir and nevirapine were drugs new to the participants and all the others were ‘recycled’. After 12 weeks of the 6-drug regimen, 9 of the 12 participants had viral loads below 400 copies of HIV RNA and most had an increase in CD4+ cells (between 30 and 220 cells). This is a situation where the participants took all the drugs that were available to them and most had good anti-HIV responses, at least for the short-term. However, it is not known whether they could have gotten a similar response if they took fewer drugs. Moreover, it is not known how well people can sustain a 6-drug anti-HIV regimen especially if they also have to take medications to prevent or treat opportunistic infections.
Another study examined the use of ritonavir + hgc saquinavir + 2 NARTIs for people who have failed (increasing HIV RNA levels and decreasing CD4+ cell counts) either hgc saquinavir or ritonavir/indinavir. In this study of 43 people, 13 had failed saquinavir and 30 had failed ritonavir/indinavir. The average viral load at study entry was about 80,000 copies HIV RNA and CD4+ counts for the saquinavir group was 122 cells but only 69 cells for the ritonavir/indinavir group. The results were as shown in Table 4.
| Viral load drop after starting ritonavir + saquinavir + 2 NARTIs | ||||
|---|---|---|---|---|
| Month 1 | Month 3 | Month 6 | Month 9 | |
| Saquinavir failure | 1.48 logs | 1.84 logs | 1.73 logs | 2.08 logs |
| Ritonavir/indinavir failure | 1.06 logs | 0.58 logs | 0.56 logs | 0.00 logs |
People who had previously taken saquinavir experienced a better response from ritonavir + saquinavir + 2 NARTIs compared to people who had previously taken ritonavir/indinavir. This may be due to the fact that they retained some sensitivity to ritonavir while at the same time getting a much higher dose of saquinavir. Whereas people who had been on ritonavir or indinavir are unlikely to get any benefit from ritonavir and only short-term response from saquinavir.
Preliminary results suggest that the antiviral activity of nelfinavir (Viracept©) taken either twice daily or three times daily is similar. Two hundred and forty-one people with an average of about 100,000 copies of HIV RNA received d4T + 3TC and either the approved dose of nelfinavir (750 mg three times a day) or 750 mg, 1000 mg or 1250 mg of nelfinavir all taken twice a day. All participants who received either 750 mg or 1000 mg twice daily subsequently switched to the 1250 mg twice daily dose. Diarrhea and nausea were the most commonly reported side effects although they were not different between the two groups. The results after 32 weeks are shown in Table 5.
| Viral load drop | CD4+cell increases | % below 400 copies HIV RNA | |
|---|---|---|---|
| NFV three times daily | 2.3 logs | 150 | 75 |
| NFV twice daily | 2.2 logs | 170 | 75 |
| NFV = nelfinavir | |||
Similarly, preliminary results show the antiviral activity of indinavir taken either twice daily (BID) or three times daily (TID) are similar. Eighty-seven people with a average CD4+ cell count of about 275, a viral load of about 50,000 copies of HIV RNA and who had not previously taken 3TC or a protease inhibitor received AZT + 3TC + one of three different doses of indinavir: (1) 800 mg TID, (2) 1000 mg BID, or (3) 1200 mg BID. The side effects were similar between the three groups. The most commonly reported side effect was nausea/vomiting. The results after 32 weeks are shown in Table 6.
| Treatment: AZT= + 3TC + | Viral load drop | CD4+cell increases | % below 500 copies HIV RNA | % below 50 copies HIV RNA |
|---|---|---|---|---|
| 800 mg IDV, TID | 1 log | 150 | 50% | 40% |
| 1000 mg IDV, BID | 2 logs | 50 | 70% | 60% |
| 1000 mg IDV, BID | 2 logs | 50 | 70% | 60% |
| IDV = indinavir TID = three times daily BID = twice daily | ||||
Based on the pharmacology of these drugs, there was always some belief that nelfinavir could be effectively used twice daily because of its long half life in the blood. But this was never the case with indinavir, which has a much shorter half life in the blood. Overall, the data from the indinavir study here seems a bit odd, in that all doses and schedules look surprising lackluster compared to other studies using the same drug. It remains to be seen based on longer-term studies with more people if twice a day dosing of indinavir and nelfinavir is truly comparable to three times a day dosing. However, if these longer-term studies truly show that twice a day dosing with the drugs are as good as three times a day dosing, then this will make these drugs far simpler to take and will most likely lead to better adherence.
Commentary
We still have only limited knowledge of how to treat people who have failed a first protease inhibitor regimen, and almost no knowledge of what to do after failing a second protease inhibitor combination. This must be a research priority as more and more people will undoubtedly begin to experience viral rebound while using these therapies. Some new drugs in development such as the fusion inhibitors and zinc finger inhibitors may be beneficial as part of a salvage regimen, however, they are still in very early clinical development and unlikely to be available to most people even if they do ultimately prove to have good anti-HIV activity. A simple way to summarize the current state of antiviral research is that things continue to look better and better for people just beginning therapy, with simpler and better regimens becoming routinely available. The outlook remains uncertain, however, for those who are most in need, the people who have already exhausted the current list of therapies.
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