One new drug under study is Abbott Laboratories' new protease inhibitor (PI), ABT-378. Preliminary results show ABT-378 is very potent and well tolerated, at least as first line therapy. In the main study reported so far, 101 people who had never received prior anti-HIV therapies participated. They were given a combination of ABT-378 and a small amount of ritonavir (Norvir®). ABT-378 will always be combined with some dose of ritonavir because ritonavir helps keep high amounts of ABT-378 active in the body for longer periods.
Volunteers began the study with an average viral load of about 70,000 copies HIV RNA and an average CD4+ cell count of about 350. Three different doses of ABT-378/ritonavir (Norvir®) were used (200/100mg, 400/100mg and 400/200mg), all of which were taken twice a day in combination with d4T (stavudine, Zerit®) + 3TC (lamivudine, Epivir®).
After 24 weeks, the drug combination suppressed viral load to less than 400 HIV RNA copies in about 85% of the participants. The ultrasensitive viral load test was performed in a smaller group of participants; and among that group, 89% had less than 50 copies HIV RNA. No one has dropped out of the study because of side effects. Most side effects noted to date have been mild to moderate in severity, with abnormal stools (less than three loose stools per day) and diarrhea (more than three loose stools per day) being the most commonly reported.
Abbott had high hopes for ABT-378, thinking it would be effective for people who have experienced renewed viral activity or breakthroughs despite using numerous protease inhibitors. More recently, they have become more realistic about how this drug will fare in the multi-protease resistant population. However, Abbott is starting new studies, including some for people who developed resistance to a single protease inhibitor.
Planned studies will test the drug in people who are resistant to several available protease inhibitors but who have not yet taken a non-nucleoside reverse transcriptase inhibitor. A committee of activists is working with Abbott to propose other study designs for third line use. Together, these studies will help determine where and how to best use the ABT-378/ritonavir combination. For now, it looks like the best-proven use will be as first line therapy.
The ATLANTIC study compared two class-sparing regimens (one of which spared both the PI class and the non-nucleoside class of drugs) to a standard PI-containing regimen. The two studies enrolled 298 participants each. Volunteers had an average viral load of 16,000 copies HIV RNA, CD4+ cell count of 418 and had not previously been on anti-HIV therapy. People receive d4T + ddI (didanosine, Videx®) + 3TC, d4T + ddI + nevirapine (Viramune®) or d4T + ddI + indinavir (Crixivan®). After 24 weeks the results, in terms of viral suppression, were as follows:
|ATLANTIC Study Results|
|Treatment Regimen||Percent <500 copies HIV RNA||Percent <50 copies HIV RNA|
These results suggest that a number of possible three-drug combinations are likely to be effective in suppressing HIV levels at least for the first 24 weeks of use. There does not appear to be a great difference whether the combination is anchored by a PI, a NNRTI [e.g. nevirapine, delavirdine (Rescriptor®) or efavirenz (Sustiva®)] or even simply a highly potent nucleoside analogue, like abacavir. It doesn't tell us, however, which strategy or combinations will last longest or prove easiest to use and tolerate over the long haul.
Another study looking at a PI-sparing regimen compared AZT (zidovudine, Retrovir®) + 3TC + abacavir (Ziagen®) to AZT + 3TC + indinavir. Five hundred and sixty-two participants in the study had an average viral load of about 65,000 copies HIV RNA, CD4+ count of 360 cells and had not previously received anti-HIV therapies.
About 65% of the participants in both groups achieved HIV RNA levels below 400 copies after 24 weeks of the study. Approximately 45% of the participants had HIV RNA levels below 50 copies based on the ultrasen-sitive viral load tests after 16 weeks of the study. People with high HIV levels (over 100,000 copies HIV RNA) at study entry seemed to respond just as well as people who started with lower HIV levels. A similar percentage in each group achieved HIV levels below 400 copies HIV RNA.
It is disturbing, however, that about a third of the participants in both groups discontinued their treatment regimens. About half of those who discontinued treatment did so because of side effects, the most common of which were nausea, fever (only among people receiving abacavir), vomiting, fatigue and skin rashes. There were 13 cases of abacavir-related hypersensitivity (5% of the group receiving abacavir) including one death reported as a result of restarting abacavir after the hypersensitivity reaction. One interesting observation showed that people receiving the indinavir regimen had significant increases in cholesterol levels compared to their pre-study levels, whereas the group receiving abacavir had no significant changes in cholesterol levels.
Another study looking at a PI-sparing regimen enrolled 152 people who had not previously received anti-HIV therapies and who had a mean viral load of approximately 200,000 copies HIV RNA and a CD4+ cell count of 200. Participants received AZT + 3TC or AZT + 3TC + delavirdine (Rescriptor®). The percentages of people who achieved suppression of viral load below the limit of detection after 24 weeks follows:
|PI-Sparing Regimen Study Results|
|Treatment Regimen||Percent <400 copies HIV RNA||Percent <40 copies HIV RNA|
These results are reasonably good given that the viral load at study entry was so high. People who entered the study with either high or low HIV levels (above or below 100,000 copies HIV RNA) were equally likely to achieve viral levels below 400 copies HIV RNA. However, far fewer people who started with higher HIV levels were able to get their HIV levels below 40 copies HIV RNA compared to people who started with lower HIV levels.
Approximately 15% of the people receiving delavirdine discontinued their regimen because of side effects. The most commonly reported side effect was rash (reported in 23% of those receiving delavirdine), but only three people (4%) had to discontinue delavirdine because of this side effect. Results from this study suggest that a combination of AZT + 3TC + delavirdine may be another reasonable "PI-sparing" option for people choosing a first line regimen.
A person may get a potent and long-lasting response from his/her first line therapy but may not be able to put together a potent second line regimen (due to cross-resistance to the other drugs or because the first line regimen used up too many treatment options). As a result, HIV levels might soon increase after starting this second regimen. Another person may have a reasonably long lasting response to both his/her first and second line therapies and end up with an overall longer-lasting response.
Many researchers believe that the first treatment regimen is the most important. Similarly, many researchers believe that it is important to drive HIV levels down as far as possible, preferably below 40 copies of HIV RNA (using the ultrasensitive viral load tests). Several studies suggests this result in a longer lasting response to therapy that people who are not able to attain this kind of viral suppression.
While all recent data are encouraging and suggest that people who have not previously received anti-HIV medications have numerous treatment options, there are little data to help determine which options may be most beneficial over the long-term. The fact remains we only have information on people who have been on these regimens for a relatively short period of time. Only results from long-term treatment strategy studies -- finally just starting -- will enable us to know if people should start with a regimen that contains a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or neither. For a thorough discussion of the advantages and disadvantages of class-sparing drugs, see "Class-Sparing Treatment Therapies" in this issue.
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