Important note: Information in this article was accurate in April 2000. The state of the art may have changed since the publication date.
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Project Inform Perspectives 29 - April, 2000
Slow but steady progress continues on a number of new anti-HIV drugs in the three drug classes. If approved, some of these represent true second-generation therapies that will offer some degree of advance over current drugs. Others are not that much different from today's drugs. The article below combines information from the most recently announced studies, including those presented at the 7th Conference on Retroviruses and Opportunistic Infections.
One combination getting wide attention lately is ritonavir + indinavir. Ritonavir greatly stabilizes indinavir blood levels and, as a result, both can be taken two instead of three times a day, while using less indinavir overall. Perhaps more importantly, this combination eliminates the food restrictions that otherwise make indinavir difficult for some people. In theory because higher sustained drug levels are achieved, the combination may also make it more difficult for HIV to develop resistance to either or both drugs. The lower total daily doses of indinavir may also decrease the risk of kidney side effects associated with indinavir. However, this point is not yet proven.
Results from a recent study show that this is indeed a potent combination. Ninety-two people with CD4+ cell counts around 200 and viral load around 220,000 copies HIV RNA participated. None had been on anti-HIV therapy before. Volunteers received ritonavir + indinavir (both 400mg twice a day) plus any two nucleoside analogue drugs. Most took either AZT + 3TC or d4T + 3TC.
After one year, 67% had less than 500 copies HIV RNA, and 64% had less than 80 copies. Participants also had about a 200 CD4+ cell increase.
One potential confounder in this study was that midway, people switched from ritonavir capsules to the liquid formula due to manufacturing problems. The most common side effects were nausea, diarrhea and numbing around the mouth (oral parasthesia). People also had increases in their triglyceride and cholesterol levels.
Other studies of this combination experiment with different doses of ritonavir and indinavir. Some have used as little as 100mg ritonavir along with up to 800 or 1,200mg indinavir twice daily. Researchers, and especially the manufacturer of ritonavir, Abbott Laboratories, debate about ritonavir's proper dose. Abbott and some researchers prefer to use 400mg ritonavir daily, arguing that this higher dose allows it to contribute its own anti-HIV activity. At lower daily doses, typically 100 or 200mg daily, there is probably little or no anti-HIV activity from ritonavir. The drug instead serves only to boost the potency of indinavir. Those who favor the lower doses cite concerns about ritonavir's toxicity, which can be troubling even at the 400mg dose. One interesting point to note is when Abbott combines ritonavir with its own new drug, lopinavir (ABT-378), it uses only 100mg of ritonavir.
The new protease inhibitor from Abbott Laboratories, lopinavir (formally known as ABT-378), continues to look extremely promising. In a study using the drug as part of a three-drug combination in people who had not taken anti-HIV therapy before (see PI Perspective # 27), about 80% continue to have viral loads below 50 copies HIV RNA after 72 weeks. Similarly, among people who failed a single protease inhibitor regimen but had not used a non-nucleoside reverse transcriptase inhibitor (see PI Perspective # 28), 70% of the participants had viral loads below 400 copies after 48 weeks. Although this is still early data and not a direct comparison, the response rate for people failing a previous protease inhibitor seems to be better than any previously seen.
Early results from a study of people who failed numerous protease inhibitors also show good activity. Volunteers took lopinavir + efavirenz (Sustiva) + nucleoside analogue drugs. After twelve weeks, about 70% had viral loads below 400 copies HIV RNA. The main limitation of this data, however, is that people had to be using NNRTIs for the first time, even though they had considerable prior experience with protease inhibitors. It is thus unclear how much of the benefit is due to the lopinavir and how much is due to efavirenz.
Lopinavir is currently distribruted free under a broad expanded access program. The drug is available to any individual who needs it to construct a viable anti-HIV treatment regimen.
Early results from several studies suggest that simpler dosing of anti-HIV drugs may be possible. New formulas of existing drugs will eventually lead to easier to take regimens, such as the use of ritonavir to boost the activity of other protease inhibitors.
Early results from a small study of ritonavir (RTV) and indinavir (IDV) suggest that it may be possible to take this combination only once a day. Three different doses were studied: 1) 800mg IDV + 100mg RTV, 2) 800mg IDV + 200mg RTV, and 3) 1,200mg IDV + 100mg RTV. Indinavir blood levels achieved 24 hours after taking dose #2 or #3 were similar to the levels seen with the standard 800mg dose taken three times daily. Planned studies will look at this dosing scheme to determine if it's as effective as the standard dose.
Another once-a-day regimen being studied is 100mg ritonavir + 1,600mg saquinavir (Fortovase). Saquinavir blood levels 24 hours after taking both drugs were higher than those with the standard 1,200mg three times daily dose. It's still early to suggest that these regimens are as effective as the standard ones.
A small Italian study suggests that it is possible to put together a potent once-a-day regimen. Volunteers who were reluctant to start one of the standard two or three times daily dosing regimens because of adherence problems received 300mg ddI + 300mg 3TC + 600mg efavirenz, all dosed once a day.
All participants had either never taken anti-HIV therapy or had been minimally treated. About a quarter of them were under observed therapy through a methadone clinic. The average viral load at study entry was about 90,000 copies HIV RNA and CD4+ cell counts were about 275.
After four months, about 60% had viral load levels below 400 copies HIV RNA (about 50% below 50) and had a mean increase of over 125 CD4+ cells. How this outcome compares to other possible dosing regimens is unclear. One observation was that people on methadone had to increase their dose presumably because efavirenz lowers methadone levels.
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