Project Inform - March, 1997

VL=Viral Load
LD=Limit of detection, 500 copies HIV RNA
Represents all HIV RNA levels at entry

Comparing the 500 and 750 mg nelfinavir groups shows that people who entered the study with HIV RNA levels greater than 100,000 fared better on the higher dose. Of the people with viral levels above 100,000 HIV RNA copies, 80% receiving the combination with the higher nelfinavir dose saw reductions in viral levels below the limit of detection, compared to 45% receiving the triple combination with the lower nelfinavir dose and 5% of people receiving the AZT + 3TC combination. Nelfinavir was generally well tolerated. The major side effect reported was diarrhea, affecting 12% of people on the lower dose and 19% of people on the higher dose.

Nelfinavir in Children

Preliminary results were reported from a study looking for the appropriate dose of nelfinavir in children. This study found that a 20-30 mg/kg dose, taken three times daily, produced roughly the same nelfinavir blood levels in children as 500-750 mg three times daily in adults. Some very preliminary results show that the children respond well to nelfinavir, with about a 2 log reduction in viral load after 4 weeks of nelfinavir as a single agent therapy. Adult studies show over 50% of people develop resistance when a protease inhibitor is used alone, so this is probably not a wise use of the drug. The sponsor of the drug, Agouron Pharmaceuticals, should be commended for initiating pediatric trials early in the development of this drug and for making the drug available to children on an expanded access basis. In this regard, Agouron has clearly raised the standard above the behavior of other companies developing protease inhibitors and AIDS drugs in general.

Long-Term Strategies

A key question facing physicians and their patients is just when, where and how to use nelfinavir in the overall mix of antiviral therapies. Unfortunately, the limited number of clinical trials with this drug presently makes it almost impossible to answer this question precisely. Nelfinavir has a somewhat different resistance pattern than other protease inhibitors and may be less toxic in some ways. Although its most common side effect, diarrhea, occurs in a relatively high percentage of users (from 15 to 26% in studies), the severity of the side effect is generally modest. This observation, however, must be tempered by the fact that the drug has still only been tested in a relatively small number of people for a modest period of time. As the resistance pattern for nelfinavir seems different from the other protease inhibitors and this might make it possible to switch to ritonavir or indinavir successfully even after acquiring resistance to nelfinavir. Resistance to nelfinavir does not appear to convey automatic cross-resistance to the other drugs. Together, these two properties of moderate side effects and a different pattern of resistance might make nelfinavir a good choice as part of a first-line combination therapy. For now, this is only a theoretical advantage as it has not been tested to any significant degree in a clinical trial.

One possible conflicting characteristic, however, is that nelfinavir might not be as potent as indinavir or ritonavir, at least at the currently recommended doses. Many researchers believe that the most potent drugs should be used first and that nelfinavir would be used as backup if the other drugs cannot be tolerated or fail. But the drugs' possible lack of cross resistance only works one way – when nelfinavir is used first. The most common mutations which lead to high level resistance to the other protease inhibitors are likely to cripple nelfinavir as well. Thus, physicians may have to weigh the possible advantages of a favorable pattern of resistance and toxicity against the disadvantages of a possibly lower dose. Even this point is not clear, however. While the drug is decidedly more potent than the standard version of saquinavir, it may only be slightly less potent than ritonavir and indinavir. The question is – how potent is potent enough? A series of clinical trials comparing nelfinavir to and combining the drug with indinavir and ritonavir are currently in the planning stages and these trials should help answer these questions.

One other advantage of nelfinavir is that it can be taken with food, so it may be easier to use.

Agouron Pharmaceuticals, the developer of nelfinavir, has filed for FDA approval of nelfinavir for children and adults. This is the first time that a developer of an HIV protease inhibitor has sought simultaneous approval for both children and adults and we applaud Agouron for this effort. However, for the first time with any HIV drug, nelfinavir will not be reviewed by the Antiviral Drugs Advisory Committee (ADAC) of the FDA or at one of the committee's public hearings. The FDA believes they have enough data to approve the drug without the input from outside advisers or the public. Project Inform, along with other advocacy groups, feels this is unwise. It sets a bad precedence as the ADAC usually gives useful advice to the FDA, and HIV-affected groups provide an important community perspective during public testimony. Additionally, the hearings provide a useful forum for other companies developing therapies to get a feel of where the FDA and the ADAC is heading. Nelfinavir and should be available in drug stores shortly.

In conclusion, these data help to put nelfinavir into the picture of treatment options. The best dose for adults seems to be 750 mg, 3x daily. The incidence of diarrhea was only slightly higher among those receiving this higher dose and the better potency may be a reasonable tradeoff. We really do not know if this is the optimum dose because so little research has been done on higher doses; a 1000 mg dose might bridge the potency gap. Also, lack of data for long term use makes us wonder if the current doses might lead to resistance. The dose of nelfinavir in children equivalent to the adult dose seems to be 20-30 mg/kg 3x daily.

Nelfinavir is easier to take than either indinavir and ritonavir. Unlike indinavir there are no food restrictions to struggle with, and unlike ritonavir, the drug does not need to be refrigerated and does not have the drug interaction problem associated with ritonavir.

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The original of this article can be found at http://www.projinf.org/pub/21/Nelfinavir.html