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Antivirals Update

December, 1998

Several new anti-HIV drugs are likely to be available in the near future. The Glaxo Wellcome drug abacavir (Ziagen®) will reach the pharmacies by the end of 1998 or early 1999. Glaxo has also requested approval for its new protease inhibitor amprenavir (Agenerase®) and there is every reason to expect it to become available by early 1999.

Although these therapies do not represent major advances beyond currently available therapies for treatment-experienced patients, they will be a welcome addition as they give people more therapeutic options and offer simplified dosing regimens. Several new anti-HIV drugs are likely to be available in the near future. These include abacavir (Ziagen®) which is likely to be available in pharmacies by the end of 1998 or early 1999 and amprenavir (Agenerase®) which is likely to be available in early 1999. Although these therapies may not offer a major advance in comparison to the currently available therapies, they will be a welcome addition as they will give people more therapeutic options and will offer simplified dosing regimens. The greatest benefit from these therapies will come for people who are just beginning treatment. Both drugs' potency can be diminished or eliminated altogether when patients have developed resistance to other similar drugs. Cross-resistance, however, is not absolute but rather it depends on how many and which drugs of the same type the patient has previously developed resistance to. More encouraging and perhaps more relevant information has been reported recently from a study of nevirapine (Viramune®), which raises the level of enthusiasm over the potency of this drug in a protease-inhibitor sparing regimen. The following article provides an overview of these and other new findings in research on anti-HIV drug therapy regimens.


Amprenavir

Results from the first large study of the protease inhibitor amprenavir (Agenerase®) shows that the drug has potent anti-HIV activity. Three hundred and thirty-two people with an average CD4+ cell count of about 400 and an average viral load of about 45,000 copies HIV RNA participated in the study. None of the participants have received previous anti-HIV therapy. Participants received AZT (zidovudine, Retrovir®) + 3TC (lamivudine, Epivir®) or AZT + 3TC + amprenavir. The dose of amprenavir was 1200mg twice a day (total daily dose of 2400mg). The results after 16 weeks of the study, using the most conservative analysis, show that about 60% of people on the 3-drug combination had HIV RNA levels below 400 copies compared to only 17% of people receiving AZT + 3TC. People with high HIV RNA levels (more than 100,000 copies) had similar anti-HIV responses compared to people with lower viral loads. These results are similar to those seen in short-term studies with other protease inhibitors and it remains to be seen how durable the anti-HIV response will be with amprenavir. There is, however, no particular reason to suspect that it will be any less durable than other drugs of this type. The most common side effects among people receiving amprenavir included rash, nausea, vomiting and oral paresthesia (a numbing around the mouth).

One of the major concerns with this study was that people risked receiving AZT + 3TC, which is, and was when this study was started, considered suboptimal therapy for people with HIV. Despite the best efforts by community advocates to change the study design so that everybody would receive optimal therapy, Glaxo Wellcome, the developers of amprenavir, refused, citing the fact that more conservative countries, like the United Kingdom, the sponsor's home county, still recommend the use of two-drug therapy. Glaxo Wellcome recently submitted results of this and other studies to the Food and Drug Administration (FDA) in order to receive approval for amprenavir, which is expected in the spring of 1999.

Small studies of amprenavir in complex multi-drug "salvage therapy" regimens have not been encouraging but there remains some hope that the drug may still be active in at least some people who have developed resistance to other protease inhibitors. Amprenavir has a somewhat, but not completely, different pattern of drug resistance than other protease inhibitors. Thus, some people who have failed one or more protease inhibitors still demonstrate sensitivity to the drug on typical tests used to determine drug resistance. Whether and how often this will result in good effectiveness in such cases remains to be seen.


Nevirapine and Delavirdine

With all the hype and promotion over efavirenz (Sustiva®), the HIV-interested public has been fed the impression that this drug is demonstrably more potent than other drugs of its type. The simple fact is that there little or no evidence to support this view. The drugs have not been directly compared, nor have then been tested in sufficiently similar studies to make a fair comparison. In the midst of the "big spin" campaign on behalf of efavirenz, the new information on the other non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine (Viramune®) and delavirdine (Rescriptor®), have been overlooked and overshadowed. However, results from a recent French study of nevirapine were very encouraging and suggest that the drug should be considered when deciding on a protease-sparing regimen. Sixty people with an average CD4+ cell count of about 400 and a viral load of about 40,000 copies HIV RNA participated in the study. None of the participants have received previous anti-HIV therapy. All of the participants received ddI (didanosine, Videx®) + d4T (stavudine, Zerit®) + nevirapine, all of which were dosed twice a day. Of the 48 people who remained in the study after 6 months, 88% had HIV RNA levels below 400 copies and 64% had HIV RNA levels below 50 copies. There was an average CD4+ increase of 162 cells. An additional 40 people are now participating in this study, however they are receiving nevirapine and ddI only once a day while still taking d4T twice a day. No data are available on the anti-HIV activity for this revised regimen as of yet.

Similarly, a study of delavirdine (Rescriptor®) in 369 people compared two different two-drug regimens (delavirdine plus AZT and AZT plus 3TC) to a three drug regimen of delavirdine plus AZT plus 3TC. As expected, the three-drug regimen was superior to either two-drug regimen at all data points. Perhaps most importantly, the three-drug regimen with delavirdine (122 people) showed excellent and durable results in suppressing viral load below the limit of detection on both standard and the most sensitive PCR test (less than 400 and less than 40 copies of HIV RNA). Although study results are not yet complete, at the most recent report, roughly 70% of those who had reached the 52 week endpoint (29 people) remained undetectable on standard viral load tests, while approximately 60% were undetectable on the super sensitive assays. It remains somewhat difficult to compare these results to studies of efavirenz. For example, the delavirdine study included people with prior histories of AZT use while the efavirenz study was limited to people beginning therapy for the first time. Yet there is nothing in the data so far that even hints that delavirdine is any less successful or potent than efavirenz when used in combination with AZT and 3TC.

The need for studies that directly compare efavirenz, delavirdine, and nevirapine has been underscored by the skillful promotional campaign that has already characterized efavirenz as the superior drug. The need is further heightened by the fact that, based on this so far unproven assertion, efavirenz has been priced dramatically higher than the other two drugs.


Protease Inhibitor Studies

Although longer-term results from a recent study shows that twice daily dosing of indinavir (Crixivan®) was not as effective in keeping viral load fully suppressed as indinavir taken three times a day (see Indinavir Box ), other twice daily dosing studies with protease inhibitors are continuing. Preliminary results from a study comparing saquinavir (Fortovase®) dosed twice versus three times a day in combination with 2 nucleoside analogue drugs (AZT, d4T, 3TC etc.) versus a combination of saquinavir + nelfinavir (Viracept®) + one nucleoside analogue drug (all dosed twice a day) shows that there are no differences in viral load or CD4+ cell count responses between the three groups after 24 weeks. Side effects were also comparable between the three groups with the exception of more diarrhea among people receiving the dual protease inhibitor containing regimen.

Another twice versus three times daily dosing study of nelfinavir shows that there are no differences in viral load or CD4+ cell levels between the two groups based on preliminary results. People received nelfinavir at 750mg three times a day or 1250mg twice a day in combination with d4T and 3TC. Approximately 65% of the participants had HIV RNA levels below 400 copies and 55% had HIV levels below 50 copies. There were also no differences in side effects between the two groups although there were slightly more cases of diarrhea among people receiving the twice daily dose of nelfinavir.

Nevertheless, the recent experience with indinavir suggest that people should cautiously consider the wisdom of switching to a twice a day dosing regimen for a drug that is approved for three times a day dosing.

Several other new protease inhibitors are at various stages of development, but none are likely to be widely available any time soon. Abbott Labs' new drug, ABT-378, has shown promise initial trials but is a long way from FDA approval. New protease inhibitors from Pharmacia &Upjohn and Bristol-Myers Squibb both show initial promise and some hope of activity in people with prior resistance to other protease inhibitors, but it is far too early to make any claims.


Salvage Therapy Studies

Salvage therapy refers to regimens that are used or being studied for people who have failed one or more protease inhibitor-containing regimens. This generally means that their treatment regimen was no longer able to suppress HIV replication to levels below the limits of detection with the viral load tests.

An interesting study conducted in Vancouver, Canada shows that the use of up to 9-drug regimens may be of benefit to people with extensive previous anti-HIV therapy experience. Eighty-three people have now been treated with a combination of up to 9 anti-HIV drugs including two NNRTIs, two protease inhibitors, 3-4 nucleoside analogue drugs plus hydroxyurea (Hydrea®). All of the drugs were dosed twice daily. The participants had an average viral load of about 50,000 copies HIV RNA, a CD4+ cell count of about 200 and had previously received, on average, 7 different anti-HIV drugs (although about half of the participants had not previously received a NNRTI). This study is still ongoing but preliminary results show that about 40% of the participants achieved viral loads below 400 copies HIV RNA after the first month of the study but by the fifth month the number was down to about 25%. As would be expected with such an intensive regimen, about 17% of participants discontinued from the study and about 16% had severe side effects, the most common being elevated liver enzyme levels. Additionally, about 34% of the participants had to have their regimens modified because of side effects. People who were most likely to benefit from this regimen were those who had been on fewer numbers of previous anti-HIV therapies and those with lower viral load levels at the start of the study.

These study results are interesting because although the participants had been on many previous anti-HIV therapies about 40% still had a very good initial anti-HIV response. One possible explanation for this is that it is unlikely for a single virus in the body to be resistant to all of the drugs, but it might be resistant to a few of them. Therefore, by using an aggressive multi-drug approach, the chances increase that a given individual virus will be suppressed by at least one or more of the drugs used in the multi-drug regimen. The trade off for the kind of approach, however, is the short- and long-term side effects of using so many drugs as well as the possible difficulty of taking so many drugs on a daily basis.

In another study primarily focused on "salvage," T-20 (pentafuside), a drug in the new class called fusion inhibitors, has demonstrated strong antiviral activity in people who had failed on prior protease inhibitor regimens. To date, the primary side effect of the drug is pain and swelling at the injection site (T-20 must be infused either intravenously or subcutaneously). Nonetheless, this drug appears to offer genuine promise in the salvage setting. Widescale use of the drug, however, remains at least a year or more away.


Commentary

Other than the few listed here, there is a dearth of new drugs in the pipeline. In fact, some companies have scaled back or stopped their HIV drug discovery programs and with the consolidation in the pharmaceutical industry there are fewer and fewer players. The most substantial and longest-lasting benefit for people who have few or no remaining anti-HIV treatment options will probably only come from drugs which block HIV replication in different ways than those currently available. There needs to be a concerted effort on the part of researchers in academia, the pharmaceutical companies and the government to discover and rapidly develop new drugs for people in this scenario. Recognizing the weakness of the current drug pipeline, the National Institutes of Allergy and Infectious Diseases has created new funding programs to encourage the development of new types of drugs. While this is helpful, it will at best produce results several years from now.

Taken together, these facts underline the importance of patients making the wisest possible use of the therapies which are already available. This begins with careful decisions about when to begin therapy in the first place. It calls for careful thought about the initial choice of therapy and the opportunity to make such decisions as independently as possible from the promotional interests of pharmaceutical sponsors. While the concept of such possible advances as protease-sparing regimens and simple dosing sound attractive, the hard fact is that there isn't a single shred of evidence that such strategies will result in longer life, nor any evidence that they won't result in shorter life. A great deal remains to be learned about the optimal way to use the available list of therapy. Each therapy decision, no matter which drugs are chosen, affects future options for each individual. For now, the best proven and most durable therapy option remains the use of 3 drug regimens that include a protease inhibitor. The best way to use those drugs remains the way they were approved for use by the FDA.

Hope remains that at least some new drugs may remain active despite prior drug resistance in at last some patients. People should not give up without trying new therapies simply based on a theoretical assumption of resistance and cross-resistance. Individual responses can always be different from the "average" experience, which is all that clinical trials report on. The more wisely each new drug is used, the more likely it will add to a patient's overall length of life. With so many drugs now available, the number of choice is very wide. It may or may not yet prove possible to "retire" some drugs long enough to restore their activity after developing resistance. Perhaps the greatest hope of all remains in the increasing amount of data that shows that maintaining an undetectable viral load, while helpful, may not be necessary for long-term clinical success. A great number of people who have "failed" therapy in the current definition of "failure" do not experience rapid rates of decline and illness following treatment  failure. On the contrary, there is little evidence that they do any worse, clinically, than those for whom therapy continues to work. The treatment of HIV disease remains a complex and far from fully understood subject that cannot be reduced to simple formulas based on lab tests. Life and quality of life do not depend solely upon the success of drugs or even a constant stream of new drugs. Treatment strategy, nutrition, belief in a future and a productive lifestyle all remain potent weapons in the fight against AIDS. Life does not depend solely on what the government or the pharmaceutical industry may or may not do.


Indinavir (Crixivan®) Twice a Day?

New information from a study of indinavir (Crixivan®) has shown that a twice daily dosing regimen is not as effective as the three times daily schedule in maintaining viral suppression. As a result, Merck, the manufacturer, is stopping the part of the study which uses twice daily dosing and has notified community groups, information providers and physicians of the new findings. Based on these findings, Merck is encouraging everyone using twice daily dosing to switch back to three times daily dosing schedules. The new findings are contrary to a previous, smaller study which suggested that twice daily dosing was at least equivalent to the standard three times daily dosing.

Percent of People With Viral Load Below the Limit of Detection
Study group at 16 weeks (287 patients) at 24 weeks (87 patients)
3 times daily 78% 91%
2 times daily 72% 64%

The study included people who had never previously taken a protease inhibitor, or 3TC (lamivudine, Epivir®) and the regimens used included twice or three times daily dosing of AZT (zidovudine, Retrovir®), 3TC and indinavir. After 24 weeks of study, 91% of those receiving three times daily dosing had reached or maintained HIV levels below the limit of detection, whereas only 64% on the twice daily regimen had experienced the same level of viral suppression. What's most important is that after only 16 weeks, the twice daily dosing schedule appeared equivalent. By 6 months, however, the superiority of three times daily dosing became very apparent.

Another regimen under study which might still permit twice daily indinavir dosing is the protease inhibitor combination of ritonavir (Norvir®) and indinavir (Crixivan®). Preliminary, short-term studies of this regimen appear to show indinavir quite suitable for twice daily dosing, while also eliminating the requirement that the drug not be taken with food. However, it's important to recognize this is based on early data, covering a short period in two small clinical trials. Another study using twice daily indinavir dosing is in combination with nelfinavir (Viracept®).

Caution about Regimen Changes

It's possible that more people than ever are currently using the indinavir twice-daily dosing regimen as news from the smaller study preceded the announcement of a shortage in supply of another protease inhibitor, ritonavir (Norvir®) capsules. When the supply problem was announced, some people may have begun rethinking their anti-HIV regimens and may have made regimen changes, possibly to an easier-to-use regimen using indinavir twice daily dosing.

The lesson learned here is something that Project Inform has been cautioning about for some time with regard to simpler and easier regimens using current available therapies. When these drugs were approved, the reason they were dosed according to schedules in their label instructions (e.g. three times daily) is because studies demonstrated these schedules were necessary to maintain optimal blood levels of drugs. While certainly people want, need and deserve simpler regimens, simply changing a regimen from three times to twice daily dosing is not the solution.


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