The Medical Merry-go-round:
Drugs for 1998 are New but not Novel

Four new anti-HIV drugs will probably reach the U.S. market in the coming year, making a grand total of 15 such agents. At first glance, the new agents represent distinct improvements over existing drugs and should result in greater treatment options and more flexible therapeutic strategies. The big drawback is that there will continue to be three classes of drugs that target just two viral enzymes (protease and reverse transcriptase). The limited number of therapeutic approaches means that the ever-mutating HIV can escape the drugs by developing broad cross-resistance against the members of each class. And the similar nature of the new and old drugs also makes for overlapping side effects, making it hard to construct tolerable combination regimens for individual patients. The resistance and side effect are interrelated in that drug interruptions or dose reductions due to side effects result in intermittent HIV suppression, which encourages the development of resistance.

At the same time, the amount of information available for each marketed drug continues to shrink as the FDA, in an effort to speed the drug approval process, has eased its requirements for anti-HIV drugs. As of last fall, all that is needed to prove efficacy for accelerated approval are data showing drug-induced HIV viral load reductions for four to six months. For the standard, permanent approval a company has to show significant HIV suppression for a year. The details of the new standards are still being worked out on a case-by-case basis, but gone is any strict demand that drug developers prove that new agents extend patients' survival or disease-free time.

The relationship between viral load alterations and overall delay in disease progression was supported by the FDA's Antiviral Drugs Advisory Committee in a meeting last July. The Committee retrospectively reviewed this relationship in a series of previous drug trials before reaching its recommendation. But that relationship has not always been borne out historically (albeit when antiviral regimens were less able to suppress HIV). Just a few years ago, for example, the Concorde and other studies found that AZT monotherapy when administered in early disease does not extend survival in the long-run, and may in fact slightly shorten it. Along the way, the side effects early use of AZT causes can equal the amount of disease it prevents (see R.D. Gelber et al. Annals of Internal Medicine, June 15 1992, pages 961-6). Nonetheless, AZT undisputedly lowers HIV levels for the first six months that a treatment-naïve patient takes it.

Saquinavir: "A New Formulation, a New Beginning"

Fortovase, Hoffman-La Roche's new version of saquinavir that comes in soft gel capsules, is not one of the four new agents, but it is the first improvement over past combination therapies to be approved by the FDA using viral load-based criteria. It was approved last November 7 and reached pharmacies ten days later. Packaged in a special lipid mixture and taken at twice the dose of the older "Invirase" formulation, Fortovase permits a total drug exposure in the body that is eight times greater than before. This is largely because the new lipids induce such a rapid absorption of saquinavir that the compound saturates the liver enzymes that can rapidly break it down. More drug therefore reaches the blood.

Roche announcements have called Fortovase "a new formulation, a new beginning" for saquinavir, whose old version, Invirase, was widely deprecated as having inferior efficacy compared to the other protease inhibitors. Fortovase, in contrast, acts like a real protease inhibitor. NV15355, the main Roche study comparing Fortovase with Invirase (in combination with two nucleoside analogs of choice), found that 60 of the 75 (80%) people on Fortovase for 16 weeks had viral loads below the PCR test's limit of quantification (400 copies of HIV RNA/ml). Only 30 of 69 (43%) of those on 16 weeks of Invirase had passed this threshold. The study population consisted of people without prior treatment. Their average initial CD4 cell count was 429, and their average initial viral load was 4.8 logs (63,000). Absolute viral load drops and CD4 count rises for each saquinavir formulation were not different enough to be statistically significant. It would take a longer, larger trial to detect any real differences between the two formulations. Of note, 15 of 81 volunteers (19%) starting Fortovase had discontinued the drug by week 16, compared to seven of 90 (8%) on Invirase. The daily 3.6-gram Fortovase dose requires taking 18 large oil-coated capsules a day. It represents a large additional pill burden and causes considerably more gastrointestinal problems than Invirase at the standard 1.8 gram/day dose.

Roche also has a study in progress to prove that Fortovase is as effective as Merck's indinavir. Very early results from this study were presented at this fall's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC abstract I-92). The study enrolled 46 persons whose only previous therapy had been less than a year on AZT. They received either AZT/3TC/Fortovase or AZT/3TC/indinavir. Average baseline viral loads were about 75,000 copies/ml and 300 cells/mm3, respectively. By ICAAC, 30 participants had reached week 12 and 39 were at week 8. The responses to both treatments did seem equivalent, with the viral load in all participants reaching week 12 below the PCR assay's limit of quantification (400 copies/ml). Although there was a tendency for the Fortovase arm to experience higher CD4 count increases, the patient population in this study is too small to make meaningful comparisons between the protease inhibitors. And the long-term effects of Fortovase, the durability of response in particular, remain to be elucidated.

Fortovase is associated with diarrhea or nausea in 10% to 20% of trial participants but otherwise has been relatively well tolerated. One way around the onerous Fortovase dose is to combine 400 mg of Fortovase with 400 mg of ritonavir every 12 hours. By blocking the liver enzymes that break down saquinavir, ritonavir achieves the same effect as saturating the liver with much larger daily doses of Fortovase. Interestingly, combining the ritonavir with 400 mg of either Invirase or Fortovase achieves the same saquinavir blood levels (see Treatment Issues, Nov. 1997).

Invirase is in the process of being phased out, so those who prefer the Invirase/ritonavir combination are out of luck. Ironically, Hoffmann-La Roche is keeping the price for a yearly supply for Fortovase (3,600 mg/day) equal to that of Invirase (whose recommended dose is only 1,800 mg/day). The price per pill is therefore half as much even though Fortovase carries with it extra manufacturing and development costs. The company stands to lose a lot of money if Fortovase's main use is to combine it with ritonavir in the twice daily 400 mg/400 mg regimen. Although the cost of the ritonavir/saquinavir combination has gone down, Roche spokesperson Bob Posch argues that taking Fortovase alone offers several advantages over the combination: "Fortovase no longer needs to be used in combination with ritonavir to increase exposure levels of [saquinavir]. This avoids the immediate need for refrigeration, the toxicity involved with taking two protease inhibitors, the dosing concerns with 400 mg ritonavir and the significant drug interaction profile of ritonavir."

Roche, however, has an extensive program to evaluate the combination of Fortovase with Agouron's protease inhibitor nelfinavir (Viracept), for which it happens to own non-U.S. marketing rights. Nelfinavir presents fewer problems than ritonavir while still boosting saquinavir levels five times by inhibiting the liver enzymes (as does indinavir, which also does not cause diarrhea to the extent that nelfinavir and Fortovase do). In one study, whose preliminary results were presented in October at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection (abstract 209), four regimens were compared: Fortovase plus two nucleoside analogs of choice, nelfinavir plus the two nucleoside analogs, and the Fortovase/nelfinavir combination (at a dose of 800 mg thrice daily for Fortovase and 750 mg thrice daily for nelfinavir) with or without two nucleoside analogs. Of the 158 participants, half were treatment-naïve. Their baseline values averaged about 60,000 for viral load and about 300 for CD4 count. The 16-week results were similar for every arm. Using an ultrasensitive assay (whose limit of quantification was 50 copies of HIV RNA/ml), the trial registered 16-week viral load reductions of about 2 to 2.5 logs (99% to 99.7%), with the arm receiving only the two protease inhibitors showing the least reduction. The two groups receiving both protease inhibitors also experienced a 35% to 46% incidence of diarrhea. By comparison, Fortovase plus two nucleoside analogs had a 19% diarrhea rate.

The New Protease Inhibitors and Cross-resistance

One of the great unanswered questions concerning Fortovase is HIV's response to the effective levels of saquinavir that it establishes. For Invirase, resistance mutations emerged at a reduced rate compared to other protease inhibitors, according to Roche analyses of before and after HIV genetic sequences obtained from saquinavir trials. Even without the advent of widespread resistance mutations, though, saquinavir trial participants' viral loads gradually rebounded on average after an initial small drop. It may be merely that the low saquinavir blood levels resulting from Invirase do not inhibit HIV enough to select for resistant strains.

Saquinavir-resistant mutants can exist as minor, undetectable subpopulations in patients' bodies. When switching to indinavir or nelfinavir, they continue to multiply because they are at least partially protected against the new protease inhibitor. This reduced sensitivity supports further evolution to complete resistance and drug failure (see International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication, St. Petersburg, Florida, June 25-28, 1997, abstracts 15, 16, 17 and 27).

One protease inhibitor now under development by Glaxo Wellcome was designed to be less vulnerable to the pitfalls introduced by such cross-resistance. Like nelfinavir, the newly rechristened amprenavir (formerly 141W94) is an adaptation of the basic, highly potent and HIV-specific saquinavir structure to achieve greater availability in the body (would that Roche had done the same). The Vertex Pharmaceuticals scientists that originally created amprenavir (before it was sold to Glaxo) went several steps beyond nelfinavir, arriving at a molecule that is yet more compact and looks even less like a peptide (a short protein-like sequence of amino acids).

In test-tube cultures, the major resistance mutation appearing after exposure to amprenavir has been at position (codon) 50 on the HIV protease gene. This mutation has not been seen with other protease inhibitors, but since amprenavir binds to the protease enzyme in similar fashion to the others, overlapping resistance can be expected. Some of the other mutations that show up in the lab, particularly the one at position 46, do occur with other protease inhibitors. Again in the lab, ritonavir-resistant HIV also resists amprenavir whereas HIV resistant to indinavir or saquinavir or maybe nelfinavir still has at least some sensitivity to the Glaxo compound.

Early results from human beings indicate that the codon 50 does appear in response to amprenavir in real life. The extent that amprenavir can be used in real life against HIV resistant to other protease inhibitors remains to be determined. One trial at the NIH tried a combination of amprenavir plus Glaxo's new nucleoside analog abacavir (see below) in ten very advanced patients whose HIV tested as highly resistant to most other drugs. The results were not impressive. Of the ten participants, three exhibited a significant viral load drop, which lasted only about three months. Glaxo has now commenced an 80-person open-label trial using DuPont Merck's experimental NNRTI efavirenz (again, see below) along with its own two new compounds in persons who can no longer put together viable antiviral combinations using the HIV drugs on the market.

One ongoing trial is testing the Glaxo triple drug combination of AZT/3TC plus several doses of amprenavir. The 80 study participants are 3TC- and protease inhibitor naïve and had a baseline viral load of about 70,000. At the highest two amprenavir doses (1050 and 1200 mg twice daily), 12-week viral load reductions of about 2.7 logs (99.8%) were achieved. These results are at least comparable with other protease inhibitors.

Testing is also in progress on administering amprenavir concurrently with other protease inhibitors, rather than before or after these other compounds. A progress report on the effects of such dual protease inhibitor combinations will be given at the Fifth Conference on Retroviruses and Opportunistic Infections, to be held in Chicago on February 1-5. The report will involve six-month data from a 48-person trial that administered just amprenavir plus either indinavir, nelfinavir, or saquinavir to volunteers without previous protease inhibitor experience. Unofficial sources indicate that the observed viral load drops have been durable and impressive -- HIV decreases on the order of 4 logs (99.99%) have occurred (measured with the ultrasensitive PCR assay). Much of this superlative combination effect may be due to drug-drug interactions that raise blood levels of the protease inhibitors: amprenavir is about as effective as indinavir or nelfinavir in blocking the liver enzyme pathway that breaks down protease inhibitors (see J. Woolley et al., 37th ICAAC, Sept. 28-Oct. 1 1997, abstract A-60).

Two-protease inhibitor combinations with amprenavir look like they may become a valuable additional treatment option and it may be useful in some salvage therapies, but as with any new agent, it is important not to get an exaggerated view of amprenavir's potential. With more details expected in February, Mike Rogers, who directs Glaxo's amprenavir development program, described amprenavir's promise in these circumspect terms: "It has similar efficacy to other protease inhibitors, but it is better tolerated and dosing is only twice a day with no food restriction or water requirement. Stay tuned on the resistance issue."

There are four other new protease inhibitors in advanced stages of development that promise to offer additional novel treatment options. More information on human trials from Abbott Laboratories ABT-378 also is expected at February's Retrovirus Conference. When mixed with small amounts of ritonavir to block its metabolism in the liver, ABT-378 is stable enough in the body to qualify for once or twice a day dosing (see R. Lal et al., 37th ICAAC, Sept. 28-Oct. 1 1997, abstract I-194). In the test tube, it is one of the most powerful protease inhibitors discovered so far. Abbott is claiming that there is little cross-resistance between its new compound and other protease inhibitors. In the test tube, though, many of the same mutations appear on exposure to ABT-378 as appear with amprenavir.

In the final analysis all these protease inhibitors bind to the protease enzyme in similar ways and hence are affected by similar mutation-driven alterations in the enzyme's structure. However: three of the four new protease inhibitors offer something a little different. The older protease inhibitors represented attempts to create molecules that mimic the way the natural polyprotein substrate binds to the enzyme's active site. Protease cleaves the natural polyprotein into the structural proteins and enzymes contained in the core of a mature virus particle. The synthetic mimics are designed to be uncleavable units that clog the protease active site. The three new inhibitors, under development by Pharmacia & Upjohn, Bristol Myers Squibb and Parke-Davis have novel sticky structures that bind to the active site in ways that are relatively little affected by the standard mutational alterations elicited by the older protease inhibitors. (See S.M. Poppe et al., Antimicrobial Agents and Chemotherapy, May 1997, pages 1058-63.)

Pharmacia & Upjohn's PNU-140,690, probably the most advanced of the three, is now undergoing dose-finding tests in a cohort of ten-persons with indinavir-resistant HIV. In the lab, this compound retained much of its activity against HIV resistant to the protease inhibitors now on the market. Bristol Myers' 232,632 (a newly purchased compound originally developed by Ciba Geigy, now a part of Novartis, and formerly called CGP 61755) is just entering human trials. Lab tests have found that it exhibited exceptional potency with only slight loss of activity against ritonavir-, indinavir- or saquinavir-resistant HIV. Parke-Davis unveiled a series of candidate compounds at this year's ICAAC (abstracts I-62, I-64, I-84 and I-199b,c,d). These compounds, structurally similar to PNU-140,690, have high bioavailability in animals and, again, seem little affected by the known protease mutations. Test-tube activity seems a little less than the standard protease inhibitors, though.

Of course, everyone expects that HIV can develop resistance to these new compounds, even if that resistance has not yet been observed. The irony is that HIV makes its own protease inhibitor that is several thousand times as potent as the synthetic ones. This inhibitor, known as Vif ("viral infectivity factor"), could be the basis of an anti-protease drug that is virtually resistance-proof.

Here is how: Vif apparently binds to the same regions on the HIV polyprotein that protease breaks apart. As the HIV virion buds from cell walls, most of the Vif sticks to the lipids in the cell membrane, exposing the polyprotein to protease at the proper moment to assemble the virus core. A truncated Vif or an analog with similar structure could be created that would latch onto the polyprotein permanently and keep the protease enzyme away. Should HIV mutate its polyprotein cleavage sites to avoid the false Vif, the real Vif would not bind either, and the protease enzyme would prematurely chop up the polyprotein. There would then be no competent virus particles produced. (See M. Kotler et al., Journal of Virology, August 1997, pages 5774-81.)

A More Powerful Nucleoside Analog Has Its Limitations

One factor adding to the complexity of current anti-HIV regimens is the weaknesses of the drugs attacking reverse transcriptase (nucleoside analogs and NNRTIs). This situation is improving with the arrival of Glaxo Wellcome's abacavir (formerly 1592U89). Now available in a limited expanded access program or "open label protocol" (see Treatment Issues, Oct. 1997 ), abacavir should enter the FDA approval process by mid-1998.

Steven La Fon, who coordinates the abacavir clinical trials at Glaxo, says of abacavir, "It's clear that in naïve patients, it has a profound potency, similar to a protease inhibitor." Indeed, abacavir produced viral load drops of 1.7 to 2.1 logs (98.1% to 99.2%) at various doses during an initial 12-week trial in 60 volunteers with little prior treatment. Nine of those volunteers came back after four to 15 months off treatment (two were getting AZT/ddI) for a 36-week open-label extension phase consisting of abacavir plus another tolerated nucleoside analog plus indinavir or ritonavir. As reported at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection (abstract 339), all study participants (except for one dropout) by week 12 had viral loads below the threshold of quantification (400 copies/ml). Starting viral load averaged 35,000 copies/ml.

But all is not so well when treatment-experienced patients are examined. The failure of the abacavir/amprenavir NIH salvage therapy trial was mentioned above. Another trial described at the Sixth European Conference involved giving abacavir to volunteers who maintained substantial viral loads (over 10,000) despite the nucleoside analogs they were taking. Those who added abacavir to ddI/d4T therapy did experience a 90% reduction in their HIV levels, but the response in those adding it to AZT was two-thirds less, and there was essentially no reduction when abacavir was added to AZT/3TC. This last group had the longest treatment history and had the most broadly resistant virus. When the association with resistance mutations was analyzed, a curious observation emerged: The likelihood of failing to respond to abacavir increased according to the number of mutations on the reverse transcriptase of an individual's HIV, regardless of whether those mutations specifically reduced sensitivity to the new drug. HIV with four or more reverse transcriptase mutations had little to no susceptibility to abacavir.

This resistance analysis only included viral load response out to four weeks. One can predict that much of the HIV with only two or three mutations would become resistant and start to rebound in the next few months as extra mutations accumulated in response to the abacavir and the other drugs the study participants were taking. It is puzzling that the specific abacavir mutations that appear in test-tube culture (at codons 184, 65, 74 and 115) do not seem to confer much resistance in themselves, although some of these mutations confer strong resistance to other drugs (for example, the mutation at codon 184 negates 3TC). Yet HIV that was coresistant to AZT and 3TC frequently was cross-resistant to abacavir in this analysis. Obviously, the intricacies of abacavir resistance have yet to be fully delineated, but as of now it is to be feared that abacavir will not work so well in people who have already taken nucleoside analogs. Those in the expanded access program, who must have failed at least two prior nucleoside analogs, may not receive much benefit if all they can add is abacavir.

Abacavir warning: Abacavir's poorly publicized life-threatening allergic reactions have become increasingly important given the swelling enrollment in the expanded access protocol (which now covers over 1,200 people). On October 30, Glaxo sent out a memorandum to investigators that detailed the problem: About 2% to 3% of those receiving abacavir come down in the first few days with a rather vague set of symptoms -- malaise, low-grade fever and nausea. A generalized rash develops secondarily. If dosing is continued, the malaise, nausea and vomiting increase until abacavir is stopped. Symptoms always resolve when the drug is discontinued. The October 30 memo relates that when ten people with these reactions were rechallenged with abacavir, the syndrome returned within hours and was so severe that eight were hospitalized for observation. Liver function tests were abnormal and white blood cell counts plummeted. Three people had abnormally low blood pressure and two had facial and/or throat swelling, the signs of a condition called anaphylaxis.

The lengthy memo warned doctors that patients with a rash and the initial systemic symptoms should not restart abacavir. But Glaxo's effort to inform the medical community was clearly insufficient: In November, at least three and possibly more individuals were hospitalized with these anaphylaxis-like symptoms after restarting abacavir. In an interview, one of these patients' doctors confirmed that the patient had nearly died and was in an Intensive Care Unit for a week. "He had kidney, lung problems, the works. It's not something I would want to live through again," this doctor said. The physician also claimed that until this case, he had never seen the warning not to restart abacavir despite having 60 patients in the abacavir expanded access program (of whom four others suffered the initial allergic syndrome, in addition to the one who resumed taking the drug).

Glaxo is now making all participants in the expanded access protocol sign a new Informed Consent Form, notifying patients, "If you think you are starting to have an allergic reaction to 1592U89 [abacavir], you should stop taking the drug and call your study doctor or nurse immediately. Do not take another dose of 1592U89 before you see your doctor again." It remains to be seen whether this step will be sufficient to prevent further drug resumptions.

Glaxo could have informed the community long ago about the danger in taking abacavir. In failing to do so, the company heightened that danger. When first queried by Treatment Issues about the rumors of anaphylactic reactions, a company spokesperson minimized the problem, remarking, "We're talking about a very small percentage of patients -- it's not our practice to publicize every adverse event that occurs."

Other Glaxo officials later defended their company's effort to notify physicians and, finally, their patients. Still, the company could be more forthright in broadly and clearly spreading the message: Do not restart abacavir if you experience the initial allergic syndrome. Your life could depend on staying off the drug.

Another Nuke Searches for a Place in the Sun

Another new antiviral heading for FDA consideration by the middle of 1998 is Gilead Sciences' adefovir (brand name Preveon) -- a nucleoside analog with a twist, or actually a tail. Adefovir, the oral prodrug version of PMEA, comes with a phosphate group attached, the first of three that cells add to nucleosides to energize them before they can be strung together to form new DNA or RNA. By skipping the first of these activation steps, which can be a real bottleneck, adefovir in theory is more readily available within cells to attack HIV than the standard nucleoside analogs (technically, adefovir is a nucleotide analog). Its intracellular stability is also higher than the nucleoside drugs.

Little information has been released about adefovir's activity. In two trials reported over a year ago, adefovir resulted in immediate viral load drops averaging 0.5 logs (68%). This viral suppression was sustained in five volunteers who remained on monotherapy for nine months. Adefovir's potency then is in the league with the older nucleoside analogs, and not up to par with the standard set by abacavir or the protease inhibitors.

Adefovir's main purpose probably is to contribute a little extra HIV suppression and hence more durability to a combination regimen that is already achieving a substantial response in an individual. The main trial (protocol 408) that will provide information for the FDA review of adefovir compares adefovir plus standard treatment to standard treatment alone. With the trial's 400 participants free to choose and switch their background combination at will, it may be hard to distinguish adefovir's modest additional contribution without a long period of observation.

James Rooney, M.D., vice-president for clinical affairs at Gilead Sciences, argues that his company's drug is comparable to d4T in that resistance mutations are rare during treatment. Given that d4T is now overtaking AZT in sales, such a comparison suggests a bright future for adefovir. d4T is useful as part of a first-line combination regimen, but at least in monotherapy, has shown only temporary effectiveness in AZT-experienced patients. Adefovir also may turn out to have less effect in treatment-experienced patients. In one of the two initial trials, researchers found that volunteers harboring HIV with specific AZT-resistance mutations responded little or not at all to adefovir even though these mutations (at codons 41 and 215) did not affect adefovir in test-tube virus culture tests. Aside from the general accretion of resistance mutations lessening the activity of any inhibitor, one of the mutations spawned by abacavir and ddI (at codon 65) does reduce adefovir's effectiveness in culture assays. Adefovir does have one clear advantage over d4T: It is active against a number of viruses besides HIV, including hepatitis B, CMV and KSHV, the suspected cause of Kaposi's sarcoma.

The other advantage to adefovir, that it accumulates within cells, can also be a disadvantage when those cells start to feel the adverse effects of the drug, which is just as inherently toxic as the nucleoside analogs. For starters, adefovir reduces cellular levels of L-carnitine, a natural substance necessary for converting lipids to energy within cells, and patients taking this drug must also take L-carnitine supplements.

Particularly sensitive to adefovir are the kidney cells. Gilead's anti-CMV drug cidofovir, also a nucleotide analog, is notorious for causing rapid kidney failure if the proper precautions are not taken. Adefovir's effect is much more gradual. To protect this organ, those on adefovir must have their kidney function checked each month, via lab tests for serum creatinine and protein in the urine. Dose reduction or drug discontinuation is necessary if abnormal values are found. So far, 12 of 300 persons on adefovir longer than six months have had their adefovir dose reduced or terminated due to abnormal kidney test results.

As it turns out, abnormal liver function tests have been more frequent, with 40 of 800 persons receiving adefovir requiring dose reductions or at least temporary discontinuation due to (reversible) signs of liver damage. Seven cases of pancreatitis have also raised concerns, but these cases may also have been associated with other drugs the patients were taking.

More information on adefovir's safety and efficacy will become available in the next few months from the preliminary analysis of Gilead trial 408. Other trials in progress are testing adefovir as part of three- or four-drug combinations in a wide variety of situations, from first-line treatment to salvage therapy. For salvage therapy, novel combinations involving new and old antiviral agents have been created.

At least one clinic already is administering hydroxyurea to increase abacavir's benefit in patients receiving that drug through expanded access. It might be a good idea to take the same approach with adefovir. Adefovir, like ddI, the usual hydroxyurea co-drug, serves as a defective stand-in for the natural nucleoside adenine, whose production hydroxyurea inhibits.

A Surprisingly Strong NNRTI Has Usual Achilles' Heel

Gilead has just launched a very restrictive expanded access program for adefovir. (The criteria for enrollment are current CD4 count below 50 with viral load above 30,000 and loss of response to two reverse transcriptase inhibitors and one protease inhibitor, although exceptions can be made in certain circumstances.) The company is discussing with community activists when and how to liberalize this program. DuPont Merck meanwhile has just announced a major enlargement of its expanded access program for its new non-nucleoside reverse transcriptase inhibitor efavirenz (brand name Sustiva, formerly known as DMP 266). With only a few months to go before DuPont Merck files with the FDA for approval of efavirenz, the expanded access program will now enroll anyone who has had a CD4 count below 400 at any time and is unable to assemble an effective treatment combination from FDA-approved drugs.

Efavirenz, like abacavir, is marked by protease inhibitor-like potency. In early trials, two weeks of 200 mg/day of efavirenz alone resulted in 1.5 log (97%) drops in viral load. A more lengthy trial followed a cohort receiving 200 mg/day of efavirenz and 800 or 1,000 mg/day of indinavir. (Note that DuPont Merck is half owned by Merck, which owns indinavir and originally developed efavirenz.) Members of this cohort averaged sustained 99.7% (2.5 log) drops in viral load lasting out to 48 weeks (37th ICAAC, abstract I-175). Eighty-eight percent of the participants (who had no prior NNRTIs or protease inhibitors) ended up with viral loads below the limit of quantification (400 copies/ml). In a later trial, treatment-naïve individuals taking efavirenz/AZT/3TC had 99% (2 log) drops in viral load over the first 16 weeks (Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, abstract 920).

In comparison, by far the best results with the NNRTI delavirdine are found in the preliminary results of an ongoing trial combining delavirdine/AZT/3TC in a population similar to the AZT/3TC/efavirenz trial. At 16 weeks, the study showed a viral load drop of 1.6 logs (97.5%), with 74% below the 400 copies/ml limit; at 32 weeks the corresponding figures were 1.5 logs (97%) and 63%. Comparable results were reported two years ago for nevirapine plus AZT/ddI (see Treatment Issues, June/July 1996, page 25), also with a slight negative trend in viral load and percent below the limit of quantification.

Delavirdine and nevirapine suffer from the ease by which HIV develops resistance to them. Resistance to either requires only a single mutation, which can occur after a few weeks of monotherapy. Efavirenz is not as much an exception to this pattern as first appeared, and once again the rule holds that broad cross-resistance can arise for a given class of drugs. In early trials, 13 of the 21 participants who received two weeks of 200 mg/day efavirenz monotherapy experienced a rebound in viral load after a subsequent 12 weeks on efavirenz plus indinavir. A mutation at codon 103 was observed in almost all these treatment failures, usually followed by a second mutation. That 103 mutation also commonly emerges with delavirdine treatment and imparts resistance to nevirapine, too.

DuPont Merck has now tripled the efavirenz dose, to 600 mg once a day. At this dose, efavirenz can largely suppress HIV containing only the codon 103 mutation in most, but not all, patients (it depends on the attained blood level of free drug). The higher dose also protects against other, poorly characterized mutations far from the area that efavirenz binds to. Efavirenz then acts in a manner analogous to ABT-378 -- it is potent enough to overwhelm the standard initial resistance mutations but it is not immune to them. But 600 mg is considered the maximum tolerated dose, and the cost is more side effects, principally such central nervous system effects as dizziness and headaches. And once someone's HIV has the codon 103 mutation, he or she is just one more mutation away from losing efavirenz's effectiveness despite the 600 mg dose. That makes efavirenz as vulnerable as the older NNRTIs, nevirapine and delavirdine, to viral escape.

Creating a True Multipronged Attack

Pharmacia & Upjohn is pushing ahead with a new NNRTI, PNU-142721, that in the test tube at least has potency similar to efavirenz and is not affected by the codon 103 mutation. Its resistance profile has yet to be delineated, though, and other common NNRTI resistance mutations may affect it.

Even when cross-resistance does not completely block the activity of a new drug like efavirenz or PNU-142721, an accumulation of mutations due to prior exposure to similar drugs may hobble it, paving the way for the emergence of fully resistant HIV. To provide a variety of feasible therapeutic options, it seems that the two enzyme targets now in use, reverse transcriptase and protease, are not sufficient. Yet there will be little departure from the two established therapeutic strategies available any time soon.

T-20 (pentafuside) is one of the few such novel (as opposed to merely "new") drugs that is exhibiting efficacy in early human trials. The compound acts by binding to the harpoon-like gp41 component of HIV's envelope protein and preventing fusion of the virus to cell membranes, the initial step in infecting new cells. As reported in September at the Annual Meeting of the Infectious Disease Society of America, four volunteers receiving 100 mg every 12 hours for 14 days experienced a 1.5 log (97%) drop in their viral loads. All achieved unquantifiable viral loads (less than 500 copies). Since this dose-finding trial only lasted two weeks, it is impossible to tell what T-20's ultimate effects are, but clearly the principle works. One problem with this compound is that it must be injected, and its half-life in the body is only about two hours. If long-term T-20 therapy were to be administered, some type of portable continuous infusion pump may be required.

Many other novel strategies, ranging from immune reconstruction to inhibitors of other HIV enzymes, are in much earlier stages of development. These are mostly the progeny of institutional research labs or small entrepreneurial companies. As is traditionally the case, the pharmaceutical industry is sticking to the tried and true, coming out with a series of "me-too" drugs. Often companies such as Roche, Glaxo, Bristol and Merck seem bent on putting together competitive analogous combination regimens composed solely of their own products. The medications developed under these conditions fit neatly into the FDA's approval standards based on short-term viral load changes, but they offer at best incremental improvements over older agents.

We have in this way arrived at half a cure. It will take risky investments of time and money to find the extra therapies that bring us all the way home.