American Foundation for AIDS Research, July 2001
Anne-Christine d’Adesky

Not only do the potent HIV drugs cause myriad side effects, but HIV can mutate to become resistant to all the existing medications. A growing number of multidrug-resistant HIV strains (MDR HIV) have emerged following the introduction of more complex and active regimens. [quote] Many people have already run out of treatment options and are urgently in need of better "salvage therapy" regimens and new drugs to control their HIV disease. Their situation serves as a warning that our ability to control HIV is decreasing over time.

Mutations in HIV occur during viral reproduction, resulting in amino acid sequence changes in key enzymes. For some drugs, a single amino acid change in the right place confers drug resistance. For others, it takes multiple changes. These mutations occur randomly with or without presence of the drugs. Drug-resistant strains fail to become detectable, though, because the nonmutated, or wild-type, HIV replicates much faster - until therapy commences and the susceptible wild-type HIV is suppressed. With more people on HIV therapy for longer periods, there is a growing opportunity for the virus to develop resistance to their combination regimens.

Enter a new series of very potent compounds designed specifically to overcome the thorny issue of MDR HIV. Over the past two years, the Belgian-based company Tibotec has tested up to a dozen of these compounds - both novel protease inhibitors and non-nucleoside reverse transcriptase inhibitors. (Tibotec, which has a branch in Rockville, MD, recently merged with Virco, a specialist in HIV drug-resistance testing.) Tibotec's compounds, which it has dubbed "resistance repellent" (RR), have a different chemical structure than existing drugs in their classes and can bind to many variants of their target HIV enzymes. The new drugs are active against drug-resistant HIV variants that carry a range of common mutations.

Other companies have also entered the race, notably DuPont Pharmaceuticals and Boehringer-Ingelheim. At last February's Conference on Retroviruses and Opportunistic Infections, all three companies showcased early data on their new agents.

Since these drugs appear to work against wild-type HIV strains as well as drug-resistant ones, they could also potentially benefit treatment-naïve individuals. Some researchers hope their use might one day prevent the emergence of drug resistance altogether. On the other hand, critics are concerned about whether the ever wily HIV might develop resistance to these latest weapons. The result could be HIV cross-resistant to a wider range of drugs than previously observed.

Tibotec's Drug Development Strategy

Since its founding in 1994, Tibotec has identified a dozen candidate drugs with strong [quote] antiretroviral activity against HIV. It is also working closely with another Belgian company, Janssen, to screen promising new compounds. There are limited and very early data about two of the Tibotec compounds, and company officials are cautious about overstating these initial results, however positive.

The first candidate is TMC120, a non-nucleoside inhibitor (NNRTI) that is active against viruses with cross-resistance to existing NNRTIs. At an earlier developmental stage is TMC126, one of a new series of protease inhibitors (PIs). TMC126 is related to amprenavir but able to inhibit strains of HIV with multiple mutations that confer resistance to existing PIs.

Results of an initial double-blind phase I/II study comparing two doses of TMC120 to placebo were revealed at the recent Retrovirus Conference. The trial enrolled 34 men and nine women, all treatment-naïve and with low viral loads (under 5,000 RNA copies). They received either 50 or 100 mg of the drug twice a day for a week. The average viral load drop was 1.51 log (97%) after seven days on the drug. TMC120 appeared safe and well tolerated. Three patients experienced mild side effects, notably sleepiness and, conversely, insomnia. TMC120 worked well against HIV with common NNRTI resistance mutations such as K103N, Y181C and G190A/S, as well as wild-type strains. However, in vitro data suggest that, over time, some degree of resistance to TMC120 does occur in HIV with the K103N and L100I mutations.

According to John Erickson, Chief Scientific Officer of Tibotec's US branch, TMC120 is very potent - "more potent than nevirapine or delavirdine, and probably has the same raw potency as efavirenz." He claimed, "What strikes me about it is you get very good blood levels with relatively small doses, and efficacy as well… One and a half log reductions [a 97% viral load decline] in seven days is about as good as you get with NNRTIs." Tibotec is also ready with a backup compound for TMC120. It is called TMC125, and Erickson said that it "is more potent than 120 against a panel of drug-resistant mutants." TMC125 is currently in phase I trials.

Although the protease inhibitor TMC126 has not yet been tested in people, it, too, has garnered early notice for its potency. At the Retrovirus Conference, Erickson was the lead author of a poster summarizing a TMC126 study that "showed that drug-resistant strains emerged more slowly and evolved using different genetic pathways than commonly observed for current PIs." In an interview, Erickson labeled TMC126 a powerhouse. "Potency is a relative term," he said, "but TMC126 is probably, as a prototype compound, on the order of tenfold more potent than the next more potent compound down there, which is saquinavir or lopinavir."

Erickson described Tibotec as "a drug discovery research lab that focuses on structure-based drug design and sort of molecular target-based methods of drug discovery." His group developed its "resistance-repellent" drugs through a process of elimination. The researchers compared the shape of wild-type HIV reverse transcriptase and protease enzymes to those with NNRTI- and PI-resistance mutations. Erickson's Belgian colleague at Tibotec, Rudy Pauwels, took a slightly different approach. He grew viruses with multiple NNRTI resistance mutations and then tested them against a battery of NNRTI compounds that Janssen scientists had identified.

Other Companies and their Candidates

DuPont Pharmaceuticals' scientists are also busy testing second-generation NNRTIs and PIs that work against multidrug-resistant HIV variants. These drugs are in phase I and II trials. DuPont has two lead PIs, DPC 681 and DPC 684, that appear potent against protease inhibitor-resistant HIV - specifically chimeric viruses constructed from clinical samples of patients who have failed to suppress HIV on existing PI regimens and carry virus with broad cross-resistance to present PIs.

DuPont's new NNRTI, DPC 083, is an attempt to achieve what efavirenz, the company's original NNRTI, proved unable to accomplish. In the lab, DPC 083 suppresses strains containing such key single resistance mutations as K103N and L100I. It is also active against some multiply mutated HIV strains detected after treatment failure with currently available NNRTIs, including efavirenz. DuPont will present phase II trial data on DPC 083 at the International Conference on Antiretrovirals and Antimicrobial Agents (ICAAC) this September.

Many observers have their eye on tipranavir, a novel, potent PI that was developed by Pharmacia and acquired in January, 2000 by Boeringher Ingelheim. Tipranavir has a different structure than existing "peptidic" PIs, which mimic the configuration of HIV proteins.

Tipranavir is synergistic with some conventional PIs, like ritonavir. In early studies, the drug inhibited the growth of 90% of existing HIV isolates cross-resistant to multiple protease inhibitors. It is being studied in clinical trials of treatment-experienced and drug-naive individuals and with ritonavir. Side effects include nausea, diarrhea and vomiting. Development has been slowed by tipranavir's enhancing effect on liver enzymes, which break down tipranavir as well as other drugs. Combining tipranavir with ritonavir, which inhibits liver activity, may reverse this hepatic influence. Among other things, the result would be to reduce the required dose of tipranavir. A long human study of the interaction between tipranavir and concurrently administered drugs is now in progress.

Other pipeline NNRTI compounds showing some activity against resistant isolates include Agouron's capravirine and Pharmacia's PNU-142721. These drugs are subject to their own delays. New enrollment in capravirine trials was halted last winter because high doses of the drug cause vasculitis in dogs. The PNU drug is in limbo because Pharmacia has ended its commitment to developing HIV drugs and would like to sell it, as the company did with tipranavir.

The Uncertainties

While the news about potency and resistance of the new drugs looks positive, there is less to say at this point about longer-term side effects. [quote] Tibotec's Erickson is quick to comment that he is not an expert on metabolism or PI-related toxicities, such as lipodystrophy. Others think too little is known about the action of these drugs to make any predictions. But the fact remains that these drugs are processed by the liver, so there is some concern that they will have the familiar liver side effects.

"I don't think this has been completely worked out yet," Erickson carefully stated. "We have done some liver studies with liver microsomes [membrane structures in liver cells that are the site of enzyme activity]. The indication is that there is some metabolism by the 3A4 cytochrome [p450 liver enzyme pathway] that traditionally metabolizes PIs." Right now, he is more concerned with elevated cholesterol levels seen with existing PIs. "This is something we're going to look at in our compounds in some surrogate models to get a look at it in advance. You don't want to give people heart disease."

In regards to such toxicities, Erickson concluded, "I don't have any reason to believe that [RR inhibitors] will be any better or worse than PIs now out there. But I hope by virtue of the fact that we can identify compounds that have a log [tenfold] more potency, then you can conceivably get away with lower long-term exposure, and that may alleviate long-term side effects." If future RR drugs are more potent, then lower doses could be used, reducing the cumulative drug burden on the body.

Tibotec recently started a phase I drug interaction study of TMC126 and ritonavir. Erickson's Belgian colleagues are also testing an analog of TMC126 called TMC114, which, he said, "has very good bioavailability in dogs and very low toxicity, so it's allowed us to do a proof of concept in terms of pharmacokinetics and acute toxicity.

The View from Outside the Companies

What do those outside Tibotec think of the newest kids on the block? Over at Northwestern University, researcher Robert Murphy is interested but cautious. "There's a lot of interest in these drugs," said Murphy. "They're new, they work against multiply drug-resistant strains, all that's good. Nowadays the preclinical work is so sophisticated that the toxicity data is pretty nicely worked out and they look safe." But he warned, "It's really early. You have to be careful not to get the buzz too high on these things. There's a lot of stuff that starts like this and goes nowhere."

At the Aaron Diamond AIDS Research Center in New York, Marty Markowitz and David Ho are keeping a close eye on Tibotec's data and have done some preclinical work trying to create resistant viruses. They, too, are cautious. Markowitz said, "Obviously the data are encouraging, but we have little toxicity data." He also pointed out, "So far, no drug has been developed that's completely resistance-proof." In other words, no one knows whether HIV can mutate and become resistant to Tibotec's "resistance-repellent" inhibitors, or how long it might take.

That is exactly what worries community-based advocate Ben Cheng of Project Inform. "One of the issues with all NNRTIs is cross resistance," he said. "What's different here?" Cheng worries about automatically turning to drugs like TMC120 for salvage therapy drugs in individuals with MDR HIV. He noted, "There is the potential for cross resistance [to blunt the potency of TMC120] even though the drug has shown activity against current NNRTI resistant viruses."

Cheng also wondered how you replace TMC120 in the case of treatment failure. He reasoned, ""People who have NNRTI resistance, especially to efavirenz, may be in a position where there may be cross resistance [with existing NNRTIs]. If you develop resistance to [TMC120], do you then become cross-resistant to other NNRTIs? My first concern would be that."

The same problem looms for Tibotec's new PIs. Cheng cited the example of indinavir. This protease inhibitor is generally regarded as being more difficult for HIV to develop resistance to because evading the drug requires multiple mutations on HIV's part. "But when you do fail indinavir, there is more cross-resistance with the other PIs," Cheng observed. "Will this be the case with the Tibotec drugs?"

Will use of the new drugs lead to even more broadly resistant, super-MDR HIV over the long run? No one can say for now, but as Markowitz conceded, "That's a loaded question."

Looking ahead, Markowitz urged persons with HIV to balance their concerns about the downside of new drugs with the urgent life and death reality many face. "Remember many people need drugs to stay alive, even if there are side effects," Markowitz said. "More people die of uncontrolled HIV infection and immunodeficiency than PI-induced liver disease, and this is likely to increase as drug resistance becomes more of an issue."

Markowitz, for one, is choosing to remain hopeful. "MDR is a big problem and will result in increased HIV-related morbidity and mortality if new drugs do not pan out," he said. But eyeing the big picture, he continued, "As far as Africa is concerned, the good news is that mistakes of the past do not need repeating - serial monotherapy, dual therapy, etc. And the prospect of developing more user-friendly regimens may avoid the degree of resistance we saw due to the complexity of earlier HAART regimens."

For now, community activists like Cheng are pushing for RR-type drugs to be tested in clinical trials enrolling volunteers with long treatment histories and MDR HIV, not just in drug-naïve persons. That would provide faster and truer "real world" answers to the critical issue of the latest drugs' risk-benefit ratio. "We need a true salvage study," Cheng stressed, "to help us really understand what each drug is contributing." Greater community input and oversight are also needed for proposed trials .

Back at Tibotec, Erickson is discussing a trial for heavily treatment-experienced individuals and future trials in infants. "Let's keep our fingers crossed," he summed up. "It's early. But we need better drugs out there right now."

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