HAART Version 2.0
What will a true second-generation antiretroviral drug be like? It's a common marketing claim and there have been several pretenders, but so far, failing to step cleanly away from the shortfalls of its forerunners has compromised every new bid for the title. Atazanavir is a fledgling protease inhibitor that may be just the ticket for knocking down virus levels in therapeutic newbies without incurring lipid problems -- so long as its few toxic quirks remain benign. But what about folks whose ship of susceptability has long since sailed? Which criteria have to be satisfied for antiretroviral therapy to become truly effective, easy to live with, resilient, flexible and safe in the long run? And what are drug developers doing to try to get there?
Potency is at the top of everyone's wish list for a new antiretroviral. Reduction of viral load by at least 1.5 log copies within a few weeks is nearly an accepted standard for first line protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). The standard for nucleoside RT inhibitors (NRTI) tends to be a little less stringent, with 1.0 log drops in viral copy numbers often deemed very good. But it's clear from the gap in the proportion of trial subjects with viral load results below 200 copies and those below 50 copies that a lot of people on the fringes of suppression are barely getting by. A breakthrough in potency should be able to push viral replication down so far that virtually everyone who goes below 400 also goes below 50. That kind of potency would effectively arrest HIV activity whenever and wherever it kicks up and will be what it takes to hold out against the inexorable pressure of drug resistant viral mutants.
There are other benefits to potency. A drug able to stop HIV in the test tube at very low concentrations may also be likely to work at doses far below the point where toxicity kicks in. Such a drug might also give the advantage of being far more tolerable in day-to-day use. And it's been demonstrated that tolerability is a big factor in keeping adherent to any particular regimen. This is the second big criterion where there's ample room for improvement: offer consumers an effective drug that they won't dread taking because of queasiness, loose bowels or nightmares, and they will vote with their feet. Good tolerability makes the bitter pill of lifetime HAART much easier to swallow.
The current Holy Grail of convenience is to achieve once-daily dosing with a coformulated product -- all your pills in one, tiny tablet in the morning. (Did someone mention The Patch?) Dosing intervals depend on the rate a drug is cleared from the body by metabolism. Most protease inhibitors have had a tendency to activate the very mechanisms responsible for flushing drugs out of the body. The big exception is ritonavir, which has the opposite effect. So powerful is ritonavir at slowing down the metabolism of PIs that its main use has turned out to be as an inhibitor of liver enzymes rather than an inhibitor of HIV. Unfortunately, PIs that rely on ritonavir for longevity have made a deal with the devil. Ritonavir brings with it tolerability problems as well as unpredictable interactions with other medications and uncertain but worrisome associations with long-term toxicity. Any drug that depends on ritonavir boosting to stay in the race is living in the past.
Which brings up another vexing quality: long-term safety. As the giddy flush of success during the first years of HAART tempered after lipodystrophy, lipoatrophy and cardiac risk factors began to show up, physicians and community members began questioning the underlying assumptions of the Hit Hard, Hit Early treatment dogma. They started looking for a middle path that treads a little more lightly without letting HIV get the upper hand. One problem is that the only way to uncover long-term side effects is to put people on drugs then wait and see; long-term effects are the most difficult aspects of drug therapy to pin down. But the consequences are finally being appreciated; if the mounting fears over cardiac risk have had a silver lining, it's that researchers are now more willing to use powerful research tools such as randomized trials in order to detect signs of toxicity before they begin cropping up everywhere at once. Nonetheless, consumer voices will need to grow louder before significant post-marketing and surveillance studies become routine responsibilities of bringing a new drug to market.
The other great long-term failing of most current generation drugs is the ease with which drug resistant mutations can erode their activity. In part, drug resistance stems from inadequacies in all of the previously mentioned criteria. A drug that inherently lacks potency will let HIV replicate in its presence, leading quickly to loss of susceptibility. Skipped doses mean inadequate drug concentrations, which can also drive resistance. And poorly tolerated drugs are more likely to be skipped than pills with benign side effects. Metabolic and genetic variations among individuals also come into play; drugs that never quite achieve maximum blood levels may dip below effective concentrations during the normal course of a day for some and not others. It remains to be seen if this variability becomes more problematic as dosage intervals are stretched to ever longer -- and more convenient -- periods. Interactions between agents affecting liver metabolism can play havoc with other drug levels. Finally, even people who have had excellent success on their regimens for many years may eventually take drug holidays due to fear about what is happening or might happen to the shape and constitution of their bodies. Unsupervised or ill-considered stopping and starting of therapy is another probable source of viral replication and resistance.
A truly next generation antiretroviral will not only need to have activity against the canonical HIV of yore -- fast becoming a museum piece -- but should also strike in a way that the multitude of variants resistant to existing drugs are also stopped cold. This dream drug would act against viruses from multiple worldwide subtypes and recombinations of subtypes, both from drug naive and drug exposed persons. Even so, having flexibility against existing mutant strains isn't enough; the new drug will need to remain resilient against end runs by HIV genes freshly mutated against its particular shape and function. The ideal drug would block HIV at such a crucial step in its life cycle that no mutation could get by. Even if replication continued in sanctuary sites receiving sub-therapeutic concentrations, the drug should be able to stand up to low level sniping and hold fast.
Taken all together, it's easy to understand why coming up with a breakaway second generation drug is such a tall order. But that doesn't stop the pharmaceutical companies from trying -- or from practicing wishful thinking. Several manufacturers have made or are making the claim for new drugs in their pipelines, but which ones have a shot at the title and which ones fall short?
While agents directed against new targets are exciting and a few candidates are on their way to the pharmacy, there's still a lot of room for improving inhibitors of the old standby HIV targets, reverse transcriptase (RT) and protease. (See "New Targets Bring New Challenges" in this issue for a look at future classes of ARV.)
Atazanavir is a protease inhibitor with efficacy comparable to current PIs in a treatment-naive trial population. As a welcome step away from the ranks of existing PIs, atazanavir seems to have a minimal impact on cholesterol and triglyceride levels. In trials, asymptomatic, elevated, bilirubin levels occurred in a third to a half of trial participants and jaundice was observed in a few others. A genetic predisposition to these side effects has been proposed, suggesting that susceptible individuals may one day be identified before putting themselves at risk. Moderate diarrhea was the main tolerability complaint. A recent bit of uncertainty over abnormal cardiac rhythmic patterns has brought out the caution flag for a very large pre-approval access program that should have started by now. Otherwise, the drug seems to retain good activity against HIV with early-stage resistance to other PIs -- although strains with multiple PI-resistance mutations probably become increasingly less susceptible to atazanavir. The good news is that viral strains developing resistance to atazanavir may still be susceptible to the existing lineup of PIs. Once-a-day dosing, low lipid toxicity and the ability to rescue emerging resistance with earlier protease inhibitors all contribute to the case for using atazanavir as a first-line agent. Its usefulness for PI failure and salvage situations is not as clear, however. Barring setbacks, Bristol Myers Squibb indicates the large expanded access program should begin shortly.
Tipranavir is a compound designed with a twist on the chemical structure that defined most earlier protease inhibitors. Although it has been tested in far fewer patients than atazanavir, tipranavir's most notable characteristic seems to be an ability to suppress multiply-PI resistant and wild-type virus with about equal efficacy. Primary resistance to tipranavir itself seems to be slow to develop. On the down side, tipranavir may share lipid-raising problems similar to earlier PIs. Furthermore, achieving sufficient blood levels to combat resistant strains and allow convenient dosing may require combining tipranavir with low-dose ritonavir, a strategy which brings the familiar set of cautions about tolerability, drug interactions and uncertain long term toxicities. In trials to date tolerability issues included gastrointestinal, neurologic and psychiatric effects.
Due to those limitations, tipranavir can't really be considered a second-generation product and it would probably never enjoy significant market acceptance if it is approved. But the drug deserves special attention because of its unique potential to patch over problems created by resistance to the first wave of PIs. It represents a solution that is urgently needed today: a lifesaver for people who've run out of treatment options. Tipranavir's conventional course of development has been limping along. Maybe the best plan for this drug is to fast track examining the dosage and safety issues, then to start making it available through compassionate use on a case-by-case basis before opening up an expanded access program for people unable to construct any other viable treatment regimen. This could conceivably start happening later this year. If sponsor Boeringer-Ingleheim is unable to consider taking extraordinary steps to move tipranavir forward, then perhaps an orphan drug development company could step in. This one is too important to treat as business-as-usual.
There are quite a few non-nucleoside reverse transcriptase inhibitors in the pipeline. The biggest failing of current generation NNRTIs is the ease with which resistant mutations develop that can also wipe out susceptibility to other drugs in the class. Coming up with a unique resistance profile is the principal goal of these newcomers.
DPC-083 is an NNRTI from Bristol Myers Squibb currently in Phase II studies in drug naive patients. The agent is chemically similar to efavirenz with similar potency against wild-type HIV but has also shown activity against virus with efavirenz-resistant mutations. On the tolerability front, early trials have reported more episodes of rash but fewer problems with dizziness compared to efavirenz. DPC-083 is also a potent inducer of a liver metabolic pathway, which could mean drug interaction issues down the line. This drug doesn't seem to be running away from the pack, but as a transitional compound, maybe valuable lessons can be learned to help guide the development of future NNRTI candidates.
Two NNRTI drugs from Belgian biotech Tibotec have also appeared on the horizon. TMC125 is in very early development but has shown activity in brief studies with both drug-naive as well as efavirenz-resistant individuals. Less is known about TMC120, another NNRTI, although short periods of dosing in people with HIV demonstrated activity.
As for new nucleoside analogs, two candidates from Triangle Pharmaceuticals merit watching. FTC (emtricitabine) is furthest along in development and may be offered to the FDA for review by the end of this year. FTC is chemically similar to 3TC and has similar potency against wild-type HIV. A longer half-life in the blood makes FTC a good candidate for once-a-day regimens. Unfortunately, overlapping resistance with 3TC means that people already resistant to its cousin won't benefit from FTC's convenience.
Further back in the pipeline is DAPD (amdoxovir), which may have excellent activity against AZT- and 3TC-resistant viral strains. Although resistance to DAPD itself can occur, it's still not certain how common or problematic that will be. It's thought that HIV with certain mutations conferring resistance to NNRTIs may actually become more susceptible to DAPD. On the whole, the drug remains attractive, especially for rescuing individuals with NRTI resistance, but its development has been slow. Triangle recently dropped one of its drug development projects and is moving FTC towards completion, so maybe DAPD is up for some long overdue attention from its sponsor.
Walk Don't Run
Last year, new enrollments to trials of capravirine, a NNRTI being developed by Agouron/Pfizer, were put on hold because of vascular inflammation observed in animal studies. No such toxicities have been seen in people who have received capravirine in clinical trials and people already on studies have continued to receive the drug. This agent is attractive because it promises to rescue individuals who have developed resistance to efavirenz (although not nevirapine). Early studies described gastrointestinal side effects, but significantly, did not report problems with rash.
A number of drugs early and not so early in development bit the dust recently. Emivirine, an NNRTI from Triangle Pharmaceuticals was canned after data from large and expensive Phase III trials told the company that their drug was not potent enough to stand up in the marketplace. Triangle also pulled the plug on DMP-450 (mozenavir), a protease inhibitor that promised little more than existing PIs offer.
Several compounds in the Dupont stable acquired by BMS after their merger last year have been left on the moving van. Two promising protease inhibitors, DPC-681 and DPC-684 were dropped due to toxicity as has an NRTI candidate, DPC-817. One NNRTI candidate, DPC-961 was tabled after an unusual number of patients reported suicidal ideation. At a major conference two and a half years ago, Dupont billed two of their new NNRTI hopefuls, DPC-081 and DPC-083, as second generation breakthroughs; these too have now been quietly scrapped. Hopefully these stillborn progeny are part of the price to be paid before a stronger and gentler generation of HIV therapy finally appears.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.