There's lots of talk these days about new targets for antiretrovirals -- fusion, integrase, zinc fingers, and other approaches. Drugs using current targets (the reverse transcriptase and protease enzymes) have plenty of problems, including difficult dosing, short- and long-term side effects, resistance -- the list goes on. The following are brief descriptions of some of the new drugs in development from currently approved classes.
As with all drugs in development, take everything you read here with a grain of salt. Today's "promising new treatment" is often tomorrow's forgotten footnote.
Nucleoside analogs were the first type of drug approved to fight HIV. While there are already six approved nucleosides (and one nucleotide), many people have become resistant to some or all of them or can't take them due to side effects. So new drugs in this class that work against resistant virus with fewer side effects and easier dosing are being studied.
Coviracil (emtricitabine, FTC) is a nucleoside analog that is chemically similar to Epivir (3TC). Both drugs stop working if HIV develops only one mutation (called M184V), so Coviracil won't work for people who are resistant to Epivir. And both drugs have a low incidence of side effects. So why develop this drug? Well, it's taken once a day, which we like, but Epivir was also approved for once-daily dosing back in June. Triangle Pharmaceuticals, the company behind Coviracil, was recently purchased by Gilead Sciences, so a pill combining Gilead's Viread (tenofovir) with Coviracil is a real possibility. That would be one pill, once a day -- cool.
Trials have shown that people taking Epivir can successfully switch to Coviracil, and that Coviracil is superior to Zerit (d4T) when used in combination with Videx (ddI) and Sustiva (efavirenz). The latter study was actually closed early due to the superiority of Coviracil (81% had viral loads below 50 after six months, compared to 70% of those on Zerit). But two things might have helped Coviracil in this situation. First, it was taken as part of a once-daily regimen, while Zerit was taken twice daily, so adherence might have been an issue. Second, people in the Zerit arm had a higher dropout rate due to side effects (possibly because they were taking it with Videx).
Coviracil is also being tested for hepatitis B, and initial trials have shown that it is quite effective. Triangle submitted their NDA (new drug application) to the Food and Drug Administration (FDA) in November. Since the FDA didn't see an urgent clinical need for Coviracil, the company was granted only a standard, rather than an accelerated, approval, so the drug probably won't be on the market until the fall of this year.
Amdoxovir (DAPD) is a twice-daily nucleoside analog that has shown activity in the test tube against virus that is resistant to certain nucleosides and non-nucleosides. And some mutations actually make HIV more sensitive to amdoxovir (again in the test tube). Taken by itself for two weeks, it lowered viral load by 1.7 logs (a decrease of 98%) -- a substantial antiviral effect. Triangle was ready to start a trial of this drug in combination with T-20 (Fuzeon), but it has been delayed while further safety tests are added in. Those kinds of trials -- drug companies working together to offer people two new drugs instead of just one -- are what people with HIV have been demanding for years. Let's hope it gets off the ground soon. Amdoxovir is also being studied in combination with CellCept, a drug used for organ transplant patients that may boost amdoxovir's effectiveness. Don't expect approval until 2004 at the earliest though.
ACH-126,443 is another once-daily nucleoside that should work against both HIV and hepatitis, and, in the test tube, is active against virus that is resistant to Epivir (3TC). Achillion Pharmaceuticals just started a Phase II trial to find out if this is also true in people, but the trial design may make it tough to enroll: you must be resistant to Epivir and have been taking it for the last four months, have a viral load within a very narrow range (1,000 to 30,000), and be willing to possibly be randomized to Epivir for another month, after which time you can get ACH-126. In the test tube, ACH-126 does not damage mitochondria like other nucleoside analogs can. If this is true in people -- and that's a big "if" right now -- it could mean that ACH-126 would be less likely to cause lipodystrophy than certain other nucleosides. Approval is a few years away at best.
This class of drugs surprised everyone by being as effective as protease inhibitors when used as part of a three-drug combination. But a single mutation (K103N) can make the entire class useless. New drugs for people who are resistant to approved NNRTIs are badly needed.
Capravirine is a twice-daily NNRTI that is active in the test tube against HIV with the dreaded K103N mutation. Other mutations can make capravirine useless, however, such as Y181C, which also creates resistance to Viramune (nevirapine). One Phase II study of capravirine taken with Viracept (nelfinavir) in people resistant to the NNRTIs found that half of them reached viral loads below 400, but was it the capravirine or Viracept that was responsible? And capravirine was no better than placebo in preventing viral load rebounds in this trial.
Research was moving along until the FDA put all capravirine trials on hold in January of 2001 due to reports of vasculitis (inflammation of blood vessels) in dogs. But Pfizer reported at the International AIDS Conference in Barcelona last July that this side effect has not been seen in people, so trials were recently re-started. Phase I trials suggested that capravirine is ten times stronger than the approved NNRTIs in people who have never taken them. Let's see if that translates into real-world use. So far, capravirine has not caused the rash that is often seen with the other NNRTIs.
DPC-083 (BMS-561390) is a Sustiva-like NNRTI that was originally developed by DuPont Pharmaceuticals. It stays in the body a very long time, so it could theoretically be taken every other day -- but everyone seems to think that's too difficult for people to do, so it will most likely be given once a day. In one trial, people who were resistant to the available NNRTIs switched to DPC-083 and added one new nucleoside -- 70% of them got their viral load below 400. But only 40% of those who did not add a new nucleoside got below 400, so you may need other new drugs available to get the full benefit of DPC-083.
Since taking over DuPont, Bristol-Myers Squibb (BMS) has put this drug on hold while they compare it to three other NNRTIs they have in the pipeline (DPC-082, DPC-961, and DPC-963). So we'll have to wait and see which drug they decide to pursue. In the past, BMS has put drugs on the back burner while they pursued a lead candidate (Zerit languished in Phase I trials for years while BMS studied Videx), so they might not study two non-nucleosides at the same time.
TMC-125 is a twice-daily NNRTI that also looks good against HIV that is resistant to currently available non-nucleosides. In one small study, sixteen people who were highly resistant to Sustiva or Viramune switched to TMC-125 for eight days and got a viral load drop of 0.9 log (a decrease of about 87%). More time on drug will hopefully lead to even greater drops -- but will they be sustained? Some people who had never taken any antiretrovirals before had viral load drops of over 3 logs (99.9%) after a week on this drug, so it may turn out to be quite strong.
An interesting study compared viral load results in people who took TMC-125 alone for a week to earlier studies of people who took five-drug combinations, none of whom had ever taken antiretrovirals before. TMC-125 by itself produced better viral load drops (almost 2 logs, a decrease of 99%) than the five-drug combinations (1.5 logs, or 97%). What this means, no one knows. Could TMC-125 be used with just one other drug? We'll have to wait and see. The answer remains a long way off, as does approval, since trials are still being done to find the best dose. Johnson & Johnson recently acquired Tibotec-Virco, the company behind this drug. Hopefully, this won't slow down the drug's development.
When protease inhibitors made their debut in 1995, they were hailed as "wonder drugs" that might even eradicate the virus from the body. That didn't happen, of course, and shortly after they were approved, side effects like lipodystrophy and elevated cholesterol and triglyceride levels began showing up. Once again, the need is for drugs that work for people who have become resistant to the approved PIs, with fewer side effects and easier dosing.
Atazanavir is a once-daily PI from Bristol Myers-Squibb with a unique quality -- it doesn't seem to cause the kind of triglyceride and cholesterol increases seen with other PIs. It can, however, raise bilirubin levels, a substance produced by the liver. As with Crixivan, however, this increase in bilirubin levels doesn't seem to mean that the drug is damaging the liver. Atazanavir worked as well as Viracept in one study, but since Viracept may not be the strongest PI, that's not particularly impressive.
The real test was a head-to-head comparison of atazanavir to Sustiva. In this trial of people who had never taken anti-HIV drugs before, 32% of people taking atazanavir had viral loads below 50 copies after 48 weeks, compared to 37% of those on Sustiva. That's about the same, but the big question is: why did Sustiva perform so poorly in this study? Other trials have found rates of 80% or more reaching 50 copies while on Sustiva. It might have been the viral load test that was used, the way the data were analyzed, or the fact that the trial was done around the world, in people with many different subtypes of HIV. Still, atazanavir's low pill burden (two pills once a day) and the fact that it does not increase lipids may make it a good candidate for use as a first-line drug.
The $64,000 question: will it work for people who are resistant to other PIs? BMS has shown that it's effective in the test tube against HIV that is resistant to other PIs, but whether that's true in people is still to be determined. The drug was submitted to the FDA for approval in December. If the FDA grants accelerated approval, it should be approved by June; if not, look to the end of the year. Atazanavir is currently available through an expanded access program (877-726-7327).
Tipranavir is a twice-daily PI that has languished for years while various drug companies searched for the right dose. It appears that Boehringer Ingelheim (BI), the new owner, has finally decided on a dose. Unfortunately it includes 400 mg of Norvir (ritonavir) a day, which many people can't tolerate. BI is also testing a lower dose of Norvir (200 mg a day) in people who have never taken antiretrovirals. Tipranavir is important because early trials have shown that it may work in people who are resistant to other PIs. One trial found that people resistant to multiple HIV drugs were still responding to tipranavir after a year, with viral load drops of up to 99%. Large-scale trials to confirm this are scheduled to begin early this year, and Boehringer Ingelheim has agreed not to wait until those trials enroll before starting an expanded access program. Instead, people who don't qualify for the trials or who live too far from a trial site will be able to get the drug through an expanded access program if they meet other requirements. Those randomized to approved drugs in the trials will be able to take tipranavir after eight weeks if the other drugs don't work.
So if you missed last year's tiny T-20 early access program (which filled up within a week), tipranavir is an option to explore. The best-case scenario for a tipranavir early access program is early this year. Since T-20's approval is expected around the same time, people in need of treatment options may be able to combine tipranavir with T-20 for the best antiviral effect. Look for approval sometime in 2004.
Fosamprenavir (GW433908) is an old drug in a new suit. One of the biggest drawbacks to Agenerase (amprenavir) has always been the pill count -- eight huge pills twice a day! Taking it with low-dose Norvir can lower that to eight pills once a day, but that's still a lot of pills. With some antiretrovirals now being dosed at one pill once a day, GlaxoSmithKline understands that Agenerase can't compete, so they've come up with this pro-drug of Agenerase. Fosamprenavir turns into Agenerase once the body absorbs it. It will probably be dosed at just two pills once a day when taken with low-dose Norvir. Efficacy so far appears similar to Agenerase, and side effects are also about the same, perhaps less. The main decision now for Glaxo is what dosing regimen to recommend -- twice daily without Norvir is still possible. Of course, if you are resistant to Agenerase, fosamprenavir won't work for you either. Application for FDA approval will most likely happen this year.
Mark Milano is a longtime AIDS treatment activist and a treatment educator at ACRIA.