A new nucleoside analogue in development by Triangle Pharmaceuticals is Coviracil (emtricitabine), formerly known as FTC. The drug is currently being studied at a dose of 200 mg, taken once a day. While the chemical structure of Coviracil looks very much like that of Epivir® (3TC), test tube studies have shown Coviracil to be four- to ten-times more powerful against HIV than its predecessor. Unfortunately, Coviracil may not be very effective for people who have already taken Epivir®. This is because one of the key changes, or mutations, in HIV's genetic structure that occurs as a result of Epivir® therapy -- the dreaded M184V mutation -- also causes resistance to Coviracil.
Gilead Sciences, still recovering from the FDA's rejection of its flagship drug Adefovir, is putting its efforts into the development of Tenofovir, its second nucleotide analogue contender. Tenofovir is active against several different viruses, including some that affect monkeys. This has permitted researchers to study the effect of the drug more extensively in animals, which has helped researchers understand what the drug might do in humans. For example, when Tenofovir was provided to monkeys immediately after becoming infected with SIV -- the primate equivalent to HIV -- the drug prevented the virus from establishing permanent infection. In turn, researchers will soon be looking at the role of Tenofovir as a potential post exposure prophylaxis pill against HIV transmission in humans.
As for Tenofovir's potential as an anti-HIV therapy, people who are resistant to either Epivir® or Coviracil might find Tenofovir to be even more active against their HIV than people who are not resistant to these drugs. This is because of the M184V mutation in HIV's genetic structure, which usually arises during therapy with Epivir® or Coviracil, appears to enhance the way in which Tenofovir binds to the virus.
A few studies of Tenofovir have found that the drug effectively reduces viral load by approximately 50% to more than 90%. In combination with other anti-HIV drugs, it is expected that Tenofovir will decrease viral loads even further.
From Agouron Pharmaceuticals, the makers of the protease inhibitor Viracept® (nelfinavir), comes capravirine (AG-1549). It's not clear what dose will be used, nor has it been determined how safe or effective it is. Test tube data suggest that capravirine will be at least partly effective against strains of the virus resistant to currently approved non-nucs. HIV only needs to develop a single key mutation (K103N) to become highly resistant to any of these older drugs. With capravirine, HIV must develop two or three key mutations in order to become highly resistant to the drug. More information about the effects of capravirine in clinical trials is expected soon.
From the depths of the South American rainforest comes a third non-nucleoside analogue: calanolide A. The drug is derived from an exotic plant (Callophylum) and is being developed by Sarawak MediChem Pharmaceuticals. While the exact dose of the drug has yet to be determined, it will likely need to be taken twice a day. Of particular interest to researchers is the way calanolide A works. Most non-nucs dramatically reduce viral load soon after the first dose is taken. calanolide A seems to have a delayed effect. According to one recent study, calanolide A didn't show any effect against HIV for the first two weeks of therapy. With respect to its potential use for patients already resistant to other non-nucs, test tube data suggest that calanolide A might be effective against some strains of the virus that are at least partly resistant to any of these drugs.
Early results are available from one study that switched patients currently failing a standard anti-HIV drug combination (one approved protease inhibitor and two nucleoside analogues) to a combination of Aluviran, Viramune®(nevirapine), and at least one new nucleoside analogue. Patients in this study had viral loads between 10,000 and 100,000 copies/mL upon switching from their first protease inhibitor-based regimen to the Aluviran-based regimen. After one year, approximately 76% of the patients who switched to Aluviran in combination with nevirapine and at least one new nucleoside analogue had undetectable viral loads (<50 copies/mL).
In terms of side effects, the most common seen thus far include diarrhea, nausea, and muscular weakness (asthenia).
Tipranavir, a protease inhibitor originally developed by Pharmacia & Upjohn and now being produced by Roxane/Boehringer-Inhelheim, is one of the more exciting compounds in the pipeline. In early studies, a dose of 1,500 mg three-times-daily was used. In order to reduce the amount and number of pills needed to be taken, researchers are experimenting with tipranavir in combination with low doses of Norvir® (ritonavir), which will increase the amount of tipranavir in the blood.
No information is yet available from clinical trials evaluating the effect of tipranavir on viral load and T-cell counts in HIV-infected people who have taken other protease inhibitors in the past. Test tube study data, presented in the Fall of 1999, suggest that tipranavir will be effective for patients who have tried and failed at least one protease inhibitor-based combination in the past. As for folks who have never taken a protease inhibitor in the past, tipranavir, when combined with two nucleoside analogues, reduced viral load in the blood by more than 90% after two weeks of therapy.
Simply put, pentafuside binds to a protein on HIV's surface called gp41. Once it does this, HIV cannot successfully bind with the surface of CD4+ cells, thus preventing the virus from infecting healthy cells. Hence, pentafuside works differently than any of the currently available anti-HIV drugs.
A dose for pentafuside has not yet been determined. Because of its fragile structure (it is a peptide), T-20 cannot be taken by mouth. It is currently being developed in an injectable form and will require twice-daily shots.
It is expected that pentafuside, when combined with other anti-HIV drugs, will have strong activity against HIV in people who have never taken anti-HIV medications in the past. According to early results from one study, pentafuside taken alone reduced viral load from anywhere between 30% to more than 90% in patients who had not taken any other anti-HIV drugs in the past.
Pentafuside also holds promise for HIV-positive patients who have taken numerous anti-HIV drugs in the past. As discussed above, pentafuside targets HIV differently than currently available drugs. This means that most people living with the virus, regardless of their treatment history, will likely benefit from using pentafuside. According to one early study, the use of pentafuside alone reduced viral loads to undetectable levels (<400 copies) in approximately 60% of heavily pre-treated patients. Results from studies combining pentafuside with other experimental and approved therapies are expected soon.
Tim Horn is the executive editor of The PRN Notebook, published by Physicians' Research Network in New York, and a member of CRIA's Research Advisory Committee.