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Hydroxyurea+ddI Returns, Franco Lori Presents: A "Virostatic" Approach to Antiretroviral Therapy: Beyond ddI/Hydroxyurea?
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HIV DART 2008, December 9-12, 2008, Rio Grande, Puerto Rico
Mark Mascolini
A group headed by Franco Lori, long-time proponent of combining didanosine (ddI) and hydroxyurea to control HIV, is sizing up a new coformulation of those two agents. Lori's company, ViroStatics, aims to develop agents of the same name that combine two mechanisms--controlling viral replication (the role of antiretrovirals like ddI) and suppressing immune activation (the role of cytostatics like hydroxyurea). But a virostatic agent on Lori's drawing board uses neither ddI nor hydroxyurea.
Lori's ViroStatics colleague Michael Stevens outlined the rationale for these novel agents by plotting a five-compartment model of immune deficiency resulting from HIV replication. (1) Viral replication sets off (2) immune activation, which promotes (3) immune deficiency. Traditional antiretrovirals block this path by quelling replication. But the multiplying virus also triggers (4) mucosal damage in the gut, which depletes CD4 cells and causes (5) microbial translocation. In turn, microbial translocation fans the flames of immune activation, further promoting immune deficiency. And immune activation fed by microbial translocation can spur further viral replication.
Antiretrovirals do little to stymie this second pathway, according to Stevens. But he argues that cytostatic agents like hydroxyurea disrupt three steps of this important pathway: microbial translocation to immune activation, immune activation to further HIV replication, and immune activation to immune deficiency.
The original rationale for pairing ddI and hydroxyurea--back in pre-HAART days--was that hydroxyurea inhibits synthesis of deoxynucleotides (which HIV needs for reverse transcription) and thereby promotes incorporation of deoxynucleoside analogs like ddI into viral DNA [2]. But regimens mating ddI with hydroxyurea never caught on because of the combined toxicity of the drugs and the development of safer, stronger nucleosides.
VS411, the first clinically tested compound in the virostatic line, coformulates ddI and hydroxyurea in a capsule that could allow once-daily administration with one or two pills. Results of a phase 1 study involving 12 people in a four-way crossover investigation of fasted and nonfasted bioavailability of ddI and hydroxyurea found a 30% lower ddI maximum concentration with VS411-2 than with standard enteric-coated ddI. But ddI area under the curve (total exposure during a dosing interval) remained equivalent to exposure with standard ddI.
In this study, taking hydroxyurea with a high-fat breakfast unexpectedly prolonged absorption and lowered concentrations of the drug. Hydroxyurea maximum concentration and area under the curve proved significantly lower with food than on an empty stomach. That finding encourages Lori and Stevens about coformulating hydroxyurea and ddI because ddI must be taken in the fasting state.
A 4-week phase 2 study of VS411-2 is exploring five doses of ddI/hydroxyurea (200/300 mg, 200/600 mg, 200/900 mg, 400/300 mg, and 400/600 mg, all once daily) in 60 people. (In an earlier trial of hydroxyurea plus ddI and stavudine, the lowest hydroxyurea dose was 600 mg [3].) Lori and Stevens also expect the phase 2 trial to yield preliminary safety and efficacy results. Meanwhile, ViroStatics is developing a new agent that exploits the dual mechanism of ddI plus hydroxyurea but does not depend on either drug
Whether virostatics can enhance HIV control depends not only on their safety and efficacy, but also on whether they quell immune activation in a more clinically meaningful way than current antiretroviral combinations. As a deluge of recent research shows, today's regimens do douse HIV-inspired inflammation and may explain lower rates of non-AIDS disease progression in people on steady therapy. But Stevens pointed out that immune activation in people with undetectable viremia never returns to normal. Even so-called elite controllers, whose viral load stays low without antiretroviral therapy, have over-excited immune systems.
Lori and Stevens are betting that virostatics like a ddI/hydroxyurea coformulation, and the new compound containing neither of these drugs, will make HIV infection in humans like SIV infection in sooty mangabey monkeys. Unlike humans with well-controlled HIV infection, mangabeys have limited immune activation throughout the course of their SIV infection, and they never get sick. Lori and Stevens want to make HIV-infected humans like SIV-infected mangabeys, and they hope that's what virostatics will do.
References
1. Lori F, Stevens M. Development of VS411, a virostatic drug fixed-dose combination designed to inhibit both HIV and immune hyperactivation. HIV DART 2008. December 9-12, 2008. Rio Grande, Puerto Rico. Abstract 11.
2. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science. 1994;266:801-805.
3. Lori F, Pollard RB, Whitman L, et al. Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency. AIDS Res Hum Retroviruses. 2005;21:263-272.
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