AIDS Alert Q&A: Italian researcher continues to focus on hydroxyurea treatment for HIV
Italian researcher continues to focus on hydroxyurea treatment for HIV
[Editor's note: In this Q&A interview, Franco Lori, MD, scientific director of the Research Institute for Genetic and Human Therapy (RIGHT) of Washington, DC, and Pavia, Italy, discusses the recent positive outcomes of his research for an optimal hydroxyurea treatment for HIV and what he calls the "Virostatic" approach to HIV treatment.]
AIDS Alert: You've named the process "Virostatic therapy," which combines antiretroviral drugs that suppress HIV with hydroxyurea for the purpose of preventing cell activation. What is it in your latest research of this approach that you think will most interest HIV clinicians and other researchers?
Lori: Virostatics are drugs combining antiviral and cytostatic properties. The cytostatic (prevention of cell proliferation) activity of Virostatics represents a novel mechanism of action, in addition to the known antiviral activity of some Virostatic combinations, such as mycophenolate and abacavir, or hydroxyurea and didanosine. Preventing cell proliferation breaks the pathogenic cycle of cell proliferation-HIV replication-cell proliferation. In fact, persistent HIV replication induces chronic immune stimulation, resulting in T cell activation and proliferation, and consequently, in the exhaustion of the immune system. Cell proliferation, in turn, sustains HIV replication, because proliferating cells produce a higher number of viral particles. At present, no antiretroviral drug addresses the issue of over-proliferation of immune competent cells. In this respect, Virostatic therapies are unique, as they attack HIV by "modulating" those cells that the virus needs to survive.
AIDS Alert: Hydroxyurea lost favor among HIV researchers and clinicians several years ago because of treatment failure and serious adverse events in clinical trials, including the deaths of some subjects. Why did you continue to pursue hydroxyurea as an HIV treatment, even in the face of these setbacks?
Lori: We are committed to developing the combination of hydroxyurea and didanosine (ddI) because hydroxyurea enhances the efficacy of ddI without increasing serious, life-threatening toxicity. A recent retrospective analysis of the AIDS Clinical Trials Group (ACTG) studies has shown that hydroxyurea does not increase the risk of pancreatic toxicity associated with ddI. The authors of the ACTG report suggest the possibility that factors other than hydroxyurea, such as lifestyle or predisposition, might have contributed to the death of those individuals.
Regarding antiviral activity, the four initial trials (>500 patients) in which hydroxyurea was added to a ddI or ddI-stavudine (d4T) backbone consistently showed that hydroxyurea increases the antiviral activity of ddI. Subsequently, hydroxyurea was used in addition to 3-4 other drugs that, by themselves, were fully suppressive. In this context, hydroxyurea could not demonstrate additional activity, and this has been interpreted as "treatment failure."
Our RIGHT 702 trial, published earlier this year, not only has confirmed the antiviral activity of the Virostatic combination of hydroxyurea and ddI, but also indicated that the optimal dosage of hydroxyurea (600 mg total daily dose) is half of the dosage used in previous trials. In the July manuscript published in AIDS, we explain the mechanism underlying this apparent paradox: by increasing hydroxyurea concentrations one does not increase the cytostatic activity of the drug, but one does increase its cytotoxic activity. In other words, lowering the hydroxyurea dosage decreases toxicity without loosing activity.
AIDS Alert: Since your most recent study was published in July, what kind of feedback have you received from other researchers regarding including the smaller dose of hydroxyurea in HIV treatment regimens? Also, have there been any pharmaceutical companies interested in pursuing your research into a single pill that contains an antiretroviral plus hydroxyurea?
Lori: Basic scientists continue to be intrigued by the concept. Among clinicians, in the United States there is a minority of strong believers, usually clinicians that had used, and continue to use, the drug. Most of the others are skeptical, and some of them clearly are against the idea. In Europe the climate is more favorable, and many colleagues believe that hydroxyurea suffered in the past from the lack of a clear, well-designed drug development plan. Several have expressed interest in revisiting the concept of a single pill that combines low-dose hydroxyurea with ddI. We are very committed to this concept. If no company is interested, we will develop the new pill ourselves.
AIDS Alert: Why do you feel it's important to continue investigating the virostatic approach? What will this add to the HIV drug arsenal that isn't already addressed?
Lori: Virostatics represent a novel class of drug combinations with a double mechanism of action. One component of the combination targets a cellular enzyme, and cellular enzymes are not prone to resistance. In addition, hydroxyurea compensates for didanosine resistance. Therefore, the resistance profile of Virostatics is unique. We expect that this unique resistance profile will endow Virostatics with the characteristics of durability; however, long-term studies are required to confirm this hypothesis. Preliminary results also suggest that Virostatics will be more "forgiving" of missed doses of drugs.
AIDS Alert: With the development of multidrug resistant HIV, particularly among HIV patients who have been in treatment for a decade or longer, do you believe the virostatic approach could prevent this trend or provide a successful salvage therapy?
Lori: A recent publication from a French group has shown that viruses that became resistant to HIV were more sensitive to hydroxyurea 14. For mutants carrying the M184V mutation or M41L+T215Y mutations, a defect could be detected by using target cells in which dATP pools had been reduced by pretreatment with hydroxyurea. The authors then found that many, but not all, viruses carrying RT resistance mutations display an increased sensitivity to hydroxyurea. Moreover, the 3D study has shown that hydroxyurea was more efficient in drug-experienced than in naïve patients. Therefore, we believe that Virostatics can be a useful component of salvage therapies in those patients that have developed drug resistance.
Editor's note: In this Q&A interview, Franco Lori, MD, scientific director of the Research Institute for Genetic and Human Therapy (RIGHT) of Washington, DC, and Pavia, Italy, discusses the recent positive outcomes of his research for an optimal hydroxyurea treatment for HIV and what he calls the "Virostatic" approach to HIV treatment.Subscribe Now for Access
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