Hydroxyurea as a Novel Approach to HIV Therapy, #2
Hydroxyurea (HU) is a continuing story which NATAP started covering in depth with articles about HU which were posted to our web site in the months following the 1997 Human Antiretroviral Conference. The July issue of our newsletter, NATAP Reports, contained an extensive article about HU. That article described the unique way in which HU works and listed the data from a series of studies demonstrating its ability to appreciably reduce viral load when used with ddI or ddI+d4T. HU when used alone does not have an HIV antiviral effect. The article also addressed concerns about using HU. In some studies where viral load was appreciably reduced when using HU with ddI or ddI+d4T, the CD4 counts did not proportionately increase; although, in some other studies CD4 increases were larger. Individuals with higher CD4 prior to using HU therapy may be more likely to achieve a better CD4 increase. HU acts in a way that may prevent CD4s from increasing. This process was detailed in our July issue. HU therapy also may cause bone marrow suppression and neutropenia, a reduction in white blood cell count, which appears to be reversible upon termination of therapy.
The development of drug resistance is a major obstacle in treating HIV. Progression of HIV disease is associated with resistance to drugs used in therapy. All approved HIV drugs developed so far (protease inhibitors, NNRTIs, NRTIs) target virus proteins. HU targets and inhibits a cellular protein. The authors of the published article reviewed here state that cellular proteins are less prone to mutations than viral proteins and that resistance of tumor cells to HU has not been reported after 35 years of clinical experience.
At recent AIDS conferences during the Fall of ‘97 results from a number of HU studies were reported. NATAP is reporting these results on our web site and in the next issue of our soon to be published newsletter.
The report addresses a recently published article, Franco Lori et al, " Combination of a Drug Targeting the Cell with a Drug Targeting the Virus Controls HIV Type 1 Resistance"; AIDS Research and Human Retroviruses, (V.13, N.16, 1997), which discusses how using HU with ddI may prevent ddI resistance from causing therapy failure. Investigators in the study found that virus with genotypic resistance to ddI were suppressed when HU was used with ddI.
Fifty-seven study participants were randomized to ddI monotherapy or HU+ddI for 24 weeks. 38 individuals received HU+ddI and had a viral load reduction of 1.32 log which was sustained for the 24 weeks of the study. Viral load was reduced by .78 log and sustained at week 24 for individuals receiving ddI monotherapy. The authors reported 34 participants receiving HU+ddI treatment for 40 weeks were able to sustain a viral load reduction of 1.21 log.
There appeared to be more patient variability in their viral load response to ddI in this study than in the group receiving HU+ddI. An official from Bristol Myers Squibb said a potential explanation could be that ddI resistance or ddI metabolism may be different when ddI is taken with a drug like HU which effects a cellular protein, allowing the drug to overcome genotypic resistance.
Most of the patients analyzed at 24 weeks had very low but still detectable viral load which allowed investigators to identify mutation or genotypic changes. Two out of eight people receiving ddI monotherapy displayed mutations at positions 65 and 74, which have been described as involved in ddI resistance. Six out of 11 people receiving HU+ddI showed mutations at position 74. The authors concluded that although HU+ddI therapy did not prevent the appearance of a ddI related mutation, suppression of viral load was nonetheless sustained.
Investigators then conducted an in vitro experiment to confirm their findings with a virus clone resistant to ddI and other nucleosides. They found that ddI was unable to suppress this virus except at such high dosages of ddI that would not be tolerable by humans. But when HU was used with ddI at doses which are comparable to that used in clinical studies for HIV treatment, HIV replication was suppressed by >99%. But a question remains. Will HU+ddI have less antiviral effect for individuals with prior ddI experience and resistance? Montaner et al in the article, " A Pilot Study of Hydroxyurea among Patients with Advanced HIV Disease Receiving Chronic Didanosine (ddI) Therapy: Canadian HIV Trials Network Protocol 080" appearing in the Journal of Infectious Diseases (1997;175:801-806) maintain a study they conducted showed that a short course of HU therapy with ddI can have an antiretroviral effect in patients chronically treated with ddI regardless of the length of prior therapy.
These results raise several questions about how HU may be effectively used in treating HIV. Additional studies are required to explore and identify such approaches. How does prior broad nucleoside experience effect subsequent HU+ddI therapy? How does prior NNRTI experience and resistance effect HU therapy? In prior studies, HU combined with AZT was not effective. However, combining HU with other nucleosides including 1592U89 should be explored. It is possible that combining HU with 1592 could prevent failure despite the development of 1592 resistance. If so, several promising treatment approaches might result.
If resistance to HU does not develop and the development of genotypic resistance to an accompanying drug in a regimen does not effect the combination’s efficacy, then it may not be necessary to suppress viral load to below detection to prevent the development of resistance from causing therapy failure. As mentioned above, at week 24, most study participants still had low levels of virus detectable. Despite this, 34 evaluable study participants sustained their viral load suppression out to 40 weeks.
The authors suggest that a HU regimen may be effective in maintenance therapy following induction therapy where viral load is suppressed below detection with a potent combination. Such an induction therapy could consist of a protease inhibitor, a nucleoside such as ddI, and HU. Learning how to use HU in the millieau of HIV treatment may be useful in developing countries where the cost of expensive regimens are prohibitive. See NATAP web site report on the concept of maintenance and induction therapy.
Bristol Myers Squibb is conducting studies exploring the use of HU in combinations including a protease inhibitor, and in a variety of stages of disease. The combination of nelfinavir+ddI+d4T and HU will be explored in acute infection, early disease (>500 CD4), and in individuals with 200-500 CD4.
Researchers should attempt to discover other drugs that target cellular proteins and may also be effective in a similar way as HU. Currently, some individuals who have exhausted treatment options are trying HU with ddI or ddI+d4T.