HIV Digest	HIV Digest Archive

Hydrea (or Hydroxyurea) has long been available to treat certain types of cancer, and recently, as a therapy for sickle cell disease. Earlier this decade, test-tube studies discovered that Hydrea enhanced the activity of some HIV antivirals, specifically ddI (Videx). Eventually a small controlled study of Hydrea/ddI was conducted in France on 12 antiviral-naive patients. Although there were no significant increases in CD4 counts for those in the study, the combo resulted in decreases in viral load levels averaging 98% (1.7 log).

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The Hydrea/ddI antiviral partnership works this way. To reproduce, HIV must take over immune cells called CD4s. To do this the virus must use certain CD4 cell compounds to build up its own genetic material. Hydrea decreases these cell compounds. The nucleoside analog ddI provides phony, defective versions of these cell compounds. With no where else to turn, HIV is forced to take up ddI's phony, debilitating compounds. Consequently, HIV is unable to take over the cell and reproduce.

The advantage of Hydrea over other HIV antivirals is that because Hydrea decreases human cellular components and not continuously mutating viral ones, HIV resistance to Hydroxyurea cannot develop. Viral resistance to ddI also develops more slowly, if at all, when used with Hydrea. That is because Hydrea confers non-resistant abilities to ddI. So ddI in combination with Hydrea seems to be able to stop ddI-resistant virus from developing. Since the first French study, larger studies have confirmed that Hydrea/ddI can suppress HIV successfully, although without significant increases in CD4 cells. Despite the lack of large CD4 increases, a Hydrea/ddI combination offers additional advantages over current antiviral regimens.

Saving for a rainy Day

Choosing a combination, then having it fail, may limit treatment options down the road, because of antiviral cross resistance. That's why planning a long-term antiviral strategy is important. When a combination fails, you should have a backup combination available that is not cross-resistant to previous ones. This second combination should also be strong enough to get viral load down to undetectable on the new ultrasensitive tests.

A Hydrea/ddI regimen uses just one HIV antiviral. This enables one to preserve other antivirals for that rainy day when Hydrea/ddI fails and its time to switch regimens. For those not yet wanting or ready to take the protease plunge, this can leave more to choose from as backup therapy, especially if you have yet to use other antivirals.

Of course, this is assuming a Hydrea/ddI combination does fail. Its effectiveness as an antiviral combination appears to last a long time and under circumstances where other antivirals lose their effect. There are now many examples of patients who for years have maintained low, detectable, HIV levels on Hydrea/ddI therapy. For these patients there has been little sign of viral rebound. This appears unique to Hydrea/ddI therapy. Usually in the presence of detectable virus, antiviral regimens develop resistance and viral load quickly returns to pre-treatment levels.

The cancer drug Hydrea enhances the efficacy of the HIV antiviral ddI (Videx). Taken together, the combination can reduce viral load averaging 98%, although usually without significant increases in CD4 cells. Because Hydrea affects human compounds, not HIV directly, the virus is unable to evolve resistance. Also, viral resistance to ddI develops more slowly, if at all, when used with Hydrea.

For those needing a more potent regimen to bring down viral load, d4T in combination with Hydrea/ddI has shown in studies to decrease viral load by an average of 99% (2.0 log), a reduction by half over Hydrea/ddI alone. But drug toxicities such as neuropathy can result when using these two "D" drugs.

If something even stronger is called for, protease inhibitors have been safely used with Hydrea/ddI. Moreover, ddI can now be taken once a day, so such a regimen will be easier to dose.

Despite these advantages, a Hydrea/ddI regimen is not for everyone. Hydrea can be mildly toxic to bone marrow and certain cells. This is why CD4 cells do not greatly increase on Hydrea therapy. If your CD4 count is below 200, or your immune system is suppressed in other ways, using Hydrea may not be a good idea. However there is evidence that Hydrea used below current HIV dosing levels (500 mg twice a day, far lower than the dose used to treat cancer) may offer some benefit, while limiting toxicities.

In addition to ddI, other drugs in the pipeline may also have their efficacy enhanced by Hydrea. They include the new nucleotides PMEA (Preveon) and PMPA, and the nucleoside F-dda (or Lodenosine). These drugs have unique resistance profiles. That means they may still work for you regardless of your antiviral history, hopefully more so with Hydrea in the equation. Trials are now enrolling for both PMEA and PMPA in combination with Hydrea. Call 800-GILEAD-5. For other Hydrea trials, call 800-TRIALS-A.

Further questions remain about the benefits and complications of Hydrea therapy. On the plus side, Hydrea may help those who have had other nucleoside analog drugs like 3TC or d4T fail by enabling these drugs to work again. In addition, a Hydrea/ddI regimen may do something else other drug combos may not do. That is, help maintain, or even improve, the body's immune response against HIV. This immune response is important. It is how the body contains the virus. Without it, HIV disease progresses more quickly.

However, although Hydrea regimens suppress HIV, the clinical benefits from increased CD4 cells resulting from antiviral therapy are only now being understood. Because Hydrea limits CD4 increases, Hydrea therapy may not offer as good an improvement in overall health as other antiviral regimens. It is yet to be determined whether the HIV suppression by a Hydrea combo offsets the immune suppression caused by the Hydrea. Like all the other HIV drugs, the long-term side effects of Hydrea are not known. All these questions need to be answered.

While it may not give the CD4 boost that other antiviral combinations do, Hydrea's effectiveness seems to last and last. Its an antiviral which increases the potency and durability of other drugs, and expands treatment options.

Author Profile:  Robert Folan-Johnson
Robert Folan-Johnson is a member of the AIDS Writers Group.
Email:	rofojo@sfac.org