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AIDS Treatment Update

HYDROXYUREA STUDIES: Licensed cancer treatment boosts effects of some anti-HIV drugs




 

AIDS Treatment Update, Issue 64, April 1998

Hydroxyurea is a cheap, licensed drug used in the treatment of some forms of leukaemia. A few years ago, researchers found that it can also boost the antiviral effects of ddI in test-tube studies (see AIDS Treatment Update issue 26). The Fifth Conference on Retroviruses and Opportunistic Infections held in Chicago in February heard the results of several treatment studies looking at its risks and benefits.

TRIAL RESULTS Swiss researchers tested hydroxyurea in a placebo-controlled trial, comparing a group of 72 people taking d4T/ddI/hydroxyurea with a control group of 72 people taking just d4T/ddI. Their average viral load at baseline was about 30,000. After 12 weeks, 54% of people receiving hydroxyurea had achieved viral load below 200, compared with only 28% of those not receiving hydroxyurea. The proportions achieving viral load below 20, measured with an ultra-sensitive viral load test, were 19% and 8% respectively (abstract 656).

In another study, 31 people with higher viral load (average 100,000) were treated with d4T/ddI/hydroxyurea. There was an average 1.3 log reduction in viral load and about 50 CD4 cell increase after 12 weeks of therapy, and after 16 weeks eight out of eleven participants had achieved viral load below 500 (abstract 653).

A number of cases have also been reported in which hydroxyurea treatment appears to be associated with disappearance of detectable HIV, even in latently infected cells containing HIV proviral DNA (the most stubbornly persistent form of HIV's genetic material). Dr Franco Lori presented data on 24 patients treated with ddI/indinavir/hydroxyurea, of whom 10 started treatment just weeks after infection. After 11 months, the average CD4 count increase was 168 and all participants had viral load below 500. Seven out of eight people who underwent lymph node biopsy had no detectable viral RNA in their lymph nodes, while two out of six had no detectable proviral DNA either (abstract LB11).

One patient in the study was investigated even more closely. Even after increasing the sensitivity of the tests for proviral DNA and HIV RNA up to 60-fold, it was only possible to detect one cell in ten million that was able to produce infectious HIV particles. This result is even more dramatic than those achieved after 2.5 years of triple therapy in David Ho's laboratory. This individual has now been off treatment for 13 months without any viral load rebound. However, it has been suggested that these impressive findings may be a consequence of the very early stage at which treatment was started, rather than of the specific drugs used.

These intriguing results are still very preliminary, and need to be confirmed in much larger studies with proper control groups for comparison.

SALVAGE THERAPY Some doctors are also using hydroxyurea as part of salvage therapy regimens for people who have developed resistance to many or all of the licensed anti-HIV drugs. One test-tube study found that even ddI-resistant strains of HIV remained susceptible to ddI when it was given in combination with hydroxyurea. Since hydroxyurea works by affecting the human cell rather than HIV (see box opposite), HIV resistance mutations are unlikely to have any effect on hydroxyurea's action.

TAKING HYDROXYUREA Most studies testing hydroxyurea are using it in combination with ddI, since this combination seemed to be the most effective in the test-tube. A report at the Retroviruses conference two years suggested that hydroxyurea did not boost the anti-HIV effects of AZT in laboratory tests. Other test-tube studies suggest that the only anti-HIV drugs whose effects are likely to be enhanced by hydroxyurea are ddI, abacavir (1592U89) and adefovir dipivoxil.

A much lower dose of hydroxyurea (often 500mg twice daily) is used when treating people with HIV, compared with the dose used for treating leukaemia. Nevertheless, the downside of hydroxyurea is that it can be quite toxic, suppressing the bone marrow and causing problems such as neutropenia, mouth ulcers and hair loss.

People adding hydroxyurea to their ddI-containing regimen may experience a greater reduction in viral load because of the increased antiviral effects, but any CD4 count rise may be smaller because of hydroxyurea's toxic effects on blood cells.

BOX 1: HOW DOES IT WORK? Hydroxyurea doesn't attack HIV directly, but instead it works indirectly to boost the effects of ddI.

Human cells use an enzyme called ribonucleotide reductase to make the building blocks of their genetic material, DNA. In HIV-infected cells, HIV uses the same building blocks to assemble its own genetic material. NRTI drugs such as AZT and ddI work by mimicking these building blocks, tricking HIV into building its DNA with the drug rather than with a real building block.

Hydroxyurea inhibits ribonucleotide reductase, reducing the number of normal building blocks within the cell. This makes it more likely that an HIV-infected cell will use an NRTI block rather than a real block, increasing the chance of interrupting HIV replication.

Since it affects a cell enzyme, rather than an HIV enzyme, there may be less chance for resistance to develop to hydroxyurea, compared with anti-HIV drugs.

There is also preliminary evidence suggesting that hydroxyurea may have other beneficial effects, such as encouraging the death of HIV-infected cells through a process called apoptosis.



 


Copy rights reserved to ATN 1998 AIDS Treatment News (ATN), the world's first treatment newsletter for people with HIV, reports on mainstream and alternative treatment, access to care, Web resources, public policy, and political action.



Information in this article was accurate in April 1, 1998. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.