AIDS TREATMENT UPDATE Issue 26 - Feburary 1995
David Campbell-Morrison

As a leukaemia treatment hydroxyurea (HU) is relatively non-toxic but it can suppress the production of blood cells by the bone marrow. When it is used to treat leukæmia the patient only needs to attend an outpatient clinic for regular blood tests perhaps monthly. This is a far cry from the level of side-effects and the monitoring required for many of the more toxic chemotherapy regimes used for treating cancer.

The blood levels of HU needed to inhibit HIV were 50 times lower than those required to treat leukæmia. Unlike other anti-HIV drugs it achieves its antiviral effect by acting on a human enzyme called ribonucleotide reductase, rather than a viral enzyme such as reverse transcriptase. The body uses ribonucleotide reductase to produce proteins called dNTPs which are normally used as building blocks to make DNA, the genetic material of cells. In HIV-infected cells, the dNTPs are used by HIV's reverse transcriptase (RT) enzyme to produce HIV DNA, which in turn enables the virus to hijack the cell's machinery to produce new HIV particles.

By blocking ribonucleotide reductase, HU depletes the pool of dNTPs, thus hindering HIV reproduction. Viral inhibition by HU was long-lasting compared with nucleoside analogue drugs such as AZT. With HU it was difficult to detect HIV in cell cultures even weeks after the drug had been removed. The possible implication is that there should be no surge of viral activity even if HU treatment had to be temporarily stopped because of toxicity. This might also allow cyclical treatment with HU given in bursts, rather than continuously, to minimise toxicity.

* COMBINATION USE

When HU was tested in conjunction with anti-HIV drugs that inhibit RT, such as AZT or ddI, the antiviral effect was synergistic. The NCI research found that adding HU to ddI gives a 20 times boost to the ddI. The combination was able to bring viral replication to a standstill at concentrations which are readily attainable in the body, and no toxicity to human cells was seen at these concentrations. The combination of HU with RT inhibitors should act in sequence at different stages of HIV's reproductive cycle, perhaps offering more hope of effective viral inhibition than combinations of drugs that act at the same stage, such as two RT inhibitors. Another advantage to HU is that because it acts against a human enzyme, it will not be possible for HIV to develop mutations that protect the virus against the drug.

HU is taken as a capsule and penetrates widely into all body tissues. Its ability to penetrate the brain means that HU has potential to treat or prevent disease caused by the direct effects of HIV on brain-tissue, such as HIV encephalopathy. HU also penetrates the lymph tissues where the majority of HIV in the body is thought to be concentrated during asymptomatic HIV infection. Studies have shown that drugs such as AZT and ddI have little effect on HIV in the lymph nodes

The top research priority for HU is a short study to ensure that no unforeseen side-effects or interactions occur when HU is given in combination with nucleoside analogues. Such a trial is being conducted in France by Professor Lucht at the Hôpital Bellevue in St Etienne. The trial, which is testing HU plus ddI in 20 people with CD4 counts between 200 and 500, has not finished yet but preliminary findings suggest that no side-effects other than those expected from ddI have occurred. The full analysis of the trial is expected in February with publication at a later date.

Bristol-Myers Squibb, the drug company that manufactures HU, is seeking to confirm the test-tube studies and to conduct a Phase I study of HU and ddI to confirm the safety of the drug combination and to determine the correct dosage levels.

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