Hydroxycarbamide (Hydrea) is an anti-cancer drug that has been in use for over 30 years. It was previously known as hydroxyurea.

Hydroxycarbamide has been shown to boost the antiviral activity of some anti-HIV drugs, particularly ddI (didanosine, Videx / VidexEC). It does this by inhibiting the human enzyme ribonucleotide reductase, which is involved in the production of DNA. Many questions remain about whether hydroxycarbamide improves the effectiveness of antiretroviral therapy and whether hydroxycarbamide with ddI is a safe and tolerable regimen in the long-term.

Interest in hydroxycarbamide has waned following revelations that it increases the risk of potentially fatal side-effects associated with ddI and d4T (stavudine, Zerit).

Bristol-Myers Squibb, the drug company that also makes ddI, makes hydroxycarbamide. It is known by the brand names Hydrea and Droxia.

How it works against HIV

As an anti-cancer drug, hydroxycarbamide stops body cells from dividing, which, in turn, slows or stops malignancies and tumours from growing.

Hydroxycarbamide is thought to work against HIV in a number of ways:

• By reducing cell replication, it may directly slow production of new HIV particles^[1][2].
• It boosts the effects of the adenosine analogues ddI and tenofovir (Viread).
• It may increase the active levels of other types of nucleoside reverse transcriptase inhibitors (NRTIs).

However, the use of hydroxycarbamide in addition to antiretroviral therapy blunts increases in CD4 cell count. This has led some doctors to be reluctant to prescribe hydroxycarbamide to people with advanced HIV infection.

When is hydroxycarbamide used?

The use of hydroxycarbamide in HIV-infected patients is experimental. There are several theories about the best way to use the drug, although the benefits of specific strategies remain unproven.

Hydroxycarbamide is sometimes used in salvage therapy regimens by people who have developed resistance to the NRTIs, in order to improve ddI’s effectiveness against resistant virus.

Given hydroxycarbamide’s ability to enhance the antiviral effects of ddI, and possibly other NRTIs, some experts advocate the use of hydroxycarbamide to intensify drug combinations that have not produced undetectable viral load.

The use of hydroxycarbamide as part of a first-line treatment regimen has also been advocated, although this is not a popular strategy due to side-effects which develop with long-term use. First-line hydroxycarbamide may enable patients to conserve future drug options and reduce the cost of treatment.

Taking it

Hydroxycarbamide is usually dosed at 500mg twice daily for HIV. This is a lower dose than that used for cancer. It is available in capsule form and needs to be taken twice a day to ensure adequate blood levels of the drug. However, taking it once a day at a dose of 600mg with ddI may reduce side-effects and maximise the drug’s potency^[3].

People with low CD4 cell counts are generally advised to avoid hydroxycarbamide due to its detrimental impact on CD4 cell count recovery. Hydroxycarbamide should not be used during pregnancy.

Taking hydroxycarbamide without anti-HIV drugs has very little effect on HIV.

Effectiveness

Overall, trials of hydroxycarbamide have produced conflicting results. Early research suggested that anti-HIV combinations that include hydroxycarbamide produce superior virological results compared to combinations that do not. However, more recent data have found that hydroxycarbamide adds no benefit to triple combination therapy, and that long-term use of ddI, d4T and hydroxycarbamide is associated with weaker viral load suppression compared with standard triple regimens as well as a higher frequency of side-effects than ddI and d4T alone^[4][5].

Many studies have concentrated on the use of hydroxycarbamide to augment the antiviral effect of ddI. However, most of these studies were small and non-randomised. One study found that just over half of the patients receiving ddI, d4T and hydroxycarbamide had achieved viral load below 200 copies/ml after twelve weeks treatment, compared with a quarter of those in the ddI, d4T and placebo arm. However, two-year follow-up showed that only 24% of the patients remained on the original regimen, and that side-effects were more common among those taking hydroxycarbamide. Of the 24 people still taking hydroxycarbamide, only 11 had viral loads below 200 copies/ml^[6].

Hydroxycarbamide has also been examined as an adjunct to treatment interruptions, being taken before or during a break from anti-HIV therapy. Although many studies have been carried out, they have generally found no consistent benefit of hydroxycarbamide treatment. For more information, see Hydroxycarbamide (Hydrea).

The use of hydroxycarbamide in ‘step-down’ or simplified regimens has also been tested. Although switching from three-drug anti-HIV combinations to hydroxycarbamide and ddI may enhance the anti-HIV activity of the immune system, it may also lead to a rapid rebound in viral load in some patients^[7][8]. Furthermore, the usefulness of a ‘step-down’ regimen associated with high levels of toxicity in the long-term is unclear.

Finally, hydroxycarbamide may be useful in salvage therapy, both for its own modest anti-HIV effects, and as a means of boosting the activity of some NRTIs. One study found that the addition of hydroxycarbamide to a failing regimen of d4T and 3TC restored the anti-viral efficacy of the combination. However, the effectiveness of the combination was short-lived^[9].

Hydroxycarbamide may improve the antiviral effect of drugs other than ddI. For example, hydroxycarbamide can improve the ability of cells to activate d4T, and improve the anti-viral effect tenofovir^[10][11]. It may also boost levels of the active forms of AZT, 3TC (lamivudine, Epivir), abacavir (Ziagen) and ddC (zalcitabine, Hivid), as well as improving the effectiveness of other anti-viral drugs such as aciclovir (Zovirax), ganciclovir (Cymevene) and cidofovir (Vistide).

Side-effects

When taken with ddI or d4T, hydroxycarbamide increases the risk of pancreatitis, liver toxicity and peripheral neuropathy^[12][13]. Reports of pancreatitis-related death among several people on hydroxycarbamide and ddI have dampened enthusiasm for this drug. A study investigating the effects of switching from indinavir, AZT and 3TC to indinavir, ddI and d4T with or without hydroxycarbamide reported excess toxicity amongst recipients of hydroxycarbamide. Amongst 202 study participants, three cases of clinical pancreatitis occurred in those receiving ddI and d4T, and four more in those receiving hydroxycarbamide. Two of these cases were fatal^[14].

Adding hydroxycarbamide to any NRTI can also increase the risk of death due to liver toxicity. Data from the United States showed that a third of liver toxicity cases among people on d4T and ddI resulted in death, compared to 55% of cases among people also taking hydroxycarbamide^[15].

Hydroxycarbamide can also suppress the bone marrow’s production of blood cells, causing blood disorders such as low white blood cell levels. It may also cause nausea, mouth or skin ulcers, hair loss, fever and changes in skin colour.