Hydroxyurea -- Ever More Fascinating!

The AIDS/HIV treatment pipeline is simply full of surprises. Hydroxyurea, a relatively powerful experimental treatment for HIV, has managed to steal the spotlight from the ever-mighty protease inhibitors and continues to baffle even the most jaded researchers and treatment advocates. For starters, hydroxyurea isn't even an antiviral; it is an anti-cancer drug -- approved as a treatment for leukemia and advanced ovarian cancer -- and has been on the market for more than thirty years.

Numerous test tube studies have shown that hydroxyurea is capable of slowing down, maybe even stopping HIV replication in virtually all immune system cells and tissues; a feat beyond that of many antiretrovirals approved to date. They also show that it does not cause resistance while somehow increasing the activity of some antiviral drugs against drug-resistant strains of the virus.

Finally, over the past year, one group of researchers studying hydroxyurea has claimed to have achieved sustained undetectable viral loads in two newly-infected people for one year after all antiviral drugs were stopped. Adding an interesting twist is the fact that Bristol Myers Squibb, the manufacturer of hydroxyurea, no longer holds the patent to the drug, allowing competing manufacturers to produce generic, low-cost versions of the same compound.

Claims about hydroxyurea's potential benefits are not new to the HIV/AIDS community. Hydroxyurea made its debut in 1993 at the IX International AIDS Conference in Berlin, when Dr. Robert Gallo, then with the National Cancer Institute (NCI), presented early test tube results involving hydroxyurea. Gallo showed that the drug had potential antiviral activity, not by manipulating parts of HIV like other antiviral drugs, but rather by altering parts of the cell which HIV targets instead.

How Does It Work Against HIV?

Hydroxyurea alters the cellular enzyme ribonucleotide reductase, a protein needed by the virus so that it can transcribe its RNA into DNA inside the cell. 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 transcribe its RNA into DNA. The viral DNA can then take over the cell's nucleus, turning it into a virtual HIV factory. Without ribonucleotide reductase, the virus cannot successfully take over the cell.

Hydroxyurea and Drug Resistance

Because hydroxyurea directly interferes with the functioning of the targeted cell and has no contact with the virus, the chances of developing resistance are much lower than it would be with most or all antiviral drugs currently approved. Those drugs -- protease inhibitors, nucleoside analogues, etc. -- directly interfere with how the virus works. Because the virus changes its structure (mutates) rather quickly, a drug or combination of drugs that directly targets HIV may become weak and unable to halt HIV production. While cells are capable of mutating and becoming resistant to the onslaught of drug therapy, they often do so at a much slower rate than viruses.

Towards the end of 1994, a paper published in Science made some startling claims regarding hydroxyurea. The paper, prepared by Dr. Franco Lori and NCI's Robert Gallo, reported that hydroxyurea surpassed the antiviral activity of all antivirals, given its capability of halting HIV replication in virtually all immune system cells and tissues, including the brain.

Its ability to penetrate the brain means that hydroxyurea has the potential to treat or prevent neurological diseases directly caused by HIV, such as HIV encephalopathy. Hydroxyurea also penetrates the lymph tissues where the majority of HIV in the body is thought to be. Studies have shown that most drugs currently approved do not easily enter these major reservoirs of HIV.

How it's given --

By mouth. One tablet in the morning and one in the evening (500 mg twice a day). The capsules should be swallowed whole with plenty of water.

Where it's available --

Hydroxyurea is available from most pharmacies, with a prescription. Because hydroxyurea is not specifically approved for the treatment of HIV, HIV-infected folks who rely on ADAP don't stand a good chance of getting access to the drug. Because Bristol Myers-Squibb no longer holds the patent or exclusive marketing rights, it is entirely possible that hydroxyurea may never be approved by the FDA as an effective treatment for HIV.

Possible side effects --

Like many anti-cancer drugs, hydroxyurea can alter the body's ability to produce new white blood cells and red blood cells. This can result in fatigue and anemia (due to low red blood cell production); risk of bruising or bleeding (due to low platelet production), and lymphopenia (reduced lymphocyte production). This effect is usually mild, especially with the low dose being studied for HIV.

Side Effects and Toxicities

The blood levels of hydroxyurea needed to slow or stop HIV are approximately 50 times lower than those required to treat leukemia and other forms of cancer. Like most cancer drugs, hydroxyurea can reduce bone marrow production of white blood cells, red blood cells, and platelets. While safety data from hydroxyurea studies involving people with HIV/AIDS seem to suggest that the standard research dose -- 500 mg twice daily -- does not appear to be associated with any major side effects, it's possible that hyroxyurea may cause low red blood cells (anemia), low white blood cells (leukopenia), and low platelets (thrombocytopenia). This may be especially true if you take hydroxyurea with other drugs that cause these problems, such as AZT and other cancer drugs.

HIV Studies

In recent years, hydroxyurea has been put to the test, most often in combination with ddI (Videx) and sometimes d4T (Zerit) -- a highly suspect combination of three Bristol Myers-Squibb drugs -- in a number of small clinical trials. According to Dr. Lori, hydroxyurea boosts ddI's strength 20 times without causing additional side effects. In test tube studies, the combination was able to bring viral replication to a virtual stand still (99.9% decrease in viral activity). Moreover, Lori has found that in both test tube and clinical studies, hydroxyurea allows ddI to work even against strains of HIV that have developed resistance to ddI. While the combination of ddI and hydroxyurea does not prevent the emergence of mutations that cause ddI resistance, resistant mutants still remain sensitive to standard doses of ddI in the presence of hydroxyurea. The reason for this is no. In test tube studies, the combination was able to bring t entirely understood and is still being investigated by Lori and other researchers. There has been a slew of small and medium sized clinical trials of hydroxyurea and ddI.

Trials have involved both previously untreated (naive) and treatment-experienced patients and have yielded fairly consistent results. The majority of patients in clinical trials were able to achieve at least a 1.5 log reduction in viral load, regardless of their prior drug experience. Not surprisingly, undetectable viral loads were most commonly reported in people with low viral loads (usually less than 10,000) and little or no drug experience. In one particular study of ddI/d4T hydroxyurea, treatment-experienced people had viral-load decreases of 30- to 300-fold.

Apparently, the proof that hydroxyurea is effective is not in its ability to elevate T-cell counts. While some studies have demonstrated an increase of more than 100 T-cells in people taking hydroxyurea/ddI therapy, this was most often the case in people who had high T-cell counts (greater than 450 cells) to start with. Because hydroxyurea can suppress the bone marrow's ability to produce new white blood cells, it is not surprising that its use did not result in substantial T-cell increases.

Data from one particular trial of hydroxyurea and ddI, reported by Dr. Jorge Vila in the British medical journal Lancet, caused quite a media frenzy. The study involved two newly-infected people who took ddI and hydroxyurea (standard doses of both). Patient A had been infected for three months and patient B had been infected for twelve months. Both volunteers had very low viral loads; patient A had 676 copies and patient B had 1,120 copies. After a year on this combination, both had undetectable viral loads and only one, patient B, was found to have a traceable amount of viral DNA in his lymph node sample.

Both volunteers agreed to stop their antiviral therapy at the end of the first year. After one year off therapy, both their blood and lymph nodes were re-checked for viral load. The researchers could not detect virus in either of their blood samples but were able to detect viral DNA, although extremely low levels, in their lymph nodes. Two years after stopping their antiretroviral treatment the volunteers still had no viral rebound.

Proviral DNA was still present, although at very low levels. As outlined above, one explanation for the continued absence of viral load going up in these people could be that this combination works in resting cells -- such as non-activated lymphocytes (including T-cells, monocytes, and macrophages) -- which are thought to harbor a significant amount of virus, and are virtually untouched by the other antivirals.

However, it is important to understand the limitations of this study. Data from newly infected individuals -- whether they involve hydroxyurea, protease inhibitors, or any possible combination of therapies -- does not necessarily apply to all people infected with HIV. Hydroxyurea, like all anti-HIV therapies, needs more carefull study. Studies should investigate every possible characteristic of HIV infection: heavy to moderate treatment experience, drug naive as well as asymptomatic and symptomatic people (men, women and children of all ages, ethnic origin and sexual orientation) with HIV.

The possibilities of hydroxyurea as a treatment option are, quite possibly, endless. Perhaps hydroxyurea's prolonged anti-HIV activity, in the absence of active drug therapy, will require only periodic bursts of treatment, rather than a continuous dosing schedule, minimizing toxicity. This carries extraordinary possibilities for further reducing perinatal transmission rates, especially in geographic locations with limited antiretroviral access. Studies to assess the potential benefits of hydroxyurea for severely immune-compromised, antiretoviral-experienced people with low T-cells must be initiated immediately.

Hydroxyurea continues to be studied in various clinical trials -- most of which are too small to answer significant questions -- in the United States and Europe, including an ACTG trial (ACTG 307), and an AmFAR sponsored trial, fully enrolled, should have results shortly.

New Data!

Numerous studies of hydroxyurea have shown how effective it can be in terms of drastically reducing viral load. But what about the immune system? Because hydroxyurea does not appear to increase T-cell counts and may even lower them, this may not be welcome news to people who already have low T-cell counts.

Does hydroxyurea offer any benefits to the immune system?

In recent months, many researchers have been scrambling to find out how strong the immune system really becomes after starting antiviral therapy. After all, someone with 100 T-cells who experiences a 200 T-cell increase after starting antiviral therapy may not be out of the danger zone just yet; we still don't know how healthy these new T-cells really are. T-cells can be broken down into two different groups: naive T-cells and memory T-cells.

Naive T-cells are new T-cells produced by the body that can respond to any disease-causing organism it encounters. Memory T-cells, on the other hand, are needed to respond to organisms that have invaded the body before; it's much easier for the immune system to respond to the presence of a familiar organism than to a new, unfamiliar one. Infections such as tuberculosis, PCP, and CMV are all kept in check by memory T-cells.

At a conference this past winter in Chicago, much new data from studies of hydroxyurea demonstrated that the drug does have an effect on both of these types of T-cells. Naive T-cells were increased quite a bit, 140% in people taking hydroxyurea. Overall, memory T-cells increased but at a much slower rate than naive T-cells. These results are similar to those from many other studies involving other antiviral drugs. The bottom line? Even if you experience a massive T-cell increase, it may take awhile, possibly a year or more, to ensure that these T-cells are capable of doing the job they're supposed to do.

Back to the September 1998 contents page.