Using drugs that inhibit HIV in different ways, and at different places in the virus' reproductive cycle may be important to maximally suppress HIV replication. Hydroxyurea appears to work against the virus differently than the currently available anti-HIV drugs, and thus it is particularly interesting.
This drug has been used in people for many years and is approved for the treatment of several types of cancer and is now "off patent" and thus relatively inexpensive. About five years ago, Dr. Gallo and his group at the National Cancer Institute (NCI) found that hydroxyurea had activity against HIV. The drug inhibits factors made by human cells that HIV needs in order to reproduce, rather than directly inhibiting viral factors. All currently approved anti-HIV drugs target viral factors. The NCI group found that the anti-HIV activity of the nucleoside analogue reverse transcriptase inhibitors (NARTIs), such as AZT (Retrovir), ddI (Videx), ddC (Hivid), d4T (Zerit), and 3TC (Epivir), was significantly enhanced when they were combined with hydroxyurea. Additionally, because hydroxyurea targets cellular rather than viral factors, it may be more difficult for the virus to become resistant to this drug. Whereas HIV mutates very rapidly with each replication cycle, cells are much more stable. In fact, there have been no reports of resistance to hydroxyurea to date.
HIV more readily infects activated CD4+ cells which in turn produce more virus than resting or `latent' cells. HIV can also infect resting CD4+ cells, however. These infected resting cells die off more slowly than the activated cells and act as a reservoir for HIV infection. Most of the approved anti-HIV therapies, with the exception of ddI, have better activity against HIV in activated cells. Hydroxyurea is more active against resting cells, however, making the combination of hydroxyurea and ddI attractive for targeting a reservoir not addressed by other anti-HIV drugs. Furthermore, recent studies have shown that virus is present, for many years, in those with viral loads below the limit of detection of currently available tests. In those studies, virus was still found in this resting pool of CD4+ cells that hydroxyurea and ddI are especially good at targeting.
If you think of the HIV replication process as similar to that of building a house using 2 by 4 wooden planks, then the NARTIs would be defective 2 by 4s, where if they are used in the building of the house the house would collapse (i.e. new virus will not be produced). But because of toxicity issues with the NARTIs, where you can only reach a certain dose before developing serious side effects, only a limited number of defective 2 by 4s will be in the wood pile and the odds of the construction worker picking up a defective 2 by 4 is small. Hydroxyurea, on the other hand, can be thought of as a shipment of functional 2 by 4s not arriving at the construction site. The house still has to be built, but now the number of functional 2 by 4s available has decreased while the number of defective 2 by 4s remains the same. Therefore, the chances of the construction worker picking up and using a defective 2 by 4 have increased resulting in many more houses collapsing.
Recent reports on hydroxyurea in combination with other anti-HIV drugs have stirred interest in the research and HIV-affected communities. Most of the excitement has centered on observations in three people receiving hydroxyurea in combination with other anti-HIV drugs who subsequently have stopped all anti-HIV therapy. After attaining "undetectable" levels of HIV RNA, these people discontinued anti-HIV therapy for a variety of reasons. Normally, withdrawal of therapy results in renewed viral activity, but these three individuals have shown no signs of viral rebound (renewed viral replication). After up to one to two years, they continue to have HIV RNA below the limit of detection on the currently available tests.
One of these three people was a recent seroconverter (he had been infected for approximately six months at the time treatment was begun) and reported a viral load of about 85,000 copies of HIV RNA prior to initiating therapy which included ddI + hydroxyurea + indinavir (Crixivan). The individual's viral load quickly went below the limit of detection (500 copies of HIV RNA) after starting the three-drug regimen. Subsequent tests also found him below the limit of detection of HIV RNA in bodily fluids and lymph tissue. This person developed hepatitis A and had to stop all three drugs after about five months. During the three weeks that the hepatitis A was active, the individual's viral load remained below the limit of detection despite having stopped anti-HIV therapy. After the hepatitis symptoms resolved, the patient restarted the three-drug regimen, but discontinued again two months later, choosing to forgo therapy altogether for the time being. Surprisingly, his viral load has remained below the limit of detection, despite stopping anti-HIV therapy, for over a year. Tests looking for viral DNA (virus already integrated into the cells) also proved negative in the blood stream. Additionally, it was very difficult to detect the presence of HIV in the lymph tissue of this individual. Only by using an extremely sensitive test was HIV genetic material (HIV DNA) found -- one cell contained HIV among 60 million. It remains unclear whether the presence of HIV DNA in such a small proportion of cells is capable of rekindling productive HIV replication. Certainly for the time the patient has been followed, it has not been able to do so.
The other two people had very low viral loads when they initiated a regimen of ddI and hydroxyurea. They received this combination for about a year, when they chose to stop taking the medications. Two years after stopping their anti-HIV medications, viral load remains below the limit of detection. However, HIV in the lymph tissue of these two individuals was much more easily detected.
These reports are very intriguing, but not the result of controlled studies and almost certainly do not reflect a common experience among people using hydroxyurea. Controlled studies of hydroxyurea have not shown quite as dramatic anti-HIV responses, although the other studies used the drug in a three-drug combination with a protease inhibitor.
One of the largest studies of hydroxyurea to date involved 142 people with CD4+ cell counts between 200 - 500, who received ddI+d4T or ddI+d4T+hydroxyurea. The dose of hydroxyurea used was 500mg twice daily. Most of the participants had received no previous anti-HIV therapy. The results after twelve weeks are shown in Table 1.
More recently a study of 24 people, 10 of whom had primary HIV infection (were newly infected with HIV), received ddI+hydroxy-urea+indinavir (Crixivan). The average duration of therapy so far is about a year. In all 24 people the combination affected viral load decreases to below the limit of detection (400 copies of HIV RNA). This finding itself is rather unusual, as few, if any, studies have reported 100% success rate in reaching "undetectable" levels of HIV RNA. On average CD4+ cell counts increased by 168. This finding too is unusual because most other studies of hydroxyurea reported little if any gain in CD4 counts. In fact, the lack of a CD4+ response has commonly been seen as a direct consequence of the unique activity of hydroxyurea. However, this is the only study which employed the drug in a combination that included a protease inhibitor. This study group included the exceptional case of the person described above who has had no return of viral activity a year after stopping therapy.
The optimal dose of hydroxyurea is still unknown. Studies have used hydroxyurea ranging from a low dose of 500mg once a day to as high as 400mg three times a day. The most studied dose is 500mg twice a day, which is shown to have relatively few side effects. Studies are now planned to determine the optimal dose and dose scheduling for this drug. A small Canadian study enrolled 26 people with CD4+ cell counts between 100-300 , who had been on ddI for at least six months prior to enrolling. Participants received one month of ddI alone and then received one month of ddI+hydroxyurea (either 500mg once daily or 500mg twice daily) followed by one month of ddI alone. People receiving the twice daily dose of hydroxyurea had greater decreases in viral load, with an average drop of about 0.6 logs after four weeks on the combination therapy, compared to 0.02 log reduction for people on the once daily dose. There were no changes in CD4+ cell counts with either dose. When hydroxyurea was discontinued, viral load increased. Based on results from this study, the 500mg daily dose of hydroxyurea is considered inadequate. Whether dosing needs to go higher than 500mg twice daily remains to be seen. Because of its unusual design and the lack of any three-drug combination arms, this study can tell us very little about the ideal way to use hydroxyurea. New studies will explore more optimal uses of the drug.
The primary side effects noted with hydroxyurea have been bone marrow suppression which has led to decreases in neutrophils (neutropenia), red blood cells (anemia) and platelets (thrombocytopenia). Other side effects have been nausea, vomiting and rash, though these are uncommon. As with many drugs, people who start hydroxyurea therapy with a low absolute neutrophil count (less than 1,500 cells/mL) were more likely to develop neutropenia, which can result in increased risk of developing bacterial infections. High dose hydroxyurea (doses used for treating cancer is about twice as high as that used for HIV) can suppress white blood cell production (in replication rate of cancerous T cells).
Most hydroxyurea studies have been in people who have relatively intact immune systems. While use of the drug in people with advanced disease has not been studied as extensively, there have been many anecdotal reports of people using hydroxyurea as part of a salvage regimen with good results.
It is very likely that hydroxyurea will play a useful role as part of a combination therapy against HIV. However, the optimal way of using this drug still has not been determined. Laboratory studies suggests that a combination of hydroxyurea and either ddI, abacavir (1592) or possibly f-ddA (a new nucleoside analogue currently in development) may result in better antiviral activity than when combined with AZT, ddC, d4T or 3TC. However, these are laboratory studies and the best NARTIs to use with hydroxyurea is still unknown. Hydroxyurea is clearly a drug that should be researched further; with its novel mechanism of action against HIV, added anti-HIV effect when combined with some, if not all, of the nucleoside analogue drugs and good side effect profile, it is likely to be a useful therapeutic option for people living with HIV. The sad thing is that it has taken so long to discover and develop the useful properties of this drug against HIV disease, when it has been readily available from the earliest days of the HIV epidemic. Because the drug is "off patent," and will likely be offered generically once approved for HIV disease, this lack of clear financial opportunity has undoubtedly slowed its development.
Hydroxyurea (HU, Hydrea) has garnered increasing attention and recent study results show that it might be particularly useful as part of a regimen for people who have not previously taken anti-HIV therapy and for people who have extensive prior use of anti-HIV therapy who are trying to creatively put together effective regimens. One of the largest studies with hydroxyurea included 183 people with an average CD4+ cell count of 350, a viral load of about 30,000 copies of HIV RNA. Volunteers had not previously received anti-HIV therapy and were assigned to AZT + ddI, ddI + d4T, ddI + hydroxyurea or ddI + d4T + hydroxyurea. The dose of hydroxyurea used in this study was 500mg twice a day (total daily dose of 1,000mg). The results after 24 weeks of the study are shown in Table 3.
A second study of hydroxyurea involved chart reviews of 18 people with advanced HIV disease and who had been on extensive prior antiretroviral therapy. All of the charts reviewed were for people who fit this description who received d4T + 3TC + hydroxyurea (500mg twice a day, total daily dose of 1,000mg). The median reduction in HIV RNA levels was almost 1.8 logs after 8 weeks of therapy. However, people experienced significantly more side effects including severe anemia (decrease in red blood cells), neutropenia (decrease in neutrophils) and hair loss. Although people with advanced HIV disease in this study experienced a good antiviral response, these results also suggest that hydroxyurea may cause serious abnormalities in blood chemistry.
The FDA has required Bristol-Myers Squibb, manufacturer of ddI (didanosine, Videx), d4T (stavudine, Zerit) and hydroxyurea (HU, Hydrea), to issue a warning about newly reported cases of fatal pancreatitis in studies using these drugs. Four recent deaths have been reported; two in studies using a combination of ddI, d4T and a protease inhibitor and two in an arm of an AIDS Clinical Trials Group study (ACTG 5025) using ddI, d4T and hydroxyurea (plus a protease inhibitor).
Pancreatitis, a painful inflammation of the pancreas, has long been associated with ddI use. Many cases, some fatal, were reported in the early ddI expanded access program nine years ago. Some cases of pancreatitis have been reported in people using any of the nucleoside analogue drugs, but the highest incidence has always been associated with ddI.
The two deaths in studies of ddI, d4T and a protease inhibitor happened in otherwise healthy people with high CD4+ cell counts (above 600) and viral load below the limit of detection (<200 copies HIV RNA).
In the ACTG study, it was unclear whether hydroxyurea or the other drugs were responsible for the pancreatitis. The researchers, however, pointed out that the group receiving hydroxyurea experienced a greater frequency of side effects overall than other groups in the study. This may be because they received higher than normal doses of hydroxyurea and/or that they were receiving more drugs in their regimen (four compared to three) than the other study group.
Bristol-Myers Squibb reported that three of the four people who died had additional risk factors for pancreatitis.
The FDA has also stated that its MedWatch system (which collects reports of drug side effects) has received additional reports of pancreatitis in people using ddI and d4T, both with and without accompanying use of hydroxyurea.
These data serve as a reminder that this potentially fatal side effect is still a serious concern regarding the use of ddI, or ddI plus d4T. The role of hydroxyurea is less clear except that one of its actions is to greatly improve ddI activity. This may account for the pancreatitis in the ACTG study.
Anyone experiencing significant pain at mid-chest level, centrally or slightly to the right of center while on these drugs should immediately report the problem to a doctor. Although these reports do not conclude that people should avoid using ddI or ddI plus d4T, they do warrant additional caution in monitoring and reporting side effects if a person uses these drugs.
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