Resistance, the ability of HIV to become unaffected by anti-viral drugs, is the thorn in the side of HIV research and PWAs. Recent reports suggest that Hydroxyurea (HU) maybe just the tweezers needed to remove the thorn. Some think using Hydroxyurea in combination with ddI may keep HIV sensitive to ddI indefinitely. One group of researchers even claim to have achieved viral eradication in two people. Another important consideration, Hydroxyurea is, relatively speaking, cheap. That's because it's an old drug which no longer has a patent. So what's the deal?
In a study completed this past year, Dr. Franco Lori of the Research Institute for Genetic and Human Therapy, reported some important findings. Fifty-seven HIV+ people with CD4 counts greater than 250 were enrolled. (For unknown reasons the baseline viral load were not included in the report.) 19 received ddI monotherapy and 38 got ddI plus Hydroxyurea. The dose of ddI was based on individual's weight, and all in the combo arm received 500mg of Hydroxyurea twice a day.
All people in the combo arm responded to treatment. An average drop in viral load of 1.18 log was reported at the end of the first month. After that point, small but constant decreases were noted throughout the study period. The results for those on monotherapy were not as good. Two of the 19 did not have any drop in viral load, and eight of the 17 who showed viral load decrease had a rebound in viral activity at some point in the study. Three of the eight had viral loads that returned to baseline. In both arms of this study small increases in CD4 cells were seen with no statistical difference.
The importance of this study is twofold. Firstly, it has shown that a different approach to fighting HIV infection can be of great benefit. Secondly, the study showed, both in vitro (test tubes) and in vivo (living people), that even when ddI resistant mutations occurred, the virus remained sensitive to ddI when used with Hydroxyurea. This was demonstrated through genotype testing. Thus a significant drop in viral loads was achieved and maintained. Similar results were seen in a number of pilot studies.
From our Northern neighbors comes a study by Dr. Julio Montaner of the University of British Columbia. He looked at a group of 26 HIV+ people who had been heavily pre-treated with ddI. All participants had a CD4 of less than 350. They were randomized into two groups, one receiving 500mg a day, and the other getting 1000mg a day. The researchers saw a statistically significant drop in viral load in the group receiving 1000mg a day (the same dose used in Lori's study) compared to the other arms of the study. Though they did not see a rise, or decline, in CD4.
A study from Spain involving 17 HIV+ people, with an average CD4 of 145, also showed good results. Eleven participants were ddI naive and the remaining 7 had been using it for more than 3 months. At the end of six months all had an average drop of 1.44 in viral load, with 7 having a greater than 1.5 log decrease. They also saw an average increase in CD4 of sixty.
Just why does Hydroxyurea seem to work so well with ddI? Here's the theory. Hydroxyurea enters the human cell and stops the production of a protein called adenosine. Adenosine is needed by HIV to replicate. ddI is a adenosine-based nucleoside analog, that means it's an adenosine impersonator. If there's no adenosine for HIV to use it has no choice but to use ddI, even in the presence of genetic mutations known to cause ddI resistance. It's like a bricklayer building a wall. He has two piles of bricks. They look and fit the same but one pile is strong and the other weak. Of course the bricklayer will look to use bricks from the strong pile. However, when the good bricks are gone he will have to use the weak ones if he wants to finish building the wall. The result - the wall crumbles. With HIV the replication cycle crumbles.
These studies all show that Hydroxyurea is "well-tolerated and no major toxicities", (that's doctor talk for not making you sick or killing you). In the Lori study bone marrow toxicity, (the primary toxic effect of hydroxyurea, though reversible), was seen in two people. Both cases were labeled "minor grade" and did not require stopping treatment. Alopecia (hair loss) was noted in three people in the Spanish study. Another Italian study, by Cecilia Simonelli, also demonstrated relative safety of this combination. Based on their individual research, both Simonelli and Montaner's believe that previous treatment with AZT negatively affects the impact of Hydroxyurea on stopping viral resistance. In non-HIV studies GI problems like nausea and diarrhea (Hello!) were reported, though less frequently than bone marrow toxicity and anemia.
Probably the most exciting, and controversial, news comes from France. In July of 1996, a group of French researchers reported the results of work they were doing with the combination of ddI and Hydroxyurea. At the end of one year of treatment with the combo all twenty of the participants had reductions in their viral load. Ten of the twenty had a viral load below detectable. All the participants were people in early HIV infection with no symptoms. An average increase in CD4 cells of over 75 was also noted.
The French doctors wanted to know if viral rebound would occur if treatment were stopped. Two of the trial participants, who had no detectable virus in their blood or lymph nodes, agreed to go off the drug combo. In August of 1997 the doctors reported their findings in a letter published in Lancet, a British medical journal. They found no detectable virus in the blood or in Lymph nodes. They did find proviral DNA however. Proviral DNA is like a blueprint of the virus. If it gets into a cell it could cause the cell to become an HIV factory and infection would start over. The French researchers say the proviral DNA they found are only bits and pieces and not whole strands. Some other researchers are still leery because of the possibility that the bits and pieces could come together and form a whole strand. A new question in the world of HIV.
An important pilot study using ddI and Hydroxyurea in combination with a protease inhibitor (Crixivan/Indinavir) comes from Berlin. Seventeen people (some naive, some pre-treated) received a combo of ddI, HU, and Crixivan for an average of 8 months. Their average CD4 count and viral load, before treatment, was 450 and 700,000 respectively.
All participants achieved and maintained an undetectable viral load during the study period. CD4 counts rose an average of 160. Of particular interest were 5 participants who had entered the study before seroconversion. They tested PCR positive for the virus but were still in the window period for antibody conversion. At study's end all 5 remained negative for Western blot (an HIV antibody test). Dr. Jessen, the lead researcher, believes this is consistent with a strong reduction of viral replication.
Some additional information on Hydroxyurea comes from an actual PWA who had personal experience with HU. He had been on ddI and d4T for about a year. His numbers began to rise so he added the HU. He choose to try HU cause he wasn't ready to try protease inhibitors. For the first 8 months his viral load continued to decline and then began to slowly rise. He is now taking a PI with AZT/3TC. He said that HU had no side effects - "so easy to take". More interesting is that it seemed to clear up his dermatitis, which had been a long standing problem. His dermatitis has returned since he stopped the HU. Since HU stops tumor cells from growing (that's what it's approved for in the US), he theorizes that it may have stopped the over-production of skin cells that results in what we call "dermatitis". He would like to start taking HU again for this condition.
Dr. Paul Bellman of New York said that HU is known to be effective in treating some forms of dermatitis. He has prescribed HU for 15 to 20 PWAs, and combines it with ddI or ddI/d4T. He has seen mixed results with some people doing very well for long periods. He cautioned about possible side effects like lowered white and/or red blood cell counts and liver toxicity. Two of his patients had to discontinue treatment due to these problems. Nevertheless, he sees HU as "a very promising therapy we need to learn more about".
To more clearly understand the role of Hydroxyurea in the treatment of HIV several trials are underway both here and abroad. In the US they are enrolling for ACTG 307 (version 6), a study of Hydroxyurea and ddI. You have to be HIV+ and over 18 yr. old, with a CD4 count between 200 and 500, and a viral load under 20,000 by Roche PCR. You may have previous antiviral use but not for 14 days before entering the trial. You must be Hydroxyurea naive. There are three arms to this placebo controlled study. For more information call (212) 241 0433 in New York, or (215) 349 8092 in Philadelphia. These studies are good news as Hydroxyurea may be the first step over the stumbling block known as resistance.
Q-zone
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Last modified: 2/23/98