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Author Topic: Hydroxyurea and didanosine treatment ANYONE know anything about it?  (Read 4992 times)

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Offline bimazek

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1999 Oct 10;15(15):1333-8.Click here to read  Links
    Hydroxyurea and didanosine long-term treatment prevents HIV breakthrough and normalizes immune parameters.

        * Lori F,
        * Rosenberg E,
        * Lieberman J,
        * Foli A,
        * Maserati R,
        * Seminari E,
        * Alberici F,
        * Walker B,
        * Lisziewicz J.

    Research Institute for Genetic and Human Therapy, Policlinico S. Matteo, Pavia, Italy.

    Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #1 on: August 29, 2007, 02:05:32 PM »
I have used Hydroxyurea and didanosine for 11 years with excellent results almost always undetectable and last t-4 at 950. Never changed meds only lessened doses of Hydroxyurea to 500mg once a day. The trick is to take 500 mg Hydroxyurea (generic is fine) once a day it one hour before Videx 400 time release (NO generic DDI) which is taken two hours after a meal. Don't take more or it might screw up your pancreas and stomach . Add a super B- Complex Vit  that helps with  balancing the blood. Take holidays and some weekends off to allow T-cell to raise and if you get any discomfort in the stomach or pancreas area take a break

Offline Miss Philicia

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #2 on: August 29, 2007, 02:16:18 PM »
Uh, I highly suspect that the combination of these two drugs gave me the majority of my lipo and neuropathy issues -- I'd be very careful advocating this myself.  Read the "Drugs" section of aidsmeds for these two medications and you'll see what I mean.

Not saying this happens to everyone but just saying.  And bimazek, you're linking to something that is almost a decade old in the first place... c'mon.  That was before or around the time they first began seeing the lipo/neuropathy issues from these meds in the first place.  I'd be more careful with your google skills in the first place.
"I’ve slept with enough men to know that I’m not gay"

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #3 on: August 29, 2007, 02:25:35 PM »
Well I just know from my own experience that none of those issue's have had any merit. I believe Hydroxyurea has been scrutinized to make way for pricier drugs

Offline Miss Philicia

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #4 on: August 29, 2007, 02:28:18 PM »
All I'm saying is that your personal experience is way outside the experience of others, and that the medical community would agree with my assessment.  Anyone consider this line of treatment should be very, very careful and have a doctor that is familiar with these facts.
"I’ve slept with enough men to know that I’m not gay"

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #5 on: August 29, 2007, 02:36:38 PM »
At which being true with any combo in what might work for one and not for others. But we are all quite capable of making our own choices. So why close the door on any possibility's.

Offline Miss Philicia

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #6 on: August 29, 2007, 02:43:34 PM »
Which is why two posts ago I said "Not saying this happens to everyone but just saying." and then followed it up that one should be prudent and consult your a very experienced doctor with these meds, much more so than about any other combo.

I'm not sure why, in the face of what I stated in regards to the warnings in the "Drugs" section of this very aidsmeds forum that you are using, that you see this as in any which way odd or radical.  And it's not as true as with any other combo as you state, it's in fact wildly much more true with this combination of Videx and hydroxyurea.

And, as I pointed out, the originating remark by the initiator of this thread is wildly out of date.  There are many, MANY safer combinations of HIV meds in regards to lipo and peripheral neuropathy.  Hence why this would never be recommended as a first line treatment for someone in 2007.  Ever.
"I’ve slept with enough men to know that I’m not gay"

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #7 on: August 29, 2007, 02:59:16 PM »
Oct 2004

Who’s Afraid of HU?

by Austin Bunn



How—and why—the government and top docs have shelved a potentially lifesaving HIV med

In the history of HIV treatment, certain drugs stop being just medicine and become social and political flashpoints. Bactrim, for instance, prevents PCP pneumonia in organ-transplant patients, but pioneering ’80s AIDS docs, challenging the medical establishment’s conservatism, used it to treat HIVers (the Food and Drug Administration wouldn’t approve the usage until 1994). After AZT arrived in 1987 at the staggering cost of $10,000 per year, ACT UP and other activists hounded Burroughs Wellcome into lowering the price and would later force the FDA to radically alter the design and pace of the drug-approval process.

No one would have predicted that the 40-year-old, generic chemotherapy drug hydroxyurea (HU) would be a candidate for such historical distinction. Used to “cool down” leukemia patients’ immune systems, which battle fatal amounts of white blood cells, HU seemed promising for HIVers dealing with immune systems run amok. But after HAART’s success—and the 1998 deaths of two HIVers taking HU—the drug became as outmoded as ACT UP die-ins. The final blow came in July 2003, when the Department of Health and Human Services’ (DHHS) HIV guidelines panel recommended to HIV docs that HU “not be used at any time” to treat HIVers.

A year later, however, HU is back from the dead. New research, as well as ongoing studies by those who never doubted the drug’s potential, suggest it could have a place in the evolving science of HIV care. What’s more, Paul Bellman, MD, a top New York City HIV specialist who has successfully prescribed HU for years, is leading a bold one-man crusade to reverse the DHHS recommendation, publicly accusing those responsible of making a “serious error,” pandering to big pharma and “potentially jeopardizing” his patients’ health. Indeed, says Bellman, there’s more at stake than the fate of HU and the patients who take it. HU, Bellman contends, symbolizes HIV treatments outside the “HAART paradigm” of combination therapy, which, he points out, dooms HIVers to “a lifetime of antiviral therapy with brand-name drugs”—and the side effects they bring with them. The brawling inside story of the controversial DHHS decision—and the skepticism a variety of top docs shared with POZ about HU—capture a pill’s twisted course from promising treatment to dangerous drug and, possibly, back to promising treatment. But first, a brief science lesson.

What HU could do for you

HAART is the undisputed standard of HIV care, but its limits, especially for HIVers who have developed drug resistance, are all too familiar: a lifetime of pills that must be taken like clockwork and the hovering threat not only of lipodystrophy, neuropathy and other side effects, but of running out of treatment options. Such limits are why some docs believe that a drug like HU could play an important role in long-term HIV survival: It doesn’t cause resistance—and could lessen HAART toxicity.

Antivirals hinder HIV replication, but HU works differently, targeting the body’s own infection-fighting CD4 cells. To proliferate, HIV needs active and dividing CD4 cells to attack and infect, so HU slows down CD4-cell division, reducing the number of cells HIV can infect and replicate in. Think of it, says leading HU researcher Franco Lori, as “predator” and “prey.” If HIV is a predator and CD4 cells are its prey, when you “decrease the number of prey, the virus has fewer chances to replicate,” he says.

That’s HU’s “immunological” effect. When taken with the antiviral Videx (ddI), it also has a “virological” effect. As it replicates, HIV needs a chemical it finds in CD4s called nucleosides, which HU reduces. If the virus enters an HU-assisted cell and doesn’t find nucleosides, it takes up ddI, which resembles nucleosides. Lori calls ddI “the poison food” that stops viral replication.

Even if you don’t get the subtleties of the science, it’s easy to grasp HU’s biggest advantage. It works on the cell’s machinery, not on the virus—avoiding the problem of drug resistance. That gives HU exciting potential uses: It could serve as another line of defense for HIVers who’ve run out of HAART treatment options, sidestep lipodystrophy (by reducing the antivirals HIVers need to take) and steady the immune system during structured treatment interruptions (STIs).

Bellman has 20 patients who have taken HU from four to six years. Most are on salvage therapy. Diagnosed in 1988, Mark once had almost no CD4s and a viral load over 100,000; over the years, he has become resistant to every class of HIV medication, including the “nukes” (NRTIs) that make up his current regimen of Viread (tenofovir), Epivir (3TC) and Ziagen (abacavir). But with HU added to that trio, his CD4s last numbered 424 and his viral load 283. “Bellman said something about HU being used [as chemotherapy] to treat leukemia and that was a red flag for me,” Mark says. “But I’ve never had an opportunistic infection. My health has been very good, and I’ve been lucky: My meds are working.” And he’s not experiencing any side effects.

To Bellman, Mark and patients like him are a compelling argument against the government’s HU prohibition. “With HU as part of their regimen, they have stabilized, despite extensive drug resistance, multiple treatment failures, very high baseline viral loads and low T cells,” he says. “I challenge people to tell me if it’s not HU contributing to Mark’s regimen’s success, what is it?”

Another compelling argument is recent research on HU and lipodystrophy. A forthcoming study in the journal AIDS followed 187 Spanish HAART patients with undetectable viral loads who switched to HU and ddI. “My patients were tired of so many drugs, lipodystrophy and the psychological problems that came with it,” says Dr. Pablo Barreiro, the lead researcher. “I said, ‘I can offer you another way.’” After 48 weeks, 58 percent of the patients had viral loads below 5,000 and 41 percent had loads below 500. CD4 counts dropped—HU is immune- suppressive—but 77 percent kept CD4 counts above 350. Most important, the majority saw improvements in lipohypertrophy (fat buildup), lipoatrophy and lowered cholesterol.

Franco Lori has also quantified HU’s viral-load suppression during STIs. In a 60-subject study, he showed that patients on ddI, Zerit (d4T), and HU had lower viral-load rebounds and were faster to return to undetectable levels than patients taking a ddI, d4T and Crixivan (indinavir) combo during a three-week on, three-week off STI. In another Spanish study, 20 patients took HU during their STI—and after nine months, 80 to 90 percent saw no viral-load rebound.

Even if they don’t justify HU’s widespread use, these and a handful of other studies are encouraging. Some recent research has been less so, and even HU proponents say more studies are needed. In high doses—higher than typically used in an HIV setting—over a long time, HU can deplete red blood cells (causing anemia) and white blood cells (neutropenia). But, says Bellman, “the fact that [antiretroviral] medications are developing severe, life-threatening illness makes us look for alternative therapies. I think it’s clear that we’ve learned enough about HU to say that we should be learning more.”

The HU controversy begins

If HU has such promise, why do the DHHS guidelines, the de facto manifesto on proper HIV treatment, stipulate that HU is “an antiretroviral component that should not be offered at any time” with “no exceptions”? That pronouncement “placed HU in a category that is almost like thalidomide [which causes birth defects] for pregnant women,” says Bellman. HU’s bad rep springs from the two HIVers who died while taking it in 1998.

After Lori published a groundbreaking HU paper in Science in 1994, a host of HU trials began, including two by the AIDS Clinical Trials Group (ACTG), a network of physicians created in 1987 to streamline drug testing. According to Lori, one of the ACTG studies—the only one referenced in the DHHS guidelines—was deeply flawed because it added HU to “completely suppressive” HAART regimens. In ACTG 5025, HU was added to Crixivan, ddI and d4T in patients with undetectable viral loads. “If you are adding a fourth drug to a regimen that is [already] completely suppressive, there’s no way you can see increased efficacy,” says Lori. “But will you see increased toxicity? You bet.” HU’s promise rapidly diminished when two patients in the 5025 study, all in its HU/ddI/d4T/Crixivan arm, died from pancreatitis. The study was stopped short.

When the research was eventually published in AIDS in 2001, Lori “found something peculiar”: Dosages for HU and ddI were much higher than in most previous HU studies. ACTG 5025 gave patients 1,200 mg of HU and 400 mg of ddI once a day, whereas previous studies had used 1,000 mg of HU and 200 mg of ddI twice a day—a small shift, but enough to damage blood chemistry, says Lori. What’s more, ddI at the time was not “enteric-coated,” or formulated for slow absorption by the body, as it is now. Lori says that a high dose of HU with a spiked dose of ddI—in the non-enteric-coated formulation that Bristol-Myers Squibb (BMS) gave to ACTG 5025—can cause the toxicity that leads to pancreatitis.

Lori’s nonprofit Research Institute for Genetic and Human Therapy, located in Washington, DC, and Pavia, Italy, recently studied 120 patients on HU and ddI to find the optimal dosage. He found that the lowest dose of HU (around 600 mg once a day) was the most effective. One patient taking 1,200 mg of HU and 400 mg ddI (identical to ACTG 5025) developed a fatal case of pancreatitis. “So the only cases of fatal pancreatitis are when ddI is used at a certain formulation and HU is at 1,200,” says Lori. Refining the new drugs’ dosage, he adds, is part of the legacy of HIV treatment. “If you look back at AZT, the initial dosages were too high and too toxic but got experimented down,” he says. “Same with ddI. We now have an optimal dose of HU—half of what was used in ACTG 5025—and I think it’s time that we try that new formulation.”

more to be adeded

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #8 on: August 29, 2007, 03:00:48 PM »
Despite Lori’s detective work, HU’s economic prospects had already suffered. In the fall of 1999, the FDA castigated Bristol-Myers Squibb, which makes ddI, d4t and two brand-name versions of HU called Hydrea and Droxia, for promoting a ddI, d4T and HU combination without mentioning ACTG 5025’s side effects. After the study’s lead researcher, Diane Havlir, MD, had presented her findings, but before the results of ACTG 5025 had been published in AIDS, the FDA sent BMS a letter saying it had promoted drugs for unapproved uses. BMS was forced to write a “Dear Doctor” letter warning physicians about pancreatitis and other potential toxicities.

In July 2003, the DHHS guidelines panel, which uses published papers in peer-reviewed journals to evaluate treatment regimens, caught up to the 2001 HU data published in AIDS. They designated HU as “not recommended” because of a lowered CD4 count, ddI-associated side effects (such as pancreatitis) and “inconsistent evidence of improved viral suppression.”

No wonder a variety of doctors queried by POZ responded with skepticism about HU. “I didn’t know anybody was still using [HU/ddI],” wrote Charles van der Horst, MD, at the AIDS Research and Treatment Unit at the University of North Carolina/Chapel Hill. Top HIV doc Michael Saag, MD, says he stopped using HU in the late ’90s “due to fears about toxicity,” adding, “I found it could lead to cases of advanced neuropathy and pancreatitis.” Dr. Marie-Josèphe Commoy of France’s Agence National Recherches sur le Sida, which oversees that country’s AIDS research, says “there are no plans to treat patients with HU in trials.” Martin Markowitz, MD, of the Aaron Diamond Research Center says the “data…would not support its routine use,” and veteran HIV doc Donald Abrams, MD, says doctors who use it “may be doing harm.”

Oncologist Paul Volberding, MD, a professor at the University of California/Los Angeles and a member of the guidelines panel, says “so many things have come along that are so much more potent without the questions of toxicity that we’ve moved on [from HU].” He uses HU in his cancer practice but not for HIV. To combat lipodystrophy, Volberding says that docs can simply juggle nukes. As for HU and ddI combined, he asks, “Why would a drug that is fairly toxic be preferable to just using more ddI?” Bellman says that “you can’t just juggle drugs and expect significant results” and argues that Volberding “lacks appreciation for the toxicity of ddI.” Bellman, however, rarely prescribes HU with ddI because of its “small band” between efficacy and toxicity.

HU’s fundamental problem, says Lori, is that it lacks a strategic “development plan.” In an era of big pharma chess-like maneuvers, it was crafted chaotically. “People threw it into all kinds of experiments, and the result of that is disaster,” he says. Now that HU is generic, “it’s very difficult to put together a development plan for it because there is no interest in its use by big pharma.” And since the July 2003 guidelines, “there are no NIH-funded trials and doctors will be reluctant to participate,” Lori adds. “There’s a definite chill on HU research.”

Bellman on a mission

Bellman heard about the guidelines changes only coincidentally. One of his patients is POZ publisher Brad Peebles, who discussed taking HU and the guidelines in his January POZ publisher’s letter. Bellman was livid when he discovered that HU had been “taken out of his tool kit.”

In April, Bellman decided to fight the panel’s decision. In a strongly worded letter to the guidelines panel, Bellman wrote that “a serious error that could potentially jeopardize the health of my patients as well as others” had been made. Because the decision was based on ACTG 5025, Bellman presented the trial’s flaws. But he went well beyond that, claiming that panel members are caught up in “the current paradigm of HIV treatment…that contains a bias towards treatment with brand-name drugs that are highly lucrative for big pharma.” That bias, he says, undermines research into generics like HU or structured treatment interruptions, which, if properly studied, could dramatically improve HIVers’ lives. Although Bellman calls this bias “unconscious,” his letter names names. Havlir, he says, is “a paid consultant to BMS.” Her coauthor on ACTG 5025, Martin Hirsch, MD, serves on the guidelines panel. Referring to Hirsch in his letter, Bellman writes, “Sometimes academic conflicts of interest can prove more compromising than financial ones.” Hirsch refused comment for this article; Havlir did not return POZ’s calls or e-mails.

Bellman’s letter, published in the newsletter of the influential Treatment Action Group, wound its way upward. By mid-June, during the guidelines’ monthly conference call, the panel addressed Bellman’s letter, agreed to look at the most recent data and “will be reviewing” its position on HU at a future meeting, said panel chair John G. Bartlett, MD.

The panel’s 33 members are a mix of academics, pharmacists, researchers and community activists; many are members of the ACTG (or as it is now called, AACTG). Bartlett and another guidelines panel member, Cornelius Baker, executive director of DC’s Whitman-Walker Clinic, deny that big pharma influences them and their colleagues. “The panel clearly has no bias for brand-name drugs,” says Bartlett. “In fact, there have been occasions when we have said some drugs were limited due to expense.” Pharmaceutical companies can lobby the panel, but Baker says it “doesn’t influence the outcome,” adding that which researchers conduct which trials is “not an important factor” in the panel review process. “That would really change our partiality,” he says. When ACTG 5025 was presented, Hirsch publicly acknowledged his involvement. Indeed, the expertise of physicians with specific drugs is vital to making recommendations, says Baker: “To deny that expertise would undermine the recommendation’s whole value.”

Not everyone, however, believes the panel works impartially. One member who requested anonymity believes that the panel’s many AACTG members means it is “somewhat dominated by their point of view” and that the two largely negative ACTG studies on HU shaped the guidelines position. (Currently, no AACTG trials explore HU.)

Bartlett acknowledges that the guidelines are “primarily driven by viral load” and that the panel looks for treatments that bring it “down to 50 [copies].” That disadvantages HU, which is less virally suppressive than HAART. But Baker stands by the panel decision. “HU is an artifact,” he says. “It first came into discussion in 1998, and since then, we’ve had 10 additional drugs approved. Instead of 10 to 24 weeks of data for some regimens, our standard is having 48 weeks of data on everything we consider.” But if it’s a matter of data, ACTG 5025, upon which the panel based its conclusions, “represents just one-quarter or one-fifth of patients tested on HU,” says Lori. “It represents the minority of patients.”

AACTG vice-chair Daniel Kuritzkes, MD, also defends the panel decision. “There was a lot of interest in HU because of preliminary data from Franco Lori, but the fatalities quashed any other interest,” he says. However, the panel member who declined to be identified called the overemphasis on ACTG 5025 “bullshit,” adding: “You had two other drugs in there with a history of pancreatitis. It was a little disingenuous to rule against HU. I wasn’t alone in thinking that HU warranted a more even handling. But we all vote, and it’s majority rule.”

The guidelines also ignored a handful of positive published reports on HU. In an upcoming issue of Drug Safety, Lori highlights three such studies, including one AACTG trial, that claimed “encouraging results” for hydroxyurea-based combinations that challenge the conclusions of the other two ACTG studies. The guidelines panel, says one member, will reexamine these studies, as well as Barreiro’s forthcoming piece in AIDS. Baker says the panel has also instituted a new 60-day “comment period” when the guidelines are changed. Bellman says he has “never seen anything in the guidelines that referred to such a period, nor is there any particular e-mail address that invites comments.”

But the guidelines process isn’t the only problem—to some docs, it’s the guidelines themselves. “I’ve never been an advocate for the guidelines,” says Robert Redfield, MD, at Baltimore’s Institute of Human Virology, run by Robert Gallo, codiscoverer of HIV. “I never bought into AZT mono-therapy or dual therapy [both recommendations at one time].” Redfield, who was skeptical of ACTG 5025 as far back as 1998, says,“It’s clear to me that somebody is driving this nail down” against HU.

When the guidelines were created in 1997, pioneering AIDS doc Joseph Sonnabend, MD, wrote a letter declaring them a step backward. “I said we don’t need guidelines—we need evidence,” he says. Sonnabend founded the Community Research Initiative on AIDS (CRIA), a community-based trial system held in doctor’s offices. (Sonnabend eventually left; the organization is now ACRIA). CRIA and similar efforts lessened the influence of big pharma by offering alternative systems to try out drugs. But HAART’s success diminished their importance, and many of these alternative channels for drug testing—for HU or even aspirin—closed.

It’s easy for a drug like HU, with medical potential but little profit potential, to get lost in the waves of pharmaceutical HAART hype. But as long-term treatment leads to serious side effects, clinicians—often spurred on by desperate patients—will reexamine their treatment options, says Bellman, and wonder what’s missing and why. As Lori says, “HU is an experimental drug. If they banned every experimental drug, nobody would experiment with anything.”


Offline Miss Philicia

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #9 on: August 29, 2007, 03:15:58 PM »
maxarl, I believe I read this with great interest a few years ago in POZ and I assume, though you provide no external link, that it's where it's from.  It's interesting that it contradicts the information on this website which is connected with POZ itself, and as such I will PM Tim Horn who writes their treatment news and perhaps he can offer some insight.

Having lived in NYC for the first 11 years of my diagnosis I know of Dr. Bellman and his HIV practice and that he's very experienced.  In fact, my first HIV doctor was very acquainted with him and often conferred.

I still stand by my commentary, and one can always google and find contrary information on these issues with a handful of outlier stuff.  It's like a global warming debate in that respect, isn't it?  I respect that you see a personal benefit, but you should respect that my face is sunken in and I have electrical jolts going through my body all day long as a result of this combo, as do MANY MANY OTHER people.  I've also been living with the disgusting side effects of this combination now for seven years.
"I’ve slept with enough men to know that I’m not gay"

Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #10 on: August 29, 2007, 03:21:48 PM »
I am more than happy to provide you with a link to this POZ article.  http://www.poz.com/articles/159_427.shtml 

Offline Ann

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #11 on: August 29, 2007, 03:22:41 PM »
Max,

Please read the Welcome thread that appears at the top of the Research forum (er, that's this forum) and follow the posting guidelines for posting studies and other articles. It's to do with copyrights and stuff.

Thanks!

Ann
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Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #12 on: August 29, 2007, 03:37:15 PM »
I find very bewildering that it your first response that you suspected these side effects a your last post is a total contradiction as it is to blame. And to the contrary of studies used Hydroxyurea to fight LIPO.   

Offline Miss Philicia

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #13 on: August 29, 2007, 03:57:27 PM »
I don't see any contradiction in what I posted, maxarl.  You need to be more specific.
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Offline maxarl

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #14 on: August 29, 2007, 04:46:20 PM »
The study shows the majority saw improvements in lipoatrophy and lowered cholesterol.

Offline Tim Horn

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #15 on: August 29, 2007, 05:13:54 PM »
Hi Guys...

I find the topic of hydroxyurea very interesting. In fact, here's a link to an article I wrote on the subject back in 1999 for The PRN Notebook, a quarterly publication for HIV-treating healthcare providers (you'll need to register with the site to access it):

http://www.prn.org/html/authorized/prnnotebook/index.php?actpage=1999/volume4_2/hydroxyurea.php

Along the lines of what Philly says, one of the original theories behind hydroxyurea -- using it to essentially increase intracellular concentrations of nucleoside analogues like Videx (ddI) -- actually makes me wince. Given what we now know about this class of drugs causing irreversible damage to cellular mitochondria, which has been linked to peripheral neuropathy and lipoatrophy (to name just a few), I'm seeing all sorts of warning signs here.

But here's the thing... the immune modulating effects of hydroxyurea may be noteworthy, given the steady of accumulation of data over the years suggesting that "immune activation" -- not so much the virus itself -- is likely a significant contributor to the progression of HIV disease. In fact, our whole concept of how HIV causes immune deficiency has shifted quite dramatically over the past ten years. Let's put it this way: antiretroviral therapy as we know it stems from research conducted in the mid-1990s indicating that relentless HIV replication is what leads to the progressive loss of CD4 cells. But now we're looking at research showing that immune activation contributes greatly to the replication of HIV and, perhaps even more significantly, the destruction of CD4 cells. So wouldn't it make sense for us to re-explore the current treatment paradigm? 

Stay with me here... I do have a point (I swear)...

There's been no shortage of data -- several key presentations at the 4th IAS Conference in Sydney included -- shedding a whole lot of light on the role of "immune activation" as a driving factor in the pathogenesis of HIV infection. And it is this research that may translate into the use of drugs that suppress the immune system -- hydroxyurea included -- as an HIV treatment strategy.

Dating back to the late 1980s and early 1990s, there were papers showing that CD4 cells in people with HIV had high levels of activation. In fact, research from the MACS published in the mid-1990s -- published by Dr. Janis Giorgi -- suggested that immune activation was a strong predictor of HIV disease progression (the greater the immune activation, the faster the progression to AIDS).

Research conducted by Michael Lederman, MD, of Case Western Reserve Unversity -- and other groups -- has shown that when the immune system becomes activated, HIV-infected CD4 cells enter what is known as "cell cycle" (that is, they're being prompted to divide). While this  prompts the cells to begin churning out HIV, it also causes the cells to die. In the end, this leaves the body short of CD4 cells... and, well, you know the rest.

What contributes to this immune activation? It could be that HIV-infected CD4 cells essentially send out distress signals, in the form of cytokines, to activate other immune system cells to work to keep the infection under control. But there may be another factor to consider as well. It turns out that HIV rapidly destroys CD4 cells and otherwise healthy immune tissue in the gut soon after infection. This leaves the gut virtually without an immunity barrier -- permanently, so it seems -- resulting in microbes, like bacteria, spilling into the body (in the form of lipopolysaccharides). These lipopolysaccharides, researchers found last year, may constantly activate the immune system, contributing greatly to the ongoing replication of HIV and the death of CD4 cells.

This all leads to a single question -- is there a role for immune modulators to suppress the activation of the immune system? We're not talking only about hydroxyurea here... we're also talking about immune suppressants like cyclosporine A and prednisone (using low doses, of course).

Unfortunately, there's so little data to draw upon. There have only been a patchwork of studies looking at the utility of drugs like hydroxyrea, cyclosporine, and prednisone. And when you consider the sheer number of studies testing brand-name pharmaceutical products, it's clear the study of generic immune modulators has repeatedly and consistently been overlooked. And this is a shame -- a scandal, even. Focusing almost exclusively on the virus may be good money, but it's horrible science. Given that our understanding of HIV pathogenesis continues to evolve, in unexpected ways, it would be nice to see treatment research keep up with this trend.

Tim Horn

« Last Edit: August 29, 2007, 05:56:02 PM by Tim Horn »

Offline Tim Horn

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  • Posts: 800
Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #16 on: August 29, 2007, 05:35:50 PM »
Max:

I do think it's necessary to take that one hydroxyurea study -- the one suggesting a reversal of lipodystrophy-related problems -- with a huge grain of salt. It was an open-label study in which everyone enrolled swtiched from a typical antiretroviral regimen to dual therapy with HU and ddI (a controlled comparison would have been better). The improvements in lipohypertrophy and lipoatrophy were subjective, meaning that standardized measurements were not employed.

This might be considered a proof-of-concept study, to drive additional research -- it's by no means conclusive that hydroxyurea, especially when combined with ddI, is an effective option for HIV-positive folks with lipodystrophy.

Tim Horn   

Offline Miss Philicia

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  • celebrity poster, faker & poser
Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #17 on: August 29, 2007, 06:00:12 PM »
Thanks for weighing in Tim.  You are, as always, a great resource.
"I’ve slept with enough men to know that I’m not gay"

Offline bimazek

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  • Posts: 781
Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #18 on: September 07, 2007, 08:21:55 PM »
Hi Guys...

I find the topic of hydroxyurea very interesting. In fact, here's a link to an article I wrote on the subject back in 1999 for The PRN Notebook, a quarterly publication for HIV-treating healthcare providers (you'll need to register with the site to access it):

http://www.prn.org/html/authorized/prnnotebook/index.php?actpage=1999/volume4_2/hydroxyurea.php

Along the lines of what Philly says, one of the original theories behind hydroxyurea -- using it to essentially increase intracellular concentrations of nucleoside analogues like Videx (ddI) -- actually makes me wince. Given what we now know about this class of drugs causing irreversible damage to cellular mitochondria, which has been linked to peripheral neuropathy and lipoatrophy (to name just a few), I'm seeing all sorts of warning signs here.

But here's the thing... the immune modulating effects of hydroxyurea may be noteworthy, given the steady of accumulation of data over the years suggesting that "immune activation" -- not so much the virus itself -- is likely a significant contributor to the progression of HIV disease. In fact, our whole concept of how HIV causes immune deficiency has shifted quite dramatically over the past ten years. Let's put it this way: antiretroviral therapy as we know it stems from research conducted in the mid-1990s indicating that relentless HIV replication is what leads to the progressive loss of CD4 cells. But now we're looking at research showing that immune activation contributes greatly to the replication of HIV and, perhaps even more significantly, the destruction of CD4 cells. So wouldn't it make sense for us to re-explore the current treatment paradigm? 

Stay with me here... I do have a point (I swear)...

There's been no shortage of data -- several key presentations at the 4th IAS Conference in Sydney included -- shedding a whole lot of light on the role of "immune activation" as a driving factor in the pathogenesis of HIV infection. And it is this research that may translate into the use of drugs that suppress the immune system -- hydroxyurea included -- as an HIV treatment strategy.

Dating back to the late 1980s and early 1990s, there were papers showing that CD4 cells in people with HIV had high levels of activation. In fact, research from the MACS published in the mid-1990s -- published by Dr. Janis Giorgi -- suggested that immune activation was a strong predictor of HIV disease progression (the greater the immune activation, the faster the progression to AIDS).

Research conducted by Michael Lederman, MD, of Case Western Reserve Unversity -- and other groups -- has shown that when the immune system becomes activated, HIV-infected CD4 cells enter what is known as "cell cycle" (that is, they're being prompted to divide). While this  prompts the cells to begin churning out HIV, it also causes the cells to die. In the end, this leaves the body short of CD4 cells... and, well, you know the rest.

What contributes to this immune activation? It could be that HIV-infected CD4 cells essentially send out distress signals, in the form of cytokines, to activate other immune system cells to work to keep the infection under control. But there may be another factor to consider as well. It turns out that HIV rapidly destroys CD4 cells and otherwise healthy immune tissue in the gut soon after infection. This leaves the gut virtually without an immunity barrier -- permanently, so it seems -- resulting in microbes, like bacteria, spilling into the body (in the form of lipopolysaccharides). These lipopolysaccharides, researchers found last year, may constantly activate the immune system, contributing greatly to the ongoing replication of HIV and the death of CD4 cells.

This all leads to a single question -- is there a role for immune modulators to suppress the activation of the immune system? We're not talking only about hydroxyurea here... we're also talking about immune suppressants like cyclosporine A and prednisone (using low doses, of course).

Unfortunately, there's so little data to draw upon. There have only been a patchwork of studies looking at the utility of drugs like hydroxyrea, cyclosporine, and prednisone. And when you consider the sheer number of studies testing brand-name pharmaceutical products, it's clear the study of generic immune modulators has repeatedly and consistently been overlooked. And this is a shame -- a scandal, even. Focusing almost exclusively on the virus may be good money, but it's horrible science. Given that our understanding of HIV pathogenesis continues to evolve, in unexpected ways, it would be nice to see treatment research keep up with this trend.

Tim Horn





tim

this is why in my humble opinion so common substance that are immune suppressants like alcohol consumption (japanese science just found the exact genes chemokines, receptors, immune mod chems that alcohol supresses, and published, was it IG or IL or one of those)

any way

this is why hiv guys who go in denial after getting hiv and start drinking can do so well with few problems for years and years, because they are suppressing the system, but eventually when the bad catches up it is much more bad because the other systems of body are so weakened

Offline Tim Horn

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Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #19 on: September 11, 2007, 10:59:32 AM »
this is why hiv guys who go in denial after getting hiv and start drinking can do so well with few problems for years and years, because they are suppressing the system, but eventually when the bad catches up it is much more bad because the other systems of body are so weakened

With all due respect, Bin, where are you getting this information from? While it can certainly be argued that moderate alcohol consumption isn't associated with any health problems in people with HIV -- notably those without insulin resistance (or diabetes), high triglycerides, or hepatitis coinfection -- I think it's a tad-bit of a stretch to theorize that alcohol works medicinally in such a manner.

If you'd like to discuss these "Japanese science" findings, fine -- but it would be extremely helpful if you'd at least provide a link to the source of your information. None of us can comment on this potentially intriguing stuff -- but without even seeing the data you're referencing, I do encourage caution when attempting to translate non-HIV research into potential HIV findings -- without at least seeing the information you're referring to.

And let's not forget that alcohol consumption has been implicated in more rapid disease progression. There was this report published last year; there was also this report that came out late last month.

The only "immune suppressant" research we've seen thus far, in terms of potentially slowing HIV disease progression, has involved medications like hydroxyurea, prednisone, and cyclosporine.

Tim Horn

Offline denniss

  • Member
  • Posts: 37
Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #20 on: September 12, 2007, 06:06:04 PM »
...........And when you consider the sheer number of studies testing brand-name pharmaceutical products, it's clear the study of generic immune modulators has repeatedly and consistently been overlooked. And this is a shame -- a scandal, even. Focusing almost exclusively on the virus may be good money, but it's horrible science. Given that our understanding of HIV pathogenesis continues to evolve, in unexpected ways, it would be nice to see treatment research keep up with this trend.

Tim Horn



Couldnt agree more!

Offline bimazek

  • Member
  • Posts: 781
Re: Hydroxyurea and didanosine treatment ANYONE know anything about it?
« Reply #21 on: September 17, 2007, 04:19:28 AM »
man i read so many articles in first year... it was a japanese study and it said that the Interluken or cytokine that that is effected by alot of alcohol consumption -- and that same Interluken 1,2,3,7,12 etc or cytokine
was critical in the modulation of hiv, i will try to find the article... on google..

i would have worded the above post differently if i had article in front of me... i am very very anti alcohol esp. if one is hiv...

it could have been this one...  to find whole article just cut and paste one line into google... i dont have time tonight to find the

Cytokines and alcohol - all 3 versions »
FT Crews, R Bechara, LA Brown, DM Guidot, P … - Alcohol Clin Exp Res, 2006 - Blackwell Synergy
... Alcohol (ethanol) is known to modulate the immune system in a complex manner.
Alcoholics have increased blood levels of circulating ...


Moderate Alcohol Intake in Humans Attenuates Monocyte Inflammatory Responses: Inhibition of Nuclear … - all 4 versions »
P Mandrekar, D Catalano, B White, G Szabo - Alcohol Clin Exp Res, 2006 - Blackwell Synergy
... Alcohol abuse interferes with the host's immune surveillance system and has been
implicated in diminished humoral and cell-mediated immune responses (Cook, 1998 ...


Alcohol Abuse Enhances Neuroinflammation and Impairs Immune Responses in an Animal Model of Human … - all 5 versions »
R Potula, J Haorah, B Knipe, J Leibhart, J … - American Journal of Pathology, 2006 - ASIP
... Mounting evidence demonstrates the adverse effects of alcohol abuse on the immune
system and progression of HIV-1 infection, including development of HIV-1 ...


Nutritional modulation of immune function - all 8 versions »
RF Grimble - Proceedings of the Nutrition Society, 2007 - Cambridge Univ Press
... riboflavin act as cofactors for the defence system. ... Alcohol Clinical and Experimental
Research 23, 1780œ1784. ... E supplementation and in vivo immune response in ...

(i didnt find it, exactly... it was in 2006 and it showed the exact gene or cytokine or IL that heavy alcohol use distroys the immune system)

i should have emphasized the destruction of the immune system

part more

it was from japan


 


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