Talk:AIDS antiretroviral drugs

Is nPEP Statistics Credible?

After reading the paragraph below, which sources an article from the Centers for Disease Control, I went and read most of the article ([1]), but was unable to find any evidence that nPEP is 100% effective if taken within a 24 hour time frame, or that effectiveness falls to 52% if treated within 72 hours. I'm interested to know the source of a such a bold and definite assertion. If it is true, it would be a significant relief for those who have been exposed to HIV within a short time frame, otherwise it will be misleading at best, or raise false hopes at worse.

In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those who have been exposed to HIV (HIV Postexposure Prophylaxis [PEP])[9]. The drugs have demonstrated effectiveness in preventing the virus nearly 100% of the time in those who received treatment within the initial 24 hours of exposure. The effectiveness falls to 52% of the time in those who are treated within 72 hours; those not treated within the first 72 hours are not recommended candidates for the regimen.

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Sequencing numbers

I was going through the sequencing numbers: AZT, ddI, ddC, d4T, 3TC, saquinavir, ritronavir, indinavir are the first eight. Which one is Ninth? I've been through about four times and can't find what comes between indinavir and nevirapine.

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I restructured the markup (but hopefully not the content) to use fewer levels of bullet-list indentation, and instead two levels of == wiki markup instead. I think I've gotten everything in the right place, but I'd apprciate it if someone more knowledgeble could doublecheck. I figure this was a good change to make, because:

• it allows more useful navigational information to appear in the page's table of contents
• it enables heading numbers (for those who've got that option turned on) which also help navigation
• it produces, IMHO, much more readable and attractive HTML
• the wiki markup is a bit easier to follow, too
• it creates h3 and h4 tags in the HTML output. Header tags such as these are used by the browsers and screen readers used by some disabled people, so having them instead of nested bulletlists makes for easier access for such folks.

-- Finlay McWalter 10:11, 17 Oct 2003 (UTC)

Question - we currently have a (dead) link to synergies. Is it likely that a specific medical page will later be produced for precisely this, or should we resolve the link to synergy? -- Finlay McWalter 12:14, 17 Oct 2003 (UTC)

fixed, thanks for proofing. -- Kstailey

(some talk moved to User talk:Kstailey) -- Finlay McWalter 16:03, 17 Oct 2003 (UTC)

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Should Fixed Combinations be considered new drugs in terms of them getting sequence numbers? They are just reformulations with no original medications in almost all cases (Kaletra® being the only exception.) Kstailey 15:37, 21 Oct 2003 (UTC)

If by sequence numbers you mean stuff like Third antiretroviral to be approved by FDA, then I have two comments:

• I'm not sure the details of the ordering are especially significant. It's certainly interesting that AZT was the first, and certainly interesting which drugs are the latest, but details of ordering beyond that seem (at least to me) not to be especially significant. So I don't think it matters much. The stuff you've added about how they work and what side-effects they have seems much more interesting to me (both from a clinical and a science-geek perspective).
• Secondly, I think you're by far the most knowledgable wikipedian active in this little section of the wikipedia. I think it's probably your call.

-- Finlay McWalter 16:59, 21 Oct 2003 (UTC)

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Abbott pharmaceuticals price gouging an old protease inhibitor

Permission to distribute this editoral was granted by the author:

I hereby give you permission to reprint and distribute The Center for AIDS editorial (available at the moment at www.centerforaids.org/abbott.htm). Please credit the source as "The Center for AIDS, Houston, Texas (www.centerforaids.org)."

Thanks,

Tom

Thomas Gegeny, MS, ELS Executive Director & Senior Editor

The Center for AIDS: Hope & Remembrance Project 1407 Hawthorne Houston TX 77006

www.centerforaids.org 713-527-8219 x102 (ph) 713-521-3679 (fax)

Editorial, The Center for AIDS (12/15/03)

In a move that startled healthcare professionals and community members alike, Abbott pharmaceuticals announced a price increase of almost 500% for its protease inhibitor ritonavir (Norvir). Norvir is widely being used as a pharmacokinetic "booster" for other protease inhibitors, including recently approved drugs such as fosamprenavir (Lexiva) and atazanavir (Reyataz).

Boosting protease inhibitors makes them more potent, a particular consideration for treatment-experienced or "salvage" patients with few or no treatment options left. The price increase went into effect on December 3, 2003-two days after World AIDS Day. Surprisingly, the price of another Abbott drug, Kaletra (itself Norvir-boosted protease inhibitor) has stayed the same, providing an unquestionable economic advantage to choosing Kaletra over other boosted protease inhibitor regimens, which may now increase in price by as much as double. Although negotiated prices for US government AIDS Drug Assistance Programs are locked in by law into 2005, prices negotiated after that time will be subject to increases.

Indeed, Abbott has modified its patient assistance program so that patients needing Norvir can more easily get the drug. However, this does not address the more important question of what will happen if third-party insurers are faced with footing the bill for boosted regimens that are much more expense than Kaletra. This has implications for salvage therapy research as well because potential therapies that require boosting with Norvir may be abandoned. What Abbott has done is unforgivable and will go into the history of the AIDS epidemic as a repugnant commercial manipulation that unnecessarily burdens people living with HIV/AIDS, especially those with fewer treatment options who can truly benefit from boosted protease-inhibitor therapy. Physicians, researchers, government officials, and patients should be outraged by these events and should take heed of such gross opportunism tainting the very nature and purpose of healthcare.

Working with the AIDS Treatment Activists Coalition (ATAC), The Center for AIDS will fight to make sure that this unjust act is brought to the attention of both local and national officials and that Abbott regrets the day it decided to hold salvage patients hostage through selfish profiteering. Contact ATAC if you'd like more information or to become involved. Also, contact your elected officials to inform them of this despicable development or call the office of Abbott CEO Miles White (847-937-6100) to give Abbott your thoughts on the matter directly. Other Abbott contacts can be found on the Abbot web site.

I quote from a second source below.

How much?!!

On December 3rd Abbott informed customers that the wholesale price of ritonavir had increased from $205.74 USD to $1028.71 for 120 100mg capsules – the equivalent of $515 a month if ritonavir is being dosed at 100mg twice daily with another protease inhibitor. The previous cost of the drug lay around $100 - $110 a month when dosing at 100mg twice daily.

My personal expericence is that my pharmacy raised the price from $91.55 USD to $528.76 for what is indended to be a one month supply. However, I only take antiretrovirals every other week aka Dr. Dybul

Kstailey 14:28, 20 Dec 2003 (UTC)

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Abstracts are in the public domain IIRC. Kstailey 14:28, 20 Dec 2003 (UTC)

Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent and relevance.

Dahan A, Altman H. Eur J Clin Nutr. 2004 Jan;58(1):1-9.

[1]Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem Israel.

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.

European Journal of Clinical Nutrition (2004) 58, 1-9. doi:10.1038/sj.ejcn.1601736

Publication Types:

   * Journal Article

PMID: 14679360 [PubMed - in process]

From PubMed

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Merke threw away combination therapy in 1993

Subject: Merck Drops Final Bid to Develop Drug For AIDS in Face of Viral Resistance 
Date: Published: 9/15/93 (66 lines)
Source: Wall Street Journal. Copyright Dow Jones & Co. Inc.

   Technology & Health:
   Merck Drops Final Bid to Develop Drug
   For AIDS in Face of Viral Resistance
   ----
   By Michael Waldholz
   Staff Reporter of The Wall Street Journal

   Merck & Co. dropped its final efforts to develop a once highly
promising AIDS drug, noting that use of the drug causes the AIDS
virus to mutate and become resistant.
   A Merck spokesman said that in recent weeks the company and
outside AIDS researchers concluded that they couldn't overcome
severe viral resistance, even when the experimental drug was used in
high doses and in combination with AZT, the drug sold by Wellcome
PLC. 
   The news is further evidence of the profound obstacles facing
researchers trying to develop new medicines against human
immunodeficiency virus, or HIV, which causes AIDS.  About a dozen
pharmaceutical companies, including Merck, are continuing to chase
after new AIDS medicines.  But viral resistance has been an
especially difficult issue to overcome.
   In composite trading on the New York Stock Exchange, Merck rose
75 cents to $32.125.
   The Merck drug, known as L661, was developed by Merck in an
unusually intense and swift research effort between 1990 and 1991.
The company then rushed the drug into human tests.  But in late 1991,
Merck's researchers were dealt a severe setback when it was
determined that the virus mutated into a resistant strain within
weeks of the drug's being administered to patients.
   Since then Merck has attempted to revive L661 by combining it
with AZT, which works against the virus through a different
mechanism, and by significantly boosting the drug's dosage.  In a
statement from its Whitehouse Station, N. J., headquarters, Merck
said recent analysis of the combination studies "concluded that the
viral resistance problem is so clinically significant ...that
development should be discontinued."
   The drug works by blocking the action of reverse transcriptase,
an enzyme crucial to viral replication.  AZT blocks the same enzyme
but in a different way.
   "It's very depressing news," said Michael Becker, a New York
lawyer and AIDS activist who closely monitors drug research efforts.
   Boehringer Ingelheim Corp., Ridgefield, Conn., is continuing to
conduct studies of a drug, called neverapine, that works in a
fashion similar to Merck's L661.  An official at the U. S. affiliate
of Boehringer Ingelheim International GmbH of Germany said its
research suggests the drug's higher potency than the Merck drug may
help it overcome viral resistance.  In another bid to surmount the
resistance issue, neverapine also is being tested in a federally
sponsored study in a so-called triple combination with AZT and DDI,
an AZT-like drug sold by Bristol-Myers Squibb Co., New York.
   Meanwhile, a dozen drug makers still are trying to find new types
of AIDS medicines.  Recently, Merck, Abbott Laboratories, Upjohn Co.,
Hoffmann-La Roche Inc., a unit of Roche Holding Ltd.  of Switzerland,
and DuPont-Merck, a joint venture of DuPont Co. and Merck, have been
testing in humans a drug that blocks another viral enzyme called
protease.  Results of those studies have yet to show whether that
class of drug will prove successful.

[This article is made available here by Dow Jones Co. for the
personal and non-commercial use of callers to this bbs, in the
hope that it will be of some help to those who are suffering
from the disease and others who are seeking to help them.]

Remeber that L661 has another name, pyridinone.

A few months earilier ATN published this article

Which I excerpt from here:

The second series of experiments detailed by Chow and others in the recent Nature paper tested combinations of two or more anti-HIV drugs, at concentrations which can be achieved in the body, to see whether they could prevent or stop an HIV infection in a laboratory culture of human cells. The combinations (1) AZT plus ddI; (2) AZT plus alpha interferon plus the Hoffmann-La Roche protease inhibitor Ro31-8959; (3) AZT plus alpha interferon plus soluble CD4; and (4) AZT plus pyridinone, all failed to do so (although AZT plus pyridinone almost worked). However, the three-drug combination AZT plus ddI plus pyridinone completely prevented the infection in the laboratory test. Even when the drugs were added at the peak of HIV infection, seven days after the virus was added, the three-drug combination of AZT plus ddI plus pyridinone stopped spread of infection in the laboratory cultures.

After 49 days of the three-drug treatment, the cells were placed in a drug-free medium for an additional 45 days, giving ideal conditions for HIV to grow. But after the 45 days, there was no evidence of the virus; nothing was found even with a PCR test so sensitive that it could detect a single copy of the HIV genetic information within DNA from 100,000 cells. This does not mean that the virus would similarly be reduced to such low levels in people -- for a number of reasons, some of which are discussed below. But it does suggest that certain combinations (for example, AZT plus ddI plus pyridinone) might work much better as antivirals than combinations now in use (for example, AZT plus ddI).

Kstailey 15:55, 17 Feb 2004 (UTC)

Drug at work?

Reading the above, I'm thinking I'm in way over my head...but I read somewhere Immune Response Corp sued when the efficacy of Remune^TM was demo zero^TM. What university did the tests? Trekphiler^TM, 15.03 22/12/05

Split article

Since this article has grown beyond Wikipedia's size recommendations, how about we use Reverse transcriptase inhibitor and Protease inhibitor (pharmacology)? The Rod 22:04, 9 January 2006 (UTC)

Integrase Inhibitors

This article gives no mention of Integrase Inhibitors, I know little about them myself except that they exist. Someone with the time and interest might want to read up on them, I will do some reading myself but don't expect anything any time soon. Bartimaeus 21:34, 19 March 2006 (UTC)

They're still investigational, and I think we normally don't write much here about drugs under development since so many of them are dead ends (e.g. I suspect we won't be talking much about CCR5 antagonists in a few years) - but there are two that are now available in expanded-access programs, and the trials so far have been promising, so I'll try to write up something soon. Some links here: [2] ←Hob 03:57, 5 November 2006 (UTC)

MK0518 seems to be the most promising - see here and here. Trezatium 13:45, 5 November 2006 (UTC)

Very promising, but I don't think it's possible to judge "most" yet: MK0518 just happens to have reached phase II trials sooner, plus the trials were designed differently (the Gilead drug was only studied as monotherapy). ←Hob 01:19, 6 November 2006 (UTC)

OK, now there's a teeny stub for integrase inhibitor. When I get a chance I'll add some more there about the mechanism of action, how it differs from other drug classes, and a summary of the current investigational drugs. More is needed in the MK-0518 article too, since we have a good deal of data now. ←Hob 01:59, 6 November 2006 (UTC)

Page split suggestion, adverse effects

I found this article in the split form somewhat confusing in its emphasis, as it currently seems to downplay PIs, NNRTIs & nRTIs which are the main HAART components. Would anyone object if I were to split off fixed-dose combinations and synergistic enhancers into separate sections, to balance this effect? I also wondered what the point of the (incomplete) listing of adverse effects was. These vary by drug and by class and the bald listing doesn't seem to provide much info, besides leaving out the important 'lipodystrophy' class of AEs (PS I'm a relatively new Wikipedian but my background is in virology in particular HIV therapy.) Espresso Addict 23:05, 17 May 2006 (UTC)

As no-one objected, I've now split off the sections fixed dose combinations and synergistic enhancers. Espresso Addict 10:58, 30 May 2006 (UTC)

Merge suggestion

The Triple Cocktail stub contains a tiny portion of what is in this article; nothing much links to it and I think it's redundant. Any objections to merging? Trezatium 20:38, 2 November 2006 (UTC)

Looks like a perfect candidate for a merge. There's only one thing that's slightly clearer in that stub than in this article: it mentions the principle of combining drugs of different classes (NRTIs and PIs), which Antiretroviral drug doesn't really say in so many words, but that's nothing that a little editing here couldn't fix. ←Hob 02:10, 3 November 2006 (UTC)

I've performed the merger. I added one sentence about common combinations, and moved the "Classes" section so that it precedes that sentence. Trezatium 12:23, 4 November 2006 (UTC)

Hey, that looks good. Thanks. ←Hob 17:30, 4 November 2006 (UTC)

Outdated guidelines

The WHO and DHHS guidelines cited in this page are out of date. Someone with time on their hands might like to check what changes are needed. Trezatium 18:44, 4 November 2006 (UTC)

Stunning lack of perspective

"Also, providing anti-retroviral treatment is costly and resource-intensive, and the majority of the world's infected individuals cannot access treatment services." Surely the fact that millions of people who need treatment can't access it merits rather more than this casual aside. Trezatium 09:45, 17 November 2006 (UTC)

Cross-referencing to anti-AIDS programs such as the Clinton initiatives to lower drug costs is needed.Cherlin 00:10, 15 December 2006 (UTC)

Viral Load

I put in quotations from a non-copyrighted US Government publication on viral load and infectiousness for treated individuals. We need a lot more on this, because it determines how much of a drop in infections we can expect from pure treatment programs, and how much of a need for education and for prevention remains.Cherlin 00:22, 15 December 2006 (UTC)

Ingrown nails???

Is in-grown nails really a proven side-effect of HAART? —The preceding unsigned comment was added by 149.99.247.70 (talk • contribs).

Reference 11 in the article lists ingrown nails as a side effect of indinavir. This Google search provides more references. Trezatium 22:48, 18 February 2007 (UTC)