Medical Consultant
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Antiretroviral Drugs and Treatment Strategies
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The last International AIDS Conference was held two years ago, just after the first three protease inhibitors were approved. It was also a mere seven months after 3TC arrived at pharmacies in the U.S., marking the final demise of the era of AZT monotherapy. Optimism was justifiably high. At this summer's event, held in Geneva and dubbed the "12th World AIDS Conference," the prevailing view was more sober as further experience with these drugs has begun to reveal their limits. Two things at least seemed clear: HIV is not going away -- we've yet to see the cure -- but the antiviral drugs we now have, all 15 of them, offer the hope of controlling the virus for many years, if not decades, in a large number of people. The trick is learning how to properly adjust therapies to prevent HIV breakthrough, and for that, Geneva could offer only some clues.
The introduction of viral load assays in the last two years has brought a revolution in monitoring the progress of HIV infection and vastly simplified clinical trials of new drugs. These days, the FDA accepts six months of viral load data as sufficient to support accelerated or conditional approval of a treatment for HIV and 48 weeks for complete approval. The result has been much shorter and narrower trials than ever before. People are forced to minutely analyse the viral load data that have come out to understand these trials' overall significance. They compare such factors as the trials' baseline viral load and final viral load results, the percent of participants with viral loads falling below test limits, the type of viral load assay used and the CD4 counts and other indicators to trial participants' health status.
Reports from Geneva and the immediately preceding Second International Workshop on HIV Drug Resistance and Treatment Strategies indicated, though, that even the most careful analyses have been overly optimistic. (Note that the official name of last year's resistance workshop -- the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication -- imparted a decidedly more sanguine tone than this year's implied assessment of therapy's limits.) At the resistance workshop, Andrew Hill (of Glaxo Wellcome, UK) described the statistical smokescreens that obscure trial reality (abstract 76). In the AVANTI-2 trial, for example, those on AZT/3TC/indinavir were found to have a week-28 viral load reduction of 1.6 to 3.1 logs (97.5% to 99.98%), depending on the statistical methods used. Similarly, the percent below the limit of quantification (%BLQ) with a viral load assay ranged from 78% by the least rigorous analysis to 46% by the most conservative one.
A major factor in these differences is whether individuals who stop taking their trial medicines are included. "On-treatment" analyses, which do not include the patients who drop out of the studies, generally yield better numbers than "intent-to-treat" analyses, which do include all patients entered in the study, regardless of their outcome. Counting in the data from dropouts tends to reduce a drug's observed efficacy because a major reason for dropping out is, obviously, poor response to the trial medications. The FDA is now advising drug companies to analyse their data according to "intent-to treat" methods. One is called "last observation carried forward" (LOCF) and the other is "noncompleter equals failure" (NC=F). LOCF takes the last results before a person drops out of the trial and counts them as if these figures occurred at the end of the trial. Each method combines all the data from the period when participants are following the trial protocol without having to worry about what happens to dropouts after they leave the trial and switch drugs.
Noncompleter equals failure is useful for trials with yes or no answers. In HIV trials, anyone who drops out is counted as a nonresponder, that is, that person failed to go below the level of detection in the viral load assay. This brings up a second major factor in reducing drugs' success rates. Until recently, trials used viral load assays that only went down to 1200 or 400 copies/ml. This threshold was due to the technological limitations and had no biological significance since considerable HIV replication is taking place below 400 copies/ml. With the introduction of the ultrasensitive PCR assay, which is accurate down to 50 copies/ml, it has been discovered that many, if not all, people with viral loads of between 50 and 400 will develop drug-resistant HIV and see their viral loads rebound. (See Douglas Richman's lecture at Geneva on Monitoring Therapy -- oral presentation 22) But measuring viral load down to 50 copies/ml cuts into the observed percent BLQ. With the ultrasensitive viral load assay only about 50% or 60% of the selected groups recruited for clinical trials are below the level of quantification, by intent-to-treat analysis.
Here are some examples of trial data presented in Geneva that include percent of trial participants with viral loads below 50 based on some sort of intent-to-treat analysis:
If half the people in trials of highly active antiretroviral therapy (HAART) have a risk of early rebound in their HIV, what about the other half that do successfully get their viral loads below 50 copies? It has been obvious for a while that they still have HIV lurking in the background. It comes back any time therapy is interrupted. A report by Richard Harrigan from Vancouver's Center for Excellence in HIV/AIDS described what happens in detail (abstract 11152). The group observed a set of patients who had had viral loads of less than 50 copies for one to three years when they stopped therapy. All exhibited an immediate resurgence of HIV, with viral loads doubling every day for the first three weeks off therapy and reaching up to the 100,000 range.
The group tried to use the size and slope of viral load rebound in about 20 patients to estimate the original total bloodbourne HIV before therapy was stopped. They found the total remaining free virus even under supposed maximal suppression was on the order of 10,000 to 1 million copies, which would indicate a considerable amount of residual HIV replication. Dr. Harrigan also noted that when you look at the number of HIV-infected cells, the therapy-influenced decline is very slow -- the number goes down by only about 50% per year. His conclusion was that the infected cells were unlikely to be eliminated by current therapies.
Many of the infected cells contain defective HIV gene sets that are incapable of producing new virus. It has been known for over a year, though, that there is a sizeable pool of latently infected cells, at least 1 million, that harbour replication competent HIV and could start producing new HIV particles when activated. One of the pioneers in exploring this cell population, Robert Siliciano of Johns Hopkins University, noted in Geneva that the pool size is stable over at least four years of therapy (abstract 11150).
There is a possibility that this pool is slowly replenished by continued rounds of viral replication even when plasma viral loads have been minimised by therapy. If such continued rounds of replication do occur then the apparent size of the long-term latent pool is enhanced by cells that actively produce HIV and have quick turnover times. Also, the latently infected cells might be the source of the rebounding HIV that Dr. Harrigan observed, but the speed of that rebound and the estimated size of the residual free virus population makes the latent cells an unlikely source.
A startling presentation by David Ho of New York's Aaron Diamond Institute revealed that this is precisely not the case (oral presentation 167). In six selected patients who started therapy very early in infection, the size of the latent pool decreased by half every six months. This half-life is the expected one if there is no replenishment and most of the latently infected cells die a natural death without ever producing HIV.
And if there is no residual replication, one would expect that the HIV in the infected cells should have a constant genetic makeup, with little sign of change over time, since it represents old, latent virus left over from the days before HAART was commenced. When looking at patients with suppressed HIV, though, Dr. Ho found accumulating mutations in the gene for HIV envelope protein. (Dr. Harrigan also found indications of this phenomenon.)
So far, Dr. Ho has detected no evidence that drug-resistant HIV is emerging from the residual replication. It may be that the cells in which HIV continues to replicate are to some extent off-limits to antiviral medication. The failure of drugs to reach all the cells could be due to metabolic or physical barriers, whether temporary and accidental or some permanent feature of body chemistry. There is yet to be any determination of where residual replication occurs, so all theories are completely speculative at this point.
Clearly, though, the potency of HAART even under the best conditions has been overestimated. If there is HIV replication in the presence of drugs, then the evolution of drug resistance and the resulting viral rebound is a "disaster waiting to happen," to quote Anthony Fauci, director of the Laboratory of Immunoregulation at the National Institutes of Health.
It was widely remarked that the 12th World AIDS Conference raised more questions than it answered. One of the greatest of these was, are all current antiviral regimens doomed to failure? With successful HAART that reduces viral loads below 50 copies, HIV might take years longer to break through than with less suppressive therapies since the residual rate of HIV replication is so low. Even so, many doctors already are seeing patients who have signs of re-emerging HIV. Dr. Michael Saag of the University of Alabama noted, "I've seen people with months of unquantifiable virus who suddenly have measurable virus. The initial response of most investigators would be to blame it on adherence, but I know some of these people wouldn't have missed a dose."
These issues are not really new. Dr Fauci's lab reported last year that it could find signs of newly infected cells in patients with suppressed HIV. (Specifically, the researchers found newly replicated HIV DNA that had not yet merged with the cell's genetic machinery -- see Proceedings of the National Academy of Science, Nov. 25, 1997, pages 13193-7.) The report faced widespread criticism that the patients it utilised were not properly selected to ensure that their HIV was completely suppressed. Another Cassandra was Dr. Saag, who met general scepticism when months ago, he calculated that with a viral load of just one copy per ml, there must be 100,000 cells actively producing HIV in the body at any one time. The Geneva conference marked the first time the medical community took these warnings seriously and started examining ways to cope with residual replication.
The most obvious strategy is just to do more of the same: If three drugs aren't enough, why not try four or five? That suggestion has already been put in practice for people who have very high untreated viral loads or who rebound on three- drug regimens. More drugs might be useful in cases of runaway HIV, but there is no proof that four or five drugs bring viral loads down lower than three drugs do. (See the results for nelfinavir/saquinavir plus two nucleoside analogues mentioned above.)
Drug resistance assays might be used to help pick the most effective drugs, and drug level monitoring could detect whether the drugs were actually reaching the bloodstream. The list of possible additions goes on and on, as the side effects and costs mount. There are already serious fears that protease inhibitors will cause heart disease in many people after a few years of use, and adherence to complicated regimens already is the major life activity of many people with HIV. As the years go by, such adherence will only decline.
Having given up on eradication for the foreseeable future, Dr. Ho is now searching for the means to achieve remission. Remission is inspired by the example of long-term nonprogressors, who survive for years and perhaps decades without treatment even as they maintain stable CD4 counts and low viral loads of a few hundred copies per ml or less. If one could mimic the nonprogressors' immunity in treated patients, it might be possible to withdraw some or all drugs. HIV would not be gone, but the body would be able to control the small amounts left without suffering any damage.
The nonprogressors are distinguished by their active anti-HIV immune responses orchestrated by the T-helper CD4 cells (abstracts 21126 by Fabrienne Hadida of the Hôpital Pitié- Salpétrière in Paris and 425 by Bruce Walker of Massachusetts General Hospital). Outside of the nonprogressors, CD4 cells that proliferate and promote the immune attack in the presence of HIV are not observed in people with chronic HIV, though they may exist during the initial or primary phase of infection. (One theory is that HIV kills off the activated CD4 cells responsible for maintaining the anti-HIV defences.) As CD4 cells come back under HAART, no return has been noted so far in anti-HIV immunity, except in people whose treatment starts during the first six months after contracting HIV.
The lack of new anti-HIV CD4 cells is curious since other immune responses do seem to return when people's HIV levels decrease. Brigitte Autran, of the Hôpital Pitié-Salpétrière in Paris, described what happened in her cohort of 18 extensively studied persons with AIDS. In half of them, CD4 cells sensitive to CMV and TB returned after a year on HAART, but there were no new cells directed at candida, tetanus or HIV (oral presentation 426). The only exceptions were those who received a tetanus vaccine. Perhaps more time is needed for the response against HIV to reappear, although Dr. Ho thinks that people with viral loads below 50 have so little HIV in their bodies that there is insufficient stimulus for anti- HIV CD4 cells to proliferate and manifest themselves, if any exist. One way to get around this would be to use an HIV vaccine, following the tetanus example.
As it happens, the Immune Response Corporation has been trying to develop and promote its HIV therapeutic vaccine (Remune) for the past dozen years without yet producing definitive proof of its effectiveness. (This vaccine consists of killed HIV stripped of its outer envelope and mixed with an immune-stimulating adjuvant. It was first proposed by the late Jonas Salk.) The company had noticed the opportunities HAART presented for the vaccine, and started a small trial over a year ago to see whether immunisations with Remune could improve on HAART alone.
In Geneva, Fred Valentine of New York University reported the preliminary results from the trial. The 43 treatment-naïve participants were all put on AZT/3TC/indinavir for the first four weeks. Their baseline mean CD4 count was 493 and their mean viral load was 8159, so these were people with relatively early stage HIV infection. After four weeks, those with viral loads reduced to below 200 were divided into two groups. One group was immunised with Remune at weeks 4, 16 and 28. The other group was vaccinated with the adjuvant alone at the same time points. Dr. Valentine summarised the week 20 results, describing what he called "enormous" new proliferative responses in the Remune group, while the adjuvant-only group showed no improvement. The CD4 cells' proliferation was checked in the test tube by culturing a sample of those cells with either Remune, the HIV p24 core protein from the Remune HIV strain, recombinant p24 made by genetically engineered cells and HIVBAL, an HIV lab strain. Cell stimulation indices increased an average of five times in the tests on cells taken from the Remune recipients. But Conference attendees wondered if these newly active CD4 cells had any protective value.
Although Dr. Valentine claims that the Remune plus HAART recipients now have immunity similar to long-term nonprogressors, there was no evidence presented to show that the new immune responses are in fact protective. Confronted by HIV that has escaped therapeutic suppression, they might prove just as inadequate as they usually do during primary infection. One piece of information from the trial that has yet to be analysed is the trial volunteers' level of proviral DNA, a measure of the number of infected cells. A Remune-associated reduction here would indicate a decline in residual replication, although it might take much longer than the trial's 32 week follow-up time for any reductions in infected cells to be apparent.
Dr. Valentine is now designing trials that would document the time to HIV rebound in people on HAART with and without immunisation. Another possible trial would be to take vaccine recipients and a control group off antiviral therapy for a few days and closely monitor them for the re- emergence of HIV. Bruce Patterson of Northwestern University described a new rapid and cheap method for assaying for proviral DNA and HIV-infected cells (abstract 41252). Monitoring trial participants with such an assay might be useful before taking such drastic action as interrupting therapy.
Dr. Ho, who is also preparing a vaccine trial, suggested in Geneva that the immunisations be accompanied by therapies to clean out the pool of latently infected cells. Such a treatment might use the natural cell-activating cytokines to stimulate these cells' HIV into production. The cells would then be killed off either by the virus or the immune system. Successful treatment of this sort would further diminish the amount of HIV that the vaccine-induced immune responses would have to contain but would probably come with a heavy price in terms of flu-like side effects. Dr. Fauci related some experiments that he has done using immune stimulants on lab samples of cells from eight patients on HAART (oral presentation 157). In only one case were the HIV-infected cells eliminated; in the other seven, they were moderately reduced. Just one round of stimulation was administered, but still, the elimination of the latent pool is obviously not a simple task. Dr. Fauci concluded by calling for more work in this area, terming it "the research agenda for the next several years."
In times of confusion, the rationale for slowing down and adopting a wait-and-see approach is very strong. When protease inhibitors came out, many people had poor experiences with them because they had followed aggressive treatment advice for years. Their HIV gradually developed resistance to all the nucleoside analogues that could complement the protease inhibitors. Having "burned through" these older agents, their viral replication frequently remained high when they added protease inhibitors, and many rapidly burned through those drugs as well. Those who put off treatment did better.
Discussions in Geneva made the important point that there is no solid reason to seek maximum viral suppression if a cure is not in sight. The body can tolerate substantial HIV levels with little apparent harm. One presentation in Geneva, by Dr. David Katzenstein of Stanford University (abstract 12124), went back to ACTG 175, an old trial of AZT, ddI and ddC, to remind attendees that people with both a viral load below 10,000 and a CD4 count above 300 nearly always remain free of major, AIDS-defining conditions over a three-year period.
Short of eradication, the big rationale for maximising HIV suppression is that it prevents or delays the evolution of drug-resistant HIV. Yet there are other strategies for avoiding drug resistance. The most obvious is to put off taking the drugs. You can afford to do that if you are basically healthy and if your viral load and, especially, your CD4 count are stable.
In a plenary address to the Geneva conference (oral presentation 159), activist Mark Harrington described how he started therapy only after his health had deteriorated and his CD4 count had crashed. By then protease inhibitors were on the market. "I'm lucky I waited," he said, showing before-and-after slides of his lymph nodes. By the time he began treatment, HIV had seriously eroded their structure. Now after two years with the lowest possible viral load, that structure seemed essentially restored.
Indeed, the best news at Geneva was likely that the immune system seems capable of slowly repairing much of the damage it has suffered (with the possible exception of the anti-HIV immunity lost early on). According to Dr. Autran, who also described the experience of a large, 300-person group with AIDS on successful therapy, the reestablishment of the CD4 cell population depends mainly on the level of viral suppression. Those with late-stage disease can slowly regenerate lost cells, too, though it may take six or seven years to reach a normal count. The trick is to know how to successfully administer anti-HIV regimens, not rush to take them at the earliest possible moment.
Delaying therapy may buy you a couple of years while the scientists elaborate wiser treatment strategies that more effectively use the available drugs. But what if your viral load already is rising and your CD4 cells declining? If you face present or imminent illness, you can't wait for treatment, but you can still develop conservative strategies that both improve your health and preserve future treatment options. The strategy would be to use as few drug classes per regimen as possible, carefully choosing agents so as to avoid sparking resistance to other drugs you might want to use later on. With 11 anti-HIV drugs now on the U.S. market and another four available through expanded access, many such narrow but potent combinations are conceivable. Geneva provided several illustrations of what can be done.
One possible regimen is a combination of d4T and ddI, with or without hydroxyurea. d4T and ddI are less susceptible to drug resistance than many competitors, and hydroxyurea helps to potentiate their action, even against drug-resistant HIV. In a 117-person Argentinean study presented in Geneva, d4T/ddI/hydroxyurea performed almost as well as many protease combinations in people without prior treatment and low viral loads. d4T/ddI by itself was also quite respectable. Other examples are efavirenz plus indinavir or another protease inhibitor; the abacavir/AZT/3TC triple- nucleoside analogue combination; and several double protease-inhibitor regimens. With little overlapping resistance, these combinations can be gradually sequenced when HIV starts rebounding, allowing many years of health. (GMHC's Treatment Issues will describe many of these regimens in greater detail next month.)
It is conceivable that you could also gain extra years of stability by sticking with a combination that used to work better but now allows modest viral loads. Reports from San Francisco General Hospital and elsewhere have indicated that this is so. But you might also be allowing the development of further drug resistance. It is hard to say which way the advantage lies, and the research presented in Geneva was of no help in planning long-term treatment strategy. Geneva may have been the conference that raised more questions than it had answers, but this high question-to-answer ratio is more than just an historical accident. Plenty of short-term viral load response trials have been done, but the more general trials that take up the larger questions are still a matter of discussion. Source: Treatment Issues, Volume 12, Number 7/8 - July/August 1998. Treatment Issues is published twelve times yearly by GMHC, Inc., The Tisch Building, 119 West 24 Street, New York, NY 10011 Fax: 212/367-1528
Treatment of HIV and AIDS in the industrialised world has seen recent success with the introduction of potent combination antiviral therapies leading to a dramatic improvement in many infected individuals. However, in developing countries, where 90% of people with HIV live, this modern approach using combination therapy has been out of reach.
Roche Pharmaceuticals, the Swiss based multi-national giant announced Wednesday the donation of supplies of its widely criticised anti- HIV medication Inviraseâ to several sub-Saharan African Countries.
The company plan to provide the drug, an HIV-protease inhibitor, along with another of it’s anti-HIV treatments Hividâ and Glaxo Wellcomes Retrovir®â (AZT). Although the company is announcing “... access to state-of-the-art HIV Treatment for Africa” the combination of drugs being provided is not even recommended as one of the preferred drug combinations under the U.S. Guidelines for the treatment of HIV.
Inviraseâ has been widely criticised because of the poor absorption of it’s active ingredient saquinavir, and it’s subsequent lack of potency when compared to the other available protease inhibitors. Due to these problems Roche had to reformulate saquinavir and have recently received approval for marketing the improved version in Europe which has the trade name Fortovase®â.
The other Roche product being donated through the scheme, Hivid®â is an anti-HIV drug of the nuceloside analogue class, which is also no longer widely used in the West due both to concerns over it’s potency and potential toxicities. It is the least prescribed of the five currently available drugs of this class.
Raffi Babakhanian, Executive Director of AIDS Treatment Project commented that “the inferior potency of this substandard therapy could easily lead to the widespread development of multi-drug resistant HIV in the developing world. If there is anything we have learned from the world- wide spread of HIV it’s that what happens in one part of the world will eventually affect other parts.” The transmission of untreatable multi-drug resistant HIV was reported in a number of presentations during the recent World AIDS Conference in Geneva causing widespread concern. “The last thing we need right now is the unchecked spread of multi-drug resistant HIV world-wide” said Mr Babakhanian.
Those involved with HIV treatment are wondering why Roche would be giving away a product which now has limited marketing potential in the developed world at the same time as trumpeting the arrival on the European markets of it’s replacement Fortovase, dubbed by Roche as “a new formulation, a new beginning”.
AIDS Treatment Project is strongly committed to making sure pharmaceutical companies provide all of their products to people with HIV in the developing world. However, Roche by making available only the two most problematic of it’s anti- HIV products is exhibiting both insulting and dangerous behaviour.
Author: Paul Blanchard.
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Roche currently has three protease inhibitor drugs in the market place (Fortovase, Viracept and Invirase). By only offering the inferior Invirase this is a clear-cut case of Roche treating the Third World as Third Class. |
The soft gel capsule formulation of the protease inhibitor saquinavir (Fortovase®) has received approval this week by the European Commission. Fortovase is indicated in combination with antiretroviral agents for the treatment of HIV-1-infected adult patients.
Fortovase will become available to people with HIV infection throughout the European Union over the coming months. Fortovase has already been launched in the USA and Switzerland. Recently, Fortovase has also been approved in Australia, India and Mexico.
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The previously available formulation of saquinavir, Invirase, was widely criticised for it's poor bioavailability and reduced potency compared with the other available PI's.
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A consensus statement has been prepared by a prominent group of community based treatment activists in the U.S. warning of the likelihood of inappropriate pricing of newer antiretroviral agents and opportunistic profiteering by the pharmaceutical industry. It concerns the eventual price of two new potent drugs: the nucleoside analogue abacavir (Ziagen) and the nNRTI efavirenz (Sustiva). Both of these compounds are under FDA review and no doubt will soon enter the market. There has been considerable speculation that either or both will be priced far higher than other nukes and nNRTIs, perhaps even in the range of the protease inhibitors that they would supplement or sometimes replace. Such a move would substantially increase the cost of health care for a great number of people with HIV. The group is calling for those with an interest in HIV- treatment to send a loud, clear and united message immediately before final pricing decisions are made by the sponsors, Dupont Pharma and Glaxo Wellcome.
The group hopes that this statement becomes the first step in a wider campaign over the cost of HIV treatments to be directed at all sponsors. "Some companies in the past year have quietly raised prices on drugs that already bore high price tags, without strong protest from the HIV-affected community. There is no justification for these increases other than "what the market will bear." But as combination regimens become ever more elaborate, people with HIV as well as their health care providers and purchasers will likely face medical costs over the course of a lifetime rising into the stratosphere. The pharmaceutical industry, meanwhile, stands to reap a windfall. Companies have less justification for squeezing high short-term profits from their drugs since people will be using them for longer periods of time. Make no mistake about it -- each unfair pricing action cuts off the lifeline of treatment for another portion of the population!" the statement urges.
The following is the text of the consensus statement which organisations and individuals involved HIV treatment issues were asked to endorse.
Consensus Statement on the Pricing of Abacavir and Efavirenz
We, the undersigned, have grave concerns regarding the overall cost of therapy for HIV disease. While we are heartened by the progress made in moving toward simpler, easier to use regimens, we are dismayed by the possibility that prices of new drugs in the nucleoside and non- nucleoside RT inhibitor class might be similar to those of protease inhibitors, rather than other drugs in their own respective classes. Such inappropriate pricing will quickly outweigh any possible added benefits of new drugs like abacavir (Ziagen) and efavirenz (Sustiva). As drugs become available which might facilitate better adherence and possibly more durable long-term treatment, manufacturers should be planning to lower the daily cost of their regimens, not increase them. The long-term survival afforded by the present generation of therapies makes it possible for manufacturers to set lower, or at least stable prices, and still have adequate incentive to reinvest in continued development of HIV/AIDS drugs. Recently cited reductions in the overall cost of health care for HIV infected people will almost certainly be reversed in coming years if manufacturers continue to increase or maintain current pricing levels. We are in a new era in the treatment of HIV disease and rethinking drug pricing which reflects this changing reality is long overdue.
To the best of our knowledge, the development costs of these drugs were not comparable to those of the first protease inhibitors, nor is on going cost of product as high. Quite the contrary, because of the efficiency of the new drugs, far fewer pills and thus much less physical product is required for dosing on a daily basis. Similarly, there has been nothing extraordinary about the cost of clinical trials required to bring these drugs to market.
Abacavir and efavirenz are likely to be used by both treatment naive and treatment experienced patient populations, making their potential market very large. If the prices are high and either or both drugs used in naive populations in place of existing drugs, the overall cost of therapy will go up. An even greater cost penalty will occur for treatment experienced patients, who are likely to use both drugs together, often in combination with a protease inhibitor. This would lead to an unacceptably high cost of therapy. We cannot stand idly by while the price of living with HIV disease escalates so rapidly.
The sponsors of abacavir and efavirenz have both expressed a strong desire to create goodwill and co-operative working relationships with the community. No one wants to see those relationships jeopardised or eroded over this issue, but that surely will happen if pricing is inappropriate. As we face another round of price setting, industry must recognise this is an issue that is now moving to the forefront.
Exploitative pricing will trigger widespread hostility, contentious debate and closer scrutiny of industry practices in general. This will have far reaching consequences. Have DuPont Pharma and Glaxo Wellcome considered the possible repercussions of opening this Pandora’s box? Are you willing to risk the aftermath of ill will within the community and to be held accountable within industry? Therefore, we must clearly state for the record that the only acceptable prices for these drugs must be in accordance with other drugs of their respective classes. We urge manufacturers to immediately begin a dialogue with the community about this pricing issue and not presume it can simply announce a price immediately prior to regulatory approval, without consequences, as a fait accompli.
Martin Delaney, Project Inform Dave Gilden, GMHC/Gay Men’s Health Crisis Ron Baker, San Francisco AIDS Foundation Linda Grinberg, FAIR/Foundation for AIDS & Immune Research Bill Bahlman, ACT UP New York John James, AIDS Treatment News
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This statement of protest required endorsement by 8th September for presentation to the pharmaceutical companies prior to upcoming regulatory hearings by the FDA in the U.S. We would however, still urge individuals, physicians and all purchasers and providers of HIV health care to make their feelings on this issue clear by contacting both Glaxo Wellcome and DuPont Pharma in Europe and the U.K. ATP would not be opposed to inflated pricing of HIV drugs in the developed world if this meant subsidies for provision in developing countries, but no such proposal has ever been made by any pharmaceutical company. |
An article in the September issue of the Journal of Infectious Diseases indicates that dual nucleoside treatment does not routinely suppress high viral levels of HIV-1 in infected patients. Dual nucleoside treatment is less costly and easier to tolerate than triple antiretroviral therapy. Dr. Julio S.G. Montaner of the University of British Columbia and colleagues evaluated dual nucleoside treatment in 245 HIV-positive patients, finding that only 39 percent of the subjects showed viral suppression to less than 500 copies/mL, with only 13 percent maintaining viral suppression at that level for more than two viral-load measurements. Additionally, there were no reliable response predictors and, therefore, the authors recommend that dual nucleoside treatment be discouraged within current therapeutic plans.
Source: CDC Daily News Update
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Less suppression, quicker failure with reduced efficacy of second line combinations, lack of lymph clearance and less evidence of immune reconstitution. Any rational role for currently available dual NA's?
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Abstract
OBJECTIVE: To determine the effectiveness and safety of adding delavirdine mesylate to a treatment regimen that included indinavir and nucleoside analogue reverse transcriptase inhibitors in patients in whom combination therapy had failed.
DESIGN: Observational study.
SETTING: Private practice.
PATIENTS: HIV-1-positive patients with peripheral blood CD4+ lymphocyte counts < 300 x 10(6)/l in whom antiretroviral therapy had failed or whose condition was deteriorating. Of the 53 patients who were eligible for the study, 47 took part; for the majority of these patients indinavir combination therapy had been unsuccessful. the majority of the patients were male (98%), white (92%) and homo/bisexuals (96%).
INTERVENTIONS: Delavirdine added to current therapy (usually zidovudine, indinavir and lamivudine); in approximately half of the patients zidovudine was replaced with stavudine.
MAIN OUTCOME MEASURES: Plasma HIV-1 RNA levels; peripheral blood CD4+ and CD8+ lymphocyte counts. Safety of the therapy was assessed by monitoring side-effects.
RESULTS: Mean baseline CD4+ lymphocyte count was 127 x 10(6)/l and mean baseline HIV-1 plasma RNA was 5 log10 copies/ml. Adding delavirdine to the therapeutic regimen produced a rapid and sustained decrease in the mean plasma HIV-1 RNA of 1.1 log10 copies/ml over 6 months; 18-21% of patients showed decreases of 2-3 log10 copies/ml. Viral burden in 33% of subjects declined below the assay's limit of detection (2.6 log10 copies/ml) after 6 months. CD4+ lymphocyte counts increased by 66-90% in each group between 1 and 9 months (mean increase approximately 60 x 10(6)/l after 6 months). Adding delavirdine to current therapy was well tolerated. Side-effects reported were: skin rash, 28%; nausea, 9%; kidney stones, 9%; diarrhoea, 6%; flank pain, 2%; proteinuria, 2%. Three patients reported serious medical events all of which resolved and none of which were attributed to delavirdine.
CONCLUSIONS: Adding delavirdine to the combination regimen of patients in whom protease inhibitor therapy had failed often resulted in a rapid and remarkable decrease in viral load, sustained improvement in CD4+ lymphocyte counts and viral load, and clinical improvement with minimal toxicity.
Ref: Bellman PC. AIDS 1998 Jul 30;12(11):1285- 1289
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This data was previously presented at Geneva and reported in DocFax. Obviously addition of an NNRTI to a failing regimen is not a recommended planned strategy, but these data do hint at the potential potency of triple class (PI+NNRTI+NA's) combinations. |
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OPPORTUNISTIC EVENTS
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In a Lancet commentary, Richard W. Price of San Francisco General Hospital discusses diffuse infiltrative lymphocytosis syndrome (DILS). The syndrome was first diagnosed as a complication of HIV-1 infection over 10 years ago, yet DILS is still relatively unusual. Price reminds that DILS neuropathy, in isolation, might be confused with distal sensory neuropathy of late HIV-1 infection or with a toxic polyneuropathy related to anti-HIV nucleoside drugs. A. Moulignier examined 12 DILS patients, finding salivary gland enlargement, Sjogren-like sicca syndrome, and lymphadenopathy. Additionally, CD8 counts were high among all the patients. Nerve biopsy showed that CD8 cells without vascular necrosis angiocentrically infiltrated the epinurium and endonurium. Despite the raised counts, it appeared that the CD8 cells did not confer a protective effect, since the neighbouring macrophages showed a high viral burden. Price suggests additional study of the disease, particularly since "unusual disease manifestation can teach about disease mechanisms." The author recommends that investigators research why the increased number of CD8 cells do not eliminate macrophage infection.
Ref: Price, Richard W. Lancet (08/22/98) Vol. 352, No. 9128, p.592. Source: CDC Daily News Update
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PATHOGENESIS
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Abstract OBJECTIVE: To address the question of whether individuals with chronic HIV-1 infection have a stable viral load set-point and to assess the influence of host and viral factors on the evolution of viral load in a subset of stable asymptomatic patients with a baseline viral load below 5000 copies/ml and CD4+ T-cell count above 500 x 10(6)/l.
METHODS: Medical visits were performed at least every 6 months including routine blood analysis, viral load and CD4+ T-cell count. HIV-1 RNA was measured in frozen (-70 degrees C) plasma samples using PCR. Patients were classified into three groups according to baseline viral load: group A, < 200 copies/ml (undetectable); group B, 201-2000 copies/ml; group C, 2001-5000 copies/ml. A survival analysis and a Cox regression model were performed to assess the influence of viral and host factors in the increase of baseline viral load. The endpoint was the time to increase viral load to a stable level > 0.5 log10 copies/ml above baseline viral load in groups B and C and to a stable detectable viral load (> 200 copies/ml) in group A.
RESULTS: A cohort of 114 patients with viral load below 5000 copies/ml was followed for a median of 12 months (6-42 months). Overall, 22 (19%) out of 114 patients had an increase > 0.5 log10 copies/ml of baseline viral load. Baseline viral load increased in two (5%) out of 37 patients in group A, four (12%) out of 33 patients in group B, and 16 (36%) out of 44 patients in group C (survival analysis, P<0.002). Patients of group C had an eight-fold higher risk of increasing baseline viral load than patients in the other two groups pooled together (hazards ratio, 8.28; 95% confidence interval, 1.78-38; P = 0.006). Patients with an increase of viral load to the virological endpoint had a threefold higher risk of decreasing baseline CD4+ T-cell counts > 100 x 10(6)/I than patients with stable viral load (hazards ratio, 2.78; 95% confidence interval, 1.12-14; P = 0.03).
CONCLUSIONS: In our cohort of chronically HIV- 1-infected asymptomatic patients with a baseline viral load < 5000 copies/ml and CD4+ cell count > 500 x 10(6)/l, a true viral load set point did not seem to exist. Patients with baseline viral load of 2000-5000 copies/ml had an eight-fold higher risk of increasing the level of viral load than patients with a baseline viral load below 2000 copies/ml.
Ref Vidal C, Garcia F, Romeu J, et al. AIDS 1998 Jul 30;12(11):1333-1340
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MEETINGS
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AIDS Treatment Project and the "Doctor Fax" is hosting a one day symposium on the role of HIV resistance assays in clinical practice.
DATE: Thursday 22nd October 1998
VENUE: Postgraduate Teaching Centre, Guys and St. Thomas' Hospital, London.
CHAIR: Professor Clive Loveday, Royal Free Hospital, London.
OPENING ADDRESS: Simon Hughes, MP.
KEYNOTE SPEAKERS INCLUDE:
For further information please call Raffi Babakhanian or Yasmin Motala, ATP, 0171 407 0777