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Issue #196: September 25, 1998
fastfax is available by fax in the 215 and 610 area codes at no cost, or by mail anywhere for $20.00 per year, by calling 215-545-6868, and by E-mail by contacting and type the message SUBSCRIBE in the message section. Sources for some articles in this issue include AIDS Treatment News, Boston Herald, Kaiser Daily Health Reports, The Lancet, Reuters.Merck discontinues twice-daily Crixivan study
Sustiva approved by FDA; activists attack price
Early, aggressive HIV therapy questioned
Abbott still seeking Norvir answer
Mutation said to slow HIV progression
Massachusetts moves toward code reporting
TPAC pres says Maurer was warned
Merck discontinues twice-daily Crixivan study
Based on data from interim analysis, Merck and Co. has discontinued the twice-daily dosing of the HIV protease inhibitor indinavir (Crixivan) in combination regimens with reverse transcriptase inhibitors, according to a Merck press release.
To ensure optimal therapy, patients participating in twice-daily dosing study arms should switch to indinavir 800 mg every eight hours, Merck officials said.
Other studies now under way by Merck to evaluate the antiviral activity of twice-daily dosing of Crixivan combined with other protease inhibitors dosed twice-daily, such as nelfinavir and ritonavir, are continuing.
Merck has been conducting two studies to compare the efficacy and tolerability of the currently approved 800 mg three-times daily dose of indinavir with a 1,200 mg twice-daily dose.
Data at 24 weeks indicate that the "...three-times daily regimen was more effective than the twice-daily regimen in reducing levels of viral RNA to below detection (less than 400 copies/mL) in patients initiating therapy," Merck officials said.
They found that 91% of the subjects on the three-times daily dosing schedule had HIV RNA load below 400 copies/mL compared with 64% of the subjects on the twice-daily dosing schedule.
These study data reinforce the potent antiviral effect of indinavir three-times daily in combination with AZT and 3TC, according to Dr. Bach-Yen Nguyen, Director, Clinical Research at Merck Research Laboratories.
However, "...the difference in efficacy between the two treatment arms over time indicates that the approved dosing regimen and the twice-daily dosing regimen are unlikely to reach equivalence," Dr. Nguyen explained.
Merck had initiated two studies to compare the antiviral efficacy and tolerability of the approved 800 mg three-times daily dosing with twice-daily dosing (1,200 mg every 12 hours) of Crixivan. The first study compared Crixivan twice-daily versus Crixivan three-times daily, each in combination with the RTIs AZT and 3TC, in patients starting antiretroviral therapy. The second, a transition study, evaluated the two dosing regimens (Crixivan twice-daily with RTIs and three-times daily with RTIs) among patients who had already achieved levels of virus below detection after six months on therapy with the approved three-times daily dosing of Crixivan with RTIs.
Sustiva approved by FDA; activists attack price
The Food and Drug Administration has approved DuPont's Sustiva (efavirenz), a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of people with HIV.
Sustiva is the first anti-HIV drug to be approved by the FDA for once-daily dosing and will be used in combination with other anti-HIV drugs in both adult and pediatric patients.
But a group of activists says that the high price of Sustiva may put it out of reach of many people with HIV/AIDS and state AIDS drug programs.
Results from more than a dozen clinical trials involving more than 2,000 patients demonstrate the efficacy, safety and flexibility of Sustiva. These results indicate that Sustiva reduces plasma viral RNA to below quantifiable levels (less than 400 copies/mL, including both those who have never taken other treatments and those who have been taking other AIDS drugs. The drug was tested in two-, three- and four-drug combinations.
Studies have shown that efavirenz penetrates into the cerebrospinal fluid, a common viral sanctuary.
Sustiva can be taken only once a day with or without food. However, a high fat meal may increase the absorption of Sustiva and should be avoided.
Sustiva will be available in 200 mg capsules for adult dosing of 600 mg per day and in 100 mg capsules and 50 mg capsules for pediatric dosing.
The accelerated approval of Sustiva was based on analysis of plasma HIV-RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV-RNA with Sustiva.
In one study, Sustiva in combination with two nucleoside analogues (AZT and 3TC) suppressed HIV-RNA to below quantifiable levels in a greater proportion of patients than did the control arm consisting of a current standard of care regimen containing Crixivan, AZT and 3TC.
More subjects from the indinavir, AZT and 3TC control arm discontinued therapy because of adverse events and this accounted for a substantial fraction of the difference between the treatment regimens, according to DuPont. The open label design of the study makes it difficult to assess the relative efficacy of the treatment arms, the company said.
In a second study of patients with extensive prior use of nucleoside analogues, the combination of Sustiva, the protease inhibitor nelfinavir and nucleoside analogues suppressed HIV-RNA to below quantifiable levels in a higher percentage of patients than did a control arm consisting of nelfinavir and nucleoside analogues.
Resistant virus emerges rapidly when NNRTIs are administered as monotherapy. Therefore, Sustiva must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. Sustiva therapy should always be initiated in combination with at least one other antiretroviral agent to which the patient has not been previously exposed.
Safety data from clinical trials show Sustiva is generally well tolerated. The most significant adverse events associated with Sustiva therapy are nervous system symptoms, which are reported in approximately half of patients (dizziness, insomnia, somnolence, impaired concentration and abnormal dreaming). The discontinuation rate for nervous system symptoms was 2.6 percent. These symptoms occur early in treatment and generally resolve within a few weeks, according to DuPont.
DuPont warned pregnant women not to take Sustiva because animal studies indicated that there might be a risk of birth defects.
Meanwhile, a coalition of AIDS advocacy and community service groups are sounding the alarm about the potential pricing of Sustiva and Ziagen (abacavir), another AIDS drug nearing FDA approval.
A consensus letter to FDA sponsored by the Fair Price Working Group "addresses concerns that the new drugs may be priced significantly higher than others in the same class," according to the AIDS Treatment News. The letter, which has been signed by 80 organizations and 141 individuals worldwide to date, notes that "inappropriate pricing will quickly outweigh any possible added benefits of new drugs." It contends that as new AIDS therapies that allow long-term survival become available, "manufacturers should be planning to lower the daily cost of their regimens, not increase them."
The letter notes that "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." In addition, the letter notes that the potential market for the drugs is large, and high costs could significantly raise the overall price of AIDS treatment, which would be especially damaging to cash-strapped state ADAP and Medicaid programs.
Neither the Pennsylvania nor New Jersey ADAP programs have decided whether or not they will be able to offer the drugs free through their special pharmaceutical benefit programs for people with HIV/AIDS.
The letter concludes that "the price of these drugs will have a pervasive impact on the overall quality of care people with HIV/AIDS receive in this country," and that a failure of drug manufacturers to price the drugs in accordance with others in their class "will trigger widespread hostility, contentious debate and closer scrutiny of industry practices in general."
The Fair Price Working Group says that it hopes the statement "becomes the first step in a wider campaign over the cost of HIV treatments," noting that some drug manufacturers "have quietly raised prices on drugs that already bore high price tags."
Early, aggressive HIV therapy questioned
The current consensus among AIDS experts is for early and aggressive antiretroviral treatment for HIV-infected patients. However, Dr. Jay Levy of the University of California in San Francisco questions this approach.
In an editorial in the September 19th issue of The Lancet, Dr. Levy makes the case for reserving certain antiretroviral therapies for a later stage of infection. He stressed that he is not referring to patients in the acute or primary stage of HIV infection, who can greatly benefit from dramatic suppression of viral load at this time, but for the majority of patients who present several months or years after seroconversion.
For these patients, the published guidelines urge commencement of triple drug therapy when CD4 counts drop below 500 per microliter and HIV RNA load exceeds 5,000 copies/mL. It is these numbers, rather than the patient's clinical status, he points out, that dictates the therapeutic course.
"In my view early treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime of the person," Dr. Levy writes.
One concern is the development of drug-resistant virus. During active HIV replication, the mutations that develop are random, he points out, whereas, mutations that emerge during antiretroviral drug treatment select for viruses resistant to these drugs.
Although the argument is made that early treatment can preserve the immune system, he points out that this overlooks the fact that "...these drugs can be toxic and can be directly detrimental to a natural immune response to HIV, which is present in most individuals during the asymptomatic phase of infection."
Recent reports indicate that patients who stop treatment experience a recurrence of viremia, sometimes at higher levels than before treatment began. "These observations strongly suggest that the immune system has either been compromised by the drugs or 'put to rest' by the therapy." Therefore, once treatment is discontinued, an effective immune response against HIV might not be possible.
Dr. Levy suggests that "...current therapeutic regimens should be reserved for those patients who have symptoms or whose CD4 cell counts have dropped substantially." A better point at which to begin treatment may be when CD4 counts are less than 400 cells per microliter and HIV RNA levels exceed 30,000 copies/mL on at least two occasions. Although these numbers are arbitrary, they are "...representative of what appears to be evidence of an early demise in the immune response, but one that can be reversed."
Dr. Levy also stressed the potential importance of immune restorative therapies, which may be administered in conjunction with antiretroviral drugs. "This approach seems important in light of the fact that current treatments appear to leave the patient in a naive immune state, like an uninfected individuals, rather than someone prepared to control HIV infection."
If viral eradication is not possible, Dr. Levy believes the ultimate objective needs to be "...to return all HIV-infected people to the state of long-term survivors who do not need treatment even after 20 years of infection."
Abbott still seeking Norvir answer
Abbott Laboratories investigators still can't find the source of a mysterious manufacturing line problem that is about to dry up the supply of the capsule form of Norvir, the company's protease inhibitor.
Supplies of capsulized Norvir will run out within the next month, unless the production glitch can be identified and remedied, a company spokeswoman said. The loss of the capsule will leave patients reliant on a liquid form of Norvir, which is in plentiful supply and effective, but foul-tasting.
Abbott reported problems making Norvir (ritonavir) capsules on July 27. The company said a manufacturing flaw produced crystals that altered the way the capsules dissolved.
None of the flawed drug was distributed. Norvir is used by about 60,000 AIDS patients.
Physicians recommend masking the taste of liquid Norvir by taking it with chocolate products such as cake or a milkshake.
Norvir, with $170 million in sales in 1997, is the fourth best-selling protease inhibitor, a category of drug used to combat HIV, usually in concert with other compounds, among them AZT.
Protease inhibitors block the production of enzymes in HIV, and their use in "cocktails" of HIV drugs is thought to be a major factor in the decline in AIDS deaths in the U.S.
Researchers at this year's World AIDS Conference in Geneva reported that Norvir increased the effectiveness of related drugs, resulting in a more potent treatment of HIV.
Abbott maintains a Web site, http://www.norvir.com, on the drug.
Mutation said to slow HIV progression
A common genetic mutation significantly delays the progression of HIV disease, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have found.
Philip Murphy, M.D. and David McDermott, M.D., of NIAID's Laboratory of Host Defenses, led a research team that screened blood samples from HIV-infected individuals for mutations in the gene for CCR5, a key HIV co-receptor. The CCR5 gene encodes a protein on human immune cells that helps HIV enter and infect those cells.
Recent studies have shown that individuals who produce mutant forms of CCR5 protein are more likely to resist HIV infection or have slower HIV disease progression than individuals who produce normal CCR5 protein.
This time, the researchers wanted to see if mutations in the promoter, a region of the CCR5 gene that regulates the quantity, rather than quality, of CCR5 protein, might also influence HIV disease progression. Their suspicions that such mutations would slow disease progression were confirmed.
The scientists discovered that individuals with promoter mutations in both of the CCR5 genes they inherited developed AIDS almost four years later, on average, than HIV-infected individuals who lacked the mutation. Laboratory analyses showed that the mutant promoter was 45 percent less active and thus less effective at promoting CCR5 protein production, than the normal promoter.
Approximately 20 percent of the HIV-infected individuals in the study possessed two copies of the mutant CCR5 promoter. Since the vast majority of these individuals were Caucasians, the researchers screened random blood samples from healthy donors to get an estimate of the promoter mutation's prevalence among the general population. They found two copies of the mutation in 32 percent of African Americans, 28 percent of Asians, 18 percent of Caucasians and 10 percent of Hispanics in the sample.
"This is the first HIV disease-modifying genetic variant found in a regulatory region of the CCR5 gene," Dr. McDermott said. "It is extremely common, has a broad racial distribution and exerts a strong protective effect against disease progression."
In addition to providing an important new piece to the puzzle of genetic protection against HIV disease, the finding could point to new opportunities in HIV treatment research. "The information may have a therapeutic application if methods can be developed to block specific regulatory factors at this or other sites that affect CCR5 production," they write.
A report of the study was published in the Sept. 12, 1998, issue of The Lancet.
Massachusetts moves toward code reporting
At a public hearing in Boston this week, yesterday, both medical professionals and AIDS activists were able to agree to a Massachusetts Department of Health plan to report HIV cases using a coded identifier system.
Pennsylvania is also considering implementing an HIV reporting program, although state officials are leaning toward a names-based system. Philadelphia health department officials announced last week that they were opposed to names reporting, instead recommending that the state look into coding systems being considered in California, Washington and other states.
The Massachusetts plan, effective January 1, 1999, would mandate that doctors report all HIV-positive patients, including past cases, to the health department via a 17-character code comprising parts of the patient's name, address, birth date and social security number.
Only the doctor would know the connection between a code and a corresponding name.
More than two dozen medical professionals and advocates for people with HIV and AIDS called a coded system a better approach than a names-based system at this week's public hearing. Bennett Klein, AIDS law project director for Gay and Lesbian Advocates and Defenders, said, "A non-name-based HIV reporting system responsibly balances the goal of obtaining more accurate and complete information about the HIV epidemic with the critical need to encourage HIV testing."
Opponents of the new plan favor a names-based system, citing concerns over accuracy, and argued that "HIV should be treated like any other communicable disease" -- including AIDS, which the state tracks by name. William Breault of the Main South Alliance said of coded reporting, "This is a procedure which compromises, probably fatally, the whole point of instituting tracking."
A final decision on the policy is expected by the Public Health Council at an Oct. 27 meeting.
TPAC pres says Maurer was warned
Mick Maurer, who was dismissed as a member of the Philadelphia AIDS Consortium Board of Directors two weeks ago, was warned that his "violations" of Roberts Rules of Order would lead to disciplinary action, according to TPAC board president Blair Durant.
TPAC allocates over $4 million in state and federal AIDS funding for the five counties of southeastern Pennsylvania. His dismissal was the first such action ever taken in the troubled eight-year history of the organization.
"The issue is his sharing with the press what was a confidential discussion held in a duly constituted executive session of the Board," Durant said. "This is a violation ... of previous Board discussions with Mick earlier in the summer. This is not the first such transgression on Mick's part. Roberts Rules state that an executive session is simply a meeting or part of a meeting where the proceedings are to be confidential."
"It is important that it is understood that the crucial issue is that confidentiality was breached. That was the main concern of the Board and myself, not what the confidential information was."
Maurer had revealed that TPAC had spent over $14,000 to send a group of board members and volunteers to the international AIDS conference earlier this summer.
"The issue of Geneva was never considered secret," Durant told fastfax. "On the contrary, many consumers and community members knew that TPAC was sending people to the conference. It is also important the people understand that conference attendance is an identified line item in the TPAC budget, which is a public document, publicly discussed, reviewed over a period of a month and voted on by the entire Board including Mick."
Durant pointed out that fastfax erred in reporting that TPAC only uses tax dollars for its activities. She said that TPAC also receives private and individual donations, corporate and foundation support, although she did not indicate whether the Geneva expenses were supported by state or private money.
Durant confirmed that half of the Board members voting to dismiss Maurer were among those receiving help from TPAC to attend the Geneva conference. "There should be no inference that their votes had anything to do with Mick's departure from the Board," Durant said. "That was an entirely separate issue regarding a violation of confidentiality."
Responding to complaints that the Board acted to dismiss Maurer without informing him that the issue would be discussed, and without giving him an opportunity to defend his actions, Durant said that she "regrets" that Maurer was not present when the vote was taken. She noted, however, that Maurer has requested to be placed on the Board's October board meeting agenda.
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