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Issue #156: December 21, 1997
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 information in this issue include American Journal of Public Health, Archives of Internal Medicine, Reuters, Wall Street Journal, US Newswire
Risk of progression under-estimated in previous treatment guidelines
HIV-ravaged immune system can be restored
HIV uses protein to bend cells at will
Chicago triples hard-drug estimate
MANNA publishes Spanish nutrition booklet
Health Law Project seek info on drug denials
Risk of Progression Under-estimated in Previous Treatment Guidelines
The US Public Health Service has issued an updated draft of its guidelines on the use of anti-HIV drugs. In perhaps the most significant change, the estimated risk of disease progression at different levels of viral load has increased sharply. Meanwhile, the pros and cons of the aggressive approach to therapy recommended in the US guidelines were debated in London at November's public information forum organized by NAM on behalf of the Treatment Action Taskforce.The US guidelines continue to recommend the "hit early, hit hard" approach to anti-HIV therapy. They advise that anyone with a viral load greater than 10,000-20,000 should consider starting therapy, and that treatment should consist of two NRTI drugs (AZT/ddI, AZT/3TC, d4T/ddI or d4T/3TC) plus a potent protease inhibitor (indinavir, ritonavir or nelfinavir).
Many British doctors are concerned that this may be an over-aggressive approach to therapy which may lead some people to use up their available treatment options too rapidly.
The changes to the draft guidelines reflect new information that has accumulated since the first draft was published in June 1997. For example, the combination of ritonavir/saquinavir, in combination with two NRTIs, is now also recommended as a possible first-line regimen, although the guidelines advise that not enough is yet known about the safety of this combination.
As before, the draft guidelines recommend that the aim of treatment should be to reduce viral load to below 500 copies/ml (the limit of detection of the most widely used viral load tests), and that a change in treatment should be considered if viral load remains above 500 at 4-6 months after starting treatment.
More recently, an "ultra-sensitive" viral load test that can measure as low as 50 copies/ml has become available through some laboratories. One study has suggested that the effects of treatment may be longer-lasting if viral load is suppressed below. However, the updated guidelines argue that not enough is known to base treatment decisions on the "ultra-sensitive" test, since the results may be very variable.
The information on changing therapy has also been updated. Recent studies have demonstrated that only a minority of people taking two NRTIs alone will achieve and sustain viral load below the limit of detection. For those who do achieve undetectable viral load on two NRTIs, the new draft suggests that they should nevertheless consider switching to a more aggressive regimen, since this may reduce the risk of their viral load rebounding to detectable levels.
The new draft sounds a gloomy note on the treatment options for people who experience a rising viral load despite treatment with a combination that includes a protease inhibitor (PI). The document notes that "It appears that viral strains that become resistant to one PI will have reduced susceptibility to most or all other PIs", because of cross-resistance. Even switching to an entirely new triple combination of two new NRTIs plus a new PI may offer only a "limited likelihood of success". To increase the chances of success, the panel says that "many experts would include 2 new PIs in the subsequent regimen".
The US guidelines have now updated estimates in the light of new evidence which suggests that the previous viral load levels may have been over-estimated in statistical analysis. They now estimate that at any given viral load level, the risk of developing AIDS within three years may be higher than was previously believed.
Guidelines debate continues
Differing approaches to treatment were discussed at the TAT forum last month, with presentations from Dr. Gabriel Torres from St Vincent's Hospital in New York, who was a member of the panel that drew up the US guidelines, and Professor Brian Gazzard, chair of the British HIV Association (BHIVA).Dr. Torres noted that the new draft had been modified to include a fuller discussion of the pros and cons of aggressive therapy. He pointed out that the new viral load predictions suggest that even among individuals with normal CD4 counts (above 750), almost 10% are likely to develop AIDS within three years if their viral load is between 20,000 and 55,000, and nearly a third of those whose viral load is greater than 55,000. "Some would say this risk is enough to warrant therapy despite the high CD4 count".
However, he acknowledged that starting treatment also involves risks, including a reduction in quality of life because of side-effects or the inconvenience of treatment regimens, and encouraging the evolution of drug-resistant HIV strains. He also noted that there remains a huge uncertainty about effective "salvage" treatment options for people whose initial therapy fails.
"The weakest point of the guidelines is the advice on salvage therapy for people who are failing on a PI-containing regimen", said Dr.Torres. "There are many possible options, but none has been adequately addressed in clinical trials". Professor Gazzard suggested that treatment guidelines have "very limited usefulness; we mustn't believe that we know any more than we did before, just because a group of like-minded people have drawn up a document".
He stressed that people with HIV should always discuss their personal treatment strategies with their doctor, "rather than going by someone else's off-the-shelf recipe". He argued that it is just as reasonable to base treatment decisions on your CD4 count, rather than putting the emphasis on viral load: "People die because their immune system is destroyed - the immune system is the crucial thing". That might mean delaying treatment if your CD4 count is still relatively high, "and not taking too much notice of viral load".
He argued that the benefits of early anti-HIV therapy remain "largely theoretical. The evidence that you'll suffer irreversible immune damage if you don't treat early is absolutely not there."
Professor Gazzard accepted that when people do decide to start treatment, "dual therapy is no longer a popular first-line option and can rarely be recommended". However, he argues that it may be wiser to start treatment with two NRTIs plus an NNRTI such as nevirapine, rather than using a protease inhibitor as the third drug. "If you start with an NNRTI you still have very powerful drugs to use later, but if you start on indinavir and develop resistance, there's nothing left that's proven effective".
HIV-ravaged Immune System Can Be Restored
Reconstitution of HIV-ravaged immune systems is possible with effective antiretroviral therapy, mouse studies suggest. The studies provide in vivo evidence that people receiving highly active antiretroviral therapy (HAART) can regain most, but not all, lost immune function. They also suggest that stem-cell replacement, possibly incorporating anti-HIV gene therapies, could fully restore immune function."Hematopoietic microenvironments in HIV-1 infected individuals might remain functional to such an extent that immune reconstitution and stem cell gene therapeutic strategies for the treatment of AIDS may be feasible, provided that virus replication can be sufficiently inhibited," proposed Elizabeth S. Withers-Ward and colleagues of the University of California, Los Angeles.
The researchers noted that immune reconstitution of CD4 cells - whether endogenous or via exogenous stem-cell gene therapeutic strategies - requires the existence of functionally intact differentiation-inducing stromal elements. To explore whether such elements can survive HIV infection, they used severe combined immunodeficient (SCID) mice reconstituted with human fetal thymus and liver (Thy/Liv) tissue implants.
These SCID-hu mice were infected with HIV-1 (strain NL4- 3). Six weeks after infection, drug-treated mice received combination antiretroviral therapy with zidovudine (AZT), didanosine (ddI), and the protease inhibitor A77003 (a less effective parent compound in the series that led to the development of ritonavir). A control group received no antiviral drugs; after seven weeks the female Thy/Liv implants of some of the animals in each group received male CD34(+) stem-cell reconstitution. Biopsies, consisting of approximately one-fourth of each Thy/Liv implant, were taken at six, nine to 11, and 13 weeks. Before drug treatment, all of the implants in the HIV infected mice had severe depletions of CD4(+)/CD8(-) and CD4(+)/CD8(+) thymocytes.
The treated animals subsequently exhibited renewal of these populations; CD4 cell renewal ranged from 32 to 65 percent of the total thymocyte population. "Renewal of the CD4(+) population was seen regardless of whether exogenous CD34(+) cells were injected into the HIV depleted implants, indicating that endogenous precursor cells could be induced to differentiate,"
Withers-Ward et al. reported. "Y chromosomal sequences were detected in two mice that received exogenous CD34(+) cells, suggesting that exogenous CD34(+) cells could repopulate HIV infected, drug- treated implants. However, because of the small number of animals, we were unable to draw any quantitative conclusions about reconstitution efficiency with exogenous cells. Unfortunately, reconstitution in this model was only temporary. While reconstitution was still significant 11 weeks after infection, by 13 weeks there was no difference between drug-treated and untreated animals.
The authors noted that detectable viral replication occurred in some drug- treated animals and may have been responsible for the transience of reconstitution. "It is possible that further optimization of antiviral therapy in this model may result in more marked and sustained reconstitution of thymopoiesis," they wrote, noting that a further experiment with other protease inhibitors showed an increased effect. Withers-Ward et al. suggested that gene therapies could be combined with HAART to improve treatment of HIV disease. "Progenitor cells isolated from HIV infected individuals may be appropriate for autologous immune reconstitution and gene transfer protocols," they wrote. "It is conceivable that the combined effect of a reduction in viral load by the administration of antiviral drugs and the protective effects of anti-HIV gene therapeutic reagents, followed by the subsequent renewal of the depleted CD4(+) population might reduce or delay the pathology associated with HIV infection, resulting in an effective therapeutic strategy."
HIV Uses Protein to Bend Cells at Will
HIV apparently hijacks the immune system's signaling system and uses it to its own ends. The culprit is the viral Vpr protein. Studies by University of Pennsylvania researchers Velpandi Ayyavoo, David B. Weiner, and colleagues show that the protein acts like a glucocorticoid (GC) hormone to inhibit immune responses, to induce the programmed cell death (apoptosis) of T cells, and to preserve antigen-stimulated T cells as long-lived "factories" for production of new virus."These data suggest that Vpr may have a role in immune suppression and CD4 cell depletion in HIV infected patients," Ayyavoo et al. wrote in the journal Nature Medicine.
The HIV protein known as viral protein R (Vpr) is the 96- amino acid, 15-kDa product of the HIV vpr gene. This gene and its sister HIV regulatory genes vif, vpu, and nef are often referred to as auxiliary genes because they are not essential for HIV replication in established cell lines and because their activities are poorly understood. But unlike the other auxiliary genes
products, Vpr is carried by HIV virions.
It was once thought that Vpr was an accessory gene product with no important function. But recent studies have changed that perception. Perhaps the most dramatic of these studies is the finding that a woman infected with a vpr-defective HIV-1 mutant - and the child to whom she
passed the infection - have remained disease free and asymptomatic for 13 years of follow-up.
Other studies have shown that extracellular Vpr makes cells more permissive to HIV replication - even cells that normally permit only low-level production of the virus.
More recently, it was shown that Vpr permits HIV to infect promyelocytic cell lines via interactions with a GC receptor. Because GCs have extensive immunosuppressive and apoptosis-influencing effects, Ayyavoo and colleagues explored the ability of Vpr to mimic GC activity. They found that:
Vpr specifically blocks T-cell proliferation. This effect can be inhibited by the antisteroid compound RU486.
Like GCs, Vpr suppresses production of the cytokines TNF- (alpha), IL-2, IL-4, IL-10, and IL-12 but not IL-7. The most dramatic inhibition was with IL-2 and IL-12. "Vpr's inhibitory effect on cytokine production could compromise the host immune response, particularly in cells that are not infected with HIV-1," Ayyavoo et al. suggested.
Like GCs, Vpr inhibits cellular NFkB (a transcription factor crucial for cytokine regulation) by inducing transcription of the IkB (inhibitor of NFkB) gene.
Like GCs, Vpr induces apoptosis of T cells. Again this effect was inhibited by RU486. But Vpr blocks apoptosis of antigen-stimulated T cells.
"Infected cells that undergo antigen-specific activation could be spared as targets for apoptosis, thus functioning as efficient, long-lived, and productive viral factories," Ayyavoo et al. wrote.
The researchers suggested that further studies will be needed to determine precisely how the Vpr activities they identified relate to clinical HIV infection. They predicted that such studies will not only help clarify HIV pathogenesis, but will also yield insights into general immune function.
Chicago Triples Hard-drug Estimate
The number of hard-core cocaine and heroin users in Cook County, IL. are three times higher than previous estimates, according to an unreleased study by President Clinton's drug czar.The finding appears to confirm what many experts have long believed, that traditional
methods substantially undercount hard-core addicts.
The undercount, if it is found elsewhere in the country, could affect how resources are allocated to fight drug abuse.
The study was conducted for the Office of National Drug Control Policy, often called the
drug czar's office, by Abt Associates Inc., a respected research firm in Cambridge, Mass.
"They chose Chicago to demonstrate the breadth of the problem," said Tom Needham, assistant to the mayor [Richard Daley]. This would be a great place to start with more drug treatment and more resources for the schools."
The findings also could influence the debate over whether to concentrate treatment resources on hard-core addicts or more casual users.
One of the study's most striking figures relates to the African-American population. The report finds that about 240,000 Cook County blacks are hard-core drug users. That is between one-fifth and one-sixth of the county's 1.3 million African-Americans.
The federal government spends about $15 billion a year on anti-drug efforts. No breakdown exists regarding how much of that goes to either hard-core or casual users.
MANNA Publishes Spanish Nutrition Booklet
The Metropolitan AIDS Neighborhood Alliance (MANNA) has put together a new nutrition booklet entitled Beuna Comida Para Una Buena Vida/ Good Food for Good Living.The booklet was composed in the same manner as its previous publication Eat Well, Think Well, Feel Well; by obtaining consumer input through focus groups and an advisory board consisting of caregivers and consumers from area AIDS Service Organizations serving the Latino Community.
The Booklet is written in both Spanish and English with the two languages side by side in an easy to read format. It contains illustrations and photographs of local residents.
This booklet is a must have for anyone seeking answers to questions regarding food, nutrition, and proper food handling.
Anyone in the 9 county Philadelphia EMA (Eligible Metropolitan Area) may receive a free copy by contacting MANNA at (215) 496-2662.
Health Law Project Seek Info on Drug Denials
Until just recently, persons on Medical Assistance (MA) had access to virtually all FDA approved drugs which were on the Department of Public Welfare's(DPW) formulary DPW, however, recently permitted HMA to implement a restrictive formulary and require prior authorization for many drugs which are on their formulary.Although HMA is permitted to exclude drugs from their formularies, they must develop a prior authorization exception process if these drugs are requested by providers. However, the formulary must comply with contract requirements.
If prior authorization is required, the HMO must provide a response to any request within 24 hours.if prior authorization is required, the HMO must immediately approve a 72-hour supply of any FDA approved medication in the interim.additionally, HMA was required to notify all of its members and providers in. writing of its restrictive formulary and the appeals process for denials. HMA was also required to send a letter to all Providers who had patients who were receiving non-formulary maintenance medications with formulary information that was specific to each patient. Patients on non-formulary maintenance medications were to be automatically pre-authorized until November 15, 1997 so that their providers could request prior authorization for these medications. It has been brought to our attention that some HMA members did not receive written notice about HMA's formulary and the appeals process for denials. Some HMA members have been sent away from their pharmacy without a 72 hour supply of medication. Other HMA members have not received a response within 24 hours of a request for prior authorization. In other situations neither the HMA member not the requesting provider received a response within 24 hours. We recently notified DPW that implementation of its restrictive formulary is not in compliance with its contract requirements. We have also requested that DPW require HMA to provide notices to consumers through pharmacists when a has a prescription hat has not been prior authorized.
A narrow window of opportunity exists for consumer advocacy groups to become involved. If your organization is aware of HMA members who are encountering difficulty in obtaining medications due to HMA's newly implemented formulary please either: 1) instruct that person to call the PHLP Help Line at 1-800-274-3258; or 2) fax summaries of these cases immediately to Pat Jacobs, DPW, HealthChoices Program, P.O. Box 9043, Harrisburg, PA 17105; (fax) 717-772-6328.
Copies of these summaries should be faxed to PHLP at 215-625-3879.
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