|In 1996 HIV treatment advanced far more than in any other year yet of the epidemic. But no one knows whether or how much this improvement will continue.|
In the most important measure, reduction in deaths, statistics beginning to emerge suggest a drop in the death rate by at least half in the past year, in diverse populations which are receiving modern treatment.
* In San Francisco, the total number of obituaries received by the BAY AREA REPORTER -- almost all due to AIDS-related deaths -- dropped by at least half between the beginning and the end of 1996. And the January 1996 rate was already much lower than the peak, which occurred several years before. (For more information, see AIDS Treatment News #260, December 6, 1996.)
* The California Medical Facility in Vacaville, California, which treats most male prisoners in California who have serious medical conditions, had far fewer deaths at its in- prison hospice (when we spoke there for World AIDS Day, in early December 1996) than a year before. We do not have final figures for the year, but as of December 6 it appeared that the total deaths for the year would be reduced at least by half. The CMF is a leader in HIV/AIDS treatment in prison; combination antiretroviral treatment including at least one protease inhibitor (ritonavir) is used there.
* The best data so far is from a study in British Columbia, Canada, which found that the death rate for that province in the last three months of 1996 was only one third what it was two and a half years ago. Julio Montaner, M.D., of the B.C. Centre for Excellence in HIV/AIDS, attributed the reduction to improved treatment. The study has not yet been formally published, but was confirmed by the researchers after it was obtained by the media (see TORONTO STAR, January 8, page A2).
The fact that similar results occurred in very different populations who all had access to modern HIV care -- in addition to anecdotal reports of even greater reductions of deaths in medical practices specializing in HIV -- strongly suggests that this large and unexpected decrease is not due to the natural history of the epidemic. Improved treatment is almost certainly the main reason.
Also, all of the treatment effect on deaths in 1996 must have been in persons with advanced illness (which is hardest to treat in any disease) -- since those with early HIV infection or only moderate progression early in 1996 would not have died in that year anyway. The new treatments might work even better in those who start them earlier. (But no one knows for sure, since it would take years to measure survival improvement due to early treatment of HIV disease -- if meaningful data can be obtained at all, which is unlikely, since most patients would change treatments during the years it would take to run such a study).
But despite the great decrease in deaths during the last year, AIDS experts are cautious and guarded in their optimism. Anecdotally there are many reports of failures of the new anti-HIV drug "cocktails" -- either because the virus develops resistance to the drugs, or because the patient becomes unable to tolerate continued treatment and the virus returns after one or more drugs are stopped. And many patients (most estimates range between 10 and 30 percent) cannot be successfully treated with the new drugs even initially, for various reasons. As would be expected, the treatments are most likely to work in those with relatively early disease, and in those who have had little or no prior treatment with any of the drugs in the combination which is being used. Historically, the drugs have become available one by one (for many years there was only AZT), so the virus populations in many patients had a chance to become resistant to the drugs one after the other.
And the great majority of people with HIV around the world, including many in the U.S., do not have access to medical care from HIV-experienced physicians, nor access to the drugs they may need. A recent article in a European newsletter noted that most patients in Estonia die within weeks of an AIDS diagnosis, and the main AIDS organization there had just seen its first case of survival for one year after diagnosis ("Countries: AIDS in Estonia," EUROPEAN AIDS Treatment News, volume 5, number 5, pages 96-99). Even in the UK, it was recently reported that persons with HIV are only half as likely to receive modern combination treatments as in other counties, due to funding problems. And in the U.S., quality of care varies greatly by social class, and by region.
Even with access to the best care, no one knows for sure if the great improvements for some groups in 1996 will be permanent. Will deaths continue to decrease, or will 1996 be looked back on as an exception? The answer will depend greatly on what we do now -- which is why the"end of AIDS" media message is so dangerously misleading. The treatments we have must be used carefully -- and continued research and development not only remain essential, but have more opportunities now than ever before to save lives.
Upcoming Retroviruses ConferenceNext week we will attend the 4th Conference on Retroviruses and Opportunistic Infections, the most important AIDS research meeting in 1997. It is difficult to learn much in advance about what will be presented (abstract books and abstracts on disks are being sent, but no copies were available until the day this issue went to press). We do not expect major surprises, but there will certainly be important, in-depth information in most areas of AIDS treatment development, which we will cover in future issues. (See " Retroviruses Conference: Where to Find Reporting on the Internet," below, for suggestions on how to follow the conference if you cannot attend.)
1997: Protease Inhibitors* An overview of the currently available protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir), by AIDS experts at San Francisco General Hospital and elsewhere, appeared in JAMA (THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION), January 8. The full text is available on the American Medical Association's Web site, at:
It is a valuable summary for physicians and patients. (Deeks SG, Smith M, Holodniy M, and Kahn, JO. HIV-1 Protease Inhibitors: A Review for Clinicians. JAMA. January 8, 1997; volume 277, number 2, pages 145-153.)
* Nelfinavir (VIRACEPT(R)) is a protease inhibitor now available to some patients through an expanded access program; it could be approved for general availability early this year. It appears to have fewer side effects than the currently-approved protease inhibitors, and a somewhat different viral resistance pattern (which might improve its usefulness for patients already resistant to one or more of the other protease inhibitors). For more information on nelfinavir, see the article below.
* An important focus of research will be treatment failures with protease inhibitors. How long will high-level viral suppression last -- and in which patients? What treatments are best for patients who have failed one or more protease inhibitor regimens?
* Another research focus will be blood tests to determine which drugs a patient's virus is resistant to. Some such tests are already available to physicians, but they are still far from official approval or widespread routine use.
1997: Other Antiretrovirals
* 1592. 1592 (1592U89), being developed by Glaxo Wellcome and now in early clinical trials, is a nucleoside analog drug (in the same general class as AZT), but is much more effective than AZT in suppressing HIV. 1592 has good penetration across the blood-brain barrier; it is also important because it is a new option for persons whose virus already became resistant to AZT or other current drugs. Because of the schedule of clinical trials, 1592 is not expected to be approved in 1997. Activists are seeking a pre-approval expanded-access program, especially for those with no other treatment options, with wider access as more safety data becomes available from the trials (see "1592: Consensus Letter on Access to New Glaxo Drug, AIDS Treatment News #261, December 20, 1996).
* Integrase inhibitors. This is a new class of anti-HIV drugs, which target a different viral enzyme than the protease inhibitors or the nucleoside analog drugs target; therefore, virus which has already developed resistance to the previous drugs would not be expected to have any cross- resistance to integrase inhibitors. There has been concern for years that large companies have been less diligent in developing integrase inhibitors than they were with other classes of drugs, resulting in a lack of treatments in the pipeline after the protease inhibitors. Government researchers screened a number of chemicals as potential integrase inhibitors and published the results in early 1993 (Fesen, MR and other, "Inhibitors of Human Immunodeficiency Virus Integrase," PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE, U.S.A., March 1993, pages 2399-2403), but government agencies alone almost never develop drugs in the U.S. Only one integrase inhibitor is in human trials, as far as we know; it is Zintevir(TM) (also known as AR 77), being developed by Aronex Pharmaceuticals, Inc.
* Drugs with new targets. The recent discovery of additional receptors (besides CD4), which HIV uses in addition to CD4 in order to enter a cell, has provided new targets for antiretroviral drug design.
Also, at least one drug which targets the zinc fingers of HIV is now in human trials.
* PMPA, being developed by Gilead Sciences, is another antiretroviral worth watching. After promising results in animal studies, a human trial has been started.
* The list above is not complete, as there are many other potential antiretrovirals in various stages of research.
Other TreatmentsDue to limited time and limited space in this issue, we cannot cover many other classes of treatments, including immune-based treatments, immune reconstitution, therapeutic or preventive vaccines, and various cytokine approaches.
Some areas that we think need more attention include:
* A major problem in researching immune-based treatments has been the practical difficulties in doing immune function tests, including control of laboratory errors. More research is needed on developing flow cytometry tests for immune function (using similar technology as now used for measuring CD4 counts), because these tests usually are easy to perform, and greatly reduce the opportunities for laboratory error.
* More attention is also needed for potential treatments now often classified as "alternative" or "complementary" -- such as NAC, glutamine, or DHEA. Treatments become "alternative" because people can obtain them now, despite lack of official approval -- which strongly correlates with them being largely or completely nonproprietary, meaning that there is little incentive for formal research. Alternative/complementary treatments are much less effective as antiretrovirals than the mainstream drug "cocktails" available today -- but they may have other uses, such as the possibility that NAC might reduce the problem of abnormal sensitivity to co-trimoxazole (Bactrim, Septra) by persons with HIV. Certain nutritional treatments might reduce drug side effects, increase absorption of drugs by certain patients, or otherwise improve general health or quality of life. Since the mainstream drug- development system will not give this work the attention it deserves, due to the relative lack of financial incentives, the community needs to be involved.
Access Issues, Compliance, Standards of CareThese areas will become even more important this year. We cannot review them here, except to mention just a few of the areas that need to be watched:
- Recently the AIDS Action Council has warned about Clinton Administration proposals to save money by restricting Medicaid -- which pays for care for 53% of adults and 90% of children with HIV or AIDS. There is particular concern about a "per capita cap" or maximum Federal payment per Medicaid beneficiary. People with HIV could be disproportionately affected by the resulting state restrictions on care.
- Private insurance issues include a growing use of much higher co-pay amounts for persons who need expensive drugs. On the other hand, a new Federal law, which will become effective in mid year, will make it easier to move from one group health insurance to another, without being excluded for prior conditions.
- Improvement in AIDS/HIV treatment -- to the extent that it is sustained and extended -- will continue to raise issues of the division of resources between drugs and services. More importantly, improved treatment will require all AIDS organizations to re-evaluate their work, and plan how it should or should not change in the new environment.