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STEP Perspective
Summer 1997


The Impact of Managed Care on People Living with HIV:
Quality vs. Cost-Saving

by Jeffrey T. Schouten, MD, JD

Despite President Clinton's failure to pass federal legislation significantly changing health care financing, delivery and access in his first term, the market has driven substantial changes in the delivery and financing of health care over the past decade. Due to the rapidly rising costs of health care, major changes have occurred in the market place resulting in an ever increasing shift to managed care. Enrollment in managed care plans increased from 29% in 1988 to 51% in 1993. The United States is the only major industrialized country which does not provide universal health care coverage, yet it spends twice as much for health care as do most other industrialized countries (15% versus 8% of the gross domestic product, respectively). Additionally, the United States is the only major industrialized country where health care is a for-profit industry at almost every level: health care providers; home-health care; long-term care; hospitals; diagnostic laboratories; and pharmaceutical companies. It is estimated that up to 39 million Americans go without health insurance every year. Unfortunately, there is not a constitutional right to health care under the United States Constitution.

A major limitation on health care reform the past few years has been the Employee Retirement Income Security Act (ERISA), enacted in 1974, which prohibits any significant regulation of health care at the state level. This law requires federal approval of any state regulations concerning health care insurance, other than control of insurance rates. In 1993, Washington State passed a law requiring all employers to provide health insurance to their employees; however, this requirement was never enacted because Congress refused to issue Washington State the waiver required under ERISA. Hawaii remains the only state to have received a federal waiver allowing it to require all employers to offer health insurance to their employees. Recently, the Health Insurance Commissioner of Washington enacted a rule that all health insurance plans must provide coverage for effective alternative therapies to all subscribers. A federal court ruled in May, 1997 that this regulation violated ERISA. As a result of ERISA and federal inaction, health care reform has been directed by the health care industry, rather than by governmental action.


Managed Care Defined

There is no universally agreed upon definition of managed care, however, the term generally refers to health care insurance plans which attempt to limit the cost of health care provided to its subscribers through controls placed on the providers of that health care. Also, there is a much closer relationship between the health care provider and the insurance plan under managed care. Coordination of care can be better under managed care because there may be better communication between the providers and the insurance plan. Another control on cost utilized by managed care plans is the use of primary care health care providers as "gatekeepers," so a specialist can only be seen if the primary care provider agrees to make the necessary referral. Because providing health care for people living with HIV may be very expensive, the rapid increase in managed care plans may have a great impact on the quality of care available to people living with HIV. Traditional health care insurance in the United States has been fee-for-service, an example of this would be the typical old Blue Cross/ Blue Shield health insurance plans. Under fee-for-service plans, an individual chose their health care provider and received whatever care they and their health care provider had agreed was necessary. The insurance company was billed and then reimbursed the person, or paid the health care provider directly, for that care. There was little or no questioning concerning the appropriateness of the care provided and pre-approval was non-existent. Under this system, the health care provider often did more rather than less, as the more services they provided the more money they made. In contrast, under managed care, a person may be restricted in their choice of health care providers, and their health care provider may be restricted in the type of care they provide under the rules of the managed care insurance provider. Generally, under managed care, the more services provided by a health care provider, the less money they make.

HMOs and PPOs

Managed care health insurance plans take many forms, but in general there are a couple of major types; health maintenance organizations (HMOs) and preferred provider organizations (PPOs). PPOs are a network of health care providers from whom members of that plan must receive their care. Care provided by a non-member health care provider may not be reimbursed at all, or there may be a higher co-pay required when using a non-member health care provider. HMOs may be either open or closed panel organizations. A closed- panel HMO employs its health care providers, who usually are paid a salary and work full-time for that HMO. An open-panel HMO contracts with many physicians in the community and the member may choose any one of those physicians, similar to a PPO. While many HMOs pay their health care providers a salary to work for that plan, under managed care, health care providers may also be paid either a prenegotiated fee for each service provided, or paid by capitation. Capitation is a payment system wherein the health care insurance plan or the provider is paid a fixed amount of money each month for each person enrolled in that health care plan. The health care provider is paid whether or not they see that individual patient. The more sick people that enroll with that health care provider, the less money they make, the healthier the "panel," the more money they make, because they do not have to provide as much care. The incentive under this type of reimbursement is for the health care provider to provide less care, in contrast to traditional fee-for-service plans.

Managed Care & HIV

A potential advantage of managed care is that effective case management can be incorporated into all aspects of a person's health care. Under traditional fee-for-service plans, there is no coordination of care. To lower costs, managed care plans employ case managers to coordinate care and eliminate overlap and duplication, encourage compliance, and possibly encourage preventative care. If a person develops PCP pneumonia, the health care provider and insurer loses money under managed care. Consequently, there is a direct financial incentive to keep a person healthy under managed care plans. HMOs place a greater emphasis on prevention, because they make more money when their members are healthy. HMOs also save money by providing suboptimal care which encourages people living with HIV to leave the HMO and join another plan if they are fortunate enough to have that option. Managed care plans have tended to limit mental health benefits, which can have a direct impact on the medical needs of many people living with HIV/AIDS.

A major disadvantage of managed care for people living with HIV is the potential restriction on physician choice and access to competent, sensitive, well-informed, and motivated health care providers. Additionally, gatekeepers may prevent needed referrals to specialists, such as, gastroenterologists, pulmonologists, and ophthalmologists. A recent study published in the January 1997 issue of the Journal of AIDS and Human Retrovirology compared patient satisfaction with fee-for-service and managed care plans. The study found that while patients in managed care were more satisfied with the financial arrangement (there are usually fewer co-payments and often times broader coverage for drugs and diagnostic procedures), they were less satisfied with health care provider selection and options than were patients in fee-for-service plans. A study conducted at an HMO in Seattle showed that the survival of people with AIDS was significantly reduced when their primary care physician treated less than 5 people with AIDS a year. Another study showed that the median survival for people with AIDS was 17 months under managed care versus 23 months for fee-for-service insurance.

There is a debate ongoing in the medical community concerning the need for specialists and specialty clinics to care for people living with HIV. Due to their emphasis on cost containment, managed care plans usually do not allow HIV specialists and specialty clinics to treat people with HIV, unless they can show that they are cost-effective. A recent study reported by the Tower Infectious Disease Medical Associates in California showed that every $1 spent for combination drug therapy was offset by a $2 reduction in overall treatment costs, and protease therapy resulted in a 58% decline in hospitalization and homecare. Another cost-effective program is pre-natal screening of pregnant women for HIV. The prevention of only two babies from becoming HIV-infected will pay for such a screening program. It is unlikely that many managed care plans will encourage the development of HIV experts to treat people living with HIV, as it is not in their best financial interest to encourage HIV-positive people to enroll in their plan. It is common for an HIV-positive individual to use more than one physician because of the variations in treatment strategies, aggressiveness, and innovativeness among health care providers. This opportunity could be lost under managed care plans.

Medicaid, Medicare, & Managed Care

The single largest payor of the health care costs for people living with HIV in the U. S. is the Medicaid program. The Medicaid program is a jointly funded, federally-designed program, administered by the states. It provides medical coverage for financially indigent (poor) and disabled people. To be eligible for Medicaid (which varies by state) income must be significantly less than the federally established poverty level. Medicare is the federal health insurance program for retirees (over 65), and people that have been on social security disability for three years. Some people living with HIV may be covered by Medicare, even if they are younger than 65. The Medicaid program pays for 53% of the costs of medical care for adults living with HIV and 90% of the costs for children living with HIV. Over 100,000 PWAs are covered by the Medicaid program. In 1996, it is estimated that the total money paid by the federal and state governments for HIV care provided under the Medicaid and Medicare program was $4 billion. The cost of protease inhibitors for all people covered by Medicaid would be $750 million- $1.3 billion per year. Due to the rising cost of Medicaid, the federal and state governments are turning to managed care in an attempt to save money. Poor and disabled people are being forced in many states to join managed care plans to continue receiving their Medicaid coverage. In 1995, 11.6 million people receiving Medicaid were enrolled in manged care plans. This results in many problems. First, the health care providers many times do not have offices near where the people live. Secondly, providers and insurers may be unwilling to enroll many people with HIV due to the higher cost of providing health care, for which they are receiving no extra money from the state. (Providers may receive as little as $15/month for each person enrolled in a Medicaid managed care plan. ) Thirdly, there is also no assurance that the health care providers chosen by the state will have any interest or expertise in providing care to people living with HIV. Today, a health care provider must spend a significant amount of time staying informed of the latest developments to provide the best care to people living with HIV.

In one state recently, all Medicaid patients were forced into a managed care plan and there were no providers identified with expertise in treating HIV, as was promised by the state. Another state, which is now shifting its HIV-positive patients into a Medicaid managed care plan, is refusing to reimburse providers any more money for care of those individuals. Prior to a state forcing Medicaid recipients into managed care, the state needs to get a waiver from the federal Health Care Financing Administration (HCFA). In New York, AIDS activist were able to prevent the approval of New York's request when they showed that 95% of the managed care groups were unable to provide specialist care for HIV. Even though the providers are required to take HIV positive patients, it is certain that some of them will find ways to discourage people from enrolling. The easiest way is to simply not provide state of the art care, and the patient will go elsewhere, if they have that option. The critical determinant in all managed care plans is the monitoring of the quality of care, and it remains to be seen how Medicaid managed care plans monitor and ensure that the quality of care is not lowered to save money.

Quality of Care under Managed Care

A potential advantage of managed care plans is the adoption of "best practice standards," or "practice guidelines," for its participating health care providers and the potential for real quality of care standards and monitoring. Under traditional fee-for-service insurance, nobody monitored the quality of care given by a health care provider to people seen in her office. Quality of care committees reviewed only the quality of care provided to hospitalized persons. This is not the case for managed care plans, which monitor both inpatient and outpatient care, at least concerning the appropriateness of the charges. Whether this monitoring is more than monitoring of expenditures, and truly monitoring for quality of care remains to be seen. A couple of recent studies have shown that people with chronic illnesses, like HIV, are the least satisfied with their care under managed care plans. A real possibility exists that managed care offers AIDS activists an opportunity to encourage the adoption of "best practice standards" that would include the prohibition of monotherapy for HIV and the monitoring of viral loads in all HIV positive persons. There needs to be constant pressure to monitor quality of care because the primary goal of most managed care plans is to maximize profits by limiting costs, i. e. providing less services. Additionally, unless access to competent health care providers is available to all people, then quality care is really not available.

Clinical Research & Medical Education under Managed Care

The major long-term impact of the shift to managed care has yet to be realized or appreciated and it has major implications for the care of people living with HIV. Both clinical research and medical training receive little or no support from managed care plans. This lack of vision and priority is already beginning to have a devastating impact on teaching and research hospitals like San Francisco General Hospital, and many others. Without a commitment to help support clinical research and medical education, there is going to be a great loss in our ability to gain information on the efficacy of new antiretroviral drug combinations, immune stimulants, and prevention and treatment of opportunistic infections. In the past, this research has been supported by hospital revenues generated by private insurance, and governmental-funded insurance plans. Managed care is resulting in the loss of this revenue. Teaching hospitals are being shut out of HMO and PPO networks, and are denied an opportunity to care for revenue generating, insured people. These hospitals are left to care for all of the uninsured people with no revenues to train new health care providers or conduct clinicial research. Many of these combined county-teaching hospitals around the country have been the leading centers in research and care of people living with HIV. With teaching hospitals unable to compete with non-teaching hospitals, who will train the experts of tomorrow? Not the for-profit managed care plans, and probably not the federal government in the current self-centered, anti-spending era. As HIV becomes a more and more complex disease to treat, there is a greater need for well-trained health care providers and more clinicial research.

Washington's Shift to Mandatory Managed Care for all SSI Recipients

Washington State has already begun to shift people receiving SSI to managed care plans. The change-over is occurring over 2 years, by county. Spokane county began voluntary enrollment on 4/1/97, and all SSI recipients in Spokane county will have to enroll in a managed care plan by 9/1/97. Planned dates for other counties are as follws: King county, voluntary enrollment begins 8/1/98 and mandatory enrollment begins 5/1/99; Pierce county shifts to managed care on 10/1/98; and Snohomish county on 7/1/98.

What does this mean to you? If you receive your health care based on SSI eligibility through the state's Department of Social and Health Services' (DSHS) Medicaid program, your medical care will be effected. The possible adverse impacts will include some loss of physician access and selection, loss of specialists' services, and delay in receipt or denial of some services. While DSHS has said that physician availability and access will not be a problem, this may not be true. The state is putting out notices to insurance and physician groups to place bids (Request for Proposals, RFPs) in order to provide care to persons on SSI. The state is only required to select the two lowest bids by federal rules. However, the state will likely select more than the two lowest bids, although they have not said how many plans they will approve in King county. Additionally, when the change occurs, participants will receive notice of the approved plans, and they will only have a short time to make a selection, otherwise they will be arbitrarily assigned by DSHS to one plan, and only have one month to request a change of that assignment. Some states have hired enrollment brokers, people to assist individuals in making this selection, but Washington State will not do this. So individuals will be forced to plow through very confusing technical descriptions of the different plans to decide for themselves which plan to enroll with. If your clinic or physician is not a member of one of these plans, you will not be able to continue to use your clinic or physician.

While out-patient drugs will continue to be provided, there may be a limitation placed on a significant number of drugs currently prescribed to people with HIV/AIDS. The term "off-label" drug use refers to the use of a drug to treat a condition for which the drug was not originally approved by the FDA. This occurs very commonly in medicine because of the cost of getting FDA approval for the use of a drug to treat a particular condition. So, once a drug is approved, if it is subsequently found to be beneficial to treat another condition, the manufacturer usually does not seek another approval by the FDA for the second condition. Therefore, many drugs are prescribed for conditions that they were not initially approved for. This is a very common situation. Many drugs used to treat cancers are used "off-label". An example for HIV is interleukin-2 (IL-2), which is approved to treat a type of cancer, but is also used by some physicians to treat HIV infection, combined with combination antiretroviral therapy. One study has estimated that up to 40% of drugs used to treat illnesses associated with HIV infection are used "off-label." In the past, insurance providers have usually paid for these drugs. Now, DSHS is threatening to no longer pay for "off-label" drug use. This change would have a tremendous impact on the quality of care received by people with HIV/AIDS in Washington.

STEP is planning a Community Forum later this year to discuss advocacy issues and if you are interested in learning how to advocate for changes in the plans of DSHS, contact STEP next month for further information about this important Community Forum.

Further Information

The information contained in this article is derived from many sources, a few references are listed below:

Henry J Kaiser Family Foundation Forum on AIDS and Managed Care. Journal of AIDS and Human Retrovirology 1995:8(Suppl 1).

Managed Care: Special Report. AIDS Alert 1996:11(5);46-60.

NYC Managed Care Threatens Women and Children on Medicaid. Nary G, J Int Assoc Physicians AIDS Care, 1995:Oct 1;9, 38.

Insurance Type and Satisfaction with Medical Care Among HIV-Infected Men. Katz MH, Marx R, Douglas JM, et al. Journal of AIDS and Human Retrovirology 1997:14;35-43.

For Teaching Hospitals, Multiple Complications. Freudenheim M, New York Times- C1, May 19, 1997

AIDS Care Under Managed Care. Palenicek J, et al. , ICAAC, New Orleans, Sept. 16, 1996.

Jeffrey Schouten is a general surgeon and co-chair of STEP's Scientific Review Committee

Update on HIV Vaccines

by Matthew Meldorf, M.D., Staff Physician, AVEU
and Lawrence Corey, M.D., Co-Principal Investigator, AVEU

Despite recent advances in antiviral therapy, there is no cure for AIDS or HIV infection. Drug therapy, although promising, remains problematic because of side effects, compliance, and expense. In addition, availability of such drugs is limited in developing countries where it is estimated that 90% of HIV infections will occur by the year 2000. For these reasons, the search continues for safe and effective vaccines to prevent HIV infection and AIDS world-wide. The AIDS Vaccine Evaluation Group (AVEG) is conducting phase I and II studies of candidate HIV-1 vaccines.

Vaccines to prevent infectious diseases have been one of the great success stories of modern medicine. However, HIV infection challenges researchers with several unique issues that limit the traditional approaches for developing vaccines. One significant stumbling block in the understanding of HIV in general, and vaccines in particular, has been the lack of appropriate animal models. In addition, we do not know the "correlates of immunity," that is, which components of the immune system are necessary for protection from natural infection.

The use of whole, inactivated virus vaccines, such as inactivated polio virus vaccine, or attenuated live virus vaccines, such as oral polio vaccine, appears too dangerous, given the various problems that have plagued the development of such vaccines in the past. The "Cutter incident" in which inadequate inactivation of the polio vaccine resulted in actual clinical polio is one concern in the manufacture of inactivated whole virus vaccines with HIV-1. Similarly, the recent studies in which attenuated live virus vaccination of SIV (Simian Immunodeficiency Virus) produced clinical infection in infant monkeys have been a sobering influence on the development of attenuated live virus HIV-1 vaccines. There is also considerable liability in growing large volumes of infectious HIV-1, especially with known laboratory acquired cases. For these reasons, most HIV-1 vaccine development has concentrated on subunit vaccines. This allows for excellent safety as only portions of the HIV-1 virus are utilized. Thus, there is no risk of infection from the vaccine product.

The difficulty with the subunit vaccine approach, however, has been the ability to produce optimal immunity. HIV-1 can be transmitted by HIV-1 infected cells and by cell-free virus (1,2). It is thought that both of these modes of transmission will need to be addressed for a vaccine to be effective, although it is not known exactly which components of the immune system are necessary for protection from natural infection. In order to prevent infection, most authorities feel a vaccine regimen must be able to elicit effector T-cell responses to eliminate virally infected cells, while also producing antibody responses to neutralize cell-free virus (3-7). Early vaccine trials have looked at recombinant subunit protein immunogens, such as the HIV-1 envelope rgp120, which have induced envelope-specific neutralizing antibodies (8-12). These immunogens, however, have rarely elicited a CD8+, class-I restricted cytotoxic T-lymphocyte (CTL) response (13-16). Other phase I HIV-1 vaccine studies have demonstrated that live recombinant vaccines can elicit class-I restricted CTL responses to HIV envelope in selected individuals (17-19). Unfortunately, antibody and cellular proliferative responses to these recombinant virus vaccines alone were poor (17, 20-24). However, immunization regimens that employ both live recombinant virus and subunit protein have, in some individuals, elicited both envelope specific CD8+ CTL and neutralizing antibody to the HIV-1 envelope (19, 22-24).

One of the first vaccination regimens to demonstrate such promising results involved a live recombinant vector based on vaccinia virus, the vaccine used to eradicate smallpox. This vector expressed HIV-1 envelope gp160 antigen and was used in association with a gp160 subunit protein. After vaccinia-naive volunteers were given two injections of the vaccinia gp160 recombinant virus, they were boosted with the recombinant gp160 subunit (25, 26). Of the twelve vaccinia-naive volunteers who received this regimen, 75% developed HIV-1 specific neutralizing antibody. Both cell fusion inhibition activity and CD4 binding-domain-blocking antibody were noted in 42% of the volunteers, while CD8+ CTL was noted in 45% of the vaccinees (26-29). Of note, the immune response to vaccinia was noted to be so great that revaccination with the vector did not achieve boosting. Even persons with distant infections did not achieve an adequate immune response. Thus, vaccinia vectors seemed to be useful only for vaccinia naive persons. Lastly, although no serious adverse reactions to vaccinia virus recombinants have been observed, there was some concern about safety and the possibility of transmission of vaccinia virus to close contacts (30-32). Specifically, there was concern that administration of vaccinia to an HIV-positive person might lead to disseminated vaccinia. While this is not an issue in the clinical trial setting, it very well might be an issue in the general clinical use of such a vaccine.

To address these safety issues, alternative viral vectors have been studied. Researchers have looked for viruses that can infect mammalian cells and cause them to produce foreign proteins, while also accommodating a large amount of foreign DNA in their genome. Canarypox, an avian pox virus vector, met these criteria, as well as being stable at room temperatures and inexpensive to produce. In addition, canarypox has the added benefit of being host-range restricted. This means that it goes through an abortive cycle of replication without producing infectious virus in mammalian cells. Canarypox virus has been utilized in clinical trials as a rabies vaccine, a measles vaccine, a Japanese encephalitis vaccine, and now as vaccines containing various HIV-1 genes (33-37). Safety data for these ALVAC vaccines has been excellent with promising immunogenicity data. Higher doses of canarypox virus have not caused any adverse effects in a wide variety of animals, including those that are profoundly immunosuppressed. This suggests that canarypox recombinants are not likely to disseminate and cause progressive disease in human recipients or be transmitted to unvaccinated contacts. One of the first studies to look at a canarypox vector as a potential HIV vaccine involved the ALVAC gp160MN recombinant (ALVAC vCP125) which expressed the envelope and transmembrane portion (gp160) from the MN strain of HIV-1. As in all of the AVEG (AIDS Vaccine Evaluation Group) trials to be discussed, this was a phase I, randomized, placebo-controlled, double-blinded, multicenter study involving healthy HIV-1 uninfected volunteers at lower risk for HIV-1 infection. This ALVAC vCP125 recombinant was directly compared to the ALVAC rabies vaccine to help ensure blinding of the study and to serve as a control for detection of non-specific pox virus-related activity in CTL assays. This trial looked at several different variables, including two doses of the ALVAC gp160MN (106 and 107 TCID50)* and various schedules of immunization (0, 1 or 2, 6 or 9 , and 12 months). It compared vaccinia-immune to vaccinia-naive volunteers to determine if immunity conferred by prior immunization interfered with the immune response to the canarypox gp160 recombinant. Also, two prime/boost immunization sequences compared the ALVAC recombinant alone to boosting with the subunit vaccine HIV-1 SF-2 rgp120 at the last two immunizations of the trial. Results of the trial demonstrated that of the 131 volunteers who were enrolled, HIV-1 MN and SF-2 neutralizing antibodies were elicited most frequently by priming with the ALVAC vCP125 followed by boosting with the rgp120 (38). At the lower dose of ALVAC vCP125 (106 TCID50), three of the fifteen volunteers tested positive for anti-HIV-1 envelope specific CTL (39). Several volunteers receiving the higher 107 TCID50 dose also tested positive for CD8+ CTL against the HIV-1 envelope-both with and without subunit boost. French vaccine trials being conducted at about the same time had even more impressive immunogenicity data. Of the twenty volunteers who received the ALVAC vCP125 vector followed by boosts with the subunit protein gp160 MN/LAI, neutralizing antibody was found in 90%, while CD8+ CTL activity was induced in 40% (40, 41). * Tissue Culture Infectious Dose

Hoping to improve on this initially promising data, a more complex canarypox recombinant vaccine was constructed in order to stimulate a more vigorous immune response. ALVAC vCP205 consists of a complex antigen containing HIV-1 gp120 (strain MN) attached to the transmembrane portion of HIV-1 gp41 (strain LAI), as well as the HIV-1 LAI genes encoding for the gag and protease proteins. This is thought to be particularly relevant given the apparent importance of gag-specific CTL which appear to predominate in HIV-infected persons and in several children born to HIV-infected mothers who were subsequently shown to be HIV negative (42). Not only does this construct provide for more antigenic material, but it also allows for its unique presentation as pseudovirions. These virus-like particles are released by cells that are infected in vitro with the ALVAC vCP205, allowing for the expression of conformational epitopes of the envelope protein in a more "natural" way. An initial French study involved 25 volunteers who received ALVAC vCP205 at a dose of 105.8 TCID50 at 0, 1, 3, and 6 months or at 0 and 1 months boosted with a peptide at 3 and 6 months. Results demonstrated that vCP205 alone is able to induce binding antibody to gp160 MN/LAI and to a V3 MN peptide as well as lymphoproliferation one month after the third injection (43).

Here in the United States, an ongoing AVEG trial is evaluating ALVAC vCP205 in two different immunization schedules (0, 1, 3, 6, 9, and 12 months or 0, 1, 6, 9, and 12 months), while also comparing immune responses in vaccinia-naive and in vaccinia-immune subjects. The safety and immunogenicity of ALVAC vCP205 is being compared to that of the ALVAC rabies glycoprotein (ALVAC RG), as well as evaluating the immunogenicity of ALVAC vCP205 with and without prior administration of ALVAC RG. This is being done in an attempt to evaluate whether repeated doses of canarypox influence the subsequent immune response. In addition, this trial has added HIV envelope booster immunizations with SF-2 rgp120 at months 9 and 12. Preliminary results at this time show that CD8+ CTL responses to HIV proteins appear to be present in about 50% of vaccinees. Boosting with gp120 generates neutralizing antibody response in nearly 100% of subjects.

A follow-up study that is further evaluating ALVAC vCP205 is currently finishing enrollment. In this trial, a higher titered preparation of vCP205 will be used as well as a variety of regimens in which the envelope subunit SF-2 rgp120 is used in combination with vCP205. The goal is to elicit consistent CTL responses for almost all vaccinees. One unique regimen administers both vaccines simultaneously at different sites in an attempt to induce a rapid and potent cellular response as well as a strong humoral response to HIV envelope proteins. Another unique aspect to this trial is the addition of individuals at higher risk for HIV infection. This is to begin a pilot evaluation of CTL responses between higher and lower risk subjects as a prelude to a larger phase II trial. Preliminary data from the trial will be forthcoming over the next year. Another equally complex canarypox recombinant vaccine, ALVAC vCP300, is currently being evaluated for safety and immunogenicity. This recombinant vector contains the same genes as vCP205, including the HIV-1 envelope gp 120 (strain MN) linked to the transmembrane portion of HIV-1 gp41 (strain LAI), as well as the gag and protease genes from strain LAI. In addition, this construct contains portions of the pol and nef genes that encode for CTL epitopes. Once again this experimental vaccine is being compared to the ALVAC rabies glycoprotein in a variety of vaccination regimens, both with and without subunit boosts of gp120. Thus, the combination vaccine approach has matured in the last year and seems to be the leading design for further clinical trials.

One issue that has emerged in the last five years is the safety of these subunit products. Recently Keefer, et al. reviewed the safety of these canarypox vector vaccines and the other candidate HIV-1 vaccines used in the AVEG trials (44). To date these phase I trials have included over 2000 participants. Local and occasional systemic reactions are the only toxicities that have been clearly attributable to the candidate vaccines. These reactions appear to be related to the adjuvant preparations contained in the vaccines and seem to be of a self-limited nature. This review looked at several different concerns that have been raised previously in the scientific community. For example, it is known that the HIV-1 envelope not only contains components that suppress a variety of immune functions, but that it also contains certain areas of homology with host regulatory and structural proteins that may lead to autoimmunity. Clinical monitoring and serial T-lymphocyte measurements have provided no evidence of important adverse immunologic effects. Possible autoimmune phenomena have been limited to three vaccinees. Two volunteers experienced arthralgias which responded to a short course of oral corticosteroids, and one volunteer was diagnosed with a mixed connective tissue disease five years after receiving one vaccination during an AVEG trial. Of note, this volunteer had experienced livedo reticularis, a lace-like rash associated with certain rheumatologic conditions, prior to entry in the AVEG trial. The oncogenic potential of candidate HIV-1 vaccines was another issue that has been discussed, given the incidence of various neoplasms in the HIV-1 infected population. No statistically significant increase in malignancies has been seen when the AVEG volunteers have been compared to a population-based SEER data base which estimates the frequency of cancer in the general population. There also was no statistical difference when comparisons were made between the vaccine and placebo groups or between the various vaccine preparations. Thus, the conclusion of the investigators and the Data Safety Monitoring Board for the HIV-vaccine trials is that there appears to be no substantive increased risk of autoimmune disease from any of the candidate HIV-1 vaccines yet tested.

Finally, concern about volunteers becoming HIV-1 infected during the vaccine trials has been addressed. A total of 20 participants (less than 1%) over the eight-year period have become infected with HIV. All of these individuals engaged in high risk behavior that put them at risk of acquiring HIV, despite the counselling provided to them during the course of the trial. This included persons who were at both lower and higher risk, as determined by sexual questionnaires, for acquiring HIV prior to the trials. To date, the clinical course of the HIV infection does not appear to be different from that observed in natural history studies.

In addition to the possible medical side-effects of the HIV-1 vaccines, consideration has been given to the psychological and social aspects of volunteers testing HIV-positive. Many volunteers, especially those who have received the gp160 subunit vaccines, have developed antibodies that cause them to test positive on ELISA/western blot assays, when they are actually seronegative. Interestingly, only 10-15% of those receiving gp120 vaccines test positive in these assays. With the increasing numbers of vaccinees in the trials, the FDA has now recognized HIV vaccination as a potential cause of a positive HIV serology. In more recent trials, western blots or other assays can be utilized to distinguish vaccination from infection because the ALVAC constructs, ALVAC vCP205 and vCP300, have deletions in part of the sequences of the envelope transmembrane region, gp41. HIV-1 infected persons demonstrate antibodies directed against the particular gp41 sequences deleted in the ALVAC constructs, whereas vaccinated voluteers do not. New gp41 ELISA assays have been developed specifically for this purpose.

In summary, the HIV-1 vaccine field has progressed greatly in the last five years. All candidate vaccines have shown superb safety profiles. Induction of humoral antibodies by subunit envelope proteins has been achieved, while recombinant vector-based vaccines have induced detectable CTL responses. Combination regimens can elicit both responses in most individuals. One challenge still to be addressed is the strain specificity of the antibody responses. In general, it has been difficult to neutralize or kill wild-type HIV-1 as compared to laboratory-adapted HIV-1 strains. Moreover, the vaccines and vaccine regimens have tended to be monovalent. Whether protection to heterologous challenge will occur is unclear. It may require a clinical trial to answer these issues. Many authorities feel that if we are to make progress in defining what standards a vaccine regimen must meet in order to interrupt HIV-1 transmission, we must study such transmission directly. Thus, a well-designed proof-of-concept vaccine efficacy trial is the next apparent step in HIV-1 vaccine development. In these authors' opinions, the safety of the current products, their current immunogenicity, and the continued spread of HIV-1, despite the best educational efforts, indicate that such a clinical trial is warranted.

Matthew Meldorf was Staff Physician at the AIDS Vaccine Evaluation Unit from 1996-1997. He is currently a Clinical Instructor at the Greater Baltimore Medical Center.

Lawrence Corey is a Co-Principal Investigator of the AIDS Vaccine Evaluation Unit, and Head of Infectious Disease at the Fred Hutchinson Cancer Research Center. HIV; Advances in Resistance & Therapy 1997; 7(1): 24-28. Reprinted courtesy of Cliggott Communications, c 1997.

Volunteers are encouraged to participate.
Volunteers must be:

* HIV negative * healthy *18-60 years of age
* living in the area for the next 18-24 months

For more information, please call 667-2300.

Studies enrolling, Summer 1997
to evaluate the safety and immunogenicity of the Therion recombinant vaccinia-HIV-1IIIB env/gag/pol vaccine (TBC-3B) and MN rgp120/HIV-1 in alum. Volunteers in 014C must never have been vaccinated for smallpox.
to study safety and immunogenicity of Apollon HIV-1 gag/pol DNA vaccine (APL-400-047) Vaccine will be given either intramuscularly by needle and syringe or by Biojector 2000r Needle-free Jet Injection SystemT
to study further safety and immunogenicity of live recombinant canarypox (ALVAC-HIV vCP205) with or without HIV-1 SF-2 rgp120
This is the second phase II study done by the AVEG.
We are also conducting a study of people who have been exposed to HIV but who remain uninfected. Individuals who fit this profile should also call 667-2300.


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16. El-Daher N, Keefer MC, Reichman RC, Dolin R, Roberts NJ. Persisting human immunodeficiency virus type 1 gp160-specific human T lymphocyte responses including CD8+ cytotoxic activity after receipt of envelope vaccines. J Infect Dis 1993; 168: 306-13.

17. Cooney EL, Collier AC, Greenberg PD, et al. Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein. Lancet 1991; 337: 567-72.

18. Mosier DE, Gulizia RJ, MacIsaac PD, Corey L, Greenburg PD. Resistance to human immunodeficiency virus 1 infection of SCID mice reconstituted with peripheral blood leukocytes form donors vaccinated with vaccinia gp160 and recombinant gp160. Proc Natl Acad Sci USA 1993; 90: 2443-47.

19. Cooney EL, McElrath MJ, Corey L, Hu SL, Collier A, Arditti D, Hoffman M, Coombs RW, Smith GE, Greenberg PD. Enhanced immunity to HIV envelope elicited by a combined vaccine regimen consisting of priming with a vaccinia recombinant expressing HIV envelope and boosting with gp160 protein. Proc Natl Acad Sci USA 1993; 90: 1882-86.

20. Shen L, Chen ZW, Miller MD et al. Recombinant virus vaccine-induced SIV specific CD8+ cytotoxic T lyphocytes. Science 1991; 252:440-43.

21. Hammond SA, Bollinger RC, Stanhope PE, Quinn TC, Schwartz D, Clements ML, Siliciano RF. Comparative clonal analysis of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ and CD8+ cytolytic T lymphocytes isolated from seronegative humans immunized with candidate HIV-1 vaccines. J Exp Med 1992; 176: 1531-42.

22. McElrath MJ, Corey L, Berger D, Hoffman MC, Klucking S, Dragavon J, Peterson E, Greenberg PD. Immune responses elicited by recombinant vaccinia- human immunodeficiency virus (HIV) envelope and HIV envelope protein: analysis of the durability of responses and effect of repeated boosting. J Infect Dis 1994; 169: 41-47.

23. Graham BS, Belshe RB, Clements ML, et al. Vaccination of vaccinia-naive adults with HIV-1 gp160 recombinant vaccinia virus in a blinded, controlled, randomized clinical trial. J Infect Dis 1992; 166: 244-52.

24. Graham BS, Matthews TJ, Belshe RB, Clements ML, Dolin R, et al. Augmentation of human immunodeficiency virus type 1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp120 in vaccinia- naive adults. J Infect Dis 1993; 167: 533-37.

25. Cooney EL, McElrath MJ, Corey L, et al. Enhanced immunity to human immunodeficiency virus (HIV) envelope elicited by a combined vaccine regimen consisting of priming with a vaccinia recombinant expressing HIV envelope and boosting with gp160 protein. Proc Natl Acad Sci USA1993; 90: 1882-1886,

26. Graham BS, Matthews TJ, Belshe RB, et al. Augmentation of HIV-1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp160 in vaccinia-naive adults. J Infect Dis1993; 167: 533-37.

27. Hammond SA, Bollinger RC, Stanhope PE, et al. Comparative clonal analysis of HIV-1 specific CD4+ and CD8+ cytolytic T lymphocytes isolated from sero- negative humans with candidate HIV-1 vaccines. J Exp Med 1992; 176: 1531-42.

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31. Redfield RR, et al. Disseminated vaccinia in a military recruit with HIV disease. N Engl J Med 1987; 316: 673-676.

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33. Taylor J, Paoletti E. Fowlpox virus as a vector in non-avian species. Vaccine 1988; 6: 466.

34. Taylor, et al. Non-replicating viral vactors as potential vaccines: Recombinant canarypox virus expressing measles virus fusion and hemaglutinin glycoproteins. J Virol 1992; 187: 321-328.

35. Taylor J, et al. Efficacy studies on a canarypox-rabies recombinant virus. Vaccine 1992; 9: 190-193.

36. Fries LF, Shahan J, Thumas B, et al. Safety and immunogenicity of a canarypox- rabies glycoprotein recombinant in adult human volunteers. 32nd ICAAC Meeting, Anaheim, California, 1992.

37. Cadoz M, et al. Immunization with canarypox virus expressing rabies glycoprotein. Lancet 1992; 339: 1429-1432.

38. Clements ML, Schwartz D, Siliciano R, et al. HIV immunity induced by canarypox-MN gp160, SF-2 rgp120, or both. American Society for Virology, Austin Texas, July 8-12, 1995 [abstract].

39. Eagan MA, Pavlat WA, Tartaglia J, et al. Induction of human immunodeficiency virus type 1 (HIV-1)-specific cytolytic T lymphocyte response in seronegative adults by a non-replicating host-range-restricted canarypox vector (ALVAC) carrying the HIV-1 MN env gene. J Infect Dis 1995; 171: 1623-1627.

40. Pialoux G, Excler JL, Riviere, et al. A prime-boost approach to HIV preventive vaccines using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein 160 (MN/LAI). AIDS Res Hum Retroviruses 1995; 11: 373-81.

41. Riviere Y, Janvier G, Fleury B, et al. Introduction of CTL activity in response to immunization of uninfected adult volunteers by a HIV-gp160 recombinant canarypox virus. 10th International Conference on AIDS, International Conference on STD, Yokohama, Japan August 7-12, 1994 [315A].

42. Rowland-Jones SL, Nixon FD, Aldhous MC, et al. HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet 1993; 341: 860-1.

43. Excler JL, Salmon D, Sicard D, et al. Safety and immunogenicity of a live recombinant canarypox virus vaccine expressing gp120/gag/protease boosted by a p24E-V3 peptide. [Annual Meeting, Laboratory of Tumor Cell Biology, August 27- September 2, 1995, Bethesda, Maryland]. AIDS Res Hum Retroviruses 11 (S1), 1995 [295].

44. Keefer MC, Wolff M, et al. Safety profile of phase I and II preventive HIV-1 vaccination: experience of the AIDS Vaccine Evaluation Group. Publication pending.

Protease Inhibitors and Food:
How to Maximize Absorption into the Blood

by Joanne Maurice, MS, RD of the Madison Clinic & Sabina Beesley, MS, RD of Chicken Soup Brigade

When you commit to yourself to improve your health, big results can happen. This is especially true when you are living with HIV/AIDS. Make the commitment to yourself to help your body fight the virus by eating well, exercising and taking your medications as prescribed. Food, exercise and medication all work as a team to build your immune system. Our last nutrition column, (Perspective, Winter 1997), discussed the immune-boosting effects of food and exercise. This column will focus on dietary strategies to maximize the use of medications called protease inhibitors. Protease inhibitors are important new players in the treatment of HIV/AIDS.

Food plays a critical role with protease inhibitors. Certain foods will increase the blood levels of the protease inhibitors in the blood stream which will help fight the virus. Other foods will decrease blood levels and weaken your fight against HIV. This column will highlight which foods to eat and which foods to avoid when you take protease inhibitors. The protease inhibitors Crixivan, Saquinavir, Ritonavir and Nelfinavir will be discussed.

Crixivan (Indinavir)

What to do

  • Take every 8 hours exactly. Take Crixivan dose on an empty stomach one hour before a meal or two hours after a meal.
  • You have the option to take your Crixivan dose with a very low fat, very low protein snack. Taking your dose with a snack may help reduce nausea and stomach pain or other related side effects of Crixivan.

This snack must contain

  • less than 300 calories
  • less than 6 grams of protein
  • less than 2 grams fat

Each day drink at least 10 cups of water or juice to avoid kidney stones. Call your health care provider right away if you get lower back pain, it may be a symptom of kidney stones.

What not to do

  • Don't take Crixivan with a meal or with foods high in fat and protein.
  • Do not take with a grapefruit or grapefruit juice, it can reduce the amount of Crixivan your body can absorb.

Good Snacks to take with your Crixivan dose.

These snacks contain less than 300 calories, 6 grams of protein and 2 grams of fat.

  • Nabisco Newton Cobbler Bars
    3 bars

  • Fig bars and juice
    2 fig bars, 1 cup juice

  • Pretzels and pop
    1 cup pretzels, 1/2 can pop

  • Bagel and Juice
    1/2 bagel (without seeds or nuts), 1 cup juice

  • Corn tortilla with rice and salsa
    1 corn tortilla
    1/2 cup steamed rice (no added oil or fat)
    3 Tbs. salsa

  • Cereal and skim milk (does not include cereal with added nuts, seeds or granola )
    1/2 cup dry cereal, 1/2 cup skim milk

  • English muffin with jam and tea
    1 English muffin, 1 Tbs. jam,
    1 cup tea with sugar

  • Rice or noodles with vegetables and soy sauce
    1/2 cup steamed rice or noodles (without butter or oil), 1 cup steamed vegetables, 1 Tbs. soy sauce

  • Angel food cake with canned fruit and coffee
    1 slice angel food cake, 1/2 cup canned fruit, 1 cup coffee

Be sure to strictly follow the serving sizes indicated. Always use standard measuring cups and spoons. Don't guess -- MEASURE!

Saquinavir (Invirase)

What to do

  • Take 3 times a day, every 6 to 8 hours through out the day.
  • Take within 2 hours of a high fat meal or snack. Taking it with high fat foods lets your body absorb 5 to 10 times more. See meal and snack ideas below.
  • Take with a 1/2 cup grapefruit juice (use frozen concentrate) if tolerated. This increases absorption into the blood stream by 50%. Other juices have no effect.

What not to do

  • Don't take it on an empty stomach.
  • Don't take it with a meal low in fat and calories.

Meal and snack suggestions for taking with Saquinavir

Hamburger and French fries
Meatloaf and potatoes
Pasta with cream sauce
Egg drop soup
1 cup of Eggnog
Steak and potatoes
1 cup of Trail mix
Breakfast sandwich made with egg, cheese and bacon or sausage
Breakfast consisting of scrambled egg made with two large eggs, 3 oz. of sausage and 2 buttered pancakes

Special Diet Concerns

If you are vegetarian it is important to eat enough fat so your body can absorb Saquinavir. Add fat to your meals with chopped eggs, grated cheeses, margarine and butter, salad dressings and sauces. If you are a vegan, other alternatives include peanut butter, nuts and vegetable oils as well as weight gain powders and formulas. Your dietitian can help you work out the best plan.

Ritonavir (Norvir)

What to do

  • Take every 12 hours.
  • Take within 2 hours of a full meal.

What not to do

  • Don't take on empty stomach, it may make side effects worse and decrease absorption of the drug.
  • Don't take it with fat-free or very low fat meals.
  • Do not drink alcohol, it can severely damage your liver.
  • Do not smoke. If you can't quit, reduce the amount you smoke since nicotine will make Ritonavir less effective.

Nelfinavir (Viracept)

What to do

  • Take 3 times a day with meals or a substantial snack. See ideas below. What not to do:
  • It is not recommended to take on an empty stomach.

Substantial Snack Suggestions to take with Nelfinavir

Cereal and milk
Tortilla with rice and beans
Fig bars and juice
Bagel and juice
cheese and crackers

National Conference for Women & HIV:
An Update

by Donna Rochon, M.A.

Over 400 HIV-positive women, out of an estimated total audience of 1,500 people, attended the National Conference on Women & HIV in Los Angeles. This meeting was vitally important because women comprise the fastest growing percentage of new HIV infections, but research into the epidemiology of and treatments for women with HIV lags seriously behind that of other groups impacted by HIV. "This conference is critical for all women in America, because while more and more women are being infected with HIV and dying of AIDS, they continue to be one of the most understudied populations affected by the epidemic," stated Alexandra Levine, M.D., co-chair of the conference and Professor of Medicine at the University of Southern California. "We are here to examine not only what we know, but what we do not know about women and HIV. We must change the course of HIV/AIDS research, treatment and prevention efforts so that women's issues receive equal attention."

Cases of AIDS in women in the United States have risen steadily since the epidemic was first recognized in 1981. But more importantly, the proportion of AIDS cases in women has increased consistently, growing from 7% in 1985 to 20% of new cases in 1996. In 1994, the proportion of cases in women attributable to heterosexual transmission surpassed the number attributable to injection drug use. In the United State, AIDS is the third leading cause of death among women 25 to 44 years of age, and the leading cause of death among African American and Hispanic women of that age group. The Centers for Disease Control and Prevention (CDC) announced recently that while HIV-related death rates among men are down 15%, deaths among women have risen three percent. And, there is a higher proportion of women of color infected with HIV: African American and Hispanic women account for 21% of the US population, but constitute 76% of cumulative AIDS cases nationally. AIDS has been the leading cause of death for African American in New York and New Jersey since 1987.

Drug companies have made huge strides in developing treatments to slow the progression of HIV infection. The availability of protease inhibitors and non-nucleoside reverse transcriptase inhibitors has given countless people living with HIV/AIDS new hope. But these new therapies have not necessarily been readily available to women. While the number of women participating in clinical trials for new AIDS products appears to reflect statistical percentages of women infected by the disease, women comprise only 12% (versus 18% of AIDS cases) of study participants in government-sponsored trials.

Historically, women have encountered unresponsiveness and reticence on the part of researchers, due in part to 21 year old restrictions on the participation of women of childbearing potential in the earliest phases of clinical trials. However, these FDA guidelines were lifted in 1993. Further, research involving women has focused on how to prevent vertical transmission of HIV to children or sexual transmission, not on how to care for the HIV-positive woman. Another large challenge in improving access for women has been in addressing issues of child care, transportation, confidentiality, disclosure and education.

During the early 1990's, there were growing concerns that the drug development process did not provide adequate information about the effects of drugs on women. In addition, there was a general consensus that women should be allowed to determine for themselves the appropriateness of participating in early clinical trails. As a result, the Food and Drug Administration has encouraged the inclusion of women in clinical trials, recommending a gender analysis of trial data. To obtain reliable data on women, recruitment and enrollment of women in clinical trials must be a high priority. Many of the National Institutes of Health (NIH) AIDS clinical trials not only include women as participants, but some have been designed specifically for women, investigating gynecological manifestations that occur in HIV-infected women. The NIH has also promulgated and implemented a more stringent policy and new guidelines concerning participation of women and minorities in all clinical trials.

New opportunities now exist to reduce the morbidity and mortality of HIV disease in women through early detection and treatment. Major ongoing studies of women include: the Women's Interagency HIV Study, a study conducted to identify the nature and rate of disease progression in women, characterize specific clinical manifestations in women and assess the effects of therapeutic regiments on HIV-infected women; and the Women and Infants Transmission Study, a multi-center study examining prenatal transmission and the course of infection in HIV-infected pregnant women and their infants. In all of these efforts, HIV-infected women, women with AIDS and other community representatives and advocates have been, and will continue to be, involved with the scientific community, not only in designing and conducting clinical trials, but also in planning and setting the scientific priorities of research programs. Investigations must continue into the development of female-controlled contraceptive products that prevent the transmission of HIV. Drug companies must be motivated to include product labeling that accurately and effectively conveys the product's relationship to the prevention and/or existence of HIV/AIDS. For example, oral contraceptives now contain an explicit statement that they do not provide protection against HIV and STD's. Pharmaceutical companies must collect and publish data about the effects of potent treatment regimens on women.

Society's current preoccupation on testing women rather than caring for women must change. The Coburn Amendment, mandating HIV testing of all pregnant women, should be replaced with legislation directed at providing comprehensive education and health care programs that inform women about treatment options and improve access to medical care. The ultimate goals of research programs must be the development of preventative methods, including vaccines, effective therapeutic agents and sustained behavioral interventions that will benefit all HIV-infected or at-risk individuals - men, women and children. The National Conference on Women & HIV brought together researchers, health care providers, policy makers and women infected and affected by HIV to share information on the latest developments in all of these areas of research. Organizers expressed the hope that "this conference will focus attention on these and other serious disparities between men and women with HIV, so that leaders across all disciplines related to HIV/AIDS can work together to re-double our efforts to close the major gaps in HIV/AIDS research, treatment, prevention and policy as they directly affect women.

Donna is a womens' Treatment Activist and editor of RITA!

Implications for HIV

by Steve Anderson, Ph.D

The excitement over chemokines and their receptors has been snowballing since the International AIDS Conference in 1996. Virtually overnight, the new field of chemokine research was born and basic research of these molecules is progressing at a frenetic pace. Study of these molecules may provide new insight into the mechanisms of HIV infection and pathogenicity. Why the furor over chemokines? In addition to protease inhibitors and drugs like AZT, chemokine-based therapies would be directed against a different point in the life cycle of HIV. These new therapies may actually prevent the virus from infecting cells and limit the transmission of HIV.

First, what are chemokines and what do they do? Chemokines are soluble proteins that attract white blood cells to an inflamed area or site of infection within the body. They are made and secreted by a variety of cells in the immune system. Each chemokine binds to a specific receptor on the surface of white blood cells such as monocytes, lymphocytes, basophils, and eosinophils. This interaction is extremely precise, meaning the chemokine will only dock to a chemokine receptor of a specific shape. This exact match-up of chemokine and receptor triggers a cascade of events within the cell leading to chemotaxis, the mobilization of immune cells to an area of the body where they are needed.

For many years the conundrum in AIDS research has been that HIV gains entry into a human cell by binding to CD4 receptors on the surface of immune cells; however, animals with CD4 receptors on their cells are not infected by HIV. Intuitively this suggests that HIV probably recruits an additional molecule or co-receptor to aid its entry into human cells, but identification of this co-receptor has eluded researchers, until recently. In December, 1996 Robert Gallo and his group at the Institute of Human Virology, in Baltimore, found 3 chemokines, MIP1a, MIP 1b, and RANTES that inhibit HIV replication. On the heels of this discovery, five research groups published evidence demonstrating chemokine receptor involvement in HIV's ability to infect cells. In essence, the virus must simultaneously bind both the chemokine receptor, for instance cysteine-cysteine chemokine receptor 5 (CCR-5), and CD4 on the cell surface to gain entry into the cell and initiate infection. This profound discovery has brought a new focus to the field of HIV research.

Exactly how are chemokine receptors involved in the AIDS disease process? Macrophage tropic HIV-1 strains are implicated in approximately 90% of sexually transmitted HIV, and it is CCR-5 that is the major co-receptor for this type of virus. These strains of HIV-1 are also known as non-synctitial inducing virus (NSI), which are associated with less severe disease. After the initial infection, the HIV-1 virus replicates and continually mutates, giving rise to new strains. Eventually, as the infection progresses, synctium inducing (SI) HIV-1 virus strains begin to predominate. These SI strains of HIV-1 use different chemokine receptors to specifically invade CD4+ T-cells and are known as T-cell lymphocyte (TCL) tropic. For example, SI strains invade T-cells by using the CXCR-4, or fusin, chemokine receptor, in conjunction with the CD4 receptor. Unfortunately, it is these SI virus strains that are especially virulent and responsible for rapid disease progression and the poor clinical outcome seen in many people with AIDS.

HIV-1 does not kill every individual that it infects, in fact, a few individuals seem entirely resistant to the virus, despite repeated exposure. Also, a small number of individuals experience a much slower disease progression. Studies focusing on the differences between these individuals and the larger number of individuals who acquire the disease more rapidly, yielded little information. Recently, it has been determined that chemokine receptors are probably responsible for this phenomenon of natural resistance in some of these individuals. Nathaniel Landau and Richard Koup's group at the Aaron Diamond AIDS Research Center , and several other research groups, have characterized this resistance to HIV-1 infection associated with changes in the CCR-5 chemokine receptor gene. Humans normally contain two copies of the CCR-5 gene. In some individuals this gene is missing 32 nucleotide base pairs and encodes a shortened, mutant protein incapable of being used as an HIV coreceptor. Approximately 10-15% of the Caucasian population have one normal CCR-5 gene and one mutant CCR-5 gene (heterozygous individuals) and only 1% have two mutant, non-functional genes (homozygous individuals). All individuals studied to date with two mutant CCR-5 genes were HIV-1 negative. Individuals with one mutant gene and one normal gene exhibited much slower disease progression and are called Longterm Non-Progressors (LTNPs). Homozygous individuals lacking the functional CCR-5 co-receptor are apparently healthy, which suggests that blocking these receptors might prevent HIV infection without adverse effects on the patient. Many naturally HIV-resistant individual possess two normal CCR-5 genes, perhaps other defective chemokine receptors are involved. Clearly more research needs to be done in this area.

The major question surrounding chemokine research is: How will chemokines and their receptors impact future treatments for HIV and AIDS? First of all, hope for any new therapies should be tempered with caution; attempts to block the CD4 co-receptor, with soluble CD4, were unsuccessful. Soluble CD4 was able to block infection by laboratory strains of HIV-1 but unable to block infection by many primary HIV-1 strains from HIV-infected individuals. With this in mind, two different strategies for chemotherapies might be envisioned. The first is to develop agents that raise natural levels of chemokines in the body which may help cells resist HIV infection. Limiting the accompanying effects of generalized inflammation and continuous white blood cell activation will be an important consideration with this and any chemokine-based approach. A second, more promising avenue might be the development of modified chemokines; in theory they would occupy the chemokine-HIV coreceptor without initiating the potential negative effects associated with chemokine binding and activation. British Biotech has developed a modified version of MIP-1a chemokine as a possible anti-HIV drug; clinical studies are planned for HIV-positive individuals. Fernando Arenzo-Seisodos, along with colleagues at the Pasteur Institute, and Swiss and Canadian researchers identified a RANTES derivative that does not induce chemotaxis. Researchers at the Geneva Biomedical Research Institute and their colleagues have also recently demonstrated that a derivative of RANTES was able to inhibit HIV-1 infection in macrophages and lymphocytes, in the laboratory. Many research groups with numerous collaborations are pursuing this type of drug discovery -identifying agents that block chemokine co-receptors without triggering inflammation.

On the vaccine front, vaccines that induce and increase the natural level of chemokines might be used to block infection of cells by HIV. Since the lack of CCR-5 chemokine receptor affords natural resistance to HIV it might also be possible to develop vaccines that cause the elimination of, or blocking of the co-receptor. At this point, the role of other chemokine receptors in natural HIV resistance is unclear. But it is plausible to think that the CXCR-4/fusin receptor, a target of synctium inducing (SI) virus in late disease, or other chemokine receptors may also be good candidates for vaccines. However, such approaches would also have to wait until the function of the co-receptors is more fully understood. Studies of other HIV-resistant individuals, but who have functional CCR-5 receptors, may clarify the potential role of other chemokine receptors in natural HIV resistance. These studies are currently underway.

HIV/AIDS infected individuals demand results from the research and clinical communities. The first practical application of chemokine research may be the development of a diagnostic test, for HIV-positive individuals, to determine presence of a mutated, non-functional CCR-5 co-receptor. Such diagnostic information may be predictive of disease progression and a consideration for clinical treatment strategies. It is clear that many questions remain for chemokine and HIV researchers to answer. Fortunately, current drug therapies are enjoying a certain amount of success in slowing HIV replication and the resulting immune collapse for a number of HIV positive individuals. Nevertheless, mutability of the virus necessitates the development of new therapies that further stymie AIDS progression, with the goal of making AIDS a manageable illness, much like diabetes is today. Chemokine research has marked a tremendous turning point in understanding HIV pathogenesis and natural resistance. The breakneck pace of current research offers the hope of new and better treatments in the battle against AIDS.

Steve is a microbiologist and member of STEP's Scientific Review Committee.


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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.