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Protease Inhibitors

The Newest Class of Anti-HIV Therapies and
Their Effects on HIV Health Care Programs

June 25, 1996

HIV has proven an elusive and deadly adversary. For more than a decade, researchers and physicians have struggled to develop potent new treatments to fight HIV and AIDS. Despite their efforts, only a handful of drugs have been approved to treat HIV disease. Unfortunately, these drugs have proved to be of limited usefulness, succeeding only in slowing the inevitable progression to full-blown AIDS. Today, however, a new class of drugs is providing fresh hope in our battle against the epidemic: protease inhibitors.

Studies of protease inhibitors demonstrate that this new family of drugs is vastly more potent than the first group of drugs used to treat HIV, reverse transcriptase inhibitors (AZT, d4T, ddI, etc.). Data suggest that when used in combination with approved antivirals such as 3TC plus AZT or ddI, protease inhibitors can dramatically lower viral levels by as much as 99 percent in 60-to 90 percent of the individuals using the therapies. Though protease inhibitors alone do not represent a cure for HIV infection or AIDS, they do provide renewed hope for improved drug and treatment options for people with HIV and AIDS.

How Do Protease Inhibitors Work?

Much like reverse transcriptase inhibitors, protease inhibitors attack a viral enzyme -- protease -- which plays a crucial role in HIV replication. This enzyme serves as a biochemical scissor late in HIV replication by cutting longer chains of proteins and enzymes in the host cell's nucleus into shorter pieces. Unlike long chains, these shorter HIV proteins form new infectious HIV particles that can infect neighboring cells.

Protease inhibitors are chemically similar to the long viral chain that the HIV protease enzyme normally cuts. This process "gums up" HIV protease enzymes that mistake the inhibitor for viral protein. As a result, the longer HIV proteins remain uncut or miscut which causes them to produce defective and therefore non-infectious new copies of HIV. Ultimately, protease inhibitors can greatly reduce the number of new, infectious copies of HIV inside the cells and curb the spread of HIV infection in the body.

Is There A Resistance Problem With Protease Inhibitors?

HIV's deadly ability to mutate and develop resistance to antiviral drugs has proven the central barrier to our efforts to develop potent and lasting therapies. Similar to all previous antiviral drugs, protease inhibitors can also fall victim to HIV's uncanny ability to develop strains that are drug resistant. However, at this time, the resistance is problematic only when the protease drugs are administered in monotherapy.

Another devastating threat posed by protease monotherapy is the development of cross-resistance because resistance to one protease inhibitor often confers multi-drug resistance to several of the other protease inhibitors. However, with more carefully chosen treatment strategies in which protease inhibitors are used in combination with approved antivirals such as 3TC plus AZT or ddI, the size and duration of the antiviral effect is greatly enhanced. Since combination therapy requires HIV to mutate its genetic structure as many as eight times, it is hoped that the newly produced virus will be much less viable.

The threat of viral resistance and cross-resistance to protease inhibitors reiterates the importance of carefully delineated treatment plans. Without carefully chosen and rigorously followed strategies, the potent effects of protease inhibitors will be short-lived and quickly followed by multi-drug cross-resistance.

The Crisis in Access to HIV Drug Therapies

Unfortunately, a large number of people living with HIV and AIDS will be unable to access what has become the new "standard of care." Because HIV disease is inevitably impoverishing for the great majority of people who become infected, over the last 15 years a fragile and intricate AIDS care infrastructure has been built to ensure that impoverished and medically needy people with AIDS have access to basic health care and life-saving drugs. Today, the myriad programs that make up this AIDS care infrastructure are threatened by pressures on federal and state health budgets. The rise in price for basic antiviral therapy -- which now runs from $3,000 for antiviral monotherapy to up to $13,000 for combination therapy -- is likely to accelerate this alarming process.

In 1994, fewer than 29 percent of people living with HIV were covered by privately funded health insurance and that number is quickly decreasing. Of those people who remain covered under some health insurance plan, a significant number have insurance that either includes no coverage for prescription drugs or caps prescription drug coverage either annually or over the life of the policy.

Another 50 percent of people living with AIDS are covered by Medicaid. Unfortunately, income caps for Medicaid average $434-per-month with many states limiting patients to three prescriptions per month. Many other state Medicaid programs include no drug coverage for "medically needy" people with AIDS -- those who are allowed to "spend down" medical expenses to qualify for Medicaid. And, now, the Medicaid program itself is under attack from congressional proposals to block grant the program to the states with no eligibility requirements -- meaning that people living with HIV and AIDS could potentially be excluded -- and with a much-diminished amount of federal funding -- a cut of up to 34 percent of federal Medicaid funding in some states.

For the tens of thousands of uninsured or underinsured people with HIV disease who do not qualify for private health insurance or for Medicaid, the only remaining options are state AIDS Drug Assistance Programs (ADAP) funded under the Ryan White CARE Act, or indigent programs operated by the pharmaceutical manufacturers. Unfortunately, long-term shortfalls in ADAP funding have resulted in severe budget crises that caused at lease three states to discontinue all formulary dispersals during 1995. Other states have canceled planned expansion of formularies, established waiting lists for new clients, restricted income eligibility levels, imposed strict new utilization controls, or removed drugs from formularies. For example, the State of Illinois has removed from its ADAP formulary 81 drugs to treat opportunistic infections in order to pay for one protease inhibitor. The National Association of State and Territorial AIDS Directors has estimated that these programs will need at least $150 million in new funding if they are to maintain current service levels. No one has yet estimated the cost of providing the new combination therapies to these programs.

For all these reasons, we are becoming a country where people living with HIV who have access to the resources necessary to afford "state-of-the-art" therapy will live longer and healthier lives than those who are dependent on public programs or who are unqualified for those programs. It is the latter who will die of a myriad of opportunistic infections -- dependent on emergency rooms for their health care.

For more information, contact:
AIDS Action Council
1875 Connecticut Avenue NW #700
Washington DC 20009
202-986-1345 (fax)
202-332-9614 (tty)

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This article was provided by AIDS Action Council.
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