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Protease inhibitors Maclean D (Fact sheet)
This document has been reviewed by CATIE's treatment information staff, but not yet by
an external reviewer.
General
Protease inhibitors are a new class of drugs taken to fight HIV infection. Saquinavir
(sold as Invirase), ritonavir (Norvir), and indinavir (Crixivan) are approved for sale in
Canada. Several other pharmaceutical companies have protease inhibitors in development.
Agouron's protease inhibitor nelfinavir (Viracept) is in Phase III clinical trials.
Glaxo-Wellcome, in partnership with Vertex, has Phase II trials underway of a product
known as 141W94 (if you're reading G-W material) or VX-478 (if you're reading Vertex
material). Pharmacia & Upjohn have a third generation protease inhibitor under
development. Many other manufacturers are also working on HIV protease inhibitors.
Drugs that fight HIV infection are called "antiretrovirals" because HIV is a
retrovirus. These drugs interfere with the viral life cycle in order to stop, or at least
slow down, the progression of HIV disease. A brief review of how HIV replicates will help
explain where and how antiretroviral drugs work.
How HIV infects cells
The core of HIV is made up of two strands of the genetic material called RNA
wrapped in a protein coat. It is surrounded by an envelope made of fat and protein. HIV is
not alive. All living things, even single-celled organisms like bacteria, fungi, or
protozoa, must breathe, eat, excrete, and reproduce. Viruses do none of these, except
reproduce.
The process of making more viruses is referred to as replication rather than
reproduction because the virus simply makes copies of itself. Replication can happen only
after HIV has inserted its genetic material into the genetic material of a cell.
Once HIV has entered the body, it infects cells which have a CD4+ receptor on their
surface. A cell is covered with different receptors, like a face can be covered with
freckles. Cells use receptors to communicate: they let information, in the form of tiny
molecules, in and out of cells. Different types of cells have different receptors. The HIV
envelope has "spikes" on it, called gp120, which happen to fit into the
CD4+ receptor on a cell's surface and act like a key, unlocking the receptor and allowing
HIV to enter the cell. Two kinds of immune system cells have CD4+ receptors and can be
infected by HIV: macrophages and CD4+ lymphocytes (also called "T4 cells" or
"CD4+ cells").
After HIV has bound to the CD4+ receptor, it enters the cell and begins the process of
replication with the help of its own chemical messengers called enzymes. First, the
enzyme reverse transcriptase converts the genetic material of the virus (RNA) to
match the genetic material of the cell (DNA). Then, this new viral DNA (also called proviral
DNA) enters the nucleus of the cell. A second enzyme, integrase, inserts the
proviral DNA into the cell's own DNA. The virus has now "hijacked" the cell and
starts making new viral RNA.
Some of this RNA will become the genetic material contained in new viruses. Other viral
RNA will go on to make the proteins which will coat the new virus. These proteins are
produced as long strands of polyprotein which must be cut into the appropriate sizes. The
enzyme protease (or proteinase) works like scissors to cut or cleave the
polyprotein. Finally, the viral proteins and viral RNA are assembled into new HIV and bud
off the cell's surface.
How protease inhibitors work...
Protease inhibitors are drugs that interfere with the action of the protease enzyme. They
block the scissors-like action of protease so that new viral proteins cannot be cut to the
right sizes. If the viral proteins are not the right size or shape, new virus cannot
mature, and as a result, will not be able to infect other cells.
Protease inhibitors not only work at a different stages in the viral replication cycle
than reverse transcriptase (RT) inhibitors, they also work in different cells. As
mentioned above, both CD4+ lymphocytes (CD4+ cells or T4 cells) and macrophages can be
infected by HIV. CD4+ lymphocytes usually die within 48 hours of being infected with HIV.
Macrophages, however, may live for several months, continually producing new virus. Thus
macrophages become "reservoirs" of HIV. RT inhibitors (like AZT, ddI, ddC, d4T,
and 3TC) seem to work only in CD4+ lymphocytes, but test-tube studies of protease
inhibitors indicate that they may work in both CD4+ lymphocytes and macrophages.
Results from studies
Results of clinical trials show that, compared to RT inhibitors, protease inhibitors
produce greater decreases in viral load and greater increases in CD4+ lymphocyte counts.
Peak drops in viral load occur after only 2-4 weeks of treatment; after that, average
viral load begins to return slowly toward pre-treatment levels. Better results are seen
when protease inhibitors are used in combination with one or two RT inhibitors.
Combination therapy seems to delay the onset of drug resistance for up to a year or more.
The first three protease inhibitors to hit the drugstores received marketing approval
from the Health Protection Branch based on improvements in viral load and CD4+ counts.
Most of the data presented to support the companies' requests for marketing approval were
taken from trials which lasted only six months. Some large Phase III trials continue to
gather information on clinical endpoints (for example, development of AIDS-defining
illnesses, long-term toxicity, death), but it may take months or years before this data is
analysed and published in peer-reviewed journals. Although two manufacturers conducted
trials with clinical endpoints, the data from these trials is difficult to interpret.
- Abbott enrolled 1090 people with less than 101 CD4+ cells in a placebo-controlled trial
of ritonavir. Participants continued their current antiretroviral treatment (AZT, ddI,
ddC, or d4T, alone or in combination) and were randomly assigned to receive either
ritonavir or a placebo. After 6.1 months, 86 of the 543 people (15.8%) who had received
ritonavir had experienced a new AIDS-defining illness or had died, compared to 181 of the
547 people (33.1%) who had received the placebo. Information presented at the Vancouver
AIDS conference in July 1996 showed the survival benefit of adding ritonavir continued for
one year. However, It is difficult to assess the true impact of ritonavir on survival or
disease progression because, after 4 months on the trial, participants who developed a new
or recurrent AIDS-related illness were allowed to switch from placebo to ritonavir.
- Roche enrolled 978 participants with CD4+ counts of 50-300 in a trial comparing ddC
alone, saquinavir alone, and ddC + saquinavir. After 73 weeks, 54 of the 308 people who
had received the combination had experienced a new AIDS-related illness or had died,
compared to 111 of the 318 who had received saquinavir alone, and 113 of the 314 people
who received ddC alone. While this trial clearly shows a survival benefit to taking ddC +
saquinavir, it does not translate well into the "real world". Since ddC was
originally approved for use only in combination with AZT, and since it is well known that
only about 4% of the saquinavir swallowed gets used by the body, very few people would
ever take either drug alone. Roche could have designed a more useful trial by using other
drugs and more likely combinations.
Drug interactions
The protease inhibitors, and many other drugs, are metabolized (broken down) in the liver
through the actions of the cytochrome p450 enzymes. Some drugs can inhibit these
enzymes, which means that they perform less effectively. Others can induce these
enzymes, which means that they perform more effectively. Potentially dangerous drug
interactions can result. For example, taking a drug which induces the actions of
p450 enzymes can cause a second drug to be metabolized more efficiently, which may lead to
reduced levels of the second drug in the body. As a result of the lower levels, that
second drug may not have a beneficial effect. A drug which inhibits the p450
enzymes can cause higher levels of a second drug to circulate in the body, which could
produce potentially dangerous side effects.
Side effects
Although protease inhibitors are more powerful drugs than nucleoside analogues, they seem
to be better tolerated. However, all three drugs can cause side effects that range from
mild and annoying to severe and potentially dangerous. In clinical trials to date, the
most commonly reported side effects of saquinavir are weakness or fatigue, nausea,
diarrhea, and headache. Ritonavir, especially in the first three or four weeks of
treatment, can cause moderate to severe nausea, vomiting, and diarrhea. "Dosing
up" from half the recommended dose to the full dose over two weeks can help reduce
the side effects. Indinavir users must drink an extra 1.5 litres of water daily in order
to prevent kidney stones.
Resistance & cross-resistance
Over time, as HIV makes copies of itself, the virus can change its structure. These
changes allow HIV to resist the effects of antiviral drugs. Resistance to protease
inhibitors seems to appear after 12 weeks of treatment. Combining protease inhibitors with
one or more nucleoside analogues may delay the development of drug resistance. To limit
the risk of developing drug resistance, protease inhibitors should be taken every day,
precisely as prescribed. If a dose is missed, the next dose should be taken as soon as
possible. Never double a dose to make up for missing one.
Some studies, both in test tubes and in people, have shown that protease inhibitors may
be cross-resistant. This means that if HIV becomes resistant to one brand of
protease inhibitor, it may also be able to resist the effects of other protease
inhibitors. The development of cross-resistance will limit the choices of antiretroviral
treatment. For example, ritonavir and indinavir are cross-resistant, which means that
someone will probably not benefit from switching from ritonavir to indinavir.
Summary: the good stuff
Many researchers, clinicians, and people living with HIV are understandably excited about
the arrival of the protease inhibitors. Dramatic results in CD4+ lymphocyte increases and
viral load drops to below detectable levels have been reported. There have also been
reports of ailments like persistent thrush or hairy leukoplakia clearing up after a few
weeks or months of using protease inhibitors. If these promising results last for two or
three years, protease inhibitors, especially when used in combination, will be a major
step forward in HIV treatment.
Unanswered questions:
- How long does the benefit last? Does the improvement in surrogate markers also
mean an improvement in overall health? Because only 6-9 months of data from various trials
have been published, it is not known if protease inhibitors will help people live longer
with fewer infections. Pharmaceutical firms must be reminded, through coercive regulations
if necessary, of the need to conduct trials with conclusive results based on AIDS-related
illnesses and survival, and to publish the information in a timely fashion in
peer-reviewed journals.
- Is cross-resistance between protease inhibitors a real concern? There is very
little information available about cross-resistance. The few published reports describe
results of small numbers of test-tube studies and even smaller numbers of blood samples
taken from people who have used protease inhibitors. Furthermore, the different
manufacturers seem to disagree about the cross-resistance of their products. For example,
Roche says its product saquinavir is not cross-resistance to Merck's product indinavir.
Merck, on the other hand, insists that saquinavir is indeed cross-resistant to indinavir.
Larger studies conducted by independent laboratories are urgently needed so that people
can make rational decisions about their treatment regimens.
- When to start? Many researchers are now strongly suggesting that people base
their decision to start antiretroviral therapy on their viral load measures. However,
there is no clinical data available to support or refute starting treatment with protease
inhibitors when CD4+ counts are above 500 cells. Members of the International AIDS Society
- USA recommend antiretroviral treatment for anyone with a viral load of more than 30,000
to 50,000 RNA copies/ml. According to this committee, those with viral loads of 5,000 to
10,000 RNA copies/ml should consider treatment. Unfortunately, viral load testing is not
readily available to most Canadians.
- Dosing schedules -- how necessary are they? The dosing schedules of protease
inhibitors, especially when used in combination with nucleoside analogues may force people
to conduct their daily lives by the clock in the kitchen. Saquinavir should be taken three
times a day with fatty foods, and/or grapefruit juice and/or ketoconazole; ritonavir can
be taken twice a day with or without food; indinavir should be taken every eight hours on
an empty stomach, but in a pinch can be taken with a light meal low in protein and
containing no fat. While volunteers in a clinical trial may be motivated to follow these
schedules for up to 6 months, in the longer term, these schedules may not be followed as
rigourously especially when people are taking other kinds of medications. As a result,
people may not experience the same dramatic benefits reported in clinical trials.
Manufacturers should be urged to reformulate their products so people don't have to worry
about taking them with food, without food, with fat, without fat.
- Cost! Herein lies the largest problem. The Health Protection Branch (HPB) of
Health Canada has reviewed the safety and efficacy of these drugs, found them acceptable,
and approved them for sale. Despite the fact that our national regulatory agency has
judged protease inhibitors to be suitable for Canadians to use, provincial governments,
insurance companies, and other funders have been refusing to pay for these drugs.
References:
Abbott Laboratories, Limited. Norvir product monograph. Saint-Laurent, PQ:
Abbott Laboratories, Limited. 1996.
Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodefiency virus
infection with saquinavir, zidovudine, and zalcitabine. New England Journal of Medicine
334(16):1011-7. 1996.
Lalezari J, Haubrich R, et al. Improved survival and decreased progression of HIV in
patients treated with saquinavir plus zalcitabine. [LB.B.6033] XIth International
Conference on AIDS, Vancouver; July, 1996.
Merck & Co. Inc. Crixivan product monograph. Whitehouse Station, NJ: Merck &
Co. 1996.
Moyle G, Gazzard B. Current knowledge and future prospects for use of HIV protease
inhibitors. Drugs 51(5):701-12, 1996.
Noble S, Faulds D. Saquinavir: A review of its pharmacology and clinical potential in
the management of HIV infection. Drugs 52(1): 93-112, 1996.
Roberts NA. Drug-resistance patterns of saquinavir and other HIV proteinase inhibitors.
AIDS, 9(Suppl 2):S27-S32, 1995.
Schmit J-C, Ruiz L, Clotet B, Raventos A, Tor J, et al. Resistance-related mutations in
the HIV-1 protease gene of patients treated for one year with the protease inhibitor
ritonavir. AIDS 10:995-9, 1996.
Stein DS, Fish DG, Bilello JA, et al. A 24-week open-label Phase I/II evaluation of the
HIV protease inhibitor MK-639 (indinavir). AIDS 10: 485-492, 1996.
Disclaimer
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information resources to help people living with HIV/AIDS who wish to manage their own
health care in partnership with their care providers. We do not recommend or advocate
particular treatments and we urge users to consult as broad a range of sources as
possible. While we update our material regularly, users should be aware that information
changes rapidly. Additional information may be available from CATIE at 1-800-263-1638 or
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Decisions about particular treatments should be made in consultation with a health care
professional knowledgeable about HIV-related illnesses and the treatments in question.
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