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HIV, AIDS ,  and Protease Inhibitors

In the three years since they were first introduced, protease inhibitors have dramatically improved the lives of people living with HIV and AIDS. Unfortunately, they are not working for everyone.

Steve is a 33 year old man living in Los Angeles, one of the areas hardest hit by HIV and AIDS. He has a successful career and is in the process of closing escrow on a new home. He enjoys an active social life, exercises regularly, and travels frequently.

Two years ago Steve was devastated when he discovered he was HIV positive. "It was a complete shock," Steve recalls. " I think I just kind of shut down for a week." But with the recent advances in AIDS drug therapy he decided that the best approach was a proactive one and he promptly started drug therapy. His doctor suggested he include a protease inhibitor in combination with two other AIDS drugs. Protease inhibitors were a relatively new type of drug which had been shown to reduce the amount of HIV in the body, otherwise known as the viral load.

Steve had heard stories about the incredible success of these new drugs which had in some cases rendered HIV undetectable in the blood stream. He started this combination therapy immediately. The outcome looked promising. "My viral load went undetectable within the first two months," Steve said. But the success was short-lived. Eight months later his viral load had risen to a rate even higher than it had been before. These results are not unusual.

In the nearly two decades since it first appeared, more than six million people have died of AIDS. Over 30 million adults and children worldwide are living with HIV and there are approximately 16,000 new infections per day.

Although the rate of infection is increasing by as much as 19% worldwide, the rate is falling in the United States. Education and new drug therapies are credited with this reduction of the infection rate; however, there has been an increase in some segments of the population. Women, minorities, and young people under the age of 22 are becoming infected at an alarming rate.

Women are the fastest growing group to become infected and AIDS is now the number one killer of women between the ages of 25 and 44. In addition, 1/4 of all new infections in the United States is in people under 22 years of age.

According to the Center for Disease Control (CDC), there are 775,000 Americans infected with HIV. About 275,00 of these people are unaware they are infected.

Three years ago protease inhibitors were introduced offering new hope in the battle against AIDS. Never before had an AIDS drug shown such promise and brought hope to so many people.

Protease inhibitors work by blocking the activity of an enzyme called protease that is essential to the replication of the virus. According to Dr. Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases, "Treatment combinations which include a class of medications that inhibit the HIV protease enzyme can control replication of HIV in many patients to a degree and duration not previously possible." By preventing the replication of the virus, the combination therapies can reduce the amount of HIV that is already in the bloodstream to a level so small that testing cannot detect it.

To many these combination therapies appeared to be the solution to the AIDS problem. AIDS would become a disease that could be easily managed using these drug combinations.

"Protease inhibitors have ushered in a new era in terms of the treatment of HIV and AIDS," said Kevin Robert Frost, the Director of Clinical Research and Information for AMFAR (the American Federation of AIDS Research). "They haven't done that single-handedly," he continued. "What protease inhibitors have done is brought in the combination therapies."

By themselves protease inhibitors were ineffective, but when used in combination with other HIV drugs, they were shown to dramatically decrease the amount of HIV in the bloodstream. Very often these combination therapies, or "cocktails" as they are often called, were able to reduce an infected person's viral load to undetectable levels and in many cases reverse symptoms of AIDS indefinitely.

When protease inhibitors were first introduced they signaled a new phase of drug therapy that prompted much speculation about the future of AIDS. Many believed that AIDS would become a treatable disease such as diabetes and that we were seeing the beginning of the end of the AIDS crisis. It appears, however, that such speculation was premature as a significant number of people with HIV do not benefit from protease inhibitors.

While there is no doubt that protease inhibitors have dramatically changed the battle against AIDS and improved the lives of many people infected with HIV, the battle is far from over.

"Unfortunately, many patients have not benefited from the currently available drugs, or have been unable to tolerate the side effects," related Dr. Fauci.

The fact is, that while combination therapies using protease inhibitors may help inhibit the progression of AIDS in some people, there are many people that do not achieve these same results. It is estimated that these new therapies may be ineffective for up to 40% of the HIV-infected population.

In some cases the drugs simply do not work. Some people on a combination therapy including a protease inhibitor will experience an initial drop in HIV viral load only to see an increase a short time later thus signaling that the combination has failed. This is especially true among those who have undergone drug therapies in the past or have been living with HIV for a long time. Very often, the virus has already developed a resistance to some of the drugs used in the combination therapy thereby increasing the chance of failure.

"Definitely, people who have no experience with medications in the past are people who have the biggest chances of getting greater benefits from these medications," said Reuben Gamundi, Program Manager for Treatment Education at AIDS Project Los Angeles. "And if a person starts earlier, they have more chances of responding, they have less chances of developing side effects, and more chances that they will be able to rebuild their immune system," he continued.

In other cases, the drug regimen, which can include anywhere between 15 and 20 pills a day, proves to be too difficult to maintain. The various drugs need to be taken at a certain time each day. Several need to be taken on a full stomach, some need to be taken without food, while others need to be kept refrigerated. If the grueling drug schedule is not strictly adhered to, the virus may become resistant to the combination therapy.

"There have been studies done that showed that even on something as relatively simple as a ten-day course of antibiotics, most people do not take their full 10 days. In fact there was one study in which they actually followed doctors, and doctors doing a ten- day course of antibiotics were abysmal in their compliance," Frost stated, "So, (with) the notion of taking drugs 3 times a day for the rest of your life, issues of compliance become enormous. The problem is (when) we start dealing with something as serious as HIV disease and the possibility of viral resistance, then the need for compliance becomes even greater."

Additionally, many people cannot endure the side effects often associated with these therapies. Common side effects include diarrhea, fatigue, and nausea. More serious side effects can include neuropathy, kidney stones, liver failure, and diabetes.

After his first combination therapy failed, Steve started another combination using a different protease inhibitor. "I started on that (the new medications) and had horrible side effects," Steve said. "The whole inside of my mouth was completely numb. I was really miserable. I was at work and my hands and feet started to go numb...I couldn't even function." He stopped taking the new drugs after three weeks.

Even for those people who can benefit from drug therapy including a protease inhibitor, there are a number of other problems.

The biggest problem is the high cost of the drugs themselves. These medications can routinely cost between $12,000-$15,000 per year. This rules out these therapies for many people in this country and for 90% of infected people worldwide.

And even if a person can get the medication and has improved, there is no guarantee of continued success. Even if the viral load is undetectable, there is still HIV in the body. The viral load is only a measurement of the amount of HIV in the bloodstream. It is possible that a person could have an undetectable level in the blood stream and have a detectable level in another part of the body. Also, the term "undetectable" does not mean that the virus has been eliminated or that the person can no longer infect someone else. It simply means that the quantity of the virus in the blood is too small to register on the test.

"There's a possibility that a person with HIV may have an undetectable level of viral load in blood and not an undetectable level in semen or cervical secretions," said Gamundi. "It does not mean that a person is not infectious. A person may continue to be infectious even if they have an undetectable level of viral load."

Since there is still HIV in the body, there is growing concern that HIV, which mutates rapidly, will become resistant to these new drugs. Protease inhibitors are relatively new and there is no long-term data to suggest how long these drug combinations will remain effective.

"Combination therapy has had a dramatic impact; it's not the answer." Frost maintained. "We don't know how long it's going to last. This could be a honeymoon period."

There are at least half-a-dozen strains of HIV worldwide. Doctors fear that a more resilient strain of the virus may develop in response to these new treatments. This is especially true in cases where people do not strictly adhere to their drug regimens. If the drugs are taken on an infrequent basis, there is a danger to not only to the patient but to the world that a stronger, deadlier strain of the virus will emerge.

As for the future, most experts agree that while protease inhibitors have greatly improved the lives of many people living with HIV, they aren't the answer. The real solution to the battle with AIDS lies in developing a vaccine and a cure.

"I think protease inhibitors have been wonderful. I'm very happy about the fact that they have ushered in the era of combination therapy, but we will never have an answer to this particular problem as long as we are dependent on drugs to control viral replication," Frost said. "We need two things. We need a cure and a preventative vaccine. That's the answer to the AIDS crisis. When we have both of those things in place, then the long term possibilities become very bright. But as long as the long term is dependent upon these viral combinations, I think the picture is not terribly optimistic because viral resistance is a significant issue. The virus will find a way to grow."

There is some fear that in light of these new therapies, people will become more relaxed in their sexual behavior believing that a treatment is just a few pills away. Gamundi cautions this is just not the case. " Some people aren't being sexually safe at this time because they think "If I get infected I can go on combination therapy and everything will be okay." These medications don't mean (there is) a cure for HIV. It's very far from that. These medications are very difficult to take. It's a very complicated regimen that people need to follow, with side effects attached to them. The reality is that I think that people should continue to be safe because this is not easy. The life of people with HIV is not an easy life. It's a very complicated life."

In 1997, President Clinton challenged the nation's scientists to find a vaccine for AIDS bringing forth a renewed effort in this lengthy battle. Research continues throughout the world as scientists continue investigating every aspect of this deadly virus in the hopes of finding a way to defeat this disease.

Until a cure is found, combination therapies using medications like protease inhibitors will be the best hope for prolonging and improving the lives of those people living with HIV and AIDS. And there is hope that perhaps the same research which produced the protease inhibitors will bring forth an even more effective treatment.

In the meantime, Steve, who is showing no symptoms of AIDS, is looking forward to moving into his new home and will soon start on his next combination therapy. He remains optimistic about his future. "Everybody's got to go, but I don't feel like I'm ready to. I know I'll be okay. "



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