Managing HIV: A Life-Long Commitment

The first cases of HIV were reported in the early eighties. At that time, virtually nothing was known about the virus that causes the disease, and there was little that clinicians could do to slow its inevitable progression to AIDS, then death. A lot has changed since then, and though there is still no cure for HIV, the HIV virus can often be controlled now with medications.

But adhering to an HIV drug regimen can pose tremendous challenges. Missing just two drug doses can result in increased levels of virus in the body, or resistance to the drug, derailing their effectiveness. Maintaining HIV control requires a near perfect score in drug adherence. But, some drug regimens for HIV are hard to stick to, to say the least. The drugs can be difficult to tolerate. Some require upwards of 20 pills per day, pills that must be refrigerated or taken at particular times during the day or pills that must be taken with or without food. For patients looking for that "perfect score", the level of difficulty is high. And the risks of failing are even higher.

Below, Dr. Susan Ball, Associate Professor at the Weill Cornell College of Medicine, talks about the importance of drug compliance in HIV treatment, and some of the issues HIV patients struggle with on a daily basis.

How do drug manufacturers determine the timing and dosing of HIV medications?
Drug companies arrive at drug dosing by trying to inhibit the virus for the longest amount of time in the body, with the lowest drug levels in the blood. Some of these drugs, depending on how they are metabolized, don't last very long in the bloodstream or in the place where they are going to be the most effective. As a result, the drug needs to be given more frequently. They work to reduce the concentration of the drug needed so that they can minimize side effects.

Often when a drug first comes to market, it will be in a form that is difficult to take: either multiple pills per day, or by injection only, or it will have side effects that make it unpleasant, if not intolerable. AZT, for instance, was one of the earlier HIV drugs, and had to be taken every four hours. Norvir, a protease inhibitor, used to be offered in doses that made most patients too nauseated to tolerate it. Manufacturers try to make the drugs more and more palatable in terms of reducing the number of pills, the side effect profile, and the number of times a day that you have to take a medication.

What happens if drug doses are missed?
This is a big issue with HIV medications. The drugs are carefully dosed to maintain blood levels that will suppress the virus. The virus will be unable to replicate because of the drug's actions. But if a person does not take the prescribed dosage, the drug level can fall and there will not be enough concentration of the drug to inhibit the virus. The virus can "escape", which means that some virus can replicate, even though there is drug there.

What is the risk to the patient in this case?
The virus can mutate and become resistant to the drug that's present in the blood.

How quickly does this happen?

In patients who skip one dose, and take the dose several hours or a day late, the drug level will drop, but the situation may be manageable. You may be able to get your drug levels back up to where they should be, so the virus is inhibited again and the replication levels are below detection.

But if you miss doses frequently enough, you'll see a reemergence of the virus levels (also known as viral load) that should be suppressed on the drugs. Suddenly the viral load will be elevated and detectable in the blood, and virus that is resistant to the drug will be replicating.

How carefully must one adhere to a drug regimen to avoid resistance?
It's very daunting. Approximately 95% of the drug doses need to be taken to prevent resistance. If a patient is on a regimen that requires taking medication twice a day and misses two doses a week, it's going to result in resistant virus. Patients have to be very strict about taking their medication.

Are there any immediate physical signs related to a missed dose?
Usually not. When a patient skips a dose, it's not like their cold becomes worse, or their allergy symptoms return, or their headache comes back. They feel fine without taking their medications. So there is not that physical illness reminder that helps them remember their medicine.

And many patients will say they just feel better without being on a medicine. There is a lot of talk about structured treatment interruption or patients taking "a drug holiday." The reality is, these are not easy drugs to take, even in the low pill burden doses that we can give patients now. But no patient should stop or interrupt their medication without consulting their doctor.

The other thing that's important to remember is, these are young people, often in their 20s and 30s. I think that people in their 60s and 70s sort of expect they will have to take a pill of some kind to maintain health as they get older - not that everybody has to do that. But for people in their 20s and 30s, it's really hard to take medicine every single day indefinitely, with no end in sight.

Is non-adherence a frustrating issue for you as a doctor?
Definitely. I've seen so many people do so well, and yet I have a few patients who just can't do it. They cannot take the medication or they won't, or they're just not able to hang in there with a regimen. So their viral load gets worse and worse. Or they get better very slightly for a brief time and then they get worse again. It's frustrating, and as their doctor, I have a sense of what's in store.

Have you ever had a patient who has gone through every available drug regimen and has become resistant to each one because of compliance issues?
Your question makes me think of a young patient of mine who died two summers ago. She had been very reluctant to take any medicine at all for quite a long time. Then in 1996, she had a serious fungal infection throughout her body called Pneumocystis Carinii Pneumonia (PCP). She was really ill. She was really within months of death.

I'm not sure what convinced her. I'm not sure it was anything I said, but she started taking medicine. At that time, protease inhibitors were available. Her numbers improved, and she improved dramatically. It was really quite miraculous to see. She gained over sixty pounds and looked like her old self again. But she was so well she went back to some previous lifestyle patterns. Then over time, she stopped taking her medicine. Over the next years she went through nearly every regimen I had to offer. She would fail and I would put her on another regimen. Then she would fail again and we'd start again. She eventually died from complications of cytomegalovirus, an opportunistic infection.

How are drug companies helping to improve adherence to HIV medications?
Drug companies are trying to make these drugs more palatable and more long-lasting so that you can take your drug once-a-day and it will last the whole day with few side effects. All regimens require a patient to take at least three different medications, but sometimes the medications can be combined. For instance, there is a pill called Trizivir, which is actually three drugs in one pill. It's a twice-a-day pill. So you have three drugs, twice-a-day, in the form of two pills, which is pretty great. In the last 18 months or so, more and more patients have been on once-a-day dosing, that is, their medications come in the form of a pill or pills taken once a day. It's a vast change from the early days of protease inhibitors where the pill burden was so high.

And the fewer times you have to take a medicine, the less likely you are to miss doses.