Helping Your Antiretrovirals Help You

Overwhelmed! That is the first word that comes to my mind when I think about an HIV patient who is about to begin antiretroviral therapy for the first time. I think of all the information being sent the way of someone starting therapy -- by physicians, nurses, patient educators, and pharmacists. All of this information is provided in order to help with the start of this important journey, but it can definitely be overwhelming.

As a pharmacist who has worked in an HIV clinic, an outpatient pharmacy, and a medication management mail-order pharmacy, I have seen patients from a variety of perspectives. In each of these different surroundings, some things have remained consistent -- patients have to deal with a myriad of things involved in starting (or switching) antiretroviral therapy, and patients do better if they understand how critical adherence is and come to terms with it. I suggest that anyone thinking about beginning a new medication regimen feel really ready for this big step before taking it.

Rarely is it imperative that antiretroviral treatment be started on an urgent basis. Therefore, you can be open with your physician if you are not yet prepared to begin therapy. Also, before beginning treatment, learn how the medications you'll be taking work in your body and the side effects they may cause. Make sure you are committed to working through complications or problems if they arise.

There are so many different opinions and suggestions about when to start antiretroviral therapy that it is hard to determine the right time for an individual person. Even though things like CD4 counts and viral loads are important factors in making this decision, the most important determinant is that the individual person is ready to start and adhere to therapy.

Adherence to an antiretroviral regimen is extremely important. If a patient starts therapy but does not take it consistently every day, or decides to stop after beginning a regimen, there is a chance of developing medication resistance. However, this does not mean that starting a particular regimen means you can never change it.

If a treatment is not working due to side effects, dosing schedule, or medication intolerability, there is always the option to change to a different combination of medications. It is crucial that the physician be informed and involved with switching therapy. Having an expert help with the change will decrease the potential for building resistance to medications.

Finding a Regimen That Suits You and Your Lifestyle

Are you ready to start your antiretroviral therapy? If so, there are a few things to keep in mind as you and your physician begin to choose a treatment that is right for you.

1. It is important to understand the goals and benefits of therapy. Antiretroviral medications are a cornerstone in the treatment of HIV-positive patients because of their ability to restore and maintain immune function, prevent illness and death, and improve quality of life. The more you understand about medication therapy, the more you will be able to make informed decisions.
2. Before starting therapy, it is a good idea to have baseline laboratory tests performed. These tests will help you and your provider understand where your body's pre-antiretroviral therapy starting point is. Knowing this starting point will help your physician understand your current health status with respect to what the HIV is doing and anything else, unrelated to HIV, that might be going on.

   Lab tests will also guide your physician in choosing appropriate treatment. For example, if lab results indicate highly elevated lipids prior to starting therapy, your physician may want to avoid most of the protease inhibitor class, or address the elevated lipids upon initiating therapy.

3. Think about what will work for you in your life. There are many combinations of drugs to choose from when starting therapy if you are "treatment naïve" -- starting your first ARV regimen ever. Things to consider when choosing a specific regimen, besides pre-treatment lab work, include:
   • total number of pills per day
   • dosing frequency
   • food considerations
   • drug interactions
   • adverse medication effects and
   • the potency of the regimen itself.
4. Whenever possible, make sure your choice provides a good "Plan B" option if some medication resistance emerges. This is called drug sequencing. You and your physician will likely choose a regimen that consists of medications in at least two different antiretroviral drug classes while also sparing as many other classes of drugs as possible for future use. These other drug classes will be reserved for use in the event that the virus becomes resistant to a specific class of drugs.

Your physician may do some drug resistance testing before you begin ARV therapy to determine if there are any medications to which your virus is already resistant. However, this test is often reserved for patients who are not responding to their current regimen ("treatment-experienced" patients).

With so many things to consider, you may wonder how you or your physician actually decides which combination of drugs to use. The good news is that there are guidelines to help with the decision-making process. It is important to remember, however, that one, guidelines change over time as new medications become available and more information is learned about existing medications, and two, these are just guidelines. Each individual person must find the regimen that will work best ... for that person.

Making it Work

Once you start your new antiretroviral therapy, you may begin to realize that you are having trouble adhering to your regimen for one reason or another. If that happens, there are a variety of strategies that may help you.

From my experience, patients find pill boxes very helpful for organizing their medications and as a way to remember if they have taken them. Calendars can also be useful because each day can be marked to indicate that a dose was taken. Pill boxes and calendars are both inexpensive tools that can be very helpful. The good news is that adherence has gotten easier as new antiretroviral therapies have been developed that require fewer pills and fewer doses throughout the day.

Sorting Out Drug Side Effects

Antiretroviral therapy has come a long way over the past decade. However, the longer medications are on the market, the more we find out about the side effects they can cause. It is unfortunate, but many of these therapies have a lot of possible short-term and long-term side effects.

It is important to remember that every medication has a list of possible side effects associated with it. That does not mean that everyone taking a particular medication will develop every side effect on the list, or any of them, for that matter. It is a good idea to understand the potential side effects associated with each of your medications, though, so you'll know what to look for if you do experience any problems after starting therapy.

If you have any side effects, or if any side effects you are experiencing become intolerable, make sure to discuss them with your physician. I have seen too many patients who have started therapy, experienced a side effect that they struggled with, then stopped therapy on their own without ever letting the doctor know there was a problem. Patients who stop therapy without speaking with the physician risk developing medication resistance because some medications need to be stopped in a particular order in order to avoid resistance.

Antiretroviral medications can have side effects that are common for the class they are in (e.g., protease inhibitors and gut distress), but there are also side effects that are specific to each medication. It would be impossible to list every side effect for every medication in this article, and probably boring. The point is this: when you start a medication, take time to learn about the side effects from your physician, pharmacist, or written information on that specific medication.

As a class, nucleoside reverse transcriptase inhibitors or NRTIs (drugs like lamivudine, abacavir, and zidovudine) all have the potential to cause some serious side effects. NRTIs can cause pancreatitis, lactic acidosis (a dangerous build-up of acid in the blood), and an enlarged, fatty liver.

Non-nucleoside reverse transcriptase inhibitors or NNRTIs (drugs like efavirenz and nevirapine) share the potential side effects of serious rash, nausea, and vomiting.

The class of protease inhibitors or PIs (drugs like ritonavir, lopinavir/ritonavir, atazanavir, and fosamprenavir) can also cause many side effects. Some of the short-term side effects include diarrhea and nausea or vomiting. Possible long-term side effects include increased cholesterol and triglyceride levels, lipodystrophy (body shape changes), cardiovascular risks, and new or worsening diabetes.

The fusion inhibitor class currently has only one medication in it -- enfuvirtide. The most common side effect is an injection site reaction (ISR) that occurs to some extent in all patients who use it.

It would be easy to think you could expect the side effects common to a class of ARV from any drug in the class, but it's not that simple. Atazanavir, for example, does not share the same lipid-raising profile of its classmates. Likewise, abacavir has the potential for a hypersensitivity reaction (HSR) that the other NRTIs do not, and it appears to be less toxic on the cellular level than some of the others in its class. Similarly, the central nervous system effects (like dizziness, vivid dreaming, and mood changes) associated with efavirenz do not extend to the other drugs in the NNRTI class.

Managing Side Effects

Managing side effects from antiretroviral therapy can sometimes be a difficult task. However, it's important to manage side effects not only because it may make you feel better, but because side effects are a leading cause of treatment non-adherence.

It is possible that a side effect could occur that cannot be managed with additional medications or other supportive measures, which could become intolerable. If that happens, it usually means discontinuing the drug(s) causing the problem and likely making a substitution, with assistance and supervision of your physician.

Some side effects occur with the start of therapy, but will resolve after a couple weeks of continued use. There are other side effects, however, that may need to be managed for the duration of therapy. If that happens, there are steps that you can take to reduce some of the more common ones.

• Nausea and vomiting often resolve without intervention within a few weeks. However, there are things that can be done to help manage these troublesome symptoms. Eating bland foods and small, frequent meals may help. In situations of severe nausea and vomiting, medications like prochlorperazine and ondansetron can also be helpful.
• Diarrhea may seem like it's just a nuisance, but it can be serious if it leads to dehydration. Remember, if you get episodes of diarrhea, it is important to drink lots of fluids in order to stay hydrated. Avoiding caffeinated beverages, alcohol, spicy foods, fried foods, and dairy products may help with diarrhea. Medications like loperamide and diphenoxylate/atropine may also help, as well as psyllium powder and the amino acid L-glutamine.
• Intestinal gas is sometimes produced from certain foods you eat, like beans and vegetable skins. Your intestines need these kinds of fiber, though, so you can talk to your doctor about adding an enzyme called alpha-galactosidase and/or a drug called simethicone. Both are available in over-the-counter products like Beano (alpha-galactosidase) and Gas-X (simethicone). These can help your stomach digest "roughage" better.
• Peripheral neuropathy is commonly caused by some NRTIs, like ddI and d4T. Medications such as ibuprofen and topical creams that contain methyl salicylate may help minor symptoms. For more moderate to severe symptoms, medications like gabapentin or amitriptyline sometimes help.
• Muscle pain may be controlled with medications like acetaminophen and ibuprofen.

Some side effects may only be found with routine lab work. Depending on the severity, these side effects may be managed under physician supervision with either concurrent drug therapy or a change in antiretroviral therapy. Your physician should be monitoring for things such as:

• decreased renal or liver function,
• increased cholesterol or triglyceride levels,
• changes in blood glucose levels, and
• changes in red and/or white blood cell counts.

Please discuss all side effects with your physician before trying to treat them yourself. Sometimes there may be underlying causes of the symptoms that need further evaluation. Also, possible drug interactions between your ARVs and other medications you might be taking need to be considered, even if you're just using a new over-the-counter medication.

Drug Interactions

The topic of drug interactions is extensive and could comprise an entire magazine issue on its own. Every medication, even ones you think are harmless, may cause drug interactions with your current regimen of antiretrovirals.

Here's a common example that I have seen in the pharmacy. A patient experiences heartburn and comes into the pharmacy to purchase Prilosec OTC, the strongest over-the-counter medication for heartburn. The patient just happens to be on ARV therapy that includes atazanavir. The Prilosec OTC may treat the heartburn, but what the patient does not realize is that a simple item like Prilosec OTC decreases the absorption of the atazanavir. This reduction in atazanavir levels in your blood could lead to the development of resistance to atazanavir.

The above example hopefully illustrates the importance of discussing any new medication with your HIV physician or pharmacist. This includes, by the way, any medication started by a physician other than your HIV physician. Providers who do not practice HIV medicine often have little or no HIV-specific knowledge -- so be sure to discuss any new medications with your HIV provider.

There is a constant flow of new information about ARVs and how they work, which makes it especially important to discuss all new medications with your HIV provider. Hopefully, you feel like you can be honest with your doctor about what you take and your doctor knows what to do with the information.

New Drugs and Combinations

For the first time in a while, there are several promising medications in the pipeline of the antiretroviral world and a few that are new to the market. Make sure your doctor is aware of and knowledgeable about newly approved drugs and those in development. This is especially important if the existing treatments are not working for you.

Following are some examples of newly approved drugs and drugs that are currently being studied.

Approved

• Atripla, a combination of efavirenz, tenofovir, and emtricitabine, was approved by the FDA on July 12, 2006. It contains no new medications but it is exciting because it consists of only one pill once daily -- the simplest regimen yet.
• Prezista (darunavir), a new protease inhibitor indicated for people with PI-resistant virus, was approved in June by the FDA. It is taken twice a day and, like most PIs, is boosted by ritonavir. The buzz is that it is supposed to have fewer side effects than currently used PIs, with less potential for resistance.

In Last Stages of Development

• Etravirine is an NNRTI that has shown activity against NNRTI-resistant virus. It is being studied using twice-daily dosing.
• Maraviroc is an entry inhibitor (it blocks the CCR5 receptor on the CD4 cell) that's causing excitement because it represents a new class of antiretrovirals. It adds another option to existing ARV therapy, making it of potential value to people who are treatment experienced. It will likely be taken twice a day with other ARVs.
• MK-0518 is likely to be the first in a whole new class of ARVs -- integrase inhibitors. It is being studied as a twice-daily drug to be taken with other ARVs. The data so far have been very promising, especially for people who are resistant to currently available medications.

Tips

• Go to an HIV specialist for treatment of your HIV. Make sure it is someone with whom you feel comfortable communicating your ideas, thoughts, and concerns. It should also be someone who is on top of the current research and will work to make sure you have access to all available options.
• Make sure you are ready to start therapy before actually starting therapy. Try to build a level of comfort with it.
• Always check with your HIV physician or pharmacist before adding anything new to your regimen, even over the counter medications or nutritional supplements.
• Never stop therapy without discussing it with your HIV physician first.

Melissa Ngo, Pharm.D., is an Ambulatory Clinical Pharmacist at the University of Wisconsin-Madison, where she is the lead pharmacist in the Medication Management Mail Order Service. She has worked in the prison clinic of the UW HIV Care Program and currently serves on its community advisory board. She may be reached at ma.ngo@uwhealth.org.

Resources

AIDS Community Research Initiative of America
In addition to a quarterly treatment newsletter and information on current clinical trials, the AIDS Community Research Initiative of America (ACRIA) offers useful publications on specific topics that can be read on-line or in hard copy. Some examples: Understanding Your Lab Results, Treatment Issues for Women, and Managing Drug Side Effects. Visit www.acria.org.

AIDSInfo
An HIV/AIDS site from the National Institutes of Health (NIH). It contains links to a variety of information, including treatment guidelines, clinical trials, and fact sheets. Call 1-800-HIV-0440 (448-0440). TTY 1-800-480-3739. Outside the U.S. call 301-519-0459. Visit www.aidsinfo.nih.gov.

TheBody.com
The Body is a collection of a huge variety of HIV information from a multitude of sources. It is a virtual "warehouse" of HIV information, which it offers in all kinds of formats -- forums, fact sheets, articles, interviews, conference coverage ... to name a few. Visit www.thebody.com.

Current information from the U.S. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (updated October 10, 2006) for treatment-naïve individuals is as follows:
Clinicians are recommended to construct a regimen by choosing one component from Column A plus one component from Column B
	Column A		Column B
	NNRTI	PI	2-NRTI
Preferred (alphabetical order)	Efavirenz1	Atazanavir + ritonavir Fosamprenavir + ritonavir (twice daily) Lopinavir/ritonavir (twice daily)	Tenofovir/emtricitabine3 Zidovudine/lamivudine3
Alternative (alphabetical order)	Nevirapine2	Atazanavir4 (unboosted) Fosamprenavir (unboosted) Fosamprenavir + ritonavir once daily Lopinavir/ritonavir once daily	Abacavir/lamivudine3 Didanosine + lamivudine3
Except during first trimester of pregnancy or in women with high pregnancy potential Nevirapine should not be initiated in women with CD4+ T-cell count greater than 250 cells/mm3 or in men with CD4+ T-cell count greater than 400 cells/mm3 Emtricitabine and lamivudine are interchangeable Atazanavir must be boosted with ritonavir if used in combination with tenofovir.
Editor's note: Above drug names are generic. Please refer to the Positively Aware January/February HIV Drug Guide for brand names, or visit www.tpan.com. For a full version of the DHHS guidelines, visit www.aidsinfo.nih.gov.