The article "A PK Primer," describes how our bodies process drugs and our growing understanding of pharmacokinetics. Just as our bodies absorb and process HIV medications (antiretrovirals), they absorb and process other substances as well.
The way that one drug is absorbed, broken down (metabolized), or eliminated from the body can affect the way another drug or other substance is absorbed, metabolized, or eliminated. This is called a drug interaction. Most interactions are harmless, some require adjustments of the dose of one of the drugs to avoid harmful effects, some are dangerous, and a few are beneficial.
Effective HIV treatment requires having enough of each of your antiretrovirals in your system to effectively lower viral load and hopefully increase CD4 counts without causing severe side effects. If a drug (or drugs) that you're taking lowers the levels of an antiretroviral in your system, the effectiveness of your HIV treatment could be severely compromised. Similarly, some drugs can increase the levels of an antiretroviral in your system, which can increase the risk and severity of side effects. It can work the other way around as well -- an antiretroviral can decrease or increase the levels of other drugs you take, possibly decreasing their effectiveness or increasing their side effects.
Interactions that might affect your health -- and your HIV treatment -- can occur between:
- Two or more HIV medications;
- An HIV medication and another prescription drug;
- An HIV medication and a recreational or illegal drug;
- An HIV medication and an over-the-counter (non-prescription) drug;
- An HIV medication and an herbal product or supplement;
- An HIV medication and food; or
- Two or more drugs not specific to HIV.
The Role of the Liver
Drugs are metabolized -- chemically process them for elimination from the body -- primarily in the liver, although your kidneys also play a role. The liver breaks down different drugs using specific systems of enzymes. Many drugs are broken down by the same enzymes, so this is where interactions usually occur.
If two drugs compete for the same enzymes to break them down, one might be metabolized too quickly, reducing drug levels in your blood and making it less effective. If it's an HIV drug, low drug levels could lead to an increase in viral load and the development of resistance to that drug (and perhaps to others in its class). Another interaction might cause a drug to be metabolized too slowly. You could end up with too high a concentration of the drug in your system because it's being metabolized too slowly. Depending on the drug, this could cause an overdose and even be fatal. If two drugs interact to make one or both drugs ineffective or dangerous, the combination is considered to be contraindicated -- they should not be taken together.
Although the liver is able to break down many drugs at once, there's a limit as to how many drugs can be metabolized within a certain amount of time if the drugs require the same system of enzymes. Think of it as two or more trains approaching a railroad tunnel. Only one train can pass, while the other train (or trains) has to wait. This is something like what can happen in the liver, and drug interactions can be the result.
It might also be useful to think of the liver as a funnel -- or many funnels, with funnels within funnels. The following are possibilities of taking two drugs at once, both competing for the same funnel or enzyme system to be properly metabolized:
- Levels of one or both drugs could increase in your system;
- Levels of one or both drugs could decrease in your system;
- Levels of one drug could increase in your system and levels of the other drug could decrease;
- Levels of one drug could increase in your system while the other drug could remain at effective levels;
- Levels of one drug could decrease in your system while the other drug could remain at effective levels; or
- Both drugs could remain at effective levels in your system.
The above example involves only two drugs. Some people with HIV take 10 or more different medications each day, for HIV and for other conditions. The more drugs or other substances you take, the more likely it is that drug interactions can occur. Breaking down drugs properly gets trickier if your liver is damaged due to chronic hepatitis B or C, long-term alcohol use, or for any other reason. If you have liver or kidney damage, your provider may need to adjust the dose of some HIV drugs.
|FDA-Approved Antiretrovirals for the Treatment of HIV|
|Nucleoside Reverse Transcriptase Inhibitors (NRTIs, nucleoside analogs or nukes):|
|Videx (didanosine, ddI) -- buffered tablets and|
enteric-coated capsules (Videx EC)
|Epivir (lamivudine, 3TC)|
|Zerit (stavudine, d4T)|
|Hivid (zalcitabine, ddC)|
|Retrovir (zidovudine, AZT)|
|Nucleotide Reverse Transcriptase Inhibitor|
| Combination formulations:|
|Combivir (Retrovir & Epivir combined in one pill)|
|Epzicom (Epivir & Ziagen combined in one pill)|
|Trizivir (Retrovir, Epivir & Ziagen combined in one pill)|
|Truvada (Viread & Emtriva combined in one pill)|
|Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs, non-nucleosides or non-nukes):|
* Fortovase will no longer be available early in 2006.
Examples of Interactions by HIV Drug Class
The table above lists the drugs approved to treat HIV by class. The drugs in each class have similarities, particularly in how they interfere with HIV reproduction. Most drugs in a class can cause some similar side effects, and some drug interactions are common within each class of antiretrovirals. But there are also significant differences between individual drugs in each class.
To list every possible interaction between HIV medications and other substances would require a book many times the length of this magazine. The following describes examples of specific interactions between HIV medications and other drugs or substances. This is by no means a comprehensive list of interactions.
Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs)
Two NRTIs, combined with a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI), make up what is often referred to as the backbone of combination therapy. Generally, the NRTIs work well together, although there are exceptions. Compared to the PIs and NNRTIs, the NRTIs have relatively few drug interactions because of the way our bodies process them. Select examples:
- Some NRTIs shouldn't be used together because they're antagonistic, meaning that they don't work well together in the body. Retrovir and Zerit should never be used together, for example.
- Some NRTIs shouldn't be used together because they can cause the same side effects. NRTIs that shouldn't be combined for this reason include Zerit and Hivid, Videx and Hivid, and, most significantly, Videx and Zerit.
Zerit, Videx, and Hivid can all cause peripheral neuropathy (painful tingling in the hands and/or feet that's sometimes irreversible). The risk of developing peripheral neuropathy and, with Videx plus Zerit, pancreatitis and high lactate levels in the blood as well, are greatly increased.
- Ribavirin, which is used as part of hepatitis C treatment, ideally shouldn't be used with Videx. Ribavirin significantly increases Videx levels, which can severely worsen Videx side effects. If Videx needs to be part of your HIV regimen while you're on HCV treatment, be sure that you're monitored closely for any Videx-related toxicities (peripheral neuropathy, high lactate levels, and pancreatitis). If any signs or symptoms of these conditions develop, Videx should be stopped immediately.
- Methadone seems to significantly decrease the absorption of Videx buffered tablets. If you're on methadone, the amount of Videx getting into your system may not be enough to do its job, possibly leading to the development of resistance. Rather than increasing the dose of Videx buffered tablets, it's probably best to switch to Videx EC, the more commonly used capsule version of the drug. Methadone doesn't seem to interact with Videx EC.
- Viread, the only nucleotide reverse transcriptase inhibitor approved to treat HIV, has some significant interactions with other HIV medications. Viread increases levels of Videx in the body, which can increase the risk of Videx side effects. Many providers avoid this combination completely. If the two drugs must be used together due to a lack of other options, the Videx dose should be reduced to 250 mg a day.
Viread also interacts significantly with the PI Reyataz. Combining these two drugs causes a significant decrease in Reyataz levels and a significant increase in Viread levels. If Reyataz is taken with Viread, low-dose Norvir (another PI) should be used to boost the level of Reyataz in your bloodstream. Kidney damage is a possible side effect of Viread, so blood tests to monitor kidney function should be performed regularly due to the increased levels of Viread.
Viread can also interact with Kaletra, a PI that contains lopinavir and low-dose Norvir (ritonavir). If Viread and Kaletra are combined, Viread can significantly decrease lopinavir levels, and Viread levels can increase. As with the combination of Reyataz and Viread, kidney function should be monitored regularly.
- Only one NRTI, Videx, has a significant dietary restriction due to an interaction with food. Videx buffered tablets and Videx EC capsules need to be taken on an empty stomach for proper absorption. (See Table 1 in "Gastrointestinal Problems and HIV" in this issue.) And Videx buffered tablets shouldn't be taken at the same time as other medications.
Two or more NRTIs combined in one pill (Combivir, Epzicom, Trizivir, and Truvada) allow you to take fewer pills each day. If one of these combination formulations is part of your regimen, be aware of the drugs that it contains. They can cause the same interactions as if you were taking each drug the combination pills contain separately.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
The three available NNRTIs have little in common except for the way that they block HIV replication, similar resistance profiles, and some shared side effects, notably rash. Otherwise, the potential side effects and drug interactions of the NNRTIs vary a lot. Of the three, Rescriptor is rarely prescribed. Rescriptor interactions are more like those of the protease inhibitors than those of the other NNRTIs. Select interaction examples:
- Sustiva and Viramune both interact with methadone, significantly decreasing methadone levels in your blood. This could make you feel as though your HIV meds are "eating" your methadone. The degree of the decrease varies from person to person. Some people experience as much as a 50% decrease in methadone levels, creating feelings of serious withdrawal. Other people experience no or very little decrease. To be effective, your methadone dose may need to be raised gradually 8 to 10 days after starting a combination that includes Sustiva or Viramune.
- Some drugs used to treat or prevent opportunistic infections interact with Sustiva, Viramune, or both. Using many of these drugs with Rescriptor can cause even more serious interactions.
Tuberculosis: Rifampin decreases Sustiva levels enough in some people that a higher dose of Sustiva may be needed. Rifampin decreases Viramune levels so much that the two drugs should not be used together. Sustiva decreases Mycobutin (rifabutin) levels, requiring a higher dose of Mycobutin. Mycobutin can decrease Viramune levels, but not enough to require a dose change. Priftin (rifapentine) should not be used with either Sustiva or Viramune (or any protease inhibitor, for that matter).
MAC (Mycobacterium avium Complex): Both Sustiva and Viramune significantly decrease levels of Biaxin (clarithromycin) in the blood, and Biaxin can increase Viramune levels. Using an alternative to Biaxin, such as Zithromax (azithromycin), may be the best option.
Thrush: Combining Viramune and Nizoral (ketoconazole) causes a two-way interaction: Nizoral levels decrease in the bloodstream, while Viramune levels increase. These drugs should not be used together. Vfend (voriconazole), another antifungal sometimes used to treat thrush, should not be used with Sustiva because of a two-way interaction that's even more pronounced than the one between Viramune and Nizoral.
- Some people are on multi-drug regimens that include an NNRTI and a PI. Sustiva and Viramune both significantly reduce levels of the PIs Reyataz, Agenerase, Lexiva, Crixivan, Kaletra, Fortovase, and Invirase. Viramune also reduces levels of Norvir and Aptivus. These interactions can lead to ineffective levels of the protease inhibitors in your bloodstream. To counter the interaction, the dose of the protease inhibitor may need to be increased or, when appropriate, low-dose Norvir may need to be added to boost levels of the PI. This latter strategy isn't an option with PIs that are already taken with low-dose Norvir (Reyataz, Lexiva, Crixivan, Fortovase, Invirase, and Aptivus).
Rescriptor can increase blood levels of almost all of the PIs, so the PI dose may need to be decreased. An exception is Aptivus, which seems to reduce Rescriptor levels so significantly that the two drugs should never be used together.
Protease Inhibitors (PIs)
The PIs block a later stage in the HIV reproduction process than the NRTIs and NNRTIs. To varying degrees, they're associated with certain long-term side effects, including increased blood sugar levels, insulin resistance, and high cholesterol and triglyceride levels. PIs come with a long list of drug interactions -- between each other, with NNRTIs, and with many drugs used to treat other conditions. Select examples:
- Because of the way that Norvir is broken down by the liver, it can cause more interactions than any other antiretroviral. Although interactions between Norvir and many other drugs can be harmful, taking a low dose of Norvir with most of the PIs can increase -- or boost -- blood concentrations of the primary PI. Boosting another PI with low-dose Norvir can mean lower and less frequent dosing and better treatment outcomes. Kaletra capsules contain the active drug, lopinavir, and a small amount of Norvir. By itself, lopinavir is a relatively weak drug, but the Norvir boosts the lopinavir, making Kaletra an effective and commonly used PI. Every other approved PI except for Viracept can (or needs to) be taken with low-dose Norvir.
- Many people with HIV have high cholesterol, and the higher your cholesterol, the higher the likelihood of developing heart disease. Providers often prescribe drugs called statins to lower LDL (low density lipoprotein) -- "bad" cholesterol -- to offset this problem. Some statins interact considerably with PIs and some of the NNRTIs. Zocor (simvastatin) and Mevacor (lovastatin) should not be used if you're on a PI or NNRTI because statin levels increase so much. If Lipitor (atorvastatin) is used, careful monitoring is necessary because the PIs and NNRTIs can increase Lipitor levels. If you take Lipitor, start with a very low dose, have your cholesterol carefully monitored and, if necessary, slowly increase the dose. Of the statins, Pravachol (pravastatin) and Lescol (fluvastatin) seem least likely to interact with most of the PIs and NNRTIs.
- Kaletra reduces methadone levels significantly enough to require an increase in some people's methadone dose to avoid withdrawal. The reduced methadone levels seem to be caused by the lopinavir in Kaletra rather than by the small amount of Norvir the capsules contain.
- Proton-pump inhibitors (PPIs) are taken for the prevention and treatment of heartburn and other symptoms of gastroesophageal reflux disease (GERD). (See "Gastrointestinal Problems and HIV" in this issue.) PPIs can be helpful, but, by changing the acidity in the stomach, they can decrease levels of some protease inhibitors in the blood, making the PI less effective. A specific example is the interaction between Reyataz and the PPI Prilosec (omeprazole).
When a previously unknown, unappreciated or unexpected serious side effect or drug interaction is identified, the company that markets the drug is required to work with the Food and Drug Administration and send out a letter to doctors around the country informing them of the new or expanded information. In December 2004, Bristol-Myers Squibb, the manufacturer of Reyataz, had to do just that based on a study of the interaction between Reyataz and Prilosec. In the study of HIV-negative participants, Reyataz was taken with a light meal, two hours after Prilosec was taken on an empty stomach. Reyataz levels were decreased so much that if the two drugs were taken by people with HIV, Reyataz would be ineffective, increasing the chance of developing resistance. Even increasing the Reyataz dose or combining it with low-dose Norvir didn't help. As a result, the combination of Reyataz and Prilosec is contraindicated, and using any PPI while you're taking Reyataz isn't recommended.
As far as we know, most of the other PIs and the NNRTIs can safely be used with PPIs, but close monitoring of your anti-HIV response is strongly recommended if you're taking a PPI regularly.
Some PPIs, including Prilosec, Nexium (esomeprazole), and Prevacid (lansoprazole) are available over the counter. Be aware that some OTC medications can cause serious interactions just as some prescription drugs can.
- Two sedatives interact severely with all of the PIs and two of the NNRTIs -- Halcion (triazolam), used for insomnia, and Versed (midazolam), an anesthetic. Taking either of these drugs with a PI or the NNRTIs Rescriptor or Sustiva could lead to a dangerous, life-threatening interaction. Halcion and Versed levels can increase so much that serious sedation could be the result, possibly leading to coma or death. Using Halcion or Versed with any of these antiretrovirals is contraindicated.
- Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil) are used to help men get and keep an erection. The three medications have similar interactions with some other drugs. Protease inhibitors increase blood concentrations of Viagra, which raises the possibility of severe side effects -- extremely low blood pressure, dizziness, fainting, vision changes, and prolonged erection (meaning hours, not a good thing).
Among the PIs, Norvir increases Viagra concentrations the most, while Fortovase and Invirase seem to have the least effect. The NNRTI Rescriptor also increases Viagra levels, as do many other drugs. Levitra and Cialis cause similar interactions with these drugs. Taking a lower dose of Viagra, Levitra or Cialis -- and taking the drug less often -- may help you avoid a possibly dangerous interaction.
- Very few studies have looked at interactions between herbal preparations and antiretrovirals. One study looked at potential interactions between St. Johns wort (hypericum), an herb often used to treat depression, and Crixivan. St John's wort significantly lowered Crixivan concentrations. Because of this study, taking St. Johns wort with any PI or NNRTI is strongly discouraged. Combining the two may significantly lower blood levels of the antiretroviral, making it much less effective against HIV and could lead to the development of resistance to the antiretroviral.
Garlic supplements, sometimes used by people to try to lower their cholesterol, were studied with Fortovase to look for potential interactions. Study participants took high doses of garlic supplements, and their blood levels of Fortovase decreased significantly. High-dose garlic supplementation could be a problem if you're taking either Fortovase or Invirase, but the much lower amount of garlic used in cooking and as seasoning isn't likely to cause the same effect.
- Ethinyl estradiol, the main ingredient in most birth control pills, interacts with many antiretrovirals. The PIs Kaletra, Viracept, Norvir, and Aptivus and the NNRTI Viramune decrease the amount of ethinyl estradiol in the bloodstream to varying degrees. If you're taking one of these drugs, use at least one additional method of non-hormonal contraception to avoid pregnancy (condoms or an IUD, for example).
The PIs Reyataz, Crixivan, and Lexiva and the NNRTIs Rescriptor and Sustiva increase levels of ethinyl estradiol in the bloodstream to varying degrees. These increased levels could cause hormone-related side effects. Since antiretrovirals are taken in combination, it's safest to use alternative or additional methods of birth control if you're taking any PI or NNRTI.
Lexiva not only increases ethinyl estradiol levels, but ethinyl estradiol decreases levels of Lexiva, possibly leading to sub-therapeutic levels of the PI. To be safe, don't take birth control pills that contain ethinyl estradiol or norethindrone with Lexiva.
Fuzeon is the only drug approved in this class so far. Only a few Fuzeon interaction studies have been conducted to date -- with Norvir, with Fortovase plus low-dose Norvir, and with rifampin, used to treat TB. No noteworthy interactions occurred in these studies. Because of the way that Fuzeon is administered (by injection) and metabolized, interactions between Fuzeon and other approved antiretrovirals, food, herbs or other drugs are unlikely.
Many of us assume that if something's natural, it must be safe. That's often true, but herbs, like most substances, are metabolized in the liver. And many herbals use the same enzyme systems in the liver as HIV drugs do, which could result in harmful interactions. Unfortunately, there isn't a lot of research about interactions between herbals and HIV drugs. Before taking an herbal product, you might want to talk to your healthcare provider or pharmacist. They may have access to information about the product that you don't. But be prepared. Many healthcare providers are unfamiliar with herbal therapies and may dismiss the idea due to their lack of familiarity and a sense of discomfort. But don't give up!
If you choose to take an herbal product, a useful though time-consuming course of action is to try to evaluate the quality of the herbal product or supplement. If you're considering a supplement sold by a particular company, you could search the Internet to find the contact information for companies that manufacture and sell the product, ask the companies how it's made (including the complete contents), and how the quality of their product is assured (quality control). It may be a red flag if the manufacturer doesn't respond to your request, and it's probably a signal to move on.
Personal Empowerment Strategies
Information about drug interactions is constantly updated as new interactions are discovered thanks to further studies and anecdotal (word-of-mouth) reports. You may want to talk with your healthcare provider or pharmacist regularly about updated information and ask questions about interactions with the drugs you're taking.
Providers, pharmacists, and researchers may not be familiar with the interactions of a new drug at first. Aptivus, the protease inhibitor approved in June, is a case in point. Like other PIs, it can cause many drug interactions. Some of these interactions are known -- either due to studies that have been conducted or because of our understanding of how it's absorbed, distributed, and metabolized. But there's still much to be learned about potential interactions with Aptivus, and it will take time for further studies to be conducted and completed before we have more complete information.
Many over-the-counter (OTC) products contain drugs that you might not expect. For example, some Alka-Seltzer products contain Tylenol (acetaminophen). If you have a cold and take an Alka-Seltzer cold preparation along with Tylenol or other pain-relievers that contain acetaminophen, you'd have high levels of acetaminophen in your system. The maximum dose of acetaminophen (4 grams a day) is safe for people without liver problems, but high doses can cause serious liver disease and could affect the liver's ability to properly break down your HIV drugs. Be sure to read the list of ingredients listed on the packages of OTC products.
Finally, when you're prescribed a new medication, read all you can about it, including its possible interactions with other substances. A good place to start is the drug's package insert (the papers attached to the bottle the pharmacist uses to dispense your medications). You can read the package insert on the Internet or ask your pharmacist for a copy. The more you're aware of potential drug interactions, the better prepared you'll be to avoid or address them.
This article isn't intended as a description of every potential interaction between antiretrovirals and other substances -- and it definitely isn't. Hopefully, the examples cited give you a better sense of the kinds of interactions that can occur. The resources listed in this issue can help you take a more active role in your health and treatment by learning about interactions that might affect you. If you're going to endure treatment's ups and downs, why not make it work as well as it can for you?
Joel L. Zive, R.Ph., Pharm.D. is vice president of Zive Pharmacy in the Bronx. He lectures nationally and internationally on various pharmacy topics. He is a member of numerous pharmacy organizations and Executive Director of Prescription for Hope (www.rxforhope.org), a nonprofit organization dedicated to understanding developing countries' pharmacy dispensing and drug distribution systems and building dispensing pharmacies in these countries to help people with HIV.
James Learned is guest editor of this issue of Positively Aware. We thank Jerome Ernst, M.D. for his review.