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Gastrointestinal Problems and HIV

The Effect on Treatment Success

Fall 2005

Gastrointestinal (GI) symptoms -- diarrhea, nausea, and stomach pain -- are among the most common problems that affect people with HIV. These symptoms can be challenging to sort out, as they can occur as side effects of HIV therapy and due to GI conditions related and unrelated to HIV. Try not to ignore GI symptoms -- they could be signs of a more serious underlying problem or require treatment for symptom relief.

Make keeping the gut healthy a priority for you and your healthcare provider -- successful HIV therapy depends on it! A healthy GI tract is necessary for proper absorption of medications. And controlling symptoms like nausea and diarrhea will improve your quality of life and help you adhere to your medications, causing better long-term treatment outcomes.

If GI symptoms persist and don't go away with standard therapy, it may be the sign of a more serious problem. Your provider may refer you to a gastroenterologist, a specialist in diseases of the digestive system, including the liver.


Table 1
Food Requirements and HIV Medications

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Use this chart as a guide to determine how to time your HIV medications with meals and, in some cases, with other HIV medications. Talk with your healthcare provider or pharmacist about the correct way to take your medications. Most HIV medications can now be taken with or without food, including Ziagen, Emtriva, Epivir, Zerit, Viread, Combivir, Epzicom, Trizivir, Truvada, Viramune, Rescriptor, and Lexiva. But taking them with food may help avoid GI side effects like nausea that you might experience if you take the medication on an empty stomach

MedicationDietary Recommendations
Nucleoside/tide reverse transcriptase inhibitors (NRTIs)
Videx buffered tablets or powder (buffered ddI, didanosine)Take on an empty stomach (at least ½ hour before or 2 hours after eating).

Buffered Videx shouldn't be taken at the same time as some protease inhibitors (especially Reyataz) or the NNRTI Rescriptor. If your combination includes buffered Videx and one of these drugs, check the amount of time required between taking the two drugs -- it varies a lot.

Videx EC capsule (enteric coated ddI, didanosine)Take on an empty stomach (at least ½ hour before or 2 hours after eating).

Videx EC should be taken with water. It should not be taken with acidic juices, soda, or milk.

Hivid (ddC, zalcitabine)Take with or without food. Taking Hivid with food may reduce stomach upset, but taking it on an empty stomach may improve absorption.
Retrovir (AZT, zidovudine)Take with or without food, but not with a high-fat meal.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Sustiva (efavirenz)Best to take on an empty stomach at bedtime (food raises drug levels and side effects).
Protease inhibitors (PIs)
Agenerase (amprenavir)Take with or without food, but not with a high-fat meal.
Reyataz (atazanavir)Take with a light meal or snack.

Buffered Videx should not be taken at the same time as Reyataz. Take Reyataz (with food) 2 hours before or 1 hour after buffered Videx.

Videx EC capsules aren't buffered and don't cause the same problem. But because Videx EC needs to be taken on an empty stomach, it should also be taken at a different time than Reyataz.

Crixivan (indinavir)Take on an empty stomach if used without Norvir (unboosted), 1 hour before or 2 hours after a meal. A low-fat snack can be eaten during that time. Avoid taking it with grapefruit juice, 1%, 2% or whole milk.

Take with or without food if used in combination with low-dose Norvir.

Kaletra (lopinavir/ritonavir)Take with food (meal or light snack) to increase absorption.
Viracept (nelfinavir)Take with a full meal, ideally one with high-fat content.
Norvir (ritonavir)Low-dose Norvir (often used to boost other protease inhibitors) is best taken with food (meal or light snack) to reduce side effects and increase absorption.
Invirase (hard-gel saquinavir capsules)Take within 2 hours after a meal -- and only with low-dose Norvir.
Fortovase (soft-gel saquinavir capsules)Take within 2 hours after a meal.
Aptivus (tipranavir)Take with a full meal, ideally one with high-fat content.

Adapted from Johns Hopkins University Pocket Guide to Adult HIV/AIDS Treatment by John Bartlett, MD, www.aidsmeds.com, and other sources.


Disorders of the Esophagus

Gastrointestinal Problems and HIV
The GI tract is a long tube with one entrance (the mouth) and one exit (the anus), and problems can occur in any section on the way down. The esophagus is the part of the tube between the mouth and the stomach. The muscles of the esophagus contract and relax to propel food down. A muscular valve at the base of the esophagus closes off the stomach so that its acidic contents can't leak back up into the esophagus.

Heartburn -- a burning sensation behind the center of the ribcage -- occurs when stomach contents travel back up the esophagus. If you experience heartburn, it usually happens thirty to sixty minutes after eating and is sometimes accompanied by a sour taste in the mouth. Heartburn can be prevented by waiting at least three hours after meals to lie down, by elevating the head of the bed or using extra pillows in bed, and by avoiding spicy or acidic foods. Other lifestyle changes to help prevent heartburn include maintaining a healthy weight and avoiding tight belts or pants.

Frequent heartburn is a side effect of some HIV medications. It may also be a sign of gastroesophageal reflux disease, called GERD for short. GERD can damage the lining of the esophagus and lead to other complications. Frequent heartburn should be discussed with your healthcare provider, as inexpensive, over-the-counter treatments are available. Further testing by your provider, including looking down the esophagus with a camera (an upper endoscopy), may be necessary if the symptoms don't go away.

Another symptom related to the esophagus is pain when swallowing or difficulty swallowing. Those symptoms should raise a red flag, especially for people with low immune function (CD4 counts less than 200), as they may be signs of a yeast infection (esophageal candidiasis), cytomegalovirus (CMV), or herpes virus (HSV), each of which requires specific therapy. Left untreated, swallowing problems can have a significant negative impact on medication adherence, nutrition, and, of course, quality of life. Treating AIDS with highly active antiretroviral therapy (HAART) helps to cure esophageal infection and to prevent future infections.

Several medications -- some used to treat HIV and opportunistic infections as well as some used to treat other illnesses and conditions -- may cause direct injury to the lining of the esophagus if the pills get stuck in the esophagus as they travel down. They should always be taken with plenty of water while you're sitting up to make sure that the medications are appropriately washed down.


Stomach Disorders

Gastritis (inflammation of the stomach lining) is a common problem regardless of HIV status. Symptoms of gastritis include stomach pain, nausea, vomiting, decreased appetite, and, in severe cases, vomiting blood. Common causes of gastritis are non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen, major health stress (patients who are sick enough to be in an Intensive Care Unit), heavy alcohol use, and infection with the bacteria H pylori. H pylori doesn't cause problems for most people who have it. And it is no more common in people with HIV than in those without HIV. But the presence of H pylori can negatively affect treatment success for people with HIV.

The breakdown of the stomach or intestinal lining causes an ulcer. Ulcers are extremely common -- 10% of adults have an ulcer at some point in their lives -- and they cause dull or gnawing pain in the upper abdomen. Contrary to popular belief, ulcers occur more frequently in the small intestine than in the stomach, and they are more commonly caused by NSAIDs, excessive acid production, or H pylori infection than by stress or too much coffee. An upper endoscopy is performed to diagnose ulcers, often accompanied by specialized testing for H pylori.

HIV gastropathy, a condition caused by decreased stomach acid secretion, makes affected patients more susceptible to bacterial infections like salmonella and shigella. These bacteria would normally be destroyed by acidic stomach contents. HIV gastropathy also decreases absorption of medications that require an acidic environment, such as Nizoral (ketoconazole) and Sporanox (itraconazole), two commonly-used antifungal drugs. There is no specific test for HIV gastropathy at this time, but your healthcare provider may make certain medication adjustments if he or she suspects this condition, such as switching to other drugs that don't depend on acid for absorption.


Intestinal Disorders

The churning action of the stomach breaks down food to help the absorption of nutrients in the small intestine. Malabsorption and diarrhea from intestinal problems are common in HIV and can result from both infectious and non-infectious causes.

Intestinal opportunistic infections are less frequent now than they were in the pre-HAART era, but people with advanced AIDS can develop Mycobacterium avium complex (MAC) or other bacterial infections of the small intestine. Cryptosporidium, a parasite which causes chronic diarrhea in people with AIDS, other parasites such as giardia and microsporidia, and some viruses can all infect the small intestine. Symptoms of small intestine infection often include upper abdominal cramping, bloating, and nausea, along with diarrhea. Stool and blood tests are necessary to check for infectious causes of diarrhea. When an infection can't be found, the diarrhea may be the result of small bowel bacterial overgrowth or HIV enteropathy -- the direct infection of the intestine with HIV. HIV enteropathy alters the lining of the small intestine, decreasing the area available to absorb nutrients. This condition may also affect drug absorption, although it's difficult to test the effects directly.

Infection in the large intestine has a distinct set of symptoms -- diarrhea with lower abdominal pain, defecating blood, or feeling the need to defecate but being unable to do so. The large intestine is a common site for infection with CMV, HSV, and bacteria like salmonella and shigella. Antibiotic therapy can alter the environment of the gut, allowing for overgrowth of the bacteria clostridium difficile in the large intestine, which causes diarrhea 3-4 times a day.


Table 2
Interactions Between GI Drugs and HIV Medications

This table includes most prescription and over-the-counter medications used to treat common GI conditions. Known interactions between GI drugs and HIV medications (antiretrovirals) are listed. Some medications for GI conditions interact with many other medications used in HIV, including antibiotics and antifungals. Always tell your healthcare provider about all medications you're taking.

Antacids -- For heartburn relief
ExamplesInteractions with AntiretroviralsNotes
Alka-Seltzer* †Some Protease Inhibitors

Rescriptor (delavirdine)

Hivid (ddC, zalcitabine)

Videx buffered tablets (ddI, didanosine)

Antacids reduce stomach acid, which decreases absorption of some antiretrovirals. Don't take antacids at the same time as Rescriptor, Hivid, or the PIs Agenerase, Reyataz, or Aptivus.

Don't take an antacid with buffered Videx -- too much antacid can cause stomach problems.

Bromo-Seltzer* ‡
Maalox*
Mylanta*
Rolaids*
Tums*
Proton-Pump Inhibitors (PPIs) -- For gastroesophageal reflux disease (GERD) and ulcers
ExamplesInteractions with AntiretroviralsNotes
AcipHex (rabeprazole)Reyataz (atazanavir)

Rescriptor (delavirdine)

Sustiva (efavirenz)

Viramune (nevirapine)

PPIs reduce stomach acid, which decreases blood levels of some antiretrovirals -- especially Reyataz and Rescriptor.

The most serious interaction is between PPIs and Reyataz -- PPIs significantly lower Reyataz levels. Do not use a PPI if you're taking Reyataz.

A few studies have looked at interactions between PPIs and some protease inhibitors:

  • Prilosec significantly reduces Crixivan levels, but adding low-dose Norvir increases Crixivan to effective levels. Crixivan hasn't been studied with the other PPIs.

  • One study found that Nexium had no effect on Lexiva levels, but that may not be the case with the other PPIs.

  • A study looking back at Kaletra levels in a few people who were also taking a PPI suggested that PPIs don't seem to affect Kaletra levels. More studies are needed to know whether this observation holds up.

If you take a PPI and any protease inhibitor, monitor antiviral activity closely.

Sustiva and Viramune speed up the metabolism of AcipHex and Prevacid, which may decrease their effectiveness against GERD/ulcers.

Nexium* (esomeprazole)

Reyataz (atazanavir)

Rescriptor (delavirdine)

Prevacid* (lansoprazole)Reyataz (atazanavir)

Rescriptor (delavirdine)

Sustiva (efavirenz)

Viramune (nevirapine)

Prilosec* (omeprazole)Reyataz (atazanavir)

Rescriptor (delavirdine)

Crixivan (indinavir)

Protonix (pantoprazole)Reyataz (atazanavir)

Rescriptor (delavirdine)

H2 Blockers -- For gastroesophageal reflux disease (GERD) and ulcers
ExamplesInteractions with AntiretroviralsNotes
Axid* (nizatidine)Reyataz (atazanavir)

Rescriptor (delavirdine)

H2 blockers reduce stomach acid, which decreases absorption of some antiretrovirals.

Unless you're also using low-dose Norvir, don't take Axid, Pepcid, or Zantac at the same time as Reyataz. Take Reyataz as far apart from any of these drugs as possible -- ideally 12 hours apart.

Tagamet raises levels of some PIs, so watch for increased side effects if you take Tagamet and a PI.

Pepcid* (famotidine)Reyataz (atazanavir)

Rescriptor (delavirdine)

Tagamet* (cimetidine)Some Protease Inhibitors

Rescriptor (delavirdine)

Zantac* (ranitidine)Reyataz (atazanavir)

Rescriptor (delavirdine)

Anti-Diarrheals
ExamplesInteractions with AntiretroviralsNotes
Imodium* (loperamide)No significant interactions
Loperamide (prescription strength)No significant interactions
Lomotil (diphenoxylate/atropine)No known interactions
Kaopectate*No known interactions
Tincture of opiumNo known interactions
Pepto-Bismol*No known interactions
Metamucil* (psyllium)No known interactionsStool bulking agent
Ultrase and Pancrease
(pancreatic enzymes)
No known interactionsTake antacids and Pancrease or Ultrase at least 2 hours apart.
Anti-Nausea/Vomiting
ExamplesInteractions with AntiretroviralsNotes
Compazine (prochlorperazine)Kaletra (lopinavir/ritonavir)

Norvir (ritonavir)

Certain medications used to treat nausea and vomiting interact with some antiretrovirals. Dose adjustments may be necessary to avoid drug interactions.
Emetrol* (cola syrup)No known interactions
Phenergan (promethazine)Rescriptor (delavirdine)

Kaletra (lopinavir/ritonavir)

Viramune (nevirapine)

Norvir (ritonavir)

Reglan (metoclopramide)No known interactions
Thorazine (chlorpromazine)Rescriptor (delavirdine)

Kaletra (lopinavir/ritonavir)

Norvir (ritonavir)

Torecan (thiethylperzaine)No known interactions
Zofran (ondansetron)Sustiva (efavirenz)

Viramune (nevirapine)

Used for chemotherapy-associated nausea and vomiting; sometimes used in HIV.

Dose adjustment may be necessary to avoid drug interactions.

Promotility Agent -- For severe GERD, unresponsive to other therapies
ExamplesInteractions with AntiretroviralsNotes
Propulsid (cisapride)

Limited availability in the U.S.

Protease Inhibitors

Non-Nucleoside Reverse Transcriptase Inhibitors

PIs and NNRTIs increase Propulsid levels, which can lead to fatal changes in heart rhythms. Do not use Propulsid with any PI or NNRTI.
Appetite Stimulant
ExamplesInteractions with AntiretroviralsNotes
Marinol (dronabinol)No known interactionsMarinol contains synthetic THC, the active ingredient in marijuana. Rescriptor and some protease inhibitors might increase Marinol levels, which would make you feel more stoned, but no information on such interactions is available.
Megace (megestrol acetate)No significant interactions

* Available over-the-counter; † Alka-Seltzer also contains aspirin; ‡ Bromo-Seltzer also contains Tylenol (acetaminophen)


Anorectal Infections

Anorectal infections -- infections in the anus or rectum -- include gonorrhea, syphilis, and herpes. Unprotected anal sex also transmits human papilloma virus (HPV), which causes anal warts and, in some cases, anorectal cancer. An anal Pap smear, similar to the Pap smear done to screen women for cervical cancer, is used to screen for anal cancer.


Gastrointestinal Cancers

Two gastrointestinal cancers are associated with HIV -- Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma. KS most often occurs in late-stage AIDS. Most people are familiar with the skin lesions of KS, but the disease can also affect the GI tract, the lungs, and other organs. KS may cause GI bleeding or malabsorption, but symptoms are rare, even though up to three-quarters of KS patients have it in their GI tract.

Non-Hodgkin's lymphoma may occur at any stage of HIV disease and may be heralded by abdominal pain, weight loss, diarrhea, or a blockage of the intestine as well as enlarged lymph nodes. Lymphomas generally start in the lymph nodes when cancerous immune cells crowd out the healthy cells. The disease can start in the GI tract or spread there from lymph nodes. Treatment options include surgery, chemotherapy, or radiation.

Colon (large intestine) cancer is the second leading cause of cancer death in the United States, behind lung cancer. Most cases of colon cancer occur in people age 50 or older. As people with HIV live longer in the era of HAART, screening for colon cancer should be performed. After age 50, a test for blood in the stool (fecal occult blood testing) should be performed every year, with a colonoscopy (examination of the colon using a tiny camera in a long flexible tube) at least every 10 years.


Medication Side Effects

Overall, effective HIV treatment improves GI disease by improving immune function and decreasing opportunistic infections. However, GI symptoms are common side effects of antiretrovirals, especially early in treatment. The best way to handle side effects is to know what to expect from each of the medications you're prescribed and to have relief readily available before taking them.


Diarrhea

If you have persistent diarrhea, your provider will run tests to rule out some of the infections described above. HIV medication may be the only culprit, however. Some of the protease inhibitors, especially Viracept (nelfinavir), are notorious for causing diarrhea. The good news is that diarrhea often improves two to four weeks after starting the medication, and your provider can suggest anti-diarrheal treatment in the meantime to help you out. You can also try some non-pharmaceutical interventions to decrease diarrhea. The most basic is dietary modification -- your provider may recommend that you leave out dairy, wheat products, and sugar. If you have long-term diarrhea and no infection or dietary intolerance is identified, work with your provider to control the symptoms as much as possible.


Nausea

Likewise, many HIV medications can cause nausea and vomiting. Nausea can get in the way of good adherence. Quite simply, if you don't feel well enough to take your pills, you might skip them. Most protease inhibitors and nucleoside reverse transcriptase inhibitors, especially Retrovir (zidovudine), can cause these symptoms, but, again, they usually go away within a few weeks. Nausea from protease inhibitors can be relieved somewhat by boosting them with low-dose Norvir (ritonavir) to decrease the overall number of pills.

Another strategy to reduce nausea is to take your medications with food. Check with your provider or pharmacist to see which drugs can be taken with food. (See Table 1 above.) Other tips to reduce nausea include eating small, frequent meals, eating bland food, sipping ginger ale, and smelling a slice of lemon. If nausea causes you to lose your appetite or otherwise interferes with adherence or your quality of life, there are medications to help with your symptoms.


Listening to the GI Tract: Clues to Three Dangerous Toxicities of HIV Medications

The medication side effects described above can get in the way of good adherence and may disrupt your daily life. But there are some toxicities associated with HIV medications that can be life-threatening. Your first clue to these serious problems may be GI symptoms, so your best bet is to report any and all GI side effects to your provider.


Lactic Acidosis

Lactic acidosis is a condition associated with NRTIs, especially Videx (didanosine) and Zerit (stavudine), but Retrovir as well. NRTIs damage mitochondria, which are inside all human cells and use oxygen, fat, and sugar to produce energy for the cells. Mitochondrial damage leads to excess lactate production, which drives up the level of lactic acid in the blood. Lactic acidosis is more common in women, and it may be accompanied by liver abnormalities, including fatty liver. Symptoms of lactic acidosis may include decreased appetite, nausea, vomiting, or abdominal pain, although many people who experience the condition may not experience or notice the symptoms right away. Your provider can run tests to check the level of lactate in your blood if he or she suspects lactic acidosis.


Pancreatitis

Some HIV medications can cause pancreatitis, an inflammation of the pancreas that is life-threatening. This condition most frequently occurs with Videx (especially if it's used with Zerit, which it shouldn't be), Bactrim, and pentamidine (used to prevent Pneumocystis pneumonia [PCP]). Pancreatitis can cause abdominal pain which radiates to the back and is worst after eating, sometimes accompanied by nausea and vomiting.


Hepatic Necrosis

Viramune (nevirapine) has caused cases of sudden liver failure (hepatic necrosis), particularly during the first four and a half months on the drug. Although this is a very rare occurrence, people most at risk include women starting their first combination with CD4 counts above 250, men starting their first combination with CD4 counts above 400, pregnant women, and people with chronic hepatitis B or C infection. Early symptoms are often flu-like, including nausea, vomiting, muscle ache, and fatigue, followed by stomach pain, jaundice (skin turning yellow), and fever, with or without a rash.


Better Treatment Outcomes With a Healthy GI Tract

GI symptoms in HIV are extremely common and can have a profound effect on treatment outcome. Symptoms like nausea and diarrhea affect quality of life and can make adherence a challenge, while changes in absorption can make some HIV drugs much less effective. Keep your healthcare providers informed of your symptoms and try different interventions to reduce them. Many over-the-counter and prescription drugs are available to relieve GI symptoms and treat infections of the GI tract. Some of these drugs interact with HIV medications, so be sure to talk with your provider and pharmacist about any drugs that you're taking or considering. (See Table 2 above.) By minimizing the impact of symptoms -- and investigating the possibility of GI infections -- you have a better shot at long-term treatment success.

Anne Monroe, M.D., is an Internal Medicine resident with a longstanding interest in HIV treatment and clinical trials. A Virginia native, she is a graduate of the University of North Carolina at Chapel Hill and the SUNY Stony Brook School of Medicine. Prior to medical school, she was a study coordinator for HIV clinical trials at New York Presbyterian Hospital. She currently resides in Miami, where she is training at Jackson Memorial Hospital and pursuing her Masters in Public Health.


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