Joyce K.

Anastasi, PhD, DrNP, RN, FAAN Bernadette Capili, DNSc, NP-C

Nausea and Vomiting in HIV/AIDS

ABSTRACT
HIV infection has become a chronic illness with the availability of potent antiretroviral agents. Many of the agents used to manage HIV, however, have been associated with distressing symptoms such as nausea and vomiting posing challenges to maintain adherence to therapy and quality of life. This article highlights the mechanism, evaluation, and management of HIV-associated nausea and vomiting. Supportive symptom management information is also presented.

he disease process and clinical management of HIV have changed tremendously over the past 15 years. With the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, AIDS defining diseases and mortality rates have rapidly declined (Mocroft et al., 2002). HIV infection is now considered a chronic and manageable disease; however, there are groups of individuals in which these regimens are less effective for various reasons including late initiation of HAART with severely compromised immune systems, nonadherence to medications, viral resistance to prescribed agents, and inability to tolerate side effects associated with treatment regimens (Karus et al., 2005). Post-HAART, the etiology of gastrointestinal (GI) symptoms commonly experienced in HIV like nausea and vomiting (NV) has also changed with improved immune function. Prior to HAART, the etiology of NV was largely caused by opportunistic infections like Toxoplasma gondii, cryptococcal meningitis, and

Received March 8, 2010; Accepted June 6, 2010. About the authors: Joyce K. Anastasi, PhD, DrNP, RN, FAAN, is the Independence Foundation Endowed Professor, and Director of the Division of Special Studies in Symptom Management, New York University, New York. Bernadette Capili, DNSc, NP-C, is Assistant Professor of Nursing, and Associate Director of the Division of Special Studies in Symptom Management, New York University, New York. Correspondence to: Joyce K. Anastasi, PhD, DrNP, RN, FAAN, Special Studies in Symptom Management, New York University, 380 Second Avenue, 3rd Floor, Suite 305, New York, NY 10010 (e-mail: ja2188@nyu.edu). DOI: 10.1097/SGA.0b013e31820b256a

esophageal candidiasis, and the symptom prevalence was reported to be as high as 50% (Mathews et al., 2000). Nausea and vomiting are now most likely multifactorial in origin, attributable to medication side effects, overlapping drug interactions, gastroparesis, or opportunistic infections in cases of poor immune status (Karus et al., 2005). Nearly all HIV medications, with the exception of enfuvirtide (fusion inhibitor), because it is administered via subcutaneous injection, can cause NV. Results from a post-HAART multicenter study found that NV are still prevalent and ranged from 42% to 57% for nausea and 28% to 32% for vomiting. The proportion rating NV as severe and distressing ranged from 26% to 40% for nausea and 8% to 40% for vomiting (Karus et al., 2005). Currently, the symptoms of NV are the most frequently cited reason for discontinuing or not adhering to HAART regimens (Carr & Amin, 2009). Clearly, NV is still a common symptom experienced in HIV and nurses will likely encounter patients with HIV experiencing these symptoms in clinical practice. This article will review the mechanisms associated with NV and the diagnosis and treatment management of NV in HIV.

Mechanisms Associated With Nausea and Vomiting

Several mechanisms can lead to NV in HIV; NV can result from multiple causes at once (Shelke, Mustian, & Morrow, 2004).

Medication-Induced
In the era of HAART, medication-induced NV are more common than those caused by opportunistic infections.
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Nausea and Vomiting in HIV/AIDS

Medication-induced NV in HIV generally occur during the first few days of initiating a new HIV medication and may subside after a few days or after several weeks. The symptoms may also lessen in intensity and frequency over time (Carr & Cooper, 2000), but in some cases, nausea can become chronic (defined as symptoms persisting for greater than 1 month) (Parkman, 2002). If NV are attributed to HAART, patients may manage the symptoms on their own by reducing or skipping doses, may ultimately terminate therapy, or avoid initiating it at all (Reynolds & Neidig, 2002). Gastrointestinal side effects of HAART, especially nausea, are correlated significantly with nonadherence or premature discontinuation of therapy (Carr & Amin, 2009). With decreasing levels of adherence, therapy failure rates increase (Johnson, Stallworth, & Neilands, 2003) and can result in viral replication, increasing the risk of viral mutation and development of resistance to one or an entire class of antiretroviral agent(s) (Carpenter et al., 2000). Nausea and vomiting are not only distressing and uncomfortable, but severe or chronic NV can have serious consequences, including malnutrition, dehydration, electrolyte imbalance, severe weight loss, esophageal tear, and deterioration in physical functioning (Thomas & Mkandawire, 2006). Because patients are now living well into middle and older age, they are also experiencing typical age-related diseases that are managed with additional medications (Sherr et al., 2009); it has been theorized that medication-related side effects appreciate as polypharmacy increases (Karus et al., 2005). Nausea is a known side effect of many HIV agents (Bonfanti et al., 2000). Most nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) can cause GI problems including nausea, vomiting, and diarrhea (National Association of People with AIDS [NAPA], 2008) (see Table 1). The NRTIs most highly associated with NV are zidovudine and didanosine (Carr & Cooper, 2000), although all agents in this class can induce NV. It is important to note that didanosine is rarely used now because of recognized risk of noncirrhotic portal hypertension (Food & Drug Administration, 2010). Protease inhibitors are also commonly associated with NV (Lucas, Chaisson, & Moore, 1999); ritonavir is an agent notorious in this class, as NV has been reported in at least 20% of patients taking it (Yuan et al., 2009) and darunavir. Among fixed-dosed HIV combination pills, lopinavir/ritonavir, zidovudine/lamivudine, and tenofovir/lamivudine/abacavir are also commonly associated with NV. Although NV are typically associated with antiretroviral drug initiation, NV may persist beyond the initial period of therapy (Reynolds & Neidig, 2002).
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There are several dangerous drug-induced reactions to antiretrovirals that involve NV and require urgent care. Hypersensitivity reactions to the NRTI, abacavir, occur in approximately 3%8% of patients taking it (Wilcox & Saag, 2008), with some studies showing a prevalence rate of up to 29% (Stekler et al., 2006). Symptoms of hypersensitivity can occur anytime within the first year but are most likely to occur within the first 6 weeks of treatment and may include NV, fever, chills, fatigue, skin rash, diarrhea, abdominal pain, myalgias, pharyngitis, dyspnea, or cough (Clay, 2002). If not recognized and managed early enough, the abacavir reaction can be fatal (Wilcox & Saag, 2008). Current recommendations for initiating abacavir should include an HLA-B*5071 genetic test to assess whether patients are at risk for hypersensitivity, enabling the avoidance of this agent (Panel on Antiretroviral Guidelines for Adults and Adolescents [PAGAA], 2009). Patients initiating abacavir should be educated about signs of hypersensitivity and instructed that, if present, medical care must be sought immediately. Nevirapine and less so, efavirenz, both NNRTIs, may cause severe or life-threatening liver toxicity that can be an acute hypersensitivity reaction or a delayed toxicity reaction, either symptomatic or asymptomatic. Reactions to the drug usually occur in the first 6 weeks of treatment, although delayed onset toxicity can occur several months after initiation (Gonzalez de Requena, Nunez, Jimenez-Nacher, & Soriano, 2002). Symptoms are often nonspecific and may include NV, fever, malaise, rash, lymphadenopathy, and facial or pharyngeal swelling; more specific symptoms include jaundice or hepatomegaly (Rivero, Mira, & Pineda, 2007). These signs and symptoms require urgent management. Nucleoside reverse transcriptase inhibitors, most commonly zidovudine, stavudine, and didanosine, can disrupt normal mitochondrial function resulting in severe hyperlactatemia and low serum pH. This condition, called lactic acidosis, is a life-threatening condition and must be managed urgently (Chariot, Bourokba, Monnet, & Gherardi, 2002). Although this condition may be asymptomatic, presenting signs and symptoms may include nausea, myalgias, abdominal pain, fatigue, dyspnea, hepatic tenderness, and hepatomegaly (Wilcox & Saag, 2008). Lactic acidosis requires vigilant monitoring and reassessment of the patients medication regimen and may require hospitalization for intravenous fluids and respiratory support (Bongiovanni & Tordato, 2007). Nucleoside reverse transcriptase inhibitors have (PAGAA, 2009) also been associated with hepatic steatosis, a serious complication that can lead to cirrhosis and ultimately liver failure (Bongiovanni & Tordato, 2007). Although often
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TABLE 1. Medications Commonly Prescribed in HIV/AIDS Associated With Nausea and Vomiting Side Effects
Class Generic (Abbreviation), Trade name NRTIs Abacavir (ABC), Ziagen Zidovudine (ZDV), Retrovir Didanosine (ddI), Videx, Videx EC Emtricitabine (FTC), Emtriva Stavudine (d4T), Zerit Lamivudine (3TC), Epivir Protease Inhibitors Atazanavir (ATV), Reyataz Lopinavir/ritonavir (LPV/r), Kaletra Darunavir (DRV), Prezista Nelfinavir (NFV), Viracept Fosamprenavir calcium (FPV), Lexiva Indinavir sulfate (IDV), Crixivan Ritonavir (RTV), Norvir Saquinivir, Invirase Amprenavir, Agenerase Fosamprenavir, Lexiva Combination agents TDF + FTC + EFV, Atripla ZDV + 3TC + ABC, Trizivir TDF + FTC, Truvada ABC + 3TC, Epzicom ZDV + 3TC, Combivir Antifungals Amphotericin B, Fungizone Fluconazole, Diflucan Flucytosine, Ancobon Itraconazole, Sporanox Ketoconazole, Nizoral Cannabinoids Dronabinol, Marinol
Note. NRTI Nucleoside reverse transcriptase inhibitor; NNRTI Nonnucleoside reverse transcriptase inhibitor. The information in this table is from Gilbert, Moellering, Eliopoulos, Chambers, and Saag (2009).

Class Generic (Abbreviation), Trade name NNRTIs Nevirapine (NVP), Viramune Tenofovir disoproxil fumarate (TDF), Viread Efavirenz (EFV), Sustiva Etravirine (ETR), Intelence Delavirdine, Rescriptor Antibiotics Trimethoprim-sulfamethoxazole (TMP-SMX), Bactrim or Septra Azithromycin, Zithromax Ciprofloxacin, Cipro Clarithromycin, Biaxin Clindamycin, Cleocin Dapsone, Dapsone USP Metronidazole, Flagyl Ofloxacin, Floxin Rifabutin, Mycobutin Streptomycin, Gratis Paromomycin, Humatin Antivirals Ribavirin, Rebetol, Virazole, Copegus, Ribasphere Acyclovir, Zovirax Cidofovir, Vistide Famciclovir, Famvir Foscarnet, Foscavir Ganciclovir, Cytovene Antiprotozoals Atovaquone, Mepron Pentamidine isethionate, NebuPent

asymptomatic, especially in the early stages, symptoms that occur are typically nonspecific, including fatigue and weakness; later stage symptoms are associated with those typical of cirrhosis (Bongiovanni & Tordato, 2007). Pancreatitis has been associated with the NRTI, didanosine, especially if combined with stavudine, tenofovir, or ribavirin (Seidlin, Lambert, Dolin, & Valentine, 1992). Combing didanosine with stavudine is currently not recommended because of the high incidence of toxicities such as pancreatitis (PAGAA, 2009). Less common causes of pancreatitis include trimethoprim/sulfamethoxazole (TMP-SMX), rifampin, and antitubercular drugs (McKenzie, 2009). HIV agents
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are also associated with exacerbation of underlying liver disease, which can also cause NV (McKenzie, 2009). Some other non-HIV drugs commonly prescribed in HIV can also cause NV, including the antibiotics TMP-SMX and macrolides (NAPA, 2008). Opioids directly stimulate serotonin and dopamine receptors in the chemoreceptor trigger zone (CTZ) and also result in delayed gastric emptying, both of which can result in NV (McKenzie, 2009).

Activation of the CTZ

The CTZ is located in the highly vascular area postrema on the floor of the fourth ventricle and is not protected
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Nausea and Vomiting in HIV/AIDS

by the bloodbrain barrier. It is activated by emetogenic chemicals in the bloodstream or cerebrospinal fluid as well as the stomach and small intestines via vagal afferents (Garrett, Tsuruta, Walker, Jackson, & Sweat, 2003). Activation of the vomiting center via the CTZ is a common cause of NV, whether directly from emetogenic chemicals in the cerebrospinal fluids or bloodstream, or by vagal afferents ascending from the viscera that connect with the CTZ in the fourth ventricle. The CTZ also responds to bloodborne stimuli such as apomorphine, digoxin, anesthetic agents, alcohol, opioids, and chemotherapeutic agents (McKenzie, 2009). Receptors in the GI tract that activate the vagal afferents respond to chemical stimuli such as toxins, chemotherapeutic agents, acid, amino acids, fatty acids, and neurotransmitters. Some medications, perhaps as a result of local GI irritation or damage, can cause cells of the GI tract to release dopamine or serotonin, which in turn activate the vagus nerve (Garrett et al., 2003). Gastroparesis may also play a role in NV in HIV (Neild et al., 2000). Gastroparesis can be a primary cause (no specific disease identified) or secondary due to hypothyroidism, diabetes mellitus, or visceral neuropathy (see Figure 1).

Cortical and Sensory Mechanisms

Psychogenic stimuli (e.g., fear, anticipation, and memory) involve higher centers of the brain that activate the vomiting center directly. Traumatic experiences and terror can induce vomiting through stimulation of the cortex and in turn the vomiting center (Garrett et al., 2003). Anticipatory vomiting involves activation of the cortex from a learned or conditioned response to certain stimuli; for example, the patient receiving chemotherapy or the patient anticipating swallowing a large number of pills can stimulate the vomiting center (Shelke et al., 2004). Other sensory inputs that can stimulate the vomiting center include visual, olfactory, gustatory, and pain (Spiller, 2001).
FIGURE 1. The emetic response: Pathways, stimuli, and receptors. Reproduced with permission from Pathways, Stimuli, and Receptors, by L. A. Lehne, D. B. Moore, R. A. Crosby, and L. J. Hamilton, 1998, In Pharmacology for Nursing Care (3rd ed., pp. 794-798), Philadelphia, PA: W. B. Saunders.

Clinical Evaluation of the Patient With HIV Nausea and Vomiting

Nausea and vomiting involve a wide range of differentials, including a normal protective physiologic response from ingested toxins to a serious disease process of the visceral organs or central nervous system (CNS). With knowledge of the principal causes of NV in HIV, a diagnosis can be reached with a thorough history and physical examination, accompanied by investigative diagnostic testing if appropriate (Quigley, Hasler, & Parkman, 2001). Possible causes of HIVNV may include medication side effects or hypersensitivity reactions (abacavir hypersensitivity, nevirapine hepatic steatosis/lactic acidosis), gastroparesis (Konturek, 1997), CNS lesions
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(HIV-associated lymphomas), GI cytomegalovirus, Mycobacterium aviumM. intracellulare affecting the gut or liver, GI involvement of Kaposis sarcoma, and other structural or functional GI disorders including viral hepatitis or gastroesophageal reflux disease. Many patients with HIV also develop lipodystrophy and patients with lipodystrophy syndrome often show signs of insulin resistance and impaired glucose tolerance that can lead to NV (Wilcox & Saag, 2008). Nausea and vomiting may also be caused by non-HIVrelated problems as well as by disorders originating outside the GI tract (see Table 2).

History
A thorough history may capture a clear cause of symptoms. Determine the character and pattern of the symptoms including time and character of onset, duration, severity, frequency, precipitating factors, relieving factors, associated symptoms, recent ingestion (medication, food, and liquids), and whether the symptoms have been improving or worsening over time. The patient may
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TABLE 2. Differential Diagnosis for Nausea and Vomiting in HIV
Cardiovascular Myocardial infarction, congestive heart failure, cerebrovascular accident, hypotension Duodenal ulcer disease, functional dyspepsia, IBS, gastric ulcer, peptic ulcer disease (PUD), gastritis, gastroenteritis, GI bleed, peritonitis, diabetic or HIV-gastroenteropathy, gastroparesis, gastroesophageal reflux, diverticular disease, Crohn disease, colon or gastric cancer, intestinal obstruction, peritonitis, appendicitis, hepatobiliary disease (cholelithiasis, cholestasis, cholecystitis, duct obstruction, hepatitis, cirrhosis, nevirapine hepatotoxicity), gastrointestinal Kaposis sarcoma, pancreatitis (with didanosine especially if combined with stavudinecontraindicated, ribavirincontraindicated, or tenofovirreduce dose of didanosine) Head injury/brain damage effecting the VC, increased intracranial pressure, inner ear disorders, motion sickness, CNS disease (mass, lesions, meningitis), vestibular dysfunction, autonomic dysfunction, hemorrhage Pregnancy (especially first trimester), hypoglycemia, hyperglycemia Diabetic ketoacidosis, adrenocortical insufficiency, uremia, hypercalcemia, lactic acidosis (stavudine, didanosine, zidovudine), hyponatremia Renal tubular acidosis, renal disease, renal failure, pyelonephritis Anxiety, trauma, fear, anticipation Cytomegalovirus, toxoplasmosis, Mycobacterium avium complex, tuberculosis, pneumocystis carinii pneumonia, cryptosporidiosis Migraine, overeating, excessive alcohol consumption, consumption of contaminated food or water, emotional stress, opiate withdrawal, surgery, unrelieved pain, drug-induced side effects (nonsteroidal anti-inflammatory drugs, opiates, antibiotics, hormone preparations, chemotherapeutic agents, antiretroviral therapies), hypersensitivity reactions (abacavir, nevirapine)

Gastrointestinal

Neurologic Endocrine Metabolic Renal Psychologic Opportunistic Infections

Lifestyle/Miscellaneous

Note. CNS central nervous system; GI gastrointestinal; NSAID nonsteroidal anti-inflammatory drug; VC vomiting center

associate his or her symptoms with certain times of day or with meals or medication administration. If the patient reports associated pain, determine the pattern and character of the pain as well as whether or not and where it radiates. Vomiting with or without nausea and other associated symptoms may point to different etiologies. Accompanying headache may point to migraine; vertigo to labyrinthine disorders or motion sickness; and blurred vision, headache, projectile vomiting, and/or focal symptoms to cerebral lesions. Toxic patients with abnormal laboratory findings may have metabolic, endocrine, or GI changes including metabolic acidosis, diabetic ketoacidosis or other electrolyte abnormalities, renal or hepatic failure, hypothyroidism, adrenal insufficiency, presence of drugs or toxins, pregnancy, food allergy or poisoning, overeating, excess alcohol ingestion, gallstones, gastroenteritis, or ulcers. Vomiting without nausea is usually due to a local GI disturbance. Vomiting associated with visceral pain is likely due to GI, hepatobiliary, or pancreatic inflammation, although it may be cardiac in origin, and myocardial infarction and congestive heart failure should be ruled out. Vomiting accompanied by abdominal distention and constipation may be due to bowel
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obstruction, and vomiting with diarrhea and fever indicate an infective cause (e.g., viral gastroenteritis).

Medical History
The patients HIV history and immune status should be established (most recent viral load and CD4 cell count). An opportunistic infection should be considered if the patients immune status is impaired (CD4 200 cells/mm3). Immune reconstitution inflammatory syndrome should also be considered if a patient starts HAART for the first time, especially if CD4 100 cells/mm3 (Michailidis et al., 2005). Immune reconstitution inflammatory syndrome can occur among HIVinfected patients coinfected with tuberculosis or other mycobacterial infections and develop an exacerbation of such conditions (Michailidis et al., 2005). If the immune system is stable (CD4 350 cells/mm3) and the patient is on HAART, then the symptoms may be due to an adverse response to the regimen. Other medical conditions, such as coinfection with hepatitis C, may exacerbate liver-related causes of NV in HIV. Be sure to rule out cardiovascular causes in a patient with a cardiac history. A history of gallstones or GI cancer may point to a recurrence and
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likely GI-related causes of current symptoms. A physical examination should follow a thorough review of systems to identify any accompanying symptoms (e.g., headaches, abdominal pain, focal problems, fatigue, recent weight loss, and malaise).

therapies to etiologic targets. Even before the primary cause of NV is determined, empiric antiemetic therapy is reasonable (Wilcox & Saag, 2008).

Managing Serious Consequences of Severe NV

Nausea and vomiting accompanied by more serious signs require urgent and intensive care. If a patient is having a hypersensitivity reaction; is severely dehydrated; and has electrolyte manifestations, intestinal obstruction, or other danger signs, the patient should be hospitalized for acute care management to prevent grave outcomes. If symptoms are mild to moderate, in the absence of more severe symptoms, the patient should be educated about self-care and signs that require urgent care, monitoring hydration status, and the patient may be given supportive therapy.

Physical Examination
Most physical examinations will be normal (Spiller, 2001). The presence of immediate danger signs (sunken eyes, fatigue, pallor, projectile vomiting, blood in vomitus, severe or prolonged abdominal pain or distension, high or persistent fever, severe headache, recent trauma, diabetes, dizziness, or jaundice) indicates the need for urgent referral. Signs that require urgent or timely referral include a palpable abdominal mass, abnormal or lack of bowel sounds, or succussion splash suggesting GI obstruction (Spiller, 2001). Abnormal vital signs such as fever may indicate a hypersensitivity reaction, viral gastroenteritis, or acute hepatitis. Tachycardia or hypotension may suggest a hypersensitivity reaction, dehydration, anemia, or other condition. Note any physical signs of dehydration, toxicity, electrolyte imbalance, malnourishment, or endocrine disorders (i.e., Addisons disease or thyrotoxicosis). The skin may reveal conjunctival pallor, jaundice, cyanosis, lesions (e.g., Kaposis sarcoma), rash (e.g., hypersensitivity), or dry mucous membranes (e.g., dehydration). The abdominal examination may reveal masses, guarding or tenderness, distention, hepatomegaly, or succussion splash (gastroparesis/obstruction). The CNS examination findings may include orthostasis or parasympathetic abnormalities. Positive physical examination findings should be evaluated for severity and extent of involvement.

Discontinuing a Medication
If the offending drug is identifiable, stopping the drug may be considered if alternative agents with less GI toxicity are available and as long as the patients health status will not be impaired. Discontinuation should be based on the severity of the reaction, need to continue the current regimen, and availability of adequate alternatives. The clinician, together with the patient, must evaluate the risk and benefit of changing the medication. Some patients may have viral strains that are resistant to other HIV agents. Other patients may have had adverse reactions to other HIV agents in the past. It is common that upon initiating any HAART regimen, patients experience side effects in the first few months of therapy, which subside with time (Reynolds & Neidig, 2002). To optimize adherence, substituting with a better tolerated HIV agent should be considered. Patients switching to a new agent should be monitored for improved tolerance or signs of hypersensitivity. Patients starting new antiretroviral agents should be informed of possible side effects, danger signs, instructions for how to manage each, and when they characteristically occur. Patients feel more in control, better prepared, and better able to cope when aware of side effects in advance; unexpected side effects are more distressing (Reynolds & Neidig, 2002). Patients should be made aware of the signs of hypersensitivity reactions.

Diagnostic Testing
Diagnostic testing should follow any clinically significant components of the history and physical examination. Laboratory testing may include (as appropriate) complete blood cell count, metabolic panel, electrolytes, liver function tests, creatinine, amylase/lipase, lactic acid, blood pH, and thyroid function tests. Gastrointestinal or CNS imaging studies may be appropriate as well if, for example, masses or obstruction is suspected. Endoscopy with biopsy may be appropriate with signs of ulceration, reflux disease, or candidiasis. Gastric emptying testing may be considered if gastroparesis is suspected (Neild et al., 2000). Urine or serum should be screened for human chorionic gonadotropin in women of childbearing age if pregnancy is a possibility.

Pharmacologic Therapy
With supportive interventions, patients may be able to continue with their current HAART regimens. Because it is likely that more than one mechanism is involved in a patients symptoms, no one antiemetic regimen will work for all patients all the time (Quigley et al., 2001). The appropriate agent should be selected according to the cause of the NV, as some agents work at the GI
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Management of HIV Nausea and Vomiting

The approach to management must begin with an attempt to identify possible etiologies and then match
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level and others at the CTZ; different agents work better for different etiologies. Antiemetic and prokinetic agents are commonly used to treat NV. There are many classes of antiemetic drugs including dopamine antagonists, serotonin antagonists, phenothiazines, antihistamines, anticholinergics, butyrophenones, cannabinoids, corticosteroids, and benzodiazepines. Phenothiazines have central antidopaminergic effects in the area postrema. Agents include prochlorperazine, promethazine, and chlorpromazine. Side effects are relatively frequent and include sedation and orthostatic hypotension (Quigley et al., 2001).

Another dopamine antagonist, metoclopramide, acts both centrally and peripherally and has both antiemetic and prokinetic properties. Its use is limited by frequent adverse effects, including hyperprolactinemia, fatigue, and extrapyramidal side effects (Yuan et al., 2009). Serotonin (5-HT) antagonists may act centrally and peripherally, because of receptors in both the area postrema and GI tract. Ondansetron, granisetron, and tropisetron are all agents within this class, which are generally well tolerated. Cannabinoids act centrally in the region of the medulla oblongata. Dronabinol is an agent from this class that

TABLE 3. Medications Used in the Treatment of Nausea and Vomiting (Examples From Each Class)
Generic Trade Name Class Substituted benzamide Potential Side Effects Confusion, seizures, depression, extrapyramidal symptoms, neuroleptic malignant syndrome, vision changes, restlessness, drowsiness, fatigue, insomnia, headaches, dizziness, nausea, diarrhea, polyuria, loss of bladder control Insomnia, restlessness, drowsiness, headache, confusion, vertigo, hair loss, photosensitivity, impotence, increased libido, constipation, diarrhea, nausea, dry mouth, blurred vision, urinary retention Drowsiness, dizziness, menstrual changes, blurred vision, dry mouth, nasal congestion, nausea, headache, constipation, impotence, urinary retention, photosensitivity, increased appetite, arrhythmia, hypotension, jaundice, breast changes, priapism, extrapyramidal symptoms, seizures, worsening of psychotic symptoms Diarrhea, constipation, abdominal pain, indigestion, weakness, headache, fever, dizziness, drowsiness, insomnia, anxiety, hair loss, chest pain, and arrhythmia Fatigue, diarrhea, dizziness, constipation, headache, anxiety, urinary retention, chest pain, and itching Dry mouth, blurred vision, drowsiness, thickening of bronchial secretions, nausea, diarrhea, abdominal pain, headaches, fatigue, nervousness, dizziness, increased appetite, weight gain, sore throat, heart palpitations and tachycardia, arrhythmia, confusion, seizures, and urinary retention Drowsiness, dry mouth, blurred vision, dizziness, tinnitus, lack of coordination, fatigue, nervousness, insomnia, shakiness, double vision, nausea and vomiting, photosensitivity, neuroleptic malignant syndrome Increased appetite, irritability, insomnia, fluid retention, indigestion, muscle weakness, impaired wound healing, hyperglycemia, headaches, dizziness, emotional instability, pancreatitis, depression, increased intracranial pressure, and glaucoma Palpitations, anxiety, confusion, somnolence, euphoria/ elation, and vasodilation/facial flush

Metoclopramide Reglan

Haloperidol

Haldol

Butyrophenone

Prochlorperazine Compazine

Phenothiazine

Granisetron

Kytril

5-HT3 antagonist

Ondansetron Meclizine

Zofran Antivert

5-HT3 antagonist Antihistamine

Promethazine

Phenergan

Phenothiazine

Dexamethasone Decadron

Glucocorticoid

Dronabinol

Marinol

Cannabinoid

Note. The information in this table is from Lacy, Armstrong, Goldman, and Lance (2009).

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TABLE 4. Nonpharmacologic Approaches to Preventing and Managing Nausea and Vomiting
Dietary Modifications Behavioral Modifications Complementary Therapies Acupressure1 Acupuncture Progressive relaxation and guided imagery Ginger (Zingiber officinale)

Intake Do Bland, light, palatable Frequent small meals foods, that is, bananas, Eat before rising from bed with crackers at apples, rice, toast the bedside (BRAT) Eat food and sip beverages slowly Low fat and low fiber foods Wait an hour after eating to drink liquids Small and frequent Eat meals sitting upright amounts of water Time medication administration with food Popsicles, ices, or frozen (if appropriate for the drug) fruit juice Rest while digesting Keep room temperature cool Keep a diary to record daily symptoms, foods, beverages, medications, alleviating strategies, and exacerbating factors Avoid stomach irritants Spicy or fried foods Dairy products Alcohol Caffeine Aspirin Avoid Skipping meals Eating and drinking at once Lying down for at least an hour after eating Eating favorite foods while nauseous to avoid developing an aversion to them Tobacco Sensory triggers of nausea and vomiting

Note. Pericardium 6 is a point that demonstrated efficacy in alleviating pregnancy and chemotherapy induced nausea and vomiting (location: three fingers breadth, between the tendons of flexor carpi radialis and palmaris longus). The information in this table is from Capili and Anastasi (2009).

has been used in HIV- and chemotherapy-induced NV (Woolridge et al., 2005). Side effects include sedation, hypotension, dizziness, and euphoria. Corticosteroids may work by reducing prostaglandin formation and are used only in refractory cases. Benzodiazepines are also used in refractory conditions (Yuan et al., 2009). Prokinetic agents are appropriate when delayed gastric emptying is suspected (Garrett et al., 2003) (see Table 3).

Supportive and Nonpharmacologic Therapy

Adding another agent to already heavy drug regimens potentiates further drug-to-drug interactions and may add to patients symptom burden (Capili & Anastasi, 1998). Supportive care is often helpful in allowing patients to continue their HAART regimens without adding to their polypharmacy. Dietary and behavior modifications can be recommended to prevent the onset of NV and are listed in Table 4 (Highleyman, 2002). If appropriate to the agent, the patient may be advised to take the medication with a meal; eat small, frequent snacks; and may be referred for dietary guidance for the reduction of NV. Patients who receive medical nutrition education can be guided toward appropriate eating habits and receive support from a nutritionist; it has been recommended that such a referral occur for all HIV-infected patients and should
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be initiated early in therapy (Thomas & Mkandawire, 2006). Some supportive complementary therapies, such as acupressure, have shown positive results in treating chronic NV in pregnancy (OBrien, Relyea, & Taerum, 1996). Ginger, or Zingiber officinale, has demonstrated efficacy in NV of various etiology including hyperemesis gravidarum (Fischer-Rasmussen, Kjaser, Dahl, & Asping, 1991) and can be ingested as a food, tea, tincture, or capsule. Studies typically test doses of 1-2 g of ginger per day (Sontakke, Thawani, & Naik, 2003). Relaxation techniques, for example, progressive muscle relaxation training and guided imagery, have shown efficacy in reducing chemotherapy-induced NV (Thomas & Mkandawire, 2006).

Conclusions
Although NV is very common in patients with HIV, studies show that these symptoms tend to be underreported, underelicited, and undertreated in clinical practice (Reynolds & Neidig, 2002). Symptoms can arise at multiple time points throughout therapy, necessitating screening for them at every visit. Patients typically experience the most severe NV during the first 2 weeks of initiating therapy. Given the danger of self-managing side effects with skipped doses, leading to treatment failure and possible drug resistance, clinicians should
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consider initiating interventions to manage antiretroviral-related NV at baseline (Reynolds & Neidig, 2002). It is important to gain an understanding of patients wishes and capacity for managing their symptoms. For example, assess whether patients are interested in and capable of making dietary modifications as a first line of therapy, or prefer to use a pharmacologic agent on a trial basis and return for follow-up in 1 month. Studies show that patients who are aware of a particular side effect before it occurs are better equipped or more able to cope with the symptom (Reynolds & Neidig, 2002). Unexpected side effects have been associated with increased anxiety and decreased coping (Reynolds & Neidig, 2002). Educating patients about potential side effects ahead of time may not only facilitate their self-care of the symptoms but also increase reporting of the symptoms if they do arise (Reynolds & Neidig, 2002).

ACKNOWLEDGMENT
This work was supported by Grant R01 NR009364 from NIH/NINR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NINR.

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