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Gastroesophageal Reflux Disease (GERD) and HIV

for Health Care Providers

Gastroesophageal Reflux Disease (GERD)

Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.

Key Points

  • Typical symptoms of GERD are heartburn and regurgitation.
  • Less common GERD symptoms (eg, cough) may mimic other conditions.
  • Evaluation of GERD in patients with HIV depends on the stage of infection.
  • In patients with a CD4 count of >350 cells/µL with typical GERD symptoms, a trial of empiric acid suppression therapy may be undertaken in lieu of other diagnostic testing.
  • In patients with more advanced HIV infection, evaluation for OIs affecting the esophagus should be considered, along with empiric GERD therapy.
  • Patients with GERD symptoms lasting >5 years should be evaluated by endoscopy for Barrett esophagus because of the increased risk of esophageal carcinoma.
  • Patients with alarm symptoms (eg, unexplained dysphagia or weight loss, hematemesis) should be evaluated by endoscopy for malignancy or other GERD complications.

Background

  • GERD is defined by the American College of Gastroenterology as "symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus." However, there is no universally accepted definition of the condition, and no gold standard for its diagnosis.
  • Uncomplicated GERD is characterized by typical symptoms of heartburn, regurgitation, or both.
  • Complicated GERD includes Barrett esophagus (see below), esophageal strictures, hemorrhage or perforation, and extraesophageal complications such as aspiration, asthma, chronic coughing, chest pain, and laryngopharyngitis.
  • Etiology involves lower esophageal sphincter (LES) dysfunction with reflux of acidic gastric contents into the esophagus, often resulting in damage to esophageal mucosa. Decreased esophageal motility and abdominal distention also may play a role.
  • Symptoms of heartburn are common in Western countries: 25% of the general population is reported to have heartburn at least once a month, 12% has heartburn at least weekly. GERD can have a very negative impact on quality of life.
  • There is no reported association of GERD with HIV infection. For HIV-infected patients, however, the differential diagnosis of GERD symptoms includes several HIV-related conditions (see Partial differential diagnosis, below).
  • Diagnosis usually depends on the presence of symptoms and/or the confirmation of esophagitis with esophagogastroduodenoscopy (EGD) or other testing.
  • Esophagitis (esophageal erosions or other mucosal damage) is seen on EGD or histology in <50% of patients. The majority of patients with GERD symptoms have no evidence of esophagitis on EGD (ie, nonerosive reflux disease, or NERD).
  • The severity and course of symptoms of esophagitis and NERD are similar.
  • The condition is often chronic, with remissions and relapses, but usually not progressive. Possible complications include:
    • Esophageal stricture
    • Esophageal ulcers
    • Barrett esophagus
    • Adenocarcinoma
    • Bleeding
    • Perforation
    • Aspiration
  • The symptoms and esophageal mucosal injuries caused by GERD usually respond to acid-suppressive treatment, though some complications (eg, Barrett esophagus) may not improve with treatment.

Veterans with HIV*

Esophageal disease: 19%

*Veterans in the VA HIV Clinical Case Registry in care in 2007 who had an ICD-9 code corresponding to this condition

Evaluation

  • There is no gold standard for diagnosis of GERD.
  • Uncomplicated GERD may be diagnosed by clinical symptoms alone.
  • EGD should be considered at presentation for patients with symptoms of complicated GERD (extraesophageal or alarm symptoms; see below) and those at risk of Barrett esophagus (see below).
  • The differential diagnosis of symptoms referable to the esophagus in patients with HIV depends on the stage of infection.
    • In patients with CD4 counts of <350 cells/mL, the differential diagnosis should include esophageal OIs, such as candidiasis and CMV infection.
    • In patients with higher CD4 counts, evaluation should focus on GERD, and on Barrett esophagus and alarm symptoms that suggest malignancy or other conditions (see below); however, the possibility of OIs should be considered as well.
  • Patients with symptoms lasting for >5 years should be evaluated for Barrett esophagus because of the associated increase in risk of esophageal adenocarcinoma.

Check for alarm symptoms:

  • Dysphagia
  • Odynophagia
  • Unexplained weight loss
  • GI bleeding (hematemesis, melena, bloody stool)
  • Anemia
  • Chest pain
  • Choking/dysphagia
  • Failure to improve with therapy

In HIV-infected patients with relatively high CD4 counts, these suggest malignancy, ulceration, or stricture. If present, refer for immediate evaluation via EGD. Consider starting trial of acid suppression therapy while awaiting further evaluation.

Barrett Esophagus

  • Metaplasia, with replacement of esophageal squamous epithelium by abnormal columnar epithelium
  • Associated with severe GERD, but may occur in asymptomatic patients
  • Increases risk of esophageal adenocarcinoma 50-fold compared with GERD alone
  • Unclear whether acid suppression prevents progression of Barrett esophagus or development of adenocarcinoma
  • Patients with a history of GERD symptoms for >5 years, especially those ≥50 years of age, should be evaluated for Barrett esophagus by EGD
  • Reflux symptoms should be controlled before EGD to maximize sensitivity and specificity of EGD
  • The surveillance interval for Barrett esophagus is determined by the grade of dysplasia at initial EGD
    • For low-grade dysplasia, EGD should be repeated within 6 months to exclude higher-grade dysplasia
    • For high-grade dysplasia, EGD should be repeated within 3 months
Risk factors
  • Obesity: 1.5- to 2-fold risk of GERD, increasing with higher BMI
  • Pregnancy
  • Fatty foods
  • Hiatal hernia
  • Stress
  • Medications: beta-blockers, calcium channel blockers, anticho-linergics (LES relaxation), NSAIDs, aspirin (mucosal injury)
  • Lifestyle factors: Many of these cause relaxation of the LES, but there is little evidence that GERD results. Associations, if true, appear to be weak, though some patients may be sensitive to these factors.
    • Diet: carbonated sodas, caffeinated beverages, chocolate, saturated fats, peppermint, acidic foods, low fiber
    • Alcohol use
    • Smoking
HistoryHistory is usually the basis of GERD diagnosis; however:
  • Patients may have atypical symptoms or be asymptomatic.
  • Severity of symptoms does not predict severity (or presence) of mucosal damage; conversely, severity of esophagitis does not predict severity of symptoms.
  • There may be great variability in symptoms and findings upon diagnostic testing, and the two may not correlate.
  • Absence of symptoms does not rule out GERD.
Symptoms:
  • Heartburn: retrosternal burning pain (because of potential for misunderstanding, it may be helpful to avoid the term "heartburn" and instead ask patients about "a burning feeling rising from the stomach or lower chest up toward the neck")
  • Regurgitation: reflux of gastric contents (acid, with or without food); very specific for GERD
  • Dysphagia
  • Odynophagia
  • Symptoms of "extraesophageal" GERD:
    • Cough
    • Asthma
    • Chest pain
    • Hoarseness/voice changes

    (Note: GERD is a common cause of chronic cough, wheezing, and chest pain.)
Associated factors:
  • Ask about risk factors, above.
  • Duration of symptoms; patients with a long history of GERD symptoms should be evaluated for Barrett esophagus (see above).
  • Symptoms after meals (symptoms after a large or fatty meal: highly specific for GERD)
  • Symptoms with recumbency (particularly after a meal)
  • Nocturnal symptoms
  • Treatments tried and symptom response (improvement with acid-lowering medications supports the diagnosis)
Physical examination
  • Performed mostly to evaluate for other causes (infections, asthma, cardiac disease, cancer)
  • Vital signs; O2 saturation
  • Inspection of oropharynx (ulcerations, candidiasis, lesions, masses), neck (nodes, masses), and lungs (wheezes, crackles)
    • Absence of oropharyngeal candidiasis does not exclude esophageal candidiasis.
  • Abdomen: masses, tenderness
  • Evaluation for malignancy and infection if history and examination suggest these diagnoses
Diagnostic tests
  • Diagnosis of GERD usually is made on the basis of clinical evaluation; in patients with symptoms consistent with GERD, history usually is sufficient to move to a trial of empiric acid-lowering therapy (4-8 weeks) without further evaluation.
  • Exceptions require immediate and appropriate evaluation:
    • Chest pain (rule out cardiac origin)
    • Other alarm symptoms (see above)
    • Other atypical symptoms or findings; high suspicion of an alternative diagnosis
  • Hematocrit and fecal occult blood testing may be indicated if anemia caused by an upper GI source is suspected.
  • Helicobacter pylori testing is of little value in evaluation of GERD.
• Empiric proton pump inhibitor (PPI) therapy
  • Response to acid-lowering therapy (typically PPI therapy) supports a diagnosis of GERD, though studies of correlation show varying results, and symptom improvement may not correlate with findings on EGD or pH monitoring. Sensitivity 78% and specificity 54% for GERD; use of high dosages of PPI may improve sensitivity.
  • If there is no clinical improvement after 4-8 weeks, consider EGD or other testing as below.
  • (Note that a small number of patients have GERD symptoms that are not related to gastric acid.)
• EGD
  • Useful for diagnosing esophagitis and complications (eg, strictures, Barrett esophagus), but is normal in >50% of patients with symptoms: high specificity (>90%) but low sensitivity (50%) (ie, normal endoscopy does not exclude GERD). Severity of mucosal injury does not necessarily correlate with symptoms.
  • The role of EGD in the initial evaluation of patients with uncomplicated GERD is somewhat controversial. The VHA Pharmacy Benefits Management Strategic Healthcare Group and the American College of Gastroenterology propose that a trial of therapy is preferable to EGD for most patients.
  • Perform EGD as part of initial evaluation for complicated GERD (eg, if alarm symptoms or other concerning symptoms are present), or if alternative diagnoses are likely (eg, candidiasis or CMV esophagitis, esophageal cancer, gastritis, and peptic ulcer disease), or if patient is at risk of Barrett esophagus (see above).
    • Consider trial of acid-lowering therapy while awaiting EGD; may result in partial (or full) remission of GERD; will improve sensitivity for detection of Barrett esophagus.
  • Perform EGD for patients whose symptoms persist despite therapy; consider for patients with long duration of symptoms (eg, >5 years).
  • The surveillance interval for Barrett esophagus is determined by the grade of dysplasia at initial EGD (see Barrett Esophagus, above).
• Ambulatory pH monitoring
  • Presence of acid in the esophagus does not correlate well with symptoms.
  • Does not detect nonacid reflux.
  • Limited availability, uncomfortable for patients.
  • Consider for patients with persistent symptoms if the EGD is negative for mucosal damage and for those with unusual, extraesophageal, or refractory symptoms.
  • Can monitor control of reflux in patients on acid-reducing medications (eg, for patients who are considering surgery).
• Barium esophagram
  • Detects severe esophagitis and strictures reliably, but is not sensitive or specific for milder or nonerosive disease.
  • Not sensitive for detection of Barrett esophagus.
Partial differential diagnosis
  • Infectious esophagitis (symptoms usually include odynophagia, dysphagia)
    • Candidiasis
    • CMV
    • Herpes simplex virus
  • Dyspepsia
  • Peptic ulcer disease
  • Gastritis
  • "Pill esophagitis"
  • Stricture
  • Hiatal hernia
  • Esophageal dysmotility
  • Cancer (esophageal, gastric)
  • Gastroparesis
  • Coronary artery disease

Management

Acute/Initial Treatment

Goals of therapy:

  • Symptom relief
  • Healing of esophageal erosions (if present)
  • Prevention of complications (data demonstrate reduction in esophageal strictures, but do not clearly show that treatment prevents or slows development of Barrett esophagus or adenocarcinoma)

As discussed in the Evaluation section, empiric acid-suppressing treatment may be initiated on the basis of GERD symptoms. The rate of symptom response to adequate therapy is high (>80%), so patients whose symptoms do not improve should be evaluated for other causes.

Medications

Acid-suppressive agents

  • Mainstay of GERD treatment.
  • Primary acid-suppressive treatments are PPIs and H2 receptor antagonists (H2RAs).
  • For symptom control and healing of esophagitis, the order of efficacy is: high-dose PPI > standard-dose PPI > half-dose PPI > high-dose H2RA > standard-dose H2RA.
  • Patients with erosive esophagitis, extraesophageal symptoms, or a history of failure to respond to H2RAs should be started on standard-dose PPI rather than an H2RA.
  • For patients with NERD, the optimal initial treatment strategy has not been defined. Some authorities prefer to start with PPIs at maximal doses and step down to less-intensive therapy after symptom remission; others prefer to start with less-intensive therapy and step up if symptom relief or esophageal healing is incomplete.
  • PPIs and H2RAs may affect serum levels of some ARVs; these drug-drug interactions may influence which type of medication is selected for initial treatment of GERD (see Potential ARV Interactions below).
  • Most GERD patients (>60%) gain symptom relief, and approximately 80% have healing of esophagitis at 8-12 weeks.

Antacids

  • No role as primary therapy (typically, patients have self-treated with antacids without symptom relief).
  • May be helpful for some patients as supplement to PPI therapy, to be used as needed for breakthrough symptoms.

Prokinetic agents

  • Metoclopramide is the only prokinetic agent available in the United States.
  • Increases LES resting tone, esophageal peristalsis, and gastric emptying.
  • Less effective than PPIs; similar to but perhaps less effective than H2RAs.
  • Associated with CNS adverse effects (eg, irreversible tardive dyskinesia).
  • Should be used only as adjunct to acid suppression, not monotherapy.
Dietary and Lifestyle Modification
  • Generally aimed at avoiding decreases in LES function, or increases in abdominal pressure or position, which promote reflux of acid above the LES.
  • Adjunct to acid suppression in selected patients; not suitable for sole therapy.
  • Limited data on efficacy from randomized controlled trials for most measures.
  • Specific modifications should be based on individual circumstances and identified triggers.
Table 1: Initial Interventions for GERD
PPIs
  • Available PPIs have comparable efficacy at equivalent dosages.
  • Greater efficacy and more rapid symptom control than H2RAs.
  • Optimal starting dosage is unclear; some authorities prefer to start with high dosages and step down to less-intensive therapy after symptom remission, others prefer to start at lower dosages and increase treatment intensity if needed.
  • Should be taken a half hour before breakfast (or dinner).
  • Usually well tolerated. Potential adverse effects include GI symptoms (abdominal pain, diarrhea, nausea), headache, rash, and liver toxicity.
  • No dosage adjustment needed for renal impairment.
  • May require lower dosage in hepatic impairment; dosage not defined.
  • Decrease absorption of drugs with pH-dependent bioavailability, particularly ATV. (See Potential ARV Interactions.)
Generic Drug NameDosage RangeComments
Dexlansoprazole30-60 mg QDIf difficulty swallowing, can open capsule and sprinkle contents on applesauce
Esomeprazole20-40 mg QDIf difficulty swallowing, can open capsule and sprinkle contents on applesauce
Lansoprazole15-30 mg QD or 30 mg BIDIf difficulty swallowing, can open capsule and sprinkle contents on applesauce
Omeprazole20-40 mg QDIf difficulty swallowing, can open capsule and sprinkle contents on applesauce; immediate-release form contraindicated with hypocalcemia or alkalosis
Pantoprazole40 mg QD or 40 mg BIDNo dosage adjustment needed for hepatic impairment; may cause false-positive THC result on urine toxicology screen
Rabeprazole20 mg QD or 20 mg BIDDelayed-release tablet
H2RAs
  • Less effective than PPIs for acid suppression, relief of symptoms, and healing of esophagitis; approximately 40% of patients gain symptom relief. Treatment with H2RAs may be adequate for some patients.
  • Potential adverse effects vary somewhat according to the specific H2RA. They include cytopenias, rash, GI intolerance, and arrhythmias.
  • Dosage adjustment is required for patients with renal insufficiency.
  • Cimetidine interacts significantly with many other drugs.
  • See Potential ARV Interactions.
Cimetidine800 mg BID or 800 mg TIDMultiple drug interactions (see Potential ARV Interactions)
Famotidine20 mg BID or 40 mg BIDMay decrease ATV absorption
Nizatidine150 mg BID or 300 mg BIDMay decrease ATV absorption
Ranitidine150 mg BID or 150 mg QIDMay decrease ATV absorption; may decrease FPV, LPV, RTV levels
Antacids
  • Typically contain aluminum hydroxide, magnesium hydroxide, calcium carbonate, sodium bicarbonate, or combinations of these compounds.
  • Liquid formulation is preferable to tablets because of more rapid action.
  • Usual dosage is 15-30 mL QID (after meals and at bedtime).
  • If tablets are used, they should be thoroughly chewed and followed by full glass of water.
  • Antacids combined with alginic acid (eg, Gaviscon) may be superior to antacids alone.
  • Adverse events:
    • Antacids containing magnesium: diarrhea
    • Antacids containing aluminum or calcium: constipation
    • Hypophosphatemia with chronic use
    • Magnesium and/or aluminum retention in chronic renal failure
  • Multiple drug interactions caused by binding to form insoluble complexes, including PIs and integrase inhibitors. (See Potential ARV Interactions.)
Prokinetic Agents
Metoclopramide10-15 mg QID (after meals and at bedtime)Associated with irreversible tardive dyskinesia, other CNS effects; may consider metoclopramide as adjunctive therapy (add-on to PPI)
Dietary and Lifestyle Modification
Dietary
  • In most patients, avoiding the following is useful:
    • Carbonated beverages
    • Voluminous meals
  • In selected patients, avoiding the following triggers may be useful:
    • Fatty meals
    • Sweets, including chocolate
    • Spicy foods/raw onions
    • Caffeinated beverages
    • Citrus products/juices
Lifestyle
  • In most patients, the following are useful:
    • Weight loss
    • Smoking cessation
    • Lying on the left side when sleeping
    • Avoiding excessive physical activity (running)
  • In selected patients, the following may be useful:
    • Avoiding alcohol
    • Elevating head of bed (for nocturnal symptoms)

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Evaluate Treatment Response (after 4-8 weeks):
Possible responses to treatmentOptions for treatment and evaluation
Adequate control of symptoms
  • Preferred: Step-down (decrease in intensity) of therapy (eg, from high-dose PPI to standard-dose PPI, or from PPI to H2RA), with goal of eventually discontinuing therapy; monitor symptoms
  • Discontinue therapy and monitor symptoms
  • Continue current therapy
Partial control of symptoms
  • Increase intensity of therapy (eg, to high-dose PPI)
  • Extend the course of treatment (reevaluate after additional 4-8 weeks)
  • Refer to GI for further evaluation
Lack of response
  • Increase intensity of therapy
  • Consider alternative diagnosis
  • Refer to GI for evaluation

More than 60% of patients respond to adequate therapy. Most authorities recommend that all patients who do not respond to a trial of PPI therapy be referred for further evaluation. In patients with low CD4 counts, consider candidiasis or CMV esophagitis, and other HIV-associated conditions.

Relapse of GERD Symptoms
  • Restart the medication at the dosage that was effective in controlling the patient's symptoms.
  • If relapse occurs on H2RA, step up therapy to PPI.
  • Consider referral for further diagnostic testing.

Chronic GERD Symptoms

Goals: Suppress symptoms, prevent relapses.

  • Limited data on optimal strategy for long-term acid suppression
    • Chronic maintenance: consider for frequent or rapid relapses, severe disease
    • Episodic treatment as needed for relapses: consider for patients with mild GERD
  • It is rational to use the lowest possible dosage of PPI or H2RA that controls symptoms, but recurrences are common with decreased intensity or discontinuation of medications; some data suggest that efficacy of H2RAs may decline over time.
  • Chronic PPI therapy appears to be safe, but data from controlled trials are not available and risks are not fully known.
    • May decease absorption of vitamin B12; use with caution for patients with risk factors for B12 deficiency.
    • May decrease serum Mg levels, consider periodic monitoring.
    • May increase risk of fractures; use with caution for patients with risk factors for osteoporosis.

Surgery and Endoscopic Treatments

Most surgical and endoscopic therapies (eg, fundoplication) alter LES function, and have variable success. Criteria for selecting patients are not completely defined, but usually include those with large-volume reflux, good responses to medical therapy, or intolerance to medical treatment. Following surgery, a high proportion of patients continue to require acid-lowering medications for control of symptoms. Refer to GI for evaluation.

When to Refer

Gastroenterology
  • Severe symptoms
  • Atypical symptoms
  • Screening for Barrett esophagus
  • Alarm symptoms suggesting malignancy, ulceration, or stricture
  • Failure to improve, incomplete response, or relapse on empiric acid-suppression therapy
  • Consider for chronic symptoms requiring continuous therapy
  • Evaluation for OIs by EGD
Surgery
  • Evaluation for fundoplication for:
    • Large-volume reflux
    • Long-term control of symptoms
    • Intolerance to medical therapy

Potential ARV Interactions

Table 2: Potential ARV Interactions

(Print table)

Acid-lowering medications have interactions with various ARVs. Consult dosing information, as certain combinations require specific dosing strategies, and some are contraindicated.

PPIs: interactions with ARVs are incompletely studied

  • All PPIs:
    • PIs
      • ↓ ATV levels (ATV requires an acidic GI environment for absorption); see specific dosing recommendations below
      • ↓ IDV (predicted)
    • NNRTIs
      • ↓ RPV levels (RPV requires an acidic GI environment for absorption; coadministration is not recommended)
    • Integrase inhibitors
      • ↑ RAL levels
  • Omeprazole (in addition to ARVs listed above):
    • ↓ NFV, ETV
    • ↓ ETR, SQV

H2RAs:

  • All H2RAs:
    • ATV: ↓ ATV levels (ATV requires an acidic GI environment for absorption); see specific dosing recommendations below
    • RPV: may ↓ RPV levels (RPV requires an acidic GI environment for absorption); if used concurrently, must give H2RA at least 12 hours before or at least 4 hours after RPV
    • RAL: may ↑ RAL levels
  • Cimetidine (in addition to All H2RAs, above):
    • ↓ NVP levels; dosage adjustment not established
    • May ↑ FPV levels; consider alternative agents
    • May ↓ DRV levels
  • Ranitidine
    • May ↓ FPV and LPV/r levels; dosage adjustments not established

Antacids

  • All antacids: May ↓ levels of RPV; give antacids at least 2 hours before or 4 hours after RPV
  • Maalox, Mylanta, Tums, milk of magnesia, others
    • May ↓ levels of ATV, FPV, TPV; separate dosing by 2 hours
  • Calcium (eg, Tums, Mylanta)
    • May bind integrase inhibitors and interfere with their activity (until further information is available, separate dosing by at least 2 hours)
Dosage Recommendations: ATV with PPIs or H2RAs
ARV-Naive PatientsARV-Experienced Patients
Source: Reyataz package label
PPI
  • ATV/r 300/100 mg QD; PPI dosage not to exceed the equivalent of omeprazole 20 mg QD, with the PPI to be taken approximately 12 hours before ATV/r.
  • Unboosted ATV is not recommended.
  • PPIs are not recommended.
H2RA
  • ATV/r 300/100 mg QD; H2RA dosage not to exceed the equivalent of famotidine 40 mg BID; give ATV/r with the H2RA and/or ≥10 hours after the H2RA.
  • Unboosted ATV is not recommended; if used with H2RA, H2RA should not exceed the equivalent of famotidine 20 mg per dose or daily total of 40 mg; give ≥2 hours after and/or ≥10 hours before ATV/r.
  • ATV/r 300/100 mg QD; H2RA dosage not to exceed the equivalent of famotidine 20 mg BID; give ATV/r with the H2RA and/or ≥10 hours after the H2RA.
  • If TDF is used in the regimen, give ATV/r 400/100 mg QD. Administer H2RA as described above.
  • Unboosted ATV is not recommended.

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References