Infectious Diseases

Educational Objectives

The goals of this program are to improve the management of Helicobacter pylori infections and to promote the appro­priate use of retrovirals for the treatment of AIDS. After hearing and assimilating this program, the clinician will be better able to:

1.   Assess patients with gastritis and dyspepsia for H pylori infections.

2.   Compare various treatment regimens for H pylori infection.

3.   Predict gastric cancer risks among patients with H pylori.

4.   Determine which early antiretroviral drug intervention is best for treatment-naive HIV-positive patients.

5.   Discuss findings of recent clinical trials on use of antiretroviral agents in the ongoing  management of HIV-positive patients.  

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Peura is a consultant and speaker for Takeda Pharmaceutical. Dr. Hare is on the Speaker’s Bureau for, receives honoraria from, and/or is a consultant for Abbott, Bristol-Meyers Squibb, Gilead, and GlaxoSmithKline.  Dr. Hare presents information related to off-label or investigational use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgments

Dr. Peura was recorded at the 18th Annual GI Symposium, held November 1, 2008, in New Brunswick, NJ, and spon­sored by the University of Medicine and Dentistry of New Jersey and the Robert Wood Johnson Medical School, De­partment of Medicine, Division of Gastroenterology/Hepatology. Dr. Hare was recorded at The Medical Management of HIV/AIDS, held December 11-13, 2008, in San Francisco, CA, and sponsored by the Division of AIDS  –Positive Health Program, San Francisco General Hospital, and the University of California, San Francisco, School of Medi­cine.  The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

H pylori: What’s Hot and What’s Not

David A. Peura, MD, Professor of Medicine, University of Virginia School of Medicine, Charlottesville

Helicobacter pylori timeline: H pylori prevalence currently decreasing in United States, with resulting dramatic changes in disease management; 1982  —  first cultured accidentally; initial attempts to publish rejected by medical community because orthodoxy convinced ulcers acidogenic and bacteria could not survive stomach; 1984  —  first paper published; Marshall ingested H pylori and successfully validated Koch’s postulates; 1988  —  first randomized controlled trial treating ulcers as infectious; 1994  —  National Institutes of Health (NIH) consensus conference con­cluded gastric ulcers share infectious etiology; H pylori labeled class 1 carcinogen by World Health Organization (WHO); 1997  —  H pylori genome sequenced

Pathogenesis: does not invade tissue; incubates beneath gut mucosal layer; produces multiple enzymes and induces development of toxins; provokes strong immune response; systemic immune response allows serologic detection; local immune response affects acid secretion via dysregulation of D cell (produces somatostatin); Western populations  —  typically experience antral-predominant gastritis with somatostatin down-regulation, gastrin up-reg­ulation, increased acid secretion and risk for duodenal ulcer, and reduced risk for gastric cancer; Eastern populations  —typically develop corpus-predominant gastritis, with somatostatin up-regulation, acid suppression, increased gastrin, and higher risk for gastric cancer; protected against duodenal ulcer and gastroesophageal reflux disease (GERD); duodenal ulcers  —increasingly rare due to widespread use of proton pump inhibitors (PPIs) and antibiotics

Nonsteroidal anti-inflammatory drug (NSAID)–induced ulcers: until mid 1990s, most ulcers attributed to H py­lori; NSAIDs currently most common etiology; virtually all complicated (bleeding) ulcers now NSAID-related

GERD and H pylori: distribution of gastritis determines treatment; GERD symptom history also critical; in patients with pre-existing GERD and typical Western antral-predominant gastritis, treatment for H pylori results in reduced acid production and improvement of reflux; in those without preexisting GERD,  new GERD unlikely to develop; in patients with Eastern corpus-predominant gastritis, treatment for H pylori increases acid production; GERD may worsen or develop from latent form; controversies surrounding treatment of H pylori result from geographic varia­tions in distribution of gastritis

Functional dyspepsia: dyspepsia lacks singular etiology; functional nonulcer dyspepsia responds poorly to treatment of H pylori (only 1 in 15 patients improve); testing dyspeptic individuals for H pylori recommended only in areas with established high demographic prevalence; H pylori infection window ends after age 5 yr; country of origin predicts risk for H pylori infection

H pylori and cancer: Correa cascade   —  H pylori induces atrophic gastritis, intestinal metaplasia, dysplasia, and can­cer; progression determined by genetics; alternative theory  —suggests 1) bone marrow produces premalignant cells, 2) chronically inflamed tissues induce pluripotent cell migration, 3) premalignant cells generate tumors at site of inflammation; disrupting migration of premalignant cells may prevent H pylori–related malignancies; pos­sible concept can be extrapolated to other cancers

Genetics and gastric cancer: H pylori strains expressing cagA protein associated with increased risk for gastric can­cers; cagA-negative strains also induce malignancies; genetics determine cancer susceptibility, especially poly­morphisms of inflammatory mediator genes , eg, interleukin-1b (IL-1b; higher in cancer patients than in controls); some relatives of patients with gastric cancer produce less stomach acid; these individuals susceptible to gastric cancer and express genetic polymorphisms affecting IL-1b, IL-8, IL-10, and tumor necrosis factor (TNF)-a; all associated with increased risk for gastric cancer; distribution of gastritis also relevant; study data  —  found early treatment of H pylori may prevent development of gastric cancer; however, preventive treatment in­effective once irreversible premalignant intestinal changes (eg, metaplasia, dysplasia) have occurred

Mucosa-associated lymphoid tissue (MALT) lymphoma: B-cell lymphoma, but dependent on stimulation of T-cells by H pylori; can be cured with antibiotics, but may require conventional lymphoma therapy when found outside gastric mucosa

Diagnosis of H pylori: serology unreliable for diagnosis, but negative predictive value good; breath test has improved positive predictive value; stool antigen testing effective; enzyme-linked immunosorbent assay (ELISA) provides excellent sensitivity and specificity; serology stays positive long after treatment; PPI therapy alters intestinal micro­organism populations, masking endoscopy results; only multiple biopsies reliably detect H pylori in patients who use PPIs; immunologic staining may improve detection

Treatment: no ideal treatment of H pylori; significant resistance rates exist among commonly used antibiotics; 10% to 11% resistance to clarithromycin; clarithromycin resistance associated with 90% failure rate in standard PPI-based triple therapy; 30% to 70% resistance to metronidazole; can overcome resistance to metronidazole by in­creasing dose, but clarithromycin resistance absolute

Suggested treatment: includes PPI, amoxicillin, and clarithromycin for 14 days (increases compliance); metronida­zole may be substituted for amoxicillin in penicillin-sensitive patients, but reduces efficacy; bismuth, metronida­zole, and tetracycline regimen also used; PPI, amoxicillin, and metronidazole least expensive regimen; useful for patients exhibiting macrolide resistance, but results poorer overall (50%-60% success rate vs 70% average); 25% to 30% of patients do not respond

Sequential therapy: involves amoxicillin and PPI twice daily for 5 days; followed by PPI, clarithromycin, and tini­dazole for 5 days; regimen demonstrates 90% eradication, (>80% with clarithromycin resistance, vs 10%-15% with triple therapy); single-pill dosing with bismuth, metronidazole, and tetracycline (Pylera) increases compliance; re­sults comparable to triple therapy (circumvents clarithromycin resistance)

Rescue therapies: prescribed after patient fails 2 previous regimens; frequently PPI, amoxicillin, and levofloxacin; rifabutin regimen costly and associated with hematologic side effects; furazolidone (uncommon in United States) available from compounding pharmacies

Guidelines for diagnosis and treatment of H pylori (American College of Gastroenterology [ACG]): ulcer dis­ease; past history of ulcer MALT lymphoma; early gastric cancer; uninvestigated dyspepsia (some populations); controversial indications  —  functional dyspepsia (endoscopy-negative), GERD, NSAID use, unexplained iron defi­ciency anemia, idiopathic thrombocytopenic purpura (ITP), populations at high risk for gastric cancer

Update on Antiretrovirals for the
Treatment of AIDS

C. Bradley Hare, MD, Assistant Clinical Professor of Medicine, University of California, San Francisco, School of Medi­cine

Case 1: 44-yr-old Latina  —  newly diagnosed HIV+; CD4 count 410 cells/mm³, HIV RNA 72,000 copies/mL, wild-type viral genotype; preexisting type 2 diabetes; patient willing to start antiretroviral drugs (ARVs)

Early intervention: facilitates immunologic preservation; 2 studies indicate CD4 count at initiation of ARVs predicts therapeutic response; Johns Hopkins HIV clinical cohort and AIDS therapy evaluation in the Netherlands (ATHENA) cohort; achieving normal CD4 counts more likely when patients start at higher CD4 baseline; pa­tients with lower counts typically experience less CD4 recovery; Antiretroviral Cohort Collaboration (ART-CC) study indicated baseline CD4s frequently predicted risk for AIDS onset or mortality with highly active antiretro­viral therapy (HAART); always weigh potential benefits against ARV side effects; North American AIDS Cohort Collaboration On Research and Design (NA-ACCORD) study found »70% increased mortality when ARV treat­ment deferred at CD4 counts of 350 to 500 cells/mm³; baseline CD4 count not independent predictor of mortality

Guidelines: 2008 International AIDS Society (IAS) guidelines suggested treating all symptomatic HIV, treating as­ymptomatic patients with CD4 counts <350 cells/mm³, and individualizing therapy for asymptomatic patients with CD4 counts >350 cells/mm³; current Department of Health and Human Services (DHHS) guidelines concur

Case 2: 48-yr-old black man  —  HIV+ 4 yr, CD4 count 290 cells/mm³, HIV RNA 123,000 copies/mL, wild type viral genotype; smoker, with hypertension and hyperlipidemia (treated with statin); creatinine 1.2 mg/dL; glomerular fil­tration rate (GFR) 70 mL/min/1.73 m² 

Comments: which nucleoside analog reverse transcriptase inhibitor (NRTI) backbone should be prescribed? 1) ab­acavir/lamivudine (Epzicom) 2) tenofovir/emtricitabine (Truvada) 3) other; AIDS Clinical Trial Group (ACTG) 5202A study  —indicated abacavir/lamivudine backbone produced reduced mortality, compared to tenofovir/em­tricitabine; Head-to-Head Epizicom And Truvada (HEAT) study  — sponsored by GlaxoSmithKline (GSK); indi­cated no statistical inferiority); ACTG 5202A versus HEAT study differences  —  1) different third drugs, may or may not offer comparable nucleoside backbone protection 2) different study design and entry criteria 3) different end points 4) potential treatment interruptions 5) adherence differences 6) resistance testing not always performed at baseline 7) unaccountable differences in baseline characteristics between populations

Cardiovascular risks with abacavir: Data collection on Adverse events of anti-HIV Drugs (D:A:D) study  —  first documented cardiovascular risks, focusing on myocardial infarction (MI); total MI rates low; Strategies for Man­agement of Antiretroviral Therapy (SMART) study  —  involved 5000 HIV-positive patients randomized for virologic suppression (VS) or drug conservation (DC; treatment interruptions based on CD4 count); patients experienced higher MI rates with abacavir and/or preexisting cardiovascular risk factors; GSK conducted end point analysis of multiple studies with abacavir; for end point of MI, acute MI, or any ischemic coronary disease no association with abacavir found; possible mechanism  —higher inflammation associated with abacavir, compared to other nucleoside analogues, may explain cardiovascular risks; in SMART study, patients on abacavir had higher levels of inflamma­tory markers, eg,interleukin (IL) 6 and C-reactive protein (CRP) than patients on other drugs; unknown whether pa­tients with higher markers same as those who had CV events; in HEAT study, level of inflammatory markers similar in both arms, and in general, inflammatory markers decreased on treatment; guideline panels disagreed on cardiovascular risk management; IAS still classifies abacavir regimens as “preferred”; DHHS reclassified abacavir regimens from “preferred” to “alternative”

Case 3: 33-yr-old man ready to start first ARV regimen  —  CD4 30 cells/mm³, HIV RNA 500,000 copies/mL, and wild type genotype; no significant comorbidities

Possible third drug: 1) atazanavir 2) lopinavir 3) darunavir 4) fosamprenavir 5) efavirenz; ACTG 5142 study  —indicated better viral load response with efavirenz, but higher CD4 counts and fewer multiclass virologic failures with lopinavir; Madero study  —  found efavirenz met criteria for virologic superiority to lopinavir, in patients with CD4 counts <200 cells/mm³; however, patients in lopinavir arm had better gain in CD4 cells; combined study re­sults confirm efficacy of nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Case 3 continued: 33–yr-old male patient returns  —  CD4 310 cells/mm³, HIV RNA 50,000 copies/mL; viral geno­type now expresses transmitted K103N mutation, ruling out efavirenz

Optimal (ritonavir-boosted) third drug: 1) atazanavir 2) lopinavir 3) darunavir 4) fosamprenavir 5) other; multiple studies compared protease inhibitors; Molina et al study  —  96-wk data show similar results with atazanavir and lopinavir in treatment-naive patients; lopinavir arm demonstrated greater gastrointestinal (GI) symptoms and cho­lesterol abnormalities; atazanavir associated with jaundice and hyperbilirubinemia; Antiretroviral therapy with TMC114 Examined In naive Subjects (ARTEMIS) study  —  demonstrated statistical superiority of darunavir/ritona­vir vs lopinavir/ritonavir in treatment-naive patients; GI side effects more common with lopinavir; cholesterol ab­normalities similar with both drugs, but statistical difference in total cholesterol and triglycerides favored darunavir/ritonavir regimen

Guideline changes: IAS recommended NNRTIs and protease inhibitors (PIs), including efavirenz, lopinavir, ata­zanavir, fosamprenavir, darunavir, saquinavir; DHHS guidelines added darunavir/ritonavir first-line therapy in 2008

Case 3 continued: 33-yr-old man returns  —  CD4 count 310 cells/mm³, HIV RNA 50,000 copies/mL, genotype K103N; patient finds multiple PIs intolerable

Third agent of choice: 1) integrase inhibitor (eg, raltegravir) 2) chemokine (c-c motif) receptor 5 (CCR5) corecep­tor antagonist (eg, maraviroc) 3) second generation NNRTIs (eg, etravirine, rilpivirine) 4) keep best tolerated PI; Lennox et al study  — found raltegravir suppression comparable with efavirenz combination regimens; raltegravir exhibits greater rapidity of viral suppression, greater tolerability, and fewer side effects; Saag et al study  —initially indicated statistical inferiority of maraviroc compared to efavirenz, despite higher CD4 gains; tropism assays with greater sensitivity improved viral genotype screening of study participants; new screening enabled more accurate exclusions for X4 HIV strains and dual HIV strain infections, eventually lessening disparities in efficacy between maraviroc and efavirenz; improved tropism assays allow precise targeting with genotype-specific drugs; reasons for discontinuation of drugs  —  in efavirenz arm, discontinuation more likely due to adverse events than to virologic failure or lack of efficacy; in maraviroc arm, adverse events uncommon, and more patients discontinued due to lack of efficacy

Experimental drug: rilpivirine second-generation once-daily NNRTI compares favorably with efavirenz; fewer rashes, central nervous system symptoms, and  neuropsychiatric events than efavirenz; current rilpivirine studies demonstrate dosage-linked QTc interval increase; uncommon NNRTI resistance mutations caused by rilpivirine re­quire further evaluation

Suggested Reading

Ernst P et al: The Translation of Helicobacter pylori Basic Research to Patient Care. Gastroenterology 130:188, 2006; Pa­patheodoridis GV et al: Effects of Helicobacter pylori and Nonsteroidal Anti-Inflammatory Drugs on Peptic Ulcer Disease: A Systematic Review. Clin Gastroenterol Hepatol 4:130, 2006; Pandolfino J et al: H. Pylori and GERD: Is Less More? Am J Gastroenterol 99:1213, 2004; Leung WK et al: H. pylori Genotypes and Cytokine Gene Polymorphisms Influence the Devel­opment of Gastric Intestinal Metaplasia in a Chinese Population. Am J Gastroenterol 101:714, 2006; Houghton J et al: Heli­cobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology 128:1567, 2005; Lu W et al: Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. Carcinogenesis 26:631, 2005; Martinelli G et al: Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti–Helicobacter pylori therapy. J Clin Oncol 23:1979, 2005; Vaira D et al: Sequential Therapy versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication A Randomized Trial. Ann Intern Med 146:556, 2007; Chey WD and Wong BCY: American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol 102:1808, 2007; Gras L et al: CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr 45:183, 2007; May M et al: Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS 21:1185, 2007; Hammer S et al: An­tiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society - USA panel. JAMA 300:555, 2008; D:A:D Study Group: Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 371:1427, 2008; Gulick RM et al: Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 359:1429, 2008.