Portal de Periódicos da CAPES

Idiopathic AIDS Enteropathy and Treatment of Gastrointestinal Opportunistic Pathogens

2009; Elsevier BV; Volume: 136; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2008.12.073

1528-0012

John P. Cello, Lukejohn W. Day,

Pneumocystis jirovecii pneumonia detection and treatment

Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients. Diarrhea in patients with acquired immune deficiency syndrome (AIDS) has proven to be both a diagnostic and treatment challenge since the discovery of the human immunodeficiency virus (HIV) virus more than 30 years ago. Among the main etiologies of diarrhea in this group of patients are infectious agents that span the array of viruses, bacteria, protozoa, parasites, and fungal organisms. In many instances, highly active antiretroviral therapy remains the cornerstone of therapy for both AIDS and AIDS-related diarrhea, but other targeted therapies have been developed as new pathogens are identified; however, some infections remain treatment challenges. Once identifiable infections as well as other causes of diarrhea are investigated and excluded, a unique entity known as AIDS enteropathy can be diagnosed. Known as an idiopathic, pathogen-negative diarrhea, this disease has been investigated extensively. Atypical viral pathogens, including HIV itself, as well as inflammatory and immunologic responses are potential leading causes of it. Although AIDS enteropathy can pose a diagnostic challenge so too does the treatment of it. Highly active antiretroviral therapy, nutritional supplementation, electrolyte replacements, targeted therapy for infection if indicated, and medications for symptom control all are key elements in the treatment regimen. Importantly, a multidisciplinary approach among the gastroenterologist, infectious disease physician, HIV specialists, oncology, and surgery is necessary for many patients. Lukejohn W. DayView Large Image Figure ViewerDownload Hi-res image Download (PPT)More than 100 million people worldwide currently are infected with the human immunodeficiency virus (HIV). Moreover, many have perished from this devastating disease. Beginning in the mid-1980s, a new disease entity, which ultimately would be named the acquired immune deficiency syndrome (AIDS), was described among patients in rural Uganda, Zaire, Tanzania, and in the United States. Because major symptom complexes involved the digestive tract with profound weight loss, malnutrition, and severe watery diarrhea, this disease was named by the indigenous African population slim disease. African patients with this poorly understood illness literally wasted away. Serwadda et al1Serwadda D. Mugerwa R.D. Sewankambo N.K. et al.Slim disease: a new disease in Uganda and its association with HTLV-III infection.Lancet. 1985; 2: 849-852Abstract PubMed Scopus (468) Google Scholar reported that slim disease appeared to occur predominantly in a heterosexual promiscuous population in Africa. At that time, they believed there were no clear indications to implicate other modes of transmission such as insect vectors or injection drug use. An uncertain, but high, percentage of HIV-infected patients worldwide initially present with or ultimately develop diarrhea with or without highly active antiretroviral therapy (HAART). Currently, substantial diarrhea occurs in about 50% of the HIV-infected individuals in the United States. In the developing world, however, diarrhea may occur with a much higher prevalence, in as many as 80% of HIV-infected individuals. Specific enteric pathogens can be isolated (if patients undergo exhaustive and intensive standard gastrointestinal [GI] evaluation) in most individuals with severe diarrhea. Currently, in areas of the world with access to sophisticated endoscopic evaluation, specific but atypical pathogens likely will be found in nearly 50% of patients with severe stool-study–negative diarrhea. Indeed, colonoscopy with intubation and biopsy of the terminal ileum together with endoscopy of the upper GI tract successfully identifies pathogens in 46% of patients with previously termed idiopathic diarrhea (Table 1).2Kearney D.J. Steuerwald M. Koch J. et al.A prospective study of endoscopy in HIV-associated diarrhea.Am J Gastroenterol. 1999; 94: 596-602Crossref PubMed Google Scholar However, not every patient with HIV-associated diarrhea needs a complete endoscopic evaluation. A full endoscopic work-up is necessary in patients with a functionally disabling diarrhea in which the etiology is unclear.Table 1Prospective Endoscopic Evaluation of 71 Patients With Stool-Study–Negative AIDS DiarrheaProceduresSensitivityFlexible sigmoidoscopy21/37 (57%)Duodenum17/37 (46%)Duodenum + flexible sigmoidoscopy29/37 (78%)Duodenum + full colonoscopy34/37 (92%)Full colonoscopy28/37 (76%)Full colonoscopy + ileum35/37 (95%)Colonoscopy + ileum + duodenum37/37 (100%)NOTE. Reprinted from Kearney DL, Koch J., Cello JP. Am J Gastro 1999;94:596–602. Open table in a new tab NOTE. Reprinted from Kearney DL, Koch J., Cello JP. Am J Gastro 1999;94:596–602. In many patients, diarrhea leads to a diminished quality of life. Small-bowel mucosal diseases routinely are associated with profound malnutrition and are a common manifestation of the HIV disease in the developing world. Diarrhea is an early and pervasive manifestation of HIV disease and is associated with increased morbidity and mortality. Diarrhea also substantially increases health care costs for many patients, particularly those with severe secretory diarrhea and malabsorption/malnutrition necessitating repeat hospitalizations. Clinical presentations vary among patients with HIV-associated diarrhea depending on the principal area of the GI tract involved. Small-bowel diarrhea tends to produce large, bulky, postprandial stools. If patients with small-bowel diarrhea fast from nutrients they do not have significant amounts of diarrhea. Conversely, after a meal, patients with small-bowel diarrhea report that almost immediately they have postprandial paraumbilical abdominal pain and voluminous diarrhea. Weight loss is characteristic of small-bowel diarrhea. On the other hand, large intestinal diarrhea, so-called colitic diarrhea, is associated with frequent, small-volume stools. These patients do not commonly become dehydrated. Colonic diarrhea also may be associated with the presence of visible blood and mucous. These patients with large-bowel diarrhea often have lower-quadrant abdominal pain and/or will have the sensation of rectal urgency. In many instances it is difficult to distinguish between large- and small-bowel diarrhea based on clinical presentation alone, thus highlighting the need for further and more exhaustive diagnostic evaluation. Over the past 2 decades a well-defined subset of HIV/AIDS patients with profound diarrhea, malnutrition, and wasting, with no infectious pathogen identified as the causative agent, has emerged. In 1987, Kotler et al3Kotler D.P. Scholes J.V. Tierney A.R. Intestinal plasma cell alterations in acquired immunodeficiency syndrome.Dig Dis Sci. 1987; 32: 129-138Crossref PubMed Scopus (77) Google Scholar noted alterations in intestinal plasma cells of AIDS patients without identifiable (at that point in time) intestinal pathogens (Figure 1). In HIV-infected patients with AIDS-related complex or fully expressed AIDS, the mean villus/height and mean villus/crypt ratios were significantly lower than those of normal controls (Figure 2). By using immunofluorescence staining, the researchers observed a decrease in immunoglobulin (Ig)A plasma cells and a relative increase in IgM plasma cells in the small bowel and in the colon. There also was decreased quantitative plasma cell fluorescence in samples that were stained for IgA and IgM, implying less cytoplasmic immunoglobulin per cell. However, the depletion of IgA from plasma cells did not always correlate with altered serum IgA concentrations. Kotler et al3Kotler D.P. Scholes J.V. Tierney A.R. Intestinal plasma cell alterations in acquired immunodeficiency syndrome.Dig Dis Sci. 1987; 32: 129-138Crossref PubMed Scopus (77) Google Scholar also noted that the lymphoid depletion in patients with AIDS might be patchy and might involve many cells in addition to the plasma cells.Figure 2Comparison of (A) mean villus/crypt ratio, (B) mean villus/height ratio, (C) and mean crypt depth among AIDS patients with and without diarrhea and normal controls. arc, AIDS-related complex. Reprinted with permission from Greenson JK et al.79Greenson J.K. Belitsos P.C. Yardley J.H. et al.AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea.Ann Intern Med. 1991; 114: 366-372Crossref PubMed Scopus (179) Google Scholar AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med 1991;141:366–327.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Initial speculation that HIV itself was infecting cells directly, both within the epithelium and the lamina propria, has been tempered by the identification of atypical viruses that rarely were searched for in the GI tract of patients with AIDS-related diarrhea. In 1998, Cunningham et al4Cunningham A.L. Grohman G.S. Harkness J. et al.Gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus.J Infect Dis. 1988; 158: 386-391Crossref PubMed Scopus (88) Google Scholar first identified rotaviruses and adenoviruses by enzyme-linked immunosorbent assay, electron microscopy, and/or cell culture analyses. These 2 viruses were found in more than 50% of HIV-positive symptomatic patients with diarrhea, but in less than 15% of HIV-negative patients, and in less than 20% of HIV-positive asymptomatic patients without diarrhea. It appeared, therefore, that these viruses occasionally were associated with a high excretion rate in HIV-infected patients with diarrhea and might be associated with acute episodes or relapses of diarrhea. Cunningham et al4Cunningham A.L. Grohman G.S. Harkness J. et al.Gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus.J Infect Dis. 1988; 158: 386-391Crossref PubMed Scopus (88) Google Scholar also postulated that there may be additional, yet to be identified, pathogens in patients with chronic or relapsing acute diarrhea. Grohmann et al,5Grohmann G.S. Glass R.I. Pereira H.G. et al.Enteric viruses and diarrhea in HIV-infected patients Enteric Opportunistic Infections Working Group.N Engl J Med. 1993; 329: 14-20Crossref PubMed Scopus (279) Google Scholar from the Centers for Disease Control, reported in 1993 on the prevalence of a wide range of enteric viruses in HIV-infected patients with and without diarrhea. Sixty-five HIV-positive patients were grouped into those with diarrhea and those without diarrhea. Adenovirus, astrovirus, and picobiranvirus, but not chronovirus, Caliciviridae, or featureless small round viruses were noted in the stools of HIV-positive patients with diarrhea compared with HIV-infected patients without diarrhea. Overall, 35% of the fecal specimens in patients with AIDS and refractory diarrhea harbored 1 or more of these viruses, compared with only 12% of the stools of patients without diarrhea (Table 2). Thus, studies and reports of so-called AIDS enteropathy always should be tempered by the reality that these viruses, as well as other infectious agents, ultimately may be found in patients with so-called idiopathic AIDS-related diarrhea. One need only recall belatedly identified pathogens such as mycobacterium-avium complex, cryptosporidium, or microsporidium in patients with previously termed idiopathic AIDS diarrhea.Table 2Viral Agents Detected in 222 Fecal Specimens From HIV-Infected Patients, According to Whether Diarrhea Was PresentDiarrhea, n (%)No diarrhea, n (%)P valueaThe 2-tailed P value was calculated by the Fisher exact test.VirusSpecimens (N = 109)Patients (N = 65)Specimens (N = 113)Patients (N = 65)SpecimensPatientsAdenovirus10 (9)10 (15)3 (3)3 (5).047.076AstrovirusbThree patients had acute episodes of astrovirus-associated diarrhea on more than one occasion.13 (12)9 (14)2 (2)2 (3).003.054Coronavirus-like particle3 (3)2 (3)2 (2)2 (3).6791.00Small round viruses SRSVcSRSVs, or Norwalk-like viruses, are considered to be members of the family Caliciviridae along with human caliciviruses. Taken together, the Caliciviridae were associated marginally with diarrhea (P = .062 for specimens, P = .115 for patients).4 (4)4 (6)1 (1)1 (2).206.365 CaliciviruscSRSVs, or Norwalk-like viruses, are considered to be members of the family Caliciviridae along with human caliciviruses. Taken together, the Caliciviridae were associated marginally with diarrhea (P = .062 for specimens, P = .115 for patients).2 (2)2 (3)00.24.496 Featureless3 (3)2 (3)3 (3)3 (5).621.619PicobirnavirusdThe 2 patients without diarrhea who shed picobirnavirus at different times had picobirnavirus-associated diarrhea. Only in this category was a patient included as both a case patient and control.10 (9)6 (9)2 (2)1 (2).017.115TotaleThe total number of specimens with virus present as a single or mixed infection. Some patients were infected with more than one type of virus.38 (35)24 (37)13 (12)8 (12)<.001.002 Infection with 1 virus31 (28)—13 (12)—.002— Mixed infectionfThe mixed infections consisted of 4 cases of adenovirus and astrovirus, 2 cases of calicivirus and coronavirus-like particle, and 1 case of adenovirus and coronavirus-like particle.7 (6)—0—.006—NOTE. A total of 110 patients contributed 222 specimens: 59 patients provided only 1 specimen and 51 patients provided 2 or more specimens. The patients who provided more than 1 specimen were those enrolled early in the study who, at different times, had either new onset of diarrhea (case patients) or a 3-month period without diarrhea (controls).a The 2-tailed P value was calculated by the Fisher exact test.b Three patients had acute episodes of astrovirus-associated diarrhea on more than one occasion.c SRSVs, or Norwalk-like viruses, are considered to be members of the family Caliciviridae along with human caliciviruses. Taken together, the Caliciviridae were associated marginally with diarrhea (P = .062 for specimens, P = .115 for patients).d The 2 patients without diarrhea who shed picobirnavirus at different times had picobirnavirus-associated diarrhea. Only in this category was a patient included as both a case patient and control.e The total number of specimens with virus present as a single or mixed infection. Some patients were infected with more than one type of virus.f The mixed infections consisted of 4 cases of adenovirus and astrovirus, 2 cases of calicivirus and coronavirus-like particle, and 1 case of adenovirus and coronavirus-like particle. Open table in a new tab NOTE. A total of 110 patients contributed 222 specimens: 59 patients provided only 1 specimen and 51 patients provided 2 or more specimens. The patients who provided more than 1 specimen were those enrolled early in the study who, at different times, had either new onset of diarrhea (case patients) or a 3-month period without diarrhea (controls). Recognizing the real potential for unsuspected or unidentified pathogens in the bowel, many investigators have found that HIV itself infects enterocytes, lamina propria cells, and submucosa. Nelson et al6Nelson J.A. Wiley C.A. Reynolds-Kohler C. et al.Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms.Lancet. 1988; 1: 259-262Abstract PubMed Scopus (363) Google Scholar in 1988, using in situ hybridization of biopsied specimens obtained from the rectum and duodenum, showed HIV-infected cells in both the base of the crypts and within the lamina propria. They postulated that the association of in situ labeling of HIV RNA in argentaffin cells strongly suggested that enterochromaffin cells derive from the neural crest tissue and may in fact be among the primary target cells of HIV. Along the same lines, Batman et al7Batman P.A. Miller A.R. Forster S.M. et al.Jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology.J Clin Pathol. 1989; 42: 275-281Crossref PubMed Scopus (122) Google Scholar described jejunal enteropathy associated with HIV; the degree of villus atrophy in the jejunal mucosa was estimated using a Widal eye piece graticule. Jejunal villus enterocytes showed mild, nonspecific abnormalities with crypt hyperplasia recurring in all stages of HIV disease, even in the absence of pathogens. They suggested that the pathogenesis of villus atrophy was actually an immune reaction within the lamina propria against cells infected with HIV. Delezay et al8Delezay O. Yahi N. Tamalet C. et al.Direct effect of type 1 human immunodeficiency virus (HIV-1) on intestinal epithelial cell differentiation: relationship to HIV-1 enteropathy.Virology. 1997; 238: 231-242Crossref PubMed Scopus (48) Google Scholar reported the findings from an in vitro study on the differentiation of an epithelial cell clone HT-29-D4. They noted that HIV impaired cellular differentiation of both barrier function and sodium-glucose co-transport. In this epithelial cell line, HIV massively disrupted microtubules, revealed by α-tubulin indirect immunofluorescence staining. The investigators suggested that HIV perturbs intestinal function with or without infecting the epithelial cells themselves. Once opportunistic disorders are excluded in patients with refractory diarrhea, HIV enteropathy can exist in a small but definite percentage of the population. Batman et al9Batman P.A. Kotler D.P. Kapembwa M.S. et al.HIV enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in HIV/Microsporidia-infected jejunal mucosa.AIDS. 2007; 21: 433-439Crossref PubMed Scopus (40) Google Scholar have studied crypt, stem, and transit cell proliferation. In a study on the kinetics of stem and transit cell lines, they noted definite villus atrophy induced by both microsporidia and HIV itself. Both these infections provoke crypt cell hypertrophy, including encroachment of the crypt cells onto the villi by stimulating cell mitoses in both stem and transit cells. Dandekar10Dandekar S. Pathogenesis of HIV in the gastrointestinal tract.Curr HIV/AIDS Rep. 2007; 4: 10-15Crossref PubMed Scopus (95) Google Scholar clarified the pathogenesis of HIV disease in the GI tract, noting that the gut-associated lymphoid tissue (GALT) was clearly an early site of HIV replication and CD4+ T-cell depletion. Additional studies have supported that HIV destroys GALT in the early stages of HIV infection.11Sankaran S. George M.D. Reay E. et al.Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration.J Virol. 2008; 82: 538-545Crossref PubMed Scopus (184) Google Scholar Initiation of HAART did not lead to complete suppression of viral replication and there was only partial restoration of CD4+ T-cells in the GALT, compared with the peripheral blood. It appeared that persistent HIV replication in GALT leads to crypt alterations and maintenance of the HIV reservoirs. Knox et al12Knox T.A. Spiegelman D. Skinner S.C. et al.Diarrhea and abnormalities of gastrointestinal function in a cohort of men and women with HIV infection.Am J Gastroenterol. 2000; 95: 3482-3489Crossref PubMed Google Scholar described the functional disruption of the GI tract caused by HIV in 2000. Among 671 patients with HIV infection, 39% had diarrhea; stool pathogens were identified in only 12% of these patients. Despite this, 48% of all patients had an abnormal D-xylose test, 22.5% had borderline or low serum B-12 levels, and 7.2% had a depressed albumin level. The investigators suggested that abnormalities of the GI tract are common even in the era of modern HAART, so the clinician therefore carefully must exclude identifiable pathogens, even in patients who are on HAART. Monkemuller et al13Monkemuller K.E. Lazenby A.J. Lee D.H. et al.Occurrence of gastrointestinal opportunistic disorders in AIDS despite the use of highly active antiretroviral therapy.Dig Dis Sci. 2005; 50: 230-234Crossref PubMed Scopus (53) Google Scholar noted that since the widespread use of HAART, there has been a dramatic decrease in the prevalence of identifiable opportunistic infections of the GI tract, but that opportunistic infections still occurred. They examined a population of 294 patients treated with HAART; 88% of the patients were men, with a mean age of 36.5 years. In this study patients had a mean CD4+ T-cell count of 64 and a mean RNA viral load of 40,357 copies per mL. Despite all being treated with HAART, 9% of patients had identifiable opportunistic disorders of the GI tract. In careful questioning, however, they identified approximately 40% of these patients with new or persistent opportunistic disorders of the GI tract as being likely or definitely noncompliant with administered HAART. Thus, GI opportunistic disorders still can occur in HIV-positive patients, including those allegedly taking HAART and especially in those with low CD4+ T-cell counts and high HIV viral loads. Unfortunately, these opportunistic disorders still can occur in patients with near-normal CD4+ T-cell counts and low HIV viral loads. Thus, HIV enteropathy is associated with increases in inflammation and immune activation and decreases in mucosal repair and regeneration—these all contribute to the presence of HIV enteropathy. In 2008, Sankaran et al11Sankaran S. George M.D. Reay E. et al.Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration.J Virol. 2008; 82: 538-545Crossref PubMed Scopus (184) Google Scholar highlighted once again the importance of GALT as an early target for HIV infection and the site of severe CD4+ T-cell depletion. They noted that viral replication occurred very early in primary HIV infection in the GALT CD4+ T cells and macrophages. There was also a decrease in the expression levels of genes that regulate epithelial barrier maintenance and digestive metabolic function. These changes coincided with a decrease in transcription of immune activation, inflammation, and apoptosis-associated genes. Consequently, HIV infection in GALT occurs at both a molecular and a cellular level even before seroconversion. Although HIV enteropathy encompasses an idiopathic, pathogen-negative diarrhea, there is an array of opportunistic infections (OIs) that invade the GI tracts of patients with advanced HIV. GI OIs include a complex milieu of bacteria, fungus, viruses, and protozoa that typically exert their devastating effects when a patient's CD4+ T-cell count decreases to less than 200 cells/μL (Figure 3). The study of GI OIs has undergone an astonishing transformation over the past 25 years, and has been marked by periods of remarkable discovery and innovation in terms of identifying new pathogens and suitable treatments. Similar to the evolving treatment of these infections, the role of the gastroenterologist under these circumstances has changed over time as well. In many cases, a multidisciplinary approach among gastroenterology, infectious disease, HIV specialists, oncology, and surgery not only is encouraged, but in many cases is required for treating HIV patients with GI OIs. The advent of HAART revolutionized the treatment of HIV and resulted in striking declines in HIV-related infections and associated mortality.14d'Arminio Monforte A. Sabin C.A. Phillips A. et al.The changing incidence of AIDS events in patients receiving highly active antiretroviral therapy.Arch Intern Med. 2005; 165: 416-423Crossref PubMed Scopus (129) Google Scholar In addition, HAART marked a sustained and continued decline in the incidence and prevalence of GI OIs.15Monkemuller K.E. Call S.A. Lazenby A.J. et al.Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy.Am J Gastroenterol. 2000; 95: 457-462Crossref PubMed Google Scholar This dramatic decline was illustrated superbly by Monkemuller et al15Monkemuller K.E. Call S.A. Lazenby A.J. et al.Declining prevalence of opportunistic gastrointestinal disease in the era of combination antiretroviral therapy.Am J Gastroenterol. 2000; 95: 457-462Crossref PubMed Google Scholar in a prospective study at the University of Alabama in Birmingham. In examining 166 AIDS patients undergoing dual endoscopy for GI complaints at 3 time periods in the 1990s (2-year intervals), they discovered the incidence of GI OIs decreased from a peak of 69% to a nadir of 13%, whereas at the same time HAART use in their patients increased from 37% to 87%. Several multifactor theories have been proposed to explain this decline of GI OIs. One is that the re-establishment of the patient's own natural immunity, with the repopulation of T cells in the enteric mucosa, combats various opportunistic pathogens that it previously could not fight. A second explanation may be the direct effect of the HAART regimen itself on specific pathogens. Within combinational HAART, protease inhibitors have been observed both in vivo and in vitro to have inhibitory properties on specific organisms via the degradation of aspartyl proteases.16Hommer V. Eichholz J. Petry F. Effect of antiretroviral protease inhibitors alone, and in combination with paromomycin, on the excystation, invasion and in vitro development of Cryptosporidium parvum.J Antimicrob Chemother. 2003; 52: 359-364Crossref PubMed Scopus (60) Google Scholar, 17Pozio E. Morales M.A. The impact of HIV-protease inhibitors on opportunistic parasites.Trends Parasitol. 2005; 21: 58-63Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Regardless of the mechanism, HAART has had extraordinary success in treating HIV-associated GI OIs since its introduction. The success of HAART spans across an entire assortment of GI OIs. For example, multiple studies uniformly have shown a decrease in the incidence of cryptosporidium and microsporidium in response to HAART.18Maggi P. Larocca A.M. Ladisa N. et al.Opportunistic parasitic infections of the intestinal tract in the era of highly active antiretroviral therapy: is the CD4(+) count so important?.Clin Infect Dis. 2001; 33: 1609-1611Crossref PubMed Scopus (19) Google Scholar, 19Miao Y.M. Awad-El-Kariem F.M. Franzen C. et al.Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy.J Acquir Immune Defic Syndr. 2000; 25: 124-129Crossref PubMed Scopus (115) Google Scholar Likewise, an influential 1998 study by Carr et al20Carr A. Marriott D. Field A. et al.Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy.Lancet. 1998; 351: 256-261Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar discovered that HIV patients infected with Cryptosporidium parvum or Enterocytozoon bieneusi (most of which had failed previous antimicrobial therapy) had a full clinical, histologic, and microbiological response to HAART. In addition, a majority of patients remained symptom free for more than 1 year and those with recurrent symptoms had declining CD4+ T-cell counts. However, this interplay between HAART and the treatment of GI OIs is not limited to parasitic and fungal organisms. This story was unraveled eloquently in several studies on the treatment of patients with cytomegalovirus (CMV) infections. HIV patients on combination HAART consistently have greater rates of survival, compared with HAART-naive patients, even when adjusting for CMV therapy.21Sungkanuparph S. Chakriyanuyok T. Butthum B. Antiretroviral therapy in AIDS patients with CMV disease: impact on the survival and long-term treatment outcome.J Infect. 2008; 56: 40-43Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Accordingly, the profound effect of HAART on treating GI OIs is unquestionable and should be front-line therapy for many GI OIs. Although the effects of HAART are compelling, some researchers have noted the oc