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HIV1 and the Gut in the Era of Highly Active Antiretroviral Therapy Esteban C. Nannini, MD and Pablo C. Okhuysen, MD Address Division of Infectious Diseases, The University of Texas, Houston Medical School, 6431 Fannin Street, Room 1.728 JFB, Houston, TX 77030, USA. E-mail: [email protected] Current Gastroenterology Reports 2002, 4:392–398 Current Science Inc. ISSN 1522-8037 Copyright © 2002 by Current Science Inc. The gut and its gut-associated lymphoid tissue serve as a preferential site for HIV1 entry, active viral replication, reservoir, and HIV-mediated CD4 cell apoptosis. The widespread use of highly active antiretroviral therapy (HAART) has resulted in a significant decrease in the incidence of opportunistic enteric pathogens as a consequence of immune recovery. Nonetheless, patients with advanced HIV1 disease who were recently diagnosed or have poor response to HAART can still suffer from opportunistic infections with pathogens such as Cryptosporidium, microsporidia, Isospora belli, Cyclospora cayetanensis, Mycobacterium avium complex, and cytomegalovirus, among others. This review describes the impact of HIV1 infection on gut immune function, the salient features of the most common opportunistic enteric pathogens and HIV-associated enteropathy, and the effects of immune reconstitution after introduction of HAART. Introduction Sexual contact is the main form of transmission of HIV1 and involves the mucosal surfaces of the genital and gastrointestinal (GI) tract. Thus, the gut is considered an important part of the immune system with implications in virus replication and dissemination. The Gut As an Immune Organ During acute HIV1 infection, the HIV can penetrate the intestinal lining through a traumatized area or can be transported by intestinal epithelial cells or the more specialized M cells. Once in the lamina propria, HIV1 attaches to several potential targets, such as local CD4 cells and macrophages, as well as to circulating monocytes and lymphocytes that express coreceptors. These events occur within the gut-associated lymphoid tissue (GALT), which is one of the largest lymphoid organs of the body and is comprised of the Peyer’s patches, solitary lymphoid follicles, and activated T cells that are distributed within the lamina propria and epithelia [1]. This compartment has been recognized as one of the most important HIV1 reservoirs in all the stages of disease [2]. This is evidenced by the finding of HIV1 proviral DNA (HIV1-derived genetic material that has been incorporated into the host cell’s chromosome) and HIV1 RNA in 100% and 77% of rectal biopsy specimens, respectively, obtained from 26 patients (CD4 cell count median, 100 cells/mm3; range, 2 to 904), 18 of whom had a prior AIDS-defining illness [3•]. Of note, all HIV isolates identified in gut tissues in this study belonged to the non-syncytium-inducing (NSI) phenotype (also known as macrophage tropic), regardless of the phenotype isolated from the same patient in blood, which may reflect a discordant viral evolution and the more frequent finding of CCR5 (the HIV coreceptor used by NSI variants) than CXCR4 (the coreceptor used by syncytium-inducing variants) in rectal mucosa [4]. CD4+ cell depletion and inverse CD4/CD8 ratio during early and late HIV infection can be observed in rectal biopsies [5], and this depletion occurs sooner and is more pronounced in the intestinal tissues than in peripheral blood [6,7]. Infection of macaques with the simian immunodeficiency virus (SIV) has yielded similar results, with selective depletion of CD4 cells in the lamina propria of the intestine within days of infection and before any changes were detected in peripheral lymphoid tissues [8]. Given the magnitude of the immunologic stress and apoptosis (programmed cell death) seen during primary HIV1 infection, it is not surprising that diarrhea is a common manifestation of the acute HIV1 infection syndrome. Apoptosis has been implicated as one of the mechanisms of CD4 cell destruction by HIV1 in vivo and has been demonstrated to occur in the GALT. One study found that the number of apoptotic cells was elevated in the lamina propria of patients in the intermediate stage of the disease and in those in advanced disease having an opportunistic infection [9]. In addition, increases in the expression of the proinflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β) in the rectal mucosa of patients with advanced HIV disease has been reported [10], and these proinflammatory cytokines have been associated with increased HIV1 replication in human macrophages [11]. The presence of the surface markers of HIV1 and the Gut • Nannini and Okhuysen the activated memory phenotype in the mucosal lymphocytes in the GALT [12], which may be secondary to the close proximity to antigenic substances in the GI tract, is another factor that facilitates HIV1 replication within this lymphoid tissue [13•]. The Gut and AIDS Opportunistic infections affecting the small bowel Diarrhea is a common symptom in HIV-infected subjects. The frequency of diarrhea has been associated with the degree of immunosuppression, with a reported prevalence of 6% in patients with less than 249 CD4 cells/mm3 and 3.2% in those with more than 700 CD4 cells/mm3 [14]. More importantly, in a prospective study, the presence of acute or chronic diarrhea was an independent predictor of mortality [15]. The incidence of the specific pathogens depends on several factors, such as the degree of the patient’s immunosuppression, the patient’s sexual practices, the specific population under study (geographic locale), the intensity in the level of diarrhea investigation, and the use of antimicrobial agents for prophylaxis. For example, trimethoprim–sulfamethoxazole (TMP–SMZ) for Pneumocystis carinii pneumonia (PCP) protects against infection with Isospora belli and Cyclospora cayetanensis, and rifabutin and azithromycin prevent Mycobacterium avium complex (MAC). Rifabutin, and to a lesser extent, clarithromycin, protect against Cryptosporidium species infection [16]. The most common organisms found in a prospective study that included extensive workup for chronic HIV-associated enteropathy in patients with less than 200 CD4 cells/mm3 were Cryptosporidium species (30.3%), Enterocytozoon bieneusi (23.8%), cytomegalovirus (CMV, 14.8%), Giardia lamblia (11.6%), and MAC (7.4%) [17]. Of note, concomitant enteric infections were reported in 37% of these patients. I. Belli and C. cayetanensis organisms were an infrequent cause of diarrhea in this study, reflecting the existing low prevalence of both in the United States. Other pathogens known to cause chronic diarrhea in HIVinfected subjects include Salmonella, Shigella, enteroaggregative Escherichia coli (EAEC), Campylobacter, Mycobacterium tuberculosis, and Histoplasma species, among others. Other causes of chronic diarrhea in these patients should also be considered, such as small bowel lymphoma, Kaposi’s sarcoma, and inflammatory bowel disease. The enteric protozoan pathogens are the most common infectious source of chronic diarrhea in patients with advanced HIV1 disease. These microorganisms are transmitted mainly through contaminated food or water; microsporidia may also be transmitted via aerosolized infected materials. Transmission of Cryptosporidium species between mammals and from person to person has been documented. Although these microorganisms usually produce disease in immunosuppressed patients, all of them, to a varied extent, have been associated with symptomatic 393 illness in nonimmunosuppressed individuals, mostly in children and in travelers. The clinical manifestations observed in HIV1-infected individuals are almost indistinguishable, including watery diarrhea, crampy abdominal pain, weight loss, anorexia, malaise, flatulence, nausea, and vomiting. Diarrhea can range from a few bowel movements a day to more than 50 stools a day. Laboratory evidence for intestinal malabsorption may be more common in microsporidiosis, and eosinophilia in isosporidiasis. These enteric pathogens affect the small intestine primarily, although Cryptosporidium species, C. cayetanensis, and microsporidia can also produce biliary tract disease [18,19], and Encephalitozoon intestinalis has been associated with dissemination to different organs (kidneys, liver, sinuses, and brain). In Cryptosporidium and Cyclospora species, after ingestion of the oocysts, the sporozoites implant in the enterocytes, primarily in the small bowel. The asexual replication allows meronts to reproduce and infect other epithelial cells. The sporogonic or sexual stage results in development of oocysts that are excreted in stools. In cryptosporidia, these oocysts do not need to be outside the host to sporulate and are immediately infectious to other hosts or can reinfect the same host without reingestion. Cryptosporidiosis is the most common infection isolated in AIDS patients with chronic diarrhea in developed as well as developing countries, and although Cryptosporidium parvum was initially the only species known to cause human disease, several non-parvum species, frequently found in animals, have also been reported in humans, especially in immunocompromised individuals [20•]. Cryptosporidia are localized in a distinctive intracellular but extracytoplasmatic niche, which may account, at least in part, for their resistance to antimicrobial agents [21]. More infections are reported during the warmer and more humid months, confirming a seasonal distribution of this pathogen. Cryptosporidiosis in patients with CD4 cell count above 180 cells/mm3 is usually cleared in less than 4 weeks, but most of the patients with less than 140 cells/ mm3 develop persistent diarrhea [22]; patients with less than 50 CD4 cells/mm3 may have a fulminant course of infection [23••]. The mechanism by which cryptosporidia produce diarrhea is not fully understood, but evidence suggests that it might be related to an enterotoxin-like product producing impaired intestinal absorption and increased secretion, to local production of several chemokines and cytokines leading to inflammation, and to enhanced apoptosis in adjacent uninfected cells [23••]. Cyclospora species reside in a supranuclear location of the enterocyte cytoplasm, distinguishing them from cryptosporidia, which are on the surface of the enterocytes. The prevalence of cyclosporiasis in the United States is low, but it is endemic in some parts of Central America, Peru, and Nepal [24]. Humans are the only known host for I. belli. I. belli oocysts can remain viable in the environment for months. 394 Small Intestine This protozoan is rarely identified as a cause of chronic diarrhea in developed countries (less than 1% or 2%), probably because of the widespread use of TMP–SMZ to prevent PCP, but it is more prevalent in tropical developing countries such as Haiti, where I. belli can account for 15% of the cases [25]. AIDS patients with isosporiasis usually respond to antimicrobial therapy with TMP–SMZ within a week [26]. The microsporidia are a unique group of obligate intracellular, spore-forming protozoa. At least 11 species of microsporidia are known to cause human disease. E. bieneusi, the most common in patients with AIDS, remains localized to the small intestine, whereas E. intestinalis has been shown to disseminate to distant organs [27]. Improvement in immune function can result in complete clinical response and normalization of intestinal architecture in conjunction with clearance of the parasites. Anther pathogen that can cause chronic diarrhea in HIV1-infected patients with advanced disease is CMV. Within the GI tract, CMV typically involves the esophagus and the colon, but it can be seen in any portion from the mouth to the anus. Diarrhea (frequently with hematochezia), fever, tenesmus, and abdominal pain are the most common presenting symptoms. The retina should be closely monitored for disease development in all patients with CMV GI disease. Diarrhea is one of the clues of disseminated MAC disease and is found in 40% of patients (usually with less than 50 CD4 cells/mm3), usually accompanied by fever (93%), night sweats (87%), weight loss (60%), hepatosplenomegaly (42%), and laboratory abnormalities such as anemia and increased alkaline phosphatase. M. tuberculosis infection can also involve the small bowel and ileocecal region, leading to masses, perforation, or fistulas. Clostridium difficile–associated diarrhea should also be included in the differential diagnosis of HIV1-infected patients with chronic diarrhea, especially in those receiving antibiotics or with prolonged hospitalization [28]. The clinical symptoms may be more severe in these patients than in those who are HIV-negative. Another pathogen that can present with diarrhea in about 50% of patients is Salmonella. Nontyphoidal salmonellosis has accounted for 35% of bloodstream isolates in HIV-infected African adults [29], and recurrent Salmonella septicemia has been listed as one of the AIDS-defining illnesses. Disseminated histoplasmosis occasionally presents as chronic diarrhea because any part of the GI tract (commonly the small bowel and right colon) is affected in 10% of patients. Diagnosis usually requires colonoscopy with visualization of lesions, such as plaques, ulcerations, small nodules, masses, or strictures. A positive urinary histoplasma antigen may provide support for the diagnosis. The prevalence of G. lamblia is relatively high in HIV1infected patients; however, in homosexual men, similar rates were found regardless of the presence of HIV. EAEC has been recovered from HIV1-infected patients with chronic diarrhea in Africa [30] and in the United States [31]; however, in some instances, EAEC can be asymptomatic. Clinical improvement in a placebo-controlled study using ciprofloxacin treatment for 1 week suggests that EAEC may be a true pathogen in this setting [32]. Other intestinal viruses, such as adenovirus, have been found in biopsy specimens of patients with chronic diarrhea, usually accompanying another more pathogenic agent. HIV1-induced enteropathy A variable proportion of patients with chronic diarrhea have no pathogen detected (15% to 46%), although this figure depends on the intensity of the diarrhea workup and the degree of immunosuppression. HIV1 enteropathy must be considered as a possibility in these cases, especially when there is no weight loss and the CD4 cell count is more than 100 cells/mm3. However, when there is poor response or no response to HAART and declining CD4 cell count, opportunistic enteric pathogens should be sought before attributing the symptoms to HIV-associated enteropathy. The mechanism by which HIV1 produces chronic diarrhea may be related to a Gp120-induced activation of a coreceptor (G-protein receptor 15/Bob) in the basal and apical surfaces of the intestinal cells leading to calcium signaling and microtubule loss, causing increased paracellular permeability and diarrhea [33•]. Biopsy specimens usually show reversal of the ratio of villus length to crypt depth. These patients should receive symptomatic therapy, and they respond satisfactorily to HAART. Diagnostic tools and therapeutic options The diagnostic workup for the HIV1-infected patient with chronic diarrhea should include stool culture, Giardia and Cryptosporidium enzyme immunoassay (EIA) or direct fluorescent-antibody assay (DFA), modified acid-fast bacilli (AFB) stain, Weber chromotrope-based stain for microsporidia (three stool samples needed to increase test sensitivity), C. difficile toxin detection test, and concentrated wet preparation for ova and parasites. If the initial tests are negative, upper endoscopy should be considered, especially in patients with less than 200 cells/mm3, obtained preferentially by biopsy from the jejunum [34]. MAC, Cryptosporidium species, microsporidia, CMV, and I. belli can cause colitis and can be identified in a colonic biopsy obtained through colonoscopy, especially if the patient has symptoms compatible with lower GI tract involvement. Specific treatment considerations for opportunistic pathogens are summarized in Table 1; however, HAART is the best option with which one can achieve clinical cure, prevention of recurrences, and parasite eradication in the case of some protozoan infections. The degree of immunosuppression prior to therapy is the major determinant of the course of the disease and the immune recovery after initiation of HAART. Nevertheless, this accomplishment can be difficult because anorexia, nausea, vomiting, and diarrhea are frequently present in these patients. Therapeutic HIV1 and the Gut • Nannini and Okhuysen 395 Table 1. Diagnosis and treatment of the most common opportunistic enteric pathogens in AIDS patients Organisms Diagnostic tests Therapeutic options Cryptosporidium species Modified AFB stains in stool (oocysts = 4 to 6 Partial response with paromomycin [50] or m in diameter); DFA and EIA tests available paromomycin + azithromycin [22]; moderate effectiveness with nitazoxanide [51];* antidiarrheal agents and hydration if severe infection; for biliary disease, therapy may include endoscopic procedure (ie, sphincterotomy) [52] Isospora belli Modified AFB stains in stool (oocysts = 20 to 33 TMP–SMZ for 10 days, followed by suppressive m × 10 to 19 m) therapy (TMP–SMZ once or 3 times a week); second choice: pyrimethamine + folinic acid or ciprofloxacin for 7 days Cyclospora cayetanensis Modified AFB stains in stool (oocysts = 8 to 12 TMP–SMZ for 10 days, followed by suppressive m in diameter) therapy (TMP–SMZ once or 3 times a week) Enterocytozoon bieneusi Weber chromotrope-based stain (modified Fumagillin for 2 to 3 weeks was shown to be trichrome) of stools effective [53]† Encephalitozoon Modified trichrome of stools, urine or Albendazole for 2 to 4 weeks intestinalis respiratory samples Cytomegalovirus (CMV) Intestinal biopsy with CMV inclusion bodies IV ganciclovir or foscarnet for 3 to 6 weeks is standard; a new attractive option is oral valganciclovir;‡ maintenance is usually not required but depends on severity of disease and response to therapy Micobacterium avium Blood, bone marrow, liver, or small bowel Macrolides (clarithromycin or azithromycin) with complex (MAC) culture; AFB stain in stool§ ethambutol ± rifabutin or fluoroquinolones or amikacin Salmonella species Blood and stool culture Fluoroquinolones for 4 to 6 weeks Clostridium difficile Detection of C. difficile toxin in stool Metronidazole for 10 days; oral vancomycin is a second option Histoplasma species Colonoscopy and biopsy; Histoplasma Amphotericin B followed by suppressive therapy urine antigen with itraconazole Giardia lamblia Trophozoites or cysts in wet mount exam; Metronidazole for 5 to 7 days antigen detection tests *Can be obtained in the US by calling 813-282-8544. †Available by phone at 800-547-1392 in US. ‡Valganciclovir (ganciclovir prodrug) was recently approved for CMV retinitis but should also work in gastrointestinal CMV. §Positive stool culture does not prove GI disease but could be a marker for subsequent disease. AFB—acid-fast bacilli; DFA—direct fluorescent-antibody assay; EIA—enzyme immunoassay; IV— intravenous; TMP–SMZ—trimethoprim–sulfamethoxazole. options, expected side effects, and significance of complete drug adherence should be carefully discussed with the patient to assure maximum compliance to obtain a satisfactory virologic and immunologic response. The Impact of HAART Changes in the spectrum of illness The introduction of HAART has dramatically affected the mortality in HIV1-infected individuals and the incidence of opportunistic infections, such as PCP, disseminated MAC disease, and CMV retinitis [35]. Furthermore, the incidence of opportunistic infections causing chronic diarrhea in patients with less than 200 cells/mm3 was also found to decrease from 53% in 1995 (the year before HAART) to 13% in 1996 and 1997 [36]. Likewise, another study, which consisted of 279 HIV1-positive patients who underwent upper and/or lower GI endoscopy, reported that the prevalence of opportunistic pathogens in biopsy specimens significantly decreased from 69% in 1995 (when none of the patients were receiving HAART) to 13% in 1998 (when 57% were on HAART) [37]. The widespread use of HAART has also shown an impact on some of the specific enteric pathogens. The incidence of cryptosporidiosis in patients with less than 350 CD4 cells/mm3 had a significant 60% reduction, from 0.76 (range, 0.44 to 1.24) to 0.31 (range, 0.14 to 0.58) episodes/100 person-years from the pre-HAART era (1990 to 1995) to the post-HAART era (1996 to 1998) [38••]. Consistently, a significant decrease in the prevalence of cryptosporidiosis (considering all the stool samples submitted for ova-and-parasite analysis), from 2.5% in 1992 to 0.7% in 1996, was reported in San Francisco [39]. The use of HAART has also affected the occurrence of other protozoan pathogens, such as microsporidia, the prevalence of which significantly declined, from 8.8% in 1993 396 Small Intestine to 2.9% in 1996, in an analysis that included more than 8000 stool samples from several clinical sites in southern California [40]. Positive effects of HAART One study assessed the impact of HIV1 protease inhibitors (PIs) on 282 patients with chronic diarrhea between 1993 and 1996 [41]. The group of patients receiving PIs was compared with the group not receiving them. About half of the patients had a pathogen identified (CMV, microsporidia, MAC, Cryptosporidium species, C. difficile, and G. lamblia were the most common), and both groups were comparable in this regard with respect to CD4 cell count and severity and duration of the diarrhea at baseline. The clinical response rate in patients receiving specific treatment for the identified organism was significantly higher in the group of patients receiving PIs than in the group not receiving them, with lower daily stool frequency and higher weight gain. Of note, decreased mortality in the group receiving PIs was also reported, especially in those with a CD4 cell count increase of at least 50 cells/mm3. These results emphasize the impact of immune recovery on the efficacy of specific therapy against the causative agent of chronic diarrhea in this population. A prospective study offered insight into the timing of clinical and microbiologic response in six HIV-positive patients with cryptosporidiosis or microsporidiosis after initiation of antiretroviral therapy. Five patients successfully responded to HAART within 1 month, and eradication of the microorganism as determined by polymerase chain reaction in stool samples was achieved in all cases only after 6 months of therapy [42]. The clearance of intestinal cryptosporidia after initiation of HAART was directly associated with rapid CD4 cell repopulation not only in peripheral blood but also at the intestinal mucosa level [43••]. Conteas et al. [44] studied 37 HIV1-infected patients with diarrhea due to E. bieneusi and found that 15 (40.5%) were able to clear the parasite infection; this clearance was directly correlated with a higher CD4 cell count increase (more than 100 cells/mm3) and the use of two or more antiretroviral agents and PIs. Diarrhea as a side effect of HAART Despite the remarkable decrease in the rate of opportunistic infections as causes of chronic diarrhea, the incidence of chronic diarrhea in HIV1-infected patients has not significantly changed from the pre- to the postHAART era, mainly because of the presence of drugrelated diarrhea [36]. Diarrhea is one of the main side effects in patients taking PIs as part of their antiretroviral regimen, and it could certainly have an impact on drug compliance and treatment efficacy through a recognized decrease in quality of life. Diarrhea is the most common side effect in patients receiving nelfinavir (up to 32%) and saquinavir (up to 19.9%). Ritonavir, amprenavir, and lopinavir have also been noted to produce diarrhea. The treatment possibilities for drug-related diarrhea include oat bran, psyllium, loperamide, calcium, diphenoxylate/ atropine, and pancreatic enzymes [45•]. PI-sparing regimens with a triple nucleoside or a nonnucleoside reverse transcriptase inhibitor are an attractive alternative that less often produces diarrhea. The gut and immune reconstitution Several studies have addressed the effect of HAART on peripheral lymph nodes, but not too many have looked at this effect on the intestinal mucosal immune system. One such study evaluated the short-term effects of antiretroviral therapy on the rectal mucosa in 15 patients (six were on a PI-containing regimen and nine were on double nucleoside therapy) 1 week after starting HIV1 therapy. These authors found a significant decrease in rectal tissue HIV1 RNA, p24 antigen content, and CD4 cell apoptosis and also a significant increase in the CD4 cell count from the rectal biopsies [46]. Despite effective suppression of HIV1 levels and CD4 increases in peripheral blood, other authors have documented less dramatic changes in the GALT of eight prospectively followed patients after 6 months on HAART [47]. A cross-sectional study of men on various antiretroviral regimens found HIV RNA in anorectal mucosa significantly less often in patients under HIV treatment (21%) than in untreated patients (49%). Among those with HIV RNA below 50 copies/mL in plasma, only 2% had detectable HIV RNA, and up to 28% had HIV DNA detected in rectal tissue [48]. This HIV DNA could represent a replicating competent virus, which certainly confirms the existence of risk for HIV1 transmission, even when the level of plasma HIV RNA is below the limit of detection. Few studies, however, have addressed the immune reconstitution that takes place after HAART initiation in patients with opportunistic pathogens. We prospectively followed seven AIDS patients with chronic cryptosporidiosis after they started a new antiretroviral regimen. Among the responders, mRNA for either IL-15 or interferon-γ and IL-4 could be detected in the jejunal biopsies [49]. This pattern of response resembles the one observed in nonimmunocompromised individuals with self-limited cryptosporidiosis. As previously reported in patients with advanced disease [10], these cytokines were barely present in the intestinal mucosa at baseline. Concomitant expansion of CD4 cells within the intestinal mucosa in a patient who recovered from cryptosporidiosis after the initiation of HAART was also reported [43••], confirming that immune recovery also takes place within the intestinal mucosa and, if it is significant enough, could be associated with parasite elimination. Conclusions The gut is currently considered an organ in which multiple immunologic interactions with HIV1 take place. The use of HIV1 and the Gut • Nannini and Okhuysen HAART has been shown to produce immune recovery in the GALT, making treatment of several opportunistic enteric pathogens possible where there had been no effective antimicrobial therapy. Many of the PIs administered as part of HAART produce diarrhea, negatively affecting quality of life, drug compliance, and regimen effectiveness. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 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