Download HIV1 and the gut in the era of highly active antiretroviral therapy

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.
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