Gastrointestinal issues in HIV and other immunocompromised hosts

David Dockrell University of Edinburgh

Disclaimers

• Discussion focused on HIV but where relevant some discussion of transplant recipients and other immunocompromised groups.

• Recently British HIV Association Guidelines on Management of Opportunistic Infections have been updated and relevant data in section on Candidiasis (HIV Med 2019) and GI infections (in consultation)

• Challenges • few new drugs and tests • limited HIV OI specific data • few RCTs and much of data historical • reliance on evidence extrapolated from other immunocompromised groups or

infections at other sites• NO CONFLICTS relevant to this talk

Outline

• Update on People Living with HIV Writing • Review of upper GI syndromes• Review of lower GI syndromes• C. difficile infection in immunocompromised hosts• Issues with CMV infection failing to respond to

treatment

Background• Combination antiretroviral therapy (ART) available

since mid 1990s has led to dramatic decline in AIDS related mortality.

• Newer combinations of ART significantly reduce side effects, drug interactions and improve adherence.

• Single tablet once a day combinations becoming the norm with integrase inhibitor-based therapy vs generic combinations vs two drug combinations with dolutegravir in some patients

• Treatment as prevention (TasP), results of START trial encouraging earlier treatment and PrEP all changing the landscape

• U=U undetectable =untransmissible and in discordant couples no evidence of linked transmissions in large RCT

Background• NA-ACCORD data

o Life expectancy at age 20 in 2006 51.4 years vs. 57-61.7 in 2009 for controls.

o Drop in early mortality in first few years of therapy.

o Survival approaches non-HIV population, particularly when IVDA excluded

• Antiretroviral Therapy cohort collaboration 88K PLWHo First year mortality declining HR0.71

(0.61-0.83) 2008-10 vs 2000-3o Life expectancy 10-16 years less than

controlso Largely due to PWID and first year

mortalityo If CD4>350 after one-year therapy life

expectancy 78 yearsSamji et al PLoS one 2013: 8; e81355ATCC Lancet HIV 2017: 4; e349

Late diagnosis

• Significant number of individuals present late (CD3 count < 350 and very late CD4 count <200 cells per µl).

• PHE data December 2015;• Late diagnosis 40%• Increased in heterosexual, Black African, North of England, Scotland and

Wales.• Changing approach to testing (BHIVA 2008 Testing Guidelines) with

expanded list of indicator diseases and opt out testing in many areas (e.g. ITU) and universal testing where incidence >2/1000 or from country where prevalence >1%.

• But variable uptake still

HIV and the oesophagus.

• Approach based on CD4 count, medical and medication history and epidemiology.

• Odynophagia or dysphagia most common symptoms.• CD4 count < 200, Candida oesophagitis most common. OPC is a marker.

Empiric approach antifungal x 1wk. • If refractory PreART data 77% have ulceration: CMV (40%), idiopathic ulceration

(27%) most common and merit OGD.• CD4 count > 200 and no OPC. GORD most common. Trial of PPI merited

if no other indications for OGD. • Other common problems motility disorders and cancer.• Pill related oesophageal problems with AZT, ddC and tetracyclines.• However care with absorption of some ARV Integrase inhibitors and antacids

only certain combinations compatible, Rilpivirine, Atazanavir in presence of acid suppression.

Aetiology Odynophagia Dysphagia Odynophagia and Dysphagian=253 n=143 n=233

CMV ulcers (n=201) 106 (41.9%) 12 (8.4%) 83 (35.6%)Idiopathic ulcers (n=167) 88 (34.8%) 9 (6.3%) 70 (30.0%)Candida 18 (7.1%) 77 (53.8%) 43 (18.5%)oesophagitis (n=138)Candida and 21 (8.3%) 5 (3.5%) 24 (10.3%)ulcerations (n=50)HSV ulcers (n=19) 12 (4.7%) 2 (1.4%) 5 (2.1%)

Miscellaneous: Lymphoma (n=7), KS (n=6), GORD (n=10), CMV+HSV (n=4), MTB (n=2), Histoplasmosis (n=1), Normal oesophagus (n=24)

629 individuals with oesophageal symptoms refractory to one wk of antifungal therapy and who had subsequent OGD. PI-HAART significantly improved outcome. Bini et al. Dig dis Sci 2000: 45; 1301

HIV and the oesophagus.

OGD in HIV

• 752 HIV+ individuals in NCGM, Tokyo (2003-09)• OGD on basis of symptoms, FOB, lab tests, CT findings, colon

carcinoma screening• Enhanced Ca screening programme for asymptomatic individuals in

Japan• Aims;• Grade oesophageal candida,• Identify range of oesophageal pathologies• Determine risk factors

Nishimura et al PLoS One 2013: 8; e58217

Oesophageal candidiasis

• Oesophageal candidiasis remains the commonest GI OI• Associated risk factors

CD4 count < 200 cells/µLViral Load > 400 copies/mlSymptoms of dysphagia or odynophagia Presence of oropharyngeal candidiasis (OPC)

• OPC and typical symptoms can be sufficient to make diagnosis without endoscopy

• OGD not usually performed if high CD4 count, asymptomatic or without OPC

Role of endoscopy in oesophageal candidiasis

• Endoscopic diagnosis should be undertaken in patients with oesophageal symptoms without oropharyngeal candidiasis, in patients who do not respond to initial treatment, and in the case of relapse (Grade 1C, low quality of evidence).BHIVA 2019

• Confirmation by endoscopy should be used in cases with o symptoms of oesophageal candidiasis which fail to respond to initial therapy or

relapse, o cases without concomitant oropharyngeal candidiasis, o or cases where an alternative oesophageal condition is suspected, such as

oesophageal carcinoma in cases with dysphagia, where barium swallow may have been the initial investigation. Primary oesophageal Ca in era of ART;

Sq or Adeno Ca, RF Alcohol, Cigs, benign oesophageal diseaseMedian CD4 -376 and median period since HIV dx 8 y

Stebbing et al Arch Intern Med 2010: 170; 203

HIV and the oesophagus.

• Dysmotility disorders increasingly recognised. One survey of HIV+ patients found 89% had manometric abnormalities.

• Nutcracker oesophagus, hypertensive lower oesophageal sphincter, diffuse oesophageal spasm, non-specific oesophageal motility disorders, oesophageal hypocontraction.

Zalar et al Dig Dis. Sci. 2003: 48; 962

Patient characteristics

• MSM 63%, Heterosexual 17%, haemophiliac 16%• CD4 count > 200 cells/mL, 56%• VL < 40 copies 53%• Antiretroviral therapy 74%• GI Symptoms 36% (dysphagia 2%)

Nishimura et al PLoS One 2013: 8; e58217

Oesophageal candidaisis

• Significant burden of unsuspected oesophageal candidiasis• 35/62 (56%) no symptoms• 19/62 (31%) CD4 count > 200 cells/µl• 21/38 (55%) no OPC

• Results not altered by endoscopic severity

• Multivariate risk factors CD4 count > 200 cells/µl and VL > 400 copies/ml

Nishimura et al PLoS One 2013: 8; e58217

Upper GI syndromes

• Analysis of three cohorts 1991-2008, n=706 HIV+ undergoing UGI endoscopy, brussels

• As compared to earlier cohorts 2005-2008 later ART cohort demonstrated;

• Increased CD4 counts• Increased GORD, inflammatory gastropathy, GU, HP• Decreased oesophageal odynophagia or dysphagia, Oesophageal candidiasis,

KS

Nkuize M, et al HIV Med 2010: 11; 412

Diagnosis in oesophagitis unresponsive to Fluconazole

• Endoscopic diagnosis by swab and/or biopsy should be undertaken in patients with oesophageal symptoms without oropharyngeal candidiasis and in patients who do not respond to initial treatment or who relapse (Grade 1C, low-quality evidence).

• “Adequate and appropriate specimens must be collected to enable histological and virologic diagnoses, together with cultures and anti-fungal susceptibility testing for the identification of azole-resistant Candidastrains”.o Ulcer distal oesophagus typically showing intranuclear inclusion bodies in endothelial

cells and infiltrate. Culture alone does not establish diagnosiso Blood tests tests usually positive with CMV end-organ disease but have poor positive

predictive value and a negative test does not effectively rule out disease (Deayton et al Lancet 2004: 363; 2116 and multiple others)

HIV and the stomach• Gastric symptoms frequent but often due to non-HIV

related causes.• Helicobacter pylori infection may be less common in

HIV+497 HIV+ patients with UGIT Sxs. 23 (5%) GDU on endoscopy. 16 full histologic work-up. 81% had AIDS.31% HP+ vs. 69% in HIV- control group.8 (50%) CMV ulcers, 2 (12.5%) Cryptosporidium.Varsky CG et al AM J Gastro. 98: 93; 935

• Achlorrhydria and gastritis common, impact drug absorption.

• Opportunistic infections in stomach; CMV, KS, Lymphoma, MAC, Cryptosporidium, Syphilis, Crytpococcal, Leishmania etc.

HIV and the intestines.• Small and large bowel pathology common.• Chronic diarrhoea in HIV+ individuals with CD4 count > 200 may

be due to Crohns diseases, Ulcerative colitis, lymphocytic or collagenous colitis. Endoscopy with biopsy after initial non-invasive tests.

• Colonic ACA associated with lack of other RFs, younger age of onset and more advanced disease at presentation, Yeguez JF et al. Am Surg 2003: 69; 981

• CD4 count < 200 Bacterial infections, CMV, MAC, parasitic infections, NHL considerations. Investigations faecal leukocytes, bacterial culture C-difficile toxin, Ova and parasites with modified AFB and trichrome stains (for Microsporidia), Cryptosporidial antigen. Then lower and/or upper endoscopy

Infectious diarrhoea

• Meta-analysis post 2008 , 38 clinical trials incidence 18% (Asmuth et al.,Int AIDS Conf Amsterdam 2018)

• In some cohorts C. difficile now most common cause (Haines et al., AIDS 2013: 27; 2799) o Incidence 8.3 per 1000 in JHCC in US and has doubled

• Shigella incidence increased in HIV-positive MSMo Shigella, Enteroaggregative E. coli and Campylobacter all commonly reported

Also LGV (Hughes et al., Sex Trans Infect 2018)

Incidence rates and rate ratios of bacterial diarrhea among persons with HIV infection, by stage of HIV disease, Adult/Adolescent Spectrum of HIV Disease Project, United States, 1992–

2002.

Sanchez T H et al. Clin Infect Dis. 2005;41:1621-1627

© 2005 by the Infectious Diseases Society of America

CDI

• HIV associated with increased incidence CDI but presentation and course as well as response to treatment similar

Collini et al Curr AIDS Reports 2013: 10; 273

Lymphogranuloma venereum (LGV)• C. trachomatis serovars L1-3 infection STI

primarily MSM• Bloody diarrhoea with procto-

sigmoiditis/colitis• Cobble-stoned granular mucosa

and ulceration on sigmoidoscopy• Lymphohistiocytic cryptitis• Diagnosis PCR and specific

detection of serovars• Rx Doxycycline• Differential Crohn’s disease, CMV, HSV,

syphilis, N. gonorrhoea

Gallegos et al World J Gastro 2012: 18; 3317

Aetiology of diarrhea BHIVA OI GUIDELINES 2019Bacteria Parasites and fungi Viruses Non-infectious causes

Campylobacter spp. Cryptosporidium spp. Cytomegalovirus ART

Clostridioides difficile Cyclospora cayetanesis Herpes simplex virus Kaposi’s sarcoma

Escherichia coli (pathotypes) Giardia lamblia Rotavirus Lymphoma

Salmonella spp. Entamoeba histolytica Norovirus Pancreatic exocrine insufficiency

Shigella spp. Isospora belli Adenovirus

Mycobacterium tuberculosis Microsporidia Astrovirus

Mycobacterium avium-intracellulare complex Strongyloides stercoralis Coronavirus

Mycobacterium kansaii

Chlamydia trachomatis/ Lymphogranuloma verereum

CMV therapy and non-response

• GCV/Valganciclovir preferred therapy.• Non-response can reflect levels, resistance or immunosuppression• Resistance

• UL97 phosphotransferase, • UL54 DNA polymerase• For UL97 mutations foscarnet/cidofovir options but SE• UL97+ UL54 higher level resistance with less response to cidofovir and

potentially also foscarnet

Resistance in HIV primarily described in retinitis not GI disease (Jabs et al J. Infect Dis 2001: 183; 333).

CMV treatment

• New agents for CM therapy in transplantation• Maribavir (400mg BD or higher),

o inhibits nuclear lamin A/C phosphorylation, o UL97 T409M emergent resistance,o preemptive trial in HSCT, + VALGCVo Treatment data in SOT/HSCT with relapsed/refractory CMV

c70% response rate• Letermovir CMV terminase binding

o trial in prophylaxis but no data in treatmento Marty et al 2017 NEJM 2017: 377; 2433

• Case reports brincidofovir use with UL97 mutations, o also for adenoviriuso Oral agent , less nephrotoxic than cidofoviro Little treatment data

Britt et al AntiviralRes 2018: 159; 153Papanicoleau, G et al Clin Infect Dis 2019:68; 1255

Chronic diarrhoea• Bacteria; Salmonella, Shigella, campylobacter, C. difficile, EaggEc

(enteroaggergative EC require tissue culture adherence assay). Fever, leukocytosis, faecal wbc.

• Spore forming parasites; Cryptosporidium parvum, Isospora belli, Microporidia, Cyclospora.Non-inflammatory, malabsorption and weight loss.

• MAC Systemic, fever, weight loss, pancytopenia, lymphadenopathy, hepatosplenomegaly.

• Viral; CMV small volume bloody diarrhoea with faecal wbc.

• HIV enteropathy. No evidence of overt malabsorption but impaired epithelial barrier function.

• HAART PI based therapy, Kaletra (Darunavir) etc associated with diarrhoea. Kartalija M et al CID 99: 28; 701

Cryptosporidiosis

• Risk factors:oCD4 < 100 cells/µl, o children, owater borneo zoonotic outbreaks.

• Occasional sexual transmission.• Non bloody watery diarrhea, fever in minority• ART first line therapy• Nitazoxanide can be used if not significantly immunocompromised

Sensitivity of tests for Cryptosporidium

Coccidian parasiteAdapted to human, dog or animal. Species C. hominis and C. parvum most frequent in humanstesting

o Culture for Cryptosporidium no roleo Cryptosporidum antigen test by immunochromatographic strip test

o Sensitivity 47-70% but less if not C. hominis or parvumo Direct microscopy by Modified acid fast (Kinyoun) stain for oocysts

o negative test doesn’t exclude, repeat x 3o Sensitivity 70%

o Direct microscopy by direct fluorescent antibodyo Sensitivity approaches 100% if liquid stool less if semi-formed

o Cryptosporidium PCRo 18s rRNA or oocyst wall proteino Extraction to disrupt oocyst key enzymatic, chemical, mechanical in combinationo Sensitivity 93-100%

https://www1.health.gov.au/

Microsporidia

• Group of spore forming parasitic fungi; Encephalitozoon intestinalis, Enterocytozoon bieneusi

• Risk factors CD4 < 100, transplant recipients, elderly, travel• Contact with case or travel associated with transmission• Symptoms watery diarrhea, malabsorption occasionally extra-

intestinal e.g. encephalitis• Diagnosis chromotrope or chemofluorescent stains of stool, PCR and

if all else negative small bowel biopsy• Treatment ART and for E. intestinalis Albendazole

Chronic diarrhoeaNon-invasive investigations, discontinue/switch PI

Stool bacterial culture, C-difficile toxin assay, ova and parasites x 3

Specific diagnosis (~50%) No diagnosis

Symptoms suggest colitis

Colonoscopy and biopsy

No localising symptoms

UGIT endoscopy and biopsy

Specific diagnosis (~30%) Tests negative, faecal elastase Diagnosis HIV enteropathy

Lymphocytic diarrhoea in HIV

• Reports of persistent HIV associated enteritis despite ART

• Chronic diarrhoea; colonic biopsy confirms significant numbers of reports of microscopic colitis, lymphocytic colitis or collagenous colitis in patients on ART

• Important to perform HIV tests in any cause of chronic diarrhoea or where biopsies show CD8 lymphocytosis

Fernandes et al Int J STD AIDS 2008: 19; 524

Hepatobiliary disease

• Acalculous cholangitis formerly seen in AIDS. Associated with CMV, cryptosporidia or microsporidia but frequently idiopathic. Thickened oedematous GB on US with failure to visualise with radionuclide scintigraphy.

• AIDS cholangiopathy. Duct dilation with extrahepatic dilation and stenosis of papilla of Vater, sclerosing cholangitis, mixed sclerosing cholangitis and papillary stenosis or choledochal long stenosis or strictures. Also ~50% CMV or cryptosporidia/microsporidia.

• Now in HAART era most billiary disease gall stones.

Acknowledgements (BHIVA OI Guidelines)• Authors GI section DR Chadwick, RK Sutherland, S Raffe, ERM Pool, M

Beadsworth Candida D O’Shea, A. Freedman J. Cartledge, A. Freedman• Catherine Nieman Sims and Jacoby Patterson for information searches and

editorial work• Community and colleagues who contributed to consultations• Expert reviewers, Writing Group and editors

• Co-badging with BIA, Anna Goodman Guidelines Sec.

• BASSH, Riina Rautemaa-Richardson, sharing draft guidelines for VVC