Published on February 26, 2014
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AN AIDS-DEFINING ILLNESS PRESENTING DURING ACUTE RETROVIRAL SYNDROME: A CASE DISCUSSION AND REVIEW OF THE LITERATURE FEBRUARY 21, 2014 LCDR Wesley Campbell, MC, USN, PGY-4
Disclosures I have no relevant financial relationships with any commercial supporters. Unlabeled/Investigational products and/or services will be mentioned in this CME offering.
Question Of the following, what is the most frequently described opportunistic infection in adult patients with acute retroviral syndrome? A) Herpes zoster B) Pneumocystis pneumonia C) CMV colitis D) CMV pneumonitis E) Cryptococcal meningitis
Answer-B Pneumocystis pneumonia Along with oral and esophageal candidiasis, the most commonly described OI in ARS OIs are rare in ARS and felt to be a consequence of transient CD4 T-cell depletion; nadir typically occurs 36 weeks post infection
Case CC: New diagnosis of HIV HPI: 21 y/o MSM college student diagnosed with acute retroviral syndrome 2 months prior in setting of prolonged gastrointestinal complaints
Pertinent History Presented with gastrointestinal symptoms, associated lethargy, and decreased appetite in early October with brief observation on general surgery to rule out appendicitis. Diagnosed with viral enteritis. After discharge from surgery service, spent time in Mexico with hospital admission there for ongoing symptoms. Received IV fluids, antibiotics and evaluation for hepatitis. Evaluated on 1 November in ED due to 2 days of worsening GI symptoms. Initiated on ciprofloxacin/metronidazole for colitis.
Physical Exam Initial Presentation: 8 Oct 2013 Afebrile; HR 62bpm; BP (111/68); RR 16/min; O2 96% RA Only diffuse abdominal discomfort on exam Re-presentation: 1 Nov 2013 Afebrile; HR 104bpm; BP (106/65); RR 16/min; O2 97% RA Only diffuse tenderness documented
Labs WBC Neut Bands Lymph CBC 10/8/2013 3.8 48% NA 40% CBC 11/1/2013 20.0 24% 37% 13% Tbili AST ALT Alk Phos LFTs 10/8/2013 0.6 52 59 67 LFTs 11/1/2013 1.1 93 85 85
Labs Viral hepatitis panel Negative C-diff PCR Negative Stool Culture Negative Fecal leukocytes Negative Stool Crypto Ag Negative Stool O&P Negative HIV rapid Positive Giardia Ag Negative RPR Negative Quantiferon Negative Toxoplasmosis serology Negative EBV serologies Negative CMV PCR 16,169 copies CMV titers Ig ordered, not collected
HIV Labs 1 Nov 2013 8 Jan 2014 CD4 count 524/6% 605/15% 390/13% CD8 8054/0.07 2823/0.21 2214/0.18 VL 3 Dec 2013 1,096,247 4,010,146 532,574 Genotype B K103S mutation HIV ELISA pos; Indeterminate western blot (1Nov)
CT Image 8 Oct 2013
CT Image 1 Nov 2013
Hospital Course Upper and lower endoscopy Upper Stomach- moderate gastropathy, mild patchy antral gastropathy Small hiatal hernia Mild duodenitis Normal esophagus Lower Patchy colitis throughout colon with ulcer on ileocecal valve Patchy ileitis Rectal inflammation Small internal hemorrhoids
Pathology Duodenal mucosa with mild intraepithelial lymphocytosis and focal villous blunting Small and large bowel with scattered Cytomegalovirus (CMV) inclusions
Discharged Diagnosed with CMV colitis/enteritis and HIV infection Started on IV ganciclovir, transitioned to oral, diarrhea resolved 3weeks thereafter Enrolled in AVRC Acute HIV study
Clinical Questions How often is acute seroconversion marked by an opportunistic infection, namely CMV colitis? What symptoms predominate in ARS that would have lead to earlier testing? What options are there for first-line therapy in setting of baseline resistance mutation and high viral load?
Acute Retroviral Syndrome & OIs Acute Retroviral Syndrome syndrome occurs in 1090% of acute HIV infections (Sterling, PPID) Opportunistic Infections in acute retroviral syndrome (ARS) are even more rare Oral/esophageal candidiasis Pneumocystis pneumonia Cryptococcal meningitis
Other OIs in Acute Retroviral Syndrome Remainder of literature is description of case reports M. Kansasii Cytomegalovirus pneumonia and hepatitis Cytomegalovirus colitis Cytomegalovirus encephalitis Focal segmental glomerulosclerosis- HIV nephropathy
CMV in HIV Historically a disease of chronic infection with progression to Acquired Immunodeficiency Syndrome (AIDS) Pre-ART: Occurred in 21-44% of patients with spectrum of targeted organ to disseminated disease (Masur 1996) Today: Estimated at 0.75-3.2 cases per 100 personyears (Salzberger 2005) Detected in up to 30% of HIV patients with CD4<100
CMV Disease in ARS 2-3 published case reports of CMV gastrointestinal disease during ARS (none with indeterminate WB) Typical mononucleosis syndrome plus: +/-Oral lesions Nausea/vomiting Moderate transaminitis Discussion of primary infection vs. reactivation of CMV
Evaluation for CMV in ARS CMV testing Documentation of IgG and IgM serology status CMV DNA PCR Tissue specific immunohistochemical staining Hepatic Pulmonary Colonic biopsy
Evaluation for CMV in ARS Early reports in pre ART era Few documented CMV complications with acute HIV infection Serologies used to discuss acute co-infection Post ART More routine use of advanced testing at diagnosis
CD4 Response in ARS with CMV Publication Diagnosis CD4 (Acute) CD4 (Conv.) VL (copies/ml) Bonetti (1989) ARS (p) 1410 30 NT Bonetti (1989) ARS (p) NT 530 NT Raffi (1990) ARS (p) NT NT NT Schindler (1990) ARS (p) NT NT NT Nguyen (1991) ARS (p) NT NT NT Gupta (1993) Colitis (p) 255 1098 Qualitative Berger (1996) Encephalitis (p) 458 (19%) 1,270 (37.1%) 121,150 Jouveshomme (1997) Alveolitis (p) 1020 999 NT Smith (2000) Colitis (r) NT 800 NT Vietri (2002) Esophagitis (?) 452 643 160,000 Capetti (2006) Colitis (?) (WB positive at diagnosis) 1305 NT 750,000 Von Both (2008) Pancolitis (r) (WB positive) 164 932 (2yrs) 3,080,000 Hong (2011) Pneumonia/hepatitis (P) 242 460 6.7log ARS- Acute Retroviral Syndrome; (p)-primary CMV; (r)- reactivation CMV; (?) unknown CMV status
Summary of Cases Data across cases changes with era of AIDS epidemic CD4 count role not completely documented or explained in ARS, but likely represents decreased functional count Our patient had a CD4 count of 6% total lymphocyte count HIV viral load over 100,000 copies may have some correlation to CMV infection Our patient had over 1 million copies
Question What constellation of symptoms would represent the highest pretest probability for primary HIV infection? A) 19 y/o MSM who is in a monogamous relationship with an HIV (+) partner with 5 days of headache, subjective fever, night sweats B) 22 y/o heterosexual male with 1 week of malaise, subjective fevers and vomiting who had an unprotected sexual encounter 2 weeks prior C) 20 y/o heterosexual male with multiple unprotected sexual encounters 2 months prior, with intermittent fever, rash, loss of appetite, myalgias, and loss of energy *based on 2002 prospective cohort at UCSF
Answer-C Prospective cohort from UCSF explored systemic complaints in patients being tested for HIV with risk factors for HIV exposure in preceding 3 months Fever was only symptom highly sensitive for HIV infection, while combinations of symptoms increased specificity and likelihood ratio for primary infection Fever with rash 91% specific in adult patients Diarrhea was of low sensitivity 46%
Recognition of Seroconversion Early identification Allows for appropriate screening Interventions during highly transmissible period “Mononucleosis-Like” syndrome Nonspecific complaints often overlooked Requires exploration of possible risk factors What constellation of symptoms would trigger evaluation?
Prospective Cohort- ARS Symptoms Hecht 2002 (UCSF)
Prospective Cohort- ARS Symptoms Hecht 2002
Prospective Cohort- Viral Load and Symptoms Kelley 2007
Question According to recent CDC assessments, the estimated rate of primary drug resistance in treatment-naïve patients is: A) 14.6% B) 25% C) 8.3% D) 12.1%
Answer- A A-14.6%: CDC data from 2006 from 10 states and 1 public health department published in 2010 (Wheeler, et al. 2010) B- 25%: Estimates for San Diego County with small cohort (Smith, et al. 2007) C- 8.3%: 2004 estimates (Weinstock, et al. 2004) D- 12.1%: East Coast cohort, industry sponsored through Merk (Huang, et al. 2008)
Transmitted Resistance- Testing Primary resistance in U.S. estimated at 8.3% (2004) Sax 2004
Resistance Testing In Unknown Duration of Infection Smith, 2007
Transmitted Resistance- Recent Estimates Huang, 2007
Transmitted Resistance- Recent Estimates ARV resistance- 12.1% NNRTI- 9.8% NRTI- 4.5% PI- 1.8% Predictors MSM CD<500 Huang, 2007
Specific NNRTI Mutation Prevalence Wheeler 2006
A Regimen for Our Patient 1 Nov 2013 8 Jan 2014 CD4 count 524/6% 605/15% 390/13% CD8 8054/0.07 2823/0.21 2214/0.18 VL 3 Dec 2013 1,096,247 4,010,146 532,574 Expressed interest in a single-pill regimen or oncedaily regimen Ease of attending classes Social constraints
Question True or false: Elvitegravir/cobicistat/tenofovir/emtricitabine (“Quad pill”) has been FDA approved for use in treatment-naïve patients with primary resistance to NRTIs and NNRTIs. A) True B) False
Answer- False Original trials excluded patients with NRTI or NNRTI or PI mutations Source- http://clinicaltrials.gov/show/NCT00869557
Unpublished Data K White*, et al. Emergent Drug Resistance from the HIV-1 Phase 3 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Studies through Week 96 Presented at CROI 2013
K White*, et al. Emergent Drug Resistance from the HIV-1 Phase 3 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Studies through Week 96 Presented at CROI 2013
Our Patient Experienced an AIDS-defining illness at diagnosis Exceedingly rare event with unknown implications on progression of disease or response to therapy CMV enteritis resolution after short course of valganciclovir and rebound of his CD4 count implies limited disease
Clinical Plan Patient has exhibited insight into complexities of his diagnosis Discuss with patient protease inhibitor vs. integrase inhibitor-based regimen given available data Choices of ART influenced by early genotype testing and viral load If placed on the “Quad pill” most likely resistance mutation to emerge is M184V and becomes apparent by approximately12 weeks* At last visit, treatment regimen was yet to be determined *K White*, et al. Emergent Drug Resistance from the HIV-1 Phase 3 Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Studies through Week 96 Presented at CROI 2013
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Thank You Dr. Blanchard, MD UCSD Pathology department UCSD GI Department Dr Bendin, MD, UCSD Med/Peds Resident
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