Wesley Campbell, MD, of U.S. Navy Medicine, presents "An AIDS-Defining Illness Presenting during Acute Retroviral Syndrome: A Case Discussion and Review of the Literature" for AIDS Clinical Rounds at UC San Diego

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2. 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

3. Disclosures


I have no relevant financial relationships with any
commercial supporters.
Unlabeled/Investigational products and/or services
will be mentioned in this CME offering.

4. 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

5. 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

6. 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

7. 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.

8. 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

9. 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

10. 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

11. 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)

12. CT Image 8 Oct 2013

13. CT Image 1 Nov 2013

14. 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


15. Endoscopy Images

16. Endoscopy Images

17. Endoscopy Images

18. Pathology


Duodenal mucosa with mild intraepithelial
lymphocytosis and focal villous blunting
Small and large bowel with scattered
Cytomegalovirus (CMV) inclusions

19. Pathology- H&E

20. Pathology- Immunohistochemical

21. 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

22. 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?

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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%

33. 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?

34. Prospective Cohort- ARS Symptoms
Hecht 2002 (UCSF)

35. Prospective Cohort- ARS Symptoms
Hecht 2002

36. Prospective Cohort- Viral Load and
Symptoms
Kelley 2007

37. 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%

38. 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)

39. Transmitted Resistance- Testing

Primary resistance in U.S. estimated at 8.3% (2004)
Sax 2004

40. Sax, 2004

41. Resistance Testing In Unknown Duration
of Infection
Smith, 2007

42. Transmitted Resistance- Recent
Estimates
Huang, 2007

43. Transmitted Resistance- Recent
Estimates

ARV resistance- 12.1%
 NNRTI-
9.8%
 NRTI- 4.5%
 PI- 1.8%

Predictors
 MSM
 CD<500
Huang, 2007

44. Specific NNRTI Mutation Prevalence
Wheeler 2006

45. 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

46. 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

47. Answer- False


Original trials excluded patients with NRTI or NNRTI
or PI mutations
Source- http://clinicaltrials.gov/show/NCT00869557

48. 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

49. 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

50. 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

51. 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

52. Works Consulted
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53. Thank You




Dr. Blanchard, MD
UCSD Pathology department
UCSD GI Department
Dr Bendin, MD, UCSD Med/Peds Resident