CROI Update: Opportunistic Infections April 8, 2016 Constance A. Benson, MD UCSD HIV & Global Health Rounds

2. Slide #1
CROI Update: Opportunistic
Infections
Constance A. Benson, MD
Professor of Medicine
Divisions of Infectious Disease and Global
Public Health
University of California, San Diego

3. Slide #2
Outline
• Introduction
• Cryptococcal meningitis
• Tuberculosis
• Toxoplasmosis
• Human papilloma virus
• Invasive pneumococcal disease
• HIV-related malignancies

4. Slide #3
Cryptococcal Meningitis

5. Slide #4
Pre-ART CRAG Screening and Pre-
Emptive Fluconazole
• Prevalence of CRAGemia 7.2% in LMIC in HIV-
infected persons with CD4 < 100
– Pre-emptive fluconazole reduces risk of progression
to cryptococcal meningitis
• CRAG screening at 18 Ugandan clinics for 2,135
pts with CD4 < 100
– CRAG+ prevalence 7.1%; 152 asymptomatic CRAG+
– If CRAG+/no evidence of CMfluconazole 800mg/d
for 2 weeks then 400 mg/d x 8 weeks + ART started
at 2 weeks Morawski B, et al. CROI 2016; Abstr. 159

6. Slide #5
Pre-ART CRAG Titers Associated with
Pre-Emptive Fluconazole Failure
• 59 (39%) CRAG > 1:160; 11 (7.3%) CM within 6 months
• 6-month risk: > 1:160 HR 9.2 (2.14, 39.58; P<0.01)
> 1:640 HR 12.10 (3.38, 43.37; P<0.001)
Morawski B, et al. CROI 2016; Abstr. 159

7. Slide #6
• Despite pre-
emptive Rx, ~25%
risk for meningitis
and/or death
• Higher risk in CRAG
> 1:160 and CD4
count < 50
Pre-ART CRAG Titer Associated with
Pre-Emptive Fluconazole Failure
Morawski B, et al. CROI 2016; Abstr. 159

8. Slide #7
CRAG Screening and Pre-Emptive
Fluconazole Therapy
• 500 screened
• CRAG+ 7.7% for CD4
<100 cells/mm3
– LP 97%; CSF CRAG+
39%
• CRAG < 1:160 in 50%
with CM vs. 80%
without CM
• 81% started on
fluconazole w/in 1d
• No difference in 6-
month mortality for
asymptomatic CRAG+
and CRAG-neg Faini D, et al. CROI 2016; Abstr. 760

9. Slide #8
CSF IL-13 Levels Distinguish Cryptococcal
Meningitis Relapse from CM-IRIS
CSF IFN-g, IL-17
Higher in IRIS
CSF IL-13 higher
In culture + relapse
*
*
*
Boulware DR, et al. CROI 2016; Abstr. 762

10. Slide #9
Tuberculosis

11. Slide #10
TB FasTrack: Empirical TB Treatment
in Advanced HIV Disease
• Can early mortality be reduced with identification
of HIV+ people at high risk of TB with rapid
initiation of TB treatment and ART?
• Study design: Clinic randomized trial in 24
primary care clinics in South Africa (N=3,030)
– High TB probability: immediate TB Rx; ART within 2
weeks
• Any one or more Hgb < 10; BMI < 18.5; + urine LAM
– Medium or low: further TB assessment within one
week and ART initiated
– Primary outcome: All cause mortality
Grant A, et al. CROI 2016; Abstr. 155

12. Slide #11
Study Assessments and Interventions

13. Slide #12
Empirical TB Treatment
and rapid ART initiation
did not reduce mortality;
risk of hospitalization
By 2m: TB Rx started in
• Intervention 61.6%
• Control 11.3%

14. Slide #13
TB Fast Track Summary
• The TB FasTrack algorithm
– Successfully identified people at highest risk of TB
– Substantially increased the proportion who
started TB treatment
– But…did not reduce the time to ART initiation
• Increased TB treatment coverage alone did
not result in a significant reduction in early
mortality
– Need better point-of-care TB diagnostic tests
– Prompt ART start for those with advanced disease

15. Slide #14
ACTG A5274: Empiric TB Treatment vs. IPT
in HIV-Infected Pts with CD4 < 50
Probability of death or AIDS progression
19.3% (95% CI: 15.8%, 23.4%) empiric
TB Rx vs. 15.3% (95% CI: 12.2%, 19.1%) IPT;
(p=0.13); no difference in time to AIDS
progression or death (p=0.11 log rank test).
Kumwenda J, et al. CROI 2016; Abstr 745

16. Slide #15
Activity of Beta-Lactams Against TB
• Groups of 15 pts with newly diagnosed,
AFB+/DS TB received one of three treatments x
14d:
– Meropenem 2gm IV or faropenem 600 mg PO both
with oral augmentin 500 mg/125mg TID or standard
RIPE
– Viable mycobacterial sputum load was significantly
reduced with both RIPE and meropenem +
augmentin
– AUC (P=0.002) and Cmax (P=0.066) were significantly
associated with meropenem activity
– 2-week activity similar to RIF/PZA/BDQ/PA-824Diacon AH, et al. CROI 2016; Abstr. 158LB

17. Slide #16
Higher TB Disease Severity is Associated
with Increased IRIS Risk
Walker NF, et al. CROI 2016, Abstr. 734
Median # days after start of TB Treatment to
ART Initiation for Non-IRIS vs. IRIS cases =
21.5d (13.8-39.8) vs. 15d (14-28)

18. Slide #17
Plasma Matrix Metalloproteinases
(MMPs) Are Elevated in TB-IRIS
Walker NF, et al. CROI 2016, Abstr. 734

19. Slide #18
Plasma MMP-8 Correlates with TB
Disease Severity
Walker NF, et al. CROI 2016, Abstr. 734
TB IRIS is associated with systemic markers of increased
tissue damage (plasma MMPs and PIIINP); may have a role
as predictive and diagnostic markers of TB-IRIS and as possible
therapeutic targets

20. Slide #19
Toxoplasmosis

21. Slide #20
Stopping Primary Prophylaxis for CNS
Toxoplasmosis in Virologically Suppressed Pts
• Collaboration of Observational HIV Epidemiological
Research in Europe (COHERE) – 10 European
cohorts with 11,015 HIV and T gondii co-infected
pts who started ART after 1997
– 99 pts with CNS toxoplasmosis during 79,220 pt-yrs F/U
– Incidence 0.7/1,000 pt-yrs in those on prophylaxis vs
0.8/1,000 pt-yrs for no prophylaxis
• Predictors of CNS toxoplasmosis
– Previous AIDS diagnosis; doubling CD4 cell count/year;
detectable viral load; use of primary prophylaxis was
not a predictor
Miro JM, et al. CROI 2016; Abstr. 765

22. Slide #21
Incidence of CNS Toxo in Virologically
Suppressed Pts with CD4 Count > 100 Very Low
Regardless of Primary Prophylaxis Use

23. Slide #22
Human Papilloma Virus

24. Slide #23
ACTG A5298: Phase 3 Trial of Quadrivalent HPV
Vaccine in Older HIV-Infected Adults
• RCT: Double blind, placebo-controlled; HIV+ age > 27 yr
– Vaccine or placebo at entry, week 8 and week 24
– Anal HRA, HPV, cytology, oral HPV at baseline and Q6m
– Primary endpointpersistent anal HPV in those without
infection at baseline Wilkin TJ, et al. CROI 2016; Abstr. 161

25. Slide #24
DSMB stopped the study
for futility 9/2015
Results suggest pts may have had
prior infection with HPV types not
found by anal HPV DNA or HPV
serologic testing  vaccination of
older HIV+ adults does not prevent
anal HPV or improve HSIL outcomes
ACTG A5298: Phase 3 Trial of Quadrivalent HPV
Vaccine in Older HIV-Infected Adults

26. Slide #25
Invasive Pneumococcal Disease

27. Slide #26
Invasive Pneumococcal Disease in
HIV-Infected Individuals
• 20-year trends in incidence, serotype, and antimicrobial
susceptibility for invasive pneumococcal disease (IPD) in HIV-
infected individuals (Toronto Invasive Bacterial Disease Network-TIBDN)
• 20.6% with IPD on prior TMP-SMX prophylaxis; 59.5% had prior
vaccination
Andany N, et al. CROI 2016; Abstr. 768

28. Slide #27
Decline in Annual Incidence of IPD in
HIV-Infected Persons 1995-2015
2011 Annual incidence still markedly higher
than that of the general population
(9.26/100,000 ) or in 15-64 yo (4.6/100,000);
isolates due to vaccine strains (PCV13,
non-PCV7) increased over time
Andany N, et al. CROI 2016; Abstr. 768

29. Slide #28
Increases in Proportion of Some Vaccine
Strains and in PCN and Ceftriaxone Resistance
• Most prominent serotype 2011-2015 is 19A (28.3%); PCN and
CTX resistance in non-meningitis strains 13.2%, but for
meningitis strains PCN-R 46% and CTX-R in 25%

30. Slide #29
HIV-Related Malignancies

31. Slide #30
Immediate ART Reduces Risk of Infection-
Related Cancers in HIV-Infected Persons
• START Study:
Immediate ART
reduced the overall
risk of cancer by
64%
– Hypothesis:
reduction higher for
infection-related vs
infection-unrelated
cancers primarily
determined by CD4
count and HIV RNA
levels

32. Slide #31
Immediate ART Reduces Risk of Infection-
Related Cancers in HIV-Infected Persons

33. Slide #32
Immediate ART Reduces Risk of Infection-
Related Cancers in HIV-Infected Persons
• Independent predictors
of infection-related
cancer were older age
(1.42 per 10yr); higher
BMI (1.08 per kg/m2); low
income region (0.32 for
high vs low); and HIV RNA
(2.32 per 1 log10 higher)
• Benefit of immediate
ART not solely
attributable to HIV RNA
suppression
Borges AH, et al. CROI 2016; Abstr. 160

34. Slide #33
Summary Messages (1)
• Screening for serum CRAG and pre-emptive
fluconazole may reduce risk of CM and possibly 6-
month mortality but failure of this strategy is more
likely the higher the titer (> 1:160)
– May not impact mortality in a low incidence setting
• Biomarkers (IL-13) may help distinguish CM-IRIS
from CM relapse
• Empirical TB treatment in advanced HIV disease
does not reduce mortality in a high TB incidence
setting but screening algorithms work
• Beta-lactam antibiotics may be useful adjuncts in TB
treatment

35. Slide #34
Summary Messages (2)
• TB disease severity is associated with
increased risk of TB-IRIS
– Biomarkers (plasma MMPs) may predict risk of or
aid in diagnosis of TB-IRIS
• Primary prophylaxis for CNS toxoplasmosis –
not necessary?
• HPV vaccination of older HIV-infected persons
does not reduce anal HPV infection or modify
outcomes (specifically HSIL)

36. Slide #35
Summary Messages (3)
• Invasive pneumococcal disease remains an
important OI in HIV-infected persons in the
current ART era
– Incidence rates still nearly 5-fold higher than in the
general population
– Increase in rates of beta-lactam resistance,
particularly for meningitis-associated strains
• Immediate/early ART initiation at high CD4
counts decreases the risk of HIV-related cancers
(specifically “infection”-related cancers)

37. Slide #36
Questions?