1. When to START During an OI
Cybele L. R. Abad, MD
Clinical Associate Professor,
Section of IDS, UP-PGH

2. Objective
To determine the optimal timing of ARV therapy in the setting of the most common opportunistic infections (OIs):
PCP TB
Cryptococcus
Others

3. The content of this discussion is taken mainly from Adult OI Treatment Guidelines

4. BACKGROUND
Mortality remains unacceptably high among patients who present with advanced immunodeficiency and serious OIs
It is as yet unclear when patients should start ART during the treatment for their OI to minimize this mortality risk

5. The rationale for either early or deferred initiation of ART is defined by a range of potential factors

6. Early START ADVANTAGES DISADVANTAGE
Prevent progressive immunodeficiency
High pill burden
More rapid immune recovery
Co-toxicity
More rapid resolution of OI
Pharmacokinetic drug interactions
Rapid reduction in mortality risk
Immune reconstitution disease
Prevention of further OIs and other morbidity
More difficult to identify drug causing toxicity
Potential advantages and disadvantages of starting antiretroviral therapy (ART) early in the course of
treatment for serious opportunistic infections (OIs)
Lawn, et al. Curr Opin Infect Dis February ; 24(1): 34–42.

7. DOH/WHO MANDATE

8. PCP

9. RECOMMENDATION
In someone not yet on ART, ART should be initiated, when possible, within 2 weeks of diagnosis of PCP (AI).

10. Zolopa, et al PLoS ONE 4(5): e5575. doi:10.1371

11. 142 123 141 283 subjects with OI/BI IA DA CD4 29, 33/M WEEK 48
In a randomized controlled trial of 282 patients with opportunistic infections (OIs) other than TB, 63%
of whom had definite or presumptive PCP, a significantly lower incidence of AIDS progression or death
(a secondary study endpoint) was seen in subjects randomized to early (median 12 days after initiation of
therapy for OI) versus deferred initiation of ART (median 45 days).
WEEK 48

12. OUTCOME IA DA
P value
DEATH or PROGRESSION
20 (14.2)
34 (24.1)
0.035

13. Of note, NO patients with PCP and respiratory failure requiring intubation were enrolled in the study
Initiating ART in such patients is problematic due to the lack of parenteral preparations and unpredictable absorption of oral medications

14. Tuberculosis

15. KEY POINT
Timing of ART in PTB/HIV depends on CD4; the lower the CD4, the earlier ART should be started

16. HIV/TB Co-treatment
Improves survival particularly for persons with CD4 cell counts <50 cells/μL and decreases the risk of additional opportunistic illnesses
Cite 130 and 134

17. Can achieve high rates of viral suppression, may improve TB treatment outcomes, and, despite higher rates of IRIS at low CD4 cell counts, is not associated with higher rates of other treatment-related adverse events.

18. PTB

19. At TB initiation vs after intensive phase vs. after completion SAPIT
POPN
INTERVENTION
RCT
OUTCOME
CD4 <500, AFB sm +
At TB initiation vs after intensive phase vs. after completion
SAPIT
Trial stopped early, mortality benefit in early ART (I and II)
CD4 <25 (median)
PTB
2 vs. 8 weeks
CAMELIA
Mortality rates decreased from / 100 PY in the
2-week arm to 8.28 /PY in the 8-week arm
CD4 77
Suspected confirmed PTB
Immediate ART (within 2 weeks) or early ART (8–12 weeks)
STRIDE
Mortality % in the immediate arm vs 26.6% on early ART experienced AIDS or death, (P = 0.02).
CD4 >220
Confirmed PTB
Early (after 2 weeks of TB treatment initiation) vs
delayed (until 6 months after initiation of TB treatment)
TB-HAART
The composite primary endpoint of TB treatment failure, recurrence and death
within 12 months of starting TB treatment occurred in 8.5% of patients in the early ART group and 9.2% in the delayed group (RR 0.91, 95% CI ; P = 0.9).
SAPIT – Africa
CAMILLA – Cambodia
Unlike SAPIT, STRIDE, and CAMELIA, the TB-HAART study concluded that ART can be delayed until after 6 months of TB treatment for patients with CD4 cell counts >220 cells/mm3.
, and CAMELIA, the TB-HAART study concluded that ART can be delayed until after 6 months of TB treatment for patients with CD4 cell counts >220 cells/mm3.

20. TB Meningitis

21. The optimal approach for initiation of ART in TB meningitis remains uncertain.

22. months after starting TB treatment RCT
POPULATION
INTERVENTION
METHOD
OUTCOME
Vietnam, TB Meningitis
n=253
ART initiation immediately (within 7 days of starting TB treatment) or 2
months after starting TB treatment
RCT
Early ART was associated with similar mortality and more frequent and severe adverse events (86%) compared to the deferred ART arm (75%).
The overall mortality rates in this study were very high (58%),
Torok et al, Clin Infect Dis (11):

23. RECOMMENDATION
ART is recommended in all HIV-infected persons with TB (AI).
ART should be started within 2 weeks after PTB treatment initiation when the CD4 cell count is <50 cells/mm3 and within 8 weeks of starting anti-TB treatment in those with higher CD4 cell counts (AI)

24. In patients with TB meningitis and low CD4 cell counts, early ART may pose a risk for severe adverse effects, and an expert should be consulted and careful monitoring provided.

25. Cryptococcosis

26. RECOMMENDATION
It is prudent to delay initiation of ART at least until after completion of antifungal induction therapy (the first 2 weeks) and possibly until the total induction/ consolidation phase (10 weeks) has been completed.

27. POPN
INTEVENTION
METHOD
OUTCOME
Africa, 2 sites
ART within 1 to
2 weeks (median 8 days) after fungal diagnosis with patients in whom ART was deferred until 5 weeks (median
36 days) after diagnosis
RCT
Amphotericin
Fluconazole
Higher 6-month mortality in the early ART group compared with the deferred ART group (45% vs 30%, P = 0.03).
Boulware et al, N Engl J Med. 2014;370(26):

28. KEY POINT
Delay in ART may be particularly important in those with ICP or in those with low CSF white blood cell counts (<5 cells/uL).
Timing of ART administration should be considered between 2 and 10 weeks after the start of antifungal therapy (BIII).

29. KEY POINT
In cases where sub-acute meningitis is suspected, caution must be exercised regarding initiation of ART

30. Others

31. OI
TIMING
Cryptosporidoisis, microsporidiosis,
PML
ART
PCP
2 weeks (AI)
Toxoplasma
2-3 weeks (CIII)
MAC
2 weeks (CIII)
PTB
2 weeks CD4 <50
8 weeks higher CD4
Bacterial pneumonia
Initiate ART early (AI)
Syphilis, Candidiasis
No special considerations
Cryptococcal meningitis
5-10 weeks (BIII)
CMV retinitis

32. TAKE HOME MESSAGE

33. Thank You!