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

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

The content of this discussion is taken mainly from Adult OI Treatment Guidelines https://aidsinfo.nih.gov/guidelines

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

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

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 . 2011 February ; 24(1): 34–42.

DOH/WHO MANDATE

PCP

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

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

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

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

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

Tuberculosis

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

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

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.

PTB

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 13.77 / 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 - 15.5% 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 0.64-1.30; 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.

TB Meningitis

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

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.2011 52 (11): 1374-1383

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)

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.

Cryptococcosis

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.

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):2487-2498

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).

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

Others

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

TAKE HOME MESSAGE

Thank You!