Opportunistic Infection Updates, 2018 Richard A. Murphy, MD, MPH Harbor-UCLA Medical Center Geffen School of Medicine at UCLA
Objectives 1. Describe context for persistence of OIs globally 2. Provide updates on the diagnosis & treatment of OIs
Deaths in HIV-infected persons with advanced HIV disease Number of deaths, millions Despite the number receiving ART >20 million globally, total deaths in those with advanced HIV have declined slowly Total number on ART Number of deaths in advanced HIV Year Calmy et al CID 2018:66 (Suppl 2)
What proportion of patients begin ART with very advanced disease with CD4 cell count <100 in South Africa today? 1. 1 in 10 patients 2. 1 in 5 patients 3. 1 in 2 patients 4. None of the above
Patients are presenting to care with advanced HIV in South Africa Nationwide lab data from South Africa (NHLS) % entering care with CD4 <100 estimated (red) From 2005-11, % entering care w/ CD4<100 declined From 2011 on, % starting ART w/ CD4<100 not 2016: 17% CD4<100 Men 2x as likely as women Clin Infect Dis. 2018 Apr 1; 66(Suppl 2)
RFs for late presentation with advanced HIV in SA In 35 PHCs from 3 high burden districts in SA, >12,000 newly diagnosed patients during 2014-15 33% had CD4 < 200 at 1 st visit Risk factors for presentation with CD4<200: >50 years old, OR 3.4 (95% CI: 2.3-4.9) Male, OR 2.7 (95% CI: 1.5-4.9) Accessing care in urban inner city or urban township ~ OR 1.5 Very late presentation in SA overly represented by older males, accessing care in urban inner cities and townships Fomundam HN, et al. SAMJ 2018
Other reasons we still see patients with advanced HIV & OIs - Not all with HIV receive continuous care - Reasons include migration, incarceration, mental illness - Not all on ART achieve durable virologic suppression - Inadequate adherence in certain patient subgroups - Failure from drug resistance with NNRTI-based regimens https://www.cdc.gov/mmwr/volumes/67/wr/mm6701a6.htm?s_cid=mm6701a6_w#modalidstring_cdctable_0
Advanced HIV disease in African hospitals: Most patients are ART-experienced Homa Bay, Kenya (N=338) prospective study of HIV-infected admitted: 85% aware of HIV status at admission 65% ART-experienced 2/3 receiving ART failing with VL>1000 Recent Edendale, SA prospective study of HIV-infected admitted: 84% aware of status 79% were currently taking ART Homa Bay City, Kenya Ousely et al CID 2018:66 (Suppl 2) Gupta-Wright et al Lancet 2018; 392: 292 301
ART-experienced patients with OIs in Africa One contributor? Late recognition of ART treatment failure One contributors may be under-recognition in clinics of 1 st line ART failure (VL > 1000) Multiple studies: Patients with 1 st line failure not identified & switched promptly with switch delays of 4-6 months common Why? Reporting delays, clinician switch reluctance, poor patient follow-up Delayed 2 nd line ART switch linked in 3 African countries with incr. risk of OI/ death Cost for 2nd line regimens <$250/year AIDS Res Hum Retroviruses. 2017 Dec;33(12):1181-1184.
Fewer deaths if 2 nd line switch occurred after 1 VL >1000 With individual-based model of HIV progression, effect of 2 policies compared: (1) Switch after 1 VL > 1000 for those failing EFV-based ART (2) Switch after 2 VL values > 1000 Shroufi et al 22 nd IAC, 2018 22 nd IAC, Amsterdam
Case 1 26 yo HIV+ male with unknown CD4 count presents with 2 months of cough, fever and wt loss Previously on EFV-based first-line ART but no ART x 12 months and not taking cotrimoxazole. Over 24 hrs, acute on chronic shortness of breath ID Images, 2006 Peter Lokken and Richard Murphy
Case 1 Exam HR 126, RR 26, Temp 37.5, BP 95/53, O2 96% RA + oral thrush, no rash, absent BS on L Data WBC 14.5, Hb 11.6, PLT 298 and bicarb 14 meq/l ABG: 7.47 / pco2 26 mm Hg / po2 161 mm Hg supplemental O 2. EKG: Sinus tachycardia
Seriously ill HIV infected patients admitted in Cape Town with cough HIV-infected + cough any length hospitalized with >1 WHO danger sign N=484 (median CD4 89), 35% on ART at admission 12% died Linked with mortality: on ART at admission, unable to walk, low CD4 Among those on ART, 1/2 initiated within 6 months and 1/3 virologically failing Other WHO danger signs not linked w/mortality WHO Danger Signs: Cannot stand Temp >39C (102) RR > 30 HR > 120 Medical officer discharge diagnosis: - TB (62%) - Pneumonia (52%) - PCP (10%) - Other (3%) Griesel et al. AIDS Res Ther (2018) 15:5
Making the diagnosis of PCP with few tools What available tests suggest PCP in adv. HIV admitted to hosp. (in absence of histological diagnosis or CT)? PCP dx ed by> 1000 copies/ml of DNA by PCR Probability of PCP: 4 pts (25%), 5 pts (42%), 6 pts (61%) Model Assuming Access to Pulse Oximetry: SAJHIVM. 2018;19(1), a851. *Refer PCP to ICU? Cape Town: Mort. in PCP with resp. failure in ICU 60% with 98% intubated 25% with TB coinfection. PCP mortality in ICU in SA similar to hi income (Chiliza N PLOS One, 2018)
Chest x-ray What is the most likely diagnosis? A. Pneumocystis pneumonia B. Pulmonary tuberculosis C. Pulmonary cryptococcosis D. Pulmonary Kaposi s sarcoma
Case 1 Sputum samples revealed acid-fast bacilli What if the patient was not able to produce sputum? Any tests that could improve diagnostic yield if tuberculosis suspected in patient with CD4 < 100?
Added yield of urine LAM in HIV-infected inpatients RCT in S Africa + Malawi of consecutive inpatients with HIV N= 2600, 1/3 had CD4<100 - Any CD4 cell count, no current TB Rx - Standard arm: Sputum Xpert MTB/RIF - Intervention: Sputum Xpert + urine LAM + urine Xpert - 56-day mortality: No difference overall - 40% confirmed TB, only LAM positive - Among CD4<100 and in severe anemia, mortality was reduced 7%, with difference appearing after d/c Ankur Gupta-Wright CROI 2018 Poster 1117 Low added yield of urine Xpert
Urine LAM Activism at IAC Amsterdam, 2018
Case 1 A chest tube was placed. CD4 results: 78 cells/mm 3
Case 1 Four drug standard TB therapy was initiated with plan for initiation of ART within 2 weeks. What is the risk for immune reconstitution inflammatory syndrome (IRIS) in this patient and what can be done?
Paradoxical TB- IRIS Paradoxical TB-IRIS is a common complication when TB patients and low CD4 start on ART Meta-analysis: Incidence ~18% Hospitalization in 25% TB IRIS-related mortality 2% Major RFs Low CD4 cell count at ART start ART started rapidly after TB diagnosis, now standard of care with advanced HIV infection Presents with new / recurrent inflammatory features typically in first 4 wks of ART Slide courtesy of Graeme Mentjes
Impact of corticosteroids in preventing IRIS in HIV-associated TB RCT in Cape Town of prednisone vs. placebo in TB among HIV-infected at high risk for IRIS - N= 240 - CD<100 + ART naïve on TB therapy - Prednisone 40 mg/day for 2 wk; then 20 mg/day for 2 wk vs. placebo at start of ART - Risk of TB IRIS lower in prednisone group: 33% vs 47%, RR 0.7 - No diff. in mortality, infections, cancer. - Fewer hospitalizations in prednisone arm Slide courtesy of Raj Gandhi, MD
Case 1 With lung re-expansion, a parenchymal cavity was evident The patient was referred for outpatient ART ART was initiated 2 wks after initiation of TB therapy (without cortiosteroids)
Case 2 43 yo man comes to clinic with 2 weeks of HA, dizziness, and according to family rapid development of confusion 9 kg weight loss over 3 months No known PMH Rapid HIV test positive
Case 2 Exam: 37.2 HR 93 BP 118/70 RR 14 97% RA Tired but arousable and oriented No nuchal rigidity, non-focal neurological exam Data: LP: 4 WBCs, 55 RBC. Glucose very depressed. Protein mildly elev. India ink stain positive Opening pressure 52 cm of H2O
Elevated intracranial pressure linked with poor outcomes in CCM but manometers not routinely available
Using CSF flow rate during LP to measure ICP In Cape Town, 32 patients with CCM underwent 89 LPs with 22-G spinal needle. ICP was first measured with a manometer and then CSF flow rate in drops/min counted. Using 40 drops/minute cut-off, sensitivity was 91% for detecting raised ICP > 25 cm of H2O Only 5% of LPs misclassified with drop rate as normal when ICP actually elevated. When manometers not available, ICP can be accurately estimated with CSF drops/min with possible threshold of >40 drops/min. J Acquir Immune Defic Syndr 2017;74:e64 e66
Case 2 This patient (USA) received liposomal amphotericin B + 5-FC as initial induction therapy He received saline hydration (1 L NS) and K before IV dosing He developed acute renal failure by day 7 with GFR of 53 ml/min (reduced from 105 ml/min)
How common is acute kidney injury (GFR to <60 ml/min) in patients with CCM who receive amphotericin B deoxycholate and is there impact on subsequent mortality? 1. 20% develop AKI with no impact on mortality as AKI is reversible 2. 20% develop AKI with increased mortality 3. 40% develop AKI with no impact on mortality as AKI is reversible 4. 40% develop AKI with increased mortality
AKI common in CCM managed with AmB and mortality Substudy of large clinical trial of AmB + fluconazole in Uganda and SA. * AKI defined as CrCl of <60 ml/min AKI developed in ~40%; mean time to onset ~ 1 wk with RFs: Development of urine protein early on treatment Hi CD4 Med. CD4: AKI (CD4 49) vs. No AKI (CD4 14) AKI was associated with mortality: AKI: 10 wk mort: 51% No AKI: 10 wk mort: 29% (P=0.01) All patients with severe AKI (GFR <30 ml/min) died In all those surviving, AKI fully resolved Future role for 5-FC? **SA recs: W/ onset of AKI (Cr 2x) - hold AmB + incr. saline hydration + monitor If no improvement, cont. with (renal adjusted) fluconazole monotherapy Schutz C et al; OFID 2017 13 Govender et al SAJHIV Cryptococcal meningitis guidelines
Induction treatment recommendations S Africa 2 wks of AmB (1 mg/kg/day) plus fluconazole 800 mg/day Based in part on Viet. study in which this regimen had mortality similar to 4 wks of AmB monotherapy but had higher rates of CSF culture clearance The study also influenced WHO recs that recommended 2 wks of AmB + fluconazole WHO now recommends 1 wk of AmB +5-FC for induction phase of treatment. Why? Day et al NEJM 368;14 April 4, 2013
ACTA CCM trial ACTA trial, N=721 with CCM randomized (median CD4 25) in Malawi, Zambia, Cameroon, Tanzania Daily therapeutic LPs performed when OP elevated Patients randomized to AmB received 1 L NS daily, K and Mg suppl. Pts randomized to oral regimen, 1 wk of AmB or 2 wks of AmB. Next, AmB recipients randomized to flucon. or 5-FC. - 1 Oral arm: - Fluconazole [1200 mg/day] + Flucytosine (5FC) [100 mg /kg/day] for 2 wks - 4 IV arms : - 1 wk of amphotericin B (1 mg/kg/day) + oral drug - 2 wks of amphotericin B (1 mg/kg/day) + oral drug Malloy SF et al NEJM 2018
Antifungal combinations Mortality by study arm: Results : - At 10 weeks, lowest mortality was in the AmB + 5-FC group 1 week group - As partner drug, 5-FC superior to fluconazole = 40% reduction in death - Fully oral regimen met non inferiority outcomes for mortality - Option if IV/monitoring not feasible? - AmB regimens of more than 1 week linked with high rates of anemia The best arm was amphotericin B + 5-FC given 7 days The worst arm was amphotericin B + fluconazole 7 days Oral regimen 1 wk amphotericin 2 wk amphotericin
Flucytosine (5-FC) access where are we? 5-FC developed in 1957 Intracellular modification to 5-FU, joins fungal RNA, inhibits prot. synth. In lab, made during synthesis of FTC - off patent for decades! US cost $$$ = price manipulation by generic co s - Valeant 5-FC access virtually non-existent in LMICs but may be changing France: 5-FC sold by Meda Pharma $120 /14 days. Acquired by Mylan 2018: Mylan filed to register it with the WHO Prequalification Team (quality auditing for LMICs) opening door to broader access Mylan must register it in countries for 5-FC to become available Next step is pushing for wider access to liposomal amphotericin B...
Case 2 The patient has persistently elevated ICP of >30 cm of H2O After 2 weeks of induction therapy a VP shunt was placed The patient was demonstrated to be culture negative and was switched to fluconazole 400 mg/day as consolidation therapy. The plan was to initiate ART after 5-6 weeks
Question: After 2 wks of induction therapy with AmB and fluconazole, what proportion of patients still have positive CSF fungal culture with viable cryptococci? A. 5% B. 20% C. 33-50% D. None of the above
Fluconazole consolidation for CCM 400 mg/day sufficient? After 2 wks of AmB-based induction, up to 50% have viable C. neoformans in CSF CSF culture (+) after induction linked mort. As consolidation, fluc. 400 mg/day common but efficacy demonstrated after AmB + 5FC Sterile CSF Non-sterile CSF Impact of high-dose fluconazole consolidation tested in 2015 substudy After induction, patients received fluconazole 800 mg/day until CSF sterile, median 40 days With this strategy, relationship the mortality impact of (+) CSF culture at end of induction no longer observed and dosing was well tolerated Mortality week 2-6, post induction CSF culture (+) 35% vs post induction CSF culture (-) 27% Open Forum Infect Dis. 2015 Dec 28;2(4)
A different consolidation paradigm until 5-FC is accessible? In the COAT study residually CSF (+) patients required a median of 40 days of high dose fluconazole 800 mg/day Overall mortality through 48 weeks AIDS Research and Hum Retro. Vol 34, No. 5, 2018
CrAg titer predicts CSF cryptococcal disease Ethiopian study, all serum CrAg positive patients were offered LP, not just symptomatic CrAg <1:80 0% CSF CrAg positive CrAg 1:160 to 1:640 65% CSF CrAg positive CrAg >1:1280 100% CSF CrAg positive Significance of CNS symptoms in CrAg (+) patients? 1/3 of CrAg (+) patients with CNS cryptococcal disease had no symptoms; all had plasma CrAg >1:160 CID 2018; 66 (S2) S152-9 Policy implications? May be worthwhile to calculate titers for plasma CrAg (+) and be more assertive with CSF eval. particularly for those with plasma CrAg of >1:160
Case 3 25 yo female HCW with a history of cough and fever initiated standard TB therapy based on CXR w/ LUL infiltrate + hilar LAN 4 wks into treatment, the patient had a seizure and was admitted. At admission the HIV status was not known. CT head was normal CSF: 4 PMLs/uL and 2 lymphs/ul, elevated protein, mildly depressed glucose, CrAg negative, no opening pressure TB meningitis was suspected
Absence of CSF pleocytosis in HIV-associated TB-M Background: Absence of pleocytosis common in CCM but can this be the case in TB meningitis? Cohort study, Uganda In 85 microbiologically-confirmed, HIV-associated TBM cases, 28 (33%) had <5 cells CSF and in this group mortality was 39% Combining cohorts in Uganda, Zimbabwe, Brazil and Vietnam absence of CSF pleocytosis in 12% of HIV-associated TB-M and was associated with poor prognosis International Journal of Infectious Diseases 68 (2018) 77 78
Case 3 The patient was found to be HIV-infected with a CD4 cell count of 42 cells/ul How can the diagnosis of TB-M be confirmed?
TB meningitis and Xpert MTB/RIF Ultra Prospective study of Xpert MTB/RIF Ultra, a re-engineered PCR-based assay N=129 HIV infected adults with suspected meningitis 22 of 129 diagnosed with TB-M by composite standard of any (+) micro test 21/22 cases captured by Xpert Ultra consistent with a 95% sensitivity. Time to + result was 1 d vs med. 7 d for MGIT. Negative predictive value of Xpert Ultra was 99% (106 of 107 negative cases) If the Xpert Ultra was negative, TB-M virtually never present Lancet Infect Dis 2018; 18: 68 75 22 patients with TB-M diagnosed by at least 1 diagnostic test
Case 3 The diagnosis of TB-M was suspected clinically. The patient initiated empirically on 4 drug antituberculosis therapy + corticosteroids.
Other updates
Ready-to-use supplementary food in advanced HIV with TB Subjects: CD4<100 and underweight with TB coinfection Peanut-based RUSF 1000 kcal/day for 12 weeks vs. none. N=1805, median CD4 34 and with BMI <18.5 in 40% Despite greater weight gain, no effect on mortality at 24 or 48 wks No benefit in those with lower BMI It was not designed to look at impact on retention and such an effect may exist Overall mortality through 48 weeks Mallewa J, et al The Lancet HIV, Volume 5, 2018
Growth of AMR as a threat to patients with HIV-infection Lab-based study of blood cultures without patient-level information from 2 Ugandan hospitals; 2011 CLSI Standards followed 462 (14%) isolates grown from ~3,000 blood cultures Gram-positive isolates most commonly S. aureus 1/3 of S. aureus were MRSA, only 4% sensitive to TMP/SMX Gram-negatives Most common: E coli, 33% sensitive to ceftriaxone, 40% sensitive to cipro Klebsiella, 15% sensitive to ceftriaxone, 23% sensitive to cipro Salmonella isolates, 50% MDR with resistance to 3 drug classes Kajumbula et al EID 2018
Thanks for listening. Resources: SA HIV Clinicians Society Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: (2013) DHHS Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents (2018) Special thanks for slides & advice to Yunus Moosa, Raj Gandhi, Graeme Meintjes
Cryptococcal antigen (CrAg) screening WHO guidelines recommend CrAg screening in HIV with CD4<100 Ag detectable median 22 days before sxs Pre-emptive antifungal therapy for CrAg (+) HIV-infected patients prevents deaths Meta-analysis suggested that globally pooled prevalence of CrAg (+) is 6.5% in at CD4<100 and 2% in CD4 101-200 CrAg prevalence in inpatients higher (~10%) versus outpatients (~6%) May be reasonable to revise CrAg screening from CD4<100 to CD4<200 & perform routine inpatient CrAg screening Dipstick lateral flow assay for serum or CSF: $2/test and takes 10 min with sensitivity ~99% CID 2018; 66 (S2) S152-9