Outline. A 41 Year-old Male COMMON PITFALLS IN HIV/AIDS MANAGEMENT: A CASE-BASED APPROACH. Q1: What anti-fungal regimen would you start?

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1 Outline COMMON PITFALLS IN HIV/AIDS MANAGEMENT: A CASE-BASED APPROACH Considerations for antiretroviral use in patients with coinfections Concerning and how to manage drug-drug interactions ARV-other drugs ARV-ARV drugs Developing ARV resistance and management Weerawat Manosuthi, MD Bamrasnaradura Infectious Diseases Institute, MOPH A 41 Year-old Male Jul 14: This patient was transferred from OSH with a symptom of chronic headache for 2 weeks with alteration of consciousness. CT scan of the brain showed diffuse leptomeningeal enchancement without mass. Serum CRAG was positive. Upon admission, PE revealed oral candidiasis and hepatosplenomegaly. He had sluggish response to command and stiff neck was positive. Anti-HIV was positive. CBC: Hct 21%, WBC 2,500/ml, N58 %, Plt 54,000/UL. BUN/Cr: 30/1.4. Amphoterin B was started and he was transferred to BIDI. CSF finding: WBC 3-5 cells/hpf, positive india ink 3-5 cells/hpf, AFB-ve, CSF C/S: Cryptococcus neoforman Q1: What anti-fungal regimen would you start? 1. Amphotericin B 2. Fluconazole 3. Amphotericin B + fluconazole 4. Amphotericin B + flucytosine 5. Something else

2 Treatment in HIV-Infected Pts Amphotericin B plus Fluconazole mg/day Successful outcomes at day 14 41% in AmpB alone 27% in AmpB+Flu 400 mg/day 54% in AmpB+Flu mg/day A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70 Combination Antifungal Therapy for Cryptococcal Meningitis: Amp B vs. Amp B + Flucytosine vs. Amp B + Fluconazole Survival Rate For mortality at 70 days, P=0.04 for the comparison of amphotericin B plus flucytosine with amphotericin B monotherapy, and P=0.13 for the comparison of amphotericin B plus fluconazole with amphotericin B monotherapy. Fungicidal Effect P<0.001 for all comparisons Efficacy end point was a composite end :1. CSF conversion to negative culture results, 2. stable neurological function, and 3. survival at day 14. Combination Antifungal Therapy for Cryptococcal Meningitis: AmB vs. AmB + Flucy vs. AmB + Fluco Pappas P, et al. Clin Infect Dis 2009; 48: Jeremy D, N Engl J Med 2013;368: Jeremy D, et al. N Engl J Med 2013;368: Induction Phase: 2 weeks IDSA 2010 Thai 2014 WHO 2011 CDC AmB FC -Lipo AmB FC Alternative Regimens -AmB + Flu -Flu +FC -Flu -Itra FC intolerance (4-6wk) - AmB Lipo AmB ABLC 5 -AmB 1.0 -AmB Flu Alternative Regimens -Flu AmB FC -AmB Flu Alternative Regimens -AmB (5-7 d) + Flu (2 wk) -Flu FC -Flu Lipo AmB FC Alternative Regimens -ABLC 5 + Flu -AmB FC -Lipo AmB Flu -AmB Flu

3 Induction Phase: 2 weeks IDSA 2010 Thai 2014 WHO 2011 CDC AmB FC -Lipo AmB FC -AmB 1.0 -AmB Flu -AmB FC -AmB Flu -Lipo AmB FC Alternative Alternative Regimens Alternative Regimens Alternative Regimens Four Regimens considerations -Flu 1200 Efficacy -AmB (5-7 Adverse -ABLC 5 + Flu events for-amb AmB, + lipo Flu AmB, FC, Fluco 1. -Flu AmB +FC vs. Lipo AmB d) + Flu (2 wk) -Flu = FC -AmB FC -Lipo AmB > Flu -Flu -Flu With FC vs. without FC > > -Itra -AmB Flu (CSF sterilization & FC intolerance (4- survival benefit) 3. 6wk) With Flu vs. without Flu > > (minimal) - AmB (Only CSF sterilization - Lipo AmB 3-4 ) - ABLC 5 4. FC vs. Flu > > A 41 Year-old Male Jul 14: This patient was transferred from OSH with a symptom of chronic headache for 2 weeks with alteration of consciousness. CT scan of the brain showed diffuse leptomeningeal enchancement without mass. Serum CRAG was positive. Upon admission, PE revealed oral candidiasis and hepatosplenomegaly. He had sluggish response to command and stiff neck was positive. Anti-HIV was positive. CBC: Hct 21%, WBC 2,500/ml, N58 %, Plt 54,000/UL. BUN/Cr: 30/1.4. Amphoterin B was started and he was transferred to BIDI. CSF finding: WBC 3-5 cells/hpf, positive india ink 3-5 cells/hpf, AFB-ve, CSF C/S: Cryptococcus neoforman Amphotericin B + Fluconazole were given. Bone marrow Biopsy: Normocellular marrow, No granuloma, No organism HBsAg-positive but anti-hcv-negative Consolidation Phase: 8 weeks IDSA 2010 Thai 2014 WHO 2011 CDC Flu 400 -Flu 400- Alternative Regimens -Itra 400 -Fluconazole 400- (after 2-wk AmB) -Fluconazole (after 1-wk AmB of Flu) -Flu 400 Alternative Regimens -Itra 400 Q2: When would you start ART after starting fungal treatment in this patient? 1 week 2 weeks 4 weeks 8 weeks Others

4 ART Improved Survival Rate in Patients with CM Potential Advantages and Disadvantages of Starting ART early in CNS OIs Probability of Survival % 87.4% 55.3% % Received ART, n=281 P <0.01 Not received ART, n=268 -Patients who did not receive ART has 5 times more likely to death when compare to those who received ART -This effect was shown in the first few months after ART Potential advantages of early initiation of ART Prevent progressive immunodeficiency More rapid immune recovery More rapid resolution of OI Rapid reduction in mortality risk Prevention of further OIs and other morbidity Potential disadvantages of early initiation of ART High pill burden Co-toxicity Pharmacokinetic drug interactions Immune reconstitution disease No No (and serious) Time (months) Chottanapund S, Manosuthi W, et al. J Med Assoc Thai 2007;90:2104. More difficult to identify drug causing toxicity Optimal timing for ART initiation in patients with HIV infection and concurrent CM Insufficient evidence in support of either early or late initiation of ART. Because of the high risk IRIS in patients with cryptococcal meningitis, we recommend that ART initiation should be delayed Njei B, et al. Cochrane Database Syst Rev Boulware D, et al. N Engl J Med 2014;26:2487.

5 Overall Survival Survival in Patients with CSF 5 and <5 Cells/mm 3 at Randomization This patient Patients entered trial after 7-11 days of antifungal treatment = 4 weeks after randomization =<48 hours after randomization Deferring ART for 5 weeks after diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebro- spinal fluid Boulware D, et al. N Engl J Med 2014;26:2487. Boulware D, et al. N Engl J Med 2014;26:2487. Q3: Would you perform HIV resistance testing before ART initiation in this case? I would I wouldn t Probably Manosuthi W, et al. AIDS Research Therapy 2015;12:12.

6 Q4: What ARV regimen would you prefer in this case? TDF/FTC + EFV TDF/FTC + NVP TDF/FTC + RPV TDF/FC + PI/r Q5: Would you change your mind to perform HIV resistance testing before ART? I would I wouldn t Probably He had a positive HBsAg. His additional history is that he had been on HBV treatment for more than one year and he had not taken it for 2 weeks during this illness. HIV Drug Resistance Report HIV and HBV co-infection FTC, 3TC, and TDF have activity against both HIV and HBV If HBV or HIV treatment is needed ART should be initiated with combination of TDF/FTC or TDF/3TC as NRTI backbone If HBV treatment is needed and TDF cannot safely be used Alternative recommended HBV therapy is entecavir in addition to a fully suppressive ARV regimen Other HBV Rx regimens include Peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC Telbivudine in addition to a fully suppressive ARV regimen DHHS Guideline 2015

7 HIV and HBV co-infection Thai HBV Treatment Guideline 2555 Entecavir, 3TC or FTC, and Tenofovir have activity against HIV Their uses for HBV treatment without ART in patients with dual infection may result in selection of M184V: Entecavir, 3TC, FTC K65R: TDF Entecavir must be used in addition to a fully suppressive ARV regimen Entecavir should not be considered to be a part of ARV regimen If ART needs to be modified due to HIV virologic failure and patient has adequate HBV suppression ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression DHHS Guideline 2015 Q6: What ARV regimen would you prefer in this case? HBV resistance to 3TC in HIV Patients TDF/FTC + NNRTI TDF/FTC + NNRTI + PI/r 3TC + NNRTI + PI/r NNRTI + PI/r Something else Hepatology 1999;30:

8 Case 2: SK 37 year-old male Case 2: SK 37 year-old male Aug 09: Presented with fever, shortness of breath and weight loss in 2 weeks. Chest X-ray showed bilateral interstitial infiltrations. PCP was diagnosed and cotrimoxazole was given. His baseline ALT was 37 U/L and Cr 0.6 mg/dl. HBs Ag and HBeAg were positive but anti-hcv was negative. Sep 09: CD4 was 102 (8%). AZT/3TC/EFV was initiated. Mar 10: CD4 was 211 (14%). Oct 10: CD4 was 113 (7%) and plasma HIV-1 RNA was 4.1 log. Genotypic resistant test showed K103N, M184V, and D67N. ART was changed to TDF/AZT/LPV/rtv. Case 2: SK 37 year-old male H2 antagonist and PPI to ATV/r Aug 09: Presented with fever, shortness of breath and weight loss in 2 weeks. Chest X-ray showed bilateral interstitial infiltrations. PCP was diagnosed and cotrimoxazole was given. His baseline ALT was 37 U/L and Cr 0.6 mg/dl. HBs Ag and HBeAg were positive but anti-hcv was negative. Sep 09: CD4 was 102 (8%). AZT/3TC/EFV was initiated. Mar 10: CD4 was 211 (14%). Oct 10: CD4 was 113 (7%) and plasma HIV-1 RNA was 4.1 log. Genotypic resistant test showed K103N, M184V, and D67N. ART was changed to TDF/AZT/LPV/rtv. He developed diarrhea and abdominal pain. Omeprazole was given. LPV/rtv was substituted to ATV/rtv. Q7: Any concern raised at this moment? 1. No, it should be fine 2. There are some issues Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January

9 H2 antagonist and PPI to ATV/r Case 1: SK 37 year-old male Aug 09: Presented with fever, shortness of breath and weight loss in 2 weeks. Chest X-ray showed bilateral interstitial infiltrations. PCP was diagnosed and cotrimoxazole was given. His baseline ALT was 37 U/L and Cr 0.6 mg/dl. Sep 09: CD4 was 102 (8%). AZT/3TC/EFV was initiated. Mar 10: CD4 was 211 (14%). Oct 10: CD4 was 113 (7%) and plasma HIV-1 RNA was 4.1 log. Genotypic resistant test showed K103N, M184V, and D67N. ART was changed to TDF/AZT/LPV/rtv. He developed diarrhea and abdominal pain. Omeprazole was given. LPV/rtv was substituted to ATV/rtv. 2 weeks later: Fever and cervical lymphadenitis occurred. TB cervical lymphadenitis was diagnosed. IRZE was started Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. January Case 1: SK 37 year-old male Aug 11: plasma HIV-1 RNA was 4.8 log. Genotypic resistant test showed multiple RAMs. Case 1: SK 37 year-old male Aug 11: plasma HIV-1 RNA was 4.8 log. Genotypic resistant test showed multiple RAMs. Q8: What is the most likely cause of treatment failure in this patients? 1. Poor adherence 2. Adverse events 3. Others

10 Rifampicin markedly decreases blood levels of all protease inhibitors TB and HIV Co-infection: Drug-Drug Interactions PI Effect of rifampicin Saquinavir 80% Ritonavir 35% Indinavir 90% Nelfinavir 82% Amprenavir 81% Lopinavir/ritonavir 75% Boosted PI cannot be given with rifampicin, since PI levels are reduced by ~90% Combination of saquinavir (400 mg twice daily) and ritonavir (400 mg twice daily) or doubling of the usual dose of lopinavir/ritonavir can be considered; however, increase risk of hepatotoxicity Veldkamp AI, et al. CID 1999:29; Gray A, et al. AIDS 2006:20; La Porte CJ, et al. AAC2004:48;1553. Rifamycins should be included in TB regimens Many potential drug interactions with rifamycins and ARVs: PIs and NNRTIs: Rifampin may be used only with EFV or NVP Rifampin may not be used with RTV-boosted PIs Rifabutin recommended with NVP, other PIs Dosage adjustment may be necessary Optimal dosage not defined (in patients on PIs + intermittent rifabutin, low rifabutin levels and rifamycin resistance has been reported); monitor drug levels if possible MVC: requires dosage increase when used with rifampin RAL: Can be used with rifampin Thai Guideline 2014: ART and anti-tb Initiation NNRTIs efavirenz nevirapine protease inhibitor 1. protease inhibitor NNRTIs (efavirenz nevirapine) integrase inhibitor ( raltegravir) 2. NNRTIs integrase inhibitor 2IEZ+quinolone/10-16IE+quinolone streptomycin 2 Case 1: SK 37 year-old male Aug 11: plasma HIV-1 RNA was 4.8 log. Genotypic resistant test showed multiple RAMs. Q9: Does Etravirine remain active? 1. It does 2. It doesn t 3. May be

11 Case 1: SK 37 year-old male Aug 11: plasma HIV-1 RNA was 4.8 log. Genotypic resistant test showed multiple RAMs. Case 1: SK 37 year-old male Aug 11: plasma HIV-1 RNA was 4.8 log. Genotypic resistant test showed multiple RAMs. (On AZT, TDF, ATV/rtv) Q10: Does Rilpivirine remain active? Oct 10: K103N, M184V, and D67N. (On AZT, 3TC, EFV) 1. It does 2. It doesn t 3. May be NNRTI RAM: K103N Outline K103N Selected frequent by EFV Considerations for antiretroviral use in patients with coinfections Concerning and how to manage drug-drug interactions ARV-other drugs ARV-ARV drugs Developing ARV resistance and management Causes high-level resistance to NVP (~50-fold reduced susceptibility) and EFV (~20-fold reduced susceptibility) No effect on ETR and RPV? susceptibility

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