HIV Treatment Update Monique Calil, Pharm.D. PGY-1 Resident Broward Health Medical Center Objectives Review antiretroviral therapy (ART) medications used for the treatment of HIV, including new combination products Outline the recommended, alternative, and other HIV regimens in treatment-naïve patients according to the updated 2015 Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents Summarize the updates on the treatment and prevention of opportunistic infections in HIV-infected individuals according to the latest 2015 DHHS Guidelines Epidemiology >1.2 million people in the U.S. are living with HIV 1 in 8 people are unaware 13,712 people with an AIDS diagnosis died in 2012 1
Who to treat with ART? Older recommendations: Based on CD4 count More recently, recommended everyone be treated with ART, but level of evidence depended on CD4 count CD4 350 to 500 cells/mm 3 (AII) and >500 cells/mm 3 (BIII) New recommendations: Results from START and TEMPRANO clinical trials published in 2015 Large, randomized, controlled trials Provided significant evidence of the benefit of early ART Strength of recommendation for all patients to be started regardless of CD4 count: (AI) INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. Jul 20 2015 Temprano ANRS 12136 Study Group. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. Jul 20 2015 Human Immunodeficiency Virus: Treatment Goals of therapy Prevent disease progression Decrease viral transmission Surrogate markers: Viral Load- Surrogate for treatment response Takes 8-24 weeks to achieve viral suppression in most patients Sub-optimal response versus virologic failure CD4- Immune response Should increase ~150 cells/mm 3 after first year of ART therapy, then 50-100 cells/mm 3 in subsequent years 15-20% patients with low CD4 count remain low Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015 ART Drug Classes Drug class Examples Comment 1) Entry Inhibitor: CCR5 antagonist Maraviroc (Selzentry) CCR5 Tropic HIV-1 2) Entry Inhibitor: Fusion Inhibitor 3) Reverse Transcriptase Inhibitors Enfuvirtide (Fuzeon) Nucleoside reverse transcriptase inhibitors (NRTI) Non-nucleoside reverse transcriptase inhibitors (NNRTI) Subcutaneous injection NRTI back-bone Abacavir+lamivudine Tenofovir+emtricitabine NNRTI - Efavirenz, nevirapine, rilpivirine, etravirine 4) Integrase Strand Transfer Inhibitor INSTI End in -tegravir 5) Protease Inhibitors PI End in -navir Darunavir, atazanavir, ritonavir (booster), fosamprenavir Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015 2
ART for HIV Infection Initial therapy generally consists of: Two NRTI s Tenofovir/ Emtricitabine Or Abacavir/ Lamivudine + One ARV from either of the following classes: INSTI NNRTI Boosted PI Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015 1) HIV Cell Entry 2) Cell Membrane Fusion 3) Reverse transcriptase converts viral RNA DNA 4) Viral DNA integrated into host DNA 5) Immature HIV strands cleaved infectious virus https://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Recommended Regimens before April, 2015 NNRTI-Based Efavirenz + tenofovir/emtricitabine Integrase Inhibitor-Based Raltegravir + tenofovir/emtricitabine Elvitegravir/cobicistat/tenofovir/emtricitabine Dolutegravir + tenofovir/emtricitabine Dolutegravir + abacavir/lamivudine Darunavir/ritonavir + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Only if baseline viral load < 100,000 copies/ml NNRTI-Based: Rilpivirine + tenofovir/emtricitabine (only if CD4 > 200 cells/mm 3 ) Efavirenz + abacavir/lamivudine Atazanavir/ritonavir + abacavir lamivudine Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015 3
ACTG A5257- A large randomized controlled trial (2014) Atazanavir/ritonavir (n=605) versus darunavir/ritonavir (n=601) or raltegravir (n=603), each with tenofovir/emtricitabine At week 96, all 3 regimens had similar virologic efficacy Lennox, Jeffrey L., et al. "Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor Sparing Antiretroviral Regimens for Treatment- Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial."Annals of internal medicine 161.7 (2014): 461-471. 2014 Analysis of 4 AIDS Clinical Trial Groups studies of efavirenz containing regimens (n=3241) and efavirenz-free regimens (n=2091) Conclusion Initial treatment with efavirenz was associated with a 2-fold increased hazard of suicidality compared with an initial regimen without efavirenz Mollan, Katie R., et al. "Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data." Annals of internal medicine 161.1 (2014): 1-10. However. D:A:D (Data collection on Adverse events of Anti- HIV Drugs) study (2014) Retrospective analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) Found no association between efavirenz use and suicidality Napoli, Andrew A., et al. "No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database." Journal of the International AIDS Society 17.1 (2014). 4
Cobicistat (Tybost) Pharmacokinetic booster that inhibits CYP3A4 Dose: 150 mg daily with Atazanavir 300 mg (Combination product Evotaz) 150 mg daily with Darunavir 800 mg (Combination product Prezcobix) 150 mg daily in combination product Elvitegravir/cobicistat/tenofovir DF/emtricitabine (Stribild) 150 mg daily in combination product Elvitegravir/cobicistat/tenofovir AF/emtricitabine (Genvoya) Misconception: Renal dose adjustments No adjustments necessary If used with tenofovir, CrCl < 70 ml/min, coadministration not recommended Tenofovir DF= disoproxil fumarate Tenofovir AF= alafenamide Pharmacokinetic enhancer: Cobicistat The 2013 Gilead Study 114 enrolled 692 treatment-native patients Atazanavir + tenofovir/emtricitabine boosted with ritonavir or cobicistat The two regimens had similar percentages of adverse events, changes in serum creatinine, and changes in bilirubin levels Gallant, Joel E., et al. "Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatmentnaive HIV type 1 infected patients: week 48 results." Journal of Infectious Diseases208.1 (2013): 32-39. Pharmacokinetic enhancer: Cobicistat 2014 Open-label, single-arm trial of darunavir/cobicistat N=313 Evaluated in combination with NRTIs (99% given tenofovir/emtricitabine) Week 48 81% of participants achieved HIV RNA < 50 copies/ml 5% discontinued due to adverse effects Tashima, Karen, et al. "Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1-infected treatment-nave adults." Journal of the International AIDS Society 17.4Suppl 3 (2014). 5
Tenofovir and renal dysfunction Tenofovir disoproxil fumerate Readily converts to tenofovir in plasma after absorption Risk factors: Advanced HIV disease Longer treatment history Low body weight, especially in females Pre-existing renal impairment Renal impairment Proximal renal tubulopathy Fanconi Syndrome Osteomalacia http://www.nature.com/ki/journal/v78/n11/full/ki2010344a.html New salt form of tenofovir: Tenofovir alafenamide Oral prodrug of tenofovir Converted to tenofovir and then to tenofovir-diphosphate intracellularly Remains stable in plasma resulting in plasma and higher intracellular tenofovir concentration Potential for adverse kidney and bone effects : tenofovir alafenamide < tenofovir disoproxil fumurate Clinical trials 2 double-blinded, phase 3, RCTs: Safety and efficacy Elvitegravir/cobicistat/emtricitabine/TDF (Stribild) versus Elvitegravir/cobicistat/emtricitabine/TAF (Genvoya) At 48 weeks, 800 of 866 (92%) in TAF arm and 784 of 867 (90%) in TDF arm: HIV RNA < 50 copies/ml Both regimens well-tolerated TAF arm: smaller decline in egfr (significant) Less proteinuria, less bone mineral density reduction in spine and hip Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. Jun 27 2015;385(9987):2606-2615 Tenofovir DF= disoproxil fumarate Tenofovir AF= alafenamide 6
Recommended Regimens after April, 2015 NNRTI-Based Efavirenz + tenofovir/emtricitabine Integrase Inhibitor-Based Raltegravir + tenofovir/emtricitabine Elvitegravir/cobicistat/tenofovir/emtricitabine Dolutegravir + tenofovir/emtricitabine Dolutegravir + abacavir/lamivudine Darunavir/ritonavir + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Only if baseline viral load < 100,000 copies/ml NNRTI-Based: Rilpivirine/tenofovir/emtricitabine (only if CD4 > 200 cells/mm 3 ) Efavirenz +abacavir/lamivudine Atazanavir/ritonavir + abacavir lamivudine Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015 Recommended Regimens after April, 2015 Integrase Inhibitor-Based Raltegravir + tenofovir/emtricitabine Elvitegravir/cobicistat/tenofovir/emtricitabine Dolutegravir + tenofovir/emtricitabine Dolutegravir + abacavir/lamivudine Darunavir/ritonavir + tenofovir/emtricitabine Alternative regimens NNRTI-Based Efavirenz/tenofovir/emtricitabine Rilpivarine/tenofovir/emtricitabine (Only with pre-treatment HIV RNA < 100,000 copies/ml & CD4 <200 cells/mm3) Atazanavir/cobicistat + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Darunavir/cobicistat or Darunavir/ritonavir + abacavir/lamivudine Darunavir/cobicistat + tenofovir/emtricitabine 7
Other regimens NNRTI-Based Efavirenz plus abacavir/lamivudine (Only with pre-treatment HIV RNA < 100,000 copes/ml) Atazanavir/cobicistat or Atazanavir/ritonavir + abacavir/lamivudine (Only with pre-treatment HIV RNA < 100,000 copes/ml) Lopinavir/ritonavir + abacavir/lamivudine Lopinavir/ritonavir + tenofovir/emtricitabine When Tenofovir or Abacavir cannot be used Darunavir/ritonavir + raltegravir (HIV RNA <100,000 copies/ml and CD4 >200 cells/mm 3 ) Lopinavir/ritonavir + lamivudine Once Daily Combination Pills Drug Name Brand Name FDA Approval date Picture Guidelines NNRTI-Based Efavirenz, emtricitabine, and tenofovir disoproxil fumarate Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine INSTI-Based Atripla July 12, 2006 Alternative Complera August 10, 2011 Alternative Elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate Stribild August 27, 2012 Genvoya November 5, 2015 Recommended Recommended Dolutegravir, abacavir, and lamivudine Triumeq August 22, 2014 Recommended https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines More Combination Pills Drug Name Brand Name FDA Approval date Lamivudine and zidovudine Combivir September 27, 1997 Lopinavir and ritonavir Kaletra September 15, 2000 Abacavir, lamivudine, and zidovudine Trizivir November 14, 2000 Emtricitabine and tenofovir Truvada August 2, 2000 Abacavir and lamivudine Atazanavir and cobicistat Epzicom August 2, 2000 Evotaz January 29, 2015 Darunavir and cobicistat Prezcobix January 29, 2015 https://aidsinfo.nih.gov/education-materials/fact-sheets/21/58/fda-approved-hiv-medicines Bold: Recommended by the DHHS Guidellines 8
Updates to the Treatment and Prevention of Opportunistic Infections in HIV-Infected Adults and Adolescents Pyrimethamine (Daraprim) Antiparasitic agent: Inhibits parasitic dihydrofolate reductase, inhibiting vital tetrahydrofolic acid synthesis Recommended for: Treatment and prophylaxis of Toxoplasma encephalitis and Isopora infection Prophylaxis of Pneumocystis pneumonia June 2015, no longer available in retail pharmacies Sold only through special pharmacy program Can no longer order from general wholesaler Be familiar with alternative agents for specific pathogens Use until pyrimethamine available Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America http://money.cnn.com/2015/11/25/news/companies/turing-pharmaceuticals daraprim-price-drop Toxoplasmosis Encephalitis Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii. Prevalence is 11% in the US Patients with CD4 counts < 50 cells/µl are at greatest risk Primary prophylaxis indications: Toxoplasma IgG (+) patients with CD4 count <100 cells/mm3 (AII) Toxoplasma seronegative patients receiving a PCP prophylaxis regimen not active against toxoplasmosis should have toxoplasma serology retested if CD4 count declines to <100 cells/mm3 (CIII) Prophylaxis against toxoplasmosis should be initiated if seroconversion occurred (AII) Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America 9
Treatment: Preferred Regimen (AI): Toxoplasmosis Encephalitis Pyrimethamine 200 mg PO once, then dose based on body weight: Body Weight 60 kg: Pyrimethamine 50 mg PO daily plus sulfadiazine 1000 mg PO q6h plus leucovorin 10 25 mg PO daily (can increase to 50 mg daily or BID) Body Weight >60 kg: Pyrimethamine 75 mg PO daily plus sulfadiazine 1500 mg PO q6h plus leucovorin 10 25 mg PO daily (can increase to 50 mg daily or BID) Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America Treatment: Preferred Regimen (AI): Toxoplasmosis Encephalitis Pyrimethamine 200 mg PO once, then dose based on body weight: Body Weight 60 kg: Pyrimethamine 50 mg PO daily plus sulfadiazine 1000 mg PO q6h plus leucovorin 10 25 mg PO daily (can increase to 50 mg daily or BID) Body Weight >60 kg: Pyrimethamine 75 mg PO daily plus sulfadiazine 1500 mg PO q6h plus leucovorin 10 25 mg PO daily (can increase to 50 mg daily or BID) Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America Toxoplasmosis Treatment: Alternative Regimens: Pyrimethamine (leucovorin) plus clindamycin 600 mg IV or PO q6h (AI TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID (BI) Atovaquoneb 1500 mg PO BID plus pyrimethamine (leucovorin) (BII) Atovaquoneb 1500 mg PO BID plus sulfadiazine (BII) Atovaquoneb 1500 mg PO BID (BII) Pyrimethamine (leucovorin) plus azithromycin 900 1200 mg PO daily (CII) Note: If pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX should be utilized in place of pyrimethaminesulfadiazine (BI). History of sulfa allergy, sulfa desensitization should be attempted using one of several published strategies (BI). Atovaquone should be administered until therapeutic doses of TMP-SMX are achieved (CIII).` Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America 10
Treatment: Toxoplasmosis Encephalitis TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg) (IV or PO) BID (BI) Small, Randomized trial (n=77) comparing trimethoprimsulfamethoxazole versus pyrimethamine-sulfadiazine 40 patients treated with TMP-SMX and 37 were treated with pyrimethamine-sulfadiazine There was no statistically significant difference in clinical efficacy during acute therapy Torre, Donato, et al. "Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS." Antimicrobial agents and chemotherapy 42.6 (1998): 1346-1349. Sulfa Desensitization Protocol example: After each dose, patients drank 6 oz. of water No pre-medication given Mild toxic effects: macular rash, fever, nausea= symptomatic treatment Anaphylactoid reactions: urticaria, dyspnea, severe vomiting, hypotension= stopped Toxoplasmosis Encephalitis Gluckstein,Ruskin. "Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ." Clinical infectious diseases 20.4 (1995) True/False: Assessment Questions Efavirenz/tenofovir/emtricitabine (Atripla) remains a preferred regimen for treatment naïve HIV-infected individuals False The two protease inhibitors darunavir and atazanavir that may require boosting with ritonavir can now be boosted with cobicistat and are included as Alternative regimens True Patients who are in need of a pyrimethamine-containing regimen for the treatment of an indicated opportunistic infection should have treatment withheld until pyrimethamine is available False 11
Conclusion New, emerging information from clinical trials are continually coming out It is important to keep up with the DHHS Guidelines on the treatment of HIV and opportunistic infections Pharmacists can serve as pivotal team members in both outpatient and inpatient settings by having the latest information accessible The Aids Info website (https://aidsinfo.nih.gov/ ) provides the guidelines from DHHS and the CDC and has pop-up announcements for updated information Questions? References Panel on Clinical Practices for Treatment of HIV Infection. "Department of Health and Human Services (DHHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. April 2015. Accessed October 2015. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed October 2015. Lennox, Jeffrey L., et al. "Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1: A Randomized, Controlled Equivalence Trial."Annals of internal medicine 161.7 (2014): 461-471 12
References Napoli, Andrew A., et al. "No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database." Journal of the International AIDS Society 17.1 (2014). Mollan, Katie R., et al. "Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data." Annals of internal medicine 161.1 (2014): 1-10. Gallant, Joel E., et al. "Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1 infected patients: week 48 results." Journal of Infectious Diseases208.1 (2013): 32-39. Tashima, Karen, et al. "Phase IIIb, open-label single-arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV-1- infected treatment-nave adults." Journal of the International AIDS Society 17.4Suppl 3 (2014). References Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, noninferiority trials. Lancet. Jun 27 2015;385(9987):2606-2615 Torre, Donato, et al. "Randomized trial of trimethoprimsulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS." Antimicrobial agents and chemotherapy 42.6 (1998): 1346-1349. Gluckstein, Daniel, and Joel Ruskin. "Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP- SMZ." Clinical infectious diseases 20.4 (1995): 849-853. 13