Objectives Identify modes HIV transmission and methods of prevention. HIV Treatment in 2010 Lisa D. Inge, Pharm.D., BCPS, AAHIVE Assistant Director, Jacksonville Campus Clinical Assistant Professor University of Florida, College of Pharmacy October 8, 2010 Describe the decisions involved in initiation of antiretroviral therapy. Defend the reasons for use of preferred, alternative and acceptable regimens in treatment naïve patient population. Recognize the potential for common side effects and drug interactions with antiretroviral therapy. HIV Infection Where are we in 2010? Are we back where we started? HIT HARD HIT EARLY 1995 NEJM Recently In 1996 the introduction of protease inhibitors decreasing the death rate of those infected by 50%. In 2007 an estimated 1.1 million US individuals infected with HIV (not diagnosed with AIDS). 1 In 2006 Schackman, Lifetime cost 24.2 years after if care is started with a CD4+ count of <350 cell/mm3 cost $618,900/pt. 2 22.5 years if care is started at a CD4+ count of <200 cells/mm3: cost $567,000/pt. 2 Ho D. Hit Hard Hit Early. NEJM 1995 1.Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report 2008, (Vol. 39) 2. Schackman BR, Gebo KA et. al. The Lifetime Cost of Current HIV Care in the US. 2006. HIV Surveillance in 2010 One million American are living with HIV 1 in 5 is unaware of their status ~56,300 new cases per year ~154 new infections daily Centers for Disease Control and Prevention. HIV Surveillance Report, 2008; vol. 20. Published June 2010. Accessed 9/15/10. 1
Case 1: Samantha A 22 year old female college student who has been sexually active for the past 5 years. She uses condoms most of the time but was recently diagnosed with bacterial vaginosis. She presents today for her annual physical. MH: recent yeast infections; herpes (last outbreak 2 yrs ago) FH: mom 46 DM; Dad 47 HTN SH: last sexual encounter 2 days ago Smoking N/A Recreational drug use none Should Samantha be offered an HIV test? Surveillance Risk Factors HIV Natural Disease Course Blood & body fluids Sexual transmission (~84 88%) MSM Heterosexual STD history IVDU (~12 16%) Surgical/Blood Transfusion Perinatal transmission Occupational exposure Hall HI, Song R, Rhodes P, et al. Estimation of HIV Incidence in the US. JAMA 2008;300: 520-29 Patient Specific Risk Factors 50 70% of transmission is associated with unknown status High viral loads Newly infected Advanced disease Other STDs Uncircumcised males Strick LB CID 2006:43 (3) 345-56 CDC Recommendations on HIV Testing: 2006 Routine testing of all persons 13 and 64 years old All health care settings (including primary care) Federally no pretest counseling required No written informed consent required opt out in areas of 0.05% or greater/ incidence unknown test until indentified Decrease stigma attached to testing CDC-MMWR Morb Mortal Wkly Rep 55:1-14,2006 2
Reasons for Routine Testing Earlier starts spares damage to body Sexual transmission to others (high viral load) Transmission during acute infection Changes in sexual behaviors Pregnancy decreased risk of transmission Test and Treat DC: Forecasting the Impact of a Comprehensive HIV Strategy in Washington DC Test and Treat annual screening with ART at time of diagnosis Decrease transmission over 5 years by 15% Indirect result of viral suppression Theory requires: Access and willingness to testing Medication access Treatment adherence Walensky RP. CID.2010;51(4):392-400 Case 1: Samantha Continued Samantha is devastated when she is diagnosed with HIV and needs some education on this diagnosis. Laboratory Results: CD4+: 430 cells/mm 3 Viral load: 172,000 copies/ml Natural History of HIV Infection What education would you provide on her new diagnosis? HIV Dynamics 10 9 new virions produced each day Cell free virus in plasma has T1/2 of 6 hours Productively infected CD4 cells have T1/2 of 1.6 days Time from release of new virion to infection of new cell and release of another new virion is 2.6 days (140 new generations of virus each year) HIV Natural Disease Course Perelson A, et al. Science 1996;271:1582-6. 3
Laboratory Markers CD4 + T lymphocytes (N: 800 1050 cells/mm 3 ) Measures the amount of immune system damage Predictive of risk for opportunistic infections Leading indicator of need for antiretroviral therapy Viral RNA ( viral load ) Best predictor of rate of progression of disease Life Expectancy Improvements in survival are significant 43% decline from 2000 to 2008 deaths Earlier initiation in ART Improved survival with earlier initiation <350 or 500 cells Factors impacting life span Lifestyle management More favorable antiretroviral agents Newer agents appear safer Hill A, Pozniak A. AIDS 2010;24:1583-84 Case 1: Samantha What else is necessary to identify whether ART should be initiated? Initial Patient Assessment HIV assessment: HIV antibody test CD4+ cell count (at least 2 values) Plasma HIV RNA Resistance testing if RNA>500 copies/ml HLA B*5701 Baseline labs: CBC, chemistry panel, transaminase levels, BUN and creatinine, urinalysis Fasting glucose and serum lipids with cardiovascular risks Opportunistic Infection Risk: RPR or VDRL, TST or IGRA, Toxoplasma gondii IgG, Hepatitis A, B, C serologies & PAP smear Resistance Testing Recommended upon diagnosis/prior to starting HAART along with treatment failure 6 16% primary infections are resistant to 1 drug 3 5% primary infections are resistant to >1 drug Genotype: Detects mutations present on viral genes that may alter the susceptibility of drug therapy Phenotype: Measures the ability of the virus to grow in various concentrations of drug therapy Virtual Phenotype: Uses a database to predict the phenotypic response to the genotype Hypersensitivity of Abacavir Abacavir **Hypersensitivity (~2 8%) Usually starts within first 4 6 weeks Fever, skin rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, shortness of breath, cough or sore throat DO NOT RECHALLENGE DEATH Linked to certain HLA haplotypes: B*5701, (? DR7,DQ3) Blood test required prior to prescribing False negatives possible use clinical judgment 4
Case 1: Samantha Continued Goals of Therapy HIV Labs: CD4+ : 410 cells/mm3 Resistance test: none identified HLA testing: negative Individual MH: Pregnancy test: negative Medications: Acyclovir (400mg po TID x 5 days PRN) Family history of HTN in father 47; Mom DM 46 Laboratory Tests RPR: NR TST Toxo IgG: negative CMV IgG: negative TST: neg (0mm) Hep A: negative Hep B sab: positive Hep C Ab: negative PAP completed All other labs within normal limits. Reduce morbidity and mortality Maximal and durable viral suppression; while increasing CD4+ cells Adherence (what is our real number?) Resistance Improve quality of life Prevent transmission to others (vertical or sexual) Preserve future treatment options (sequencing) DHHS Initiation Criteria SHOULD START: All patients with an AIDS defining illness CD4 count <350 cells/mm 3 HIVAN Hepatitis B initiation of treatment Pregnant women DHHS Guidelines for Treatment Naïve Adults & Adolescents 12/1/09 DHHS Initiation Criteria RECOMMENDED: CD4 count between 350 500 cells/mm 3 Cohort studies versus RCT data MAY OFFER BENEFIT: CD4 > 500 cells/mm 3 Increased survival in one cohort Decrease in non AIDS defining illness Cardiovascular, kidney, liver diseases & malignancy Decrease transmission to others DHHS Guidelines for Treatment Naïve Adults & Adolescents 12/1/09 Benefits vs. Limitations IAS Initiation Criteria 2010 Benefits: Immune recovery HIV associated inflammation protection Cardiovascular disease 10% of deaths Renal protective in HIVAN Neurological Concerns Transmission Limitations: Long term toxicity Development of resistance nonadherence Greater cumulative therapy effects? Quality of life Cost READINESS IS KEY! RECOMMENDED (AIa) or (AIIa) Symptomatic disease Pregnancy CD4 count of <350 cells; <500 (AIIa) >100 CD4 cell count decline/year HIV 1 RNA >100,000 copies/ml DHHS Guidelines for Treatment Naïve Adults & Adolescents 12/1/09 JAMA 2010 5
IAS Initiation Criteria 2010 SHOULD INITIATE: BIIa Active HBV or HCV Active or high risk for cardiovascular disease >60 years of age HIV associated nephropathy Symptomatic primary HIV infection HIV serodiscordant couples CONSIDER INITIATION: CIII CD4 count >500cells Samantha s Case Continued.. She would like to start ART early to avoid looking like one of those sick patients. Your adherence education appeared to be of value. Her parents are aware of her status and want to assist in her treatment success. What medications should be started at this time? JAMA 2010 HIV Lifecycle Fusion Entry inhibition Replication Integration Protein cleavage Relative Levels Current Goal of HAART CD4+ T-cells 100-150 cell increase Plasma HIV Viremia < 50 copies/ml or lowest limit of detection Limit of detection Months Years After HIV Infection University of Buffalo HIV website: artist unknown Acute HIV infection Symptom Are All HIV Patients the Same? Treatment Considerations Resistance /Tropism Contraindications (CD4 count/hla typing etc) Co morbidities (i.e. hepatitis) Adherence potential (>95%) Dosing frequency Number and size of pills Food & fluid restrictions Adverse drug reactions Potential drug interactions Pregnancy potential 6
DHHS Selection Categories Preferred: RCT have shown optimal & durable virologic efficacy, favorable tolerability; limited toxicities; easy to use Alternative: Effective but potential disadvantages compared to preferred Acceptable: Less virologic activity; lack of efficacy or greater toxicities May be acceptable; more data needed: Used with Caution: DHHS Guidelines for Treatment Naïve Adults & Adolescents 12/1/09 Preferred DHHS HAART Medications Nucleoside Reverse Transcriptase Inhibitors: Tenofovir/ emtricitabine (Truvada) Non-nucleoside reverse Efavirenz (Sustiva) transcriptase inhibitors: Protease inhibitors: Atazanavir (Reyataz)/ ritonavir Darunavir (Prezista)/ ritonavir Integrase inhibitors: Raltegravir (Isentress) Pregnancy: Lopinavir/ ritonavir (Kaletra) Administered with Combivir -both BID Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (AZT) Retrovir Zalcitabine (ddc) Hivid Didanosine (ddi) Videx & Videx EC Stavudine (d4t) Zerit Lamivudine (3TC) Epivir Emtricitabine (FTC) Emtriva Abacavir (ABC) Ziagen Tenofovir (TNF) Viread Nucleoside/ Nucleotide Class Dosing convenience: combination Truvada (Tenofovir/ emtricitabine) Atripla (Tenofovir/ emtricitabine/ efavirenz) Epzicom (Abacavir/ lamivudine) Combivir (Zidovudine/ lamivudine) Trizivir (Zidovudine/ lamivudine/ abacavir) Class Administration: Daily; except zidovudine & stavudine which are BID No food restrictions except didanosine Adjust for renal dysfunction (except abacavir) Class Side Effects: gastrointestinal (nausea, vomiting & diarrhea) lactic acidosis DHHS Preferred NRTI DHHS Alternative NRTI Tenofovir/emtricitabine Benefits: Well tolerated Daily dosing HBV Long half life less resistance Greater effectiveness when VL >100,000 copies/ml Concerns: Renal impairmentincreases in creatinine Glycosuria Hypophosphatemia Acute tubular necrosis Increased risk with boosting Do not use with Nevirapine Abacavir/lamivudine HLA B*5701 test Greater CD4 increase over zidovudine Once daily dosing >100,000 copies had increased drug failure Potential cardiac risks; MI Zidovudine/ Lamivudine: Preferred in pregnancy! Twice daily dosing Increase risk of M184V Bone marrow suppression GI toxicity HA, fatigue Mitochondrial toxicity Lipoatrophy 7
DHHS Acceptable NRTIs Didanosine + (emtricitabine or lamivudine) ONLY WITH EFAVIRENZ Concerns: Can not be given with atazanavir inc failures Pancreatitis risk Peripheral neuropathy Noncirrhotic portal hypertension? Increased of MI IAS NRTIs Stavudine and Didanosine NOT RECOMMENDED Increase toxicities Preferred: Tenofovir/Emtricitabine Treatment of HBV/HIV NOT in renal dysfunction Alternative: Abacavir/lamivudine Increased risk of lipid abnormalities NOT in RNA >100,000 copies/ml Possible MI risk? May use: Zidovudine/lamivudine Tolerability concerns Lipodystrophy/ hyperlipidemia JAMA 2010 Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Efavirenz (EFV) Sustiva Nervirapine (NVP) Viramune Delavirdine (DLV) Rescriptor Etravirine (ETV)# Intelence Concerns: possible cross resistance All potentially cause a rash NVP>~ Etravirine=EFV Use saves the PI and ISTI classes ** Not effective therapy for HIV 2 # Currently not a first line option Preferred: Efavirenz Low pill burden Virologically superior to lopinavir/ritonavir Comparable to atazanavir/ritonavir & raltegravir More CNS side effects Pregnancy concerns Baseline resistance risk (8.1%) Limited lipid concerns DHHS & IAS NNRTIs Alternative/May Use: Nevirapine: CD4 cell cut offs <400 men <250 women Increased risk of hepatotoxicity Lead in dosing Greater risk of rash Fewer clinical trials Not Used as a first line agent: Etravirine Protease Inhibitors Atazanavir (ATV) Reyataz Darunavir (DRV) Prezista Fosamprenavir (FPV) Lexiva Indinavir (IDV) Crixivan Lopinavir/ritonavir (LPV/RIT) Kaletra Nelfinavir (NFV) Viracept Ritonavir (RIT) Norvir Saquinavir (SQV) Invirase Tipranavir (TPV) Aptivus Protease Inhibitor Choices Potency increased CD4 T cell response Resistance Higher Barrier & Sequencing Pharmacokinetic interactions Antiretrovirals (boosting) increasing Cmin and t1/2 Food and fluid restrictions Dosing /formulations (pill size and number) Adverse effect profile Hepatic effects Cardiovascular/Lipid/glucose effects (vary) Bleeding with Hemophilia 8
DHHS: Factors of Consideration for PIs Dosing Frequency* Food requirements Pill burden* Daily ritonavir dose (toxicity vs. potency)* Drug interactions Hepatic function Toxicity profile* Pregnancy status * Considered in FIRST LINE PIs Known PI Toxicities Dyslipidemia Insulin resistance Related to ritonavir dose Lopinavir/ritonavir & indinavir MI; Coronary Heart Disease & Stroke Amprenavir/Fosamprenavir: MI Atazanavir/ritonavir 300mg/100mg With food Non inferior to Kaletra at 96wks CASTLE Two pills daily 100mg ritonavir only Requires acid ph Adverse effectshyperbilirubinemia Rare nephrolithiasis DHHS Preferred PIs Darunavir/ritonavir 800mg/100mg With food Superior to Kaletra at 96wks ARTEMIS 3 pills once daily 100mg ritonavir only Good tolerability less diarrhea DHHS Alternative PIs Fosamprenavir/ritonavir KLEAN trial similar to lopinavir/ritonavir when prescribed twice daily Similar adverse effects Dosing: Once 1400mg/200mg or 700mg/100mg twice daily Lopinavir/ritonavir 800mg/200mg daily or 400mg/100mg BID Ritonavir 200mg Increase GI & hyperlipidemia Greater risk of toxicities Greater CD4 count response /less virologic compared with efavirenz Other Alternative PIs Acceptable PIs Regimens Saquinavir/ ritonavir 1000mg/100mg BID with food Pill burden Twice daily dosing Well tolerated Less lipid abnormalities QTc prolongation (after current guidelines) Atazanavir unboosted 400mg daily with food NOT didanosine/emtricitabine! NOT with tenofovir No Proton pump inhibitors Concerns over other acid reduction products Fosamprenavir BID unboosted 1400mg May select for darunavir and lopinavir mutations 9
Atazanavir/ritonavir: Greater virological response over unboosted Similar to lopinavir/ritonavir Hyperbilirubinemia Rare nephrolithiasis Requires acid gastric ph for dissolution IAS Preferred PIs: Darunavir/ritonavir Better virologic response compared to lopinavir/ritonavir at VL >100,000 copies/ml Well tolerated May be saved for treatment experienced patients JAMA 2010 IAS PIs PIs with Cardiovascular risks by cumulative exposure : indinavir/r; lopinavir/r; fosamprenavir/r Avoid in patients with cardiovascular risks! Alternatives Lopinavir/ritonavir Better CD4 count response than efavirenz Lower virological response than efavirenz Insulin resistance and hyperlipidemia Fosamprenavir/ritonavir: Twice daily dosing superior Saquinavir/ritonavir: Less lipid concerns than lopinavir/ritonavir QTc prolongation risk JAMA 2010 PIs Not Recommend Integrase Strand Transfer Inhibitor Indinavir TID dosing fluid and food restrictions Boosted BID dosingincreased nephrolithiasis Ritonavir High pill burden GI intolerance Lipids (triglycerides) Nelfinavir Inferior potency High incidence diarrhea Tipranavir Inferior virologic efficacy Black Box intracranial hemorrhages Induction properties Raltegravir Benefits: Comparative to efavirenz virologically at 96 wks Well tolerated No food restrictions Limited drug interactions Limitations: Low genetic barrier to resistance May be favored for treatment resistance Dosed twice daily JAMA 2010 Chemokine Co-receptor Attachment CD4 attachment Co-receptor binding Fusion Maraviroc Resistance: Tropism CCR5 Did you lock both doors or just one? CXCR4 10
Entry Inhibitors CCR5 Antagonists Alternative: Maraviroc Compared efavirenz with zidovudine/lamivudine backbone 48 weeks :<50 copies (65% vs 69%) Fewer discontinuations for toxicities (13.6% vs. 4.2%) More discontinuations for efficacy (4.2% vs. 11.9%) Tropism assays improvement/costs considerations Now Back to Our Patients. Case 1: Samantha What is the most appropriate first line regimen? A. lopinavir/ritonavir + abacavir/lamivudine BID B. efavirenz +tenofovir +emtricitabine daily C. atazanavir + tenofovir + emtricitabine daily D. atazanavir + ritonavir +tenofovir + emtricitabine daily Key Points Kaletra is a first line option, but only in pregnancy. Abacavir/ lamivudine is an acceptable NRTI backbone Efavirenz in women of child bearing age not utilizing 2 forms of contraception is a concern. Atazanavir is a first line PI but with boosting When tenofovir is used, atazanavir must be boosted to overcome the drug interaction daily **Atazanavir/r + tenofovir + emtricitabine Case 2: Dan Dan, a 33 year old male, is diagnosed and referred to your clinic for ART initiation. CD4: 201 cells/mm 3 VL: 87,000 copies/ml Resistance: none HLA B*5701 negative MH: Depression; Chronic Renal Insufficiency; Anemia (from renal disease); Hepatitis C; Intermittent diarrhea of unknown etiology. SH: no alcohol since HCV diagnosis; occasion drug use Meds: Celexa 20mg; MVI Case 2: Dan Treatment: A. tenofovir + emtricitabine+ efavirenz (Atripla) B. zidovudine + lamivudine + maraviroc BID C. abacavir + lamivudine + nevirapine daily D. abacavir + lamivudine + atazanavir daily MH: Depression; Chronic Renal Insufficiency; Anemia (from renal disease); Hepatitis C; Intermittent diarrhea of unknown etiology. What ART therapy could be started at this time? 11
Case 2: Key Points While not directly contraindicated, efavirenz in patients with psychiatric illness is not a good first choice. Tenofovir use in patients with renal dysfunction should be a risk versus benefit of treatment. Zidovudine will contribute to Dan s anemia. Maraviroc may be an option if we had a tropism assay Although Dan meets the requirements for use of nevirapine, use in patients with hepatitis is not recommended. Closing Points HIV testing is necessary Adherence must be assessed Starting points and ARV toxicities of long term still elude science Treatment of co morbid diseases is also necessary Treat the patient, the situation and the numbers! Guidelines are just that guide lines! **abacavir + lamivudine + atazanavir daily 12