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HIV: Practice and Prevention, 2013 Robert D. Harrington, M.D. Professor of Medicine University of Washington HIV: Practice and Prevention, 2012 Epidemiology Who should be tested The initial visit/Routine testing and Prophylaxis Starting antiretroviral therapy Antiretroviral agents Resistance Side effects Drug interactions Adults and children estimated to be living with HIV, 2008 Western & Eastern Europe Central Europe & Central Asia North America 1.4 million [1.2 – 1.6 million] Caribbean 240 000 [220 000 – 260 000] 850 000 [710 000 – 970 000] 1.5 million [1.4 – 1.7 million] East Asia Middle East & North Africa 310 000 [250 000 – 380 000] Sub-Saharan Africa Latin America 2.0 million [1.8 – 2.2 million] 22.4 million [20.8 – 24.1 million] 850 000 [700 000 – 1.0 million] South & South-East Asia 3.8 million [3.4 – 4.3 million] Oceania 59 000 [51 000 – 68 000] Total: 33.4 million (31.1 – 35.8 million) Awareness of HIV Status among Persons with HIV, United States Number HIV infected 1,039,000 -1,185,00 Number unaware of their HIV infection 252,000 - 312,000 (24%-27%) Estimated new infections annually 56,000 Glynn M, Rhodes P. 2005 HIV Prevention Conference HIV/AIDS – Washington State as of June 30, 2012 Average HIV Rates by County, 2006-2010 New HIV Case Rates by Race/Ethnicity and Gender, Washington State 2006-2010 HIV: Practice and Prevention, 2011 Who should be tested? Case 1 • A 32 year old woman comes to your office for her annual pap smear. She is G2P1 (son is 4 years old). She has a remote history of HPV but no other medical problems. • She is divorced from her first husband for 4 years and recently remarried. • Her review of symptoms and exam are normal. Case 1 Should she be tested for HIV? YES! Testing Guidelines: Who to Test • Which of the following patients should have HIV testing? – 30 year old heterosexual man in monogamous relationship – 22 year old MSM, multiple partners – 45 year old man diagnosed with TB – 34 year old pregnant woman – 38 year old married woman with no identifiable risk factors CDC Testing Guidelines CDC Guidelines ● HIV screening is recommended for patients in all health-care settings after the patient is notified that testing will be performed unless the patient declines (opt-out screening). ● Persons at high risk for HIV infection should be screened for HIV at least annually. ● Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing. ● Prevention counseling should not be required with HIV diagnostic testing or as part of HIV screening programs in health-care settings. Rationale for Testing Guidelines • • • • Increase testing Diagnose early before symptomatic Decrease stigma associated with testing Remove barriers to clinicians to implement testing Awareness of Serostatus Among People with HIV and Estimates of Transmission ~25% Unaware of Infection Accounting for: ~55% of new infections ~75% Aware of Infection ~45% of new infections People Living with HIV/AIDS: ~1,050,000 New Infections Each Year: ~56,000 New Washington State HIV Testing Recommendations, 2010 • No longer linked to counseling and partner services • Obtain informed consent separately or with general consent for care • Inform patient in writing or verbally that HIV testing is included • Offer opportunity to ask questions or decline testing • Notify local health officer of + test results • Pregnant women – must still document patient refusal HIV Care Cascade: USA Only 28% of HIV+ persons in the US are engaged in care, on therapy, and have suppressed HIV (MMWR, 2011) HIV Care Cascade: King County, WA HIV: Practice and Prevention, 2012 The initial visit: Routine Testing and Opportunistic Infection Prophylaxis Case 2 • A 23 year-old gay man tested + for HIV at a night-club. He has several anonymous sex partners per week and regularly uses methamphetamine. • His past history is notable for resolved hepatitis A and multiple STDs. • He’s a waiter, smokes ½ ppd and drinks to excess on weekends. • His exam in notable for poor dentition and seborrheic dermatitis • You confirm that he is HIV + Case 2 • What other history and testing do you want on this newly diagnosed patient? • What recommendations should you make at this first visit? Case 2 • What other history and testing do you want on this newly diagnosed patient? – Sexual, travel, exposures (TB, food, pets) – CD4, HIVRNA, CBC, M-7 and U/A, LFTs, Hep A,B,C serologies, Toxoplasma serology, G6PD, PPD or IGRA, RPR and STD evaluation, lipids – HSV serology? – HIV genotypic resistance test – If female, pregnancy test • What recommendations should you make at this first visit? – Safe sex practices, drug rehabilitation, partner notification Case 2 • His CD4 count returns at 110 cells/mL and his HIV RNA is 85,000 copies/mL • What opportunistic infections is he at risk of getting? • For which infections should he receive prophylaxis? MMWR 1981 Risk of Opportunistic Infection Normal CD4 = 750-1500 Mycobacterium tuberculosis (TB) Bacterial Pneumonia, HSV, Zoster, Diarrhea Oral Candidiasis (Thrush), Molluscum Contagiosum, Dermatitis, Folliculitis Pneumocystis jirovecii Pneumonia (PCP), Kaposi’s Sarcoma Cryptococcal Meningitis, Toxoplasmosis, Non-Hodgkin’s Lymphoma Mycobacterium avium (MAC), CMV (Retinitis, Colitis), Progressive Multifocal Leukoencephalopathy (PML), Microsporidiosis, Primary CNS Lymphoma (EBV) Opportunistic Infections and Geography North America Common OIs • PCP • MAC • Candida Regional Effects • Southwest: – Coccidiodomycosis • Midwest: – Histoplasmosis and Blastomycosis • South: – Blastomycosis and Toxoplasmosis Opportunistic Infections and Geography The World Candida PCP MAC PCP TB Cryptococcus Isospora Cryptosporidiosis Microsporidia PCP, TB Candida, MAC Cryptococcus Leishmaniasis PCP TB Candida Cryptococcus Penicilliosis TB Bacteria Malaria Cryptococcus Holmes, CID, 03 Putong, SEA Trop Med, 02 Margues, Med Mycol, 2000 Amornkul, CID, 03 HIV-Associated and Opportunistic Infections • • • • • • • • • • • PCP MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus • • • • • • • • • • • • Toxoplasmosis Candida TB Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Leshmaniasis HIV ASSOCIATED MALIGNANCIES • • • • AIDS Defining Malignancies Kaposi’s sarcoma Primary CNS lymphoma (PCNSL) Non-Hodgkin’s lymphoma (NHL) Invasive cervical cancer Prophylaxis to Prevent Opportunistic Infections Considerations for Prophylaxis • Infection should be common and/or predictable • Infection should be clinically significant • Treatment (prophylaxis) should be effective, non-toxic and affordable Prophylaxis to Prevent Opportunistic Infections Infection Criteria Treatment PCP CD4 < 200 TMP/SMX or dapsone or atovaquone or aerolsolized pentamidine Tuberculosis PPD > 5 mm INH Toxoplasmosis IgG+ and CD4 < 100 TMP/SMX or dapsone+pyrimethamine+leukovo rin MAC CD4 < 50 Azithromycin VZV CD4 > 200 Vaccine HAV Vaccine HBV Vaccine Streptococcus pneumoniae Vaccine Influenza Vaccine HIV: Practice and Prevention, 2012 When to start? What to use? Case 3 • A 72 yo male has been your patient for 15 years. He first tested + for HIV in 1985. He has never had any HIV related problems. His CD4 count has never been below 600 and his HIV RNA has never been > 9000. He is ARV naïve. • His other medical problems include porphyria, mild HTN, osteoarthritis, GERD, chronic dizziness and BPH. • He smokes 1ppd (for 50 yrs), doesn’t drink or use illicit drugs. His meds include HCTZ, omeprazole, ibuprofen, sildenafil and tamsulosin. • His family history is notable for longevity – both parents are still alive as are 2 siblings. Case 3 • At his most recent visit he is cantankerous but without worrisome complaints. He has a new partner with whom he is sexually active. His partner is HIV negative. • His most recent CD4 is 598 and his HIV RNA is 8500. • Who wants to start him on anti-retroviral therapy? HIV Infection: Pathogenesis Anti-HIV T-cell response Sero-conversion Antibody response Typical Course 10,000,000 AIDS Plasma HIV RNA 1,000,000 100,000 Plasma RNA Copies 10,000 Viral set point 1,000 CD4 Cell Count Intermediate Stage 1,000 100 CD4 Cells 10 500 1 4-8 Weeks Up to 12 Years A lot of important stuff happens here 2-3 Years Long Term Non-progression HIV-CTL Sero-conversion 10,000,000 CD4 Cell Count Plasma HIV RNA 1,000,000 100,000 10,000 CD4 Cells 1,000 1,000 100 Plasma RNA Copies 10 500 1 4-8 Weeks Up to 12 Years 2-3 Years Some CD4 death, good HIV-CTL, good HIV control Rapid Progression CTL response Seroconversion 10,000,000 CD4 Cell Count AIDS Plasma HIV RNA 1,000,000 Plasma RNA Copies 100,000 10,000 1,000 1,000 100 500 CD4 Cells 10 1 4-8 Weeks Up to 12 Years 2-3 Years Lots of CD4 death, poor HIV-CTL, poor HIV control Early Vs Standard HAART in Haiti (Severe, et.al NEJM, 2010;263:257-65) • Randomized, open label study ARV (AZT+3TC+EFV) given when – CD4 cells were > 200 and < 350 cells/uL and no h/o AIDS Vs – CD4 cells were < 200 cells/uL or when patients had a clinical AIDS diagnosis • N = 816 (408 in each group) • Baseline CD4 ~ 280 in each group • All patients received TMP/SMX, daily MVI and food supplements and those who were PPD + received INH Early Vs Standard HAART in Haiti (Severe, et.al NEJM, 2010;263:257-65) 23 deaths in the standard Rx group Vs 6 in the early Rx group 36 incident cases of TB in the standard Rx group Vs 18 in the early Rx group Survival Incident TB Impact of Age on Risk of HIV Progression Predicted Risk (%) Predicted 6-Month Risk of Progression to AIDS in Patient With HIV RNA of 30,000 c/mL CD4 Cell Count (cells/mm3) Phillips A et al. AIDS. 2004;18:51-58. When to Initiate ARV Therapy: Starting at a Higher CD4 Count? Johns Hopkins HIV Clinical Cohort – >350 cells/mm3: CD4 counts significantly increased and returned to near-normal levels – 201–350 and <200 cells/mm3: CD4 counts significantly increased and plateaued after 4 years below normal levels • Differences in CD4 counts associated with differences in morbidity and mortality Moore RD, Keruly JC. Clin Infect Dis. 2007;44(3):441-446. CD4 Count (cells/mm3) • Analysis of CD4-count recovery in ARV-treated patients (n=655) with sustained HIV RNA suppression (<400 c/mL) up to 6 years, stratified by BL CD4 counts Median CD4 Counts Over 6 Years Stratified by Baseline CD4 Count 900 800 700 600 500 400 300 200 100 0 201–350 <200 0 1 2 3 4 >350 5 Years After Starting HAART 6 Early Vs Deferred HAART (Kitahata, et.al NEJM, 2009) NA-ACCORD study • Observational study of 17,517 asymptomatic patients in US and Canada • Two analyses: – 1: Start HAART b/n 350-500 Vs deferred. • N= 8362, 2084 (25%) started at 350-500, 6278 deferred • RR of death for deferred group 1.69 (P<0.001) – 2: Start HAART at > 500 Vs deferred • N=9155, 2220 (24%) started at > 500, 6935 deferred • RR of death for deferred group 1.94 (P<0.001) Early Vs Delayed HAART, 2011 CASCADE Study (Arch Int Med, 2011, 171:1560) • Observational cohort study of 9455 ARV naïve patients with known date of HIV infection CD4 count AHR for AIDS or Death AHR for Death 0-49 0.32 (0.17-0.59) 0.23 (0.14-0.95) 50-199 0.48 (0.31-0.74) 0.55 (0.28-1.07) 200-349 0.59 (0.43-0.81) 0.71 (0.44-1.15) 350-499 0.75 (0.49-1.14) 0.51 (0.33-0.80) 500-799 1.10 (0.67-1.79) 1.02 (0.49-2.12) HAART, 2012: Simple Regimens Simple Regimens Drugs • • • • • • • • • • RLP/TDF/FTC R-ATZ - TDF/FTC R-LPV - TDF/FTC R-DRV – TDF/FTC R-FAMP - TDF/FTC EFV/TDF/FTC R-LPV - AZT/3TC EFV - AZT/3TC RAL – TDF/FTC ELV/COB/TDF/FTC Number of pills 1 pills 3 pills 5 pills Schedule QD QD QD 3 pills 5 pills 1 pill 6 pills QD QD QD BID 3 pills 3 pills 1 pill BID BID QD HAART, 2012: Effect on Transmission What about his new partner? HPTN 052: Immediate vs Delayed ART for HIV Prevention in Sero-discordant Couples HIV-infected, heterosexual sero-discordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Immediate HAART* Initiate HAART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) Delayed HAART Initiate HAART at CD4+ cell count ≤ 250 cells/mm3† (n = 877 couples) • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Cohen MS, et al. N Engl J Med. 2011;365:493-505. HAART, 2012: Effect on Transmission HPTN 052: HIV Transmission Reduced by 96% in Sero-discordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P < .001) Linked Transmissions: 28 Immediate Arm: 1 Delayed Arm: 27 P < .001 Cohen MS, et al. N Engl J Med. 2011;365:493-505. Unlinked or TBD Transmissions: 11 Early Vs Delayed HAART, 2011 CASCADE Study (Lodi, CID, 2011, 53:817) • Observational cohort study of 9455 ARV naïve patients with known date of HIV infection • Analyzed time from seroconversion to CD4 threshholds Median time to < 500: 1.2 yrs Median time to < 350: 4.2 yrs Median time to < 200: 7.9 yrs When to Treat? • • • • • Prevent Immune system destruction • More effective when started early • Mortality benefit even at high CD4 • Prevent clinical “events” • Prevent transmission & truncate the epidemic Early Toxicities of treatment Increased risk of resistance Low rate of disease progression? Cost Later DHHS Guidelines 2012: When To Treat ART is recommend for all HIV infected patients: only the strength of the recommendation varies by CD4 count CD4+ Cell Count Recommendation < 350 cells/mm³ Start ART (AI) 350-500 cells/mm³ Start ART (AII) > 500 cells/mm³ Start ART (BIII) Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count History of AIDS-defining illness (AI) Pregnancy (AI) HIV-associated nephropathy (AII) HBV co-infection (AII) Patients at risk of transmitting HIV to sexual partners (AI, heterosexuals; AIII, others) HCV co-infection* (BII) Patients > 50 years of age (BIII) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, 2012. HIV: Practice and Prevention, 2012 When to start? What to use? Antiretroviral Therapy Five Drug Classes • • • • • Nucleoside Reverse Transcriptase Inhibitors (NRTI) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Protease Inhibitors (PI) Integrase Inhibitors Cell Entry Inhibitors HIV Life Cycle Antiretroviral Therapy NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) AZT (zidovudine; Retrovir) 3TC (lamivudine; Epivir) d4T (stavudine; Zerit) ddI (didanosine; Videx) Abacavir (Ziagen) ddC (zalcitabine; Hivid) Tenofovir (Viread)* Emtricitabine (Emtriva) Antiretroviral Therapy NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) Efavirenz (Sustiva) Nevirapine (Viramune) Delavirdine (Rescriptor) Etravirine (Intelence) Rilpivirine (Endurant) Efavirenz + Tenofovir + FTC (Atripla) Rilpivirine + Tenofovir + FTC (Complera) Antiretroviral Therapy PROTEASE INHIBITORS Ritonavir (Norvir) Saquinavir (Fortavase; Invirase) Nelfinavir (Viracept) Indinavir (Crixivan) Fosamprenavir (Lexiva) Lopinavir/ritonavir (Kaletra) Atazanavir (Reyataz) Tipranavir (Aptivus) Darunavir (Prezista) Antiretroviral Therapy INTEGRASE INHIBITORS Raltegravir (Isentress) • Only member of its class, twice a day medicine • Initially approved for salvage therapy, now recommended as a preferred drug for initial treatment Stribild • Elvitegravir + Cobicistat + TDF + FTC: 1 pill QD Antiretroviral Therapy CELL ENTRY INHIBITORS T-20 (Enfuvirtide) • • • • • • Synthetic peptide – blocks gp41 mediated fusion Subcutaneous injection twice/day Indicated for “salvage therapy” (use with at least one other active drug or in patients with high risk of disease progression/death) Maraviroc (Selzentry) Only effective against HIV isolates that utilize CCR5 co-receptor Must screen patients for the absence of CXCR4 using virus Not clear where to use it since “salvage patients” more likely to have CXCR4 virus NNRTI or PI or Integrase Inhibitor? NNRTIs • High efficacy • Simplicity—lowest pill burden • Relatively well tolerated • Limited toxicity • Low genetic barrier to resistance • Drug-drug interactions PIs • High efficacy • Getting simpler, but regimen ≥3 pills per day • High genetic barrier to resistance • Relatively well tolerated except for GI • Fat accumulation and lipid problems persist • Drug-drug interactions, especially with RTV GI = gastrointestinal; RTV = ritonavir. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008. NNRTI or PI or Raltegravir? Raltegravir • High efficacy • Very well tolerated (maybe increased depression?) • No Drug-drug interations • Low genetic barrier to resistance • BID dosing Initiating Antiretroviral Therapy DHHS Recommendations (2012) Preferred Regimens NNRTI-Based EFV QD + TDF/FTC PI-Based Atazanavir/R QD Darunavir/R QD + TDF/FTC + TDF/FTC Integrase-Based Raltegravir BID + TDF/FTC Conclusions • A patient’s CD4 T-cell count is used to stage disease and determine the need for ART. The current threshold for initiating treatment is < 500 cells – Factors to consider include viral load, rate of CD4 decline, co-morbidities, transmission risk, age, patient readiness and the likelihood of adherence - may want to start at CD4 > 500 • TDF/FTC in once-daily fixed-dose combination plus an EFV or ATZ/r or DRV/r or RAL are proven and preferred initial choice HIV: Practice and Prevention, 2012 Failure and Drug Resistance Case 4 • A 38 year old man with AIDS was started on HAART (EFV, TDF, FTC) a year ago with an excellent response: his HIV RNA dropped from 248,000 copies to < 30 copies and his CD4 increased from 87 to 360 cells. • Unfortunately, he’s missed several recent appointments and when he finally does make it to the office you find he has thrush and seborrheic dermatitis. His CD4 count has decreased to 240 cells and his HIV RNA is now detectable at 37,000 copies. • What is going on? • What, in particular, are you worried about? HIV: Practice and Prevention, 2012 Social/personal issues Regimen issues Toxicities Poor potency Wrong dose Host genetics Poor adherence Poor absorption Insufficient drug level Rapid clearance Viral replication in the presence of drug Poor activation Drug interactions Resistant virus Adherence and Drug Resistance Relationship When to Use Resistance Testing IAS-USA1 DHHS2 European3 Recommend Recommend‡ Recommend — — Recommend Consider* Recommend‡ Strongly consider* Failure Recommend Recommend Recommend Pregnancy Recommend† Recommend Recommend† — — Recommend† Patient Status Primary/acute Post-exposure prophylaxis Chronic, treatment naïve Pediatric *Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug resistance in untreated patients ≥5% (European: ≥10%); †When viral load is detectable; ‡December 1, 2007: The panel recommends performing genotypic drug resistance testing for all treatment-naïve patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated. 1. Hirsch MS et al. Clin Infect Dis. 2003;37(1):113-128; 2. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008; 3. Vandamme AM et al. Antivir Ther. 2004;9(6):829-848. Overview of Antiretroviral Resistance Testing How do we test for resistance? Genotype: most common, least expensive Phenotype: useful for viruses with multiple PI mutations Virtual Phenotype: less expensive than a phenotype Genotypic Resistance Assay • Sequences relevant portions of the HIV genome coding for Reverse Transcriptase and Protease enzymes • Detects and reports variations in the sequences of these genes that are known or suspected to confer antiretroviral resistance pol LTR LTR gag env RT Codon PR INT Mutation AAA GAC AGT AAA AAC AGC Lys Asp Ser Lys Asn Ser Adapted from Winters. Reviewed in Wilson. AIDS Read 2000;10:469. Silent Mutation Antiretroviral Drug Resistance Testing Some Key Mutations • • • • • • • • AZT D4T TNF ABC • NVP • • DDI 3TC/FTC The class EFV ETR 210, 215 70 65 65, 74, 115, 184 65, 74 184 151, 69 103 181,188, 190,230 103, 188,190 100, 181, 188, 190 • • • • • • • • • NLF 30, 90 SQV 48, 90 IDV 46, 82 RTV 82 APV 50 LPV 82 ATZ 50, 84, 88 DRV 32,33,47,50,54,76,84 TPV 33, 82, 84 • RTV 143,148,155 • MRV R5 only virus • Website: http://hivdb.stanford.edu/ Phenotypic Resistance Testing • Tests viability of a chimeric version of the patient’s HIV in the presence of antiretroviral agents • Similar to traditional bacterial antibiotic susceptibility assays • Results reported as foldchange in susceptibility to antiretroviral agents HIV: Practice and Prevention, 2012 Drug Side effects Case 5 • A 23 year old woman with HIV is switched from a failing HAART regimen to abacavir, lamivudine and atazanavir. • She does well for a week and then starts to feel poorly with muscle aches, fever, nausea and then a rash. • What’s going on? Abacavir hypersensitivity Case 5 Abacavir Hypersensitivity • Multiple organs involved • Four most common symptoms: – Fever, rash, GI, malaise/fatigue • Less common symptoms: – Edema, musculoskeletal, respiratory, mucous membrane, headache, paresthesia • Resolves upon stopping ABC • Reappears on re-challenge and can be fatal (DO NOT RECHALLENGE) Hetherington S et al. 7th CROI 2000: Abst. 60. Time to Onset of ABC Hypersensitivity 60 Median time to onset 11 days 50 No. of Cases 40 93% of reported cases occurred within the first 6 weeks of initiating abacavir 30 20 10 0 1 8 15 22 29 36 43 50 57 64 71 78 85 92 Days N = 636 cases 99 106 113 120 127 134 141 148 155 162 169 176 * One additional ABC hypersensitivity reaction reported at 318 days Hetherington S et al. 7th CROI 2000: Abst. 60. HLA-B*5701 Screening for ABC HSR PREDICT Study Results1 9 8 Control arm Prospective HLA-B*5701 screening arm 7 Incidence (%) HLA-B*5701 Screening2 OR 0.40 (0.25, 0.62) P<.0001 6 Skin testing 5 OR 0.03 90, 0.18) P<.0001 4 3 2 1 7.8 (66/847) 3.4 (27/803) 0 Clinically Suspected HSR 2.7 0.0 (23/842) (0/802) • Screen before starting patients on an ABC-containing regimen • HLA-B*5701(+) patients should not receive ABC – Record as an ABC allergy • HLA-B*5701(–) does not absolutely rule out ABC HSR – Screening is not a substitute for clinical judgment or vigilance • If screening is not available, initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR Immunol Confirmed HSR OR = odds ratio; ABC = abacavir; HSR = hypersensitivity reaction. 1. Molina JM et al. 11th European AIDS Conference/EACS; October 24-27, 2007; Madrid, Spain. Abstract PS5/1; 2. Adapted from US Department of Health and Human Services Guidelines; Revised January 29, 2008. Available at: http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf. Accessed March 13, 2008. Case 6 • A 45 year old woman with HIV has been on a stable regimen of FTC, TDF and lopinavir/ritonavir for years with excellent HIV control (plasma HIV level < 30 copies/mL) and a steady increase in CD4 cells to 800 cells/uL. • At a regular follow-up visit she complains of “getting really fat” plus a change in her face such that the DMV officer didn’t think it was her when she renewed her drivers license. • What has developed? Lypodystrophy syndrome Antiretroviral Toxicity METABOLIC COMPLICATIONS OF HIV AND HAART • • • • • • Lipodystrophy Syndrome (LDS) Dyslipidemia Lactic acidosis Hyperglycemia Osteopenia Avasular necrosis Antiretroviral Toxicity LYPODYSTROPHY SYNDROME • Reported in 40-50% of HIV outpatients • Lipoatrophy (loss of fat in the buttocks, face and limbs) > Lipoaccumulation (development of central fat: buffalo hump, visceral fat, breast hypertrophy) • Pathogenesis: – PIs inhibit adipocyte differentiation, increase lipolysis and may also induce an insulin resistant state – NRTIs associated with lipolysis • Risk factors: older age, female sex, duration of HAART facial lipoatrophy breast enlargement central adiposity peripheral lipoatrophy Facial lipoatrophy peripheral lipoatrophy Dorso-cervical Fat Pad Lipoatrophy and Fat Accumulation in HIV-Infected Adults Grinspoon, S. et al. N Engl J Med 2005;352:48-62 Antiretroviral Toxicity LDS: TREATMENT • Lipoatrophy – Switch D4T/AZT to other NTRTI (abacavir/tenofovir) – Cosmetic surgery (polylactic acid implants) • Lipoaccumulation – – – – – Diet and exercise Recombinant HGH - incomplete and reversible Metformin/rosiglitazone Cosmetic surgery (buffalo hump) TH9507: synthetic GHRF: Decreases visceral fat and improves lipids (Falutz, CROI, 2007) HIV: Practice and Prevention, 2012 Drug interactions Case 7 • A 25 year old woman is recently diagnosed with advanced HIV. Her CD4 count is 10, her plasma HIV RNA level is > 1,000,000. • Her PMH is notable for GERD, anxiety, opiate addiction, hyperlipidemia, primary pulmonary hypertension, hepatitis C, hepatitis B and a seizure disorder. • Current medications are omeprazole, diazepam, methadone, lovastatin, sildenafil, dilantin, pegylated interferon, ribavirin and estridiol. • Besides bactrim and azithromycin you prescribe HAART selecting ddI, 3TC and atazanavir/ritonavir. • The clinic pharmacist approaches you shaking her head in disgust. What is the problem? Case 7 Drug Interactions • • • • NNRTIs (EFV and NVP) induce the cytochrome P450 system Protease inhibitors (esp RTV) inhibit the cytochrome P450 system Ribavirin increases the toxicity due to ddI NNRTIs decrease estradiol concentrations and, paradoxically, so do protease inhibitors • Methadone metabolism is increased by NNRTIs and variably affected by protease inhibitors • Atazanavir absorption is decreased with co-administration of PPI • Watch out for significant drug interactions with all antiretrovirals, especially those metabolized through the cytochrome P450 system Case 7 For this patient: • • • • • • • • • Change omeprazole to ranitidine Change diazepam to lorazepam Watch for methadone withdrawl Change lovastatin to pravistatin Talk to pulmonologist about sildenafil dose Transition from dilantin to other anticonvulsant (Keppra) Don’t use ddI with ribavirin Don’t use 3TC alone in patient with hepatitis B Don’t rely on OCPs alone for birth control in patient on HAART Madison Clinic Website www.madisonclinic.org