Clinical Case. Update in HIV Medicine: Think Globally, Act Locally May 22, Think Globally, Act Locally

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1 Think Globally, Act Locally Update in HIV Medicine: Think Globally, Act Locally May 22, 2007 Meg D. Newman, M.D. UCSF-PHP San Francisco General Hospital Epidemiology: Not much has changed Clinical Case: Don t t miss it When to Start ARV s? What are we Using? New Information on the Side Effects of HIV and or the Therapy to Treat HIV More Clinical Cases on how to Recognize the Essentials in HIV Medicine Clinical Case You are in the ER seeing a 29 y/o physics post-doc S/He presents with a fever to 102, mod myalgias, a sore throat, and a rash on the torso and lesions in the mouth. Her/His PMH is benign. Family history is benign. What is your differential diagnosis?? 1

2 Oral Ulcers in Acute HIV Infection From: Walker, B. 40 th IDSA, Chicago Acute HIV Infection Rash Mucosal Lesions Trunk and face > limbs Small pink macules Oral ulcers, thrush (Kahn, NEJM, 1998) Acute HIV DDX Sensitivity and Specificity for Diagnostic Tests for Primary HIV Hecht/Kahn et al-options Project Influenza Epstein-Barr virus mononucleosis Severe (streptococcal) pharyngitis Secondary syphilis Primary CMV infection Toxoplasmosis Drug reaction Viral hepatitis Primary HSV infection Rubella Brucellosis Malaria West Nile Virus 408 Screened 118 infected chronically. 105 with AHI Fevers Rash Pharyngitis Oral Ulcers Wt Loss 5lbs 105 with AHI Sensitivity % with AHI Specificity % OR Not available 2

3 Day 0 Day 0-2 Day 4-11 Day 11 onward Kahn JO, Walker BD. N Engl J Med. 1998;339: Exposure to HIV at mucosal surface (sex) Virus collected by dendritic cells, carried to lymph node HIV replicates in CD4 cells, released into blood Virus spreads to other organs Acute HIV Infection (AHI) Nearly 60 million individuals diagnosed with HIV, fewer than 1,000 cases have been diagnosed in AHI [1] 1/60,000 detection rate In NYC, fewer than 20 cases of AHI have been diagnosed [2] 1% of patients with negative tests for EBV had AHI [3] 1% of patients with any viral syndrome in a Boston urgent care center had AHI [5] In a Malawi STD clinic, 2.8% of all male clients with acute STD had AHI [1] [ 1] Pilcher, et al AIDS 2004, 2] NYC DOH STARHS, 3] Rosenberg, et al N Engl J Med 1999 [4] Pincus, et al Clin Infect Dis 2003 Acute HIV: Missed Opportunity The symptoms especially in mild cases are nonspecific and resolve spontaneously without treatment. Clinicians may be uncomfortable raising the question of sexual exposure or intravenous drug-use, use, especially with patients whom they only see infrequently such as young, previously healthy individuals. Primary care physicians may not be aware of high- risk behavior even in patients they know well. Patients may not perceive themselves to be at risk. CD4 T Cells/mm Typical Course of HIV Infection Primary Infection Possible acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs Clinical Latency Constitutional symptoms Opportunistic disease Death Weeks Years Pantaleo et al, NEJM, :512 1:256 1:128 1:64 1:32 1:16 1:8 1:4 1:2 0 Plasma Viremia Titer Antiretroviral Therapy When Should we Start? Old Paradigm: Hit early and hit hard. VL > 20K and CD4 < 500 New Paradigm: Start later and hit hard always use maximally suppressive therapy CD4 around Ideal CD4 still TBD VL is not a primary criteria for most of us Any signs of clinical illness independent of CD4 and VL are an indication for initiating treatment Pill Burden : 1997 AZT + 3TC + Indinavir (crixivan) MORNING NOON NIGHT 3

4 Pill Burden for ART 2005 This is a Q day Regimen FTC + tenofovir (truvada ) PLUS truvada Pill Burden: 2006 (2) Q Day Regimens! Choice of 2 Highly Potent Regimens Column A reyataz Column B Column C truvada sustiva Efavirenz (sustiva) efavirenz norvir epzicom OR Pill Burden 2007: 1 pill: once a day Atripla: EFV (Sustiva), FTC (emtricitabine),( tenofovir) TDF Potential Side-Effects and Sequalae of AIDS and or ART Body Habitus Changes Extremity and facial fat loss Truncal fat accumulation Hip and breast fat accumulation-esp. in women Dorsocervical fat pads The etiology has not been completely elucidated NRTI s s that have great affinity for human mitochondria play a large role (d4t > ddi > AZT > 3TC > ABC > TNF) Remember body habitus changes antedated PI s HIV Related Dorsocervical Fat Pad Lipoatrophy Female Pt Male pt 4

5 DIFFERENTIAL EFFECTS OF NRTI REGIMENS ON ADIPOCYTE MITOCHONDRIAL DNA DEPLETION IN Nolan et al, Abstract 16 HIV-INFECTED PATIENTS 3-12 months months MtDNA depletion Pathophysiological effects: Clinical lipoatrophy Cellular Toxicity cellular toxicity ABC/TDF 1707 copies/cell BMI=24 Zidovudine 537 copies/cell Severity Severity BMI=24 leg fat = 24% leg fat = 17% LIPODYSTROPHY MODEL NRTIs d4t>zdv Mitochondrial toxicity Adipocyte loss and/or function Subcutaneous fat wasting HAART (PI) Insulin resistance Dyslipidemia Visceral fat accumulation DETERMINANTS OF PHENOTYPE/SEVERITY? Stavudine 234 copies/cell mitochondrion BMI=24 leg fat = 11% White Race, Age, TNF HOST FACTORS Not White, Sedentary, Diet NRTI Choice Therapy?PI Choice (RTV, new PIs) MO3-613: Fat Changes With LPV/RTV Monotherapy vs EFV + ZDV/3TC Median Change in Limb Fat, ITT (%) EFV+ZDV/3TC LPV/rtv P <.001 P < Week ~ 2.3 kg LPV/RTV monotherapy associated with significantly less lipoatrophy than EFV + ZDV/3TC No other risk factors identified Trunk fat changes similar between arms Low baseline CD4+ cell count only factor associated with > 20% increase in trunk fat (P <.001) Study reinforces association of thymidine analogue NRTIs with lipoatrophy LPV/RTV EFV + ZDV/3TC A woman with breast, hip, trunk and abdomen fat gain Cameron DW, et al. CROI Abstract 44LB. HIV Related Fat Accumulation CT Scan Measurement of VAT Abdominal weight gain. This pt never had this before. Patient 1 week 12 He has been off d4t for 6 years and things are much improved Significant Visceral Adipose Tissue is Seen 5

6 Metabolic Side-Effects and Sequalae of AIDS and or ART Insulin resistance ( ritonavir, lopinavir, indinavir) Abnormal Lipids ( ( Trig, Tchol and LDL, HDL) Ritonavir / indinavir / fortovase / lopinavir / nelfinavir Even when ritonavir is used as just a booster **Atazanavir and saquinavir are the PI exceptions Nelfinavir increases LDL and TG but decreases HDL HIV Lipoatrophy, Dyslipidemia, and Impaired Glucose Tolerance TG Peripheral fat loss FFA Van Wijk JP, et al. J Clin Endocrinol Metab. 2005;90: VLDL Steatosis β-cell dysfunction Impaired glucose metabolism CHD Potential Side-Effects and Sequalae of AIDS and or ART Skin Disease Rash associated with many newer ARV s s (NVP, EFV, ABC) % of the time. Always consider Abacavir hypersensitivity. This is a systemic syndrome with resp symptoms, fever, GI sx Hyperpigmentation from emtricitabine (FTC) Nevirapine rash is 11 fold more common in women New Warts with immune enhancement (especially intraoral, facial and anal warts) More eosinophilic folliculitis Peripheral Neuropathy Lots of potential side effects of antiretroviral therapy Abacavir (ziagen) Hypersensitivity Hyperpigmentation from Emtricitabine Human Papilloma Virus 6

7 Eosinophilic Folliculitis Potential Side-Effects and Sequalae Of AIDS and or ART Mitochondrial Toxicity Lactic acidosis and hepatic steatosis Onset is often insidious. Patients may present with anorexia, weight loss and malaise or more focused syndromes with myopathy or peripheral neuropathy Check bicarbonate, and if a gap is present draw a lactate level. POLYMERASE GAMMA (γ) HYPOTHESIS NRTIs Are these problems really occurring more often in people with HIV/AIDS (PWHA)? Osteopenia Osteoporosis Avascular Necrosis Both bone changes appear to be a cohort effect Polymerase γ mtdna mtdna Mitochondrion 1. mtdna depletion mtdna encoded protein function 3. dysfunction 2. mtdna encoded protein End organ cardiovascular or neurological sequalae? CAD Renal Insufficiency HTN CVA 1,2 Nolan D et al. Antiviral Therapy 2003; 8: Hammond E et al. AIDS 2004; 18: Quick View: Adverse Rx to HIV Meds Abacavir: hypersensitivity syndrome AZT: HA, N,V, anemia, mt toxicity d4t / ddi: mt toxicity, peripheral neuropathy, pancreatitis Efavirenz: Neuropsychiatric effects, teratogenic Tenofovir: Renal insufficiency, HTN, Fanconi s s Syndrome (K, Phos, cr. abnl ) TMP/SMZ: Everything: rash, Stevens-Johnson syndrome, hypotension-sepsis sepsis syndrome, HA, N, IV: hyperkalemia etc. Take Home Points 2007 Acute HIV: have a low threshold to consider this diagnosis Watch for medication side-effects effects.. Evaluate your patients medication lists for potential drug interactions. Be alert for abacavir hypersensitivity Be alert for lactic acidosis syndrome with d4t**, AZT or ddi HELP is available! Warmline, PEPline and Perinatal Hotline 7

8 Important Web Sites / Resources HIVinsite All you want and more with links to everything HIV. This is a UCSF site. Drug interactions/side-effects: effects: aidsmeds.com, or or AETC (AIDS Education and Training Center) IAS-USA (International AIDS Society-USA) National HIV/AIDS Clinicians Consultation Center UCSF San Francisco General Hospital Warmline (800) National HIV Telephone Consultation Service Consultation on all aspects of HIV testing and clinical care PEPline (888) National Clinicians Post-Exposure Prophylaxis Hotline Recommendations on managing occupational exposures to HIV and hepatitis B & C Perinatal Hotline (888) National Perinatal HIV Consultation & Referral Service Advice on testing and care of HIV-infected pregnant women and their infants HRSA AIDS-ETC Program & Community Based Programs, HIV/AIDS Bureau & Centers for Disease Control and Prevention (CDC) Disclosure Statements Current ACCME guidelines state that participants in CME activities should be made aware of any affiliation or financial interest that may affect the t faculty member s contributions. Each faculty member has completed a statement of disclosure, which includes funding sources other than the honorarium received d for this program. The faculty have provided the following information on sources of funding that may be perceived as a potential conflict of interest. Meg D. Newman, M.D. has no affiliation or financial interests that may influence the content of this presentation. 8