Care Primary Care Issues in HIV David H. Spach, MD The International AIDS Society–USA DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June 2005.

Slide #2 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Primary Care Issues in HIV Hepatitis B Vaccination Hepatitis A Vaccination Screening for Cervical Abnormalities Evaluation of Renal Disease Adverse Drug Effects: Case Studies DHS/HIV//PP

Slide #3 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Hepatitis A and B Vaccination

Slide #4 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Hepatitis A & B Vaccination Practices for Ambulatory Patients with HIV-Infection  Methods - 9 Clinic (HOPS) Sites - N = 1071 in study - Analysis of HOPS data base Study DesignResults From: Tedalid EM et al. Clin Infect Dis 2004;38:

Slide #5 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Hepatitis A & B Vaccination Practices for Ambulatory Patients with HIV-Infection Provider Reasons for Not Vaccinating (1) Patient did not regularly attend clinic (2) Patient not considered high risk (3) CD4 cell count considered too low (4) Insurance would not pay for immunization DHS/HIV/PP From: Tedalid EM et al. Clin Infect Dis 2004;38:

Slide #6 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Hepatitis A & B Vaccination Practices for Ambulatory Patients with HIV-Infection Conclusions “Although there were low rates of complete hepatitis vaccination in this cohort of ambulatory patients, prompt efforts to vaccinate patients entering care, receipt of antiretroviral therapy, and practice reminder systems may enhance vaccination practices.” DHS/HIV/PP From: Tedalid EM et al. Clin Infect Dis 2004;38:

Slide #7 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS//HIV/PP ACIP: Hepatitis B Vaccine Recommendations  Vaccine Indications - All HIV-infected persons without evidence of prior HBV infection  Vaccine Schedule (Adults) - ENGERIX-B: 20 ug (0,1,6 m) - RECOMBIVAX HB: 10 ug (0,1,6m) - TWINRIX*: 0,1,6m  Post-Vaccine Antibody Testing - Test 1-6 months after series Indications & ScheduleHBV: anti-HBs Titers *TWINRIX= HAVRIX 720 EL.U plus ENGERIX 20 ug From: CDC National Immunization Program ACIP Recommendations.

Slide #8 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June HBV: Isolated anti-HBc  Definition of Isolated anti-HBc -HBsAg negative -anti-HBs negative -anti-HBc positive  Possible Explanations (1) False positive (2) Remote infection (resolved) (3) Remote infection (persistent/occult) (4) Acute infection IgM+ (window) DHS/HIV/PP Hepatitis B Core (Capsid)

Slide #9 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/PP HBV Vaccine: Naive & Anamnestic Responses Naive Response Anamnestic Response HBV Vaccination Series 10 IU/L

Slide #10 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Isolated anti-HBc in HIV-Infected Persons  Methods - N = 69 HIV-infected adults - All HBsAg(-) and anti-HBs(-) - 40 (58%) of 69 anti-HBc(-) - 29 (42%) of 69 anti-HBc(+) Approx 50% of anti-HBc(+) also anti-HBe(+)  Intervention: HBV Vaccine - Outcome: Anamnestic Response Study DesignPatients with Anamnestic Response From: Gandi RT, et al. J Infect Dis 2005;191: *Defined as anti-HBs titer > 10 IU/L within 4 weeks of vaccination DHS/HIV//PP anti-HBc+

Slide #11 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Isolated HBcAb in HIV-Infected Persons Conclusions “After hepatitis B vaccination, the anamnestic response rate in HIV-1–positive subjects who tested positive for isolated anti-HBc but negative for anti-HBe was low and was comparable to that in subjects who tested negative for anti-HBc.” “This finding suggests that testing for anti-HBc alone may not be a reliable assessment of protection from HBV infection.” DHS/HIV/PP From: Gandi RT, et al. J Infect Dis 2005;191:

Slide #12 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June HIV and Hepatitis B Vaccine Standard Dose versus Double Dose Patients (%) AllCD4 > 350 CD4 < 350 Standard Double-Dose  Methods - N = 210 HIV-infected adults - HBV negatives  HBV Vaccine (Engerix): Dosing - Standard: 20 ug at 0,1,& 6 m - Double dose: 40 ug at 0,1 & 6m  Major Measurement - anti-HBsAb Study DesignSeroconversion* Rate From: Fonseca MO, et al. Vaccine 2005;23: *Anti-HBsAB titer > 10 IU/L

Slide #13 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/PP ACIP: Hepatitis A Vaccine Recommendations  Vaccine Indications - Travel to endemic region - Male-male sex - Injection-drug use - Chronic liver disease - Clotting factor disorders  Vaccine Schedule (Adults) - HAVRIX: 1440 EL.U (0, 6-12m) - VAQTA: 50 U (0, 6-12m) - TWINRIX: 0,1,6m Indications & ScheduleProtective Titers Used In Studies From: CDC National Immunization Program ACIP Recommendations. Cut-Off, Range (Modified Enzyme Immunoassay) *TWINRIX= HAVRIX 720 EL.U plus ENGERIX 20 ug Cut-Off, Range (Radioimmunoassay)

Slide #14 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Hepatitis A Vaccine in HIV-Infected Adults  Methods - N = 133 HIV-infected adults - HAV seronegative  Study Groups (0, 6 months) - HAV vaccine (HAVRIX):1440 EIU - Saline placebo  Outcomes - Vaccine responses - Affect on HIV RNA & CD4 Study DesignHAV Seroconversion* From: Kemper CA et al. JID 2003;187: *Anti-HAV antibody titer > 33 mIU/ml Vaccine had no effect on HIV RNA or CD4 count

Slide #15 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Hepatitis A Vaccine in HIV-Infected Adults  Methods - N = 90 HIV-infected adults - N = 90 HIV-seronegative adults - HAV seronegative  Study Groups (0, 6 months) - HAV vaccine (VAQTA):50 EIU - Saline placebo  Outcomes - Vaccine responses - Affect on HIV RNA & CD4 Study DesignHAV Seroconversion Week 28* From: Wallace MR, et al. CID 2004;39: *Anti-HAV antibody titer > 10 mIU/ml Vaccine had no effect on HIV RNA or CD4 count

Slide #16 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Screening for Cervical Abnormalities

Slide #17 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/PP HIV Classification HPV-Related Conditions  Category B Conditions - Cervical Dysplasia (Moderate or Severe) - Cervical Carcinoma in Situ  Category C Conditions - Invasive Cervical Cancer From: CDC & Prevention. MMWR. 1992;41 (RR-17):1-19. Cancer

Slide #18 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June PAP Smears in HIV-Infected Persons Recommendations from IDSA OI Prophylaxis Guidelines DHS/PP Picture Initial Evaluation: Twice in First Year after HIV Diagnosis Manage According to NCI Consensus Panel Interim Guidelines for Abnormal Cervical Cytology Annual Screening From: 2001 USPHS/IDSA Prevention of OI Guidelines [ Normal Abnormal Rescreen Annually Abnormal Normal

Slide #19 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV//PP Guidelines for Approach to Abnormal Cervical Cytology Pap Smear ResultRecommendation ASCUS (with Severe Inflammation) Evaluate for infection; if found, treat and recheck PAP in 2-3 months ASCUS Follow-up PAP q 4-6 months x 2 yrs (until 3 consecutive PAPs negative) If another ASCUS, consider colposcopy ASCUS (Neoplastic Process Suspected) Follow-up PAP q 4-6 months; OR Colposcopy & biopsy if LSIL persists; OR Immediate colposcopy Low-grade squamous intraepithelial lesion (LSIL) Follow-up PAP q 4-6 months; OR Colposcopy & biopsy if LSIL persists; OR Immediate colposcopy High-grade squamous intraepithelial lesion (CIN 2 or 3, carcinoma in situ) OR Squamous cell carcinoma Colposcopy & biopsy of Abnormal Area; From: 2001 USPHS/IDSA Prevention of OI Guidelines [

Slide #20 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/Women/PP HIV & Women: Frequency of Pap Smears A Guide to the Clinical Care of Women with HIV/AIDS ASCUS = atypical squamous cells of undetermined significance LGSIL = low grade squamous intraepithelial lesion Clinical ScenarioScreening Frequency Normal Pap1 Year Symptomatic Infection CD4 < Months ASCUS/LGSIL (evaluated and followed without Rx) 4-6 Months Following treatment of preinvasive lesions 3-4 Months for first year, then 6 Months

Slide #21 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/Women/PP HIV & Women Improving Screening for Cervical Abnormalities  Incorporate into Quality Improvement Project*  Computerized Records with Reminders  Feedback to Providers  Incorporate Quality Improvement with Provider Performance Indicators Information on Quality Improvement in HIV Clinics*

Slide #22 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June HPV-16 Vaccine in Women  Background - N = Females aged Randomized, double-blind - F/U: Median 17.4 months  Vaccines (0, 2, and 6 months) - HPV-16 Vaccine*: 40 ug - Placebo Study DesignPersistent HPV-16 Infection From: Koutsky L et al. N Engl J Med 2002;347: P < *HPV virus-like particle vaccine Cervical Intraepithelial Neoplasia - Placebo: 9 cases - Vaccine: 0 cases

Slide #23 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/PP HPV-16 & HPV-18 Vaccine in Women  Background - N = Females aged Randomized, double-blind - F/U: up to 27 months  Vaccines (0, 1, and 6 months) - HPV-16 Vaccine*: 40 ug - Placebo Study DesignPersistent HPV-16/18 Infection From: Harper D et al. Lancet 2004;364: P < *HPV virus-like particle vaccine P < 0.001

Slide #24 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Evaluation & Management of Renal Disease Recommendations from HIVMA-IDSA

Slide #25 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Screening for Renal Disease in HIV-Infected Persons Recommendations from HIVMA-IDSA DHS/PP Picture Screening Studies at Initial Evaluation - Urine analysis (for proteinuria) - Serum Creatinine (to estimate C cl or GFR) Abnormal Value - Grade > 1 proteinuria by dipstick - C cl or GFR < 60 mL/min per 1.73m 2 No Abnormal Value From: Gupta SK, et al. Clin Infect Dis 2005;40: Risk Factors Present - Rescreen Annually Risk Factors Absent - Follow Clinically Further Evaluation - Spot Urine Prot/Creat Ratio - Renal Ultrasound - Consider Nephrology Referral

Slide #26 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Screening for Renal Disease in HIV-Infected Persons Recommendations from HIVMA-IDSA DHS/PP Picture Screening Studies at Initial Evaluation - Urine analysis (for proteinuria) - Serum Creatinine (to estimate C cl or GFR) No Abnormal Value Risk Factors* for Developing Proteinuric Renal Disease - African American - CD4 4,000 copies/ml - Diabetes mellitus - HTN - Chronic HCV Infection From: Gupta SK, et al. Clin Infect Dis 2005;40: Risk Factors* Present - Rescreen Annually Risk Factors* Absent - Follow Clinically

Slide #27 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/PP  1. Control BP < 125/75 mm Hg - Preferential use of ACE Inhibitors or ARBs if proteinuria - Avoid calcium-channel blockers if patient taking PI  2. Treat HIVAN with HAART at Diagnosis  3. Use Additional Therapies for HIVAN Refractory to HAART - ACE Inhibitors, ARBs, Corticosteroids  4. Perform Dialysis if Indicated  5. Consider Renal Transplant for ESRD Management of Nephropathy in HIV-Infected Persons Key Recommendations from HIVMA-IDSA From: Gupta SK, et al. Clin Infect Dis 2005;40:

Slide #28 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/HIV/PP Medication-Related Adverse Effects Case Studies

Slide #29 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Case History A 38-year-old HIV-infected man with a CD4 count of 188 cells/mm 3 starts on a regimen of tenofovir plus lamivudine plus lopinavir-ritonavir. Other medications include inhaled fluticasone, montelukast, and trimethoprim-sulfamethoxazole. Three months later his HIV RNA is < 50 copies/ml, but at the 3- month visit, he complains of new weakness in his upper arms and legs as well as puffy cheeks. He also has new onset hypertension and hyperglycemia. What do you think is the most likely cause of his new problems? 1. Rapid onset protease inhibitor-related lipodystrophy 2. Iatrogenic Cushing’s syndrome from fluticasone 3. Renal toxicity caused by tenofovir 4. Lopinavir-ritonavir hepatotoxicity DHS/HIV/PP

Slide #30 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June Case History A 43-year-old HIV-infected woman with a CD4 count of 374 cells/mm 3 is admitted to the hospital with a severe buttock MRSA abscess. The patient is discharged on a 7-day course of linezolid. Two days after leaving the hospital, the patient comes to the clinic with mental status changes, increased muscle tone, tremor, and diarrhea. Examination shows T = 38.5°, agitation, hyperreflexia, and clonus. Medications (Chronic) - Abacavir-lamivudine - Atazanavir - Citalopram - Methadone What do you think would best explain the clinical course in this patient? 1. Linezolid-induced opiate withdrawal (decrease in methadone level) 2. Abacavir hypersensitivity syndrome 3. Serotonin syndrome 4. Malignant hyperthermia DHS/HIV/PP

Slide #31 DH Spach, MD. Presented at IAS–USA/RWCA Clinical Conference, June DHS/ HIV/PP Case History  A 29-year-old man has a CD4 count of 41 and an HIV RNA of 134,000 and is admitted to the hospital with moderately severe PCP (pO2 = 73). He has a history of Stevens-Johnson syndrome from TMP/SMX; he receives IV pentamidine 4 mg/kg/d. He is on no ARV therapy.  On the 6th day after admission, the patient’s respiratory status has improved, but he complains of sudden onset of headache and blurred vision. The nurse notes he is acutely confused and minimally responsive. You are immediately called. What is likely to be the most effective diagnostic measure you could take? 1. Emergent contrast brain CT scan 2. Stat cryptococcal antigen 3. Finger stick for glucose level 4. Stat sodium level