Pneumococcal Polysaccharide (PV) Vaccine Failures among HIV-infected Veterans Compared to Non-HIV-infected controls. Maria C. Rodriguez-Barradas, MD Director, HIV Program Houston VAMC

Epidemiology 40-50% of all adult cases of invasive pneumococcal disease occur in HIV(+) individuals HIV(+) compared to HIV(-) patients: Higher frequency of bacteremia (50% vs. 20%, 9.4 vs. 0.07/1000 person years respectively) Higher rate of relapse and recurrence Frequent reports of vaccine failures. Higher incidence of infection with PRP. Lower or comparable substantial mortality (5-20%).

Invasive pneumococcal disease (San Francisco, 1994-1997)

Consider for patients with CD4 <200 Recommendations for Pneumococcal Vaccine (2001 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons with HIV) All HIV infected patients with CD4 cell count >200/mm3 at the time of initial presentation. Consider for patients with CD4 <200 Consider revaccination at 5-6 years. Consider revaccination sooner for those who had CD4 <200 at initial vaccine and have increased to >200 with HAART.

Is PV effective against pneumococcal disease? Double-blind, randomized and placebo controlled trial (697 vaccinated, 695 not ); conducted in Uganda Primary endpoints: invasive pneumococcal disease. Secondary endpoints: vaccine serogroup-specific invasive disease, all pneumococcal events, all-cause pneumonia and death First invasive events in 25 patients (15 in the vaccine arm); 24 bacteremias, 1 polymyositis All pneumococcal events: similar distribution in both arms All-cause pneumonia: more frequent in the vaccine arm Mortality: unaffected by vaccination French et al Lancet 2000;355:2106-11

Is PV effective against pneumococcal disease Is PV effective against pneumococcal disease? Case-control study; HIV(+) patients with pneumococcal disease seen in a 4 year period (n=85) matched to HIV(+) controls (Johns Hopkins Hospital, 1989-1994). Gebo et al JID 1996 Apr;173:857-62

Is PV effective against pneumococcal disease? Retrospective case-control study among HIV(+) patients (176 cases and 327 controls) in San Francisco and Atlanta who were admitted (in a 3 year period, 1992-1995) and S. pneumoniae was isolated from a sterile site Pneumococcal disease more frequent among blacks, current smokers, and those with close contact with children. Among controls, vaccination less common among blacks. Overall adjusted vaccine effectiveness 49% (CI 12-70%): 76% for whites (CI 35-91%), 24% for blacks (CI 50-61%) . Breiman et al Arch Intern Med 2000 Sep 25;160(17):2633-8

Is PV effective against pneumococcal disease? Adult and adolescent Spectrum of HIV Disease Project, Jan 1990-98. Incidence of pneumococcal disease: 8.2 episodes/1000py. Factors associated with decreased risk of pneumococcal disease: Treatment: RR 0.6, 0.7, 0.5 mono-, dual-, and triple therapy. PV: RR 0.5 for vaccination at CD4 >500. Dworkin et al. CID 2001

Is PV effective against pneumococcal disease?

Is PV effective against pneumonia? Guerrero et al. AIDS 1999;13:1971-5

Impact of HAART on bacteremia and pneumonia Taconelli et al. (CID 1998). Causes of bacteremia at Catholic Univ. Hosp (Rome) for 2 periods 1/94-12/95 and 1-12/97 (188 episodes among 1,847 subjects). Decreased incidence of all bacteremias and community acquired bacteremia (from 6 to 3.3 episodes/100 PY). Paul S et al. (AIDS 1999). Cause for admission in NY Hosp-Cornell Medical Center 1-6/95 and 1-6/97. Decreased incidence of bacterial pneumonia (8.0 vs. 3.6/100 PY). CDC/ASD Project (CID 2000). Decreased incidence of recurrent pneumonia.

Impact of HAART on bacterial pneumonia Paul et al. AIDS 1999

Incidence of invasive pneumococcal disease per 100,000 Groups A-A Non-A-A All 50-64 y. gen. pop. 50.7 20.8 65-79 y. gen. pop. 79.6 37.2 >85 y. gen. pop. 169 118.4 >50 y. high risk pop. 121 61.6 18-64 y. AIDS pre-HAART 2,385 532 13->60 y. HIV+ 1,180 820

Using VA national database following was done: Is there an increase risk of pneumococcal disease after immunization with the 23-valent PPS? Methods: Collaborative effort with the VAMC Health Research Service: Nancy Petersen, PhD. Using VA national database following was done: 26,758 unique HIV-infected patients were identified in either the VA Patient Treatment Files or the Outpatient Clinic Files in FY 98-00. HIV infected patients are defined as those with an ICD-9 code of 042 or V08 for any listed diagnosis. A patient was classified as having pneumococcal vaccination if the appropriate codes were found in the PTF or OPC files. All cases were identified solely in the OPC files. 5,550 patients were identified. The FY 98-00 PTF files were searched to determine if the vaccinated patients had a hospital discharge with an admission date within the predetermined range and with any listed ICD-9 code of pneumonia, pneumococcal pneumonia, bacteremia or septicemia due to pneumococci.

HIV-infected patients in the VA system for the indicated FY

Number and percent of hospitalizations for pneumonia

Characteristics of Patients

Number and percent of hospitalizations for pneumonia

PV VACS Proposal Hypothesis The protective effectiveness of revaccination is similar to that of initial vaccine among HIV-infected and non-HIV-infected individuals. Effectiveness diminishes with time and the reduction is more pronounced among those with medical conditions that places them at risk for pneumococcal disease.

PV VACS Proposal Research Questions Is the protective effect of revaccination similar to that of initial vaccination among HIV-infected patients Is the protective effect of revaccination similar to that of initial vaccination among non-HIV infected patients. Are the effects different between the HIV-infected and non-HIV-infected groups. Is the protective effect different between HIV-infected patients with medical comorbid conditions and HIV-infected patients without medical comorbid conditions.

PV VACS Proposal AIMS Describe the rate of vaccination and revaccination among HIV-infected and non-HIV-infected individuals among the participating centers. Evaluate the yearly rate of pneumonia after vaccination and after revaccination for HIV-infected and non-HIV-infected subjects. Assess risk factors for post-vaccination pneumococcal disease among initial vaccination and re-vaccination groups.

Study Design All patients participating in VACS 5. Vaccine dates established by PTF or OPC files’ codes. ICD9 discharge diagnosis of pneumonia or pneumococcal pneumonia, bacteremia, meningitis, or sepsis within 1 year of PV. Medical comorbidities: COPD, DM, CHF, renal failure, malignancies. Other variables: Age, CD4 cell count, smoking status, OH use, antiretroviral use, PCP or MAC prophylaxis use. Bivariate and univariate analysis including incidence rates and rate ratios were performed using Stata version 8.1.

Results HIV+ HIV- P N 1,029 743 Age 49 ± 9 55 ± 10 <0.01 A-A 58% 47% PV 604 (59%) 279 (38%) 59 ± 10 56% 42% PV failures 23 (3.8%) 1 (0.36%)

Incidence rate ratio (IRR) for PV failure HIV+ IRR All 9.35 A-A 4.1 Smokers 5.3 DM 1.5 COPD 3.8

Problems identified and work to be done PV data: Need to confirm, need to validate. ICD9 codes used: Validity of all cause pneumonia code. Need to review charts of PV failures to confirm diagnosis. CD4 cell count at time of PV HAART at time of PV Logistic regression analysis to control for confounders (age, ethnicity, CD4, Rx, co-morbidities)

More work to be done Identify 1st time PV vs. revaccination Follow rate of PV failures for 5 years Determine rate of PV failure ICD9 discharge diagnosis among non-vaccinated HIV+ and HIV-

PV VACS Proposal Team Joseph Wagner, MPH Melissa Skanderson Sheldon Brown, MD Matthew Goetz, MD David Rimland, MD Michael Simberkoff, MD Amy Justice