Chun Chao

HIV INFECTION AND THE RISK OF CANCERS WITH AND WITHOUT A KNOWN INFECTIOUS CAUSE

Objective:To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. Design:Retrospective cohort study. Methods:Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkins lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). Results:We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7–44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7–11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkins lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2–1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). Conclusion:In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

HIV Infection, Immunodeficiency, Viral Replication, and the Risk of Cancer

Background: Few studies have compared cancer risk between HIV-infected individuals and a demographically similar HIV-uninfected internal comparison group, adjusting for cancer risk factors. Methods: We followed 20,775 HIV-infected and 215,158 HIV-uninfected individuals enrolled in Kaiser Permanente (KP) California for incident cancer from 1996 to 2008. Rate ratios (RR) were obtained from Poisson models comparing HIV-infected (overall and stratified by recent CD4 count and HIV RNA) with HIV-uninfected individuals, adjusted for age, sex, race/ethnicity, calendar period, KP region, smoking, alcohol/drug abuse, and overweight/obesity. Results: We observed elevated RRs for Kaposi sarcoma (KS; RR = 199; P < 0.001), non-Hodgkin lymphoma (NHL; RR = 15; P < 0.001), anal cancer (RR = 55; P < 0.001), Hodgkin lymphoma (HL; RR = 19; P < 0.001), melanoma (RR = 1.8; P = 0.001), and liver cancer (RR = 1.8; P = 0.013), a reduced RR for prostate cancer (RR = 0.8; P = 0.012), and no increased risk for oral cavity/pharynx (RR = 1.4; P = 0.14), lung (RR = 1.2; P = 0.15), or colorectal (RR = 0.9; P = 0.34) cancers. Lung and oral cavity/pharynx cancers were elevated for HIV-infected subjects in models adjusted only for demographics. KS, NHL, anal cancer, HL, and colorectal cancer had significant (P < 0.05) trends for increasing RRs with decreasing recent CD4. The RRs for lung and oral cavity/pharynx cancer were significantly elevated with CD4 < 200 cells/μL and for melanoma and liver cancer with CD4 < 500 cells/μL. Only KS and NHL were associated with HIV RNA. Conclusion: Immunodeficiency was positively associated with all cancers examined except prostate cancer among HIV-infected compared with HIV-uninfected individuals, after adjustment for several cancer risk factors. Impact: Earlier antiretroviral therapy initiation to maintain high CD4 levels might reduce the burden of cancer in this population. Cancer Epidemiol Biomarkers Prev; 20(12); 2551–9. ©2011 AACR.

Correlates for Human Papillomavirus Vaccination of Adolescent Girls and Young Women in a Managed Care Organization

The authors studied the characteristics of those who initiated the human papillomavirus (HPV) vaccine versus those who did not. Female members of Kaiser Permanente Southern California aged 9-26 years were identified and assessed for HPV vaccination between October 2006 and March 2008. Multivariable log-binomial regression was used to examine the association of the following factors with vaccine initiation: 1) demographics, 2) provider characteristics, 3) health care utilization, 4) womens health-related conditions, and 5) selected immune-related conditions. The study included 285,265 females. All analyses were stratified by 2 age groups: 9-17 years and 18-26 years. Black race (relative risk (RR)(9-17 years) = 0.93, RR(18-26 years) = 0.82), having a male primary care provider (RR(9-17 years) = 0.93, RR(18-26 years) = 0.84), and history of hospitalizations were associated with a lower likelihood of vaccine initiation. Higher neighborhood income level, physician office visits, and history of influenza vaccination (RR(9-17 years) = 1.20, RR(18-26 years) = 1.34) were associated with higher HPV vaccine uptake. Those with a history of sexually transmitted diseases were more likely and those with immune-related conditions were not less likely to initiate the HPV vaccine. These findings are helpful for interpreting the results of observational safety studies and providing insights for developing targeted HPV vaccination programs.

Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine.

Abstract.  Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H, Ackerson B, Cheetham TC, Hansen J, Deosaransingh K, Emery M, Liaw K‐L, Jacobsen SJ (Kaiser Permanente Southern California, Pasadena, CA; Kaiser Permanente Vaccine Study Center, Kaiser Permanente Northern California, Oakland, CA; Merck Research Laboratories, Upper Gwynedd, PA; South Bay Medical Center, Kaiser Permanente Southern California, Los Angeles, CA; and Kaiser Permanente Southern California, Downey, CA, USA). Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med 2012; 271: 193–203.

Safety of quadrivalent human papillomavirus vaccine administered routinely to females.

OBJECTIVE To assess the safety of the quadrivalent human papillomavirus vaccine (HPV4) in females following routine administration. DESIGN In a cohort of vaccinated females, we compared the risk of emergency department visits and hospitalizations during the interval soon after vaccination with risk during a comparison interval more remote from vaccination. SETTING Kaiser Permanente in California. PARTICIPANTS All females who received the HPV4 vaccine. MAIN EXPOSURE One or more doses of HPV4 between August 2006 and March 2008. MAIN OUTCOME MEASURES Outcomes were emergency department visits and hospitalizations, grouped into predefined diagnostic categories. Within diagnostic groups, we used odds ratios (ORs) to estimate whether each subject had any outcome in postvaccination risk intervals (days 1-60, days 1-14, and day 0), compared with a control interval distant in time from vaccination. RESULTS One hundred eighty-nine thousand six hundred twenty-nine females received at least 1 dose and 44 001 received 3 HPV4 doses. Fifty categories had significantly elevated ORs during at least 1 risk interval. Medical record review revealed that most diagnoses were present before vaccination or diagnostic workups were initiated at the vaccine visit. Only skin infections during days 1 to 14 (OR, 1.8; 95% CI, 1.3-2.4) and syncope on day of vaccination (OR, 6.0; 95% CI, 3.9-9.2) were noted by an independent Safety Review Committee as likely associations with HPV4. CONCLUSIONS The quadrivalent human papillomavirus vaccine was associated with same-day syncope and skin infections in the 2 weeks after vaccination. This study did not detect evidence of new safety concerns among females 9 to 26 years of age secondary to vaccination with HPV4.

Correlates for Completion of 3-Dose Regimen of HPV Vaccine in Female Members of a Managed Care Organization

OBJECTIVE To examine the rate and correlates of completion of the quadrivalent human papillomavirus vaccine (HPV4) 3-dose regimen because nonadherence to the regimen may adversely affect vaccine efficacy. PARTICIPANTS AND METHODS Female members of Kaiser Permanente Southern California who were 9 to 26 years old, received the first dose of HPV4 between October 2006 and March 2007, and maintained health plan membership 12 months afterward were identified and followed up for regimen completion. We examined the following: (1) demographics/socioeconomic status, (2) primary care physician characteristics, (3) historical health service utilization, (4) womens health-related conditions, and (5) selected immune-related conditions for their association with completion in 2 age groups: 9 to 17 years and 18 to 26 years. Multivariable log-binomial regression was used to directly estimate relative risk (RR). RESULTS Of the 34,193 females who initiated HPV4, the completion rate was 41.9% in the 9- to 17-year-old group and 47.1% in the 18- to 26-year-old group. Black race (RR, 0.70; 95% confidence interval [CI], 0.64-0.77) and lower neighborhood education level were associated with lower regimen completion. However, those in the 9- to 17-year-old group who were covered by the state-subsidized program Medi-Cal were more likely to complete the regimen (RR, 1.14; 95% CI, 1.07-1.22). Historical hospitalizations and emergency department visits (RR, 0.92; 95% CI, 0.87-0.96; and RR, 0.96; 95% CI, 0.94-0.98 per visit, respectively) and having a pediatrician were also predictors of noncompletion. A history of sexually transmitted diseases, abnormal Papanicolaou test results, and immune-related conditions (eg, asthma/infections) were not associated with regimen completion. CONCLUSION These findings suggest that factors such as race or socioeconomic status should be considered when human papillomavirus vaccination programs are being designed and evaluated.

Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases

IMPORTANCE Because vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health. OBJECTIVE To determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS. DESIGN, SETTING, AND PARTICIPANTS A nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code. EXPOSURES Vaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system. MAIN OUTCOMES AND MEASURES All forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset. RESULTS We identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57). CONCLUSIONS AND RELEVANCE We found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study

PURPOSE Cardiovascular diseases (CVDs), including ischemic heart disease, stroke, and heart failure, are well-established late effects of therapy in survivors of childhood and young adult (< 40 years at diagnosis) cancers; less is known regarding CVD in long-term survivors of adult-onset (≥ 40 years) cancer. METHODS A retrospective cohort study design was used to describe the magnitude of CVD risk in 36,232 ≥ 2-year survivors of adult-onset cancer compared with matched (age, sex, and residential ZIP code) noncancer controls (n = 73,545) within a large integrated managed care organization. Multivariable regression was used to examine the impact of cardiovascular risk factors (CVRFs; hypertension, diabetes, dyslipidemia) on long-term CVD risk in cancer survivors. RESULTS Survivors of multiple myeloma (incidence rate ratio [IRR], 1.70; P < .01), carcinoma of the lung/bronchus (IRR, 1.58; P < .01), non-Hodgkin lymphoma (IRR, 1.41; P < .01), and breast cancer (IRR, 1.13; P < .01) had significantly higher CVD risk when compared with noncancer controls. Conversely, prostate cancer survivors had a lower CVD risk (IRR, 0.89; P < .01) compared with controls. Cancer survivors with two or more CVRFs had the highest risk of CVD when compared with noncancer controls with less than two CVRFs (IRR, 1.83 to 2.59; P < .01). Eight-year overall survival was significantly worse among cancer survivors who developed CVD (60%) when compared with cancer survivors without CVD (81%; P < .01). CONCLUSION The magnitude of subsequent CVD risk varies according to cancer subtype and by the presence of CVRFs. Overall survival in survivors who develop CVD is poor, emphasizing the need for targeted prevention strategies for individuals at highest risk of developing CVD.

Survival of Non-Hodgkin Lymphoma Patients with and without HIV-Infection in the Era of Combined Antiretroviral Therapy

Objective:To investigate the survival outcomes for non-Hodgkin lymphoma (NHL) in HIV-infected vs. uninfected patients from the same integrated healthcare system, and to identify prognostic factors for HIV-related NHL in the era of combined antiretroviral therapy. Design:A cohort study. Methods:Incident NHL diagnosed between 1996 and 2005 were identified from members of Kaiser Permanente California Health Plans. Two-year all-cause and lymphoma-specific mortality by HIV status were examined using multivariable Poisson regression. Among HIV-infected patients, prognostic factors of demographics, lymphoma, and HIV-related characteristics for the same outcomes were also examined. Results:A total of 259 HIV-infected and 8230 HIV-uninfected incident NHL patients were evaluated. Fifty-nine percent of HIV-infected patients died within 2 years after NHL diagnosis as compared with 30% of HIV-uninfected patients. HIV status was independently associated with a doubling of 2-year all-cause mortality (relative risk = 2.0, 95% confidence interval 1.7–2.3). This elevated mortality risk for HIV-infected patients was similar for all race groups, lymphoma stages, and histologic subtypes. HIV-infected patients with CD4 cell count below 200 cells/μl, prior AIDS-defining illness, or both were also at increased risk for lymphoma-specific mortality as compared with HIV-uninfected patients. Among HIV-infected NHL patients, significant prognostic factors for overall mortality included prior AIDS-defining illness and Burkitts subtype. Conclusion:HIV-infected patients with NHL in the combined antiretroviral therapy era continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL. Better management and therapeutic approaches to extend survival time for HIV-related NHL are needed.

Exposure to antiretroviral therapy and risk of cancer in HIV-infected persons.

Objective:The incidence of certain non-AIDS-defining cancers (NADCs) in HIV patients has been reported to have increased in the combination antiretroviral therapy (ART) era. Studies are needed to directly evaluate the effect of ART use on cancer risk. Design:We followed 12 872 HIV-infected Kaiser Permanente members whose complete ART history was known for incident cancers between 1996 and 2008. Methods:Cancers, identified from Surveillance, Epidemiology, and End Results (SEER)-based cancer registries, were grouped as ADCs, infection-related NADCs, or infection-unrelated NADCs. We also evaluated the most common individual cancer types. Rate ratios for ART use (yes/no) and cumulative duration of any ART, protease inhibitor, and nonnucleotide reverse transcriptase inhibitor (NNRTI) therapy were obtained from Poisson models adjusting for demographics, pretreatment or recent CD4 cell count and HIV RNA levels, years known HIV-infected, prior antiretroviral use, HIV risk, smoking, alcohol/drug abuse, overweight/obesity, and calendar year. Results:The cohort experienced 32 368 person-years of ART, 21 249 person-years of protease inhibitor therapy, and 15 643 person-years of NNRTI therapy. The mean follow-up duration was 4.5 years. ADC rates decrease with increased duration of ART use [rate ratio per year = 0.61 (95% confidence interval 0.56–0.66)]; the effect was similar by therapy class. ART, protease inhibitor, or NNRTI therapy duration was not associated with infection-related or infection-unrelated NADC [rate ratio per year ART = 1.00 (0.91–1.11) and 0.96 (0.90–1.01), respectively], except a higher anal cancer risk with longer protease inhibitor therapy [rate ratio per year = 1.16 (1.02–1.31)]. Conclusion:No therapy class-specific effect was found for ADC. ART exposure was generally not associated with NADC risk, except for long-term use of protease inhibitor, which might be associated with increased anal cancer risk.