Lanfang Xu

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.

Immunodeficiency and risk of myocardial infarction among HIV-positive individuals with access to care.

Background:We sought to clarify the association of HIV infection and immunodeficiency on myocardial infarction (MI) risk. Methods:We conducted a cohort study from 1996 to 2009 of HIV-positive (HIV+) and demographically matched HIV-negative (HIV−) Kaiser Permanente California health plan members. Rate ratios (RRs) were obtained from Poisson regression models comparing MI incidence rates between HIV+ (overall and stratified by recent and nadir CD4 count, and recent HIV RNA levels) and HIV− subjects, adjusting for age, sex, calendar era, race/ethnicity, census-based socioeconomic status, smoking, alcohol/drug abuse, overweight/obesity, diabetes, hypertension, and lipid-lowering therapy. Among HIV+ subjects, we also evaluated the independent association of CD4, HIV RNA, and antiretroviral therapy (ART) use. Results:The study population included 22,081 HIV+ and 230,069 HIV− subjects. The crude MI incidence rate per 100,000 person-years was 283 and 165 for HIV+ and HIV− subjects, respectively, with an adjusted RR of 1.4 [95% confidence interval (CI): 1.3 to 1.6]. Compared with HIV− subjects (reference), MI rates were similar for HIV+ subjects with recent CD4 ≥500 cells per microliter (RR = 1.18; 95% CI: 0.96 to 1.45) and those with nadir CD4 ≥500 cells per microliter (RR = 0.85; 95% CI: 0.55 to 1.33). Among HIV+ subjects, nadir CD4 was the only HIV-specific factor associated with MIs (RR per 100 cells = 0.88; 95% CI: 0.81 to 0.96), whereas recent CD4 and HIV RNA, prior ART use, and duration of protease inhibitors and nonnucleoside reverse transcriptase inhibitors were not associated with MIs. Conclusion:HIV+ subjects with recent or nadir CD4 ≥500 cells per microliter had similar MI rates compared with HIV− subjects. Lower nadir CD4, in particular, seems to be independently associated with MIs. These results strengthen recommendations for earlier ART initiation.

Narrowing the Gap in Life Expectancy Between HIV-Infected and HIV-Uninfected Individuals With Access to Care.

Background:It is unknown if a survival gap remains between HIV-infected and HIV-uninfected individuals with access to care. Methods:We conducted a cohort study within Kaiser Permanente California during 1996–2011, using abridged life tables to estimate the expected years of life remaining (“life expectancy”) at age 20. Results:Among 24,768 HIV-infected and 257,600 HIV-uninfected individuals, there were 2229 and 4970 deaths, with mortality rates of 1827 and 326 per 100,000 person-years, respectively. In 1996–1997, life expectancies at age 20 for HIV-infected and HIV-uninfected individuals were 19.1 and 63.4 years, respectively, corresponding with a gap of 44.3 years (95% confidence interval: 38.4 to 50.2). Life expectancy at age 20 for HIV-infected individuals increased to 47.1 years in 2008 and 53.1 years by 2011, narrowing the gap to 11.8 years (8.9–14.8 years) in 2011. In 2008–2011, life expectancies at age 20 for HIV-infected individuals ranged from a low of 45.8 years for blacks and 46.0 years for those with a history of injection drug use to a high of 52.2 years for Hispanics. HIV-infected individuals who initiated antiretroviral therapy with CD4 ≥500 cells per microliter had a life expectancy at age 20 of 54.5 years in 2008–2011, narrowing the gap relative to HIV-uninfected individuals to 7.9 years (5.1–10.6 years). For these HIV-infected individuals, the gap narrowed further in subgroups with no history of hepatitis B or C infection, smoking, drug/alcohol abuse, or any of these risk factors. Conclusions:Even with early treatment and access to care, an 8-year gap in life expectancy remains for HIV-infected compared with HIV-uninfected individuals.

Declining Relative Risk for Myocardial Infarction Among HIV-Positive Compared With HIV-Negative Individuals With Access to Care

Concerns remain for an increased myocardial infarction (MI) risk among individuals infected with human immunodeficiency virus (HIV). We conducted a cohort study evaluating MI risk from 1996 to 2011 by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (95% confidence interval, .7-1.4) in 2010-2011, the most recent study period.

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.

Survival among HIV-Infected and HIV-Uninfected Individuals with Common Non–AIDS-Defining Cancers

Background: Non–AIDS-defining cancers increasingly contribute to mortality among human immunodeficiency virus (HIV)–infected individuals. However, few studies have compared cancer prognosis by HIV status with adjustment for risk factors. Methods: We conducted a cohort study of HIV-infected and HIV-uninfected adults in Kaiser Permanente California during 1996 to 2011, following subjects diagnosed with Hodgkin lymphoma or anal, prostate, colorectal, or lung cancers. We used Kaplan–Meier curves and Cox regression to assess cancer-related mortality within 5 years, comparing HIV-infected with HIV-uninfected subjects. Adjusted models included age, race/ethnicity, sex, cancer stage, cancer treatment, and smoking. Results: Among HIV-infected and HIV-uninfected subjects, there were 68 and 51 cases of Hodgkin lymphoma, 120 and 28 of anal cancer, 150 and 2,050 of prostate cancer, 53 and 646 of colorectal cancer, and 80 and 507 of lung cancer, respectively. Five-year cancer-related survival was reduced for HIV-infected compared with HIV-uninfected subjects, reaching statistical significance for lung cancer (10% vs. 19%, P = 0.002) but not Hodgkin lymphoma (83% vs. 89%, P = 0.40) or anal (64% vs. 74%, P = 0.38), prostate (86% vs. 92%, P = 0.074), or colorectal cancers (49% vs. 58%, P = 0.55). Adjusted results were similar, with lung cancer [HR, 1.3; 95% confidence interval (CI), 1.0–1.7] and prostate cancer (HR, 2.1; 95% CI, 1.1–4.1) reaching significance. Conclusions: Cancer-related mortality was higher among HIV-infected compared with HIV-uninfected individuals for prostate and lung cancers, but not Hodgkin lymphoma, anal cancer, or colorectal cancer. Impact: Our findings emphasize the need for a focus on prevention, early detection, and adequate treatment of cancer among HIV-infected individuals. Cancer Epidemiol Biomarkers Prev; 24(8); 1167–73. ©2015 AACR. See related commentary by Coghill and Engels, p. 1165

HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons

Objective:Experimental studies suggested that HMG-CoA reductase inhibitors (statins’) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. Design:A nested case–control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. Methods:Cases were incident HIV+ NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanentes electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV + NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). Results:A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV + NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31–0.95), 0.64 (0.31–1.28), and 0.50 (0.23–1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed. Conclusion:Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.

Use of Abacavir and Risk of Cardiovascular Disease Among HIV-Infected Individuals.

Background:Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction. Methods:We conducted a cohort study in Kaiser Permanente California during 1998–2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid-lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate <60 mL·min−1·1.73 m−2). Results:Among 8154 subjects, 178 had ≥1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P < 0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for ≥1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0). Conclusions:Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors.