Chad J. Achenbach

Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era

BACKGROUND Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era. METHODS We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan-Meier curves and Cox proportional hazards. RESULTS Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year. CONCLUSIONS HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes.

Mortality after cancer diagnosis in HIV-infected individuals treated with antiretroviral therapy

Objectives:To evaluate survival and predictors of mortality after cancer diagnosis among HIV-infected persons receiving combination antiretroviral therapy (cART). Design:Multisite cohort study. Methods:We examined all-cause mortality among HIV-infected patients treated with cART in routine care at eight US sites and diagnosed with cancer between 1996 and 2009, and predictors of mortality using Cox proportional hazards regression models. Non-AIDS-defining cancers (NADCs) were classified as related and unrelated to viral coinfections. Results:Out of 20 677 persons in the Centers for AIDS Research Network of Integrated Clinical Systems cohort, 650 cART-treated individuals developed invasive cancer. Of these, 305 died during 1480 person-years of follow-up; crude mortality rate was 20.6 per 100 person-years [95% confidence interval (CI) 18.4, 23.1] and overall 2-year survival was 58% (95% CI 54, 62). Highest mortality was seen in primary central nervous system non-Hodgkins lymphoma, liver, and lung cancer with rates of 90.6, 84.3, and 68.1 per 100 person-years, respectively. Adjusted hazard of death was higher among those who were older and had stage IV cancer. Adjusted hazard of death was lower among those with higher CD4 cell counts at cancer diagnosis, who achieved HIV-RNA suppression (≤400 copies/ml) on cART, received any cancer treatment, and had AIDS-defining cancer or infection-related NADCs compared to infection-unrelated NADCs. Conclusion:Independent predictors of mortality after cancer diagnosis among HIV-infected persons include poor immune status, failure to suppress HIV-RNA on cART, cancer stage, and lack of cancer treatment. Modification of these factors with improved strategies for the prevention and treatment of HIV and HIV-associated malignancies are needed.

Paradoxical Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Treated With Combination Antiretroviral Therapy After AIDS-Defining Opportunistic Infection

BACKGROUND The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs. METHODS We examined patients in the University of Washington Human Immunodeficiency Virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics, and immunologic changes in patients with and without IRIS. RESULTS Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7%-16%) developed paradoxical IRIS in the first year on ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs 7% [1/15], P < .01). Patients with mucocutaneous KS and tuberculosis-IRIS experienced greater median increase in CD4(+) cell count during the first 6 months of ART compared with those without IRIS (+158 vs +53 cells/μL, P = .04, mucocutaneous KS; +261 vs +113, P = .04, tuberculosis). CONCLUSIONS Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in >10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality.

Cumulative Incidence of Cancer Among Persons With HIV in North America: A Cohort Study

BACKGROUND Cancer is increasingly common among persons with HIV. OBJECTIVE To examine calendar trends in cumulative cancer incidence and hazard rate by HIV status. DESIGN Cohort study. SETTING North American AIDS Cohort Collaboration on Research and Design during 1996 to 2009. PARTICIPANTS 86 620 persons with HIV and 196 987 uninfected adults. MEASUREMENTS Cancer type-specific cumulative incidence by age 75 years and calendar trends in cumulative incidence and hazard rates, each by HIV status. RESULTS Cumulative incidences of cancer by age 75 years for persons with and without HIV, respectively, were as follows: Kaposi sarcoma, 4.4% and 0.01%; non-Hodgkin lymphoma, 4.5% and 0.7%; lung cancer, 3.4% and 2.8%; anal cancer, 1.5% and 0.05%; colorectal cancer, 1.0% and 1.5%; liver cancer, 1.1% and 0.4%; Hodgkin lymphoma, 0.9% and 0.09%; melanoma, 0.5% and 0.6%; and oral cavity/pharyngeal cancer, 0.8% and 0.8%. Among persons with HIV, calendar trends in cumulative incidence and hazard rate decreased for Kaposi sarcoma and non-Hodgkin lymphoma. For anal, colorectal, and liver cancer, increasing cumulative incidence, but not hazard rate trends, were due to the decreasing mortality rate trend (-9% per year), allowing greater opportunity to be diagnosed. Despite decreasing hazard rate trends for lung cancer, Hodgkin lymphoma, and melanoma, cumulative incidence trends were not seen because of the compensating effect of the declining mortality rate. LIMITATION Secular trends in screening, smoking, and viral co-infections were not evaluated. CONCLUSION Cumulative cancer incidence by age 75 years, approximating lifetime risk in persons with HIV, may have clinical utility in this population. The high cumulative incidences by age 75 years for Kaposi sarcoma, non-Hodgkin lymphoma, and lung cancer support early and sustained antiretroviral therapy and smoking cessation.

Antiretroviral durability and tolerability in HIV-infected adults living in urban Kenya

Background:Insufficient data exist on the durability and tolerability of first-line antiretroviral therapy (ART) regimens provided by HIV treatment programs implemented in developing countries. Methods:Longitudinal observation of clinical, immunologic, and treatment parameters of all HIV-infected adult patients initiated on ART was performed at Saint Marys Mission Hospital in Nairobi, Kenya from September 2004 until August 2006. Results:A total of 1286 patients were analyzed (59.1% female). Initial ART regimens were primarily stavudine, lamivudine, and nevirapine (62.1%). Median ART duration was 350 days (11.6 months). Significant improvements in clinical and immunologic status were noted after 12 months of therapy. ART switches occurred in 701 (54.5%) patients. The cumulative incidence of ART switch at 12 months was 78.4%. Concurrent ART-related toxicities (40.6%) and tuberculosis treatment interactions (28.1%) were the most frequent reasons for ART switch. Baseline AIDS symptoms (hazard rate [HR] = 1.59, 95% confidence interval [CI]: 1.28 to 1.98; P < 0.01) and a CD4 count ≤100 cells/mm3 (HR = 1.20, CI: 1.01 to 1.43; P = 0.04) were independent predictors of ART switch. ART-related clinical toxicity occurred in 341 (26.5%) patients. Peripheral neuropathy was reported most frequently (20.7%). A CD4 count ≤100 cells/mm3 was an independent predictor of clinical toxicity. Conclusions:Excellent clinical and immunologic responses to ART were observed in this urban Kenyan population; however, frequent switches in ART among medication classes because of toxicity or drug interactions may limit the durability of these responses.

Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy

BACKGROUND Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized. METHODS We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation. RESULTS At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000-2007) and median CD4 count was 202 cells/mm(3) (IQR, 61-338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%-13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus-related cancer. Calendar year of ART initiation was not associated with cancer incidence. CONCLUSIONS KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care.

Patterns of Cardiovascular Mortality for HIV-Infected Adults in the United States: 1999 to 2013.

With widespread availability and the use of antiretroviral therapy, patients with human immunodeficiency virus (HIV) in the United States are living long enough to experience non-AIDS-defining illnesses. HIV is associated with an increased risk for cardiovascular disease (CVD) because of traditional CVD risk factors, residual virally mediated inflammation despite HIV treatment, and side effects of antiretroviral therapy. No United States population-wide studies have evaluated patterns of CVD mortality for HIV-infected subjects. Our central hypothesis was that the proportionate mortality from CVD (CVD mortality/total mortality) in the HIV-infected population increased from 1999 to 2013. We used the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research online database of the United States public health data to assess proportionate CVD mortality from 1999 to 2013 in the HIV-infected, general, and inflammatory polyarthropathy populations; the inflammatory polyarthropathy population was included as a positive control group. Total mortality in the HIV-infected population decreased from 15,739 in 1999 to 8,660 in 2013; however, CVD mortality increased from 307 to 400 during the same period. Thus, proportionate CVD mortality for the HIV-infected population increased significantly from 1999 to 2013 (p <0.0001); this pattern was consistent across races, particularly for men. In contrast, proportionate CVD mortality decreased for the general and inflammatory polyarthropathy populations from 1999 to 2013. In conclusion, CVD has become an increasingly common cause of death in HIV-infected subjects since 1999; understanding evolving mortality risks in the HIV-infected population is essential to inform routine clinical care of HIV-infected subjects as well as CVD prevention and treatment.

A Systematic Review of the Usefulness of Statin Therapy in HIV-Infected Patients

HIV-infected patients have a greater prevalence of dyslipidemia, earlier incidence and progression of atherosclerosis, and a nearly twofold increased risk for myocardial infarction compared with those not infected with HIV. Pre-existing cardiovascular risk factors, viral replication, and antiviral treatments all contribute to this accelerated and increased risk for cardiovascular disease in HIV-infected subjects. Given this risk and the proven benefit of statins reducing cardiovascular events across numerous patient groups, statin therapy might be particularly beneficial for patients with HIV. However, safety concerns and a dearth of quality trial data evaluating clinical outcomes in HIV-infected patients on simultaneous antiretroviral therapy (ART) and statin therapy have likely limited statin use in HIV-infected patients chronically taking ART. We performed a systematic review evaluating 18 clinical trials of statins in HIV-infected subjects receiving ART. Simvastatin is contraindicated in the setting of protease inhibitor use because of toxic drug-drug interactions when the 2 drugs are taken concomitantly. Meanwhile, atorvastatin appears to be relatively safe at submaximal doses if monitored. Pravastatin, rosuvastatin, and pitavastatin appear to have the most benign safety profiles among statins when co-administered with ART and may not require dose adjustment. In conclusion, clinicians should be mindful of the elevated risk for atherosclerotic cardiovascular disease in HIV-infected patients when assessing the need for lifestyle interventions and statin therapy.

Moving forward in HIV-associated cancer.

Cancer has been linked to HIV since the earliest days of the epidemic. The unusually frequent occurrence of Kaposi sarcoma (KS) among men who have sex with men (MSM) in 1981 was a sentinel observation leading to the inclusion of KS in the first AIDS case definition.1,2 More than three decades later, major research investments have led to striking advances in understanding HIV pathogenesis, with antiretroviral therapy (ART) reducing AIDS complications and allowing HIV-infected individuals to experience life expectancy approaching that of persons without HIV.3,4

HIV viremia and incidence of non-Hodgkin lymphoma in patients successfully treated with antiretroviral therapy

BACKGROUND The incidence of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients remains high despite treatment with antiretroviral therapy (ART). METHODS We evaluated NHL incidence in HIV-infected patients followed in the Centers for AIDS Research Network of Integrated Clinical Systems who started combination ART and achieved suppression of HIV. We estimated the hazard ratio for NHL by time-varying HIV viremia categories, accounting for time-varying CD4 cell count using marginal structural models. RESULTS We observed 37 incident NHL diagnoses during 21 607 person-years of follow-up in 6036 patients (incidence rate, 171 per 100 000 person-years; 95% confidence interval [CI], 124-236). NHL incidence was high even among patients with nadir CD4 cell count >200 cells/µL (140 per 100 000 person-years [95% CI, 80-247]). Compared with ≤50 copies/mL, hazard ratios (HRs) for NHL were higher among those with HIV viremia of 51-500 copies/mL (HR current = 1.66 [95% CI, .70-3.94]; HR 3-month lagged = 2.10 [95% CI, .84-5.22]; and HR 6-month lagged = 1.46 [95% CI, .60-3.60]) and >500 copies/mL (HR current = 2.39 [95% CI, .92-6.21]; HR 3-month lagged = 3.56 [95% CI, 1.21-10.49]; and HR 6-month lagged = 2.50 [95% CI, .91-6.84]). Current HIV RNA as a continuous variable was also associated with NHL (HR = 1.42 per log10 copies/mL [95% CI, 1.05-1.92]). CONCLUSIONS Our findings demonstrate a high incidence of NHL among HIV-infected patients on ART and suggest a role of HIV viremia in the pathogenesis of NHL. Earlier initiation of potent ART and maximal continuous suppression of HIV viremia may further reduce NHL risk.