Modern cART Era Research Articles

Trends in Hepatocellular Carcinoma Incidence and Risk Among Persons With HIV in the US and Canada, 1996-2015

People with HIV (PWH) are often coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), leading to increased risk of developing hepatocellular carcinoma (HCC), but few cohort studies have had sufficient power to describe the trends of HCC incidence and risk among PWH in the combination antiretroviral therapy (cART) era. To determine the temporal trends of HCC incidence rates (IRs) and to compare rates by risk factors among PWH in the cART era. This cohort study used data from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study, which was conducted between 1996 and 2015. NA-ACCORD pooled individual-level data from 22 HIV clinical and interval cohorts of PWH in the US and Canada. PWH aged 18 years or older with available CD4 cell counts and HIV RNA data were enrolled. Data analyses were completed in March 2020. HBV infection was defined as detection of either HBV surface antigen, HBV e antigen, or HBV DNA in serum or plasma any time during observation. HCV infection was defined by detection of anti-HCV seropositivity, HCV RNA, or detectable genotype in serum or plasma at any time under observation. HCC diagnoses were identified on the basis of review of medical records or cancer registry linkage. Of 109 283 PWH with 723 441 person-years of follow-up, the median (interquartile range) age at baseline was 43 (36-51) years, 93 017 (85.1%) were male, 44 752 (40.9%) were White, 44 322 (40.6%) were Black, 21 343 (19.5%) had HCV coinfection, 6348 (5.8%) had HBV coinfection, and 2082 (1.9%) had triple infection; 451 individuals received a diagnosis of HCC by 2015. Between the early (1996-2000) and modern (2006-2015) cART eras, the crude HCC IR increased from 0.28 to 0.75 case per 1000 person-years. HCC IRs remained constant among HIV-monoinfected persons or those coinfected with HBV, but from 1996 to 2015, IRs increased among PWH coinfected with HCV (from 0.34 cases/1000 person-years in 1996 to 2.39 cases/1000 person-years in 2015) or those with triple infection (from 0.65 cases/1000 person-years in 1996 to 4.49 cases/1000 person-years in 2015). Recent HIV RNA levels greater than or equal to 500 copies/mL (IR ratio, 1.8; 95% CI, 1.4-2.4) and CD4 cell counts less than or equal to 500 cells/μL (IR ratio, 1.3; 95% CI, 1.0-1.6) were associated with higher HCC risk in the modern cART era. People who injected drugs had higher HCC risk compared with men who had sex with men (IR ratio, 2.0; 95% CI, 1.3-2.9), adjusted for HBV-HCV coinfection. HCC rates among PWH increased significantly over time from 1996 to 2015. PWH coinfected with viral hepatitis, those with higher HIV RNA levels or lower CD4 cell counts, and those who inject drugs had higher HCC risk.

Prospective evaluation of blood Epstein-Barr virus DNA load and antibody profile in HIV-related non-Hodgkin lymphomas.

The value of Epstein-Barr virus (EBV) biomarkers on the prognosis of HIV-related non-Hodgkin's lymphoma (NHL) has been poorly explored in the combined antiretroviral therapy (cART) era. We evaluated EBV DNA load and EBV antibodies in HIV-NHL patients enrolled in the French ANRS-CO16 Lymphovir Cohort between 2008 and 2015. Whole blood and plasma EBV DNA load and serological profiles were analyzed in 76 HIV-infected patients at diagnosis of NHL and 6 months after the initiation of chemotherapy. Prechemotherapy whole blood (WB) and plasma EBV DNA loads were positive for 80 and 45% of HIV-NHL patients, respectively. Pretreatment WB EBV DNA positivity was associated with a positive plasma HIV-1 RNA load (relative risk (RR), 4.42 [1.33; 14.72]) and plasma EBV DNA positivity with EBV in situ detection (RR 10.62 [2.38; 47.49]). Following chemotherapy, the proportions of patients with positive WB or plasma EBV DNA declined from 81 to 23% (P < 0.0001) and from 43 to 8% (P < 0.0001), respectively. Estimated 2-year progression-free survival did not differ according to prechemotherapy WB positivity (82% versus 67%, P = 0.15) or plasma EBV DNA positivity (76% versus 81%, P = 0.52). The plasma EBV DNA load correlates with in situ EBV detection. The WB EBV DNA load correlates with HIV load. WB and plasma EBV DNA loads at NHL diagnosis do not constitute prognostic markers for HIV-NHL patients in the modern cART era.

Clinical characteristics and outcomes in HIV-associated diffuse large B-cell lymphoma in China: A retrospective single-center study.

Human immunodeficiency virus (HIV) infection is associated with an increased risk of aggressive lymphoma, especially diffuse large B cell lymphoma (DLBCL). There are few data regarding HIV-associated DLBCL in China. Therefore, we analyzed the characteristics and outcomes of patients with HIV-associated DLBCL from our center. We retrospectively studied HIV-infected patients with DLBCL from 2011 to 2019. Data on HIV infection and lymphoma characteristics, treatments and outcomes were retrieved and analyzed. In 78 patients with HIV-associated DLBCL, most had poor performance status (PS) (74%), elevated lactate dehydrogenase (LDH) levels (95%), B symptoms (74%), advanced Ann Arbor stages (81%), bulky diseases (64%) and extranodal involvement (70%) at diagnosis. The median CD4+ T cell count was 162/µl, and 26 patients were already on combination antiretroviral therapy (cART) treatment at diagnosis of DLBCL. Elevated whole blood EBV DNA copy number was detected in 38 patients (66%, 38/58). Of the 45 patients evaluated at the end of treatment, 26 (58%) achieved CR, 6 (13%) achieved PR and 6 (13%) experienced progressive disease. The 2-year progression-free survival (PFS) and overall survival (OS) rates were 56.4% and 62.7%, respectively. Factors associated with decreased PFS and OS in univariate analysis were unfavorable PS and high international prognostic index. Elevated EBV DNA copy number was inclined to be associated with worse outcome. We did not observe a significant difference in survival between R-EPOCH and R-CHOP regimens. In our population, patients with HIV-associated DLBCL presented with aggressive characteristics and exhibited poor survival outcomes, even in the modern cART era.

Clinical outcomes of people living with human immunodeficiency virus (HIV) with diffuse large B-cell lymphoma (DLBCL) in Shanghai, China.

Background:Numerous studies have focused on lymphoma among patients infected with human immunodeficiency virus (HIV). However, little is known about the treatment options and survival rate of lymphoma in the Chinese people living with HIV (PLHIV). Our study aimed to investigate the prognosis and compare outcome of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab(R-CHOP) as front line therapy for PLHIV with diffuse large B-cell lymphoma (DLBCL) receiving modern combined antiretroviral therapy (cART).Methods:A retrospective analysis evaluating PLHIV with DLBCL was performed in Shanghai Public Health Clinical Center from July 2012 to September 2019. The demographic and clinical data were collected, and overall survival (OS) and progression-free survival (PFS) analyses of patients receiving R-CHOP or DA-EPOCH-R therapy were performed by Kaplan-Meier analysis. Additionally, a Cox multiple regression model was constructed to identify related factors for OS.Results:A total of 54 eligible patients were included in the final analysis with a median follow-up of 14 months (interquartile range [IQR]: 8–29 months). The proportion of high international prognostic index (IPI) patients was much larger in the DA-EPOCH-R group (n = 29) than that in the R-CHOP group (n = 25). The CD4 cell counts and HIV RNA levels were not significantly different between the two groups. The 2-year OS for all patients was 73%. However, OS was not significantly different between the two groups, with a 2-year OS rate of 78% for the DA-EPOCH-R group and 66% for the R-CHOP group. Only an IPI greater than 3 was associated with a decrease in OS, with a hazard ratio of 5.0. The occurrence of grade 3 and 4 adverse events of chemotherapy was not significantly different between the two groups.Conclusions:Outcomes of R-CHOP therapy do not differ from those of DA-EPOCH-R therapy. No HIV-related factors were found to be associated with the OS of PLHIV in the modern cART era.

Hepatitis C virus or hepatitis B virus coinfection and lymphoma risk in people living with HIV.

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are associated with increased risks of lymphomas in the non-HIV setting. Their impacts on HIV-associated lymphomas deserved further studies in the modern combined antiretroviral therapy (cART) era. We evaluated the associations between HCV, HBV and HIV-related lymphomas in the Lymphovir-ANRS-CO16 cohort. Prevalence of HCV seropositivity and chronic HBV infections were compared with those observed in the French Hospital Database on HIV (FHDH-ANRS-CO4). Between 2008 and 2015, 179 patients with HIV-related lymphomas from 32 French hospitals were enrolled, 69 had Hodgkin's lymphoma (39%), and 110 non-Hodgkin's lymphoma (NHL) (61%). The prevalence of HCV infection was higher in patients with NHL than in the FHDH-ANRS-CO4 [26 versus 14%, odd ratio (OR): 2.15; 95% confidence interval (1.35-3.32)] whereas there was no association between Hodgkin's lymphoma and chronic HCV infection. Chronic HBV infection was not associated with NHL in our cohort with a prevalence of 5 versus 7% in FHDH-ANRS-CO4 but tended to be associated with Hodgkin's lymphoma [prevalence of 14%, OR: 2.16 (0.98-4.27)]. Chronic HCV infection tended to pejoratively impact 2-year overall survival in patients with NHL: 72% [57%, 91%] versus 82% [74%, 91%], hazard ratio: 2.14 [0.95-4.84]. In contrast, chronic HBV infection did not correlate with outcome. In the modern cART era, chronic HCV infection is associated with an increased risk of NHL in PLWHIV and tends to pejoratively impact overall survival. HBV infection is not associated with the risk of NHL but with a borderline increase of Hodgkin's lymphoma risk.

Bloodstream infections in patients living with HIV in the modern cART era

Retrospective multicentre study aiming at analysing the etiology, characteristics and outcome of bloodstream infections (BSI) in people living with HIV (PLWHIV) in an era of modern antiretroviral therapy. Between 2008 and 2015, 79 PLWHIV had at least 1 BSI, for a total of 119 pathogens isolated. Patients were mainly male (72.1%), previous intravenous drug users (55.7%), co-infected with HCV or HBV (58.2%) and in CDC stage C (60.8%). Gram-positive (G+) pathogens caused 44.5% of BSI, followed by Gram-negative (G−), 40.3%, fungi, 10.9%, and mycobacteria, 4.2%. Candida spp. and coagulase-negative staphylococci were the most frequent pathogens found in nosocomial BSI (17% each), while E.coli was prevalent in community-acquired BSI (25%). At the last available follow-up, (mean 3.2 ± 2.7 years) the overall crude mortality was 40.5%. Factors associated with mortality in the final multivariate analysis were older age, (p = 0.02; HR 3.8, 95%CI 1.2–11.7) CDC stage C (p = 0.02; HR 3.3, 95%CI 1.2–9.1), malignancies, (p = 0.004; HR 3.2, 95%CI 1.4–7.0) and end stage liver disease (p = 0.006; HR 3.4, 95%CI 1.4–8.0). In conclusion, the study found high mortality following BSI in PLWHIV. Older age, neoplastic comorbidities, end stage liver disease and advanced HIV stage were the main factors correlated to mortality.

Epstein-Barr virus biomarkers have no prognostic value in HIV-related Hodgkin lymphoma in the modern combined antiretroviral therapy era.

Epstein-Barr virus (EBV) has been implicated in lymphomagenesis of HIV-related classical Hodgkin lymphoma (HIV-cHL). The utility of EBV molecular and serological biomarkers has scarcely been examined in HIV-cHL in the recent combined antiretroviral therapy (cART) era. We evaluated EBV DNA load and a panel of EBV antibodies in HIV-cHL patients prospectively enrolled in the French ANRS-CO16 Lymphovir cohort between 2008 and 2015. Pretreatment whole blood, plasma EBV DNA load and serological profiles were analysed in 63 HIV-infected patients diagnosed with cHL. For the 42 patients with available material, comparisons were performed between values at diagnosis and 6 months after the initiation of chemotherapy. Pretreatment whole blood and plasma EBV DNA loads were positive in 84 and 59% of HIV-cHL patients, respectively. Two-year progression-free survival estimates did not differ between the patients with pretreatment whole blood (n = 53) or plasma (n = 37) EBV DNA(+) and the patients with pretreatment whole blood (n = 10) or plasma (n = 26) EBV DNA(-) (92 vs. 80% or 89 vs. 92%, P = 0.36 and 0.47, respectively). At diagnosis, 47% of patients harboured an EBV reactivation serological profile. Following chemotherapy, whole blood and plasma EBV DNA levels significantly declined from medians of 1570 [interquartile range, 230-3760) and 73 (0-320) copies/ml to 690 (0-1830) and 0 (0-0) copies/ml, respectively (P = 0.02 and P < 0.0001, respectively]. Anti-EBV IgG antibody level significantly dropped at 6-month follow-up (P = 0.004). Whole blood and plasma EBV DNA loads do not constitute prognostic markers in HIV-cHL patients in the modern cART era.

Mortality among people living with HIV/AIDS with non-small-cell lung cancer in the modern HAART Era

ABSTRACTPeople living with HIV (PLWHA) with adequate access to modern combination antiretroviral therapy (cART) are living longer and experiencing reduced AIDS-related morbidity and mortality. However, increases in non-AIDS related conditions, such as certain cancers, have accompanied these therapeutic advances over time. As such, our study objective was to determine the impact of HIV on all-cause and lung cancer-specific mortality amongst PLWHA with diagnoses of non-small-cell lung cancer (NSCLC) and HIV-negative individuals with NSCLC. This analysis was inclusive of PLWHA on and off cART over the age of 19 years and a 10% comparison sample from the BC population ≥19 years, over a 13-year period (2000–2013). Kaplan-Meier estimates, Cox PH models, and competing risk analysis for all-cause and cause-specific mortality (respectively) compared PLWHA to HIV-negative individuals, controlling for age, gender, cancer stage, co-morbidities; and nadir CD4 count, viral load, and injection drug use for a HIV-positive specific analysis. We identified 71 PLWHA and 2463 HIV-negative individuals diagnosed with NSCLC between 2000 and 2013. PLWHA with NSCLC were diagnosed at a significantly younger age than HIV-negative individuals (median age 57 vs 71 years, p < 0.01). We found no significant difference in lung cancer-specific mortality. However, in multivariate analysis, HIV was associated with greater all-cause mortality (adjusted hazard ratio [aHR]:1.44; 95% confidence interval [CI]: 1.08–1.90), with median survival of 4 months for PLWHA, and 10 months for HIV-negative. Higher nadir CD4 count was protective against mortality (aHR: 0.33, 95% CI: 0.17–0.64) amongst PLWHA in multivariate analysis. Our analysis suggests that PLWHA in the modern cART era experience similar lung cancer survival outcomes compared to the general BC population with NSCLC. However, we also observed significantly higher all-cause mortality among PLWHA with NSCLC, which may warrant further inquiry into the role of HIV in exacerbating mortality among PLWHA with comorbidities and cancer.

High Risk Features Contrast With Favorable Outcomes in HIV-associated Hodgkin Lymphoma in the Modern cART Era, ANRS CO16 LYMPHOVIR Cohort.

Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkin's lymphoma (cHL) in the combined antiretroviral therapy (cART) era. We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL. Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/µL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients. Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.

A pooled analysis of 1,546 patients with AIDS-related lymphoma (ARL): An assessment of prognostic factors by treatment era.

8524 Background: Management of ARL evolved in the last 2 decades. We previously reported prognostic factors in a pooled analysis of 1,546 patients with ARL, and here present analysis of these factors over time to determine if their prognostic significance has changed. Methods: Following a systematic review, we assembled individual patient data from 19 prospective phase 2/3 clinical trials (published 1993-2010) for ARL (n=1,546). Factors analyzed include age, sex, histology, CD4 count, prior history of (h/o) AIDS, &amp; age-adjusted (aa) IPI. The endpoint was overall survival (OS) expressed as the hazard ratio (HR) for death. We used separate Cox proportional hazard models adjusted for the other covariates to determine the significance of each variable in the following time periods: pre-cART [combination antiretroviral therapy] (&lt;1996; n=388), early cART (‘96-‘00; n=694), modern cART (‘01-‘04; n=282) &amp; current era (‘05-‘10; n=182). We also combined all enrollments in one Cox model to test for difference in association with OS over enrollment periods. Results: Rituximab use was limited in the early cART (20%) compared with the modern cART (83%) and current (93%) eras. Histology &amp; sex were not significantly associated with OS in any time period. Increasing age was associated with worse OS in the pre-cART (HR 1.02; p&lt;0.01) and current (HR 1.05, p=0.04) eras. A prior h/o AIDS increased risk of death during early cART (HR 1.31, p=0.047) but was not significant after 2000. Meanwhile, baseline CD4 count &lt;50 was a poor prognostic factor during early (HR 1.78, p&lt;0.01) and modern cART (HR 2.76, p=0.001) eras, but not in the current era. The aaIPI predicted worse OS in each time period (pre-cART: HR 1.54, p&lt;0.0001; early cART: HR 1.49, p&lt;0.0001; modern cART: HR 1.52, p&lt;0.01; current era: HR 2.34, p&lt;0.0001). No significant interaction between each prognostic factor with enrollment was found. Conclusions: In this pooled analysis of 1,546 patients with ARL, aaIPI was the only consistently significant prognostic factor and its effect was magnified in the current era. HIV-related factors gained prognostic relevance in the early and modern cART era but may not be as relevant with current treatment strategies.