People living with HIV (PLHIV) have an increased risk of developing a hematological malignancy compared to the general population.1 Since the introduction of combination antiretroviral therapy (ART), there has been an increase in the proportion of deaths attributed to malignancies and a change in the types of malignancies commonly seen. Diagnoses of Hodgkin lymphoma (HL), lung cancer, and nonmelanoma skin cancers have risen. Cervical cancer and Burkitt lymphoma incidence has not changed,2 whereas the incidence of Kaposi sarcoma (KS), central nervous system lymphoma, and diffuse large B-cell lymphoma has fallen.3
Hematological malignancies, particularly non-Hodgkin lymphoma (NHL), remain highly prevalent among PLHIV and are considered to be associated with the most common cancer-related cause of death.2 In resource-rich settings, the most reported cancers were NHL, followed by lung cancer, KS, anal cancer, prostate cancer, liver cancer, and HL.4 In sub-Saharan Africa, KS is the most common and is often associated with high mortality.5 Other highly prevalent cancers include cervical cancer, breast cancer, and NHL.6
In Asia, there are limited data on malignancies among PLHIV, which may differ from other regions due to genetic and environmental factors, including differing incidence of infections with oncogenic viruses associated with malignancy. For example, breast cancer incidence in Taiwan occurs at a lower median age compared to Western countries, with different molecular subtypes.7 In a linkage study conducted in India, no cases of KS were reported, which was in contrast to reported findings from the African region.8 The European COHERE cohort found a significant risk of AIDS-related NHL among male-to-male sex (men who have sex with men) and older age groups9; however, the risk in South African women was reportedly higher than those in Europe.10
The aim of this study was to investigate the occurrence, risk factors, and survival outcomes associated with hematological and nonhematological malignancies, in PLHIV in Asia enrolled in the TREAT Asia HIV Observational Database (TAHOD) of IeDEA Asia-Pacific.
Patients enrolled in TAHOD who had ever initiated ART with at least 1 day of follow-up after cohort entry were included in the analysis. The TAHOD cohort profile has been described elsewhere,11,12 but briefly TAHOD is an adult HIV observational database that enrolls selected number of patients from each participating site based on their likelihood of remaining in follow-up. Due to the prospective nature of TAHOD data collection, we limited our analyses to first malignancy diagnosed either before or after ART initiation but after cohort entry. Malignancies were reported descriptively, and categorized as either hematological or nonhematological. We calculated incidence rates [per 100 person-years (/100PY)] and assessed factors associated with hematological and nonhematological malignancy using Fine and Gray competing risk methods. Time-fixed covariates included age at cohort entry, sex, HIV mode of exposure, hepatitis B/C coinfection, prior AIDS diagnosis, and World Bank country income level. CD4, viral load, ART duration, and calendar year of follow-up were the time-updated variables. With the exception of the ART duration variable, covariates in the univariate analysis with P < 0.10 were fitted in the multivariate model using backward stepwise selection process. Covariates with P < 0.05 in the multivariate model were considered significant. Survival time from malignancy diagnosis was plotted using Kaplan–Meier curves and compared using the log-rank test.
Ethics approvals were obtained from respective local ethics committees of all participating sites, the data management and biostatistical center (UNSW Sydney Ethics Committee), and the coordinating center (TREAT Asia/amfAR). Data management and statistical analyses were performed using SAS software version 9.4 (SAS Institute, Inc., Cary, NC) and Stata software version 14.2 (Stata Corp., College Station, TX).
A total of 7455 patients were included from Cambodia, China and Hong Kong SAR, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam. There were 70% males, with 63% reporting heterosexual mode of HIV exposure. At cohort entry, the median age was 35 years [interquartile range (IQR): 30–42] and the median CD4 cell count was 248 cells/µL (IQR: 117–397). The median nadir CD4 count within 1 year before cohort entry was 206 cells/µL (IQR: 82–339). In the group with hematological malignancy, the median nadir CD4 count was lower at 142 cells/µL (IQR: 27–264). Those with nonhematological malignancy had a median nadir CD4 count of 133 cells/µL (IQR: 78–266). World Bank high-income countries had the highest proportions of cancers (47% for hematological and 44% for nonhematological) and 60% of the patients with a malignancy were diagnosed from the year 2010 onward (Table 1). The median time on ART up to the date of malignancy diagnosis or analysis censoring date was 6.3 years (IQR: 4.0–9.6).
Between years 2001 and 2016, 107 patients (1%) had a malignancy diagnosis recorded: 34 (0.5%) hematological malignancies and 73 (1%) nonhematological malignancies. Of the hematological malignancies, NHL was the most common (26 patients, 76%): immunoblastic lymphoma (6 patients, 18%), Burkitt lymphoma (5 patients, 15%), diffuse large B-cell lymphoma (5 patients, 15%), and unspecified NHL (n = 10, 30%). Other hematological malignancies were central nervous system lymphoma (7 patients, 21%) and myelodysplastic syndrome (1 patient, 3%). The most common nonhematological malignancies were KS (12 patients, 16%), cervical (10 patients, 14%), liver (8 patients, 11%), colon (7 patients, 10%), lung (5 patients, 7%), and colon cancer (5 patients, 7%).
With a median cohort follow-up time of 5.5 years, the incidence rates for hematological and nonhematological malignancy were 0.08 and 0.17/100PY, respectively. The incidence rates for hematological malignancies by calendar year of follow-up were: 0.16/100PY for ≤2005, 0.10/100PY for 2006–2009, and 0.06/100PY for 2010–2016. For nonhematological malignancies, the rates were 0.16/100PY, 0.21/100PY, and 0.16/100PY for the 3 periods, respectively. Factors associated with developing a malignancy after cohort entry were analyzed and reported in Table 2. In the univariate competing risk analysis, factors associated with developing a hematological malignancy were older age (P < 0.001), lower CD4 cell count categories (P = 0.005), shorter ART duration (P = 0.073), and World Bank high-income level (P = 0.001). No significant trend in calendar year was observed (P-value = 0.920). In multivariate analysis controlling for ART duration, age >50 years compared to ≤30 years at cohort entry [subhazard ratio (SHR) = 6.48, 95% confidence interval (CI): 1.79 to 23.43, P = 0.004] and being from a World Bank high-income country (SHR = 3.97, 95% CI: 1.45 to 10.84, P = 0.007) were associated with a hematological malignancy diagnosis. The hazard was reduced with higher CD4 count compared to CD4 ≤200 cells/µL (CD4 351–500 cells/µL: SHR = 0.20, 95% CI: 0.05 to 0.74, P = 0.016; CD4 >500 cells/µL: SHR = 0.14, 95% CI: 0.04 to 0.78, P = 0.022). ART duration was not associated with hematological malignancy diagnosis (P = 0.286).
Multivariate risk factors associated with nonhematological malignancy were older age 41–50 years (SHR = 2.67, 95% CI: 1.11 to 6.38, P = 0.028) and age >50 years (SHR = 6.60, 95% CI: 2.88 to 15.13, P < 0.001), compared to ≤30 years, and living in an upper-middle-income country (SHR = 2.15, 95% CI: 1.11 to 4.15, P = 0.023) or a high-income country (SHR = 3.96, 95% CI: 2.09 to 7.50, P < 0.001), compared to a lower-middle-income country. Having prior AIDS diagnosis (SHR = 1.60, 95% CI: 0.99 to 2.59, P = 0.054) was borderline-significant and was included in the multivariate model. Higher CD4 cell count showed a protective effect (CD4 201–350 cells/µL: SHR = 0.34, 95% CI: 0.16 to 0.72, P = 0.005; CD4 351–500 cells/µL: SHR = 0.24, 95% CI: 0.11 to 0.51, P < 0.001; and CD4 >500 cells/µL: SHR = 0.45, 95% CI: 0.23 to 0.88, P = 0.019), compared to CD4 ≤200 cells/µL. Similar to the hematological malignancy analysis, ART duration was not statistically significant (P = 0.206), but was adjusted for in the final model.
Of the 107 patients with a malignancy, 77 (72%) had survival information available after the diagnosis and were included in the plot (see Fig. S1, Supplemental Digital Content http://links.lww.com/QAI/B249). There were 27 deaths (mortality rate 15/100PY). Among those with a hematological malignancy, there were 13/25 deaths (52%) with a mortality rate of 29/100PY, which was higher than 10/100PY mortality rate for the 14/52 deaths (27%) in the nonhematological malignancy group (P = 0.009). PLHIV diagnosed with a hematological malignancy had poorer survival time compared to those with a nonhematological malignancy (P log-rank = 0.008).
There is a significant burden of malignancies in PLHIV across the Asian region. In our cohort, nonhematological malignancies were more common than hematological malignancies. However, NHL was the most predominant diagnosis overall. PLHIV of older age and from high-income countries were more likely to develop a hematological malignancy, whereas the risk was reduced in those with higher CD4 count. Similar risk factors were seen for nonhematological malignancy, with prior AIDS diagnosis showing a weak association. Survival time from malignancy diagnosis was longer in those with nonhematological malignancies.
The proportion of patients with hematological malignancies, mostly NHL, in our cohort was 0.5%, which was within the range of 0.3%–2.5% reported in other cohorts.13,14 For nonhematological malignancies, liver and lung cancers are known to be 2 of the most common types of cancers in Asia, with lung cancer being the most common cause of cancer-related mortality and the second most common cancer in PLHIV.4,7,15 In our study, liver cancer was the third most common nonhematological cancer after KS and cervical cancer.
Our study found that there was a reduced risk of developing malignancies with higher CD4 cell count, supporting the role of immunodeficiency as a risk factor for malignancies in PLHIV.16 Other factors such as time on ART and year of follow-up could also play an important role. Incidence rates for malignancy, particularly for KS and NHL, have been shown to decrease with increasing duration of ART use, after controlling for CD4 cell count, suggesting that ART may have anticancer benefits.17 Our study found that although the hazards for malignancy diagnosis were reduced with longer ART duration, the effects were not statistically significant after adjusting for CD4 cell count and other significant confounders. Furthermore, due to effective ART, the incidence of malignancy diagnosis in PLHIV has decreased over time with future decline predicted for many malignancy types.18 Our study, however, did not show a decreasing trend for malignancy in both groups.
The relationship between age and malignancies is well established; however, we found that people living in high-income countries were more likely to be diagnosed with either of the 2 types of malignancies. This may reflect the limited availability of diagnostic and treatment facilities in lower-income areas contributing to underdiagnosis of malignant disorders.19 Other confounders may include earlier ART initiation, availability of more potent ART, and less opportunistic infections causing competing mortality in high-income sites.20,21
Previous literatures have reported an association between HIV viremia and the development of malignancy.16,22 A Spanish cohort study has shown that low-level viremia can also lead to increased risk of AIDS-defining events and/or mortality.23 Viral load was not a significant predictor in our analyses; however, the weak effect of prior AIDS illnesses on non-hematological malignancy occurrence seen in our cohort is unlikely to be direct, more probably reflecting underlying interactions with either HIV viral replication, inflammation, or immune dysfunction.
Survival time after malignancy diagnosis was found to be shorter in those with a hematological malignancy. Poorer survival prognosis in those with hematological malignancies could be explained by the high proportion of aggressive forms of NHL in this group. NHL has been shown to be associated with lower survival rates compared to KS and cervical cancer, the 2 most common nonhematological malignancies in our cohort.24
The limitations of our study included not being able to obtain histological or pathological reports from sites. These reports were not collected as part of TAHOD data transfers, and therefore, we were not able to reassess the accuracy of the malignancy classifications. We did not have detailed clinical parameters and treatment protocols associated with a new malignancy diagnosis and were not able to analyze survival outcomes across different malignancy types in detail. Furthermore, because TAHOD does not collect data on HIV-negative patients, direct comparison with the HIV-negative population could not be attempted. Finally, because TAHOD patients were enrolled based on the likelihood of remaining in care with small number of malignancies diagnosed, the generalizability of our findings may be limited.
Although there was a higher proportion of nonhematological malignancies in our cohort with KS and cervical cancer being the 2 most common, NHL was predominant overall. Malignancy occurrence was more likely in PLHIV from high-income countries, indicating that there is a possible underdiagnosis in resource-limited settings. Further systematic data on incidence are needed, as are novel diagnostic tools applicable in low- and middle-income countries.
The TREAT Asia HIV Observational Database: PS Ly* and V Khol, National Center for HIV/AIDS, Dermatology & STDs, Phnom Penh, Cambodia; FJ Zhang*,†, HX Zhao, and N Han, Beijing Ditan Hospital, Capital Medical University, Beijing, China; MP Lee*, PCK Li, W Lam, and YT Chan, Queen Elizabeth Hospital, Hong Kong SAR; N Kumarasamy*, S Saghayam, and C Ezhilarasi, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), YRGCARE Medical Centre, VHS, Chennai, India; S Pujari*, K Joshi, S Gaikwad, and A Chitalikar, Institute of Infectious Diseases, Pune, India; S Sangle*, V Mave, and I Marbaniang, BJ Government Medical College and Sassoon General Hospital, Pune, India; TP Merati*, DN Wirawan, and F Yuliana, Faculty of Medicine Udayana University & Sanglah Hospital, Bali, Indonesia; E Yunihastuti*, D Imran, and A Widhani, Faculty of Medicine Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia; J Tanuma*, S Oka, and T Nishijima, National Center for Global Health and Medicine, Tokyo, Japan; JY Choi*, Na S, and JM Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; BLH Sim*, YM Gani, and NB Rudi, Hospital Sungai Buloh, Sungai Buloh, Malaysia; A Kamarulzaman*, SF Syed Omar, S Ponnampalavanar, and I Azwa, University Malaya Medical Centre, Kuala Lumpur, Malaysia; R Ditangco*, MK Pasayan, and ML Mationg, Research Institute for Tropical Medicine, Muntinlupa City, Philippines; WW Wong*, WW Ku, and PC Wu, Taipei Veterans General Hospital, Taipei, Taiwan; OT Ng*,‡, PL Lim, LS Lee, and Z Ferdous, Tan Tock Seng Hospital, Singapore; A Avihingsanon*, S Gatechompol, P Phanuphak, and C Phadungphon, HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; S Kiertiburanakul*, A Phuphuakrat, L Chumla, and N Sanmeema, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; R Chaiwarith*, T Sirisanthana, W Kotarathititum, and J Praparattanapan, Research Institute for Health Sciences, Chiang Mai, Thailand; S Khusuwan*, P Kantipong, and P Kambua, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; KV Nguyen*, HV Bui, DTH Nguyen, and DT Nguyen, National Hospital for Tropical Diseases, Hanoi, Vietnam; CD Do*, AV Ngo and LT Nguyen, Bach Mai Hospital, Hanoi, Vietnam; AH Sohn*, JL Ross*, and B Petersen, TREAT Asia, amfAR—The Foundation for AIDS Research, Bangkok, Thailand; DA Cooper, MG Law*, A Jiamsakul*, and D Rupasinghe, The Kirby Institute, UNSW Sydney, NSW, Australia.
*TAHOD Steering Committee member; †Steering Committee Chair; ‡co-Chair.
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