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Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study (HACM)
 
 
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Download the PDF here
 
Cancer risk in people living with HIV - Commentary
 
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In the HACM Study, anal cancer rates increased 3% per year during 1996-2010 [29] (Fig. 1b), reflecting increasing rates in the general United States population [29], whereas other studies reported no change in incidence rates over time or increases only among women [30,31,34,35]. Most studies reported significant increases in liver cancer rates over time (6% per year in the HACM Study) [10,29,34], and significant decreases in lung cancer rates (-6% per year) (Fig. 1b) [22,29,31,34], though other studies reported no changes in the rates of these cancers over time [30,35].
 
Evolving epidemiology of HIV-associated malignancies - (01/27/17)
 
"In the United States during 2006-2010, HIV-infected people continued to have elevated rates for anal cancer (32-fold elevation compared with the general population), lung cancer (two-fold), liver cancer (three-fold) and Hodgkin lymphoma (10-fold) [29]. In the HAART era, the probability of HIV-infected people in North America developing these cancers by age 65 was 1.3% for anal cancer, 2.2% for lung cancer, 0.8% for liver cancer and 0.9% for Hodgkin lymphoma". "In the United States in 2010, the most common cancers diagnosed among HIV-infected people were NHL (n = 1650; 21% of incident cancer cases) and Kaposi sarcoma (n = 910; 12%), but these were followed closely by lung cancer (n = 840; 11%), anal cancer (n = 760; 10%) and prostate cancer (n = 570; 7%) [5⋅]. As the HIV-infected population continues to grow and age, the burden of cancer (particularly non-AIDS-defining cancers) will continue to rise, as will the need for cancer prevention, early detection and treatment.". Given the strong effects on immune status and longevity, it is therefore not surprising that HAART has had a major effect on the epidemiology of cancer among HIV-infected people.
 
Cancer risk among the HIV-infected elderly in the United States - (06/07/16)
 
.....Conclusion: In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention.
 
"We conducted a case-cohort study including a 5% sample of U.S. Medicare enrollees and all cancer cases aged at least 65 in linked cancer registries.".....In conclusion, the absolute risk of cancer in the U.S. HIV-infected elderly is sizeable, reflecting effects of both HIV and aging...."Cancer incidence was approximately 50% higher in HIV-infected compared with HIV-uninfected individuals (aHR = 1.52, 95%CI = 1.32-1.75; Table 1)
 
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Lancet HIV study published in Sept 25 2017
 
We identified diagnoses of cancer in this population through linkage with corresponding cancer registries and calculated standardised incidence ratios (SIRs) to measure cancer risk in people with HIV compared with the USA general population, by dividing the observed number of cases in people with HIV by the expected number (estimated by applying general population cancer-incidence rates to person-time in the HIV population based on sex, age, race or ethnic group, calendar year, and registry). We tested SIR differences by AIDS status and over time using Poisson regression. We tested SIR differences by AIDS status and over time. For this analysis we assessed a cohort of HIV-infected people from HACM identified in HIV registries from Colorado (1996-2007), Connecticut (2005-10), Georgia (2004-12), Maryland (2008-12), Michigan (1996-2010), New Jersey (1996-2012), New York (2001-12), Puerto Rico (2003-12), and Texas (1999-2009).
 
Findings
 
Among 448 258 people with HIV (who contributed 3 093 033 person-years), 21 294 incident cancers were diagnosed during 1996-2012. In these people, compared with the general population, risk was elevated (p<0⋅0001 for all) for cancer overall (SIR 1⋅69, 95% CI 1⋅67-1⋅72), AIDS-defining cancers (Kaposi's sarcoma [498⋅11, 477⋅82-519⋅03], non-Hodgkin lymphoma [11⋅51, 11⋅14-11⋅89], and cervix [3⋅24, 2⋅94-3⋅56]), most other virus-related cancers (eg, anus [19⋅06, 18⋅13-20⋅03], liver [3⋅21, 3⋅02-3⋅41], and Hodgkin's lymphoma [7⋅70, 7⋅20-8⋅23]), and some virus-unrelated cancers (eg, lung [1⋅97, 1⋅89-2⋅05]), but not for other common cancers. Risk for several cancers was higher after AIDS onset and declined across calendar periods. After multivariable adjustment, SIRs decreased significantly across 1996-2012 for Kaposi's sarcoma, two subtypes of non-Hodgkin lymphoma, and cancer of the anus, liver, and lung, but remained elevated. SIRs did not increase over time for any cancer.
 
Overall, cancer risk was 69% higher among HIV-infected people than in the general population (SIR 1⋅69, 95% CI 1⋅67-1⋅72). Risks were also elevated in the HIV-infected population for AIDS-defining cancers and for non-AIDS-defining cancers, driven by the elevation for virus-related non-AIDS-defining cancers; the risk for virus-unrelated non-AIDS-defining cancers was slightly decreased (table 2).

 
The most common individual cancer types were AIDS-defining non-Hodgkin lymphomas, lung cancer, Kaposi's sarcoma, anal cancer, prostate cancer, liver cancer, and Hodgkin's lymphoma (table 2). Risks were elevated (p<0⋅0001) for almost all virus-related cancers, except for Merkel cell carcinoma (p=0⋅0133), and elevated for each subtype of AIDS-defining non-Hodgkin lymphoma, cancers of the (human papillomavirus-unrelated) oral cavity or pharynx, nasal cavity, larynx, lung, scrotum, and conjunctiva, as well as non-AIDS-defining non-Hodgkin lymphomas, polycythaemia vera, myelodysplastic syndrome, and miscellaneous cancers. By contrast, risks were significantly decreased for cancers of the stomach, colon, rectum or rectosigmoid junction, female breast, uterus, prostate, kidney or renal pelvis, brain, and thyroid (table 2). Correcting SIRs for potential out-migration (ie, individuals moving out of registry areas) did not substantially affect the estimates (appendix p 4).
 
Evidence indicates that HIV-infected people, especially those with AIDS, have an elevated risk for many cancers, especially those from viral causes. Additionally, after the introduction of ART in 1996, the incidence of two AIDS-defining cancers, Kaposi's sarcoma and non-Hodgkin lymphoma, decreased. However, trends for other cancers are less clear, and there is a shortage of recent and comprehensive population-based data about cancer risks for people with HIV.
 
Compared with people with HIV only, those with AIDS had significantly higher SIRs for grouped AIDS-defining cancers, virus-related non-AIDS-defining cancers, and virus-unrelated non-AIDS-defining cancers (table 3). This pattern was also present for each individual AIDS-defining cancer and virus-related non-AIDS-defining cancer, except liver and vaginal cancers, and Merkel cell carcinoma. SIRs were also higher for people with AIDS compared with those with HIV only for the following virus-unrelated non-AIDS-defining cancers: cancers of the (human papillomavirus-unrelated) oral cavity or pharynx, oesophagus, and lung, non-AIDS-defining non-Hodgkin lymphomas, myeloid and monocytic leukaemias, and myelodysplastic syndrome.
 
We found that, compared with the general population, HIV-infected people (including those without AIDS) had a greater risk for various cancers, including AIDS-defining cancers, many other virus-related cancers, and lung cancer. Although the risk for Kaposi's sarcoma, non-Hodgkin lymphoma, and some non-AIDS-defining cancers (anus, liver, and lung) decreased over time, risks generally have remained high.
 
Implications of all the available evidence
 
The decreases in cancer risk in people with HIV over time probably reflect the sustained and widened use of ART. Despite these decreases, however, cancer risks in HIV-infected people have remained elevated during the modern treatment era, indicating that continued cancer control efforts are warranted with additional efforts aimed at cancer prevention and screening.
 
The risk for some types of cancers might continue to decline as ART regimens improve, treatment is initiated at earlier stages of HIV disease, and access to ART increases.13 However, treatment might not fully reverse the effect of early immune suppression, and immune dysfunction and chronic inflammation can persist among people receiving ART.2 HIV-infected people, including those who have not developed AIDS, might therefore still have an elevated risk of cancer. Furthermore, many cancer types have latency periods of decades, and the modern ART era is only 20 years old; elevated risks for some cancers might, therefore, emerge over time. Finally, with prolonged survival the HIV population is ageing, and the effect of HIV-related immunosuppression in an ageing population is unclear.10, 14 For these reasons, continued monitoring of cancer risks in this population is vital. In this study, we describe the range of cancer risks among HIV-infected people in the USA during the modern ART era by use of linked data from several population-based HIV and cancer registries.
 
Interpretation
 
For several virus-related cancers and lung cancer, declining risks over time in HIV-infected people probably reflect the expansion of ART since 1996. Additional efforts aimed at cancer prevention and screening in people with HIV are warranted.
 
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Cancer risk in people living with HIV - Commentary
 
- full article below
 
HIV Lancet *Nancy A Hessol, Howard D Strickler
Departments of Clinical Pharmacy and of Medicine, University of
California, San Francisco, CA, USA (NAH); Albert Einstein College
of Medicine, Bronx, NY, USA (HDS)
Published: 10 August 2017
 
Much has been learned about the risk of malignant diseases in people with HIV from observational and clinical cohort studies, multicohort and meta analyses, and population-based HIV/AIDS and cancer registry-match studies. Specific cancers have been reported either in excess or deficit in people with HIV, relative to the general population, and studies have quantified changes in those risks over time. Most importantly, since 1996, the use of effective antiretroviral therapy (ART) to control HIV infection has led to a striking reduction in HIV-related mortality.1 However, ART does not fully restore host immune status and, despite the decreases in AIDS-defining cancers-most notably Kaposi's sarcoma and non-Hodgkin lymphoma-the incidence of many cancers, especially those which have viral causes such as Kaposi's sarcoma from human herpesvirus 8 and non-Hodgkin lymphoma from the Epstein-Barr virus, remains high.2, 3, 4 Furthermore, because people living with HIV increasingly reach the age with the highest rates of cancer but still live with compromised host immunity, greater longevity might increase their cumulative exposure to systemic inflammation, oncogenic viral infections, and carcinogens, as well as the accumulation of somatic mutations and epigenetic changes related to carcinogenesis. Because the total burden and predominant types of cancers are likely to change over time, ongoing surveillance of cancer rates in people with HIV is important. In The Lancet HIV, Raul Hernandez-Ramírez and colleagues5 report an analysis of cancer risk in a cohort of individuals from the USA HIV/AIDS Cancer Match Study, the largest population-based study of malignancies in people with HIV in the world. The investigators used standardised incidence ratios (SIRs) to estimate cancer risk in HIV-infected people compared with the USA general population between 1996 and 2012. In additional analyses, the SIRs were stratified by AIDS diagnosis (AIDS vs HIV only), to serve as a proxy of severe immunosuppression to assess its effect on cancer risk. Hernandez-Ramírez and colleagues5 also assessed temporal trends in cancer risks and used calendar time as a surrogate for the effect of ART on cancer incidence.
 
The greatest excess cancer risk in people with HIV was for AIDS-associated and other virus-related tumours, especially Kaposi's sarcoma (SIR 498⋅11, 95% CI 477⋅82-519⋅03) and non-Hodgkin lymphoma (11⋅51, 11⋅14-11⋅89).5 Two subtypes of non-Hodgkin lymphoma and Kaposi's sarcoma also showed the largest and most immediate reductions in incidence after the introduction of ART. These results suggest a high sensitivity of these tumours to immunosuppression.
 
The incidences of all human papillomavirus-related tumours were also significantly higher in people living with HIV than in the general population, including cervical cancer (an AIDS-defining malignancy), and cancers of the anus, vulva, vagina, penis, and oropharynx (p<0⋅0001 for all). However, the excess incidence of HPV-related tumours was several-times weaker than those of Kaposi's sarcoma and non-Hodgkin lymphoma, and the decrease in risk of human papillomavirus-related tumours over time was more gradual.
 
An excess risk for liver cancer and Hodgkin's lymphoma, two additional tumours with a viral cause, also gradually declined over time in people living with HIV.
 
The risks of several virus-unrelated tumours were also greater in people living with HIV, including cancers of the lung, lip, human papillomavirus-unrelated oral cavity or pharynx, larynx, or nasal cavity,5 which might be a result of high rates of cigarette smoking among people living with HIV.6
 
Conversely, several virus-unrelated tumours-cancers of the breast, endometrium, ovary, prostate, colon, rectum, kidneys, brain, and thyroid-had a lower incidence in people living with HIV than in the general population.5 What causal factors are common to these disparate tumours is not immediately apparent. However, each of these tumours or their major subtypes has been associated with obesity and they are thought to have potential associations with obesity related hormones and inflammation.7, 8, 9, 10 If this theory is correct, the lower incidence among people with HIV might suggest that inflammation is not a major risk factor for these obesity related cancers, given that people living with HIV have high systemic inflammation. Reassuringly, none of the SIRs increased for any cancer during the study period, and SIRs decreased over time for Kaposi's sarcoma, two subtypes of non-Hodgkin lymphoma, and cancers of the anus, liver, and lung.5 A similar, albeit non-significant, reduction occurred for cervical cancer, Burkitt's lymphoma, and Hodgkin's lymphoma.
 
This study has important strengths, including the large number of reported cancer cases and extensive person-years of observation that encompassed most of the ART era, and the use of population-based registry data from eight USA states and Puerto Rico. However, registry-based studies such as this are not without limitations and the authors were forthright in reporting them. Foremost, there is an absence of information about many individual-level characteristics, including tobacco and alcohol use, viral co-infections, use and duration of ART, CD4 cell count, and HIV RNA viral loads. Other types of studies, such as observational and clinical cohort studies, are better equipped to address the effect of specific cancer-risk factors.
 
Results from the current study are important for public health surveillance of cancer risks in people with HIV, and an essential ongoing effort is needed to inform clinical programmes and interventions at local, state, and national levels. Epidemiological investigations that exploit high quality HIV/AIDS and cancer registries, with their large population-based data sets and established methodology, are especially useful for this purpose. These data are fundamental to setting cancer-screening priorities and treatment guidelines for individuals living with HIV. Therefore, studies such as this from Hernandez-Ramírez and colleagues will continue to be on the frontline to detect emerging trends in the spectrum of cancer risk in people living with HIV, and must be maintained as a public health resource.
 
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Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study
 
Raul U Hernandez-Ramírez, Meredith S Shiels, Robert Dubrow, Eric A Engels Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
(R U Hernandez-Ramírez MS, M S Shiels PhD, E A Engels MD); and Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale School of Medicine, New Haven, CT, USA
 
Summary
 
Background

 
Monitoring cancer risk among HIV-infected people in the modern antiretroviral therapy (ART) era is essential given their elevated risk for many cancers and prolonged survival with immunosuppression, ART exposure, and ageing. We aimed to examine cancer risk in HIV-infected people in the USA as compared with that in the general population.
 
Methods
 
We did a registry-linkage study with data from population-based HIV and cancer registries in the USA (the HIV/AIDS Cancer Match Study). We assessed a cohort of HIV-infected people identified in HIV registries in Colorado, Connecticut, Georgia, Maryland, Michigan, New Jersey, New York, Puerto Rico, and Texas from 1996 to 2012. Follow-up started 3 months after either the latest of the beginning of systematic name-based state HIV registration, HIV report date (or AIDS diagnosis, if this was earlier), start of cancer registration, or Jan 1, 1996, and ended at the earliest of either death, end of cancer-registry coverage, or Dec 31, 2012. We identified diagnoses of cancer in this population through linkage with corresponding cancer registries and calculated standardised incidence ratios (SIRs) to measure cancer risk in people with HIV compared with the USA general population, by dividing the observed number of cases in people with HIV by the expected number (estimated by applying general population cancer-incidence rates to person-time in the HIV population based on sex, age, race or ethnic group, calendar year, and registry). We tested SIR differences by AIDS status and over time using Poisson regression.
 
Findings
 
Among 448 258 people with HIV (who contributed 3 093 033 person-years), 21 294 incident cancers were diagnosed during 1996-2012. In these people, compared with the general population, risk was elevated (p<0⋅0001 for all) for cancer overall (SIR 1⋅69, 95% CI 1⋅67-1⋅72), AIDS-defining cancers (Kaposi's sarcoma [498⋅11, 477⋅82-519⋅03], non-Hodgkin lymphoma [11⋅51, 11⋅14-11⋅89], and cervix [3⋅24, 2⋅94-3⋅56]), most other virus-related cancers (eg, anus [19⋅06, 18⋅13-20⋅03], liver [3⋅21, 3⋅02-3⋅41], and Hodgkin's lymphoma [7⋅70, 7⋅20-8⋅23]), and some virus-unrelated cancers (eg, lung [1⋅97, 1⋅89-2⋅05]), but not for other common cancers. Risk for several cancers was higher after AIDS onset and declined across calendar periods. After multivariable adjustment, SIRs decreased significantly across 1996-2012 for Kaposi's sarcoma, two subtypes of non-Hodgkin lymphoma, and cancer of the anus, liver, and lung, but remained elevated. SIRs did not increase over time for any cancer.
 
Interpretation
 
For several virus-related cancers and lung cancer, declining risks over time in HIV-infected people probably reflect the expansion of ART since 1996. Additional efforts aimed at cancer prevention and screening in people with HIV are warranted.
 
Funding
 
National Cancer Institute.
 
Introduction

 
HIV-infected people have a higher risk for many cancers than do healthy people, largely as a result of HIV-related immunosuppression, which impairs control of oncogenic viral infections.1, 2, 3 A high prevalence of these infections and other cancer-risk factors (eg, smoking and alcohol use) contribute to the elevated risk.1, 2, 3, 4 Kaposi's sarcoma, some subtypes of non-Hodgkin lymphoma, and cervical cancer are caused by viruses (Kaposi sarcoma-associated herpesvirus, Epstein-Barr virus, and human papillomavirus, respectively) and are among conditions that can mark the onset of AIDS.3 HIV-infected people have elevated risks for these AIDS-defining cancers and other virus-related non-AIDS-defining cancers, but not for most virus-unrelated non-AIDS-defining cancers.1, 2, 3
 
After the introduction of effective antiretroviral therapy (ART) in 1996, the risks for AIDS and death decreased strikingly in HIV-infected people.3 The incidences of Kaposi's sarcoma and non-Hodgkin lymphomas have also decreased, but remain higher in HIV-infected people than in the general population; trends for other cancers are less clear.3, 5, 6, 7, 8, 9, 10, 11, 12 Few recent comprehensive population-based data exist about cancer risks for HIV-infected people.6, 8, 9, 10, 12
 
The risk for some types of cancers might continue to decline as ART regimens improve, treatment is initiated at earlier stages of HIV disease, and access to ART increases.13 However, treatment might not fully reverse the effect of early immune suppression, and immune dysfunction and chronic inflammation can persist among people receiving ART.2 HIV-infected people, including those who have not developed AIDS, might therefore still have an elevated risk of cancer. Furthermore, many cancer types have latency periods of decades, and the modern ART era is only 20 years old; elevated risks for some cancers might, therefore, emerge over time. Finally, with prolonged survival the HIV population is ageing, and the effect of HIV-related immunosuppression in an ageing population is unclear.10, 14 For these reasons, continued monitoring of cancer risks in this population is vital. In this study, we describe the range of cancer risks among HIV-infected people in the USA during the modern ART era by use of linked data from several population-based HIV and cancer registries.
 
Discussion
 
During 1996-2012, HIV-infected people in the USA, including those who had not developed AIDS, had elevated risks for many cancer types, especially those with viral causes. There was a decrease in risk during this period for several virus-related cancers and lung cancer, presumably resulting, at least partly, from improved efficacy, earlier use, and wider access to ART over time.12, 13 Although risk remained elevated for several cancers even in the most recent years of the analysis (2009-12), we did not observe increasing trends in SIRs for any cancer. The elevated risk for many cancers, especially after AIDS onset, highlights the continuing contribution of immunosuppression to cancer risk in this population.
 
A decline in risk for AIDS-defining cancers, especially Kaposi's sarcoma and non-Hodgkin lymphoma, has been well established in the ART era in the USA and other high-income countries.3, 5, 6, 8, 10, 11, 12 Trends for Kaposi's sarcoma and non-Hodgkin lymphoma (mainly diffuse large B-cell lymphoma and CNS non-Hodgkin lymphoma) have steeply decreased,3, 5, 6, 8, 10, 11, 12, 15, 16, 17 but we observed that they have moderated in recent years. The trend for Burkitt's lymphoma has been less clear,15, 16, 17 and, in this study, after accounting for demographic changes, the decrease between 1996 and 2012 was not significant. Furthermore, our finding that the difference in risk between people with HIV only and those with AIDS was much smaller for Burkitt's lymphoma than for Kaposi's sarcoma and other AIDS-defining non-Hodgkin lymphomas confirms findings from a previous analysis of the HACM Study.17 These observations for Burkitt's lymphoma, along with evidence that Epstein-Barr virus is less frequently detected in AIDS-related Burkitt's lymphoma tumour cells than in other subtypes of non-Hodgkin lymphoma,16 suggest a complex causal relation with immunosuppression.18
 
Some data suggest that the risk of cervical cancer in HIV-infected women might also be decreasing.3, 8, 10 Although SIRs for cervical cancer appeared to decrease over time in our analysis, this trend was not significant after multivariable adjustments. We also noted that risk of cervical cancer was most highly elevated in women with a previous AIDS diagnosis, consistent with a causal role for long-term immunosuppression. An AIDS diagnosis could also be a marker for an absence of appropriate medical care and inadequate screening for cervical cancer.19
 
The elevated risks for virus-related non-AIDS-defining cancers, particularly after an AIDS diagnosis, highlight the biological relevance of immunosuppression for these cancers as well. In previous studies,1, 2, 3, 5, 6, 7, 9, 10, 12, 20, 21, 22 risk for each virus-related non-AIDS-defining cancer was also elevated, and risk for Hodgkin's lymphoma and some cancers related to human papillomavirus increased in relation to AIDS onset. Consistent with findings from some studies9, 12 we noted decreasing trends in risk relative to the general population for anal and liver cancers, but other studies showed null or increasing trends.5, 6, 7, 9, 10, 12 These discrepancies among studies might partly be explained by differences in the included calendar years, since our plots suggest an increasing trend for these cancers in the earliest years, followed by a more recent decrease.
 
Risks were also elevated in HIV-infected people compared with those in the general population for lung cancer and several other virus-unrelated AIDS-defining cancers. Among HIV-infected people in our study, lung cancer was second only to AIDS-defining non-Hodgkin lymphomas in incidence. The elevated risk of lung cancer has been previously documented, and is partly, although not entirely, accounted for by a high prevalence of smoking among HIV-infected people.1, 2, 3, 4, 23 The more pronounced risk for lung cancer among people with AIDS and the decrease in SIRs over time (which is consistent with findings from other studies5, 9, 10 and with widened access to effective ART) both support a contribution from immunosuppression.23 HIV-related chronic pulmonary inflammation, abnormal immune activation, and repeated lung infections might also play a role.20, 23, 24 Smoking probably contributes to the elevated risk observed for cancers of the oral cavity or pharynx, nasal cavity, and larynx.25 We also noted elevated risks for scrotal cancer, conjunctival cancer, polycythaemia vera, and myelodysplastic syndrome. Scrotal cancer, like other anogenital cancers, might be caused by human papillomavirus, as suggested by reported detection of this virus in some tumours.26 An elevated risk of conjunctival cancer has been noted previously, especially in people with HIV in Africa, although an infectious agent has not been clearly identified.27, 28 Risks for polycythaemia vera and myelodysplastic syndrome are elevated among immunosuppressed transplantation recipients,29 although they do not have known viral causes.
 
Most virus-unrelated non-AIDS-defining cancers did not have elevated risks, consistent with findings from previous studies in the ART era.1, 2, 3, 5, 6, 10, 12, 22 Indeed, risks for some of these cancers were actually decreased compared with the risks in the general population. These deficits confirmed previous observations for breast and prostate cancers, and identified new deficits for other cancers with previously inconclusive results (eg, uterine and colorectal cancers) or modest elevations (eg, stomach and kidney or renal pelvis cancers).1, 2, 3, 5, 6, 10, 12, 22 We considered that the deficits might reflect under-ascertainment of cancers, specifically from out-migration (eg, people moving from registry areas). However, these deficits persisted after we allowed for 27% out-migration at least 10 years after the HIV report or AIDS diagnosis, even though out-migration to such an extent seems unlikely. The deficits might have biological explanations (eg, hormonal or metabolic abnormalities),1 which could be assessed in future studies.
 
Limitations of our study include the absence of individual-level data about ART use and HIV disease markers (ie, CD4 cell count and HIV viral load). Instead, we used calendar year as a population-level measure of ART use (with more recent calendar years associated with more effective ART, wider use, and earlier initiation), and AIDS onset as an indicator of ever having had advanced immune suppression. Changes in the prevalence of oncogenic viral infections and other cancer risk factors (eg, smoking and alcohol use) over time might have potentially affected our results, but the absence of data for these factors precluded us from assessing them as confounders for the patterns we observed. Finally, we assessed many cancers, so some findings could be due to chance. However, we used a stringent threshold (p<0⋅001) to identify cancers for which risk differed significantly from the general population, and to test differences in risk by AIDS status and over time.
 
A major strength of our study was its population-based design. The study covered eight states and Puerto Rico across a calendar period of 17 years during the ART era. The study population comprised all people with known HIV infection living in these areas, including all HIV-risk groups and ages. The approximate similarity between the distribution of the demographic characteristics of our population and the USA HIV population14 upholds the representativeness of our sample and the generalisability of our results. Moreover, cancers were ascertained using linked data from cancer registries, which have greater validity than other data sources.22 HACM is the largest study of cancer in HIV-infected people, which enabled the examination of a range of individual cancers, including subtypes of non-Hodgkin lymphoma and rare cancers. Furthermore, since ageing and other changes in the demographic characteristics of the HIV population could have affected time trends in the SIRs, we adjusted the calendar trends by use of multivariable regression. Finally, in the sensitivity analysis, we observed similar trends when excluding one registry area at a time, which suggested that the observed overall trends were not disproportionally affected by one registry or the varying calendar intervals by registry.
 
Additional efforts aimed at cancer prevention and screening in HIV-infected people are warranted. Although SIRs did not increase for any cancer, and have decreased over time for several cancers, SIRs were still elevated in HIV-infected people in the most recent period of our analysis.3, 8, 9, 10, 12 Because the HIV population is ageing and growing in size,3, 14 the burden of cancer might increase in this population even in the absence of increasing incidence rates.11 Early diagnosis of HIV infection, prompt and sustained ART after diagnosis, and reduction of non-HIV cancer risk factors are crucial for cancer prevention.2, 4, 30 With further improvement of ART and expansion of ART use, reductions in the risk of Kaposi's sarcoma, AIDS-defining non-Hodgkin lymphomas, and potentially other cancers can be expected. Because ART does not completely restore immunological health,2 close monitoring of cancer risk factors and assessment of symptoms possibly related to cancer is needed, even in virally suppressed patients. Efforts should aim to optimise cessation of smoking and alcohol, and treatment of infections with hepatitis C and B.30 Screening for cervical cancer, and possibly for anal, liver, and lung cancers, is appropriate for high-risk populations.30
 
In conclusion, cancer risk has decreased in HIV-infected people in the USA, but remains elevated for a range of cancers, notably for AIDS-defining cancers, many other virus-related cancers, and lung cancer. Sustained and widened access to ART has probably contributed to the decreases in cancer risk, but improvements are needed to reduce the cancer burden further.
 
Research in context
 
Evidence before this study

 
We searched PubMed for citations published in English during Jan 1, 2000, to Dec 31, 2016, with MeSH terms "cancer", "incidence", and "HIV infections", reviewed personal collections of study reports and reviews, and examined reference lists of reviewed publications to identify publications about cancer risk in people with HIV, compared with the general population or uninfected groups. Specifically, we examined publications that reported risk estimates overall and by AIDS onset, and recent trends covering the era of effective antiretroviral therapy (ART) beginning in 1996. Evidence indicates that HIV-infected people, especially those with AIDS, have an elevated risk for many cancers, especially those from viral causes. Additionally, after the introduction of ART in 1996, the incidence of two AIDS-defining cancers, Kaposi's sarcoma and non-Hodgkin lymphoma, decreased. However, trends for other cancers are less clear, and there is a shortage of recent and comprehensive population-based data about cancer risks for people with HIV.
 
Added value of this study
 
The HIV/AIDS Cancer Match (HACM) Study is the largest population-based study of cancer in HIV-infected people. We used data from the study to assess the risk of cancers in a sample of 448 258 people with HIV in the USA during 1996-2012. We found that, compared with the general population, HIV-infected people (including those without AIDS) had a greater risk for various cancers, including AIDS-defining cancers, many other virus-related cancers, and lung cancer. Although the risk for Kaposi's sarcoma, non-Hodgkin lymphoma, and some non-AIDS-defining cancers (anus, liver, and lung) decreased over time, risks generally have remained high.
 
Implications of all the available evidence
 
The decreases in cancer risk in people with HIV over time probably reflect the sustained and widened use of ART. Despite these decreases, however, cancer risks in HIV-infected people have remained elevated during the modern treatment era, indicating that continued cancer control efforts are warranted with additional efforts aimed at cancer prevention and screening.
 
Methods
 
Study design, participants, and data sources

 
We used data from the HIV/AIDS Cancer Match (HACM) Study, which examines linked data collected by USA HIV and cancer registries.15 The study was approved by institutional review boards at participating registries as required, and received exemption from review at the USA National Institutes of Health. Because the study used data collected for public health surveillance, consent of participants was not required.
 
For this analysis we assessed a cohort of HIV-infected people from HACM identified in HIV registries from Colorado (1996-2007), Connecticut (2005-10), Georgia (2004-12), Maryland (2008-12), Michigan (1996-2010), New Jersey (1996-2012), New York (2001-12), Puerto Rico (2003-12), and Texas (1999-2009). For each registry, follow-up for each cohort member started 3 months after the latest of the beginning of systematic name-based state HIV registration, HIV report date (or AIDS diagnosis if this was earlier), the start of cancer registration, or Jan 1, 1996, and ended at the earliest of death, end of cancer registry coverage, or Dec 31, 2012. The first 3 months of follow-up were excluded to remove prevalent cancers; ie, cancer cases that prompted HIV testing and reporting. Cancer diagnoses were identified through linkage with the corresponding cancer registries (appendix pp 2-3). We assessed individual cancer types and several broad categories, including all cancers, AIDS-defining cancers (Kaposi's sarcoma; AIDS-defining non-Hodgkin lymphomas: diffuse large B-cell lymphoma, Burkitt's lymphoma, unspecified non-Hodgkin lymphoma, and CNS non-Hodgkin lymphoma; and cervical cancer), and non-AIDS-defining cancers, which were subclassified as either virus-related (cancers of the anus, vagina, vulva, penis, and selected oral cavity or pharynx sites [caused by human papillomavirus]; liver cancer [hepatitis B and C viruses]; Hodgkin's lymphoma [Epstein-Barr virus]; and Merkel cell carcinoma [Merkel cell polyomavirus]) or virus-unrelated (remaining cancers).
 
Statistical analysis
 
We used standardised incidence ratios (SIRs) to measure cancer risk in people with HIV compared with the USA general population. SIRs were calculated by dividing the observed number of cases in HIV-infected people by the expected number, estimated by applying general population cancer-incidence rates to person-time in the HIV population based on sex, age, race or ethnic group, calendar year, and registry. For Kaposi's sarcoma and CNS non-Hodgkin lymphoma (for which contemporaneous general population rates largely reflect HIV-related cases), expected rates were based on data collected by the Surveillance, Epidemiology, and End Results (SEER) cancer registries before the AIDS epidemic (1973-79).15 To calculate SIRs, we counted all cancers (not just first cancers), including multiple cancers of the same type.
 
In preliminary analyses, we observed that the SIR for a miscellaneous cancers category was significantly raised. We therefore reviewed this category and extracted additional cancer types with at least ten cases for separate assessment (cancers of the extrahepatic bile duct, nasal cavity, accessory sinuses, scrotum, conjunctiva, and thymus, Merkel cell carcinoma, appendageal carcinoma of the skin, sarcomas of the skin, polycythaemia vera, essential thrombocythaemia, and myelodysplastic syndrome), which are included separately in the results.
 
To assess the association of cancer risk with advancing immunosuppression, we calculated SIRs separately for person-time with AIDS and without AIDS (ie, HIV only). The AIDS onset month was considered the end of the HIV-only period, so some AIDS-defining cancers were counted as occurring in people with HIV only. We compared SIRs for the HIV-only and AIDS periods by use of Poisson regression. These models yielded SIR ratios adjusted for sex or HIV-risk group (men who have sex with men, other males, and females), attained age (<30, 30-39, 40-49, 50-59, and ≥60 years), race or ethnic group (non-Hispanic white, non-Hispanic black, and Hispanic or Latino), calendar year (modelled as one continuous variable, except for Kaposi's sarcoma, diffuse large B-cell lymphoma, and CNS non-Hodgkin lymphoma, which were modelled as separate segments as informed by Joinpoint analysis [version 4.3.1, National Cancer Institute]), registry, and early versus late attained follow-up duration (<10 vs ≥10 years after the latest of HIV report or AIDS diagnosis). We considered calendar trends in cancer risk to reflect increasing use of ART at the population level. To screen for time trends, we first calculated SIRs for four calendar periods (1996-99, 2000-04, 2005-08, and 2009-12) and tested for a trend in SIRs across the periods with unadjusted Poisson models. For selected cancers for which the SIR was elevated overall and the trend across periods was significant, we further assessed trends across individual calendar years. We first used Joinpoint to identify significant changes in SIR trends over calendar time, allowing up to four calendar segments. Incorporating the interval parameterisation identified in Joinpoint, we then used Poisson regression to characterise calendar trends adjusted for sex or HIV-risk group, attained age, race or ethnic group, registry, and attained follow-up duration.
 
If individuals move out of cancer registry areas, SIRs might be underestimated, especially with extended time after HIV registration. In a sensitivity analysis to address this possible bias, we recalculated SIRs after decreasing the expected cancer counts by 27% for the late follow-up period defined above (appendix p 1). Participating registries provided data for varying calendar intervals, which might have affected overall calendar trends, so in another sensitivity analysis we recalculated trends excluding one registry at a time. We did all statistical analyses, except the Joinpoint analysis, with SAS (version 9.3). We present values with 95% CIs, but because we made multiple comparisons, we used a conservative two-sided p value of 0⋅001 to determine significance.
 
Role of the funding source
 
The funder of the study reviewed and approved the final submitted report but had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the aggregate data in the study and had final responsibility for the decision to submit for publication. Results 448 258 HIV-infected people contributed 3 090 033 person-years of follow-up (table 1). Across calendar periods during 1996-2012, the contribution by women and older age groups increased, while the contribution from non-Hispanic whites and injection drug users decreased. The proportion of follow-up time of at least 10 years after an HIV report or AIDS diagnosis increased from <1% (1996-99) to 24% (2009-12).
 
21 294 cases of cancer were diagnosed during 1996-2012 (incidence: 689 per 100 000 person-years), of which 6384 (30%) were AIDS-defining cancers, 14 344 (67%) were non-AIDS-defining cancers, and 566 (3%) were poorly specified (table 2). Overall, cancer risk was 69% higher among HIV-infected people than in the general population (SIR 1⋅69, 95% CI 1⋅67-1⋅72). Risks were also elevated in the HIV-infected population for AIDS-defining cancers and for non-AIDS-defining cancers, driven by the elevation for virus-related non-AIDS-defining cancers; the risk for virus-unrelated non-AIDS-defining cancers was slightly decreased (table 2).
 
The most common individual cancer types were AIDS-defining non-Hodgkin lymphomas, lung cancer, Kaposi's sarcoma, anal cancer, prostate cancer, liver cancer, and Hodgkin's lymphoma (table 2). Risks were elevated (p<0⋅0001) for almost all virus-related cancers, except for Merkel cell carcinoma (p=0⋅0133), and elevated for each subtype of AIDS-defining non-Hodgkin lymphoma, cancers of the (human papillomavirus-unrelated) oral cavity or pharynx, nasal cavity, larynx, lung, scrotum, and conjunctiva, as well as non-AIDS-defining non-Hodgkin lymphomas, polycythaemia vera, myelodysplastic syndrome, and miscellaneous cancers. By contrast, risks were significantly decreased for cancers of the stomach, colon, rectum or rectosigmoid junction, female breast, uterus, prostate, kidney or renal pelvis, brain, and thyroid (table 2). Correcting SIRs for potential out-migration (ie, individuals moving out of registry areas) did not substantially affect the estimates (appendix p 4).
 
Compared with people with HIV only, those with AIDS had significantly higher SIRs for grouped AIDS-defining cancers, virus-related non-AIDS-defining cancers, and virus-unrelated non-AIDS-defining cancers (table 3). This pattern was also present for each individual AIDS-defining cancer and virus-related non-AIDS-defining cancer, except liver and vaginal cancers, and Merkel cell carcinoma. SIRs were also higher for people with AIDS compared with those with HIV only for the following virus-unrelated non-AIDS-defining cancers: cancers of the (human papillomavirus-unrelated) oral cavity or pharynx, oesophagus, and lung, non-AIDS-defining non-Hodgkin lymphomas, myeloid and monocytic leukaemias, and myelodysplastic syndrome.
 
SIRs did not increase across calendar periods for any cancer (appendix pp 5-6). Moreover, SIRs decreased significantly for many cancer types, including some for which risk was elevated overall (grouped AIDS-defining cancers, Kaposi's sarcoma, each AIDS-defining non-Hodgkin lymphoma, grouped virus-related non-AIDS-defining cancers, cancers of the anus, liver, and lung, non-AIDS-defining non-Hodgkin lymphomas, and miscellaneous cancers), grouped virus-unrelated non-AIDS-defining cancers and myeloma; decreasing trends bordering on significance were also observed for cervical cancer and Hodgkin's lymphoma. Despite these decreases, SIRs remained elevated during the most recent period of analysis from 2009 to 2012, with 95% CIs excluding 1⋅00, for several cancer types (appendix pp 5-6).
 
For most cancers selected for detailed calendar trend analysis, SIRs appeared to decrease steadily over time (figure). For Kaposi's sarcoma, diffuse large B-cell lymphoma, and CNS non-Hodgkin lymphoma, moderating changes in slope were identified; ie, steep early decreases became attenuated after 1998, 2001, and 1999, respectively. For anal cancer, liver cancer, and Hodgkin's lymphoma, there was a suggestive increase in the earliest years of the analysis, but Joinpoint identified only a single decreasing trend for these cancers across 1996-2012. After multivariable adjustment, calendar trends in SIRs significantly decreased for Kaposi's sarcoma, diffuse large B-cell lymphoma, CNS non-Hodgkin lymphoma, and cancers of the anus, liver, and lung. Adjusted calendar trends were not significant for Burkitt's lymphoma, cervical cancer, or Hodgkin's lymphoma. In a sensitivity analysis, exclusion of one registry at a time did not change the trends appreciably (data not shown).

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