Abstract
HIV-infected individuals are at increased risk for most types of cancer, including those typically classified as non-AIDS-defining cancers (NADCs). This increased risk is likely multifactorial, but a prominent risk factor for the increased rate of some cancers is co-infection with oncogenic viruses. Anal cancer, hepatocellular carcinoma, and Hodgkin lymphoma are three of the most common NADCs, and they are associated with co-infection with human papillomavirus, hepatitis B and C, and Epstein Barr virus, respectively. This review will examine the epidemiology, pathogenesis, and future trends around these virally associated NADCs frequently found in HIV-infected individuals.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Non-AIDS-defining cancers (NADCs) are typically defined in contrast to the three AIDS-defining cancers (ADCs)—Kaposi sarcoma, non-Hodgkin lymphoma (NHL), and cervical cancer. NADCs are then any cancer that does not fall into the ADC category. The incidence of NADCs has been rising over the last decade as more effective antiretroviral therapy (ART) has contributed to longer life span in the HIV-infected population. Additionally, with more effective ART, the rates of ADCs have decreased, and so NADCs have supplanted ADCs as major causes of morbidity and mortality in the later ART era [1, 2]. In fact NADCs have become one of the leading causes of mortality among HIV-infected individuals in general [3, 4].
The reasons for the increased risk for NADCs are multifactorial. Factors that likely contribute to the increased risk for NADCs include HIV viremia, co-infection with oncogenic viruses, chronic immunosuppression and immune activation, exposure to high levels of carcinogens (e.g., tobacco and alcohol), aging of the HIV population, and possibly ART itself [5•, 6]. Despite being combined in the same generic category, not all NADCs share the same pathogenesis and risk factors. Recently, an effort has been made to differentiate the various NADCs based on an association with co-infecting oncogenic viruses [7•], in contrast to those NADCs that are likely infection unrelated (e.g., lung cancer or melanoma). Virally associated NADCs include anal, vaginal, vulvar, penile, and some oropharyngeal cancers (human papillomavirus (HPV)), hepatocellular cancer (hepatitis B and C), Hodgkin lymphoma (Epstein Barr virus)) and Merkel cell carcinoma (Merkel cell polyomavirus) [8]. The close association between these cancers and underlying infection with oncogenic viruses makes them much more similar to ADCs, which are all typically linked with underlying oncogenic viral infection: human herpesvirus 8 with Kaposi sarcoma, Epstein Barr Virus (EBV) with non-Hodgkin lymphoma, and HPV with cervical cancer.
Various theories have been proposed to explain the increased risk for these virally associated NADCs, including the higher prevalence of viral co-infection in the HIV-infected population [7•], HIV-induced chronic immunosuppression permitting uncontrolled replication of the co-infecting virus, and possibly synergistic effects of HIV with the co-infecting virus. The purpose of this review is to examine the current state of knowledge for three of the most common virally associated NADCs—anal cancer, hepatocellular cancer (HCC), and Hodgkin lymphoma—and to determine what trends can be predicted based on the trajectory of the HIV epidemic.
Anal Cancer
Epidemiology
The annual incidence of anal cancer is approximately 1–2 cases per 100,000 persons globally, which is relatively low compared to the incidence of cervical cancer, which ranges from 7 cases per 100,000 in the USA [9] to 40 per 100,000 in many sub-Saharan African countries [10]. However, anal cancer is one of the most common cancers among HIV-infected individuals [11]. In a country such as the USA, the incidence of anal cancer in HIV-infected individuals is at least 30 times higher than in the general population [12, 13]. In a recent study comprised of 13 North American cohorts, anal cancer incidence was 131 in HIV-infected men who have sex with men (MSM), 46 in other HIV-infected men, and only 2 per 100,000 in HIV-uninfected men [14]. Among HIV-infected women, anal cancer incidence was 30 per 100,000, with no cases in HIV-uninfected women. In addition, anal cancer incidence continues to increase despite widespread use of highly active antiretroviral therapy (HAART) [15–17], in contrast to the observed declines in AIDS-defining cancers and other opportunistic conditions in HIV-infected individuals. One US-based study with data from 1985–2008 estimated the incidence of anal cancer in HIV-infected men to be 11 per 100,000 in the pre-HAART era, increasing to 55 per 100,000 in the post-HAART era overall, with the rate in 2006–2008 reaching 128 cases per 100,000 men [18]. Risk factors for anal cancer, in addition to HIV infection itself, include high-risk human papillomavirus (HR-HPV) infection, multiple HPV infections, high HPV viral load, receptive anal intercourse, high lifetime number of sexual partners, smoking, and older age [19]. Five-year survival after anal cancer diagnosis is quite variable by stage, cancer treatment, HAART, and CD4 count, ranging from 39–64 %, and is found to be lower than in HIV-uninfected individuals in some studies but not all [20, 21••, 22].
Pathogenesis
Anal cancer, like cervical cancer, is primarily caused by infection with high-risk oncogenic types of human papillomavirus (HR-HPV). Over 80 % of anal cancers have been attributed to HR-HPV infection, with HPV-16 the predominate type in 70 % of HPV-positive cases [23–25]. Although less is known about the natural history of anal HPV infection and its progression to cancer, it is believed to follow a course similar to the development of cervical cancer: 1) sexually transmitted HPV infects the basal layer of the squamous epithelium through micro abrasions; 2) persistent infections induce malignant transformation of the epithelial cells, which are ultimately detectable as precancerous lesions known as high-grade anal intraepithelial neoplasia (HGAIN); and 3) over time, a subset of lesions progress in the anal canal to invasive anal cancer.
Evidence suggests that HIV is a major factor in the natural history of anal cancer. Not only do HIV-infected individuals have a higher prevalence of single and multiple anal HR-HPV infections (over 90 % in some HIV-infected MSM populations [26–28]), but they are also more likely to have persistent HR-HPV infections compared to HIV-uninfected individuals [29], likely due to the weakened immune system’s inability to control the infection. However, the exact relationship between CD4 count and HPV persistence and progression remains unclear. Nevertheless, HIV-infected individuals have higher incidence of anal pre-cancer and cancer as compared to HIV-uninfected individuals.
Future Directions/Trends
There are three important areas for anal cancer research and prevention. First, the role of ART, CD4 count, and HIV viral load on the natural history of anal cancer needs to be clarified. Currently, the epidemiological literature on the effect of HAART and CD4 count on the natural history of anal cancer is inconsistent and inconclusive [30, 31, 28, 32, 33, 18]. Although many support an increased risk among HIV-infected individuals with low CD4 counts, studies differ in the use or duration of ART, timing of CD4 measurement prior to cancer diagnosis, and in the examination of current versus nadir CD4 count. It is likely that the benefits that ART provides with regard to immune system recovery and reducing opportunistic conditions are outweighed by the increase in life expectancy, whereby HIV-infected individuals age into the highest risk periods for anal cancer incidence (ages 56 and 60 years in the general population for females and males, respectively [34]). The increased lifespan of HIV-infected individuals with the use of ART provides additional time for low- and high-grade precancerous lesions to progress to cancer.
Second, the performance of anal cancer screening methods needs to be improved, and clinical guidelines for screening HIV-infected individuals need to be developed and implemented. The main ways in which we can currently screen for anal pre-cancer, in order to prevent the development of invasive anal cancer, are HPV testing, anal Pap smear, and high-resolution anoscopy (HRA). Unfortunately, each method has significant limitations, such as specificity as low as 25 % for anal HPV testing in HIV-infected MSM [35], highly variable performance of anal Pap smears across settings and populations (69–98 % for sensitivity; 69–98 % for specificity) [36], and limited availability of HRA. No randomized control trial has been conducted to compare these screening modalities. Further, treatment of precancerous lesions is quite invasive, and controversy remains regarding how and when to treat based on positive screening tests [37]. A related issue is that there are currently no consensus guidelines for screening for anal cancer in HIV-infected individuals, despite their greatly increased risk, likely due to the paucity of evidence on best screening and treatment algorithms. All of these factors likely contribute to ongoing HIV provider ambivalence about anal cancer screening [38•], which has led to nominal usage of the various techniques in the clinic. However, cost-effectiveness analyses do support routine screening in HIV-positive men and women under specific conditions and intervals [39–41].
Finally, for the maximum benefit against HPV-associated cancers for all individuals, HPV vaccine coverage needs to be increased, especially in the recommended age ranges for young boys and girls prior to sexual debut. Although there are currently no data on the effectiveness of the vaccine specifically against anal cancer in HIV-infected individuals, a study of MSM nested within a larger RCT found a 54 % reduction in anal intraepithelial neoplasia 2/3 [42] and new evidence supports the efficacy of HPV vaccination in HIV-infected individuals [43, 44]. Importantly, by vaccinating universally prior to sexually debut, when rates of HIV are much lower and before high-risk sexual behaviors such as receptive anal intercourse, we can ensure equitable and high levels of protection against HPV and anal and other associated cancers.
Hepatocellular Carcinoma
Epidemiology
HCC comprises the vast majority of primary liver cancers—accounting for over 90 % of cases. Chronic hepatitis B (HBV) and hepatitis C (HCV) are the main risk factors for development of HCC. Due to shared risk factors, the prevalence of HCV, HBV, and HIV co-infection is high. In the USA, the prevalence of HCV infection among people living with HIV ranges from 17–37 % [45, 46], while HBV co-infection is substantially lower (7 % in one large HIV cohort [47]).
As ART for HIV has reduced AIDS-related mortality, liver disease from HBV and HCV, and the NADC HCC have become more important as causes of morbidity and mortality in HIV-infected individuals [48–51, 52••]. One study found a relative risk for HCC of 3.3 (95 % CI 2.1–5.4) in HIV-infected individuals compared to the uninfected population [7•]. In one large French study, liver disease-related deaths due to HCC increased from 15 % in 2000 to 25 % in 2005 [49].
Pathogenesis
HBV can cause HCC directly; however, the majority of cases of HCC from chronic HCV infection arise from a cirrhotic liver [53]. The molecular mechanisms of virally induced HCC are still being defined. Chronic viral infection causes an ongoing cycle of inflammation, progressive hepatic fibrosis, initiation of neoplastic clones accompanied by irreversible somatic genetic/epigenetic alterations, and progression of the malignant clones in a carcinogenic tissue microenvironment [54]. The interaction between HIV and HBV with respect to the development of HCC is also less clearly established. One study found an increased risk for HCC in HBV-HIV co-infected individuals with lower CD4 cell counts [55]. A more recent study found that a greater CD4 cell count response after starting ART was associated with a decreased incidence of HCC in HBV and HCV co-infected individuals [56].
HIV infection itself has not been associated with an increased risk of HCC [57, 58]. A PubMed literature search for HIV infection and HCC yielded few studies from the USA and Europe that looked at the effect of HIV infection on the incidence, characteristics, and progression of HCC (summarized in Table 1). Most individuals in the HIV cohorts were HCV co-infected, and cumulatively, the findings of these studies support HCV as the predominant risk factor. Whereas HIV-HCV co-infection among US veterans did not increase HCC risk compared to HCV mono-infected veterans in one study [57], the risk of both cirrhosis and HCC was significantly increased among HIV-HCV co-infected veterans compared to HIV mono-infected in a second study [59]. Five of the studies compared patient and tumor characteristics between those with HIV and those without [58, 60–63]. These studies support the additive effect of HIV and HCV on risk, characteristics, and survival from HCC: reporting younger age at HCC diagnosis [60–63], more advanced disease [62, 63], faster progression from HCV diagnosis to HCC diagnosis [60, 58, 61], and worse survival [62, 63]. Accelerated development of cirrhosis among individuals with HIV-HCV co-infection compared to those with HCV mono-infection has been reported in multiple studies [64–67], but the pathogenesis of accelerated liver fibrosis that may be associated with HIV co-infection with HCV has not been established. Some suggest a role of CD4 T-cell depletion [68, 69]; however, this has not been supported by other studies that found no significant difference in CD4 counts between rapid progressors and non-rapid progressors [66, 67].
Future Directions/Trends
The widespread adoption of the HBV vaccination program has contributed to an overall decrease in HCC incidence in endemic areas. A vaccination for HCV, however, remains elusive. Furthermore, with over 300 million people currently infected worldwide with HBV, secondary prevention of HCC through chronic suppression of HBV and HCV treatment remains important.
Secondary Prevention of HCC Associated with Chronic HBV and HCV Infection
As with HBV mono-infected patients, the goal of HBV treatment in HIV-HBV co-infected patients is the same: to reduce liver-related mortality outcomes. Improvement in liver fibrosis score in HIV-HBV co-infected patients with advanced fibrosis or cirrhosis receiving tenofovir has been demonstrated [70]. Piroth et al. compared the management of HBV infection in HIV-infected individuals, most of whom were on ART, compared to HIV-uninfected individuals in France [71] and found that participants with HIV were more likely to be on HBV treatment. Liver fibrosis staging did not vary significantly between the two groups. Only 3 % of patients developed HCC, with significantly lower incidence among those with HIV-HBV co-infection (0.7 vs. 4.7 %, P = 0.002). In multivariate analysis, age, male gender, and cirrhosis correlated positively with HCC, whereas being HIV-infected was inversely correlated with HCC (OR 0.15, 95 % CI 0.03–0.67, P = 0.01). The authors concluded that their findings suggest a decreased impact of HIV-HBV co-infection on liver-related complications such as cirrhosis and HCC and that this may be related to long-term suppression of HBV. Puoti et al. demonstrated that the use of lamivudine-containing ART in 2041 HIV-HBV co-infected patients was found to have a protective effect for liver-related deaths [72]. This study, however, did not describe how many of the liver-related deaths were due to HCC. The findings of Bruyand et al., suggesting a reduced incidence of HCC with CD4 recovery to over 500, support that a reduced incidence of HCC may be related to ART therapy with one study [73].
The treatment of HCV with attainment of sustained virologic response (SVR) has been shown to reduce all-cause and liver-related mortality and liver decompensation, although studies to date have not shown reduced incidence of HCC (when not considered as part of a composite outcome) in co-infected individuals [74–76]. The benefit of SVR on HCC incidence has been reported in HCV mono-infection [74]; however, whether this difference is due to ongoing non-HCV-mediated liver injury in HIV-infected patients or is simply a phenomenon of small numbers of SVR in HIV-HCV cohorts remains unclear. As the response to treatment for HCV has improved from interferon-based therapy to directly acting antiviral (DAA)-based regimens, with over 90 % cure rates in clinical trials, their effect on incidence of HCV-associated HCC among HIV-infected individuals needs to be evaluated in future longitudinal studies but is expected to have a significant positive benefit.
Tertiary Prevention of HBV- and HCV-associated HCC
Relapse of HCC after initial curative treatment is high. Adjunctive antiviral therapy has been shown to be effective in reducing relapse of HBV-associated (mono-infected) HCC after curative treatment [77]. In HCV mono-infection, reduction in HCC recurrence with SVR from curative HCV treatments with interferon (IFN) has been demonstrated [78, 79], but the impact of HCV cure with DAA-based treatment on HCC outcomes has yet to be addressed. To date, there is scarce data demonstrating the efficacy of HBV or HCV antiviral treatment to prevent recurrence in patients with HIV co-infection.
Role of HCV in Non-HCC Cancers
HCV mono-infection has been associated with the development of NHL [80•, 81], a classical ADC. However, more recent literature supports an association between HCV and an increased risk for other NADCs [82]. In this study, cancer rates were nearly two times higher among HCV-infected patients after excluding liver cancers [82]. Since a significant proportion of HIV-infected patients are also HCV co-infected, HCV may be playing a role in the increased risk for some of these NADCs.
In conclusion, the field of virally induced HCC remains dynamic. The oncogenic mechanisms associated with chronic HBV and HCV continue to be elusive, and the additive role of HIV co-infection is yet to be clearly defined. The high efficacy of both HBV and current HCV treatment presents a significant opportunity to reduce the incidence and associated mortality of HCC in HIV-infected individuals.
Hodgkin Lymphoma
Epidemiology
The risk for Hodgkin lymphoma in HIV-infected individuals is substantially higher than in the general population. One meta-analysis found the risk to be 11-fold higher [83], while other studies have found standardized incidence ratios from 14.7 (95 % CI, 11.6 to 18.2) to 32.35 (95 % CI, 20.27 to 48.98) [84, 15]. One recent study analyzed the impact of HIV-infected Hodgkin lymphoma cases on the general population burden of Hodgkin lymphoma in the USA [85•]. Despite the fact that HIV-infected individuals represent only about 1 % of the general US population, Shiels et al. found that 3.8 % (848) of 22,355 Hodgkin lymphoma cases during 2000 to 2010 had HIV infection at the time of their lymphoma diagnosis. The proportion of HL cases with HIV was greater for males than females (6 vs. 1 %) and among non-Hispanic blacks (11 %) and Hispanics (7 %) compared to non-Hispanic whites (2 %).
Over the first decade of the ART era (1996–2005), the number of cases of HL in the HIV-infected population has been increasing, although the actual incidence rates have not increased [83]. Very little data have been published on HL incidence rates after 2010 in the USA or Europe.
Age
The relationship of age with HL is complicated since the incidence is bimodal or U-shaped, occurring most frequently in young and elderly adults in the general population [86]. Many NADCs have been noted to occur at younger ages in the HIV-infected population compared to the general population, although more recent analyses have shown that after adjusting for the differing age structures of the two populations, this observation is less strong. In contrast, however, individuals with AIDS were found to be significantly older than cases in the general population 42 vs. 40 years) [87]. Interestingly, in this study [87], the age distribution of AIDS individuals diagnosed with HL did not show the typical bimodal pattern seen in the general population, instead having only a single peak. The authors speculated that this difference was due to the overall lack of very young and very old individuals with AIDS in the population structure and possibly due to intermingling of the various HL subtypes in this population. A more recent study by the same group that included HIV-infected cases (not just AIDS cases) found a median age at HL diagnosis between 40 and 44 years for HIV-infected cases and between 35 and 39 years for HIV-uninfected cases [85•]. In this study, the vast majority (83 %) of cases in HIV-infected individuals were diagnosed in 30- to 59-year-olds [85•], creating a clear unimodal peak in this age range.
Timing
Recent work has examined the timing of HL diagnosis in HIV-infected individuals with respect to ART initiation. Several reports have noted an increased incidence of HL diagnosis in the first 3 to 6 months after ART initiation [88, 89, 90••], hypothesizing that there is an element of immune reconstitution inflammatory syndrome (IRIS) contributing to development of some cases. The first study was from a large French cohort of 187 HL cases among 64,368 total individuals [88]. HL risk was significantly elevated in the first 1–3 months after ART initiation (relative risk (RR) 2.95, 95 % CI 1.64 to 5.31) and was not associated with the type of ART used. A similar study from a collaboration of eight US cohorts found the incidence of HL to be nearly 2.5 times higher from 0 to 6 months after starting ART compared to the subsequent period up to 10 years [89]. Subsequent work from a prospective US lymphoma cohort extended this concept by specifying a definition of IRIS that requires the HL diagnosis within 6 months after ART initiation with reduction of viremia ≥0.5 log or full virologic suppression [90••]. This study found 15 % of HL cases met the definition for IRIS by occurring within the first 6 months after ART initiation. Cumulatively, these studies identify a substantially increased risk of HL development soon after ART initiation.
Pathogenesis
Epstein Barr Virus
One of the main differences between HIV-associated HL and HL in HIV-uninfected individuals is the strong association with EBV in the former. EBV is typically demonstrated by histopathology with latent membrane protein-1 (LMP1) in nearly all HIV-associated HL cases [91, 92]; in contrast, EBV is much less frequently (20–50 %) expressed in HL of HIV-uninfected individuals [5•]. This difference is partly due to the skewed distribution of subtypes in HIV-infected individuals, as they are more likely to have HL of mixed cellularity and lymphocyte-depleted subtypes [93, 94], which are more closely associated with EBV (see next section). LMP1 activates cellular proliferation which can promote B-cell survival and lymphomagenesis [95]. There remains some uncertainty about the interaction between EBV, the immune system, and ART in the etiologic progression to HL diagnosis, although it is generally accepted that EBV plays an etiologic role in HIV-associated HL.
Peripheral blood EBV DNA viremia has been noted to be a negative prognostic marker for survival in HIV-associated NHL [96], but the same has not been evaluated in HIV-associated HL to date. Another possible approach would be to screen for HIV-associated HL with EBV DNA viremia in certain individuals thought to be at high risk for HL or those exhibiting B symptoms. This strategy has been successful in the post-transplant setting for early detection of post-transplant lymphoproliferative disease and has not been pursued to date in HIV-associated HL but could represent a method for making earlier diagnosis possible.
Pathological Features/Subtypes
Another important difference between HIV-associated HL and HL in HIV-negative individuals is the shift in the usual proportions of the four primary HL subtypes in the former group, with a predominance of more unfavorable histological subtypes, namely lymphocyte depleted and mixed cellularity [85•, 93, 94]. In one large US-based study, the proportion of lymphocyte-depleted and mixed cellularity subtypes in the HIV cases were roughly double than that of the HIV-uninfected cases, while the nodular sclerosis subtype was twice as frequent in HIV-uninfected cases [85•]. These two HL subtypes are more frequently associated with EBV positivity than the nodular sclerosis subtype (more common in the general population) [97•], but the etiologic reason for this shift has not been determined outside of the close relationship to EBV.
Relationship to CD4 Cell Counts
HIV-associated HL also has a complicated association with CD4 cell count. Unlike HIV-associated NHL, the risk of HL does not peak with the greatest degree of immunosuppression, i.e., the lowest CD4 counts (<50) but instead rises as CD4 increases above 50 and then declines again above 350 in an inverted U-shape. For example, a study from a large European collaboration of multiple cohorts found the highest risk for HL at a CD4 of 100–199 [98], while a large US-based study found the highest incidence in the CD4 range of 150–199 [99]. In general, the risk for HIV-associated HL has been the highest in individuals with moderate immunosuppression, a finding sharply contrasted by the progressively increased risk for NHL as immunosuppression worsens. A definitive explanation for this association has not been found, but one theory is that development of HL requires a CD4-based cellular immune response since CD4+ cells are typically found in the milieu surrounding prototypical Reed Sternberg cells [86, 100].
Epidemiologic studies of this phenomenon have also been complicated by the changing nature of CD4 cell counts prior to the diagnosis of HL in HIV-infected individuals. Frequently, peripheral CD4 cell counts decline in the months leading up to an HL diagnosis, and it is not unusual for this decrease to be a presenting sign of the developing malignancy [101]. Indeed, one large case–control study of 61 HL individuals matched to 1652 controls found during the year prior to HL diagnosis; CD4 cell counts declined by 98 cells despite suppressed HIV viremia, whereas controls gained 35 cells [98]. A second case–control study found a CD4 drop of nearly 150 cells in the year preceding HL diagnosis [102]. This finding lends further support to the necessary involvement of CD4 cells in the pathogenesis of HIV-associated HL but can complicate generalized statements about the time-updated CD4 at the time of HL diagnosis and subsequent stratification of incidence and risk. For clinicians, a falling CD4 in a virologically suppressed patient could represent a developing HL and should prompt a careful search for any signs or symptoms that could indicate an underlying malignancy.
Future Directions/Trends
Although the risk for NHL has been declining over the last decade, plus of the ART era, the incidence rates for HL have not followed. Instead, studies have generally shown a stable incidence over time with no particular protection afforded by suppressive ART [103]. With the current push for earlier initiation of ART (i.e., prior to development of AIDS) with the potential for enhanced immune control of latent EBV infection, there is a possibility that incidence rates for HIV-associated HL could begin to fall back closer to those of the general population. However, continued epidemiologic studies are needed to determine the effects of ART on incidence trends.
Conclusions
In recent years, NADCs, and particularly those associated with viral co-infections, have been dramatically increasing in incidence, and as important causes of morbidity and mortality, in HIV-infected individuals. With the current international movement toward earlier testing and treatment of all HIV-infected individuals, there is a prospect for having a significant impact on the incidence of these malignancies through earlier and better immune control. Until then, future work should concentrate on developing a better understanding of the pathogenesis of these cancers in the HIV-infected patient along with the complex interplay between the co-infecting viruses and the immune system. Improved knowledge about the biology and development of these virus-associated cancers, possible screening mechanisms, and optimal treatment options would go a long way toward improving the clinical outcomes for many individuals that are benefitting so greatly from ART.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384(9939):241–8. doi:10.1016/S0140-6736(14)60604-8.
Morlat P, Roussillon C, Henard S, Salmon D, Bonnet F, Cacoub P, et al. Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000. AIDS. 2014;28(8):1181–91.
Bonnet F, Burty C, Lewden C, Costagliola D, May T, Bouteloup V, et al. Changes in cancer mortality among HIV-infected patients: the Mortalite 2005 Survey. Clin Infect Dis. 2009;48(5):633–9.
Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis. 2010;50(10):1387–96. doi:10.1086/652283.
Deeken JF, Tjen ALA, Rudek MA, Okuliar C, Young M, Little RF, et al. The rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin Infect Dis. 2012;55(9):1228–35. doi:10.1093/cid/cis613. This is a comprehensive overview of NADC epidemiology, etiology, screening, and treatment. It also takes note of the many areas where data is lacking and potential future research questions.
Bruyand M, Ryom L, Shepherd L, Fatkenheuer G, Grulich A, Reiss P, et al. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D: A: D study. J Acquir Immune Defic Syndr. 2015;68(5):568–77. doi:10.1097/QAI.0000000000000523.
Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23(17):2337–45. doi:10.1097/QAD.0b013e3283319184. This retrospective cohort study from the Kaiser Permanente population was the first to divide NADCs by their association with underlying infectious (predominantly viral) cause. The risk of infection-associated cancers was found to be most highly elevated.
Lanoy E, Costagliola D, Engels EA. Skin cancers associated with HIV infection and solid-organ transplantation among elderly adults. Int J Cancer. 2010;126(7):1724–31. doi:10.1002/ijc.24931.
Rositch AF, Nowak RG, Gravitt PE. Increased age and race-specific incidence of cervical cancer after correction for hysterectomy prevalence in the United States from 2000 to 2009. Cancer. 2014;120(13):2032–8. doi:10.1002/cncr.28548.
Bray F, Ren J-S, Masuyer E, Ferlay J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013;132(5):1133–45. doi:10.1002/ijc.27711.
Riedel DJ, Mwangi EI, Fantry LE, Alexander C, Hossain MB, Pauza CD, et al. High cancer-related mortality in an urban, predominantly African-American. HIV-Infect Populat AIDS. 2013;27(7):1109–17. doi:10.1097/QAD.0b013e32835dc068.
Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67. doi:10.1016/S0140-6736(07)61050-2.
Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52(5):611–22. doi:10.1097/QAI.0b013e3181b327ca.
Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis. 2012;54(7):1026–34. doi:10.1093/cid/cir1012.
Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, Gazzard B, et al. Highly active antiretroviral therapy and the incidence of non-AIDS-defining cancers in people with HIV infection. J Clin Oncol. 2009;27(6):884–90. doi:10.1200/JCO.2008.19.6626.
Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, et al. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS. 2008;22(10):1203–11. doi:10.1097/QAD.0b013e3283023f78.
Seaberg EC, Wiley D, Martinez-Maza O, Chmiel JS, Kingsley L, Tang Y, et al. Cancer incidence in the multicenter AIDS Cohort Study before and during the HAART era: 1984 to 2007. Cancer. 2010;116(23):5507–16. doi:10.1002/cncr.25530.
Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, et al. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS. 2010;24(4):535–43. doi:10.1097/QAD.0b013e328331f6e2.
Bertisch B, Franceschi S, Lise M, Vernazza P, Keiser O, Schoni-Affolter F, et al. Risk factors for anal cancer in persons infected with HIV: a nested case–control study in the Swiss HIV cohort study. Am J Epidemiol. 2013. doi:10.1093/aje/kwt153.
Munoz-Bongrand N, Poghosyan T, Zohar S, Gerard L, Chirica M, Quero L, et al. Anal carcinoma in HIV-infected patients in the era of antiretroviral therapy: a comparative study. Dis Colon Rectum. 2011;54(6):729–35. doi:10.1007/DCR.0b013e3182137de9.
Marcus JL, Chao C, Leyden WA, Xu L, Yu J, Horberg MA, et al. Survival among HIV-infected and HIV-uninfected individuals with common non-AIDS-defining cancers. Cancer Epidemiol Biomarkers Prev. 2015. doi:10.1158/1055-9965.EPI-14-1079. This retrospective cohort study from the Kaiser Permanente database compared survival in HIV-infected vs. uninfected patients after a NADC diagnosis. Cancer-related mortality for lung and prostate cancers was higher in the HIV-infected cohort compared with the HIV-uninfected cohort, but there was no difference for anal or colorectal cancer and Hodgkin lymphoma.
Oehler-Janne C, Huguet F, Provencher S, Seifert B, Negretti L, Riener MO, et al. HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy. J Clin Oncol : Off J Am Soc Clin Oncol. 2008;26(15):2550–7. doi:10.1200/JCO.2007.15.2348.
De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer J Int Cancer. 2009;124(7):1626–36. doi:10.1002/ijc.24116.
Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer J Int Cancer. 2009;124(10):2375–83. doi:10.1002/ijc.24215.
Steinau M, Unger ER, Hernandez BY, Goodman MT, Copeland G, Hopenhayn C, et al. Human papillomavirus prevalence in invasive anal cancers in the United States before vaccine introduction. J Lower Genit Tract Dis. 2013;17(4):397–403. doi:10.1097/LGT.0b013e31827ed372.
Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13(5):487–500. doi:10.1016/S1470-2045(12)70080-3.
de Pokomandy A, Rouleau D, Ghattas G, Vezina S, Cote P, Macleod J, et al. Prevalence, clearance, and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis. 2009;199(7):965–73. doi:10.1086/597207.
Conley L, Bush T, Darragh TM, Palefsky JM, Unger ER, Patel P, et al. Factors associated with prevalent abnormal anal cytology in a large cohort of HIV-infected adults in the United States. J Infect Dis. 2010;202(10):1567–76. doi:10.1086/656775.
Critchlow CW, Hawes SE, Kuypers JM, Goldbaum GM, Holmes KK, Surawicz CM, et al. Effect of HIV infection on the natural history of anal human papillomavirus infection. AIDS. 1998;12(10):1177–84.
Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. Aids. 2005;19(13):1407–14.
Clifford GM, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst. 2005;97(6):425–32. doi:10.1093/jnci/dji072.
Palefsky JM, Holly EA, Ralston ML, Da Costa M, Bonner H, Jay N, et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr. 2001;28(5):422–8.
Piketty C, Darragh TM, Heard I, Da Costa M, Bruneval P, Kazatchkine MD, et al. High prevalence of anal squamous intraepithelial lesions in HIV-positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis. 2004;31(2):96–9. doi:10.1097/01.OLQ.0000109515.75864.2B.
Centers for Disease C, Prevention. Human papillomavirus-associated cancers—United States, 2004–2008. MMWR Morb Mortal Wkly Rep. 2012;61:258–61.
Wentzensen N, Follansbee S, Borgonovo S, Tokugawa D, Sahasrabuddhe VV, Chen J, et al. Analytic and clinical performance of cobas HPV testing in anal specimens from HIV-positive men who have sex with men. J Clin Microbiol. 2014;52(8):2892–7. doi:10.1128/jcm.03517-13.
Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis : Off Public Infect Dis Soc Am. 2006;43(2):223–33. doi:10.1086/505219.
Wentzensen N. Screening for anal cancer: endpoints needed. Lancet Oncol. 2012;13(5):438–40. doi:10.1016/S1470-2045(12)70101-8.
Ong JJ, Temple-Smith M, Chen M, Walker S, Grulich A, Hoy J, et al. Why are we not screening for anal cancer routinely—HIV physicians’ perspectives on anal cancer and its screening in HIV-positive men who have sex with men: a qualitative study. BMC Public Health. 2015;15:67. doi:10.1186/s12889-015-1430-1. This small Australian study described interviews from 20 HIV physicians and assessed attitudes toward anal cancer screening. Multiple barriers to screening were noted, and the providers were found to be ambivalent toward anal cancer screening. More research is clearly needed in this field.
Kim JJ. Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis. Lancet Infect Dis. 2010;10(12):845–52. doi:10.1016/s1473-3099(10)70219-x.
Lazenby GB, Unal ER, Andrews AL, Simpson K. A cost-effectiveness analysis of anal cancer screening in HIV-positive women. J Lower Genit Tract Dis. 2012;16(3):275–80. doi:10.1097/LGT.0b013e31823cde2f.
Lam JM, Hoch JS, Tinmouth J, Sano M, Raboud J, Salit IE. Cost-effectiveness of screening for anal precancers in HIV-positive men. AIDS. 2011;25(5):635–42. doi:10.1097/QAD.0b013e3283434594.
Palefsky JM, Giuliano AR, Goldstone S, Moreira Jr ED, Aranda C, Jessen H, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011;365(17):1576–85. doi:10.1056/NEJMoa1010971.
Kojic EM, Kang M, Cespedes MS, Umbleja T, Godfrey C, Allen RT, et al. Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women. Clin Infect Dis. 2014;59(1):127–35. doi:10.1093/cid/ciu238.
Wilkin T, Lee JY, Lensing SY, Stier EA, Goldstone SE, Berry JM, et al. Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men. J Infect Dis. 2010;202(8):1246–53. doi:10.1086/656320.
Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34(6):831–7. doi:10.1086/339042.
Backus LI, Boothroyd D, Deyton LR. HIV, hepatitis C and HIV/hepatitis C virus co-infection in vulnerable populations. AIDS. 2005;19 Suppl 3:S13–9.
Kellerman SE, Hanson DL, McNaghten AD, Fleming PL. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human immunodeficiency virus-infected subjects. J Infect Dis. 2003;188(4):571–7. doi:10.1086/377135.
Puoti M, Spinetti A, Ghezzi A, Donato F, Zaltron S, Putzolu V, et al. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr. 2000;24(3):211–7.
Salmon-Ceron D, Rosenthal E, Lewden C, Bouteloup V, May T, Burty C, et al. Emerging role of hepatocellular carcinoma among liver-related causes of deaths in HIV-infected patients: the French national Mortalité 2005 study. J Hepatol. 2009;50(4):736–45. doi:10.1016/j.jhep.2008.11.018.
Smith C, Sabin CA, Lundgren JD, Thiebaut R, Weber R, Law M, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D study. AIDS. 2010;24(10):1537–48. doi:10.1097/QAD.0b013e32833a0918.
Spaulding AC, Sharma A, Messina LC, Zlotorzynska M, Miller L, Binswanger IA. A comparison of liver disease mortality with HIV and overdose mortality among Georgia prisoners and releasees: a 2-decade cohort study of prisoners incarcerated in 1991. Am J Public Health. 2015;105(5):e51–7. doi:10.2105/AJPH.2014.302546.
Grint D, Peters L, Rockstroh JK, Rakmanova A, Trofimova T, Lacombe K, et al. Liver-related death among HIV/hepatitis C virus-co-infected individuals: implications for the era of directly acting antivirals. AIDS. 2015. doi:10.1097/QAD.0000000000000674. This retrospective study from the EuroSIDA cohort found that liver-related deaths accounted for nearly 22% of all deaths in the HIV/HCV co-infected population. Risk factors for liver-related deaths included advanced fibrosis (≥ F2) and low CD4 count. The authors suggested that directly acting antivirals for HCV treatment should be prioritized for all patients with ≥ F2 fibrosis.
Simonetti RG, Cammà C, Fiorello F, Politi F, D’Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 1991;36(7):962–72.
Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol. 2014;61(1 Suppl):S79–90. doi:10.1016/j.jhep.2014.07.010.
Clifford GM, Rickenbach M, Polesel J, Dal Maso L, Steffen I, Ledergerber B, et al. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS. 2008;22(16):2135–41. doi:10.1097/QAD.0b013e32831103ad.
Yanik EL, Napravnik S, Cole SR, Achenbach CJ, Gopal S, Dittmer DP, et al. Relationship of immunologic response to antiretroviral therapy with non-AIDS defining cancer incidence. AIDS. 2014;28(7):979–87. doi:10.1097/QAD.0000000000000167.
Kramer JR, Giordano TP, Souchek J, Richardson P, Hwang LY, El-Serag HB. The effect of HIV coinfection on the risk of cirrhosis and hepatocellular carcinoma in U.S. veterans with hepatitis C. Am J Gastroenterol. 2005;100(1):56–63. doi:10.1111/j.1572-0241.2005.40670.x.
García-García JA, Romero-Gómez M, Girón-González JA, Rivera-Irigoin R, Torre-Cisneros J, Montero JL, et al. Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis. AIDS Res Hum Retrovirus. 2006;22(12):1236–41. doi:10.1089/aid.2006.22.1236.
Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992–2001. Arch Intern Med. 2004;164(21):2349–54. doi:10.1001/archinte.164.21.2349.
García-Samaniego J, Rodríguez M, Berenguer J, Rodríguez-Rosado R, Carbó J, Asensi V, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96(1):179–83. doi:10.1111/j.1572-0241.2001.03374.x.
Bräu N, Fox RK, Xiao P, Marks K, Naqvi Z, Taylor LE, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol. 2007;47(4):527–37. doi:10.1016/j.jhep.2007.06.010.
Bourcier V, Winnock M, Ait Ahmed M, Sogni P, Pambrun E, Poizot-Martin I, et al. Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir). Clin Res Hepatol Gastroenterol. 2012;36(3):214–21. doi:10.1016/j.clinre.2011.11.002.
Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS. 2004;18(17):2285–93.
Soto B, Sánchez-Quijano A, Rodrigo L, del Olmo JA, García-Bengoechea M, Hernández-Quero J, et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol. 1997;26(1):1–5.
Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Multivirc Group Hepatol. 1999;30(4):1054–8. doi:10.1002/hep.510300409.
Bonnard P, Lescure FX, Amiel C, Guiard-Schmid JB, Callard P, Gharakhanian S, et al. Documented rapid course of hepatic fibrosis between two biopsies in patients coinfected by HIV and HCV despite high CD4 cell count. J Viral Hepat. 2007;14(11):806–11. doi:10.1111/j.1365-2893.2007.00874.x.
Sulkowski MS, Mehta SH, Torbenson MS, Higgins Y, Brinkley SC, de Oca RM, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS. 2007;21(16):2209–16. doi:10.1097/QAD.0b013e3282f10de9.
Martín-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study. Clin Infect Dis. 2004;38(1):128–33. doi:10.1086/380130.
Puoti M, Bonacini M, Spinetti A, Putzolu V, Govindarajan S, Zaltron S, et al. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183(1):134–7. doi:10.1086/317644.
Boyd A, Lasnier E, Molina JM, Lascoux-Combe C, Bonnard P, Miailhes P, et al. Liver fibrosis changes in HIV-HBV-coinfected patients: clinical, biochemical and histological effect of long-term tenofovir disoproxil fumarate use. Antivir Ther. 2010;15(7):963–74. doi:10.3851/IMP1649.
Piroth L, Pol S, Miailhes P, Lacombe K, Lopes A, Fillion A, et al. Therapeutic management and evolution of chronic hepatitis B: does HIV still have an impact? The EPIB 2012 study. Liver Int. 2015. doi:10.1111/liv.12777.
Puoti M, Cozzi-Lepri A, Paraninfo G, Arici C, Moller NF, Lundgren JD, et al. Impact of lamivudine on the risk of liver-related death in 2,041 HBsAg- and HIV-positive individuals: results from an inter-cohort analysis. Antivir Ther. 2006;11(5):567–74.
Bruyand M, Dabis F, Vandenhende MA, Lazaro E, Neau D, Leleux O, et al. HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998–2008. J Hepatol. 2011;55(5):1058–62. doi:10.1016/j.jhep.2011.02.017.
van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584–93. doi:10.1001/jama.2012.144878.
Berenguer J, Alvarez-Pellicer J, Martin PM, Lopez-Aldeguer J, Von-Wichmann MA, Quereda C, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology. 2009;50(2):407–13. doi:10.1002/hep.23020.
Limketkai BN, Mehta SH, Sutcliffe CG, Higgins YM, Torbenson MS, Brinkley SC, et al. Relationship of liver disease stage and antiviral therapy with liver-related events and death in adults coinfected with HIV/HCV. JAMA. 2012;308(4):370–8. doi:10.1001/jama.2012.7844.
Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013;31(29):3647–55. doi:10.1200/JCO.2012.48.5896.
Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138(4):299–306.
Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, et al. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44(6):1543–54. doi:10.1002/hep.21415.
Giordano TP, Henderson L, Landgren O, Chiao EY, Kramer JR, El-Serag H, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297(18):2010–7. doi:10.1001/jama.297.18.2010.
Omland LH, Farkas DK, Jepsen P, Obel N, Pedersen L. Hepatitis C virus infection and risk of cancer: a population-based cohort study. Clin Epidemiol. 2010;2:179–86.
Nyberg AH, Chung JW, Shi JM, Cheetham TC, Chiang KM, Haque R et al. Increased cancer rates in patients with chronic hepatitis C: an analysis of the cancer registry in a large U.S. health maintenance organization. 50th Annual Meeting of the European Association for the Study of the Liver; Vienna, Austria. 2015.
Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753–62. doi:10.1093/jnci/djr076.
Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728–36.
Shiels MS, Koritzinsky EH, Clarke CA, Suneja G, Morton LM, Engels EA. Prevalence of HIV infection among U.S. Hodgkin lymphoma cases. Cancer Epidemiol Biomarkers Prev. 2014;23(2):274–81. doi:10.1158/1055-9965.EPI-13-0865. This SEER-based study found nearly 4% of US Hodgkin lymphoma cases were in HIV-infected individuals, a disproportionate number based on the US HIV prevalence (<1%). Additionally, the 5-year mortality in HIV-infected Hodgkin lymphoma cases was twice that of HIV-uninfected cases (37% vs. 18%).
Goedert JJ, Bower M. Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection. Curr Opin Oncol. 2012;24(5):531–6. doi:10.1097/CCO.0b013e3283560697.
Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Ann Intern Med. 2010;153(7):452–60. doi:10.1059/0003-4819-153-7-201010050-00008.
Lanoy E, Rosenberg PS, Fily F, Lascaux AS, Martinez V, Partisani M, et al. HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy. Blood. 2011;118(1):44–9. doi:10.1182/blood-2011-02-339275.
Yanik EL, Napravnik S, Cole SR, Achenbach CJ, Gopal S, Olshan A, et al. Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. Clin Infect Dis. 2013;57(5):756–64. doi:10.1093/cid/cit369.
Gopal S, Patel MR, Achenbach CJ, Yanik EL, Cole SR, Napravnik S, et al. Lymphoma immune reconstitution inflammatory syndrome in the center for AIDS research network of integrated clinical systems cohort. Clin Infect Dis. 2014;59(2):279–86. doi:10.1093/cid/ciu270. This study integrating multiple US cohorts examined the timing of lymphoma diagnosis after ART initiation. 15% of Hodgkin cases met the definition for unmasking immune reconstitution inflammatory syndrome, signifying the importance of CD4 cells in the pathogenesis of the disease.
Carbone A, Gloghini A, Larocca LM, Antinori A, Falini B, Tirelli U, et al. Human immunodeficiency virus-associated Hodgkin’s disease derives from post-germinal center B cells. Blood. 1999;93(7):2319–26.
Thompson LD, Fisher SI, Chu WS, Nelson A, Abbondanzo SL. HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol. 2004;121(5):727–38. doi:10.1309/PNVQ-0PQG-XHVY-6L7G.
Carbone A, Gloghini A, Serraino D, Spina M. HIV-associated Hodgkin lymphoma. Curr Opin HIV AIDS. 2009;4(1):3–10. doi:10.1097/COH.0b013e32831a722b.
Engels EA. Non-AIDS-defining malignancies in HIV-infected persons: etiologic puzzles, epidemiologic perils, prevention opportunities. AIDS. 2009;23(8):875–85. doi:10.1097/QAD.0b013e328329216a.
Dunleavy K, Wilson WH. How I treat HIV-associated lymphoma. Blood. 2012;119(14):3245–55. doi:10.1182/blood-2011-08-373738.
Tedeschi R, Bortolin MT, Bidoli E, Zanussi S, Pratesi C, Vaccher E, et al. Assessment of immunovirological features in HIV related non-Hodgkin lymphoma patients and their impact on outcome. J Clin Virol. 2012;53(4):297–301. doi:10.1016/j.jcv.2011.12.021.
Carbone A, Vaccher E, Gloghini A, Pantanowitz L, Abayomi A, de Paoli P, et al. Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat Rev Clin Oncol. 2014;11(4):223–38. doi:10.1038/nrclinonc.2014.31. This in-depth review article discusses the association of viruses with HIV-related lymphomas along with the pathogenesis, molecular genetics, and virology.
Bohlius J, Schmidlin K, Boue F, Fatkenheuer G, May M, Caro-Murillo AM, et al. HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral therapy: incidence and evolution of CD4+ T-cell lymphocytes. Blood. 2011;117(23):6100–8. doi:10.1182/blood-2010-08-301531.
Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108(12):3786–91. doi:10.1182/blood-2006-05-024109.
Gloghini A, Carbone A. Why would the incidence of HIV-associated Hodgkin lymphoma increase in the setting of improved immunity? Int J Cancer. 2007;120(12):2753–4. doi:10.1002/ijc.22650.
Clifford GM, Rickenbach M, Lise M, Dal Maso L, Battegay M, Bohlius J, et al. Hodgkin lymphoma in the Swiss HIV Cohort Study. Blood. 2009;113(23):5737–42. doi:10.1182/blood-2009-02-204172.
Clifford G, Franceschi S, Rickenbach M. Lymphocyte counts prior to Hodgkin lymphoma development response. Blood. 2009;114(11):2354–5. doi:10.1182/blood-2009-06-227264.
Hoffmann C, Hentrich M, Gillor D, Behrens G, Jensen B, Stoehr A, et al. Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study. HIV Med. 2015;16(4):261–4. doi:10.1111/hiv.12200.
Acknowledgments
Anne F. Rositch was supported, in part, through a 2015 developmental grant from the Johns Hopkins University Center for AIDS Research, an NIH-funded program (P30AI094189).
Compliance with Ethics Guidelines
ᅟ
Conflict of Interest
The authors declare that they have no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Co-infections and Comorbidity
Rights and permissions
About this article
Cite this article
Riedel, D.J., Tang, L.S. & Rositch, A.F. The Role of Viral Co-Infection in HIV-Associated Non-AIDS-Related Cancers. Curr HIV/AIDS Rep 12, 362–372 (2015). https://doi.org/10.1007/s11904-015-0276-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11904-015-0276-6