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Low CD4 Measures Predict Virus-Related Cancers in HIV-Negative Gay/Bisexual Men
 
 
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The HIV-negative MSM were from the MACS. Low CD4 counts in these men could not be attributed to specific medical conditions or to use of immunosuppressive drugs. But a subset of participants with low CD4 counts had lab findings indicating advanced liver disease. Dana Gabuzda and colleagues think it makes sense to screen otherwise healthy MSM with past or current HBV infection and low CD4 measures for treatable cancer-causing viral infections or precancerous lesions.
 
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[this study below finds recent trends in T-Cell subsets over last 6-10 years may predict cancer onset, and over lifetime low CD4s, low CD4 nadir, and low differential between CD4 nadir and current CD4 predict cancers in HIV- in MACS, the study also looks at platelet counts & White Blood Cell counts and liver fibrosis suggesting low CD4 or low CD4 nadr may be associated with developing liver cancer and that having HBV was associated. Suggesting to pay attention to recent trends in T cells. Jules
 
from Jules: cancers are among many comorbidities disproportionately occurring in HIV+ aging individuals: Cancer risk among the HIV-infected elderly in the United States 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......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).....Total cancer burden was high among the HIV-infected U.S. elderly, with one out of 10 people getting cancer over 5 years.....excess cancer risk remained among patients with long-term suppression.......the RR remained elevated in persons with long-term suppression....."Among HIV-infected men, 11.5% (95%CI = 9.6-13.3%) were diagnosed with cancer over 5 years, whereas 6.7% (95%CI = 4.7-8.6%) of HIV-infected women were diagnosed with cancer over 5 years (Fig. 1). The most frequent cancers among men were prostate cancer (5-year cumulative incidence = 2.7%), lung cancer (2.4%), NHL (0.9%), colorectal cancer (0.9%), and anal cancer (0.8%). Among women, the most frequent cancers were lung cancer (5-year cumulative incidence = 1.6%), colorectal cancer (1.0%), breast cancer (1.0%), NHL (0.4%), and pancreatic cancer (0.3%)......The most frequently diagnosed cancers were those associated with aging: lung, prostate, colorectal, and breast cancers, and NHL. Lung cancer and NHL risks are likely impacted by both HIV and age-related processes [13-16]. Lung cancer was the most common cancer, and it is a common cause of death in HIV-infected people [17,18]. These observations point to the potential importance of smoking cessation. Given the high incidence of lung cancer overall, current smokers in the elderly HIV population might particularly benefit from lung cancer screening with low-dose computed tomography [19]."
 
"Regarding the question of 'when to begin HAART', risk for non-AIDS cancers are 2-fold higher (100% higher) when CD4s are below 700 and 3.7 fold higher when CD4 is 200-349 in the pre-HAART era in this study and also 2-fold higher for AIDS-defining risk when CD4s are <500 in the pre-HAART era (see tables 5a and 5d)."]
 
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Low CD4 Measures Predict Virus-Related Cancers in HIV-Negative Gay/Bisexual Men
 
Summary by Mark Mascolini
 
Low recent CD4 count, CD4 nadir, and CD4/CD8 ratio nadir predicted subsequent diagnosis of virus-related cancer in HIV-negative men who have sex with men (MSM) [1]. This case-control study involving MSM in the US Multicenter AIDS Cohort Study (MACS) found that men in whom cancer developed had a lower CD4 count and white blood cell (WBC) count in the 6 years before cancer diagnosis. Dana Farber Cancer Institute researchers tied markers of advanced liver disease to low CD4 measures.
 
Together, these findings underscore the importance of CD4 T cells in natural immune protection against viral cancers in healthy HIV-seronegative people.
 
Low CD4:CD8 ratios correlate with immune activation in virally suppressed HIV-infected individuals, and have prognostic significance for AIDS-related morbidity including some viral cancers. Heavy smoking was associated with a three to fourfold increased risk of virus-associated cancers. Our data suggest these prognostic markers have predictive value for risk of virus-associated cancers over a 6- to 8-year window prior to diagnosis; a subset of cases had chronically low CD4 and/or low CD8 counts as long as 10 years or longer prior to diagnosis. In cohort, the percentage of cases positive for anti-HBc among those with CD4 nadir < 500 cells/μl was higher than that of cases with CD4 nadir ≥ 500 cells/μl (73.3% vs. 47.1%), raising the possibility that prior HBV infection may impact immune functions that protect against some non-hepatic viral cancer.
 
In summary, our study shows that HIV-seronegative MSM with low nadir CD4 counts or low CD4:CD8 ratio nadirs have elevated risk of developing virus-associated cancers within a 6-year time window. Furthermore, our studies suggest that past or current HBV infection coupled with low CD4 count or nadir or low CD4:CD8 ratio is a profile associated with increased risk of developing virus-associated cancers in otherwise healthy HIV-seronegative men. Such individuals might be candidates to screen for treatable oncogenic viral infections or pre-malignant lesions to reduce their cancer risk.
 
Background
 
⋅ Viruses can contribute to development of genital, anal, oral, and liver cancer, as well as to Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), and Kaposi sarcoma.
⋅ Discerning the impact of viruses on cancer development remains difficult because so many factors may contribute to cancer.
⋅ Viral cancers occur more often in individuals with a weakened immune system, including people with HIV and transplant patients.
⋅ Immunologic variables associated with cancers in the general population are unclear.
 
Study objective
 
⋅ Researchers from the Dana Farber Cancer Institute conducted a longitudinal study of HIV-negative MSM in the MACS to assess immunologic predictors of virus-associated cancers.
 
Methods
 
⋅ The study involved HIV-negative cancer-free MSM enrolled in the MACS in 1984-2010. The MACS is a longitudinal US study of HIV-positive MSM and HIV-negative MSM at risk for HIV infection [2].
⋅ MACS database analysis identified 32 incident (newly diagnosed) virus-related cancers in 3408 HIV-negative MSM.
⋅ Researchers matched each of these 32 cases by age, race, smoking, and calendar period to 20 HIV-negative MACS MSM without a cancer diagnosis.
⋅ For each study participant the researchers determined clinical and immunologic cancer risk factors up to 1 year before the last follow-up visit, including CD4 and CD8 count, CD4/CD8 ratio, WBC, Fibrosis-4 (FIB-4) score, liver enzymes, and platelet count.
⋅ Mixed-effects and Cox regression models assessed associations between immunologic parameters (CD4 count and so on) and subsequent diagnosis of virus-associated cancers.
 
Key Findings
 
⋅ The 32 cancer case patients were significantly older than the 500 no-cancer controls at the first study visit (median 42 versus 35 years, P < 0.001) and had fewer years of follow-up (median 15 versus 22, P = 0.003).
⋅ Compared with the 500 no-cancer controls, the 32 cancer case patients had a lower nadir CD4 count (median 512 versus 620, P = 0.007), a lower nadir CD4/CD8 ratio (0.92 versus 1.2, P = 0.001), a higher proportion with a CD4 nadir below 500 (46.9% versus 27.4%, P = 0.03), and a higher proportion with a nadir CD4/CD8 ratio below 1.0 (56.2% versus 29.2%, P = 0.003).
⋅ Hepatitis B infection was significantly more prevalent in cases than controls (21.9% versus 3.0%, P < 0.001).
⋅ Cases did not differ significantly from controls in race, smoking, calendar period, HCV infection, or number of sex partners or sexually transmitted infections (STIs).
The most frequently diagnosed cancers were 9 anal cancers, 9 NHLs, and 6 liver cancers.
⋅ All participants with liver cancer had evidence of past or current HBV or HCV infection.
⋅ A FIB-4 score above 1.45, a common fibrosis marker, occurred nearly twice as often in MSM with a nadir CD4 count below 500 as in those with a higher CD4 nadir. ⋅ Mixed-effects models adjusted for age, race, heavy smoking, and FIB-4 above 1.45 linked lower CD4 count (P = 0.001) and lower WBC (P = 0.03) within a 6-year window to subsequent diagnosis of virus-associated cancer.
⋅ Cox regression models adjusted for age, race, and heavy smoking identified several independent associations between immunologic measures and incident virus-associated cancer:
o Lower CD4 nadir: adjusted hazard ratio (aHR) 1.31 per 100-cell lower, 95% confidence interval (CI) 1.13 to 1.51, P < 0.001
o Difference between current and nadir CD4 count: aHR 1.27 per 100-cell lower, 95% CI 1.09 to 1.48, P= 0.002
° Lower recent CD4 count: aHR 1.17 per 100-cell lower, 95% CI 1.03 to 1.33, P = 0.014
° Lower CD4/CD8 ratio nadir: aHR 1.18 per 0.1-unit lower, 95% CI 1.06 to 1.31, P = 0.002
⋅ Heavy smoking was associated with 3- to 4-fold higher risk of incident virus-associated cancer in Cox regression models.
⋅ Low CD4 counts in the MSM studied could not be attributed to specific medical conditions or to use of immunosuppressive drugs. But a subset of participants with low CD4 counts had lab findings indicating advanced liver disease.
 
Conclusions

 
⋅ In HIV-negative US MSM at risk for HIV infection, lower CD4-cell measures predicted risk of subsequent virus-associated cancers, including anal cancer, NHL, and liver cancer.
⋅ Low CD4 parameters may have predictive value 6 to 8 years before cancer diagnosis.
 
Implications and Remaining Questions
 
⋅ "These findings underscore the importance of CD4 T cells in natural immune protection against viral cancers in healthy HIV-seronegative people."
⋅ In some participants lab evidence of advanced liver disease, a condition previously linked to low T-cell counts, suggests liver disease could be one factor involved in decreasing natural immune protection against virus-associated cancers.
⋅ "The impact of past or current HBV infection on risk of non-hepatic viral cancers is an open question that warrants further study."
MSM typically have higher prevalence of certain cancer risk factors than the general population, including smoking, HBV/HCV infection, compromised liver function, and STIs. As a result, the findings of this study may not apply to the general population.
⋅ Otherwise healthy MSM with past or current HBV infection and low CD4 measures may be candidates to screen for treatable cancer-causing viral infections or precancerous lesions.
 
References
1. Dutta A, Uno H, Lorenz DR, Wolinsky SM, Gabuzda D. Low T-cell subsets prior to development of virus-associated cancer in HIV-seronegative men who have sex with men. Cancer Causes Control. 2018 Oct 12. doi 10.1007/s10552-018-1090-4. Epub ahead of print. Complete article available at https://link.springer.com/article/10.1007%2Fs10552-018-1090-4
 
2. The Multicenter AIDS Cohort Study (MACS) is a 30-year study of HIV-1 infection in gay and bisexual men. http://aidscohortstudy.org/
 
The study population of 32 virus-associated cancer cases and 500 matched controls had a median (IQR) age and follow-up of 35 (30-42) and 21 (8-26) years, respectively (Table 1). The majority of incident cancers were anal cancers and NHL (n = 9 cases each) followed by liver cancer (n = 6 cases), while incident HL, HNSCC, and KS accounted for three cases or less (Supplemental Material 2). Virus-associated cancers comprised the first diagnosis among two of four subjects with multiple cancer diagnoses (Supplemental Material 3); in the remaining two cases, virus-associated cancers were the second primary malignancy, diagnosed 17 and 2 years after previous diagnoses of thyroid cancer and prostate cancer, respectively. Compared to controls, virus-associated cancer cases were slightly older at entry, with shorter follow-up and higher percentage with HBV infection (p ≤ 0.003). Cases were similar to controls with regard to race, smoking, calendar period, HCV infection, number of sexual partners, and sexually transmitted infections (Table 1). Cases had a non-significant trend toward lower median CD4 cell counts compared to controls (858 vs. 947 cells/μl, respectively; p = 0.15), while CD4 nadir was significantly lower (512 vs. 620 cells/μl; p = 0.007) and percentage with CD4 nadir < 500 cells/μl was higher (46.9% vs. 27.4%; p = 0.03). There was a trend toward lower median CD4:CD8 ratio nadir in cases compared to controls (1.62 vs. 1.85, respectively; p = 0.08), while the percentage with CD4:CD8 ratio nadir < 1 was higher (56.2% vs. 29.2%; p = 0.003). Median time from CD4, CD4:CD8, CD8, and WBC nadir to cancer diagnosis ranged from 7.25 to 9.75 years.
 
To examine the prognostic value of CD4 and CD8 T-cell parameters relative to incident virus-associated cancers, Cox regression models were fit to CD4 cell count, CD4 cell count-nadir differential, and CD4:CD8 ratio and nadir with adjustments for age (as the time scale), race, and heavy smoking (Table 3). Lower CD4 cell count nadir showed a strong association with risk of incident virus-associated cancers (adjusted HRs/100 cells/μl decrease [95% CI] 1.31 [1.13, 1.51]; p < 0.001). Current CD4 cell count-nadir differential was a better predictor of incident virus-associated cancers (adjusted HRs/100 cells/μl decrease and 95% CI 1.27 [1.09, 1.48], p = 0.002) than recent CD4 count (adjusted HRs/100 cells/μl decrease [95% CI] 1.17 [1.03-1.33]; p = 0.014). Current CD4:CD8 ratios were not associated with increased risk of virus-associated cancers (p = 0.179); however, nadir CD4:CD8 ratio was associated with a three to fourfold increased risk of virus-associated cancers (adjusted HRs, 0.1 unit decrease and 95% CI 1.18 [1.06, 1.31]; p = 0.002). Heavy smoking was associated with a three to fourfold increased risk of virus-associated cancers, while race had no significant associations in these models (Table 3).
 
Low CD4 cell counts could not be attributed to specific medical conditions, nor use of immunosuppressive drugs, in most virus-associated cancer cases in the study cohort. Twenty-nine subjects (4 cases and 25 controls) met criteria for idiopathic CD4 lymphopenia, defined by CD4 cell count < 300 for at least one visit. One liver cancer case was lymphophenic at multiple visits, with CD4 and CD8 cell counts < 300 and 100, respectively (Fig. 1, left panels); these observations together with our finding that FIB-4 > 1.45 is more frequent among subjects with CD4 nadir < 500compared to those with CD4 nadir ≥ 500 are consistent with other studies linking lymphopenias with advanced liver disease [16, 18]. Lower platelet counts in groups with CD4 nadir < 500 may also reflect liver disease in some subjects. Antibiotic use was more frequent among cases and controls with CD4 nadir < 500 compared to subjects that maintained CD4 nadir ≥ 500. The significance of this finding remains unclear, but it could reflect increased susceptibility to bacterial infections in the setting of low CD4 counts or microbiome changes that influence immune function [24, 26, 29].
 
Distinct immunological profiles and trends were observed for subjects that developed NHL compared to those that developed solid-tissue cancers (Fig. 3), which may reflect differences in the natural history of EBV infection and EBV-related cancer compared to other oncogenic virus infections. Greater than 90% of the general population is exposed to EBV infection by their mid-twenties [4]; in addition to immunosuppression, host co-factors, oncogenic hits, and virus re-activation from latency play a role in development of EBV-related cancers [2]. The relative increase in mean CD4 and CD8 T-cell count trajectories prior to diagnosis in NHL cases compared to controls (Fig. 3) may reflect lymphocytosis driven by EBV-induced B-cell proliferation [30]. However, previous studies suggest that B-cell activation markers (e.g., sCD27, sCD30) and immunodeficiency markers (e.g., low CD4 and low CD4:CD8 ratio) represent different classes of early detection markers, linked to NHL through distinct mechanisms [8, 31].
 
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