HIV treatment decreases cancer but still elevated risk


A large VA study found that overall cancer risk decreased with improved HIV viral suppression, but an increased residual risk remained (see hiv cancer dec still elevated AIM2018 in dropbox, or doi:10.7326/M16-2094

Details:
--42,441 HIV-positive veterans were compared to 104,712 demographically matched uninfected veterans, from 1999-2015
-- 64% were 40-60 years old, 98% male, 40% non-Hispanic white/50% non-Hispanic black/9% Hispanic, 67% ever-smokers/27% never-smokers, 35% alcohol use disorder, 63% HCV negative/ 15% chronic HCV, 75% diabetes
-- comparing the groups: similar distribution of age, sex, race/ethnicity, smoking status, alcohol use. Those with HIV had more chronic hepatitis C and a lower prevalence of diabetes
-- HIV control: 22% unsuppressed (suppression defined as < 500 copies/mL), 27% early suppression (initial period up to 2 years of continuous suppressed observation time, but also includes those who were suppressed but then became unsuppressed), 37% long-term suppression (continued suppression after 2 years)
    -- 62% achieved long-term viral suppression at some point during follow-up (median duration 3 years)
-- HIV-positive: 3821 developed 4169 cases of cancer: 616 were AIDS defining cancers (ADC), 817 virus derived non-AIDS defining cancers (NADC), 2683 non-virus-related NADC
-- HIV-negative: 7163 developed 7879 cancers: 223 ADC, 715 virus NADC, 6850 non-virus NADC
-- median follow-up 7.8 years for HIV-positive than 10.1 years for uninfected

Results:
-- overall cancer incidence for HIV-positive (HIV negative veterans had 742 cases per 100,000/person-yrs):
    --in those with persistent HIV virus: RR= 2.35 (2.19-2.51), 1748 cases/ 100,000 person-yrs
    --in those with early suppressed HIV virus: RR= 1.99 (1.87-2.12), 1475 cases/ 100,000 person-yrs
    --in those with long-term suppressed HIV virus: RR= 1.52 (1.44-1.61), 1155 cases/100,000 person-yrs
-- for AIDS defining cancers (vs 22 cases/ 100,000 person-yrs in HIV negative veterans):
    --in those with persistent HIV virus: RR= 22.73 (19.01-27.19), 474 cases/ 100,000 person-yrs
    --in those with early suppressed HIV virus: RR= 9.48 (7.78 –11.55), to 11 cases/ 100,000 person-yrs
    --in those with long-term suppressed HIV virus: RR= 2.22 (1.69 -2.93), 56 cases/ 100,000 person-yrs
    -- the main ADCs for all groups were non-Hodgkin lymphoma and Kaposi sarcoma
-- for non-AIDS defining cancers (vs 653 cases/100,000 person-yrs in HIV negative veterans):
    --in those with persistent HIV virus: RR= 3.82 (3.24-4.49), 989 cases/ 100,000 person-yrs
    --in those with early suppressed HIV virus: RR= 3.42 (2.95-3.97), 980 cases/100,000 person-yrs
    --in those with long-term suppressed HIV virus: RR= 3.17 (2.78-3.62), 863 cases/100,000 person-yrs
    -- the only cancer exhibiting a significant decreasing trend was renal squamous cell carcinoma, though the relative risk still remain markedly elevated even with long-term suppression, RR 34.70
    -- there was no relationship between HIV control and NADC which were not related to viruses.
        -- But, there was a significant trend to decreasing cancers in non-virus NADC with increasing HIV control in those with lung cancer, larynx cancer, melanoma of the skin, and leukemia (the latter 3 had no increased risk over the HIV-uninfected group). There was a negative correlation however with prostate cancer
-- sensitivity analysis showed no outcome difference with a HIV viral suppression threshold of <50 vs < 500 copies/mL

Commentary:
-- long-term viral suppression was associated with >90% reduction in excess risk of AIDS defining cancers but only a 23% reduction for virus associated non-AIDS defining cancers.
    --Though there was no association between HIV control and non-virus associated NADC, some specific cancers (lung, larynx, melanoma, leukemia) decreased with better HIV control
    --Unfortunately, NADC cancers overall are by far the most common ones
-- however, there is a persistent excess cancer risk even with long-term viral suppression.  Though, from this study one cannot ascertain the cancer risk in patients who were truly HIV virally-suppressed for decades
-- The SMART trial also found that continuous antiretroviral treatment (vs treatment interruption) was associated with a significant decrease in ADC but not in NADC, though small numbers or cancers in this study: 8 Kaposi sarcoma with HR 7.0, which had p=0.07, and 5 lymphoma which did not reach statistical significance (however, these numbers compared HIV patients on continuous vs intermittent HIV therapy and not with HIV-uninfected controls, see Silverberg MJ. AIDS. 2007; 21: 1957.)
-- unclear why the risk of prostate cancer seems to be increased with better viral suppression. May be related to more screening for those who are doing better, with pick up of more asymptomatic prostate cancer cases.
-- Some limitations of this long-term study (which had 16 years of follow-up) include changing definitions of HIV suppression, the very few women in the study (though there was one case of invasive cervical cancer), and potential changes in viral suppression not found in the intermittent screenings done and leading to misclassification of suppression status
-- There does seem to be some residual immune dysfunction even in patients who have long-term suppressed HIV viral loads. For example, there are studies documenting “accelerated aging” (increased frailty in the elderly, cardiovascular disease, osteoporosis), felt to be related to chronic inflammation, immune senescence, and immune activation in patients. This has been referred to as the residual immune dysregulation syndrome (RIDS), more common but not exclusively in those who failed to achieve normal CD4 counts with viral suppression. For example, those with persistently low CD4 counts despite ART-associated viral suppression have an increased risk for the combined non-AIDS morbidity and mortality, including cancers. Especially in those with higher IL-6 and CRP levels as well as D-dimer (see doi.org/10.1016/B978-0-12-407707-2.00002-3). For example, several non-AIDS defining cancers, such as lung, liver, kidney, anus, head and neck, skin, and Hodgkin’s lymphoma seem to be increased even after controlling for the known cancer risk factors. (see Deeken JF. Clin Inf Dis 2012; 55(9):1228)

So, the effect of viral suppression with antiretroviral therapy has been dramatic: HIV is now relegated to the list of chronic diseases requiring long-term therapy, a huge change from its prior reality of being a death sentence. However, this study does suggest that we clinicians (and patients) should still have a heightened awareness of persistent increased cancer risk…  and, I would add, persistent increased cardiovascular risk that perhaps should lead to more aggressive attempts to control those risk factors.

geoff​

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