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CROI 2016
Co-morbidities in HIV: Stroke, Cancer, Liver Disease
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David H Shepp, MD
Associate Professor of Medicine
Hofstra-Northwell School of Medicine
Manhasset, NY
".....all cancer, including non-AIDS-related types, exceeds cardiovascular and liver disease as a cause of death in most analyses of HIV-related mortality in high-income countries. Rates of many cancers are increased in HIV compared to the HIV-uninfected population.... ART should be initiated as early as possible to suppress viral load, avoid advanced immune deficiency, and reduce systemic inflammation.... abstracts highlight stroke as another very important medical comorbidity in HIV.....traditional risk factors correlate with increased risk, but uncontrolled viral load and low CD4 are also important factors. ART appears to be protective. The excess of strokes in younger HIV-infected women seen in some of these reports is alarming and not adequately explained."
Contemporary antiretroviral therapy (ART) controls HIV replication and improves immune function in most treated patients, conferring freedom from AIDS-related illnesses and greatly improved life expectancy. However, because of aging, a high prevalence of conventional risk factors, and chronic inflammation that persists during otherwise effective ART, chronic co-morbidities including cardiovascular disease, cancer, cirrhosis, osteoporosis, and kidney disease are now common in HIV. Most health care providers working with HIV-infected patients now spend the majority of their time managing these illnesses. At CROI 2016, the increasing dominance of medical comorbidities was highlighted in a study by Buchaz et al (abstract 708). They reported trends in the cause of hospitalization from 1994 to 2014 among 8,368 participants in the HIV Out-Patient Cohort (HOPS). Admissions for AID-related opportunistic illnesses declined from 41% to 6%, while chronic conditions causing organ system dysfunction rose from 4% to 17%. Special sessions at this year's CROI focused on several important comorbid illnesses complicating HIV.
Stroke. Atherosclerotic arterial diseases are increased in patients with HIV infection because of a high prevalence of traditional risk factors such as smoking, diabetes, hypertension, chronic kidney disease and chronic systemic and vascular inflammation. Coronary artery disease in HIV has been studied extensively, but stroke, which also causes major morbidity and mortality, is less well studied. The diagnosis of cerebral infarction is harder to validate than myocardial infarction, which can be diagnosed using well-defined laboratory criteria. Stroke pathogenesis is more diverse, involving ischemia, hemorrhage, thrombosis and embolization. Conditions other than atherosclerosis, including acute infections and substance abuse, more common in HIV, may trigger stroke. Several presentations at CROI 2016 provided valuable information regarding stroke in HIV.
Chow (abstract 43) examined the incidence and risk factors for stroke or transient ischemic attack (TIA) in 6933 participants in the ALLRT cohort, which provides long-term follow-up to ACTG ART trials. The average age of the study cohort was 37 and 20% were women. Active injection drug use was rare (<1%). Stroke/TIA incidence was higher in women (2.88 vs. 1.40/1000 person-years in men) and in non-Hispanic blacks (2.51 vs. 1.56 in white vs. 0.77/1000 person–years in Hispanics). In multivariable Poisson regression analysis using time-varying covariates, HIV RNA >200, hypertension, LDL >160, age (per 10 year increase) and renal dysfunction were associated with elevated relative risk (RR) (3.1, 2.8, 2.5, 2.1, 1.9, respectively). The risk associated with unsuppressed viral load was equivalent to 15 years of aging. After adjustment, female gender had a RR of 1.6 but was no longer significant. Hispanic ethnicity and, paradoxically, obesity were associated with lower risk in this analysis. The reason for latter association was unclear.
A second analysis (Chow, abstract 638) focused on stroke in women. HIV-infected women (n=1212) and HIV-uninfected demographically matched controls (n=12,040) followed by a Boston health care system were compared for ischemic stroke incidence and risk factors. Cases were identified by billing codes. Stroke incidence was increased in HIV-infected women age 18-55 but did not differ greatly in older women. ART was found to be protective with a 13% reduction in stroke hazard for every year of treatment. Cox proportional hazards modeling showed the HIV-infection was associated with a stroke hazard ratio (HR) ranging for 1.9-2.4 depending on components of the model. In these analyses, adjustment was made for age, demographics, traditional and gender specific risk factors such as pregnancy history, menopausal status and hormone use.
Crane et al (abstract 636) analyzed the CNICs cohort (n=16,924) to characterize the features of and risk factors for stroke in HIV. Unlike many other studies that have relied on billing codes to identify cases, in this study all diagnoses were adjudicated by 2 neurologists using record review and standardized case definitions. Data from 212 adjudicated stroke cases were presented; 81% were ischemic, 10% hemorrhagic and 9% were indeterminate. Twenty percent occurred in the context of acute infection and 19% with drug abuse. Because adjudications were ongoing, incidence data was not presented. In a multivariable analysis, age (per year) and HIV RNA (per log) increased stroke risk by 7% and 8% respectively. Smoking, diabetes and black race all were associated with a 2-fold or greater increased risk. Higher CD4 reduced risk by 12% per 100 cells, but the effect of ART exposure was not specifically examined.
Investigators for the D:A:D used their very large (n=43,564) and long-term (339,979 person-years) to determine if risk factors for ischemic and hemorrhagic stoke differed (Hatleberg abstract 637). Using Cox proportional hazards models to adjust for covariates, age, hypertension and CD4<200 were independently associated with both types of stroke. The effect of hypertension was stronger for hemorrhagic stroke. The traditional risk factors smoking, diabetes, dyslipidemia, previous cardiovascular disease, and male gender were significantly associated only with ischemic stroke. Risks associated with exposure to individual antivirals was not examined but there was no difference in exposure ART drug classes. History of injection drug use and AIDS diagnosis were also associated with risk of ischemic stroke.
Berenguer et al (abstract 639) reported trends in stroke incidence for HIV-infected individuals in Spain from 1997 to 2011. Cases were identified from hospitalization records using billing codes. The database captured 98% of admissions to public hospitals. HCV-co-infection was present in 29%. Marked differences in stroke incidence trends were seen when HIV-mono-infected and co-infected were compared. Stroke was initially much higher in mono-infection and declined throughout the study period, while the opposite trend was seen in co-infection. This pattern held for both ischemic and hemorrhagic stroke. By the end of the study period, incidence of both types of stroke had become higher in co-infected individuals. The reason for this divergent trend, and why stroke was much lower in co-infected patients during the early years of the analysis, is unclear. Reported drug use preceding stroke diagnosis was not different between the groups. Information on traditional risk factors, ART use, HIV RNA and CD4 counts were not described.
Taken together, these abstracts highlight stroke as another very important medical comorbidity in HIV that deserves more research and clinical focus. Traditional risk factors correlate with increased risk, but uncontrolled viral load and low CD4 are also important factors. ART appears to be protective. The excess of strokes in younger HIV-infected women seen in some but not all of these reports is alarming and not adequately explained. The observation should be validated by additional studies and its causes better understood. The decline of stroke rates in Spanish HIV-mono-infection individuals is consistent with reports of declining rates of coronary artery disease in HIV and in the general population, and may be attributable to better virologic and immunologic control along with improved management of traditional risk factors. The reported rising incidence of stroke in the HIV-co-infected individuals in Spain is very concerning. Further studies in Spain and elsewhere are need to confirm that the problem is real and understand its underlying cause. A substantial number of strokes were found to be associated with infection and drug use. Therefore, stroke prevention for HIV-infected patients must address these factors, control traditional risk factor, and employ early introduction of ART.
Cancer: With broad access to ART, cancers traditionally classified as AIDS-related have declined. However all cancer, including non-AIDS-related types, exceeds cardiovascular and liver disease as a cause of death in most analyses of HIV-related mortality in high-income countries. Rates of many cancers are increased in HIV compared to the HIV-uninfected population. The increase is attributable in part to higher rates cancer risk factors such as smoking and alcohol use, and the aging of the HIV population. Increased cancer incidence is most striking for the infection-related cancers Kaposi's sarcoma, Hodgkin's and non-Hodgkin's lymphoma (NHL), cervical, anal and head and neck cancer, and hepatocellular cancer, suggesting an important role for immune dysfunction in cancer pathogenesis in HIV. Since ART improves immune function, early ART use should help decrease the excess cancer risk seen in HIV. An analysis of cancer in the START trial addressed this issue.
The START trial randomized individuals with a baseline CD4 above 500 to immediate or deferred initiation of ART. The trial proved that immediate ART conferred protection against AIDS- or non-AIDS-related clinical events or death. Cancer was an important component of that composite clinical endpoint. Borges (abstract 160) analyzed the START trial data to determine factors associated with the effect of ART on cancer risk. There were 6 vs. 23 cases of infection-related cancer and 8 vs.16 cases of non-infection-related cancer in the immediate and deferred ART arms, respectively. The reduction in infection-related cancers was highly significant (HR 0.26, p=0.003). The trend toward fewer non-infection-related cancers was not significant (HR 0.49, p=0.1), but longer follow-up may have been needed to realize the full effect. Multivariable models adjusting for most recent CD4 and HIV RNA appeared to attenuate the effect of immediate ART more for non-infection related cancers suggesting other mechanisms not captured by viral load and CD4 measurement may be present and affect these categories of cancer differently.
Although tuberculosis and other infections cause the predominant burden of HIV-related illness in low-income countries, cancer is also important. Sengayi et al (abstract 613) cross-referenced clinical databases from two South African HIV programs and a cancer registry to identify patients with both cancer and HIV. Among 23,120 patients with 59,101 person-years of follow-up during the period 2004 to 2011, 851 cases of cancer were diagnosed. The incidence was 1325/10,000 person-years. Infection-related cancers were more twice as frequent as non-infection-related cancers. In Botswana, a low-income country where ART coverage rates over 90% have been achieved, cancer is overtaking tuberculosis as the leading cause of AIDS-related deaths (Dryden- abstract 615). Using data from the Botswana National Cancer Registry, cancer survival rates for HIV-infected patients were estimated. During the study period cancer mortality increased 1.2%/year. Cervical cancer mortality increased the most (13%/year). During the same period, tuberculosis mortality declined precipitously. Mortality for Kaposi's sarcoma declined by 4%/year and was the only cancer studied with a 5 year survival above 50%.
Cancer mortality appears to increase substantially when it occurs in HIV-infected individuals. Coghill et al (abstract 616) used data from the National Center for Health Statistics and the HIV/AIDS Cancer Match Study from 1996-2010 to determine mortality rates by age, gender and race for those without HIV or cancer, those with cancer but no HIV, those with HIV but no cancer and those with HIV and cancer. The expected death rate for cancer in HIV was the sum of the HIV/no cancer mortality rate plus the rate for no HIV/cancer. Any increase in the observed mortality in those with HIV/cancer was considered excess mortality. Excess mortality in HIV was seen in some or all demographic groups with NHL, lung, colorectal, breast and anal cancer. No excess mortality was seen for prostate cancer. Large excesses in the range of 500/1000 person-years occurred in men below the age of 50 for HIV/lung cancer. Excess mortality was found in all demographics for HIV/NHL and was over 200/1000 person-years for men and women younger than 50. Excess mortality for breast cancer was seen only in non-white women and for colorectal cancer only in younger men.
Prevention of anal cancer is one of the most difficult management problems in HIV care. Compared to the general population, where it is a rare disease, the incidence of this HPV-related malignancy is markedly elevated in men whom have sex with men. Other groups may also be at risk. Screening with anal cytology yields frequent abnormal results and the optimal management is not known. Current treatment options are difficult for patients to undergo and must often be repeated. A highly effective HPV vaccine is approved only for use in males and females age 9-26, since younger individuals are less likely to have already been infected by HPV. The development of this vaccine raised the hope that it could be useful therapeutically in HIV. Immunization of individuals already infected by HPV might prevent acquisition of additional oncogenic HPV types or boost HPV-specific immune responses in individuals with anal dysplasia, clearing HPV and preventing progression to cancer. Wilkins et al (abstract 161) presented the disappointing results of a clinical trial conducted in 575 HIV-infected men reporting receptive anal intercourse and women (20% of the study population) who were 27 years of age or older. Participants were randomized to 3 doses of the quadrivalent HPV vaccine or placebo. Abnormal anal cytology, including high-grade intraepithelial lesions (HSIL) were common at study entry, as was detection of vaccine HPV types. After 2.6 years, the study was stopped for futility. The vaccine was highly immunogenic but compared to placebo, failed to reduce persistent detection of anal HPV, improve clearance of vaccine HPV types, or reduce abnormal cytology or the detection of HSIL.
Cancer has emerged as a major comorbidity in HIV-infected individuals living longer lives on ART. With better preservation of immune function as a result of the worldwide trend toward earlier diagnosis and initiation of ART, the classical AIDS-related cancers should continue to decline, but non-AIDS cancers, both infection-related and non-infection-related, will likely be the greatest cause of mortality, not only high-income countries but also in low-income countries that have high rates of ART. The excess mortality that occurs when cancer complicates HIV may be due to reduced access to or increased toxicity with treatment, poorer access to care or patient and health care provider attitudes towards cancer treatment. The causes need to be understood and addressed. Much of the excess cancer risk in HIV is attributable to smoking. Cancer prevention efforts should focus on smoking cessation and appropriate screening based on recommendations for the general population. Prevention of anal cancer continues to be an unmet need. It does not appear that adjunctive vaccination will help.
Liver Disease. HCV co-infection is a greatest cause of chronic liver disease in HIV-infected individuals. The recent development of safe and efficacious directly-acting antiviral agents (DAAs) to treat HCV has altered the management of HIV/HCV dramatically. Multiple abstracts presented at CROI 2016 confirmed the success of DAA treatment in co-infection (abstracts 581-587). However, there are a variety factors that will likely make liver disease an ongoing problem in HIV. Treatment will not be accessible for all, mostly because of extraordinary cost, but also because many co-infected patients are still not diagnosed or stably linked to care. When treatment is given, most will be cured and most will have regression of fibrosis. However, if cirrhosis is already present, improvement may not be sufficient to avoid subsequent decompensation events or hepatocellular carcinoma (HCC). Even when infection HCV is not a factor, other causes of liver damage may be present, including alcoholic and non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Chronic inflammation due to HIV itself may also play a role. Several cohort studies evaluated the role of HIV-related, and non-HIV-related risk factors for liver disease in HIV.
Using data from the CNICS cohort Kim assessed risk factors for development of advanced fibrosis, as defined by a FIB-4 index ≥3.25, among 14,198 patients without significant fibrosis at baseline (abstract 558); 12% had HCV co-infection. Nearly 10% progressed during a median of 3 years follow-up. In multivariate analysis using time varying values, higher HIV RNA and lower CD4 counts were significantly associated with progression to advanced fibrosis. The effect was seen in both HIV-mono-infected and HCV co-infected patients. Also associated were chronic HBV, alcohol use disorder, diabetes and higher baseline FIB-4 index. Similar findings were reported by Mohr et al in a cross-section of 432 German patients, who underwent transient elastography (abstract 560). Eight percent had significant and 2% severe fibrosis. In HIV-mono-infected participants, who made up 84% of the cohort, independent risk factors for fibrosis were detectable HIV RNA, diabetes and higher BMI. The duration of antiretroviral therapy (ART) was associated with reduced risk. The effect of alcohol use was not reported in this study.
Althoff et al analyzed the NA-ACCORD database to identify risk factors for development of end-stage liver disease (ESLD) as defined by the occurrence clinical hepatic decompensation events or HCC (abstract 150). The cohort was very large (n=34,044) and assessment of alcohol use was available in 36%. Results for each risk factor were expressed as the population attributable fraction (PAF), the product of the adjusted hazard ratio and the prevalence of the risk factor in the study population. After a median follow-up of 3.1 years, ESLD was diagnosed in 387 individuals. The PAFs for HCV co-infection, at risk alcohol use (≥3/day or >7 drinks/week for women and >4 drinks/day ≥14 drinks/week for men), CD4 <200, and HBV co-infection were 35%, 33%, 25%, and 10%, respectively. In this analysis, detectable HIV RNA did not impart significant risk.
Hepatic steatosis may complicate chronic HCV, and much of the liver disease in HIV that is not attributable to viral co-infection may be due to NAFLD and NASH. These conditions are often associated with obesity, insulin resistance, diabetes, dyslipidemia. Chronic inflammation is an important component of the pathogenesis of these conditions. To define the pattern of inflammation in HIV-infected individuals with NASH, investigators at the NIAID compared cytokine profiles in patients with virologic suppression on ART, with and without NASH, and in normal controls (Krakora et al. abstract 561). TNF-α sCD163, CXCL10 (IP-10) and IL-8 were elevated only in the group with HIV and NASH. IL-6, CCL2 (MCP-1), sCD14, were higher in HIV-NASH than in HIV-negative controls but were similar to HIV-infected controls. CRP and d-dimer did not differ among the 3 groups.
There is currently no therapy proven effective for NAFLD in the general population. Statins improve dyslipemia and have anti-inflammatory effects and so are potential candidates for treatment or prevention of NAFLD. Two cohort studies conducted using VA databases examined the effect of statin use on progression of liver disease in HCV. Simon et al. (abstract 551) calculated serial FIB-4 values in 9135 mono-infected patients. In a multivariable analysis, those with the greatest exposure to statins had a 40% lower risk of advanced fibrosis and a 49% lower risk HCC. Oliver et al (abstract 550) also found statin use was associated with reduced risk of development of cirrhosis, as determined by billing codes, in 5985 HIV/HCV-co-infected patients. A Cox proportional hazard analysis found a 32% lower rate of cirrhosis for every 30% increase in time on statins. Although these cohort studies suggest an association between statin and reduced liver disease progression in HCV, a direct effect cannot be inferred because there is great potential for unadjusted confounding. A third study suggested a possible mechanism for statin benefit. Lo et al (abstract 553) did CT scans to quantitate liver fat in HIV-infected patients participating in a randomized, placebo-controlled trial to evaluate the effect of 48 weeks of atorvastatin on coronary plaque. Despite the tiny number of evaluable patient with NAFLD at baseline (n=7), there was significantly greater improvement in liver/spleen density ratio (an indication of reduced liver fat) in those on atorvastatin.
These studies have implications for clinical management of liver disease in HIV. All patients with HCV should be treated with DAAs, but for those who cannot receive treatment, ART should be initiated as early as possible to suppress viral load, avoid advanced immune deficiency, and reduce systemic inflammation. For all patients, screening for and treating alcohol use disorders, maintaining ideal body weight, screening for and treating diabetes all may help slow the risk of progressive liver fibrosis. Although statin use cannot yet be recommended for treatment or prevention of any liver disease, they should be considered for use in all patients with HIV at risk for coronary artery disease and should not be avoided because of the presence of concurrent liver disease.
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