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Marissa Fahlberg

HIV and SIV research aficionado, monkey enthusiast.


Side-effects related to long-term antiretroviral therapy for HIV are only now being discovered.

In 10 seconds? The population of people living with HIV and long-term antiretroviral therapy (ART) is aging, and these patients are suffering from an increased rate and frequency of progression to typically age related diseases.

How do we know this is really happening? Numerous studies in ART-treated humans have shown premature aging of the immune system, harmful metabolic changes and a predisposition to diabetes, an increased likelihood of cardiovascular disease at an earlier-than-usual age, accelerated kidney complications, decreased bone mineral density, greater and earlier occurrence of frailty, and an increased likelihood of dementia.

ART has been around for decades! Why are we only now hearing about this? ART was first developed and implemented in the late 90s, and the first people infected with the virus were mostly young men. It is only since this original population has been on ART for over twenty years that scientists and clinicians are seeing the long-term side effects of the medication, as well as effects of the virus hanging around for so long.

What's causing the accelerated aging?

The Virus - Recent discoveries have pointed to increased inflammation being an indicator of progression to disease. The source of the inflammation is unclear and a topic of current research, but one possible theory is that life-long viral replication is overstimulating the immune system and causing inflammation.

The Treatment - Another possibility is that the drugs impart damage to liver and fat tissue. This could cause problems with insulin and hormone imbalances, leading to metabolic problems and heart disease.

Lifestyle and Behavior - Scientists are also investigating the idea that risky past behavior of the HIV+ population, such as intravenous drug use, might be more common than in the HIV- population, possibly causing the rapid and increased development of age-related diseases.

Can drug interactions affect the aging population, too? Absolutely. The elderly are commonly on multiple medications, potentially exacerbating ART toxicity. It is very challenging for doctors to find the best treatment combinations for their aging patients.


Aging and inflammation in patients with HIV infection.

Abstract: HIV+ patients have nowadays an expected life span that is only slightly shorter than healthy individuals. For this reason, along with the fact that infection can be acquired in a relatively advanced age, the effects of aging on HIV+ persons have begun to be evident. Successful antiviral treatment is, on the one side, responsible for the development of side effects related to drug toxicity, on the other is not able to inhibit the onset of several complications caused by persistent immune activation and chronic inflammation. Then, patients with a relatively advanced age, i.e., over 50 years old, can experience pathologies that affect much older citizens. HIV+ individuals with non-AIDS related complications can thus arrive to the attention of clinicians because of the presence of neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV associated cancers. Chronic inflammation and immune activation that are typically observed in elderly people and were defined "inflammaging" can be present in HIV+ patients, who experience a sort of premature aging, which affects heavily the quality of life. This relatively new condition is very complex, and important factors have been identified beside the traditional behavioral risk factors, that are the toxicity of antiretroviral treatments and the above-mentioned chronic inflammation leading to a functional decline and a vulnerability to injury or pathologies. Here, we discuss the role of inflammation and immune activation on the most important non-AIDS related complications of chronic HIV infection, and the contribution of aging per se to this scenario. This article is protected by copyright. All rights reserved.

Pub.: 21 May '16, Pinned: 16 Apr '17

Accelerated and accentuated neurocognitive aging in HIV infection.

Abstract: There is debate as to whether the neurocognitive changes associated with HIV infection represent an acceleration of the typical aging process or more simply reflect a greater accentuated risk for age-related declines. We aimed to determine whether accelerated neurocognitive aging is observable in a sample of older HIV-infected individuals compared to age-matched seronegatives and older old (i.e., aged ≥65) seronegative adults. Participants in a cross-sectional design included 48 HIV-seronegative (O-) and 40 HIV-positive (O+) participants between the ages of 50-65 (mean ages = 55 and 56, respectively) and 40 HIV-seronegative participants aged ≥65 (OO-; mean age = 74) who were comparable for other demographics. All participants were administered a brief neurocognitive battery of attention, episodic memory, speeded executive functions, and confrontation naming (i.e., Boston Naming Test). The O+ group performed more poorly than the O- group (i.e., accentuated aging), but not differently from the OO- on digit span and initial recall of a supraspan word list, consistent with an accelerating aging profile. However, the O+ group's performance was comparable to the O- group on all other neurocognitive tests (ps > 0.05). These data partially support a model of accelerated neurocognitive aging in HIV infection, which was observed in the domain of auditory verbal attention, but not in the areas of memory, language, or speeded executive functions. Future studies should examine whether HIV-infected adults over 65 evidence accelerated aging in downstream neurocognitive domains and subsequent everyday functioning outcomes.

Pub.: 23 Mar '17, Pinned: 12 Apr '17

Significant health impact of accelerated aging in young HIV-infected individuals on antiretroviral therapy in Malaysia.

Abstract: Aging among HIV-infected individuals on antiretroviral therapy (ART) is a significant clinical challenge however, studies assessing multidimensional aspects of aging are lacking. We characterised ten geriatric conditions (GCs) encompassing multiple functional domains, its health impact and associated risk factors in HIV-infected and age-matched uninfected controls.HIV-infected individuals were recruited from the out-patient clinic in University Malaya Medical Centre, Malaysia and controls from the community. All participants were aged ≥25years, no acute illness and HIV-infected individuals were on stable ART. GCs were assessed and the burden scored as a composite of GCs present in an individual (total score = 10). Multivariate regression analysis was performed to determine the risk factors and health impact associated with the burden of GCs.We analysed data from 336 HIV-infected individuals (total HIV+), of whom 172 were matched for age, gender and ethnicity with 172 HIV-uninfected controls (matched subset). In the total HIV+ cohort, median (interquartile range) age was 44 (38-51)years and CD4 T-cell count was 562 (398-737)cells/μl. The burden of GCs was significantly higher in the HIV-infected group compared to controls (p < 0.001). With an increasing GC burden, quality of life scores were 2.2-times poorer, health-care utilisation 5-times greater and mortality risk scores 4-times higher in the HIV-infected group compared to matched controls. Both socio-behavioural and HIV-related clinical factors were independently associated with an increasing burden of GC in HIV.A high burden of GCs with significant impact on health outcomes, including mortality risk scores are observed among HIV-infected individuals on ART in a resource-limited setting.

Pub.: 31 Mar '17, Pinned: 12 Apr '17

Faces of Frailty in Aging with HIV Infection.

Abstract: The number of adults who are aging successfully and have HIV infection is increasing. More effective antiretroviral therapy (ART) regimens are preventing individuals infected with HIV from reaching end stages of the HIV infection and developing AIDS (acquired immunodeficiency syndrome). However, even at lower viral loads, chronic HIV infection appears to have consequences on aging processes, including the development of frailty.Frailty is a term used to describe vulnerability in aging. Frailty indices such as the Fried Frailty Index (FFI), the Veterans Aging Cohort Study (VACS) Index, and the Center for Epidemiologic Studies Depression scale (CES-D), an index of emotional frailty, associate with or predict clinical outcomes and death. However, even among existing frailty definitions, components require rigorous and consistent standardization. In the Women's Interagency HIV Study (WIHS), we have shown that frailty does not exist in isolation, even in midlife, and we use frailty to predict death. Frailty indices should be systematically used by health professionals to evaluate health and future risks for adverse events. Frailty prevention efforts, especially among those with HIV infection, appear to be essential for "successful aging" or aging without disability or loss of independence and may prevent HIV transmission. Taking care of elderly people is one of the major challenges of this century, and we must expect and be prepared for an increase in the number of aging adults, some of whom are patients with many co-morbidities and HIV infection.

Pub.: 18 Feb '17, Pinned: 12 Apr '17

Brain and liver pathology, amyloid deposition, and interferon responses among older HIV-positive patients in the late HAART era.

Abstract: HIV+ patients on highly active antiretroviral therapy (HAART) with suppressed viral loads have a low incidence of HIV-associated dementia, but increased prevalence of milder forms of HIV-associated neurocognitive disorders (HAND). These milder forms of HAND are often associated with minimal histological abnormalities, and their pathophysiology is unclear. Comorbidities, altered amyloid metabolism, accelerated brain aging, and activated interferon responses are suspected to play a role in HAND pathogenesis in HAART-treated persons.To investigate associations between liver disease, accelerated brain aging, and HAND in HIV+ patients in the late HAART era (2002-2015), we studied liver and brain autopsy tissues from 53 older subjects evaluated at UCLA and BWH using histopathological stains, a sensitive fluorescent amyloid stain (AmyloGlo), and targeted gene expression profiling (NanoString).The majority of HIV+ subjects (median age 56) were on HAART (89.3%) with last pre-mortem plasma viral load <400 copies/mL (81.5%); 50% had CD4+ counts <200 cells/μL. Compared to HIV- controls (median age 65), HIV+ subjects had more cancer (p = 0.04), illicit drug use (p <0.00001), and HCV co-infection (p = 0.002), less cardiovascular disease (p = 0.03), and similar prevalence of cerebrovascular disease (~40%), hypertension, hyperlipidemia, and diabetes. Deep frontal white matter showed increased gliosis in HIV+ subjects vs. HIV- controls (p = 0.09), but no significant differences in myelin loss, blood vessel thickening, or inflammation. Liver showed more severe fibrosis/cirrhosis (p = 0.02) and less steatosis (p = 0.03) in HIV+ subjects, but no significant differences in inflammation, blood vessel thickness, or pigment deposition. There were no significant associations between liver and brain pathologies. AmyloGlo staining detected large amyloid deposits in only one HIV+ case (age 69 with Alzheimer's disease pathology) and two HIV- controls (ages 66 and 74). White matter from HIV+ cases vs. HIV- seronegative controls showed a trend (p = 0.06) towards increased interferon response gene expression (ISG15, MX1, IFIT1, IFIT2, and IFITM1).Gliosis and cerebrovascular disease, but not accelerated amyloid deposition, are common brain pathologies among older HIV+ patients in the late HAART era. Although HIV+ subjects had more cirrhosis, liver pathology was not associated with any consistent pattern of brain pathology. Cerebrovascular disease, interferon responses, and neuroinflammation are likely factors contributing to brain aging and HAND in older HIV+ patients on current HAART regimens.

Pub.: 19 Feb '17, Pinned: 12 Apr '17

TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects.

Abstract: Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known.We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects.Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls.Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.

Pub.: 12 Jul '14, Pinned: 12 Apr '17

Cancer Risk among the HIV-Infected Elderly in the United States.

Abstract: HIV-infected people and elderly people have higher risk of cancer, but the combined effects of aging and HIV are not well described. As the HIV population is aging, we aimed to evaluate the magnitude of cancer risk in the HIV-infected elderly population.We conducted a case-cohort study including a 5% sample of US Medicare enrollees and all cancer cases aged ≥65 in linked cancer registries.HIV was identified through Medicare claims. Among the HIV-infected, absolute cancer risk was calculated accounting for the competing risk of death. Associations between HIV and cancer were estimated with weighted Cox regression adjusting for demographic characteristics.Among 469,954 people in the 5% sample, 0.08% had an HIV diagnosis. Overall, 825,776 cancer cases were identified in cancer registries. Over five years, 10.1% of the HIV-infected elderly developed cancer, the most common diagnoses comprising lung (5-year cumulative incidence=2.2%), prostate (2.7%, among men), and colorectal cancer (0.9%), and non-Hodgkin lymphoma (0.8%). HIV was strongly associated with incidence of Kaposi sarcoma (adjusted hazard ratio [aHR]=94.4, 95%CI=54.6-163), anal cancer (aHR=34.2, 95%CI=23.9-49.0) and Hodgkin lymphoma (aHR=6.3, 95%CI=2.8-14.3). HIV was also associated with incidence of liver cancer (aHR=3.4, 95%CI=2.2-5.1), non-Hodgkin lymphoma (aHR=2.6, 95%CI=1.9-3.4), and lung cancer (aHR=1.6, 95%CI=1.3-2.0).In the elderly, HIV infection is associated with higher risk for many cancers, although some associations were weaker than expected, perhaps reflecting effects of non-HIV pathways on cancer development. Due to the effects of HIV and aging, the HIV-infected elderly have a sizeable absolute risk, highlighting a need for cancer prevention.

Pub.: 08 Mar '16, Pinned: 12 Apr '17

Infection‐related and ‐unrelated malignancies, HIV and the aging population

Abstract: HIV‐positive people have increased risk of infection‐related malignancies (IRMs) and infection‐unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence.People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence.A total of 15 648 people contributed 95 033 person‐years of follow‐up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count < 200 cells/μL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40–4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5‐year period from 3.1 (95% CI 1.5–5.9) per 1000 person‐years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2–7.2) per 1000 person‐years over the same period.Demographic and HIV‐related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV‐infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost−benefit of screening for IURMs in HIV‐infected populations.

Pub.: 18 Feb '16, Pinned: 12 Apr '17

Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment.

Abstract: HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment.Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls).Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R.Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF.Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging.

Pub.: 23 Apr '14, Pinned: 12 Apr '17