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Brain Damage, Comorbidities and Early Death Threaten HIV+
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HIV Damages The Brain and Neurological Damage Persists
Reported by Jules Levin
CROI 2009
High rates of comordities and deaths due to these comorboidities, and at early ages, were reported at CROI. This is not surprising. Reported at CROI were increased rates of certain cancers, kidney disease, liver disease/failure, bone disease, and cardiovascular disease, all exacerbated by aging, and these comorbidities occurred in the studies at average ages of patients in their 40s. Also at CROI were a series of studies of cognitive function, neuropathy, and the brain all suggesting finding high rates of cognitive impairment & neuropathy, and the rates remain high, they have not gone down despite HAART. There were 2 studies both with links to them below, finding brain damage from HIV despite HAART and early aging of the brain, accelerated aging estimated to be 15-20 years! There were a number of studies on aging suggesting exactly what I have been suggesting, that HIV causes early aging, early senesence, aging of the T-cell repertoire similar to that seen in elderly HIV-negative individuals, and inflammation and immune activation due to HIV are also causative.
The big question is, are we going to deal with this or not, and in a timely way? I don't see good signs regarding this. It is time for the research community to get serious and not delay making a serious commitment to addressing these questions, and finding interventions. We have been giddy for years with the success of HAART, but now it appears we could be facing an era of increased sickness and death. We have diverted attention and many resources to overseas but to the neglect of what appears to be very serious potential problems right here in the USA and the developed or Western world. Researchers, the NIH, NIAID, ACTG, drug companies, and community must wake up now and discuss solutions or soon it might be too late. 25% of HIV-infected in the USA are 50 yrs of age and older and this percent will increase quickly over the near coming years, meaning that aging will seriously affect HIV+ individuals. What are our governments doing about this: USA, Western Europe, Australia, New Zealand, Canada. Not much. The NIH has issued this year 3 requests for funding for research in HIV and aging. These studies could take years to complete and then years to discuss, you know how scientists love to discourse. This is NOT good enough. I urge you all to take this seriously. Simultaneously, reimbursement and quality of care is suffering, and good doctors are leaving practice and aging themselves. It's time to raise concerns with your officials and researchers. It's also important for patients and clinicians to discuss proper evaluation, lab testing, and monitoring for these comorbid conditions.
In a cohort study from EuroSida, CD4 and viral load was associated with developing these so-called non-AIDS events: In an adjusted analysis, people with a latest CD4 count twice that of a comparable patient had a 23% lower incidence of a non-AIDS illness (P < 0.0001). People who spent more than 2 years with a CD4 count below 200 had a 40% higher incidence of non-AIDS illness (P = 0.017). Every 10-fold higher viral load raised the incidence of a non-AIDS diagnosis 11% (P = 0.017).
A large study from Kaiser reports HIV+ individuals have higher cancer rates than HIV-negatives. Despite improvements in antiretroviral therapy, HIV-infected people with non-Hodgkin lymphoma (NHL) still have a higher 2-year all-cause death rate than NHL patients without HIV, according to results of the 10,000-person study in California's Kaiser Permanente health system. Infection-related Non-AIDS-defining Cancer Risk in HIV-infected and -uninfected Persons: Increased Rates in HIV+ vs HIV-negatives in Kaiser.
Rates (per 10,000 person-years) for infection-related non-AIDS-defining cancers were 29.7 for HIV+ and 4.4 for HIV- (RR = 6.8; p <0.001); the RR did not change over time. The increased risk of non-AIDS-defining cancers in HIV+ persons has not changed much during the ART era. Significant results for infection-related non-AIDS-defining cancers were anal (RR 81.4; p <0.001), Hodgkin's lymphoma (RR 17.4; p <0.001), head and neck (RR 2.1; p <0.001), and gynecologic (RR 2.9; p = 0.001). Significant results for infection-unrelated non-AIDS-defining cancers were kidney (RR 1.8; p = 0.045), lung (RR 1.7; p = 0.004), melanoma (RR 1.7; p = 0.002), and prostate (RR 0.7; p = 0.007).
Colette Smith and D:A:D colleagues analyzed records of 33,347 HIV-infected people, 74% of them men, 34% current smokers, 20% with HCV antibody, 14% with HBV surface antigen, and 3% with diabetes. Median age stood at 39 years (interquartile range [IQR] 35-45), median body mass index at 23 kg/m(2) (IQR 21-25), median systolic blood pressure at 120 mm Hg (IQR 110-130), median viral load at 1000 copies (IQR 50 to 15,000 copies), and median CD4 count at 408 (IQR 248-600). Median cumulative antiretroviral exposure measured only 3.1 years (IQR 1.6-4.8). Multicohort D:A:D Study Pinpoints Non-HIV Death Risk Factors People Can Change . During follow-up, 2192 people died to yield a death rate of 13.8 per 1000 person-years. The principal causes of death were AIDS (accounting for 32% of deaths), liver disease (14%), non-AIDS malignancies (12%), and heart disease (11%). Every 10 years of age raised the risk of death 22%. Current smoking, smoking in the past, and unknown smoking status all independently raised the risk of all-cause death compared with never smoking. Hypertension independently boosted the overall death risk and the risk associated with liver disease and heart disease. The study also disclosed a strong trend toward a higher risk of AIDS death among people with hypertension. Diabetes independently raised the risk of death from all causes, AIDS, liver disease, and heart disease, with a trend toward a higher death risk from non-AIDS malignancies. HCV seropositivity hoisted the overall death risk and nearly quintupled the risk of liver-related mortality. HBV positivity made all-cause death more likely, as well as death from liver disease and cardiovascular disease. Every 100-cell higher CD4 count lowered the overall death risk, as well as the risk of death from AIDS, liver disease, heart disease, and non-AIDS cancers. Compared with a viral load below 400 copies while on antiretroviral therapy, a load above 400 while on therapy heightened the risk of death from all causes, from AIDS, and from liver disease. Compared with a sub-400 load on therapy, a load below 10,000 copies from while off therapy made death more likely from all causes, AIDS, liver disease, and non-AIDS cancers. A viral load between 10,000 and 100,000 copies while off therapy made death more likely from all causes and from AIDS. And a viral load above 100,000 copies while off therapy raised the risk of every death category considered except non-AIDS malignancies.
Below are links to numerous studies at CROI on neurologic and brain disorders among HIV+ individuals. These studies find high levels of cognitive impairment, about 50% that persists despite successful HAART, high levels of neuropathy, 50%, that persist despite HAART. Metabolic syndrome contributes to cognitive impairment & neuropathy, just like in the general population. One study reported below performed brain MRIs and found brain damage and inflammation. A 2nd study did brain scans and found HIV slows cerebral blood flow in the brain and finds a 15-20 year aging of the brain due to HIV-infection. Together, these findings indicated that HIV and aging produce similar additive--but not interactive-effects. The reason for these effects remains unknown, but Ances speculated that HIV-induced decreases in endothelial function or platelet function could lead to decreases in cerebral blood flow. In addition, he suggested that HIV-driven increases in inflammation could lead to increases in metabolic demands, and that could translate into increased functional cerebral blood flow in response to a visual stimulus.
Neurocognitive Disorders Threaten HIV+ - (02/20/09)
Here are several poster reports from CROI on neurocognitive disorders and function in HIV+ individuals. The first 2 posters report high prevalence (51% and 24%) of neurocognitive disorders despite using HAART. The 3rd study suggests cytokine dysfunction may persist in the brain despite HAART in patients with neurocognitive disorder. Another study reports CD4 nadir is associated with neurologic dysfunction despite HAART and this has been found in many studies CD4 nadir appears to predict neurologic dysfunction. A study from the CHARTER Study group found 41% of patients with undetectable HIV in the blood had HIV in the CSF when they used a sensitive assay (<2 copies/ml) and having these low levels was associated with cognitive impairment than patients with detectable HIV in both the blood and the CSF, the authors suggest this is because their HAART regimen was not effective enough in the CSF, didn't have enoiugh CSF penetration.
Cognitive Impairment & Neuropathy Persist Despite HAART and Are Associated With Metabolic Syndrome - (02/27/09)
Prevalence of neurocognitive impairment (NCI) was 53 of 145 (37%), consistent with other estimates in the HAART era. In univariate models, correlates of NCI included greater waist circumference, lower LDL-C (89 vs 106 mg/dL), and higher prevalence of type II diabetes. Despite HAART the prevalence of cognitive dysfunction and neuropathy persists, and two reports at CROI find elements of metabolic dysfunction are associated with both cognitive dysfunction and neuropathy. These findings are not unexpected and have been observed in the literature in published studies
Neurocognitive (and neuropathy 57%) Impairment Rate Remains High (50%) in Diverse US Cohort - (02/18/09)
47% of the 1555 cohort members had normal neurocognitive performance scores, 21% had mild impairment, 30% moderate impairment, and 2% severe impairment..."impairment has remained the same, no improvement"
More than a dozen years into the HAART era, neurocognitive impairment remains common in the diverse US CHARTER cohort, even in people without other conditions that may affect cognitive function [1]. Impairment rates were significantly lower in antiretroviral-treated people whose CD4 count never dipped below 200. But nadir CD4 <200 was associated with cognitive impairment and the speaker Grant said we should research if such low CD4s before HAART allow permanent damage of the brain (from Jules: I think so).
--All told, 53% of the cohort had HIV-associated neurocognitive disorder (HAND) despite the dawn of HAART. HAND was less likely in antiretroviral-treated people with an undetectable blood plasma load and no history of severe immunosuppression. But people taking antiretrovirals were more likely to have peripheral neuropathy. And despite a steep drop in prescription of d-nucleosides, 57% of the cohort had evidence of peripheral neuropathy. One third of the cohort had evidence of a brain white matter abnormality, a signal of worse neurocognitive performance.
--Grant proposed that future research should examine whether earlier antiretroviral therapy--especially with drugs that penetrate the CNS--can "abort the neuropathogenic cascade."
Antiretrovirals Have Not Banished Brain Injury in 7-Center US Imaging Study: brain damage persists despite HAART- inflammation and neuronal damage - (02/18/09)
People without neurologic symptoms showed diffuse inflammatory changes, whereas frank neuronal injury occured in people with cognitive impairment. Taken together, these results suggested that brain injury persists in HIV-infected people taking antiretroviral therapy for chronic disease. Navia proposed that these findings suggest a two-stage model of brain injury--inflammatory processes followed by basal ganglia disease as ADC is developing
HIV-Associated Peripheral Neuropathy in the HAART Era: Results from AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) Protocol A5001 - (03/02/09)
"The prevalence of peripheral neuropathy and symptomatic peripheral neuropathy increases with time after ARV initiation in ARV-naive patients despite increased virologic control and immune function, and the decline of d-drug use. Age and d-drug use are notable risk factors for PN and SPN."
Persisting High Prevalence of HIV Distal Sensory Peripheral Neuropathy in the Era of Combination ART: Correlates in the CHARTER Study - (03/04/09)
57% had at least 1 sign of neuropathy. Average age of study participants is 46 yrs. Distal Sensory Polyneuropathy was found to affect more than half of individuals living with HIV, with a particularly high prevalence among those currently taking ART. These findings suggest that the recovery of peripheral nerves with ART I it occurs, is incomplete. Significant risk factors for DSPN in the multivariate regression were lower CD4 nadir, advanced age, current ART use, prior d-drug use and prior opiate abuse/dependence.
Metabolic Syndrome, Diabetes, and Cognitive Impairment in the Era of Combination Antiretroviral Therapy - (03/02/09)
Results from CHARTER Study: in univariate analysis, higher BMI, lower HDL (43 vs 50), higher triglycerides (184 vs 136) and lower LDL (90 vs 103) were found in patients with cognitive impairment; type 2 diabetics were more likely to be impaired (17 vs 42%). In multivariate analysis type 2 diabetes was significantly (Odds Ratio 7.6) associated with increased odds of being impaired.
HIGH FREQUENCY (50%) OF NEUROCOGNITIVE DISORDERS IN OLDER (>60 yrs) HIV-INFECTED PATIENTS DESPITE A SUSTAINED VIROLOGICAL AND IMMUNOLOGICAL RESPONSE ON CART: THE SIGMA STUDY - (03/02/09)
Despite a sustained response to cART, neurocognitive impairment (NCI) can be detected in 49% of HIV+ patients aged of 60 years and more, using a brief neuropsychological battery. In our 37 patients, cardio-vascular risk factors are highly prevalent (68%), but are not associated with NCI.
HIV Infection May Make the Brain 15 to 20 Years Older: HIV slows cerebral blood flow and stimulus response in MRI study - (02/23/09)
Ances hypothesized that HIV and aging affect cardiac, liver, endocrine, kidney, bone, and possibly brain function. To test the effect of HIV and aging on the brain, he measured cerebral blood flow with arterial spin labeling magnetic resonance imaging in people with and without HIV. Older age and HIV infection both upset cerebral blood flow, regardless of viral load, current CD4 count, or lowest-ever (nadir) CD4 count, according to results of a brain scan comparison involving older and younger people with and without HIV. By these measures, the brain of an HIV-infected person may be up to 20 years older than the brain of a person without HIV.
"If this trend in aging (in the slide below) in the Swiss cohort table continues by 2015 we think over 50% of HIV-infected individuals will be over 50 yrs old."..... "There is about a 15-year brain aging because of HIV-infection"..... "How do we link this all together and how is this creating a strain on the brain. HIV and aging both have a lot of similar parallels for naive and memory T-cell function, replicative sinesence as all as even increased cytokine production, so they could have parallel streams that could be developing. So when we have a younger HIV+ individual (represented in slide below) they have aging that is present and they may have co-morbidities present, as well HIV being present contributes to stress on the brain. As they get older the comorbidities present as well as aging may put a strain on the brain on top of HIV".
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