Didactic Series Non-Infectious Complications of HIV Ankita Kadakia, MD UC San Diego, Owen Clinic November 8, 2018 1
Disclosures The following presenter have disclosed the following relationship with a commercial interest. Ankita Kadakia,MD Type of relationship: Spouse, Proteus Digital Resolution: This presentation has been reviewed by the PAETC Clinical Director, who reports the above disclosures have had no affect on the content of this presentation. All other presenters of this continuing medical education activity have indicated that neither they nor their spouse/legally recognized domestic partner has any financial relationships with commercial interests related to the content of this activity. 2
Learning Objectives 1) To understand how HIV/AIDS affects multiple organ systems and the related noninfectious complications 2) To understand how the use of ART affects multiple organ systems and related noninfectious complications 3) To understand the role of HIV/AIDS in the aging process 3
Poll Question Which of the following are risk factors for osteoporosis in PLWHIV? A. Smoking B. HIV C. Hypogonadism D. Low BMI E. Only A and D F. All of the above 4 http://natap.org/2013/ias/ias_53.htm
2489 patient with HIV followed for 3 years for hip fracture vs noninfected cohort When traditional risk factors of smoking, low BMI, age, gender, glucocorticoid use, hypogonadism, comorbid conditions were adjusted for they showed that HIV was independently was higher risk than non-hiv patients May be related to proinflammatory affects of HIV and side effects of ART 5
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Effective Treatment Saves Lives 7
HIV and Aging PLWHIV are living longer and now seeing diseases of older age which was not previously seen before due to the success of cart PLWHIV who take ART are more likely to die of noninfectious complications vs infectious complications of HIV HIV can accelerate noninfectious diseases such as CV events since HIV acts as a proinflammatory state What are PLWHIV on successful ART dying from? Frailty Cardiovascular events- MI/CVA Diabetes related complications Malignancies
Analysis of longitudinal data from Modena HIV Metabolic Clinic (MHMC) cohort study in Modena, Italy Measuring frailty as a predictor of mortality using a frailty index score in 963 participants Frailty index scores at baseline and either died or were followed for four years
Frailty Index Frailty index score is calculated as the proportion of health deficits present out of all health variables considered Health variables can include CKD, osteoporosis, hypercholesterolemia, proteinuria and many others CD4 nadir, years of ART, age at diagnosis, co-morbidities, viral hepatitis Greater the frailty index score the higher the mortality rate
Female sex, higher current and nadir CD4 cell counts, and fewer smoking pack years had lower frailty index scores indicating lower mortality rates Frailty index scores can change over time with modifiable risks such as smoking How well someone with HIV ages depends on how frail they are
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Increased prevalence of smoking 2-3 times higher than general population in PLWHIV Increase due to low socioeconomic and educational levels, psychiatric comorbidity, concurrent illicit drug and alcohol use, and mental stress which are all higher in PLWHIV Current smokers had a significantly higher risk for all-cause mortality than former smokers and never smokers when controlling for age, race, sex, CD4 count, viral load COPD is more common and emphysema is accelerated in HIV-infected patients Other diseases such as periodontal disease, osteoporosis, HPV oral cancer and anal cancer increased with HIV + smoking than HIV alone or general population HIV/AIDS CID 2013:57 (15 July) 275
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Bone Loss and HIV Bone loss may occur not only due to HIV/AIDS but also as a consequence of HAART Estimated that 15% of PLWHIV develop osteoporosis and 52% osteopenia Protease inhibitors and TDF are highest amongst ART regimens for causing osteoporosis Bone loss is multifactorial- unclear if direct effect of HIV or as a consequence of traditional osteoporosis risk factors associated with patient lifestyle (smoking and alcohol consumption) Other AIDS-associated diseases like muscle wasting, kidney disease, and hypogonadism, low vitamin D levels increase bone loss Curr Opin Endocrinol Diabetes Obes. 2010 Dec; 17(6): 523 529.
Meta-analysis of 20 studies conducted Jan 1966- Nov 2005 Compared HIV-positive vs HIV-negative; ART-treated vs ART-naive;protease inhibitor (PI)- treated vs PI-untreated Of the 884 HIV-infected patients, 67% had reduced BMD, of whom 15% had osteoporosis compared with HIV-uninfected controls (n.654) using 11 studies with available data. Compared with ART-naive patients (n.202, 10 studies),art-treated individuals (n.824) had a 2.5-fold increased odds of prevalent reduced BMD. The risk of prevalent osteoporosis (seven studies) was similarly elevated in ARTtreated individuals. Compared with non-pi-treated HIV patients (n.410, 14 studies),pi-treated patients (n.791) had increased odds of reduced BMD and osteoporosis (12 studies) Prevalence of osteoporosis in HIV-infected individuals is more than three times greater compared with HIV-uninfected controls. ART-exposed and PI exposed individuals had a higher prevalence of reduced BMD and osteoporosis compared with their respective controls CIDS 2006, 20:2165 2174
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Poll Question Distal sensory polyneuropathy is the most common form of HIV associated neuropathy. Which of the following are risk factors for the development of neuropathy in PLWHIV? A. Low CD4 count B. Longer duration of untreated HIV C. High viral load D. Older age E. A, B, and C F. All of the above 22
HIV associated Neuropathy MC pain syndrome ~ 33% of PLWHIV affected Can occur as a complication of HIV/AIDS or related to ART NRTIs most common ART, incidence of neuropathy is related to the degree of mitrochondrial toxicity with certain nucleoside reverse transcriptase inhibitors (NRTIs) Didanosine and stavudine inhibit mitochondrial DNA synthesis more tightly than zidovudine, lamivudine Hypothesized that the HIV-1 envelope protein (gp120) may cause neuronal injury indirectly through Schwann cells by inducing upregulation of TNF-alpha, which may result in apoptotic death of sensory neurons https://www.practicalpainmanagement.com/pain/neuropathic/hiv-neuropathy/neuropathy-hiv-patients-pain-management-concerns
https://www.practicalpainmanagement.com/pain/neuropathic/hiv-neuropathy/neuropathy-hiv-patients-pain-management-concerns
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Grand Rounds Michael Rubin, MD Department of Ophthalmology and Visual Science The University of Chicago 2587840 HIV Retinopathy Most common retinal pathology in HIV, occurs in as many as 50-70% of PLWHIV Often manifests as cotton-wool spots Etiology is increased plasma viscosity, immune-complex deposition, and a direct cytopathic effect of HIV on the retinal vascular endothelium The arteriolar occlusion in HIV microvasculopathy leads to interruption of the axoplasmic flow, which manifests as cotton-wool spots No treatment except ART
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Noninfectious Pulmonary HIV Malignancy Inflammatory Pulmonary Vasculature AIDS Defining Non-AIDs Defining LIP NSIP Pulmonary HTN
Lung Malignancy AIDS-Defining HHV-8, EBV Kaposi s sarcoma Primary effusion lymphoma Non-Hodgkin s Lymphoma Am J Med Sci. 2014 Dec;348(6):502-11
Lung Malignancy Non-AIDS Defining Higher incidence than general population even with ART use Unclear etiology but increased tobacco use and level of immunosuppression related Occur at younger age, ~48 compared with gen population ~60, more aggressive advanced forms Adenocarcinoma is MC form Screening is similar to general population 32
Inflammatory Lymphocyte Interstitial Pneumonia- influx of lymphocytes into alveolar space, includes NSIP HIV-related proteins in germinal centers, pulmonary interstitium and BAL as likely a direct cause of HIV May be related to immune reconstitution inflammatory syndrome
Pulmonary Vasculature Pulmonary HTN Incidence estimated at 0.5% which represents relative risk of 1000 fold compared with general population Worse prognosis for PLWHIV + PH compared to PLWHIV alone Inflammation, genetics, intravenous drug use, coinfections and viral proteins may contribute Gp120 has been shown to target pulmonary endothelial cells and increase secretion of endothelin-1, a potent vasoconstrictor
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Noninfectious Gastrointestinal HIV Complications Nausea and Vomiting 2/2 to ART Chronic diarrhea 2/2 HIV enteropathy Pancreatitis 2/2 ART stavudine, didanosine, NRTIs, dolutegravir
HIV Enteropathy Chronic, well-established diarrhea (> 1 month duration) with no identified infectious cause after thorough evaluation Related to direct or indirect effects of HIV on the enteric mucosa a diagnosis of exclusion made after other forms of diarrheal illness have been ruled out Diarrhea 2/2 to ART : PI > NRTI> NNRTI > INSTI Gut-associated lymphoid tissue (GALT) is the largest collection of lymphoid tissue in the human body Persistent stimulation of the immune system by HIV in the gut Baseline inflammatory state that encourages the production of proinflammatory chemokines which mediate the movement of lymphocytes into the mucosal tissues, damage to gut epithelial cells ( gp 120), depletion of gut CD4 cells but increased CD8 cell that are primed to produce cytokines which may damage the mucosal barrier Even after starting ART, diarrhea can persists due to the damage of gut mucosa by HIV Dig Dis Sci. 2015; 60(8): 2236 2245.
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Poll Question 60 Y AA M with CD4 20, VL 1mil, new dx, presents on initial visit with flank pain. You obtain an UA which shows 3+ proteinuria and Cr 4.0, no baseline to compare. What should you do next? A. Obtain a renal biopsy to confirm FSGS B. Start ART immediately C. Obtain a renal US D. A and C 41
HIV Associated Nephropathy (HIVAN) Complication of untreated advanced HIV/AIDS Most predominant in African Americans with 90% of cases Rapidly progressive renal failure Moderate to nephrotic range proteinuria Bland urinary sediment Ultrasound findings of large, highly echogenic kidneys HIVAN is a collapsing glomerulopathy of focal segmental glomerulosclerosis (FSGS)
HIVAN Pathogenesis of HIVAN requires local HIV infection of the kidney, with the virus infecting tubular and glomerular epithelial cells ART is effective at preventing and reversing HIVAN hence should be started immediately even without a genotype HIVAN has become less prevalent with ART use
Semin Nephrol. 2008 Nov; 28(6): 513 522.
Tenofovir related Fanconi Syndrome Tenofovir disoproxil fumarate affects the proximal renal tubule Glucosuria, proteinuria, elevated urine potassium Hypokalemia, hypophophatemia, metabolic acidosis TDF has higher circulating plasma levels leading to more renal and bone disease vs TAF which goes directly to tissue causing lower plasma concentrations
HIV affects every organ Cardiovascular Bone Dermatologic Neurologic Ocular Pulmonary GI tract Renal Endocrine system
Hypogonadism Occurs more frequently in poorly controlled or uncontrolled HIV/AIDS but prevalence is decreasing with ART Measured by morning (before 10am) total testosterone Male hypogonadism can lead to osteoporosis, erectile dysfunction/decreased libido, reduced lean body mass/muscle strength, depression, and the metabolic syndrome Used to be more frequent among men with the AIDS and was attributed to testicular dysfunction due to opportunistic infections, cancers, wasting syndrome, and cytokine disorders With ART use, now found to be related to hypothalamicpituitary axis impairment, aging,and comorbidities (alcoholism, hepatitis C, and injecting drug use) AIDS: January 28th, 2017 - Volume 31 - Issue 3 - p 451 453
Prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point 744 patients or incidence rate of 5.72 per 1,000 person year follow up The incidence of diabetes increased with cumulative exposure to cart, an association that remained significant after adjustment for potential risk factors for diabetes NRTIs and Protease Inhibitors cause insulin resistance leading to increased blood glucose levels and Type 2 diabetes Do not need to stop or change ART, lifestyle modification followed by diabetes medication Consider avoiding PI if a patient already has diabetes prior to HIV diagnosis
Thank you! 49