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1
Didactic Series
Non-Infectious Complications of HIV
Ankita Kadakia, MD
UC San Diego, Owen Clinic
November 8, 2018
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DisclosuresThe 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.
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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
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
5555
• 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
HIV affects every organ
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
HIV/AIDS • CID 2013:57 (15 July) • 275
• 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 affects every organ
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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 above22
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
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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
Grand Rounds Michael Rubin, MD Department of Ophthalmology and Visual Science The University of Chicago 2587840
HIV affects every organ
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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 population32
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
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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
• With discontinuation of TDF most patients
HIV affects every organ
system• Cardiovascular
• Bone
• Dermatologic
• Neurologic
• Ocular
• Pulmonary
• GI tract
• Renal
• Endocrine
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 hypothalamic-pituitary 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!
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