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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

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http://natap.org/2013/IAS/IAS_53.htm

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• 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

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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

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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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