hiv 2012: you are only as young as your immune system.. daniel nixon do, phd associate professor of...
TRANSCRIPT
HIV 2012: You are only as YOUNG as
your Immune System..
Daniel Nixon DO, PhDAssociate Professor of Medicine Director – VCU HIV/AIDS Center (http://www.hivcenter.vcu.edu/)
[email protected] Office 804-828-4510
HIV…we now know where it came from and when (slide from Paul Sharp’s 2006 CROI
lecture)
When? Between ~ 1884 and 1924Nature. Oct 2, 2008
“Rumble in the Jungle”
Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases
Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010
> 500 VL>5K VL>10K
350-500
VL>5K VL>5K
200-350
<200
CD4 1996
1998
2000
2002
2004
2006
2008
2010
Guidelines 2012: When to Start ART
Guideline HIV with symptoms or Hep B/C
Asymptomatic/No Hepatitis – CD4
<200 200-350 350-500
DHHSMar2012 Yes Yes Yes Yes (mod Rec)
IAS-USA Yes Yes Yes Yes
BHIVAFeb2012 Yes Yes Yes Defer
EACSOct2011 Yes Yes Yes Concider
WHO Yes1 Yes Yes No
1initiate at any CD4 if Hep B or active TBGuidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents - www.aidsinfo.nih.gov
Conflicting Evidence from Observational Studies for Initiating ART with CD4 > 350
Comparison CD4+ count strata HR for death
NA ACCORD <350 vs 350-500 1.7 (1.3 - 2.3) 350-500 vs > 500 1.9 (1.4 – 2.8)
ART CC 251-350 vs 351-450 1.1 (0.8 - 1.6)
351-450 vs 451-550 0.9 (0.6 - 1.4)
HIV-Causal 350 vs 500 1.0 (0.8-1.2)
• Kitahata MM et al, N Engl J Med 2009 • When to Start Consortium, Lancet 2009• HIV Causal Collaboration, Annals Int Med, 2011
CD4 at Initiation of ARV Therapy Predicts Extent of CD4 RecoveryCD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery
• 1,378 Patients at 10 US Clinics followed From 1996-2007
• Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001)
• Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD4 50-199 (HR=2.6) compared to 350 cells/mm3
• Lower baseline CD4 at initiation also associated with increased risk of death from non-AIDS-related causes
Med
ian
CD
4+ c
ell c
ou
nt
Palella F, et al. 17th CROI, 2010
Evidence from Randomized Trials for Initiating Treatment at CD4 200-350
• CIPRA-HT001 – a single center trial in Haiti – 2/3 of patients were clinical stage 2 or 3 and the median CD4+ count
at initiation in the deferred ART group was 166 cells/mm3 (IQR: 130, 190).
• SMART study - post-hoc analysis – Only involved 477 patients and of these only 249 were ART-naïve.
• HPTN 052 – Deferral strategy was 200-250 cells; significant difference in
extrapulmonary TB; not powered to address survival (10 versus 13 deaths).
Continuous ART at CD4> 350 associated with decreased serious non-AIDS Events in Subset of “relatively” Naïve to ART in SMART
DC Group VS GroupHR (DC/VS)
Deferred vs. EarlyP-valueN Rate N Rate 95% CI
• OD or death 15 4.8 4 1.1 4.4 [1.5, 13.2]0.009
• OD fatal or non-fatal 11 3.5 3 0.8 4.4 [1.2, 15.8]0.02
• Serious non-AIDS 12 3.9 2 0.5 7.1 [1.6, 31.5]0.01
• Composite 21* 7.0 5 1.3 5.1 [1.9, 13.5]
0.001Emery et al, JID, April 2008
HPTN 052:ART prevents HIV transmission
• 1763 discordant couples (one HIV-infected partner)• Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand,
Zimbabwe (+ single US couple)• CD4 count at entry: 350 – 550 cells/mm 䔡
• Index case randomized to IMMEDIATE ART vs DEFERRED ART– Deferral until CD4 count drops to < 250 cells/mm 䔡 or disease
– RESULTS:
• 1 new HIV infection in partners of those on ART• 27 new HIV infections in partners of those deferring ART• 96% efficacy of ART to prevent transmission in this
population!!
•
START Study
HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3
Early ART Group
Initiate ART immediately following randomization
N=2,000
Deferred ART Group
Defer ART until the CD4+ count declines to < 350 cells/mm3 or
AIDS develops
N=2,000
What to Start 2012: DHHS Initial ART Recs
NNRTI based • Efavirenz1 + Tenofovir/Emtricitibine (TDF/FTC) daily
Protease-Inhibitor based
• Atazanvir or Darunavir with low dose Ritonavir “boosting agent”+ TDF/FTC daily
Integrase Inhibitor based
• Raltegravir bid + TDF/FTC daily
Pregnant Women • Lopinavir/Ritonavir bid + AZT and Lamiviudine bid
1. EFV NOT to be used during the 1st trimester of pregnancy or in women who are not using effective and consistent contraception.
HIV drugs and especially protease inhibitors have many Interactions..
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. March 29, 2012. www.aidsinfo.nih.gov.
FDA drug safety communication, March 1, 2012, www.fda.gov
Statins Interacting Protease Inhibitor
Prescribing recommendation
Atorvastatin Tipranavir/r
Lopinavir/r
Darunavir/rFosamprenavir
Fosamprenavir/rSaquinavir/r
Nelfinavir
Avoid concurrent administration
Use with caution and lowest dose
Do not exceed 20 mg atorvastatin
Do not exceed 40 mg atorvastatin
Fluvastatin No data available
Lovastatin/Simvastatin Contraindicated
Pitavastatin Atazanavir/rDarunavir/rLopinavir/r
No dose limitations
Pravastatin Darunavir/rLopinavir/r
No dose limitions
Rosuvastatin Atazanavir/rLopinavir/r
Do not exceed 10mg
Statins
Survival Trends in HIV-infected Patients Have Changed Since the
Adoption of HAART
Survival Trends in HIV-infected Patients Have Changed Since the
Adoption of HAART
Lohse N, et al. Ann Int Med. 2007
Cumulative survival curve for HIV-infected persons (without hepatitis C coinfection) and persons from the general population. N=383,862 (HIV-infected patients, n=3990; General population controls, n=379,872)
Survival From Age 25 Years
1
0.75
0.5
0.25
0
25 30 35 40 45 50 55 60 65 70
Age (years)
Pro
ba
bil
ity
of
Su
rviv
al
Population
Controls
Late HAART (2000-2005)
Early HAART (1997-1999)
Pre-HAART (1995-1996)
HIV - the Good News & the Bad• Antiretroviral drugs have tripled average life
expectancy over the last decade, by reducing opportunistic infections, however:
•
– In ART era only ~10% deaths in HIV infected clinical trials subjects were due to AIDS defining illnesses.
Non-AIDS malig ~ 21%CVD ~ 9%
Liver Disease ~ 9%Non-AIDS Infection ~8%
In addition to reducing AIDS/Death, ART reduces serious Non-AIDS Outcomes
No. of Patients with EventsEndpoints
Major CVD, hepatic or renal disease 104 1.8 1.1CVD+ 79 1.3 0.8
Hazard Ratio (95% CI)
RateDC VS
Renal (ESRD) 11 0.2 0.1
1.4Hepatic (Cirrhosis) 17 0.3 0.2
0.1 1 10
1.4
4.5
1.7
Non-AIDS Malig++ 47 0.8 0.5
1.8
1.6
Favors DC Favors VS
Other non-AIDS death 51 0.9 0.5
Any of the above 186 3.2 2.0
1.6
+ MI (clinical or silent), stroke, surgery for CAD++ Except non-melanoma skin
The SMART Study Group. N Engl J Med 2006
INFLAMMATION?? Inflammatory Biomakers are Elevated with HIV (SMART) compared to non-HIV (MESA)
Neuhaus J et al. JID 2010
SMART Nested Case Control Biomarker Study (85 cases/170con)
Conditional logistic used to estimate ORs for mortality (lowest quartile as reference)
Adjusted OR consider covariates corresponding to: age, race, ART, HIV RNA, CD4+ count, BMI, total/HDL cholesterol, smoking, diabetes, Hep B/C co-infection, use of lipid and BP lowering medication
Baseline Biomarkers and All Cause Mortality
Un-adjusted Adjusted
Marker OR (4th/1st) P-value OR (4th/1st) P-value
hs-CRP 2.0 0.05 3.1 0.02
Amyloid A 2.2 0.07 3.1 0.05
Amyloid P 0.7 0.39 1.1 0.78
IL-6 8.3 <0.0001 12.4 <0.0001
D-dimer 12.4 <0.0001 41.2 <0.0001
F1.2 1.0 0.92 1.3 0.64
Kuller L et al, PLoS Med 2008
D-dimer: Effect of ART Interruption (DC) for Participants on ART and with an HIV-RNA ≤ 400 copies/mL
0
0.2
0.4
0.6
0.8
DC Group
VS Group
Baseline Month 1
Med
ian
(IQ
R)
D-d
imer
(µ
g/m
L)
P<0.001 (27% increase in DC)
Kuller L et al, PLoS Med 2008
D-dimer: Effect of ART Initiation (VS) for Participants Not on ART at Entry
Stored plasma for 254 subjects (126 DC arm, 128 VS arm), naïve to ART or off ART >6 mo analyzed for IL-6, hs-CRP, & D-dimer (baseline, mo 2 & 6)
0
0.5
1
Med
ian
(IQR
)D-d
imer
(µg/
mL)
Baseline Month 6Month 2
P<0.001P=0.002
DC Group
VS Group
Baker JV et al. JAIDS 2010
(22% lower for VS)
Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals
Biomarker Odds ratios*: 1st vs 4th Quartile Effect of HAART Other HIV disease Associations
D-dimer 12.4 (SMART), 2.4 (FIRST) 2.6 (Phidisa)
Decreases CVD
hs-CRP 2.0 (SMART), 2.1 (FIRST), 3.6 (Phidisa)
No decrease CVD, OD
IL-6 8.3 (SMART), 1.8 (FIRST), 3.8 (Phidisa), 1.5** (ACTG 384 and 5015 )
May decrease CVD, OD
sCD14 6.0 (SMART) Unknown Microbial translocation
• While HAART partially reduces some biomarker levels, they still remain elevated compared with healthy non-HIV infected individuals
But where would the inflammation be coming from??
Infection destroys gut-associated lymphoid tissue within 4 weeks of infection
-> Recovery is impaired, even with ART..
Brenchley JM et al J Exp Med. 2004
HIV-induced gut CD4+ T-cell depletion leads to LPS/microbial translocation into the circulation
-> CHRONIC IMMUNE ACTIVATION
Brenchley, JM et al. Nature Medicine 2006
Excessive CD8+T-cell stimulation and activation predicts CD4+ depletion and AIDS
• CD8+ T-cell activation is predictive of HIV disease progression, independent of HIV viral load (Giorgi JV et al. JID 1999 Calbone J et al. AIDS 2000)
• Patients with HIV viremia fully suppressed by ART that have blunted CD4 recovery show continued CD8+ T-cell activation (Anthony KB et al. JAIDS. 2003, Hunt PW et al. JID 2003)
• Elite controllers not on ART with undetectable HIV RNA & CD4 depletion have CD8+ T-cell activation (Hunt PW et al. JID 2008)
– Note: that CD8 “activation” refers to expression of cell surface markers (e.g. CD38 and HLA-DR)..in REALITY, the CD4/CD8 cells are hypoactive/anergic functionally in setting of HIV infection
“Inflamm-aging” - Francesch C. et al. Ann NY Acad Sc 2000
De Martinis M et al. Exp and Mol Path 2006
HIV and “Inflamm-aging”• HIV infection shares numerous clinical similarities w/ aging
– increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
HIV and “Inflamm-aging”• HIV infection shares numerous clinical similarities w/ aging
– increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
• HIV infection results in T-cell activation and Immunosenescence
– In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
– Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people
HIV and “Inflamm-aging”• HIV infection shares numerous clinical similarities w/ aging
– increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
• HIV infection results in T-cell activation and Immunosenescence
– In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
– Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people
• HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009)
HIV and “Inflamm-aging”• HIV infection shares numerous clinical similarities w/ aging
– increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
• HIV infection results in T-cell activation and Immunosenescence
– In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
– Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people
• HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009)
• As with increased CD8+ T-cell activation, increased senescence (reduced CD28 expression on CD8+ & CD4+ T cells) associated with more rapid HIV disease progression (Cao W et al. JAIDS 2009)
CMV and “Inflamm-aging”• CMV+ adults over ~ 65y/o have a much greater expansion
of CD28- cells than age-matched CMV- controls – many of these cells reflect the oligoclonal expansion of CMV-
specific T cells Hadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005
CMV and “Inflamm-aging”• CMV+ adults over ~ 65y/o have a much greater expansion
of CD28- cells than age-matched CMV- controls – many of these cells reflect the oligoclonal expansion of CMV-
specific T cells Hadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005
• Clinical significance of these findings is not clear, however, it has already been shown that:– CMV+ older persons are less likely to respond to vaccines
than age-matched, CMV- persons Trzonkowski P et al. Vaccine 2003
– CMV-associated changes in the immune system are predictive of early mortality among older persons Hadrup SR et al. J Immuno 2006, Wikby A et al. J Gerontol 2005
CMV & the Swedish OCTO and NONA
studies• 231/240 individuals– mean age of ~ 90 years– followed longitudinally x 4+yrs– Grouped by Immune Risk
Profile
.
Pawelec G et al. Immuno Reviews 2005
T-cells are not the only problem…HIV infection Associated w/ BOTH Adaptive
and Innate Immune System Activation • Excess CD4 and CD8 T-cell activation observed in
patients with HIV– Increased CD8 HLA-DR/CD38 expression associated with rapid
CD4 loss, impaired CD4 recovery, poor immunologic responder on ART, & accelerated immune senescence
• Excess B-cell activation observed in patients w/ HIV – Hypergammaglobulinemia, Autoantibodies
• Excess Platelet activation observed in patients w/ HIV – Increased expression of TF, P-selectin, sCD40
• Excess Monocyte/Macrophage activation w/ HIV– Increased expression of TF, CD14/sCD14 – NOTE: CMV infection of monocytes differentiation to
proinflammatory “M1” macrophages (Chan G et al. J Immun 2008)
•
Macrophage Activation and HIV-Associated Vascular Disease
Moore KJ Cell 2011
HIV+ persons are at 2-fold risk for CHD “risk equivalent”
Freiberg CROI 2011
CHD Risk Factors:Traditional and HIV-specific
CHD Risk
HIV Infection
AntiretroviralTherapy
Lipids & Lipoproteins
EndothelialInjury and
Inflammation
Hypertension
Smoking
Metabolic Disease(hyperglycemia, insulin resistance, and obesity)
Age Gender FamilyHistory
Biomarkers and Cardiovascular Disease:SMART: HDL, D-dimer, IL-6, CRP, & NT-pro-B BNP associated with CVD
• Baseline hsCRP (p<0.0001), IL-6 (p<0.0001), & D-dimer (p=0.0008) elevated in CVD cases
• Total HDL (p<0.0001) was reduced in CVD cases– HDL negatively associated with D-
dimer and IL-6 (R= -0.25)
• N-terminal pro-B-type Natriuretic Peptide elevated in CVD (OR highest vs. lowest quartile – adjusted = 2.3, P =0.02)
Duprez D.A. et al. Atherosclerosis 2009Duprez D.A. et al. 17th CROI 2010
Modulating Immune Activation:
AspirinPopulation ASA
doseDesign CRP IL-6 TNF-α
Chronic stable angina 300mg Placebo controlled
--
Metabolic syndrome 300mg Placebo controlled
Metabolic syndrome 100mg Placebo controlled
NS NS
Post-myocardial infarction
160mg vs. warfarin --
Diabetes (Type 2)* 300/100mg
Dose comparison
NS* NS* --
Healthy volunteers 325mg Cross-over NS NS NS
Circulation 1999, Diab. Ob. Met 2008, JPP 2009, AJC 2003, AJC 2003
*Levels declined after starting aspirin but did not reach significance for either dose (n=20/arm)
Relative Risk of MI by baseline CRP Stratified by Aspirin (325mg QOD) versus Placebo
Ridker et. al. NEJM 1997
However, A 2009 Lancet Meta-analysis of RCTs found that: Aspirin is of uncertain net value as primary prevention of vascular diseaseHowever, A 2009 Lancet Meta-analysis of RCTs found that: Aspirin is of uncertain net value as primary prevention of vascular disease
Modulating Immune Activation: ACTG A5275 - Atorvastatin
• Why look at statins in (non-hyperlipidemic) HIV+ patients?– Blocking HMG-CoA reductase with a statin reduces activation of GTP-
binding proteins RAS and Rho - “molecular switches” that regulate transcription of inflammatory response genes
– Statins inhibit expression of IL-6 (hs- CRP), TF (d-dimer), sCD14, and TNF-a– Statins decrease CD8+ T-cell activation– Statins reduce these biomarkers in numerous settings (e.g. sepsis,
pneumonia, influenza, COPD, hepatocellular CA, CVD)
• JUPITER Study– Rosuvastatin decreased mortality and venous thrombotic disease in
subjects with hsCRP>2 mg/L and “normal” LDL (<130 mg/dl)
– Individuals achieving hsCRP < 2 mg/L (entry criteria >2) had 62% decrease in events
–
• Ridker et al. NEJM 2008, Ridker et al. Lancet 2009
MI Rates by SBP & HIV Status in VACS
<120 120-124 125-129 130-134 135-139 140-144 145-149 150-154 155-159 >160 .0
200
400
600
800
1000
HIV(-) HIV(+)
Systolic BP (mmHg)
AMI r
ate
per 1
0,00
0 p-
y
Armah & Freiberg CROI 2012
SBP Category (mmHg):
<120 120-139 <140 (on Rx) ≥140
aHR for HIV uninfected ref 1.1 1.2 1.4
aHR for HIV infected ref 1.7 2.8 2.8
* Adjusted for age, race/ethnicity, diabetes cholesterol, smoking, HCV, BMI, renal disease, and cocain/EtOH
Brusselle et al. Lancet 2011
Macrophage Activation and HIV-Associated Pulmonary Disease
• Alveolar Macrophage expression of Matrix MP from HIV+ smokers w/ early emphysema >> than in HIV- smokers w/ early emphysema – Kaner RJ et al. J. Leuk Bio 2009
• HIV and Matrix MP co-localize to areas of empysema at autopsy
Crothers K et al. Am J Resp Crit Care Med 2011
VA Cohort (n=100,000 matched)
Yearsly MM et al. Diag Mol Path 2005
Macrophage Activation and HIV-Associated Bone Density Loss
• HIV infection associated with an increased risk (~3X higher that HIV neg) of osteopenia, fracture, and avascular necrosis of bone
• Bone is an immunologically rich tissue & activated macrophages, T-cells, osteoclasts, & inflammatory cytokines play a central role in accelerated bone loss
Mansky KC Clin Interventions in Aging 2010
HIV and Osteopenia – Some Issues
• DXA Scanning if >50 y/o (McComskey et al. CID 2010)
• Quit Smoking and Drinking (>3drinks/d)!• Treat Hypogonadism or Hypothyroidism• Weight Bearing Exercise• Safe Home • Vit D – treating low Vit D (<25 ng/dl) reasonable
– Efavirenz is associated with reduction in 25-hydroxy vit D levels – Limited data on vitamin D supplementation in HIV-positive
patients have shown transient, beneficial effects on PTH, but no effects on BMD.
• Bisphosphonates effective (6 RCTs) – Treat with t-score ≤ 2.5 or -1.0-2.5 with FRAX 10 year fracture
prob score >20 (NOF 2008) • Protease Inhibitors and Tenofovir as Risks?
– Avoid starting protease inhibitors if possible with t-score ≤ 2.5
Biomarker DC-arm VS-arm p-value forInteraction
OR (95% CI)a p-value OR (95% CI)
p-value
sCD14 (x106 pg/ml) 3.5 (1.5,8.3) 0.004 2.0 (0.8,5.4)
0.15 0.43
LPS (pg/ml) 1.0 (0.6,1.7) 0.96 0.7 (0.3,1.7)
0.40 0.63
I-FABP (pg/ml) 0.9 (0.4,2.1) 0.84 2.3 (0.6,8.8)
0.19 0.58
16S rDNA (copies/l) 0.9 (0.3,2.2) 0.90 0.5 (0.2,1.4)
0.21 0.26
EndoCAb (MMU/ml) 1.1 (0.8,1.6) 0.49 0.9 (0.5,1.4)
0.66 0.57
Macrophage Activation and HIV-Associated Mortality
Only sCD14 levels* (a marker of monocyte/macrophage activation) are associated with mortality among microbial translocation biomarkers
*after adjustment for other risk factors/biomarkers 1st/4th OR = 4.1 (p=0.02)
Sandler N. et al J. Infect Dis. 2011
Model of HIV induced “Aging”
Desai S and Landay A Curr HIV/AIDS Rep 2010
Model of VIRAL induced “Aging”
Activated Macrophages and T-cells produce IL-6, MMP, etc. in brain, bone, lung, liver, vasculature ~ tissue level
HCVCMV
Bact 16sDNA
LPS
CMV
HIV
Take Home Points• Chronic antigen (HIV, LPS, CMV, HCV, etc.) stimulation
leads to excessive stimulation/activation of ALL arms of the immune system
• Chronic immune activation leads to an immune system more likely to cause tissue inflammation & less likely to do its job! This has implications that extend well beyond HIV!– Premature aging – senescence and hypofunction of
the immune system– Progression to AIDS– End organ damage
• Inflammation correlates with many bad outcomes– Treating HIV helps & should be done but doesn’t
entirely halt this problem– Numerous strategies to modulate immune
activation/inflammation under study
Take Home Points• Inflammation also increased by:
– Smoking: e.g. a study found that HIV - women who stopped smoking showed decreased levels of CRP, IL-6, TNF-alpha within weeks after quitting
– Diet / Obesity: adipocytes are “cytokine factories”
– Other common disease processes like diabetes
• Role of PCP: Managing these sources of inflammation, CVD risk reduction (e.g. BP, ASA, Statin), alcohol cessation, expanded cancer and bone density screening, helping with adherence, watch drug-drug interactions, & STD risk reduction
• Don’t forget routine OPT-OUT HIV testing.. Inpatient, outpatient, ED
THANK YOU for your ATTENTION!