1

Challenging Cases from the CCC: Substance Use and ARV Switching in Medically-

Complex Patients

Benjamin Smith, MD MPH; Jason Tokumoto, MD Clinician Consultation Center

January 12, 2017

“Inheriting” Patients in the Era of the Opioid Epidemic

Benjamin Smith, MD MPH

CCC Substance Use Warmline

http://nccc.ucsf.edu/clinician-consultation/ substance-use-management/

Gaining Press

4

Learning Objectives

1) Convey the scope of the opioid epidemic 2) Highlight similarities in approaches to

addressing both the HIV epidemic and opioid epidemic

3) Review risk stratification in opioid users 4) Review best practices for care of opioid

users 5) Emphasize harms reduction approach

Rising Epidemic of Opioid Deaths

CDC.gov, 2016

Echoes of HIV Epidemic

CDC.gov, 2016

Two Epidemics

0

10000

20000

30000

40000

50000

60000

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Chart Title

AIDS Deaths Opioid Deaths

CDC.gov, 2016

Similar Approaches to Epidemics

Williams, 2016

Lessons from HIV Epidemic that can be transferred to Opioid Epidemic

Training and support of front-line providers (AETC) Increased coverage for medical treatment (AIDS Drug Assistance Program) Funding and enrollment into psychosocial services (Ryan White) Harms reduction approaches to patients Rapport-building and relationship-centered care

“Too often, treatment centers operate under outdated institutional ideologies favoring abstinence-only approaches that are modeled on mid-20th-century alcoholism treatment involving traditional counseling.”

Case Discussion Mr. G is a 34yo male with HIV (Dx @ age 29) on ARVs. He has a h/o PTSD from childhood abuse as well as chronic LBP from a MVA 7 years ago, treated with Oxycodone/ Acetaminophen 10/325mg. He’s currently prescribed 200 tablets per month but still reports “10/10” pain. He’s transferring to you because his last provider ”made me feel like a drug addict.” Other social history: sexually active with other men, and periodically homeless

What More Do You Want to Know?

A) History of treatment modalities (past opioid, behavioral, non-opioid, etc.)? B) History of substance use, diversion, “doctor shopping?” C) Response to opioid treatment, side effects, pain relief, level of functioning? D) Details about homelessness, mental health, social circumstances? E) Information about symptoms of withdrawal, tolerance, cravings?

34yo HIV+ with chronic pain, on Oxy/APAP 10/325mg #200 tabs/month.

No longer in care with last provider because “he made me feel like an addict”. Co-morbid PTSD, unstable housing.

Schuckit MA. N Engl J Med 2016;375:357-368.

Diagnostic Criteria for Opioid-Use Disorder

Schuckit MA. N Engl J Med 2016;375:357-368.

Diagnostic Criteria for Opioid-Use Disorder

Different Ways of Risk Stratifying

Gourlay, 2009

Risk Stratifying Leads to Placement Decisions

ASAM, 2017

Mr. G, cont’d Mr. G has always been on time for his appts, and typically has not requested early refills. He has had urine toxicology screens that show no evidence of misuse. His dose has increased over time, with his previous physician initially prescribing oxy/APAP 10/325mg #60 per month one year ago, increasing to #200 per month at present. He was actively seen by psychiatry, and is on venlafaxine for anxiety and pain. Immediately after each dose, he feels less pain and is able to function better, but has needed to increase the # of tablets because “6/day doesn’t quite cut it.” He states he has increasing pain, cramping, and some nausea right before his next dose. Review of past records brings up his previous doctor’s reluctance to prescribe higher amounts over time.

What is the Patient’s Diagnosis?

A) Opioid Use Disorder, Severe

B) Opioid Use Disorder, Moderate

C) Opioid Use Disorder, Mild

D) Substance Dependence

E) Disordered Use

What is your next step?

A) Discontinue opioids

B) Taper opioids

C) Controlled substance contract

D) Discuss methadone/buprenorphine

E) Refer

Lum 2011

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Discuss substanceuse issues

Urine Tox Screening Screening for Misuse Use of PrescriptionMonitoring

Chart Title

Routinely Selectively Never

Opioid Prescribing: HIV Providers’ Comfort with Best Practices

Lum, 2011

Best Practices for Chronic Opioids

CDC, 2016

What’s Driving Mortality Uptick?

Compton WM et al. N Engl J Med 2016;374:154-163.

Decline in Prescription Opioids, Rise in Heroin

Opioids Epidemic Leads to HIV Outbreak

NPR.org, 2016

Harms Reduction is Efficacious

Fiellin, 2015

Opioid Harms Reduction Can Happen in HIV Primary Care

HRSA.gov, 2012

25

References • "American Society of Addiction Medicine." What is the ASAM Criteria. N.p., n.d. Web. 04 Jan. 2017. • Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 12 Dec. 2016. Web. 04

Jan. 2017. • Fiellin, David, Christopher J. Cutter, Brent A. Moore, Declan Barry, Patrick OTm)Connor, and Richard S.

Schottenfeld. "Primary care buprenorphine detoxification vs. maintenance for prescription opioid dependence." Drug and Alcohol Dependence146 (2015): n. pag. Web.

• Gourlay, Douglas L., and Howard A. Heit. "Universal Precautions Revisited: Managing the Inherited Pain Patient." Pain Medicine 10.Suppl 2 (2009): n. pag. Web.

• "Integrating Buprenorphine Therapy Into HIV Primary Care ..." N.p., n.d. Web. 4 Jan. 2017. • Lum, Paula J., Sherri Little, Michael Botsko, David Hersh, Robert E. Thawley, James E. Egan, Jennifer Mitty,

Joshua Boverman, and David A. Fiellin. "Opioid-Prescribing Practices and Provider Confidence Recognizing Opioid Analgesic Abuse in HIV Primary Care Settings." JAIDS Journal of Acquired Immune Deficiency Syndromes56 (2011): n. pag. Web.

• Rudd, Rose A., Puja Seth, Felicita David, and Lawrence Scholl. "Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015."MMWR. Morbidity and Mortality Weekly Report65.5051 (2016): 1445-452. Web.

• Schuckit, Marc A. "Treatment of Opioid-Use Disorders." New England Journal of Medicine 375.4 (2016): 357-68. Web.

• Williams, Arthur R., and Adam Bisaga. "From AIDS to Opioids — How to Combat an Epidemic."New England Journal of Medicine375.9 (2016): 813-15. Web.

• "Inside A Small Brick House At The Heart Of Indiana's Opioid Crisis." NPR. NPR, n.d. Web. 04 Jan. 2017.

Questions?

26

ARV Switching in Medically-Complex Patients: HBV

Reactivation and HIV

Jason Tokumoto, MD CCC HIV Warmline, Perinatal HIV Hotline http://nccc.ucsf.edu/clinician-consultation/

hiv-aids-management/

28

Learning Objectives 1) Define HBV reactivation 2) Describe the interplay between HBV

serological status, level of HBV viremia, and “trigger” potency

3) Assess risk for HBV reactivation among PLWH

4) Identify appropriate ARV regimen options that can prevent HBV reactivation

Group Poll: What Would You Start?

60yo M undergoing chemotherapy for lymphoma, recently diagnosed with HIV (CD4 = 120 cells/mm3, VL = 130k copies/mL) Baseline GT: no significant RT, PI, INSTI resistance HLA-B*5701 negative Normal renal and hepatic function HbsAg neg, HBcAb pos, HBsAb neg, HCV Ab neg

Group Poll: What Would You Start?

60yo M on chemotherapy, new Dx HIV (CD4 = 120 cells/mm3, VL = 130k copies/mL) Baseline GT: no resistance Normal renal, liver function HLA-B*5701 negative Isolated HBcAb positive

A) ABC/3TC/DTG D) TAF/FTC + once-daily DRV/r B) TAF/FTC/RPV E) Other C) EVG/cobi/TAF/FTC

CCC HIV Warmline Call

53yo M has been on TDF/FTC + once-daily DTG x 2 years (CD4 = 60s, VL = undetectable) Other history: CKD (CrCl = 37.5 mL/min); autoimmune hemolytic anemia (treated with rituximab & high-dose prednisone); remotely-treated hepatitis C; portal hypertension; hypothyroidism; MAC Other Rx: rifabutin, clarithromycin, furosemide, spironolactone, levothyroxine, iron, folic acid, omeprazole Labs: Hgb 8, platelets 114k AST/ALT 29/18, total bili 0.9, INR normal HbsAg neg, HBcAb pos, HBsAb neg, HBV DNA UD

Caller’s Question

Is TDF/FTC + DTG the best regimen for this patient, all things considered?

33

HBV life cycle

34

Natural History of HBV Chronic HBV: prevalence HIV-negative 5-10% HIV-positive 20% Acute HBV infection: serologic recovery HBcAb positive HBsAg negative HBsAb positive or negative Serum HBV DNA undetectable However, HBV DNA persists in minute amounts in the hepatocyte nucleus as covalently closed circular (ccc) HBV DNA - ccc HBV DNA is competent to undergo replication!

Virologic & serologic response to HBV (http://depts.washington.edu/hepstudy)

35

What about HIV-HBV co-infection?

HIV’s effect on HBV: – ↑ progression of liver disease in

those with chronic HBV – ↑ risk for cirrhosis – ↑ mortality from HBV-related

liver disease HIV also appears to ↑ HBV reactivation risk

HIV associated with “occult” HBV: most common serological pattern is “isolated positive HBcAb”

“Occult” HBV • Prevalence: 0.63% to 88.4%

• Presence of HBV DNA (low level, < 200

IU/mL) with undetectable HBsAg • Most common serologic presentation is

“isolated positive HBcAb” • Clinical significance of occult HBV infection in

HIV unknown, but it does place patient at risk for HBV reactivation (few case reports)

36

37

Isolated HBcAb in HIV Up to 42-45% of HIV-positive patients have isolated positive HBcAb*

– Occult HBV frequency in isolated positive HBcAb controversial – Swiss Cohort Study: 60% of patients who had isolated HBcAb had

occult HBV infection – In another study of 85 HIV-positive patients with isolated HBcAb,

none had occult HBV infection

In some studies, isolated HBcAb is associated with HCV infection [*Note: 4 interpretations]

38

Isolated HBcAb and HCV

(Gandhi CID,2003)

HBV reactivation HBV reactivation = sudden increase in serum HBV DNA levels associated with increasing ALT (flare)

39

HBV serologic status

Degree of HBV

viremia Potency

of “trigger”

Risk for reactivation Host factors? (i.e. HIV status)

40

HBV reactivation • No established “standard” definition • 2 key elements:

– Abrupt rise in HBV DNA of 1 log (10-fold) – 2-fold or greater ALT increase

• Mechanism: disruption of host’s immune control over viral replication

• Clinical spectrum: clinically inapparent acute liver failure and death (overall mortality rate ~10%)

• Most useful predictor: – Baseline serum HBV DNA level > 2000 IU/mL (HBeAg positive is also predictive of ↑ risk– it generally implies serum HBV DNA is > 20,000 IU/mL)

Serological status and risk for HBV reactivation

Resolved infection:

HBcAb + Serum HBV DNA undetectable

Occult infection: HBcAb + Low level serum HBV DNA (< 200 IU/mL)

Inactive HBsAg carrier:

HBcAb + Low level serum HBV DNA HBsAg +

Active chronic HBV: HBcAb + High serum HBV DNA HBeAg +

41

Serological status and risk for HBV reactivation

Resolved infection:

HBcAb + Serum HBV DNA undetectable

Occult infection: HBcAb + Low level serum HBV DNA (< 200 IU/mL)

Inactive HBsAg carrier:

HBcAb + Low level serum HBV DNA HBsAg +

Active chronic HBV: HBcAb + High serum HBV DNA HBeAg +

42

Drugs associated with HBV reactivation

43

High potency

Intermediate potency

HCV DAAs

Risk of HBV reactivation

44

45

HBV Reactivation: Prevention Antiviral prophylaxis (studies based on patients with various malignancies)

• Drugs with high genetic barrier to resistance preferred

– Tenofovir (includes TAF) – Entecavir

• 3TC associated with resistance

• ETV more effective in preventing reactivation than 3TC

Causes of HBV reactivation in PLWH

• Interruption of ART that includes agents that also have HBV activity – Lamivudine (or emtricitabine) withdrawal

• Development of HBV resistance to 3TC (or FTC) • Appearance of HBV “escape mutants”

– Involves mutations in the S gene – HBV strains that have the ability to escape HBsAb

detection and neutralization • ART..?

46

HBV reactivation in patients treated with HCV DAAs

47

Potential HCV DAA-mediated mechanisms of HBVr

• Each interferes with replication of the other virus

• HCV frequently is the “dominant” virus – More marked decrease in HBV replication – HCV core protein binds to HBV DNA and suppresses HBV

replication

Treatment of HCV with DAAs removes the HCV-suppressive effect on HBV, allowing for HBV reactivation. HBV reactivation was not seen when IFN and RBV used widely for HCV, because IFN suppresses HBV replication.

48

Back to the call! What would you recommend for this caller?

A) ABC 600mg daily + renally-dosed 3TC (150mg daily) + DTG 50mg daily + renally-dosed entecavir (0.25 mg daily) B) ABC 600mg daily + renally-dosed 3TC + DTG 50mg daily C) TAF/FTC 1 tab daily + DTG 50mg daily D) Other

49

52yo M virologically suppressed on TDF/FTC + DTG, on rituxumab and high-dose steroids for AIHA; co-morbid CKD; portal hypertension; remotely-treated HCV; hypothyroidism; MAC

References • Manegold C et al. Clin Infect Dis 2001; 32:144-8. • Gandhi RT et al. Clin Infect Dis 2003; l36:1602-5. • Maldonado-Rodriguez A et al. World J Hepatol 2015; 7(2): 253-260. • Chu CJ and Lee SD. Journal of Gastroenterology and Hepatology

2008; 23:512-520. • Thio CL. Current Hepatitis Reports 2004; 3:91-97. • Gonzalez SA and Perrillo RP. Clin Infect Dis 2016; 62(S4):S306-13. • Hoofnagle JH. Hepatology 2009; 49:S156-S165. • Dharel N and Sterling RK. Gastroenterology and Hepatology 2014;

10(12). • Fix OK, Locarnini SA, Peters MG. PRN Notebook 2007; 11:20-27. • Brito M and Alhyraba M. Hospital Physician 2008; 17-23, 30. • Takayama H et al. Hepatology Research 2015

50

Questions?

51

• (800) 933-3413 • 6 am – 5 pm PST, M-F • Online consultation services - nccc.ucsf.edu

HIV/AIDS Management*

• (888) 448-8765 • 24 hours, 7 days/wk

Perinatal HIV

• (855) 448-7737|(855) HIV-PrEP • 6 am – 5 pm PST, M-F

PrEP: Pre-Exposure Prophylaxis

• (855) 300-3595 • 7 am – 3 pm PST, M - F

Substance Use

• (888) 448-4911 • 6 am – 11 pm PST, 7 days/wk

PEP: Post-Exposure Prophylaxis