Overview and Update on HIV

Jared Bullard MD FRCPC Pediatric Infectious Diseases and Medical Microbiology

Associate Medical Director, Cadham Provincial Laboratory Assistant Professor, Departments of Medical Microbiology and Pediatrics & Child

Health WRHA Population and Public Health Staff Development Session

December 11, 2013

Conflict of Interest Disclosure

• Honoraria from Janssen and Merck for Manitoba HIV Program Continuing Medical Education

1. Understand the host-pathogen interaction

2. Use “real-world” analogies to illustrate host immune responses to infections

3. Discuss HIV and other STBBI testing in Manitoba

4. Review pediatric HIV in Manitoba

5. Appreciate the effectiveness of HIV prevention of mother to child transmission (PMTCT)

Objectives

What is a virus?

A relatively simple question

Virology 101

• Absolute host dependence!

• Very basic components: – Viral proteins for

attachment

– Viral proteins for key functions

– Nucleic acids

– Envelopes (usually)

• Could almost call viruses undead...

What viruses do to you

• Must get in contact with susceptible host:

– Droplet

– Airborne

– Fecal-oral

– Direct contact

• Must proliferate in appropriate cells and tissues:

– Symptoms often first clue to primary site of infection

What viruses do to you

• Lead to death or lysis of infected cell: – Primary viremia

– Seeding of secondary cell/tissue sites

– More disseminated symptoms

• Disseminated infection: – Multiple sites involved

producing virus

– Secondary viremia to spread even further

• Lytic infection:

– Destruction of host cell

– High level of viral replication

– Susceptible to host defences and antiviral medications

– Examples: influenza, adenovirus, RSV, rhinovirus

Latent versus Lytic Infections

• Latent infection:

– Integrates in host cells

– Only low level replication

– Very resistant (to antivirals and immune system)

– Reactivates when immune system is suppressed

– Examples: HSV, VZV, EBV, CMV, HIV

Latent versus Lytic Infections

• Prevention and minimization of virus:

– Viral particles encounter physical barriers (skin, mucous membranes, mucous, cilia)

– Encounter the innate immune system (neutrophils, macrophages, NK cells, IgA)

• Initial infection:

– Lead to generalized cytokine proliferation

– Put immune system on alert

What you do to viruses

• Infected cells signal for help:

– MHC-I molecules display viral antigen

– Lead to cell-mediated immunity (CMI) activation and elimination of that cell

• Lots of viral protein around:

– Humoral-mediated immunity activated (HMI)

– Antibody to specific viral proteins made

– Enhances elimination of infecting virus

What you do to viruses

• Primary infection:

– Host is immunologically-naïve to virus

– Associated with higher viremia and more severe clinical presentation

• Secondary infection:

– Host is immunonologically-experienced to virus

– Can mount very strong response much more quickly

Primary versus secondary infections

Viruses = Zombies?

Real World Analogy

• Farmer Joe calls up Sheriff Wall

– “These 3 strange creepy bastards broke through the fence on my property!”

– “Cujo took one down and I shot the other two for trespassing”

– “Just letting you know!”

The story continues

• Just as Sheriff Wall hangs up, Rick the mortician calls:

– “Weirdest thing ever. This guy who died from a bear mauling or something…”

– “…he just got up and he’s stuck in the cooler”

Sheriff Wall figures out something’s up when…

• Deputies Cuvelier, Seftel and Kumar walk into the office

– “We were just out seriously busting heads of some whackos!”

– “What’s going on out there?”

– “Something’s up. Follow me, boys.” says Sheriff Wall

At the town hall meeting

• Sheriff Wall gets information from the town residents about the now numerous zombie sightings and attacks

• Quickly finds out who would be best to help get rid of the pesky zombies: – The Deputies – Trapper Jake – Bobby the Hooligan

• “Okay. Let’s move out!”

• In a coordinated effort led by Sheriff Wall: – Get rid of all the obvious zombies – Some town residents are bitten:

• Some ask to be “put down” • Others go into hiding in their houses

– Come up with a Zombie Town Defence Plan – Key town residents are always on edge, ready for the next invasion

• The town is saved.... • ...for now.

Getting down to business

Cast

Sheriff Wall ......................

The Deputies....................

Farmer Joe.........................

Cujo...................................

Ricky the Mortician.........

Trapper Jake.....................

Bobby the Hooligan........

Zombies...........................

T-helper cell

Cytotoxic T-cells

Neutrophils

Immunoglobulin A (IgA)

Macrophages

B-cells

Natural killer cell

Viruses and TB

Any questions at this point?

So we’re all on the same page

• What are ARVs?

• What is HAART?

• How do I diagnose HIV?

Nucleoside reverse transcriptase inhibitors

• NRTIs

–Cornerstone of HAART

–Nucleoside analogues

– Incorporated into both active and resting cells depending on NRTI class

–Should use one from each class to maximize viral suppression

Nucleoside reverse transcriptase inhibitors

• NRTIs: – Azidothymidine

(AZT/ZDV/Retrovir): first ARV approved in the Tx of HIV/AIDS

– Didanosine (dideoxyinosine/ddI/Videx)

– Stavudine (d4T/Zerit)

– Lamivudine (3TC/Epivir)

– Abacavir (Ziagen)

– Tenofovir (TDF)

– Emtricitabine (Emtriva)

Non-nucleoside reverse transcriptase inhibitors

• NNRTIs:

– Inhibit HIV reverse transcriptase

–Resistance to one confers cross-resistance

Non-nucleoside reverse transcriptase inhibitors

• NNRTIs:

– Nevirapine (NVP/Viramune)

– Delaviridine (Rescriptor)

– Efavirenz (Sustiva): • numerous birth defect in animal

models, therefore, contraindicated in pregnancy

– Etravirine (ETR)

Protease inhibitors

• PIs

–Prevent release of HIV proteins and maturation of infectious virions

–Resistance requires multiple mutations

Protease inhibitors

• PIs

– Saquinavir (Fortovase)

– Ritonavir (Norvir)

– Indinavir (Crixivan)

– Nelfinavir (Viracept)

– Lopinavir/Ritonavir (Kaletra)

– Atazanavir (Reyataz)

– Duranavir (Prezista)

Newer ARVs

• CCR5 antagonists:

– Maraviroc (Selzentry)

• Integrase Strand Transferase Inhibitors (INSTI)

– Raltegravir (Isentress)

• Fusion inhibitors (FIs):

– Enfuvertide (Fuzeon)

• Etravirine* (Intelence)

Highly-active Anti-Retroviral Therapy (HAART)

• As of November 2012: – 22 ARVs available for adult patients

– 19 available for pediatric patients; majority available in pediatric formulation or capsules

• Consists of 2 NRTIs and either an NNRTI or a PI: – ZDV/3TC + LPV/rtv (Combivir + Kaletra)

– ABC/3TC + EFV (Kivexa + Sustiva)

– TDF/FTC + ATV/rtv

Diagnosis and monitoring of HIV infection

• Serology – Enzyme immunoassay (EIA)

and confirmatory immunoblot (IB)

– Window period: +15-25 days

• Point of care testing (POCT) – Comparable

sensitivity/specificity to EIA – Results within 15-30

minutes – Needs confirmation with

standard EIA/IB protocol

• Nucleic acid amplification tests (NAAT) – DNA assay: detects

provirus – RNA assay: measures viral

load

• CD4 cell count – Helps guide initiation of

HAART, opportunistic infection PPx

– Indicates patient’s immunological status

Approximate risk of HIV transmission by bloodborne exposure

• Blood transfusion (90-95 in 100)

• IDU/needle sharing (7 in 1000)

• Healthcare-associated percutaneous needlestick (3 in 1000)

• Healthcare-associated mucous membrane exposure (9 in 10,000)

• Community needlestick (not reported in literature!!)

Approximate risk of HIV transmission by unprotected sexual exposure

• Receptive anal intercourse (5-32 in 1000)

• Insertive anal intercourse (6.5 in 10,000)

• Receptive vaginal intercourse (1-3 in 1000)

• Insertive vaginal intercourse (3-9 in 10,000)

• Receptive oral intercourse (1 in 10,000)

• Insertive oral intercourse (1 in 20,000)

Percentage of positive STBBI tests in Manitoba in 2012

0

1

2

3

4

5

6

7

Ct HBV HCV GC HIV Syphilis

Percentage of tests positive 6.4 2.9 3.4 1.3 0.2 0.3

Pe

rce

nta

ge o

f te

sts

po

siti

ve

Number of HIV screening tests performed in Manitoba from 2000 to 2012

0

10000

20000

30000

40000

50000

60000

70000

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Nu

mb

er

of

Test

s

Year of test

Number of HIV Screening Tests

Comparison of testing for Chlamydia/Gonorrhea and HIV by Age in Manitoba in 2012

0.00

50.00

100.00

150.00

200.00

250.00

300.00

<10 10-14 15-19 20-24 25-29 30-39 40-49 50-59 60+ Total

STB

BI t

est

pe

r 1

00

0

Age Groups (Years)

GC/Ct

HIV

0

2000

4000

6000

8000

10000

12000

Ct GC HBsAg HCV Syphilis HIV

Nu

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of

Test

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STBBI

STBBI Testing and Results in 0-19 year old Youths in Manitoba 2012

Tests (F)

Tests (M)

0

2000

4000

6000

8000

10000

12000

Ct GC HBsAg HCV Syphilis HIV

Nu

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Test

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STBBI

STBBI Testing and Positive Results in 0-19 year old Female Youths in Manitoba 2012

Tests (F)

Positive (F)

0

500

1000

1500

2000

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Ct GC HBsAg HCV Syphilis HIV

Nu

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Test

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STBBI

STBBI Testing and Positive Results in 0-19 year old Male Youths in Manitoba 2012

Tests (M)

Positive (M)

Take Home Message for STBBI Testing

• Test boys more often

• Test girls more completely

How many kids with HIV have we seen?

• Just over 20

• Currently following 10:

– Range in age from 3 to 17 years

– 5 children of Aboriginal background

– 4 children of African background

– 1 child bi-racial (African-Aboriginal)

More info on our HIV-positive kids

• 9 acquired HIV via MTCT

• 1 acquired iatrogenically (in Africa)

• Median viral load (VL) is undetectable (range from undetectable to 150,000 copies mL)

• Mean CD4 count/% of 950 cells/mm3 and 31%

• All are now on ARVs

Comparison of Prenatal Testing and Live Births in Manitoba from 1998 to 2011

-

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

18,000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Nu

mb

er o

f P

ren

atal

Tes

ts a

nd

Liv

e B

irth

s

Year

HIV

Hepatitis B

Rubella

Live Births

The approximate risk of HIV mother-to-child-transmission (MTCT) in an

HIV-positive woman on no antiretrovirals is closest to?

A. 0.1%

B. 1%

C. 25%

D. 67%

The approximate risk of HIV mother-to-child-transmission (MTCT) in an

HIV-positive woman on 3 antiretrovirals is closest to?

A. 0.1%

B. 1%

C. 25%

D. 67%

Mom’s story… • Ms. MP, 22 y.o. woman, transferred from The

Pas to Women’s Hospital Aug 29, 2010

– 35 weeks + pregnant (LNMP – Dec 2009)

– HIV positive, HCV positive

– No prenatal care

– Presented to The Pas Health Complex with per vaginal bleeding (abdominal cramping, N/V x 3)

• Assessed & prenatal screening

• Medical transport to Women’s: no prenatal care, HIV+, no antiretroviral meds, antepartum hemorrhage and pre-term

Her history…

• G3 P1 TA1

- 2004/5 SVD – Wpg - SBGH

- 2006 ectopic – Saskatoon – Royal University

• Currently living in The Pas, MB (From Saskatchewan First Nations – lived in SK and MB)

• History of IVDU

• HIV – diagnosed in 2007; ARV treatment naive

• HCV co-infection – diagnosed in 2003; no treatment

History of her HIV care in Manitoba… • Referral sent to Nine Circles early 2009; at the time

was incarcerated in Portage Correctional Facility

• First seen at Nine Circles May 8, 2009 for intake appointment

– CD4 478 cells/mm3 (28%)

– Viral load = 1590 copies/mL

• Plans for continuation of care/follow up

– Aug 11, 2009: MD appt and RN appt (still in Portage Corrections) – CD4 368/403 (28%) - f/u booked for Oct 2009

– Did not attend Oct 2009 appt

History of her HIV care in Manitoba…

• Call to Portage Corrections Oct 15, 2009 – Released 2 weeks ago (Sept 2009) and told pt

aware of Nine Circles appt

– Not informed of release by institution, no contact information

– Multiple phone call attempts by Nine Circles RN to locate

• Never linked back into care/lost to care

Fast forward…to Aug, 2010-Women’s • Bleeding resolved; fetus OK; treatment for

Trichomoniasis

• Seen by multiple specialists:

– Adult ID/HIV team, Peds ID, Neonatology, Aboriginal liaison, Social Work (Women’s)

• Started on ARVs for PMTCT - Aug 30th

• CD4 = 654 (31%); VL= 3810 copies/mL

• Plans for c-section in ~2 weeks

– EDC Oct 10, 2010 (by ultrasound)

Fast forward…to Aug, 2010-Women’s • Bleeding resolved; fetus OK; treatment for

Trichomoniasis

• Seen by multiple specialists: – Adult ID/HIV team, Peds ID, Neonatology, Aboriginal

liaison, Social Work (Women’s)

• Started on ARVs for PMTCT - Aug 30th – Combivir® 1 tab po BID and Kaletra® 2 tabs po BID

• CD4 = 654 (31%); VL= 3810 copies/mL

• Plans for c-section in ~2 weeks – EDC Oct 10, 2010 (by ultrasound)

• Arrangements to stay in Wpg and discharged Aug 31st to Lennox Bell with plans for follow up in the HIV clinic. Outpatient prescription for antiretroviral meds arranged.

• Presented to Women’s Triage Sept 1st evening (next day)

– Abdominal pain, purulent discharge, no fetal movement

– Assessed, good fetal HR, closed cervix – d/c home

• Presented to Women’s Sept 4, 2010 (4 days post discharge) @ 0715h in active labour (5-6 cm dilated; premature SROM ~0600h)

• Non-adherent to her HIV meds (~50%)

• Consulted – Med ID, Neonatology, Peds ID

• Presented to Women’s Sept 4, 2010 (4 days post discharge) @ 0715h in active labour (5-6 cm dilated; premature SROM membrane ~0600h)

• Non-adherent to her HIV meds

• Consulted – Med ID, Neonatology, Peds ID

– Taken to OBS OR for emergency C-section

– Only received 20% of IV Zidovudine 2 mg/kg loading dose, single dose oral Nevirapine 200 mg prior to delivery

Post-partum status

• Ms. MP

– Uncomplicated C/S

– Discharged on day 4 (Sept 9, 2010) with remainder of ARV supply of Combivir & Kaletra to continue for at least 1 week; visit with Nine Circles SW and RN same day at Lennox Bell

– Continued follow-up has been challenging…

And now the baby...

• Infant girl born at 35+ weeks by emergency C-section to 22 year old G3P2 mother:

– HIV positive

– Hepatitis B unknown

– Hepatitis C positive

– Chlamydia test positive

• Birth weight 2668 grams, Apgars 81/85

• Mom had been seen by PID earlier in pregnancy

– Routine HIV MTCT prevention discussed

Treatment approach

What was done by PID:

• Begin AZT prophylaxis

• Give single dose NVP

• Administer 3TC for 7-10 days

• Administer HepB vaccine and HBIG

• Obtain mom’s HepB status

• Eye swab and NPA for NAAT for C. trachomatis

• Administer erythromycin for 10-14 days

The first 3 days

• Started on erythromycin

• Given 1st dose of hepatitis B vaccine – Mom found to be hep B negative; HBIG deferred

• AZT given at 2 mg/kg/day divided q8h

• 3TC given at 2 mg/kg/dose BID for 10 days

• Single dose of NVP given at 48 hours of age

• Baseline bloodwork drawn to monitor for ARV ADR: – CBC, electrolyes, RFTs, LFTs

The first 3 days

• Seen by Neonatology:

– Ballard performed placing neonate at 38+ weeks

• Seen by Anne Russell:

– “Did anyone notice the dose of AZT is only 1/3 of what it should have been?”

– Written as “1.8 mg PO q8h (2 mg/kg/dose)”

PMTCT Infant Order Sheet

PMTCT Infant Order Sheet

Corrections made

• Dose of AZT increased to 5.4 mg PO q6h

• Continued on 3TC and erythromycin

• Incident report filed

– Dosing error missed by numerous HCW

• Discharge planning arranged:

– Rx for AZT given for entire 6 week course

– Rx for 3TC given for 6 more days

– Follow-up in PID clinic arranged for 2 weeks of age

1st follow-up

• Doing well

• No missed doses of AZT

– Dose increased to reflect weight change

– No ADR or side effects from medication

• Repeat CBC, electrolytes, RFTs, LFTs all normal

• 1st HIV RNA PCR:

– Negative (LOD at 80 copies/mL due to insufficient sample)

2nd follow-up • Infant now 1 month of age • Obvious stridor, especially noted when upset

– Seen by ENT; Dx with laryngomalacia

• Again CBC, electrolytes, RFTs and LFTs normal (no ADR despite more aggressive ARV PPx)

• 2nd HIV RNA PCR returns negative

3rd follow-up

• Doing well

• Mild oral thrush; on nystatin

• Completed AZT PPx with excellent adherence – Mild anemia (Hgb 94)

• 3rd HIV RNA PCR sent: – Returns positive

– VL of 343 copies/mL

• Foster mother contacted and asked to return for repeat testing

HIV screening in the newborn and infant

• Serology of limited usefulness due to maternal IgG transfer

• Positive serological screen only considered if child >18 months

• Requires a minimum of 3 NAAT:

– At 14 days, 1 to 2 months and 3 to 6 months

– Any positive test is immediately repeated

HIV screening in the newborn and infant

Presumptive Exclusion of HIV Infection

• Non breastfeeding • 2 negative virologic tests at ≥2

weeks and ≥4 weeks OR • 1 negative virologic test at ≥8

weeks AND 1 negative antibody test at ≥6 months of age OR

• If 1 positive virologic test, need 2 subsequent negative virologic tests with at least 1 at ≥8 weeks of age

• 1 negative antibody test at ≥6 months

Definitive Exclusion of HIV Infection

• Non breastfeeding

• 2 negative virologic tests at 1 month and at 4 months of age OR

• 2 negative antibody tests at 6 months of age AND

– No other lab or clinical evidence of HIV-infection

• Often repeat antibody test at 12 to 18 months

Confirmation

• Infant returns following week

• Infant now has diffuse LN, no HSM

• Had been seen in the CHED – URTI with exacerbation of

laryngomalacia – Mild CAP on CXR; Rx for

cefprozil given

• Repeat HIV RNA PCR – VL returns at 5.12 x 106

copies/mL

• Other investigations performed: – Sample sent to Ottawa for

provirus and p24 confirmation

– HLA B5701 – HIV genotypic resistance

profile – Lymphocyte subsets (CD4) – CBC, electrolytes, RFTs,

LFTs

• TMP/SMX PPx Rx given

Additional information

• WBC 9.4 Hgb 110 Plts 288

• Lymphocyte subsets: – CD4 2467 cells/m3 (55%)

– CD4/CD8 ratio 2.90

• Electrolytes, RFTs, LFTs all N

• HLA B5701 negative

• Ottawa testing: – p24 reactive

– Provirus detected

– Clade B (trend to complex B)

• Resistance analysis: – NRTI maximal response

– NNRTI susceptible

– PI maximal response

– Confirmed R profile from provirus

HAART initiated

• Started on:

– AZT 70 mg PO q12h (240 mg/m2/dose)

– 3TC 20 mg PO q12h (4 mg/kg/dose)

– LPV/rtv 90 mg PO q12h (300 mg/m2/dose)

– Extensive review of ARVs given by Shanna (Manitoba HIV Program Pharmacist) to foster mother

Follow-up

• Tolerating HAART well after excellent education • Clinically well; all lymphadenopathy and oral

thrush resolved: – Viral load from 5.12 million to 203 copies/mL

• Seen approximately 1 month ago: – Clinically improving – VL now 55 copies/mL – CD4 2904 cells/mm3 (54 %)

• Most recent follow-up: – VL undetectable; excellent ARV adherence

HIV MTCT in Manitoba

• 7 confirmed cases of MTCT from 1989 to 2013

• Total of 186 HIV-exposed infants; HIV MTCT rate of 3.8%

• Circumstances of MTCT: – 1 case suspected secondary to breastfeeding

– 3 cases from poor maternal ARV compliance

– 1 case of unknown maternal HIV status

– 2 cases unknown

1. Understand the host-pathogen interaction

2. Use “real-world” analogies to illustrate host immune responses to infections

3. Discuss HIV and other STBBI testing in Manitoba

4. Review pediatric HIV in Manitoba

5. Appreciate the effectiveness of HIV prevention of mother to child transmission (PMTCT)

Objectives

Thank you for your attention!