HIV Cases“What to Start”

Dr Anton PozniakChelsea and Westminster Hospital

London

Case-SP• A 57 year old caucasian man presented to the emergency

department with progressive difficulty in swallowing over the last 4 weeks.

• He is hypertensive and has diet controlled diabetes and asthma and takes inhaled B2 agonists and inhaled steroids

• He had seen his family practitioner who saw oral thrush and thought it was related to his diabetes/ inhalers and gave him amphotericin lozenges

• He had been diagnosed with HIV a year before but had not attended any clinics as he “felt well”

Case-SP• He had extensive oral thrush and had severe dysphagia• BP 145/90 mmHg• He was admitted and treated with fluconazole

• Social History– Lives alone is MSM– Smokes 15 a day– Alcohol 20 units a week, no recreational drugs

• Drugs– Salbutamol inhaler – Fluticasone Inhaler– Amlodopine– St Johns Wort for depression

Case-SP• Labs• STD screen negative • FBC,U and Es, LFTs Normal ,• Cr CL 69 mls/min, Urine protein +no glucose• CD4 33 cells/uL• VL 365000 copies/ml• Hep B immune • Hep C negative • STS negative• Resistance test and HLA B5701 awaited• Framingham 10 year risk risk 18%

You decide to start ARVs Regimen DHHS[1] IAS[2] EACS[3]

EFV/TDF/FTC Preferred Recommended RecommendedATV/RTV + TDF/FTC Preferred Recommended RecommendedDRV/RTV + TDF/FTC Preferred Recommended RecommendedRAL + TDF/FTC Preferred Recommended RecommendedLPV/RTV + TDF/FTC Alternative Alternative Recommended

EFV + ABC/3TC Alternative Alternative Recommended

ATV/RTV + ABC/3TC Alternative Alternative Recommended

DRV/RTV + ABC/3TC Alternative Alternative Recommended

NVP + TDF /FTC Acceptable Alternative Recommended

MVC + TDF/FTC Acceptable Alternative Alternative

RPV + TDF /FTC Alternative No recommendation No recommendation

RAL + ABC/3TC Alternative No recommendation No recommendation

1. DHHS Guidelines, March 2012. 2. T. JAMA. 2012;304:321-333. 3. EACS Guidelines, November 2011.

You decide to start ARVs

What is your choice of main agent?• NNRTI• PI/r• Integrase• other

Difficulties in choosing-which 3rd agent?

• NNRTI-– may have transmitted dug resistance– RPV may not be effective in High viral load

• Integrase– BD – and may have NRTI transmitted dug resistance

• PI/r– drug interactions,– diabetes, lipids

NNRTI/NRTI and Prevalence of Transmitted Drug Resistance

2.5%2.9%

5.0%

8.9%

0.8% 0.4%

0%

2%

4%

6%

8%

10%

12%

Any class NRTI NNRTI PI Multi DrugRestistance (2

classes)

Multi DrugResistance (3

classes)

prev

alen

ce o

f mut

atio

ns

Eacs 2011 SPREAD

If you decide to give a boosted PIDrug Interactions

• What Drugs have significant interactions with a boosted PI?

1 St Johns Wort 2 Fluticasone 3 Amlodopine 4 None5 all

What NRTI back bone?

• AZT/3TC• ABC/3TC• TDF/FTC• DDI/3TC• OTHER

Difficulties in choice of NRTI

• AZT-– lipodystrophy– BD

• ABC– High Viral load– Cardiovascular risk(smoker and diabetic and BP)

• TDF– Renal changes,– Bone changes

CVD – Do drugs matter? D:A:D: Recent and/or cumulative ARV exposure and risk of MI

Adapted from Lundgren JD, et al. CROI 2009. Oral presentation 44LB.

RR

of c

umul

ativ

e ex

posu

re/y

ear

95%

CI

# PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157# MI: 523 331 148 405 554 221 139

RR

of r

ecen

t* e

xpos

ure

yes/

no95

%C

I

1.9

1.51.2

1.0

0.8

0.6ZDV ddI ddC d4T 3TC ABC TDF

# PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221

IDV NFV LPV/RTV SQV NVP EFV

PI† NNRTI1.2

1.13

1.0

1.1

0.9

1.9

1.51.2

1.0

0.8

0.6

*Current or within past 6 months; †Approximate test for heterogeneity: p=0.02; **not shown due to low number of patients receiving ddC

RR

of c

umul

ativ

e ex

posu

re/y

ear

95%

CI

NRTI

CVD=cardiovascular disease; ARV=antiretroviral; MI=myocardial infarction; RR=relative risk; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor; PYFU=patient years of follow up

**

0.27

0.21

0.51

1.16

-0.26

-0.43

-0.45

-0.53

0.008

-0.11

0.03

0.31

-0.8 -0.4 0 0.4 0.8 1.2

Mantel-Haenszel Risk Difference % (95% CI)

All Trials n=26

GSK Trials n=16

NIH Trials n=5

Academic Trials n=5

Created from Ding X, et al. CROI 2011. Poster presentation 808.

• Meta-analysis of Phase II–IV RCTs including ABC – Mean follow up 1.6

person-years per subject– Patients: 80% male (mean

age=39 years)• Limitations

– Young adults, so underlying MI risk low

– Other CV risk factors usually unknown

– Unvalidated MIs– Some studies had a PI

control group

CVD: Do drugs matter?FDA meta-analysis of abacavir and MI

CVD=cardiovascular disease; FDA=Food and Drug Administration; MI=myocardial infarction; RCTs=randomised controlled trials; CV=cardiovascular; PI=protease inhibitor

Chronic renal disease: ART risk factors

• 6,843 patients (5,136 male), median age 43 yrs, 90.1% exposed to cART, CD4 450 cells/mm3, 21.7% hypertension, 4.9% diabetes

• Median follow up 3.7 years• 2-fold increased risk if hepatitis C RNA+

Adapted from Mocroft A, et al. AIDS. 2010;24:1667–8.

Multivariate analysis

IRR/ year p

Tenofovir 1.16 <0.0001Indinavir 1.12 <0.0001Atazanavir 1.21 0.0003Lopinavir/r 1.08 0.030%

pro

gre s

sed

to C

KD

Incidence: 1.05 (0.91–1.18)/100 PYFU

MonthsART=antiretroviral therapy; PYFU=patient years follow up; IRR=incidence rate ratio

1. Adapted from McComsey G, et al. JID. 2011;203:1791–801.

ACTG 5224 & SMART: BMD loss with ART initiation ~2-4% at 1-2 yrs1

Low bone density/fracture: Relationship to ART

NRTI ComponentPrimary Analysis

NNRTI/PI ComponentSecondary Analysis

TDF/FTCABC/3TC

p=.004*

0-1

-2-3

-4-5Spi

ne B

MD

per

cent

cha

nge

from

wee

k 0

0 24 48 96 144 192Visit Week from Randomization

No. of subjectsTDF/FTC 128 111 105 97 87 53

130ABC/3TC 122 106 101 80 53

* - two-sample t-testNo significant interaction of NRTI and NNRTI/PI components (p=0.63)

Visit Week from RandomizationNo. of subjects

EFVATV/rtv

133 117 109 107 86 58125 116 102 91 81 48

EFVATV/rtv

p=.035*

0-1

-2-3

-4-5

0 24 48 96 144 192

p=.004*

ART=antiretroviral therapy; BMD=bone mineral density; DC=drug conservation; VS=viral suppression; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor; PI=protease inhibitor; DXA=dual-energy X-ray absorptiometry

Case-SP

• Resistance was wild type

• He starts EFV TDF FTC

Case AP

• 35 year old Asian women presents with• Night sweats, weight loss and cough• CXR - RUL cavity and infiltrates• AAFB - smear positive and started on RZHE• Had an HIV test and was positive CD4 was 35

cells/uL

Case AP• As her CD4 was<50 cells/uL she was offered

ARVs within 2 weeks of starting and tolerating her TB meds

What ARV combination would you offer her? What is your choice of main agent?

• NNRTI-Efavirenz• PI/r-Lopinavir/r• Integrase-Raltegravir• other

Case AP

• Started Efavirenz but couldn't tolerate it• What would you offer her?

• NNRTI-Nevirapine• PI/r-Lopinavir/r• Integrase-Raltegravir• other

Case AP• What would you offer her?• NNRTI-Nevirapine-less efficacy ? Drug

interaction• PI/r-Lopinavir/r major interaction with

rifampicin so switch to rifabutin or double dose lopinavir/r or high dose ritonavir 400mg bd

• Integrase-Raltegravir 400 or 800mg bd• Other-4 nucleosides