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HIV 201

Laura N Armas-Kolostroubis MDClinical Director

Texas/Oklahoma AIDS Education and Training Center

Christine, 2008

• 40 yo AAF with asymptomatic HIV diagnosed in 2003

• No co-infections• HTN well controlled on

lisinopril/HCTZ 10/12.5• Cocaine dependence• CD 4 = 876 cells/mL• VL = <400• Had all her immunizations in

2004-2005

Christine 2008

• You consider this patient to be:

a)A long-term non-progressor

b)A elite controller

c)Not infected with HIV

d)Infected with non-HIV-1 virus

e)None of the above

Christine 2009

• Lost to follow up x 6 months (was in jail)• CD4=734 c/mL; VL=1,207 c/mL• AST= 156, ALT= 98; GGT = 389• Reports occassional etoh binging• No hepatomegaly• HBsAg (+); HBsAb (-); HBcAb (+)• HBcIgG (+), HBcIgM (+)• HBV Quant= 657,433 c/mL• HBeAg (+), HBeAb (-)

Christine, 2008

HBV HBsAg HBsAb

HBc Ab

HBeAg HBeAbIgG IgM

Incubating + - - - +/- -

Acute Infection + - +/- + + -Chronic Carrier + - + - - +Chronic Infection + - + - + -

Resolved Infection - + + - - +

Immune - + - - - -

Christine, 2008

HBV HBsAg HBsAb

HBc Ab

HBeAg HBeAbIgG IgM

Incubating + - - - +/- -

Acute Acute InfectionInfection ++ -- +/-+/- ++ ++ --

Chronic Carrier + - + - - +

Chronic Infection + - + - + -

Resolved Infection - + + - - +

Immune - + - - - -

Hepatitis B Vaccination

• Series of 3 vaccines– Baseline– 6 weeks– 6 months

• Recheck to verify immunity

• Double dose

Hepatitis B Vaccination

• Accelerated HBV Vaccine Schedule624

– Standard dose at T0,1 and 3 wks

– Non-inferior efficacy only for those with CD4 >500

• Alternate 4-part high dose HBV Vaccine Schedule623

– Double dose at T0,4,8,and 24 wks

– Better response than standard 3 dose series, especially:- Older age- VL >50- Males- CD4 <350

CROI 2010: Launay O #623; de Vries-Sluijs T #624

Christine 2008

• Do you start cART?

a)Yes

b)No

c)Maybe if she stops cocaine

d)Don’t know

http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7

Indications for Treatment

• AIDS defining illness

• Asymptomatic with CD4 <350

• Hepatitis B co-infection– When HBV treatment is indicated

• HIV Associated Nephropathy (HIVAN)

• Pregnancy

ARV Initiation

• CD4 350-500– 55% Panel – Strong Recommendation– 45% Panel - Moderate Recommendation

• CD4 >500– 50% Panel recommend initiating– 50% Is ‘optional’

“Patients initiating ARV therapy should be able and willing to commit to lifelong treatmentand shouold

understand the benefits and risks of therapy and the importance of

adherence”

Christine 2008

• Agree to start, what would you use?

a)ABC/3TC/LPV/rtv

b)FTC/TDF

c)FTC/TDF/EFV

d)FTC/TDF/boosted PI

e)c or d

Christine 2010

• Started of FTC/TDF/EFV

• 70% adherent to medical appointments

• 100% adherent to cART

• CD4= 1126 c/mL; VL <48 c/mL

• HBV Quant <357 c/mL

• Hbe Ag (-), HBeAb (+)

Christine 2010

• Do you continue regimen?

a)Yes

b)Check HBsAg if negative and HBsAb (+) stop, her infection is resolved

c)Even if above is true, don’t stop, she could have a flare

d) Switch to FTC/TDF only

Mark

• 26 yo AAM with HIV diagnosed in 2006

• Nadir CD4=265 c/mL VL 345,987 c/ml

• Started on FTC/TDF/EFV

• Undetectable by month 4

• CD4= 471 c/mL, VL<48

• Comes in complaining of rash

A few months ago noticed the following lesion, but did not seek medical attention

Mark

• Your diagnosis is

a)Disseminated Herpes

b)Acne

c)Secondary Syphilis

d)Lymphogranuloma Venreum

High Prevalence of Asymptomatic STI’s in

HIV-Positive MSM, Visiting HIV Outpatient Clinics i

• 659 MSM (median age 45.4) – HIV outpatient clinic

of 2 academic hospitals

– STI screening during a routine visit

• Patients spontaneously reporting STI symptoms were excluded

• MSM completed questionnaire about sexual behaviour previous 6 months.

Heiligenberg M; Netherlands; Poster 1022; CROI 2010

STDSTD LOCATIONLOCATION TESTTEST

C. tracomatis

Oral swabs, anal self

swabs, urine

PCR

N. gonorrhea

Oral swabs, anal self

swabs, urine

PCR

HBV serum ABs

HCV serum ABs

T. pallidum serum RPR

Syphilis and HIV 1

• Increasing prevalence• HIV does not alter course of Syphilis, but

– Multiple chancres more common in HIV infected vs. non-HIV infected individuals (70 % vs 25%)

– Have earlier neurological involvement– Rapid development of aortitis– May present as encephalitis or arteritis– Condyloma latum is more common– Other unusual and more systemic manifestations

Prevention and Management of STDs in People Living with HIV/AIDS; The Eastern Quadrant STD/HIV/AIDS Prevention Centers, 2002

Mark

• Treated with Benzathine PCN 2.4 Million Units x once

• Recommended treatment for partner (s)• Any CNS or ophthalmic symptom should prompt

CSF evaluation• If unknown duration or > 1 year treatment is

Benzathine G PCN 2.4 Million Units qweek x 3• RPR 3, 6, 9, 12 and 24 months after treatment

Juan

• 53 yo HM diagnosed 2 years ago with AIDS after an episode of CNS toxoplasmosis

• Nadir CD4= 12 c/mL, VL 267,998 c/mL at diagnosis

• Started on FTC/TDF/DRV/rtv qday• Tolerating well, suppressed within 5 months• CD4 now is 214 c/mL• Same regimen + leveteracitam 500 mg bid

Juan

• Initial Body Mass Index (BMI) was 22.2

• A year after treatment is 27.3, two years after treatment is 31

Your diagnosis is:a)Overweightb)Obesity class Ic)Obesity class IId)Morbid Obesitye)Normal

Juan

• Smoker, no CV Family history, BP 137/82

• Lipid panel at one and two years shows:– Total cholesterol 183 207– Triglycerides 267

356– HDL 37 28– LDL 98 113

• You start treatment of TG with omega 3 fatty acid

Juan

Cardiovascular Risk Factors• Hypertension: >140/90 or on treatment• Men >50, Women >60• Total Cholesterol >200• HDL <40 (if >60 deduct 1 point)• Smoking• Family History of premature CAD (men

<45, women <55)

ATP III NCEP Guidelines

Juan

Cardiovascular risk calculation

http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof

Risk factors of MI in HIV infected patients

Controls N=1151

Cases N=278

OR [95% CI ]

CV risk factors

0 173 5 1

1 or 2 710 166 16.8 (5.9 – 48.4)

3 or more 268 107 49.4 (16.4 – 149,0)

Plasma HIV-1 RNA

<= 50 copies/ml 573 121 1

> 50 copies/ml 578 157 1.6 (1,1 – 2,1)

CD4 / CD8 ratio

>= 1 135 19 1

< 1 1016 259 1.8 (1,0 – 3,0)

Costagliola, IAS 2009

Rates of MIs

• 3,851 HIV infected patients • 1,044,589 non-HIV infected controls

Juan

• Repeat fasting glucose is 102 and 107After the second glucose you:a)Order a 2 hr. oral glucose tolerance testb)Stress diet and exercisec)Change regimend)Check a HbA1ce)a, b and cf) All of the above

Juan

• Two-hour glucose tolerance test showed a fasting glucose of 102 and a 2 hour after glucose challenge of 175

• HbA1c is 6.2

Your diagnosis is:

a)Uncontrolled Diabetes

b)Pre-diabetes

c)Normal

Juan

Your management is:

a)Glyburide 5 mg po bid

b)Change ARV regimen

c)Nutritionist referral for a 1,200 cal diet and 20 minutes aerobic exercise

d)Continue same medications, recommend to diet and exercise

Lessons

• Cardiovascular and metabolic changes are prevalent

• Monitor – Weight/ BMI– BP– Lipids– Glucose

• Diagnose early, treat aggressively

Fred

• 32 yo BM with AIDS, diagnosed in 2003

• ARV history include– AZT/3TC/EFV x 18 months– FTC/TDF/EFV

• Failed after 2 years of last regimen:

• VL= 6,457, CD4=245

Fred

• Genotype shows:

• NRTI: M184V, D67N, R211K

• NNRTI: K103N

http://hivdb.stanford.edu/pages/algs/sierra_mutation.html

Tools

• IAS-USA Mutations Card– Updated

Yearly

– Published in Topics in HIV

Medicine

http://www.iasusa.org/resistance_mutations/

Three Pathways to NRTI Cross-Resistance

• TAMs– 41L, 44D, 67N, 70R, 118I, 210W, 215Y/F, 219Q/E

• Selected by ZDV and d4T in sequential fashion• Associated with cross resistance to all NRTIs

• ABC/ddI/TDF cross-resistance– 65R: ddI, ABC, TDF– 74V: ddI, ABC

• Multi-nucleoside resistance– Q151M complex: all NRTIs– T69 insertion: all NRTIs + TDF

Two Groups of NRTIs

• Group 1: AZT, d4T, TFV– M184V mutation increases susceptibility to

these drugs

• Group 2: 3TC/FTC, ddC, ddI, ABC– M184V mutation decreases susceptibility to

these drugs

Fred

• Continue FTC/TDF

• Discontinue EFV

• Start DDI, LPV/rtv

• Well suppressed x 1 year, then lost to follow up for 15 months

• CD4=107, VL= 234,000

• Genotype shows: No major mutations

Fred

• What happened?

a)He is cured from resistance

b)Lost resistant virus

c)Resistance mutations are archived and will express under drug pressure

d)He will respond to Atripla

HIV Variability

Worldwide Single Worldwide Worldwide

Annual HIV+ Single All HIV

Influenza Person HIV Subtype Subtypes

Viral Genetic Sequence Diversity

Desrosiers Abstract 91, CROI 2008

HIV REVERSE TRANSCRIPTASE HIV REVERSE TRANSCRIPTASE CANNOT PROOF READCANNOT PROOF READ

HIV RNA

T U T

T

A

G

A

A

G

G A G

C C T

C

HIV DNA

CC

Fred

When facing a patient with an HIV-resistant strain the following factors could be involved:

a)Patient non-adherence

b)Pharmaco-kinetic interactions

c)Time related prescription patterns

d)Transmission of resistant strain

e)All of the above

0%

10%

20%

30%

40%

50%

60%

70%

100% 80% - 99% <80%

P<0.01

% of PI Doses Taken

RELATIONSHIP BETWEEN ADHERENCE AND VIRAL LOAD

EFFECTS OF SPONTANEOUS EFFECTS OF SPONTANEOUS MUTATIONS ON VIRAL SWARMSMUTATIONS ON VIRAL SWARMS

EFFECTS OF SPONTANEOUS EFFECTS OF SPONTANEOUS MUTATIONS ON VIRAL SWARMSMUTATIONS ON VIRAL SWARMS

Wild TypeHIV

Dead EndHIV

ResistantHIV

EFFECT OF SELECTIVE PRESSURE OF INSUFFICIENT ART

EFFECT OF SELECTIVE PRESSURE OF INSUFFICIENT ART

Wild TypeHIV

ResistantHIV

Dead EndHIV

WHAT IS RESISTANCE?

• Genotypic– Point mutations in HIV genome associated with failure of anti-

retroviral drugs

• Phenotypic– Ability of HIV to grow in the presence of therapeutic levels of

drug

• Virtual Phenotype– Prediction of phenotype bases on mutations using linear

regression

• Clinical– Clinical deterioration despite the patient taking the medication

Genotypic Testing

Plasma Amplified HIV DNAHIV RNA

RT/PCRAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

AAAAA

AAAAA

AAAAA

• Sequence HIV protease and reverse transcriptase

Sequence Analysis• Translate into amino

acids• Compare to reference

sequences

• Identify resistance and apply algorithm

Fred

When facing a patient with an HIV-resistant strain the following factors could be involved:

a)Patient non-adherence

b)Pharmaco-kinetic interactions

c)Time related prescription patterns

d)Transmission of resistant strain

e)All of the above

Fred

• Tolerated ARV regimen well, intermittent diarrhea

• Was on fenofibrate for elevated TG

• Self discontinued because of development of lipo-dystrophy

• Got injections for lipo-atrophy of cheeks

AdherenceAccess to care

Access to medicationLife situationDisease stage

Challenges to Successful ART:Considerations When Initiating Therapy

Replication rate (Viral load)

Mutation rate (Resistance)

Latent HIV reservoirs

PotencyPharmacokinetics (dosage schedule)

TolerabilityToxicityConvenienceResistance

Clinician experienceCommunication skills

Virus Drug

Clinician

Patient

Declining Incidence of Initial ART Failure During 1st Year of

Treatment

• 5 observational cohorts from Europe and North America

• Started 3-drug ART between 1996 and 2002 (N = 4143)

• Incidence of virologic failure (VL > 500 c/mL 6-12 months after initiating ART) evaluated by calendar year

• VL failure declined significantly from 1996 to 2002 (P < .001)

• Risk of VL failure was lower with

– Older age– MSM– Lower baseline VL– Absence of AIDS diagnosis at time

of ART initiation

Lampe F, et al. CROI 2005. Abstract 593.

Patients With Virologic Failure by

Year of Starting ART

25

303134

3942

40

0

10

20

30

40

50

1996 1997 1998 1999 2000 2001 2002

Pat

ien

ts (

%)

Fred

At this time you:

a)Order a tropism test

b)Start TMP/SMX

c)Refer to adherence counseling

d)Screen and treat for depression

e)All of the above

Fred

After discussing with patient you choose:

a)FTC/TDF/RGV/DRV/rtv

b)FTC/TDF/ETV/MVC

c)FTC/TDF/MVC/RGV

d)MVC/RGV/ETV

e)RGV/ETV/DRV/RTV

DUET-1 & -2: Predictors of ETR Response

ETR mutations (n = 17) weighted based upon impact on response (weighting factor)– 3.0: Y181I/V– 2.5: L100I, K101P, Y181C,

M230L– 1.5: V106I, V179F, E138A,

G190S– 1.0: V90I, A98G, K101E/H,

V179D/T, G190A

Vingerhoets Resistance Workshop 2008 #24

HIV

-1 R

NA

< 5

0 co

pie

s/m

L

at W

k 2

4 (%

)

Weighted Score Category

0-2.0 2.5-3.5 > 3.50

10

20

30

40

50

60

70

80

100

74%

52%

38%

Etravirine

ScoreScore Response RateResponse Rate

0-2 74%

2.5-3.5 52%

4 or greater 38%