guest lecture jan 2015: art update

Antiretroviral Therapy Update

Dr. N. KumarasamyDr. N. KumarasamyChief Medical OfficerChief Medical Officer

YRGCARE Medical CentreYRGCARE Medical Centre

Chief-Chennai Antiviral Research and Treatment (CART) Clinical Research SiteChief-Chennai Antiviral Research and Treatment (CART) Clinical Research Site

Consultant- World Health OrganizationConsultant- World Health Organization

Chennai, IndiaChennai, India

HIV in Sri Lanka

• First case diagnosed in 1987First case diagnosed in 1987

• Around 2077 HIV+ cases reported till Dec 2014Around 2077 HIV+ cases reported till Dec 2014

• >90% Sexual transmission>90% Sexual transmission

• Mostly 25-49yrsMostly 25-49yrs

HIV Scenario in India ( 2014)

2 to 3 million infections2 to 3 million infections

Heterosexual transmissionHeterosexual transmission

` ` 0.25%0.25% of adult population of adult population (1.2billion population)(1.2billion population)

Growing number of AIDS casesGrowing number of AIDS cases

HIV-1; Subtype CHIV-1; Subtype C

Source : NACOSource : NACO

HIV-1 Virion

Pathogenesis of HIV Infection

1 3 about 6mths // 5 10 yrs

Acute HIV

Opportunisticinfections

asymptomatic

CD4 countcells/ul

800

200

HIV RNAcopies/ml

10^6

10^2

†

Virologic set-point Varies from patient to patient

Natural History of HIV disease in Resource limitted settings

HIV antibodies

Kumarasamy, et al. Clin Infect Dis 2003

HIV disease

• Marked by progressive decline in the number of circulating CD4+ T helper cells- immunological decline and death from opportunistic infections and neoplasms (Fauci AS et al, 1996)

• Clinical course and pattern of Opportunistic infections varies from patient to patient and from country to country (d’Arminio Monfote A, et al 1992; Mohar A, et al 1992; Bem C, et al 1993; Kumarasamy N, et al 1995)

4035

1110 8

4 3 2 1 105

10152025303540

Per

cent

ages

Opportunistic Infections

Oral Candidiasis Pulmonary tuberculosisHerpes Simplex Extra Pulmonary TuberculosisHerpes Zoster PCPToxoplasmosis Cryptococcal MeningitisCryptosporidial Diarrhoea CMV Retinitis

Spectrum of OI (n= 6815) –YRGCARE cohort: Jun1996- Aug 2004 Kumarasamy et al. IJMR 2005.

Co-factors relating to progression of patients with HIV disease

Kumarasamy et al., CID Jan 2003

Co-factors OR 95% CI P-value HIV associated illness Pulmonary TB PCP Cryptococcal Toxoplasmosis Co-infection HCV

3.524.476.982.57

7.84

1.96-6.322.67-7.514.1-11.971.27-5.2

1.61-38.22

<0.001<0.001<0.0010.01

0.01

HIV disease

• Effective chemoprophylaxis for Opportunistic infections and use of antiretroviral therapy-

delay in the onset of AIDS, a longer survival and a change in the pattern of opportunistic infections in the developed World ( Porter K, et al 1996; Brodt HR, et al 1997;) and in the developing world( Kumarasamy N et al 2005)

Antiretroviral Agents Approved by US FDA

NRTIsNRTIs NNRTIsNNRTIs PIsPIszidovudinezidovudine (AZT) (AZT) nevirapinenevirapine (NVP), (NVP), efavirenzefavirenz

(EFV) (EFV) saquinavirsaquinavir (SQV) (SQV)

didanosinedidanosine (ddI) (ddI) Rilviprine (RLP)Rilviprine (RLP) indinavirindinavir (IDV) (IDV)

etravirine (ETV) etravirine (ETV) ritonavirritonavir (RTV) (RTV)

stavudinestavudine (d4T) (d4T) Nucleotide RTIsNucleotide RTIs nelfinavirnelfinavir (NFV) (NFV)

lamivudinelamivudine (3TC) (3TC) tenofovir DFtenofovir DF (TDF) (TDF) lopinavir/ritonavirlopinavir/ritonavir (LPV/r) (LPV/r)

abacavirabacavir (ABC) (ABC) Entry InhibitorsEntry Inhibitors atazanavir (ATV)atazanavir (ATV)

emtricitabineemtricitabine (FTC) (FTC) Maraviroc (CCR5)Maraviroc (CCR5)enfuvirtide (ENF, T20)enfuvirtide (ENF, T20)

Integrase InhibitorsIntegrase InhibitorsRaltegravir (RAL)Raltegravir (RAL)Elvitegravir(ELV), Elvitegravir(ELV), Dolutegravir(DLG)Dolutegravir(DLG)

Darunavir(DRV)Darunavir(DRV)

RT inhibitors XX

Integrase inhibitors

XProtease inhibitors

CCR5 analogues

HIV life cycle, inhibition targets & antiretrovirals

XFusioninhibitors

Generic Antiretroviral Drugs from India- 1994……………..

NRTIsNRTIs NNRTIsNNRTIs PIsPIszidovudinezidovudine (AZT) (AZT) nevirapinenevirapine (NVP), (NVP), efavirenzefavirenz

(EFV) (EFV) saquinavirsaquinavir (SQV) (SQV)

didanosinedidanosine (ddI) (ddI) Rilviprine (RLP)Rilviprine (RLP) indinavirindinavir (IDV) (IDV)

etravirine (ETV) etravirine (ETV) ritonavirritonavir (RTV) (RTV)

stavudinestavudine (d4T) (d4T) Nucleotide RTIsNucleotide RTIs nelfinavirnelfinavir (NFV) (NFV)

lamivudinelamivudine (3TC) (3TC) tenofovir DFtenofovir DF (TDF) (TDF) lopinavir/ritonavirlopinavir/ritonavir (LPV/r) (LPV/r)

abacavirabacavir (ABC) (ABC) Entry InhibitorsEntry Inhibitors atazanavir (ATV)atazanavir (ATV)

emtricitabineemtricitabine (FTC) (FTC) Maraviroc (CCR5)Maraviroc (CCR5)enfuvirtide (ENF, T20)enfuvirtide (ENF, T20)

Integrase InhibitorsIntegrase InhibitorsRaltegravir (RAL)Raltegravir (RAL)Elvitegravir(ELV), Elvitegravir(ELV), Dolutegravir(DLG)Dolutegravir(DLG)

Darunavir(DRV)Darunavir(DRV)

Safety, Tolerability and Effectiveness of Generic Antiretroviral Drug Regimens for

HIV-infected Patients in South India

GGeneric HAART was safe, well tolerated and effectiveeneric HAART was safe, well tolerated and effective at at increasing CD4 T-lymphocytes in advanced patients, increasing CD4 T-lymphocytes in advanced patients,

comparable to the experience with proprietary HAART. comparable to the experience with proprietary HAART.

Kumarasamy et al. AIDS 2003 Vol 17 No 15:2267-9

Kumarasamy et al.. Clinical Infectious Diseases 2005

Figure 2 : Incidence of opportunistic infection in patients with and without HAART, 1996-2003

0

2

4

6

8

10

12

1996 1997 1998 1999 2000 2001 2002 2003Year

Case

s per

100

per

son

year

sIncidence of any OI in people without HAARTIncidence of any OI in people with HAARTIncidence of TB in people without HAARTIncidence of TB in people with HAART

Reduction in death rate following HAARTKumarasamy, et al. Clin Infect Dis 2005

0

5

10

15

20

25

30

1997 1998 1999 2000 2001 2002 2003

Year

Deat

hs p

er 1

00 P

atie

nt Y

ears

O

bser

ved

0

10

20

30

40

50

60

Perc

ent o

f Pat

ient

s w

ith C

D4 <

20

0 on

HAA

RT

38% decline

Source: UNAIDS.

People receiving antiretroviral therapy, 2005 to June 2014, all countries

Estimated number of AIDS-related deaths, with and without antiretroviral therapy, in low- and middle-income countries, and by

region, 1995–2012 [1/2]

Source: UNAIDS 2012 estimates.


Acute HIV

Opportunisticinfections

asymptomatic

Minor HIV-relatedsymptoms

CD4 countcells/ul

800

200

HIV RNAcopies/ml

10^6

10^2†


Typical course of HIV infection in an untreated person

HIV antibodies

When to initiate Antiretroviral Therapy?

Risk of progression Risk of AEAdherence commitmentResistance developmentCost and readiness

<200

<250

<350350-500

HPTN052/ACTG5245

HPTN 052HPTN 052

A Randomized Trial to Evaluate the Effectiveness of A Randomized Trial to Evaluate the Effectiveness of Antiretroviral Therapy Plus HIV Primary Care versus Antiretroviral Therapy Plus HIV Primary Care versus HIV Primary Care Alone to Prevent the Sexual HIV Primary Care Alone to Prevent the Sexual Transmission of HIV-1 Serodiscordant CouplesTransmission of HIV-1 Serodiscordant Couples

Multisite, HPTN/NIH trialMultisite, HPTN/NIH trialIndia India (NARI,YRGCARE),(NARI,YRGCARE), Thailand,Malawi,Zimbawe, Thailand,Malawi,Zimbawe, Brazil,USA)Brazil,USA) n= 1750 serodiscordant couples n= 1750 serodiscordant couples CD4: 350- 550CD4: 350- 550 250 couples in Chennai site250 couples in Chennai siteDuration: 7 yearsDuration: 7 years

Can ART prevent secondary HIV transmission?Can ART prevent secondary HIV transmission?

Stable, healthy, serodiscordant couples, sexually activeCD4 count: 350 to 550 cells/mm3

Primary Transmission EndpointVirologically-linked transmission events

Primary Clinical EndpointWHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial

infection and/or death

HPTN 052 Study Design

Immediate ART CD4 350-550

Delayed ART CD4 <250

Randomization

RegionRegion SiteSite CouplesCouples

AmericasAmericas(278)(278)

Porto Alegre, BrazilPorto Alegre, Brazil 9090

Rio de Janeiro, BrazilRio de Janeiro, Brazil 186186

Boston, United StatesBoston, United States 22

AsiaAsia(531)(531)

Chennai, IndiaChennai, India 250250

Pune, IndiaPune, India 175175

Chiang Mai, ThailandChiang Mai, Thailand 106106

AfricaAfrica(954)(954)

Gaborone, BotswanaGaborone, Botswana 7777

Kisumu, KenyaKisumu, Kenya 6060

Blantyre, MalawiBlantyre, Malawi 230230

Lilongwe, MalawiLilongwe, Malawi 251251

Johannesburg, South AfricaJohannesburg, South Africa 4646

Soweto, South AfricaSoweto, South Africa 5050

Harare, ZimbabweHarare, Zimbabwe 240240

TotalTotal 17631763

HPTN 052 Enrollment

Total HIV-1 Transmission Events: 39

HPTN 052: HIV-1 Transmission

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

p < 0.001

Immediate Arm: 1

Delayed Arm: 27 • 96% reduction in the risk of

transmission following ART

IAS 2011;NEJM 2011

HPTN 052• 1,750 heterosexual serodiscordant couples in 1,750 heterosexual serodiscordant couples in

resource-constrained countries randomized to receive resource-constrained countries randomized to receive ART early (CD4 350-550 cells/µL) or defer until CD4 < ART early (CD4 350-550 cells/µL) or defer until CD4 < 250 cells/µL250 cells/µLEvent Rates Early ART Deferred ART HR P-value

Transmission Rate per 100 pt-years

(95% CI)

0.3 (0.1-0.6)

2.2 (1.6-3.1)

0.11(0.04-0.32)

< 0.001

Clinical Event Rate per 100 pt-years

(95% CI)

2.4(1.7-3.3)

4.0(3.5-5.0)

0.59(0.40-0.88)

<0.001

Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC,Kumarasamy N et al, NEJM, 2011

• In South Africa, early ART was cost-saving over a 5-year period.In South Africa, early ART was cost-saving over a 5-year period.• In both South Africa and India, early ART was projected to be In both South Africa and India, early ART was projected to be

very cost-effective over a lifetime. very cost-effective over a lifetime. • With individual, public health, and economic benefits, there is a With individual, public health, and economic benefits, there is a

compelling case for early ART for serodiscordant couples in compelling case for early ART for serodiscordant couples in resource-limited settings. resource-limited settings.

Summary of Changes in Recommendations in WHO 2013 ART Guidelines-When to Start in Adults

Rate / 100 person yrs (95% CI)

Higher CD4 count is associated with decreased risk of non-AIDS death

Non-AIDS deaths Deaths from all causes

200 – 350 – > 500 349 499

200 – 350 – > 500 349 499

Current CD4 count (/L)D:A:D, Arch Intern Med 2006

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Changing patterns of mortality in D·A·D are consistent with SMART

START design

HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3

Early ART GroupInitiate ART immediately following randomization

N=2,000

Deferred ART GroupDefer ART until the CD4+ count declines to < 350 cells/mm3 or

AIDS develops

N=2,000

33

Low-income Lower middle-income

High-incomeUpper middle-income

Year of starting ART

Mea

n C

D c

ount

(cel

ls/µ

L)

Estimates from random-effects model adjusted for age, sex and year of starting ART, 2002-2009

Mean CD4 count at ART initiation is below 200 in LMIC

Source: Egger M. CROI 2012

2002 2009 2002 2009 2002 2009 2002 2009

IeDEA JAIDS 2014

Disease progression on HAART1040 patients on HAART with 18 months followup1040 patients on HAART with 18 months followup10.8% developed ADI within < 3 months- TB10.8% developed ADI within < 3 months- TBCD4< 100 , 1.3 times more likely to develop an ADICD4< 100 , 1.3 times more likely to develop an ADI

Kumarasamy et al. CROI 2009Kumarasamy et al. CROI 2009

Among 69 patients who died while on HAART - 55% died within three months of initiating HAART- median CD4 was 64. Kumarasamy et. Int J Infect.Dis 2009

Mortality of HIV-1-infected patients in the first year of antiretroviral therapy Mortality of HIV-1-infected patients in the first year of antiretroviral therapy is high in low-income countries comparison to high-income countries. is high in low-income countries comparison to high-income countries. Braitstein P, et al. Lancet 2006Braitstein P, et al. Lancet 2006

• Simulation model of HIV testing and treatmentSimulation model of HIV testing and treatment- Prevalence and Incidence in different groupsPrevalence and Incidence in different groups- Cost of testingCost of testing

Conclusion:Conclusion: Voluntary HIV screening among National Voluntary HIV screening among National population population every 5 yrs every 5 yrs offers substantial clinical benefit and offers substantial clinical benefit and cost effective. cost effective. Annual screening Annual screening is cost effective among high is cost effective among high risk population and in high prevalent districtsrisk population and in high prevalent districts

Numbers of people living with HIV, new HIV infections,

and AIDS deaths, 2001-2012, globally

Source: UNAIDS 2012 estimates.

When to Start ART in TB

A5221/ STRIDECAMELIA SAPIT

N 806 660 429

Sites Africa, Asia, S Am, N Am Cambodia S. Africa

Arms Imm vs 8-12 wk Imm vs 8 wk Early vs 24 wk

Endpt Death/AIDS <50 CD4 Death Death

CD4 (IQR) 77 (36,145) 25 (11,56) 150 (77, 254)

Havilr- NEJM 2011, Blanc- NEJM 2011, Abdool Karim, NEJM, 2011

Estimated change in tuberculosis-related deaths among people living with HIV in 41 tuberculosis/HIV high-burden countries,

2004–2012


Acute HIV

asymptomatic

CD4 countcells/ul

800

200

HIV RNAcopies/ml

10^6

10^2

†

Changing course of HIV disease in a treated person

HIV antibodies


d4T phased out of WHO guidelines

•Severe peripheral neuropathy Severe peripheral neuropathy • Lipoatrophy- mean 20 monthsLipoatrophy- mean 20 months•(Saghayam S,Chaguturu S, Kumarasamy N, et (Saghayam S,Chaguturu S, Kumarasamy N, et al. CID 2004)al. CID 2004)

•Substitute AZT/TDF after 6 -12 months with d4T Substitute AZT/TDF after 6 -12 months with d4T containing HAART in ARV roll outs…containing HAART in ARV roll outs…

•Risk to anemia after AZT substitution is < 1%.Risk to anemia after AZT substitution is < 1%.(( Kumarasamy et al – IJID 2009)Kumarasamy et al – IJID 2009)

Study regimens: n= 1571 participants; Study regimens: n= 1571 participants;

Arm 1A: ZDV + 3TC + EFV- (Bid)Arm 1A: ZDV + 3TC + EFV- (Bid)Arm 1B: ddI+ FTC + ATZ- (Qd)Arm 1B: ddI+ FTC + ATZ- (Qd)Arm 1C: TDF + FTC + EFV-(Qd)Arm 1C: TDF + FTC + EFV-(Qd)

ACTG/NIAID/NIHACTG/NIAID/NIH

Primary Efficacy Findings

• No differences in risk of regimen failure or any of the primary No differences in risk of regimen failure or any of the primary efficacy endpoint components between armsefficacy endpoint components between arms

• Similar low cumulative probabilities of regimen failure over timeSimilar low cumulative probabilities of regimen failure over time• No significant statistical interactions between treatment effect and No significant statistical interactions between treatment effect and

gender, race and ethnicity, country or viral load stratum gender, race and ethnicity, country or viral load stratum

IAS 2011; Plos Medicine 2012

Primary Safety Findings• Lower risk of Safety Endpoints for

FTC/TDF vs 3TC/ZDV– ARV dose modification difference driven by

neutropenia and anemia (0 vs 59 cases)

– Lab abnormalities difference driven by neutropenia, anemia, AST/ALT (67 vs 135 cases)

– Grade 3/4 creatinine 5 vs 2 cases

– Fewer serious metabolic dx in FTC/TDF arm (3 vs 19 cases; P < 0.001; lipodystrophy, pancreatitis, lactic acidosis)

• Interaction between sex and treatment arm for primary safety endpoint (P = 0.005):

– HR for Women 0.48 (0.37-0.63)

– HR for Men 0.83 (0.64-1.08)

• No significant interaction with race and ethnicity, country or viral load stratum

• Difference in probabilities of safety events similar over timeIAS 2011; Plos Medicine 2012

• We evaluated the clinical outcomes and cost-effectiveness of first-line ART using tenofovir in India, compared with current practice using stavudine or zidovudine.

• We used a state-transition model of HIV disease to examine strategies using different NRTs, combined with lamivudine and nevirapine,

Conclusions: Using tenofovir as part of first-line ART in India will improve survival, is cost-effective by international standards, and should be considered for initial therapy for HIV-infected patients in India.

Clin Infect Dis. 2010

Summary of Changes in WHO 2013 Treatment Guidelines : What to Start in Adults

Sequencing Therapy in 2015

Tenofovir(TDF)+ Tenofovir(TDF)+ Lamivudine(3TC)/Emtricitabine(FTCLamivudine(3TC)/Emtricitabine(FTC) -2NRTIs) -2NRTIs

+ + Efavirenz (EFV) -1NNRTI Efavirenz (EFV) -1NNRTI

Response to HAART

RNA

RNA

Ideal Response

Common Response

Treatment Failure and Drug Resistance:Virologic, Immunologic, and Clinical Definitions

CD4 Count

Viral Load

Virologic failure

Immunologic failure

Clinical failureDrug

Resistance

Why patients fail ART?

Non-adherenceNon-adherenceCostCostDepressionDepressionToxicityToxicitySense of fatigueSense of fatigue

PharmacologicPharmacologicInteractionsInteractionsPoor absorptionPoor absorptionAltered intracellular Altered intracellular metabolismmetabolism

ResistanceResistancePrescription errorsPrescription errorsSequential addingSequential addingPrimary resistantPrimary resistant

NVP for MTCTNVP for MTCTSuperinfectionSuperinfection

Spouse on failing ARTSpouse on failing ARTDiseaseDisease

AdvancedAdvancedLow baseline CD4Low baseline CD4High baseline PVL High baseline PVL

Resistance Patterns After Initial Failure of Common NRTI Backbones

ZDV/3TC

d4T/3TC

ABC/3TC

TDF/3TC

M184V

M184V

M184V

TAMs

L74V, K65R

K65R

Failure of first line regimen

TDF/ABC

+

3TC/FTC

+

NVP/EFV

M184VK103N

V106M

G190A

K65R

L74V

Sequencing Therapy in Resource Limited Settings

2 NRTIs(TDF/3TC) + 2 NRTIs(TDF/3TC) + 1 NNRTI(EFV)1 NNRTI(EFV)2 NRTIs(AZT/3TC) + 2 NRTIs(AZT/3TC) + 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)

Pattern of mutations on ATVr containing 2nd line HAART

ATV/r containing 2ATV/r containing 2ndnd line HAART- 918 patients line HAART- 918 patientsMedian followup- 24 monthsMedian followup- 24 months

Virologic failure- 145 (16%)Virologic failure- 145 (16%)Genotyping 32 ( 22%)- ATV mutations: 3(9%) I50L,I84V,N88SGenotyping 32 ( 22%)- ATV mutations: 3(9%) I50L,I84V,N88S

LPV mutations: 2 (6%) V82A,V32ILPV mutations: 2 (6%) V82A,V32I

Major DRV RAMS: 2(6%) I54L, I84VMajor DRV RAMS: 2(6%) I54L, I84VMinor DRV RAMS : 1 (3%) V32IMinor DRV RAMS : 1 (3%) V32I

Kumarasamy N, et al. CART study cohort . WHO GDG meet 2012Kumarasamy N, et al. CART study cohort . WHO GDG meet 2012


2 NRTIs(TDF+3TC/FTC) + 2 NRTIs(TDF+3TC/FTC) + 1 NNRTI (EFV)1 NNRTI (EFV)2 NRTIs(AZT+3TC) + 2 NRTIs(AZT+3TC) + 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)1 PI/RTV(DRVr) + 1 PI/RTV(DRVr) + Integrase Integrase ± / CCR5 ± / CCR5

inhibitor /inhibitor / 2 2ndnd Gen NNRTI (ETV) Gen NNRTI (ETV)ENF + other CCR5 inhibitor ± PI/RTVENF + other CCR5 inhibitor ± PI/RTV

Sequencing Therapy before 2013

2 NRTIs(AZT or d4T) + 2 NRTIs(AZT or d4T) + 1 NNRTI1 NNRTI2 NRTIs(TDF/3TC) + 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)1 PI/RTV(DRVr) + 1 PI/RTV(DRVr) + IntegraseIntegrase/CCR5 inhibitor /CCR5 inhibitor //

22ndnd Gen NNRTI (ETV) Gen NNRTI (ETV)

Treatment Failure and Drug Resistance:Virologic, Immunologic, and Clinical Definitions

CD4 Count

Viral Load

Virologic failure

Immunologic failure

Clinical failureDrug

Resistance

Criteria to switch Criteria to switch following Rx failurefollowing Rx failure

N % (40/1443)N % (40/1443)

New OIsNew OIs 18 (45%)18 (45%)

Return of CD4 to baselineReturn of CD4 to baseline 19 (46%)19 (46%)

>50% fall in peak CD4>50% fall in peak CD4 10 (24%)10 (24%)

OtherOther 5 (12%)5 (12%)

79% of them had M184V, 79% of them had M184V, 71 % had NNRTI mutations, (K103N,Y181C,G190A)71 % had NNRTI mutations, (K103N,Y181C,G190A)60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)11% had Q151M11% had Q151M5% had K65R and 5% had K65R and 5% had L74V. 5% had L74V.

26% had 3 or more NNRTI mutations26% had 3 or more NNRTI mutations

This data clearly warns that patients with immunological failure with standard WHO criteria have This data clearly warns that patients with immunological failure with standard WHO criteria have severe mutations and severe mutations and which can jeopardize future 2nd line NRTI options and newer drugs. which can jeopardize future 2nd line NRTI options and newer drugs. Urgent need for VIRAL LOAD monitoringUrgent need for VIRAL LOAD monitoring

Sequencing Therapy before 2013 in the absence of Viral load monitoring

2 NRTIs(AZT or d4T) + 2 NRTIs(AZT or d4T) + 1 NNRTI1 NNRTI2 NRTIs(TDF/3TC)/2 NRTIs(TDF/3TC)/IntegraseIntegrase + + 1 PI/RTV1 PI/RTV1 PI/RTV(DRVr) 1 PI/RTV(DRVr) + + 22ndnd Gen NNRTI Gen NNRTI/CCR5 /CCR5

inhibitor ± NRTIsinhibitor ± NRTIs

Kumarasamy N, CID 2009;Kumarasamy N, CID 2009;Hosseinipour M, AIDS 2009; Lyagoba Lyagoba F,JAID 2010; Boyd MA, Kumarasamy N, et al Lancet 2013;Pozniak F,JAID 2010; Boyd MA, Kumarasamy N, et al Lancet 2013;Pozniak A, ARHR 2008A, ARHR 2008

WHO Consolidated ARV Guidelines 2013

What drugs to start with in Children

• < 3yrs of age:< 3yrs of age: 3TC + ABC + LPv/r3TC + ABC + LPv/r 3TC + AZT + LPv/r3TC + AZT + LPv/r(NB: do not use D4T )(NB: do not use D4T )

>3yrs of age >3yrs of age 3TC + ABC + EFV3TC + ABC + EFV 3TC + AZT + EFV3TC + AZT + EFV

ARV Toxicities

Initial problems tolerating therapyInitial problems tolerating therapyHypersensitivity reactionsHypersensitivity reactionsImmune-reconstitution relatedImmune-reconstitution relatedChronic toxicitiesChronic toxicitiesDrug-drug interactionsDrug-drug interactions

CART Cohort study at YRGCARE, Chennai• Between 1996-Oct 2013, the total number of HIV infected individuals registered for care- 19,500Between 1996-Oct 2013, the total number of HIV infected individuals registered for care- 19,500

• > 10 yrs living with HIV disease- 919> 10 yrs living with HIV disease- 919

• Median duration on ART-10.3yrsMedian duration on ART-10.3yrs• Median latest CD4- 510Median latest CD4- 510

• % of people with suppressed viral load(<400 copies/ml)-82%% of people with suppressed viral load(<400 copies/ml)-82%• % of people on 1% of people on 1stst line ART after 10yrs - 58% line ART after 10yrs - 58%

• Number people died after 10 yrs of ART- 20 ( 2%)Number people died after 10 yrs of ART- 20 ( 2%)

Kumarasamy N, et al. CART Cohort study. Cell-The Lancet Translational Medicine Conf. San Kumarasamy N, et al. CART Cohort study. Cell-The Lancet Translational Medicine Conf. San Francisco, Nov 3-5,2013Francisco, Nov 3-5,2013

Non AIDS causes of mortality• Cardiovascular- Cardiovascular- drugs,inflammationdrugs,inflammation

• Renal- Renal- drugs,HIVdrugs,HIV

• Diabetes-Diabetes-drugs,HIVdrugs,HIV

• HCV- HCV- as co-infection in IDUs &hemophiliacsas co-infection in IDUs &hemophiliacs

• Cancers- Cancers- HPV,HHV-8HPV,HHV-8

• Neurocognitive effects- Neurocognitive effects- drugs, HIVdrugs, HIV

Between 1986 and 2007, 3530 patients with a median follow up 3.9yrs. 24.6% died.

Role of Chronic Inflammation in Non-Infectious Co-Morbidities

• Diabetes MellitusDiabetes Mellitus• Cardiovascular DiseaseCardiovascular Disease• CancerCancer• Kidney ProblemsKidney Problems• Cognitive ProblemsCognitive Problems• OsteoporosisOsteoporosis• Low TestosteroneLow Testosterone

Aging

HIV

Inflammation

69

Integration of HIV in health service delivery

Source: GARPR 2013.

HIV Reservoir Persists during ART

Limit of detection

Circ

ulat

ing

viru

s

Time

STARTSTOP

HAART

Antiretroviral drugs are capable of suppressing HIV to undetectable levels

HIV rebounds after stopping therapy

HIV infection is characterized by high levels of circulating

viruses in the blood

What is a reservoir?

Blood

CSF GS GUT

Local Inflammation, infection,

HIV replication, etc.

Inflammatory markers on ARTNWCS 319/A5175 -Summary

• Pre-ART elevations in inflammation and immune Pre-ART elevations in inflammation and immune activation markers were commonactivation markers were common– Pre-ART marker levels differed by country and sexPre-ART marker levels differed by country and sex– Some pre-ART marker levels were associated with risk Some pre-ART marker levels were associated with risk

of HIV dz progression or death after initiation of ARTof HIV dz progression or death after initiation of ART

• Initiation of ART produced only a modest decline in Initiation of ART produced only a modest decline in inflammatory and activation markersinflammatory and activation markers

CROI 2013CROI 2013

Why we need Eradication?• Tissue sanctuaries (reservoirs)Tissue sanctuaries (reservoirs)

-Brain, Lymphnode, Gut-Brain, Lymphnode, Gut

• Chronically Infected macrophagesChronically Infected macrophages- RTIs,PIsRTIs,PIs

• Residual viremia-chronic inflammationResidual viremia-chronic inflammation- cardiovascular diseasecardiovascular disease-nephropathy-nephropathy-faster evolution of viral hepatitis-faster evolution of viral hepatitis-cancer-cancer

Cure-is it possible?

• Sterlizing cureSterlizing cure- total eradication of all HIV infected cells including quiescent - total eradication of all HIV infected cells including quiescent reservoirsreservoirs

• Functional CureFunctional Cure- < 50copies- < 50copies

Eradication of HIV following transplantation of CCR5-deficient Eradication of HIV following transplantation of CCR5-deficient haematopoietic stem cellshaematopoietic stem cells

Novel strategies- purging reservoirs followed by aggressive HAARTNovel strategies- purging reservoirs followed by aggressive HAART

HIV Eradication - What We Need To Learn

• The Primary Question: What is the full extent of the latent The Primary Question: What is the full extent of the latent pool and how do we eliminate it?pool and how do we eliminate it?

1 in 106 CD4 cells

Clearing out the Latent Pool: the Players

Uninfected SusceptibleCD4 Cell

CD4 Precursor Cell

Latently Infected CD4 Cell Activated Lytically Infected CD4 Cell

Purging reservoirs

• Immune Activation therapy- to activate T cellsImmune Activation therapy- to activate T cells• IL-7-T cell homeostasisIL-7-T cell homeostasis• IL-7 to reduce the size of the reservoir-ERAMUNEIL-7 to reduce the size of the reservoir-ERAMUNE• HAART+ IL-7HAART+ IL-7

• Flush out HIV from latency-epigenetic regulationFlush out HIV from latency-epigenetic regulation- Histone deacetylase (HDAC)- Histone deacetylase (HDAC)-DNA methyl transferase(DNMTs)-DNA methyl transferase(DNMTs)-Proteins from SWI/SNF chromatin complexes-Proteins from SWI/SNF chromatin complexes

Why Should Eradication Be A Major Research Goal?

• We might actually succeedWe might actually succeed• If we fail, there are a tremendous number of If we fail, there are a tremendous number of

things we might learnthings we might learn– HIV immunobiologyHIV immunobiology– HIV regulationHIV regulation– Stem cell biologyStem cell biology– Genetic approaches to other disease entitiesGenetic approaches to other disease entities

Benefits of ART in prevention

• Preventing Mother to child transmissionPreventing Mother to child transmission

• Post exposure prophylaxis (PEP)Post exposure prophylaxis (PEP)– OccupationalOccupational– Sexual (NPEP)Sexual (NPEP)

• Primary prevention (PREP) Primary prevention (PREP)

• Secondary prevention ( Prevention of sexual transmission of Secondary prevention ( Prevention of sexual transmission of HIV-HPTN052)HIV-HPTN052)

USPHS recommendations for postexposure prophylaxis: Percutaneous

ExposureExposure RegimenRegimen

Intact skin Do not offer

Mucous membrane Tenofovir+FTC/3TC+ Tenofovir+FTC/3TC+ RaltegravirRaltegravirAlternate:Alternate:TDF/AZT+3TC/FTC+ATVr/LPVr/TDF/AZT+3TC/FTC+ATVr/LPVr/DRVr/ELVc/DRVr/ELVc/EFV*EFV*

Percutaneous

Post Exposure prophylaxis

• Antiretrovirals- 28 days-Antiretrovirals- 28 days-should be initiated should be initiated within 2hrswithin 2hrs-preferably before 72 hrs-preferably before 72 hrs

• HIV antibody test: Baseline, 6HIV antibody test: Baseline, 6thth week, week, 1212thth week, 6week, 6thth month month ( 4( 4thth month) month)

• Safe sex, Avoid blood donation , avoid Safe sex, Avoid blood donation , avoid breast feedingbreast feeding

AIDS-related deaths to be averted due to the new treatment guidelines

Conclusions

• Global progress on scale-up of ART has been extraordinary. Global progress on scale-up of ART has been extraordinary. Countries show the way! Countries show the way!

• Decrease in morbidity and mortalityDecrease in morbidity and mortality• Declining incidence of HIVDeclining incidence of HIV• Sustainability of ARVs-Sustainability of ARVs-This will require forward-looking policies, more This will require forward-looking policies, more

effective and innovative approaches, together with further effective and innovative approaches, together with further investments investments

• Prevention of transmission of resistance strainsPrevention of transmission of resistance strains• Prevention and management of NCDsPrevention and management of NCDs• Ongoing training of HCWsOngoing training of HCWs• ARVs for treatment and prevention are a powerful tool towards ending ARVs for treatment and prevention are a powerful tool towards ending

the HIV epidemicthe HIV epidemic

YRGCARE Medical Centre>20,000 patients registered for care>20,000 patients registered for care

- >10,000 patients on HAART - >10,000 patients on HAART

VCT VCT (OPD,Acute care inpatient facility,adherence/couple/family (OPD,Acute care inpatient facility,adherence/couple/family counseling,Nutritional Counseling, Pharmacy)counseling,Nutritional Counseling, Pharmacy)

AIDS Clinical Trials Group (ACTG)/NIHAIDS Clinical Trials Group (ACTG)/NIHHIV Prevention Trial Network (HPTN)/NIHHIV Prevention Trial Network (HPTN)/NIHSTART/NIHSTART/NIH

Brown University-RI, UCSD-California, Johns Hopkins Brown University-RI, UCSD-California, Johns Hopkins Univ-MD, UCSF-California, Harvard Univ-MA,Emory Univ-Univ-MD, UCSF-California, Harvard Univ-MA,Emory Univ-Atlanta,Stanford Univ-California,Treat Asia-amFar,Atlanta,Stanford Univ-California,Treat Asia-amFar,Kirby Inst-UNSW,Karolinska Inst-Sweden.Kirby Inst-UNSW,Karolinska Inst-Sweden.

guest lecture jan 2015: art update

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