Guest Lecture Jan 2015: ART update

Antiretroviral Therapy Update
Dr. N. KumarasamyDr. N. Kumarasamy
Chief Medical OfficerChief Medical Officer
YRGCARE Medical CentreYRGCARE Medical Centre
Chief-Chennai Antiviral Research and TreatmentChief-Chennai Antiviral Research and Treatment
(CART) Clinical Research Site(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 populationof 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

1 3 about 6mths // 5 10 yrs
Acute HIV
Opportunistic
infections
asymptomatic
CD4 count
cells/ul
800
200
HIV RNA
copies/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)

40
35
11
10
8
4 3 2 1 1
0
5
10
15
20
25
30
35
40
Percentages
Opportunistic Infections
Oral Candidiasis Pulmonary tuberculosis
Herpes Simplex Extra Pulmonary Tuberculosis
Herpes Zoster PCP
Toxoplasmosis Cryptococcal Meningitis
Cryptosporidial 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
3.52
4.47
6.98
2.57
7.84
1.96-6.32
2.67-7.51
4.1-11.97
1.27-5.2
1.61-38.22
<0.001
<0.001
<0.001
0.01
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 PIsPIs
zidovudinezidovudine (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 Inhibitors
Raltegravir (RAL)Raltegravir (RAL)
Elvitegravir(ELV),Elvitegravir(ELV),
Dolutegravir(DLG)Dolutegravir(DLG)
Darunavir(DRV)Darunavir(DRV)

RT inhibitors
X
X
Integrase inhibitors
X
Protease inhibitors
CCR5 analogues
HIV life cycle, inhibition targets & antiretrovirals
XFusion
inhibitors

Generic Antiretroviral Drugs from India- 1994……………..
NRTIsNRTIs NNRTIsNNRTIs PIsPIs
zidovudinezidovudine (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 Inhibitors
Raltegravir (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 atat
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 2003
Year
Casesper100personyears
Incidence of any OI in people without HAART
Incidence of any OI in people with HAART
Incidence of TB in people without HAART
Incidence of TB in people with HAART

Reduction in death rate following HAART
Kumarasamy, et al. Clin Infect Dis 2005
0
5
10
15
20
25
30
1997 1998 1999 2000 2001 2002 2003
Year
Deathsper100PatientYears
Observed
0
10
20
30
40
50
60
PercentofPatientswithCD4<
200onHAART

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
Opportunistic
infections
asymptomatic
Minor HIV-related
symptoms
CD4 count
cells/ul
800
200
HIV RNA
copies/ml
10^6
10^2
†
Virologic set-point
Varies from patient
to patient
Typical course of HIV infection in an untreated person
HIV antibodies

When to initiate Antiretroviral Therapy?
Risk of progression
Risk of AE
Adherence commitment
Resistance development
Cost and readiness
<200
<250
<350
350-500
HPTN052/ACTG5245

HPTN 052HPTN 052
A Randomized Trial to Evaluate the Effectiveness ofA Randomized Trial to Evaluate the Effectiveness of
Antiretroviral Therapy Plus HIV Primary Care versusAntiretroviral Therapy Plus HIV Primary Care versus
HIV Primary Care Alone to Prevent the SexualHIV Primary Care Alone to Prevent the Sexual
Transmission of HIV-1 Serodiscordant CouplesTransmission of HIV-1 Serodiscordant Couples
Multisite, HPTN/NIH trialMultisite, HPTN/NIH trial
IndiaIndia (NARI,YRGCARE),(NARI,YRGCARE), Thailand,Malawi,Zimbawe,Thailand,Malawi,Zimbawe,
Brazil,USA)Brazil,USA)
n= 1750 serodiscordant couplesn= 1750 serodiscordant couples CD4: 350- 550CD4: 350- 550
250 couples in Chennai site250 couples in Chennai site
Duration: 7 yearsDuration: 7 years
Can ART prevent secondary HIV transmission?Can ART prevent secondary HIV transmission?

Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Primary Transmission Endpoint
Virologically-linked transmission events
Primary Clinical Endpoint
WHO 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 in1,750 heterosexual serodiscordant couples in
resource-constrained countries randomized to receiveresource-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/µL
Event 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-yearIn South Africa, early ART was cost-saving over a 5-year
period.period.
• In both South Africa and India, early ART was projected to beIn 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 isWith individual, public health, and economic benefits, there is
a compelling case for early ART for serodiscordant couplesa compelling case for early ART for serodiscordant couples
in resource-limited settings.in 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 (/µL)
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 Group
Initiate ART immediately
following randomization
N=2,000
Deferred ART Group
Defer 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
MeanCDcount(cells/µL)
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 HAART
1040 patients on HAART with 18 months followup1040 patients on HAART with 18 months followup
10.8% developed ADI within < 3 months- TB10.8% developed ADI within < 3 months- TB
CD4< 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 ofMortality of HIV-1-infected patients in the first year of
antiretroviral therapy is high in low-income countriesantiretroviral therapy is high in low-income countries
comparison to high-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 NationalVoluntary HIV screening among National
populationpopulation every 5 yrsevery 5 yrs offers substantial clinical benefitoffers substantial clinical benefit
and cost effective.and cost effective. Annual screeningAnnual screening is cost effectiveis cost effective
among high risk population and in high prevalentamong high risk population and in high prevalent
districtsdistricts

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/ STRIDE
CAMELIA 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
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 count
cells/ul
800
200
HIV RNA
copies/ml
10^6
10^2
†
Changing course of HIV disease in a treated person
HIV antibodies
Virologic set-point
Varies from patient to
patient

d4T phased out of WHO guidelines
•Severe peripheral neuropathySevere peripheral neuropathy
• Lipoatrophy- mean 20 monthsLipoatrophy- mean 20 months
•(Saghayam S,Chaguturu S,(Saghayam S,Chaguturu S,
Kumarasamy N, et al. CID 2004)Kumarasamy N, et al. CID 2004)
•Substitute AZT/TDF after 6 -12Substitute AZT/TDF after 6 -12
months with d4T containing HAARTmonths with d4T containing HAART
in ARV roll outs…in ARV roll outs…
•Risk to anemia after AZTRisk to anemia after AZT
substitution is < 1%.(substitution is < 1%.( Kumarasamy etKumarasamy et
al – IJID 2009)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 primaryNo 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 andNo significant statistical interactions between treatment effect and
gender, race and ethnicity, country or viral load stratumgender, 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 time
IAS 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) -1NNRTIEfavirenz (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-adherence
CostCost
DepressionDepression
ToxicityToxicity
Sense of fatigueSense of fatigue
PharmacologicPharmacologic
InteractionsInteractions
Poor absorptionPoor absorption
Altered intracellularAltered intracellular
metabolismmetabolism
ResistanceResistance
Prescription errorsPrescription errors
Sequential addingSequential adding
Primary resistantPrimary resistant
NVP for MTCTNVP for MTCT
SuperinfectionSuperinfection
Spouse on failing ARTSpouse on failing ART
DiseaseDisease
AdvancedAdvanced
Low baseline CD4Low baseline CD4
High baseline PVLHigh 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
M184V
K103N
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 patientsline HAART- 918 patients
Median 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, I84V
Minor 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

Sequencing Therapy in 2015
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) + IntegraseIntegrase ± / CCR5± / CCR5
inhibitor /inhibitor / 22ndnd
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 NNRTI
2 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)

Criteria to switchCriteria 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 Q151M
5% had K65R and5% 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 standardThis data clearly warns that patients with immunological failure with standard
WHO criteria have severe mutations andWHO criteria have severe mutations and which can jeopardize future 2ndwhich can jeopardize future 2nd
line NRTI options and newer drugs.line NRTI options and newer drugs. Urgent need for VIRAL LOADUrgent need for VIRAL LOAD
monitoringmonitoring

Sequencing Therapy before 2013 in the absence
of Viral load monitoring
2 NRTIs(AZT or d4T) +2 NRTIs(AZT or d4T) + 1 NNRTI1 NNRTI
2 NRTIs(TDF/3TC)/2 NRTIs(TDF/3TC)/IntegraseIntegrase ++ 1 PI/RTV1 PI/RTV
1 PI/RTV(DRVr)1 PI/RTV(DRVr) ++ 22ndnd
Gen NNRTIGen NNRTI/CCR5/CCR5
inhibitor ± NRTIsinhibitor ± NRTIs
Kumarasamy N, CID 2009;Kumarasamy N, CID 2009;Hosseinipour M, AIDS 2009; LyagobaLyagoba
F,JAID 2010; Boyd MA, Kumarasamy N, et al LancetF,JAID 2010; Boyd MA, Kumarasamy N, et al Lancet
2013;Pozniak A, ARHR 20082013;Pozniak A, ARHR 2008

WHO Consolidated ARV Guidelines 2

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 therapy
Hypersensitivity reactionsHypersensitivity reactions
Immune-reconstitution relatedImmune-reconstitution related
Chronic toxicitiesChronic toxicities
Drug-drug interactionsDrug-drug interactions

CART Cohort study at YRGCARE, Chennai
• Between 1996-Oct 2013, the total number of HIV infectedBetween 1996-Oct 2013, the total number of HIV infected
individuals registered for care- 19,500individuals 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 LancetKumarasamy N, et al. CART Cohort study. Cell-The Lancet
Translational Medicine Conf. San Francisco, Nov 3-5,2013Translational Medicine Conf. San Francisco, 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
Circulatingvirus
Time
START
STOP
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.
Local Inflammation,
infection,
HIV replication, etc.

Inflammatory markers on ART
NWCS 319/A5175 -Summary
• Pre-ART elevations in inflammation and immunePre-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 withSome pre-ART marker levels were associated with
risk of HIV dz progression or death after initiation ofrisk of HIV dz progression or death after initiation of
ARTART
• Initiation of ART produced only a modest decline inInitiation 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- total eradication of all HIV infected cells including
quiescent reservoirsquiescent reservoirs
• Functional CureFunctional Cure
- < 50copies- < 50copies
Eradication of HIV following transplantation of CCR5-Eradication of HIV following transplantation of CCR5-
deficient haematopoietic stem cellsdeficient haematopoietic stem cells
Novel strategies- purging reservoirs followed byNovel strategies- purging reservoirs followed by
aggressive HAARTaggressive HAART

HIV Eradication - What We Need To Learn
• The Primary Question: What is the full extent of the latentThe 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 ofIf 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 sexualSecondary prevention ( Prevention of sexual
transmission of HIV-HPTN052)transmission of HIV-HPTN052)

USPHS recommendations for postexposure
prophylaxis: Percutaneous
ExposureExposure RegimenRegimen
Intact skin Do not offer
Mucous membrane Tenofovir+FTC/3TC+Tenofovir+FTC/3TC+
RaltegravirRaltegravir
Alternate: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 initiatedshould 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
monthmonth ( 4( 4thth
month)month)
• Safe sex, Avoid blood donation , avoidSafe 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 beenGlobal progress on scale-up of ART has been
extraordinary. Countries show the way!extraordinary. 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-lookingThis will require forward-looking
policies, more effective and innovative approaches,policies, more effective and innovative approaches,
together with further investmentstogether with further 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 toolARVs for treatment and prevention are a powerful tool
towards ending the HIV epidemictowards ending the 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
VCTVCT
(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)/NIH
HIV Prevention Trial Network (HPTN)/NIHHIV Prevention Trial Network (HPTN)/NIH
START/NIHSTART/NIH
Brown University-RI, UCSD-California, Johns HopkinsBrown 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

Guest Lecture Jan 2015: ART update

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