Post on 17-Jan-2017
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
18
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.
1 3 about 6mths // 5 10 yrs
Acute HIV
Opportunisticinfections
asymptomatic
Minor HIV-relatedsymptoms
CD4 countcells/ul
800
200
HIV RNAcopies/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 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
1 3 about 6mths // 5 10 yrs
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
Virologic set-point Varies from patient to patient
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
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) + 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
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) + 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
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
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) + 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
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 disease- cardiovascular 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.