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![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.](https://image.slidesharecdn.com/artupdate-dr-151109063440-lva1-app6891/85/Guest-Lecture-Jan-2015-ART-update-21-320.jpg)
Guest Lecture Jan 2015: ART update
This document summarizes findings from the HPTN 052 clinical trial which showed that early initiation of antiretroviral therapy (ART) in HIV-infected individuals significantly reduces sexual transmission of HIV to their uninfected partners. The trial involved 1,750 serodiscordant couples across nine countries. Couples were randomized to either receive ART immediately if CD4 count was 350-550 cells/μL or defer ART until CD4 dropped below 250 cells/μL. Results showed a 96% reduction in risk of HIV transmission in the immediate ART arm compared to the deferred ART arm. Early ART was also found to be very cost-effective over a lifetime in South Africa and India based on individual and public health benefits
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Guest Lecture Jan 2015: ART update
- 1. 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
- 3. HIV in SriLanka • 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
- 4. HIV Scenario inIndia ( 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
- 5.
- 6. Pathogenesis of HIVInfection
- 7. 1 3 about6mths // 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
- 8. HIV disease • Markedby 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)
- 9. 40 35 11 10 8 4 3 21 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.
- 10. Co-factors relating toprogression 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
- 11. HIV disease • Effectivechemoprophylaxis 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)
- 12. Antiretroviral Agents Approvedby 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)
- 13. RT inhibitors X X Integrase inhibitors X Proteaseinhibitors CCR5 analogues HIV life cycle, inhibition targets & antiretrovirals XFusion inhibitors
- 14. Generic Antiretroviral Drugsfrom 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)
- 15. Safety, Tolerability andEffectiveness 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
- 16. 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
- 17. Reduction in deathrate 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
- 18.
- 19.
- 20. People receiving antiretroviraltherapy, 2005 to June 2014, all countries
- 21. Estimated number ofAIDS-related deaths, with and without antiretroviral therapy, in low- and middle-income countries, and by region, 1995–2012 [1/2] Source: UNAIDS 2012 estimates.
- 22. 1 3 about6mths // 5 10 yrs 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
- 23. When to initiateAntiretroviral Therapy? Risk of progression Risk of AE Adherence commitment Resistance development Cost and readiness <200 <250 <350 350-500 HPTN052/ACTG5245
- 24. HPTN 052HPTN 052 ARandomized 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?
- 25. Stable, healthy, serodiscordantcouples, 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
- 26. RegionRegion SiteSite CouplesCouples AmericasAmericas (278)(278) PortoAlegre, 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
- 27. Total HIV-1 TransmissionEvents: 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
- 28. HPTN 052 • 1,750heterosexual 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
- 29. • In SouthAfrica, 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.
- 30. Summary of Changesin Recommendations in WHO 2013 ART Guidelines-When to Start in Adults
- 31. Rate / 100person 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
- 32. START design HIV-infected individualswho 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. 33 Low-income Lower middle- income High-incomeUppermiddle- 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
- 34. Disease progression onHAART 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
- 35. • Simulation modelof 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
- 36. Numbers of peopleliving with HIV, new HIV infections, and AIDS deaths, 2001-2012, globally Source: UNAIDS 2012 estimates.
- 38. When to StartART 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
- 39. Estimated change intuberculosis-related deaths among people living with HIV in 41 tuberculosis/HIV high-burden countries, 2004–2012
- 40. 1 3 about6mths // 5 10 yrs 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
- 41. d4T phased outof 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)
- 42. 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
- 43. 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
- 44. 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
- 45. • We evaluatedthe 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
- 46. Summary of Changesin WHO 2013 Treatment Guidelines : What to Start in Adults
- 47. Sequencing Therapy in2015 Tenofovir(TDF)+Tenofovir(TDF)+ Lamivudine(3TC)/Emtricitabine(FTCLamivudine(3TC)/Emtricitabine(FTC ) -2NRTIs) -2NRTIs ++ Efavirenz (EFV) -1NNRTIEfavirenz (EFV) -1NNRTI
- 48. Response to HAART RNA RNA IdealResponse Common Response
- 49. Treatment Failure andDrug Resistance: Virologic, Immunologic, and Clinical Definitions CD4 Count Viral Load Virologic failure Immunologic failure Clinical failureDrug Resistance
- 50. Why patients failART? 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
- 51. Resistance Patterns AfterInitial Failure of Common NRTI Backbones ZDV/3TC d4T/3TC ABC/3TC TDF/3TC M184V M184V M184V TAMs L74V, K65R K65R
- 52. Failure of firstline regimen TDF/ABC + 3TC/FTC + NVP/EFV M184V K103N V106M G190A K65R L74V
- 53. Sequencing Therapy inResource 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)
- 54. Pattern of mutationson 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
- 55. Sequencing Therapy in2015 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
- 56. Sequencing Therapy before2013 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)
- 57. Treatment Failure andDrug Resistance: Virologic, Immunologic, and Clinical Definitions CD4 Count Viral Load Virologic failure Immunologic failure Clinical failureDrug Resistance
- 58. Criteria to switchCriteriato 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%)
- 59. 79% of themhad 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
- 60. Sequencing Therapy before2013 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
- 61. Sequencing Therapy in2015 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
- 62. WHO Consolidated ARVGuidelines 2
- 63. What drugs tostart 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
- 64. ARV Toxicities Initial problemstolerating therapyInitial problems tolerating therapy Hypersensitivity reactionsHypersensitivity reactions Immune-reconstitution relatedImmune-reconstitution related Chronic toxicitiesChronic toxicities Drug-drug interactionsDrug-drug interactions
- 65. Sequencing Therapy in2015 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
- 66. CART Cohort studyat 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
- 67. Non AIDS causesof 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
- 68. Between 1986 and2007, 3530 patients with a median follow up 3.9yrs. 24.6% died.
- 69. Role of ChronicInflammation 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
- 70. Integration of HIVin health service delivery Source: GARPR 2013.
- 71. HIV Reservoir Persistsduring 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
- 72. What is areservoir? Blood CSF GS GUT Local Inflammation, infection, HIV replication, etc. Local Inflammation, infection, HIV replication, etc.
- 73. Inflammatory markers onART 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
- 74. Why we needEradication? • 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
- 75. 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
- 76. 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
- 77. Clearing out theLatent Pool: the Players Uninfected SusceptibleCD4 Cell CD4 Precursor Cell Latently Infected CD4 Cell Activated Lytically Infected CD4 Cell
- 78. Purging reservoirs • ImmuneActivation 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
- 80. Why Should EradicationBe 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
- 81. Benefits of ARTin 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)
- 83. USPHS recommendations forpostexposure 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
- 84. 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
- 85. AIDS-related deaths tobe averted due to the new treatment guidelines
- 86. Conclusions • Global progresson 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
- 87. YRGCARE Medical Centre >20,000patients 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.
Editor's Notes
- #26 HPTN 052 enrolled serodiscordant couples and the infected participant required CD4 counts between 350 and 550. Infected participants were either offered immediate combination ART, or ART was delayed until CD4 fell between 20 and 250, but as close to 250 as possible. Two points to be made: when the study was designed WHO guidelines recommended that ART be initiated before CD4 fell below 200. Second, discordant couples are special and even a little unusual, because HIV transmission has not occurred. The primary endpoint of this study was measurement of linke transmission of HIV. We also messured clinical events and death as a stand alone endpoint, and as part of a composite endpoint that considered prevention and treatment benefits concomitantly. The composite endpoint served as a pre-arranged intervention boundary for the DSMB.
- #27 WE NEED A MAP WITH n by site OR A LIST OF SITE and N??
- #28 We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men (WE NEED TO DELETE SOME DETAIL!!)
- #31 INITIATE ART REGARDLESS OF CD4 COUNT OR CLINICAL STAGE RECOMMENDATION ADULTS WITH HIV… …and active TB disease Strong, low-quality evidence …and HBV co-infection with severe liver disease Strong, low-quality evidence …who are pregnant or breastfeeding Strong, moderate-quality of evidence …in a HIV serodiscordant partnership Strong, high-quality evidence CHILDREN &lt; 5 YEARS OLD WITH HIV Infants diagnosed in the first year of life Strong, moderate-quality of evidence Children infected with HIV between one and below five years of age Conditional, very-low-quality evidence
- #47 Rationale: One Regimen For All Preferred 1st line regimen: TDF + 3TC (or FTC) + EFV Simplicity: regimen is very effective, well tolerated and available as a single, once-daily FDC and therefore easy to prescribe and easy to take for patients – facilitates adherence Harmonizes regimens across range of populations (Adults, Pregnant Women (1st trimester), Children &gt;3 years, TB and Hepatitis B) Simplifies drug procurement and supply chain by reducing number of preferred regimens (phasing out d4T) Safety in pregnancy Efficacy against HBV EFV is preferred NNRTI for people with HIV and TB (pharmacological compatibility with TB drugs) and HIV and HBV coinfection (less risk of hepatic toxicity) Affordability (cost declined significantly since 2010)