HIV treatment & ARV resistance issues in India Dr. N. Kumarasamy Dr. N. Kumarasamy Chief Medical Officer Chief Medical Officer YRG Centre for AIDS Research and Education YRG Centre for AIDS Research and Education VHS, Chennai, India VHS, Chennai, India Principal Investigator- - Chennai ACTG International Principal Investigator Chennai ACTG International Clinical Trials Unit/NIH Clinical Trials Unit/NIH
HIV Scenario in India ( 2009) 2 to 3 million infections 2 to 3 million infections Heterosexual transmission Heterosexual transmission ` 0.35% 0.35% of adult population of adult population (1.2billion population) (1.2billion population) ` Growing number of AIDS cases Growing number of AIDS cases HIV- -1; Subtype C 1; Subtype C HIV Source : NACO Source : NACO
Natural history of HIV disease in South India (Kumarasamy et al.CID Jan 2003) 325 300 275 250 225 200 Mean CD4 175 150 125 100 H H D C O T M O P E P R C P G C o u x a C e e e r H r e M a r o y y x a t r r r l p c s l m r P p L V p p p m o l l u a u . t e e t p C e t o p l B a o s o a R s s r l n t s a c a u a o c r e o S Z p u n a l o s c e m p p t o m d r c o m t i n i y r n m h . o c s r i u t d i o R i y e a t d C T n r t p i i e t s a i s r l i u a e l e o t a i o e r i m s s r s n b c l p x I y i p n s e d t a e e a i r T f r n i r t e a g c a h B u i c u n r i t y o o t l g i o s i s u Opportunistic Infections
Antiretroviral Drugs in India 1996…………….. nRTIs NNRTIs Nucleotide Protease Fusion RTIs inhibitors inhibitors Zidovudine (AZT) Nevirapine Tenofovir Ritonavir Enfuvirtide Lamivudine (3TC) Efavirenz Indinavir (T20) Didanosine (ddI) Delaviridine Saquinavir Stavudine (d4T) Nelfinavir Abacavir (ABC) Amprenavir Emitricitabine(FTC) Atazanavir Zalcitabine (ddC ) Lopinavir/ Ritonavir
Figure 2 : Incidence of opportunistic infection in patients with and without HAART, 1996-2003 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 12 10 Cases per 100 person years 8 6 4 2 0 1996 1997 1998 1999 2000 2001 2002 2003 Year Kumarasamy et al.. Clinical Infectious Diseases 2005
Reduction in death rate following HAART Kumarasamy, et al. Clin Infect Dis 2005 30 60 Percent of Patients with CD4 < Deaths per 100 Patient Years 25 50 20 40 200 on HAART Observed 15 30 10 20 5 10 0 0 1997 1998 1999 2000 2001 2002 2003 Year
GOI supported Access to ART • NACO NACO - - 25 Centers- - April 2004 April 2004 • 25 Centers • Central Government Health Scheme (CGHS), Central Government Health Scheme (CGHS), • Employees State Insurance Corporation (ESIC), 9 • Employees State Insurance Corporation (ESIC), 9 • centers ~ 400 patiens patiens centers ~ 400 Armed Forces Medical Services, 3 centers, ~700 • Armed Forces Medical Services, 3 centers, ~700 • patients patients • Hospitals administered by the Railways Hospitals administered by the Railways 16 Centers, 16 Centers, • ~500 patients ~500 patients
Access to ART in India (n=250,000approxi) till May 2009 Govt. programs (200 ART centres centres): ` ): ` Govt. programs (200 ART 220,000 220,000 Private hospitals and NGOs: ~ 30,000 Private hospitals and NGOs: ~ 30,000
Treatment policy NACO ART Guidelines NACO ART Guidelines
1 st line HAART AZT/d4T d4T + 3TC + NVP/EFV + 3TC + NVP/EFV AZT/ TDF + FTC + EFV TDF + FTC + EFV
Switching to Second-Line Treatment WHO Guidelines 2006
Treatment Failure and Drug Resistance: Virologic, Immunologic, and Clinical Definitions Immunologic Virologic Clinical failure failure failure Drug CD4 Count Resistance Viral Load
YRGCARE >15,000 patients registered for care >15,000 patients registered for care - >7000 patients on HAART >7000 patients on HAART - VCT VCT (OPD,Acute OPD,Acute care inpatient care inpatient facility,adherence facility,adherence/couple/family /couple/family ( counseling,Nutritional Counseling, Pharmacy) Counseling, Pharmacy) counseling,Nutritional AIDS Clinical Trials Group (ICTU- AIDS Clinical Trials Group (ICTU -ACTG)/NIH ACTG)/NIH HIV Prevention Trial Network (HPTN)/NIH HIV Prevention Trial Network (HPTN)/NIH Brown University- Brown University -RI, UCSD RI, UCSD- -California, Johns Hopkins California, Johns Hopkins Univ- -MD, UCSF MD, UCSF- -California, Rush California, Rush Univ Univ- -Chicago, Harvard Chicago, Harvard Univ Univ- -MA, Emory MA, Emory Univ Univ- -Atlanta, Stanford Atlanta, Stanford Univ Univ- - Univ California,Treat Asia Asia- -NCHECR, NCHECR, Karolinska Karolinska Inst Inst- -Sweden. Sweden. California,Treat www.yrgcare.org www.yrgcare.org
Virology & Molecular Biology Lab
Regional HIV Genotyping Lab for NIH
• 30 subtype C, 18 subtype B and 2 subtype D Clinical (ART treated and failing patients) n = 29 • Proficiency testing (PT) panels n=21 • VQA, Rush University, USA n = 10 Teragenix, Abbott, USA n = 6 TAQAS, NRL, Australia n = 5
ViroSeq TM v2.0 vs. In-house
In-house assay performed well, which costs about 50% ($ 100) of the ViroSeqTM ($230), demonstrated a similar capacity to identify clinically relevant mutations compared to the ViroSeqTM.
Severe mutations following WHO immunologic failure- Chennai HIV cohort study Total no.of no.of patients registered for care: 10127 patients registered for care: 10127 Total st line HAART: 3739 No.pts initiated on 1 initiated on 1 st line HAART: 3739 No.pts (AZT/d4T+3TC+NVP/EFV) (AZT/d4T+3TC+NVP/EFV) Median CD4 at HAART initiation: 69 IQ (40- -125) 125) Median CD4 at HAART initiation: 69 IQ (40 pts switched to 2 nd nd line: No.of pts switched to 2 line: 336 (9%) 336 (9%) No.of Median CD4 at switch : 144 (90- -199) 199) Median CD4 at switch : 144 (90 st line 3.7yrs ( 2.2 Median duration on 1 st line 3.7yrs ( 2.2- -6.3) 6.3) Median duration on 1 Kumarasamy et al CID 2009; CROI 2008 et al CID 2009; CROI 2008 Kumarasamy
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 Q151M 11% had Q151M 5% had K65R and 5% had K65R and 5% had L74V. 5% had L74V. 26% had 3 or more NNRTI mutations 26% had 3 or more NNRTI mutations This data clearly warns that patients with immunological failure with standard This data clearly warns that patients with immunological failure with standard WHO criteria have severe mutations and which can jeopardize future 2nd which can jeopardize future 2nd WHO criteria have severe mutations and line NRTI options and newer drugs. line NRTI options and newer drugs.
Second line ARV drugs in adults and adolescents ddI or TDF PI/r EFV or NVP ABC or 3TC ( ± AZT )
Sequencing Therapy in 2009 and Beyond: How Many Tries Do You Get? 2 NRTIs NRTIs + + 1 NNRTI 1 NNRTI 2 3 NRTIs NRTIs + + 1 PI/RTV 1 PI/RTV 3 1 PI/RTV + Integrase Integrase/CCR5 inhibitor /CCR5 inhibitor ± ± NRTIs NRTIs 1 PI/RTV + nd Gen NNRTI + ENF + other CCR5 inhibitor 2 nd Gen NNRTI + ENF + other CCR5 inhibitor 2 ± PI/RTV PI/RTV ± Maturation inhibitor + Maturation inhibitor + other entry inhibitor(s inhibitor(s) + ? ) + ? other entry
Sequencing Therapy in 2009 and Beyond: How Many Tries Do You Get? 2 NRTIs NRTIs + + 1 NNRTI 1 NNRTI 2 3 NRTIs NRTIs + + 1 PI/RTV 1 PI/RTV 3 1 PI/RTV + Integrase Integrase/CCR5 inhibitor /CCR5 inhibitor ± ± NRTIs NRTIs 1 PI/RTV + nd Gen NNRTI + ENF + other CCR5 inhibitor 2 nd Gen NNRTI + ENF + other CCR5 inhibitor 2 ± PI/RTV PI/RTV ± Maturation inhibitor + Maturation inhibitor + other entry inhibitor(s inhibitor(s) + ? ) + ? other entry
Sequencing Therapy in 2009 and Beyond: How Many Tries Do You Get? 2 NRTIs NRTIs + + 1 NNRTI 1 NNRTI 2 3 NRTIs/ NRTIs/Integrase Integrase + + 1 PI/RTV 1 PI/RTV 3 nd Gen NNRTI/CCR5 inhibitor 1 PI/RTV + 2 nd Gen NNRTI/CCR5 inhibitor ± ± 1 PI/RTV + 2 NRTIs NRTIs ENF + other CCR5 inhibitor ± ± PI/RTV PI/RTV ENF + other CCR5 inhibitor Maturation inhibitor + Maturation inhibitor + other entry inhibitor(s inhibitor(s) + ? ) + ? other entry
Saravanan et al., 17th CROI 2010, San Francisco, USA
PR and RT Mutations
Genotyping in Naïve population-Indian studies Primary drug resistance has been reported ranging from 2.5% 2.5% Primary drug resistance has been reported ranging from to 17.5% ( (Hira Hira et al.,2 004, Deshpande Deshpande et al .,2005 ; Balakrishnan Balakrishnan to 17.5% et al.,2 004, et al .,2005 ; et al., 2005 ; 2005 ; Arora Arora et al., 2008 ; et al., 2008 ; Lal Lal et al., 2008 et al., 2008 ). ). et al., Few studies reported no major resistance ( Few studies reported no major resistance (Eshleman Eshleman et al., et al., 2005 ; Kandathil Kandathil et al., et al., 2008). 2008). 2005 ;
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