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HIV-infection and Tuberculosis in Russian Federation Alexey V. Kravchenko MD, PhD, Professor Russia AIDS Federal Center Vera N. Zimina MD, PhD, associate Professor Moscow City TB Center, Russia AIDS Federal Center The growth of the cumulative number of reported HIV cases among Russian citizens from 1987 to 2012. 721 264 800000 700000 600000 500000 400000 300000 200000 101 576 100000 0 1987 1989 1991 1993 The cumulative number of deaths 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 The cumulative number of registered HIV-infected persons, excluding deaths According to the individual record of cases of HIV infection among the citizens of the Russian Federation The number of new cases of HIV infection in the Russian citizens in 1995 - 2012 years 90000 2012 y.: 56% - IVDU; 42% - Heterosexual 80000 70000 70453 62387 58286 58181 60000 50000 40000 54856 37773 30000 20000 10000 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 The number of new cases of HIV infection According to the individual record of cases of HIV infection among the citizens of the Russian Federation Dynamics of the number of HIV-infected patients who had the secondary diseases and diagnosis of AIDS in the Russian Federation 120000 99548 100000 86811 80000 63424 53735 60000 44558 40000 34290 20000 0 62579 15229 16970 2673 2000 7443 2001 5767 2002 6016 2003 10197 2004 3051 2005 2006 HIV-infected patients who have secondary diseases These forms of federal statistical number 61 4480 7772 2007 18183 29452 23435 11783 2008 2009 2010 2011 2012 The number of persons with AIDS New cases of TB associated with HIV infection in the Russian Federation (1999-2012) including the Federal Penitentiary Service (FPS -2007-2012) 2012 y. - 12334 14000 The incidence of co-infection (TB/HIV) 2292 1896 12000 10000 1945 In 2012, among all new TB cases 9% were HIV-infected patients Krasnoyarsk region – 30% 1949 1304 8000 1157 6000 4000 2000 271 0 310 576 833 990 1407 2926 3907 4828 6083 7304 8668 9547 10438 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Identified in the resident population Identified in FPS These forms of federal statistical number 61 The number of patients with active tuberculosis with HIV infection, who are under supervision (2002-2012), Including FPS (2007-2012) 35000 2012 y. -29708 The incidence of co-infection (TB/HIV) 30000 25000 6123 5640 23054 24068 2011 2012 5225 20000 4370 15000 3600 2862 10000 5000 0 2454 3133 2002 2003 4506 2004 6850 9102 2005 2006 11431 13213 2007 2008 TB/HIV-patients among the resident population These forms of federal statistical number 61 16405 2009 19738 2010 TB/HIV-patients in FPS TB cases among HIV-infected patients: • - 41.9% - were or are in prison institutions • - 76.5% - were infected with HIV through intravenous drug use • - 23% -85% (depending on region) - are registered with the drug dispensaries • - 61.5% of them are screened for TB Dynamics of the number of registered deaths among people living with HIV in the Russian Federation 25000 20304 18473 20000 15888 14599 13123 15000 11159 8542 10000 9851 14899 15955 12740 10938 8547 6122 5000 2745 3252 3920 4948 1446 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Of the registered died in the year Of those who are under the supervision died in the year These forms of federal statistical number 61 2010 2011 2012 Distribution of HIV patients accordingly the reasons of death In 2011, the deaths of people living with HIV from dying of diseases associated with HIV - 39.8% from other causes - 60.2% 80% 68,7% 64,2% 60% 61,0% 60,8% 56,7% 40% 20% 10,7% 3,4%6,5% 11,4% 3,5%7,6% 16,5% 7,6% 3,6% 15,1% 8,3% 3,4% 12,3% 3,6%6,3% 0% TB 2007 PCP 2008 Recurrent pneumonia These forms of federal statistical number 61 2009 2010 The other secondary diseases 2011 Main directions of antituberculosis care for the patients with HIV • TB prevention in patients with HIV early HAART prescription; tuberculosis chemoprophylaxis • Early tuberculosis diagnostics: active fluorography; clinical symptoms screening; on the uptake • Tuberculosis diagnosis confirmation: modern complex of measures for the patients survey that could help to diagnose tuberculosis signs and symptoms • Treatment: antituberculosis therapy, HAART, treatment of another secondary diseases Detection of TB in HIV-infected patients • According to the Resolution of the Government of the Russian Federation " On prevention of tuberculosis in the Russian Federation" of 25.12.2001 y . №892 patients with HIV infection are subject to preventive examinations fluorography 2 times a year • With decreasing CD4 + lymphocytes identify the role of FG loses its significance • This is due to the fact that the manifestation of tuberculosis in HIVinfected patients is significantly different from the current start in TB patients with intact immune system Early tuberculosis diagnostics in HIV-infected patients *4,5,6 *4,5,6 *5,6 *1,2 *1,2,3 *1,2,3 0.80% 1.50% 7.30% 27.00% 15.80% 33.30% 99.20% 98.50% 92.70% 84.20% 66.70% CD4<100 СD4:100-199 СD4:200-349 HIV-patients Zimina V.N., Batyrov F.A., Kravchenko A.V., Klimov G.V., Vasilyeva I.A., Tuberculosis and lung diseases 2011.- №12. СD4:350-499 CD4>500 On the uptake 73% TB Active fluorography *- p<0.05 DISTRIBUTION OF CO-INFECTED (HIV/TB) PATIENTS ACCORDINGLY THE COUNT OF CD4+CELLS % 50 45 40 35 30 25 20 15 10 5 0 42.9 29.4 13.4 <100 100-349 350-500 CD4+ cells/mm3 14.4 >500 Complex of the morphological biopsy study at the patients with HIV-infection Microscopy Cytological study Microscopy Hystobacterioscopy with the CillNielsen stunning OBLIGATORY!!! Immunohystochemistry DESIRABLE!!! PCR Zimina V.N., MD dissertation.-2012– 44 с. The proportion of patients with HIVinfection screened for TB in 2010 Of the patients passed dispensary screening for HIV infection 86,7% Of the patients who are registered in regional AIDS-centers 75,0% 55,6% These forms of federal statistical number 61 Of all patients with HIV infection Range of MBT Drug Resistance in TB and HIV/TB Patients Depending on the Degree of Immunosuppression (Absolute Concentration Method) DR Definition HIV/TB n % TB р n % Monoresistance 9 7,1 20 19,4 <0,05 Polyresistance 19 15,1 16 15,5 >0,05 MDR including XDR 37 4 29,4 3,2 21 0 20,4 0 >0,05 MDR + first-line drugs 12 9,5 7 8,0 >0,05 MDR + first- and second-line drugs 25 19,8 14 13,6 >0,05 DR to А, К, Сар 16 12,7 11 10,7 >0,05 DR to Fq 9 7,1 1 1,0 >0,05 Total number of DR patients 65 51,6 57 55,3 >0,05 Total number of patients tested for DR 126 100 103 100 MDR-TB Rate in HIV patients depending on the number of CD4 lymphocytes 35,4% HIV/TB CD4<200 19,2% 20,4% HIV/TB CD4>200 TB Zimina V.N., MD dissertation.-2012. PolyR 15% MonoR 7% Sens 48% TB/HIV preXDR 13% MDR 30% MDR (non preXDR and XDR) 14% XDR 3% TB pre-XDR 23% PolyR 28% MonoR 35% MDR 37% MDR (non preXDR and XDR) 14% XDR 0% Zimina V.N., MD dissertation.-2012. MBT Malty Drug Resistance in TB and HIV/TB Patients (WHO, 2011 г.) Estonia Эстония - Primary MDR MBT– 22% - Secondary MDR MBT – 45,2% - Primary MDR MBT in HIV/TB patients – 7,2% - Primary MDR MBT– 16% Ukraine - Secondary MDR MBT – 54,4% - Primary MDR MBT in HIV/TB patients – 23,8% Russia • Primary MDR MBT– 16% • Secondary MDR MBT – 42% • Primary MDR MBT in HIV/TB patients – ND WHO PROGRESS REPORT 2011 Recommendations of the Russian Scientific Society of infectious diseases, 2012 CD4-lymphocytes, cells/mm3 When to start ART? <100 When the TB-therapy is well tolerated, as early as possible (within 2-3 weeks) attached ART 100–350 Within 2 months (possibly after intensive phase of TB-therapy). By reducing the number of CD4-lymphocytes <100 cells / mm3 prescribe ART immediately. >350 When the background of the number of CD4-lymphocytes is <350 cells / mm3. Attach ART after the main course of TBtherapy, regardless of the number of CD4cells (prevention of relapse TB) Pokrovsky VV, Yurin OG, AV Kravchenko et al. Protocols of regular check-up and treatment of patients with HIV infection 2013 / / Epidemiology and Infectious Diseases . Topical issues . - 2012 . - № 6 , Annex . – P.1- 28 . Chemotherapy regimens for empirical treatment of TB and in different types of drug susceptibility of M.tuberculosis (DST) in patients with HIV infection DST Phase of TB chemotherapy Intensive phase Empirical 3 H Rb/R Z E [Str/Km/Am] treatment or DS The continuation phase 6 или 9* H Rb/R Е [Z] H E (S) 3 Кm/Аm Rb/R Z Fq [E] MDR 8Cm Fq Z Cs/Trd PAS Pt [ Km/Аm] [E] 12-18 Fq Z Cs/Trd PAS Pto/Eto [ E] 9 R/Rb Z Fq [E] * - In tuberculous meningitis and osteo-articular tuberculosis Abbreviations : H - isoniazid , R - rifampicin , Rb - rifabutin , Z - pyrazinamide , E - ethambutol S - streptomycin ; Km - kanamycin , Am- amikacin , Pto - protionamid , Eto - ethionamide Cm - capreomycin , Fq- latest-generation fluoroquinolones , Cs - cycloserine , Trd - terizidone , PAS – Pasco J. Bartlett et al. Clinical aspects of HIV, 2013 (Russian edition) The preferred first-line ART regimens in patients with HIV infection and tuberculosis: (The regimens of TB-therapy including Rifampicin) • ZDV (TDF or ABC) + 3TC + EFV • ABC/3TC or TDF/FTC + EFV When the patient's body weight 60 kg or more daily dose of EFV be increased to 800 mg/day. Pokrovsky VV, Yurin OG, Kravchenko AV et al. Protocols of regular check-up and treatment of patients with HIV infection 2013 // Epidemiology and Infectious Diseases . Topical issues . - 2012 . - № 6 , Annex . – P.1- 28 . Alternative regimens of ART: When used in the regimens of TB-therapy Rifampicin • At the level of VL < 100000/ml - ZDV/3TC/ABC in a fixed combination ( Trizivir ®) • RAL 0,8 g ( 2 tablets ) x 2 times daily + TDF ( or ZDV) + 3TC • MVC 600 mg 2 times daily + 2 NRTIs ( when applied dose of rifabutin MVC - 300 mg x 2 times / day ) • When used in the regime of ART HIV PI/r must be replaced by rifampicin , rifabutin (150 mg/day) Pokrovsky VV, Yurin OG, Kravchenko AV et al. Protocols of regular check-up and treatment of patients with HIV infection 2013 // Epidemiology and Infectious Diseases . Topical issues . - 2012 . - № 6 , Annex . – P.1- 28 . Immunological efficacy of HIV-infection treatment based on the increase of CD4-cells median CD4-cells/mm3 600 500 196 400 300 200 78 100 0 before treatment 581 440 394 288 228 +187 cells/mm3 193 224 + 92 cells/mm3 4 weeks +146 cells/mm3 Antituberculosis treatment + HAART HAART 12 weeks Antituberculosis treatment Kanestri V.G., Zimina V.N., Kravchenko A.V., et al.,. HIV and Tuberculosis co-infection: analysis of safety and tolerabiloity// Infectious diseases.2012.- 10. № 3.; 5-9 Therapy and adverse events (%) Azotemia Granulocytopenia TB-treatment + HAART Anemia Skin reactions Gastrointestinal ALT/AST 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% Azotemia TB-treatment Granulocitopenia Grage 1 Anemia Grade 2 Skin reactions Grade 3 Gastrointestinal Grade 4 ALT/AST 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% 30,0% 35,0% 40,0% Azotemia Granulocytopenia HAART Anemia Skin reactions Gastrointestinal ALT/AST 0,0% 5,0% 10,0% 15,0% 20,0% 25,0% Kanestri V.G., Zimina V.N., Kravchenko A.V. et al. //Infectious diseases, 2012.- V.10, N3.- P.5-9. 30,0% 35,0% 40,0% The recommended chemoprophylaxis regimens of TB in HIV-infected patients Recommendations WHO, 2011 CDC, 2011 Russia, 2013 Indications for use CP Regime of CP HIV (+) (regardless of the number of Н - at least 6 months CD4-lymphocytes, Mantoux test and the availability of ART) Mantoux test >5 mm Н - at least 9 months IGRA-test (+) HIV (+) (regardless of the number of Н - at least 6 months CD4-lymphocytes, Mantoux test and the 3 months HZ/Е +3Н availability of ART) (prevention by contact with TB patients) WHO policy on collaborative TB / HIV activities in 2012 J. Bartlett et al. Clinical aspects of HIV, 2013 (Russian edition) Tuberculosis diagnostic and treatment perspectives at the patients with HIV Registration in Russian Federation Urinary test for the detection of lipoarabinomannan (LAM) at the patients with HIV-infection (test advances: sensitivity increases as soon as immunodefficinecy progresses and low cost) The possibility of diagnostic algorithm changing with the using of different test combinations depending on the patient immunosupression stage and hospital type New antituberculosis drugs registration for the treatment of tuberculosis with MDR