Jaime C. Montoya, MD, MSc, FPCP, FACP, FPSMID Professor, UP College of Medicine Philippine Council for Health Research and Development

Transcription

1 Jaime C. Montoya, MD, MSc, FPCP, FACP, FPSMID Professor, UP College of Medicine Philippine Council for Health Research and Development 1

2 Outline Epidemiology of TB and HIV and TB-HIV coinfections Characteristics of TB and HIV as to: Molecular characteristics/clade Clinical Course Interaction between TB and HIV Effect of TB on HIV Effect of HIV on TB Prospects for TB and HIV Control: Attainment of MDG Targets Prospects for Vaccines for TB and HIV 2

3 Epidemiology of TB Tuberculosis (TB) is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent. In 2011, 8.7 million people fell ill with TB and 1.4 million died from TB. Over 95% of TB deaths occur in low- and middle-income countries, and it is among the top three causes of death for women aged 15 to 44 TB is the leading cause of HV related deaths 3

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5 Prevalence and Mortality Rates - Philippines, (per 100,000 population) 1,100 1,000 (SOURCE: WHO Global Tuberculosis Control ) Prev, All forms Mortality, All forms This is where we are

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7 Estimated % of New TB cases with MDR TB Estimated % of Retreatment TB cases with MDR TB Global Western Pacific Region (WPR) High MDR TB Burden Countries Estimated Proportion of TB Cases that Have MDR - TB Philippines Global tuberculosis control: WHO report 2011

8 Epidemiology of HIV Prevalence is still below 1% Incidence rates are steadily increasing at unprecedented rates HIV and AIDS epidemic in Philippines labeled as low and slow in the past Now changed to hidden and growing in the years from 2007 onwards

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12 Increasing number of New Cases 2010: FOUR new cases a day! 2009: Two new cases a day 2007: One new case a day 2000: One new case every 3 days Source: Philippine HIV & AIDS Registry National Epidemiology Center

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14 Decreasing Age of Male Patients 70% Percentage of Age-Groups 60% 50% 40% 30% 20% 20-29yo 30-39yo 10% 0% & older 1-19yo Source: Philippine HIV & AIDS Registry National Epidemiology Center

15 Decreasing Age of Female Patients 60% 50% 20-29yo Percentage of Age-Groups 40% 30% 20% 10% 30-39yo 40 & older 1-19yo 0% Source: Philippine HIV & AIDS Registry National Epidemiology Center

16 The Sexual Flip: Heterosexual Transmission to MSM National Epidemiology Center

17 Tuberculosis among HIV Patients 17

18 Tuberculosis in HIV Patients About one in three of the 42 million people living with HIV are co-infected with TB 90% of them will die within a few months without the right treatment WHO, 2012

19 Tuberculosis in Filipino HIV Patients 49% of HIV patients, overall, regardless of CD4 count were shown to have mycobacterial disease either by AFB smear or culture Of those with a CD4 < 200, 80% were positive for tuberculosis by culture Montoya et al. PJMID,1998,27(3):97-102

20 Tuberculosis in Filipino HIV Patients 23% of those confirmed to have pulmonary tuberculosis had normal chest x-rays Majority of those who had abnormal chest x-rays showed the typical apical infiltrates There was no apparent correlation between between level of CD4 and radiographic pattern of tuberculosis Montoya et al. PJMID,1998,27(3):97-102

21 HIV among Tuberculosis Patients 21

22 HIV Among TB Patients PICT HIV Positive (.08%) (.12%) (.23%) 2012* (.20%) * 1 st & 2 nd quarter only

23 Characteristics of the Organism 23

24 Mycobacterium tuberculosis Hardy, slowly dividing intracellular bacteria Always pathogenic Populations composed of actively dividing, intermittently dividing and dormant bacilli Airborne transmission High potential for drug resistance 24

25 Mutations associated with TB Resistance rpob for Rifampicin katg and promoter region of the maba(fabg1) for isoniazid embb for ethambutol pnca for pyrazinamide rpsl and rrs for streptomycin gyra for ofloxacin

26 Prevalent Clade of TB in Philippines Isolates of M. tuberculosis from Filipino patients without HIV infection were found to belong to a distinct family of TB strains, which may be called the Manila Family of M. tuberculosis Manila Family unique and different from the identified strains in the region based on RFLP and spoligotyping analysis Douglas JT, Qian L, Montoya JC, et al. J Clin Microbiol 2003; 41(6):

27 Molecular Epidemiology of TB in a suburban community in the Philippines Sputum were collected consecutively from all adult patients (age years old) who consulted at the City Health Office and the Barangay Health Stations of Santa Rosa City, Laguna, Philippines for evaluation and management of possible pulmonary TB from March 2009 to June 2010 Montoya et al (unpublished)

28 Prevalent Clade of TB Majority (96 / 116, 82.8%) of the strains belonged to EAI2_Manilla clade, followed by U (3 / 116, 2.6%), and one strain each to LAM2, EAI3_IND and MANU2 14 strains or 12.1% were unclassified as a clade or a lineage Montoya et al (unpublished)

29 Prevalent Spoligotype of TB SIT19 predominated with 81/116 (69.8%), followed by SIT 758 with 7/116 (6.0%), 2/116 or 1.7% each of SIT 1490, SIT 483 and SIT1419, and one strain each of SIT 894, SIT1169, SIT287, SIT897, SIT1189, SIT17, SIT 1247 and SIT strains were unclassified (12.1%) Montoya et al (unpublished)

30 Analysis of Trends EAI Family is prevalent in Southeast Asia, mainly in the Philippines, in Myanmar and Malaysia EAI2_Manilla clade was also identified in other countries where large Filipino immigrant communities are located EAI2_Manilla clade now recognized as reference clade in the International Database and all isolates share the same spoligotype (SIT19) Montoya et al (unpublished)

31 Human Immunodeficiency Virus Retrovirus Relatively weak organism outside of a living cell Bloodborne and body fluids transmission High potential for drug resistance 31

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33 Clade of HIV in the Philippines: 2013 and beyond? Assess HIV-1 diversity - Source of new epidemic? Subtype B moved from Africa to Haiti ~1966; spread there for some years. Pandemic clade emerged after a single migration of the virus out of Haiti ~1969. Encompasses vast majority of non-haitian subtype B infections in the USA and elsewhere around the world. Gilbert, et al., PNAS 2007

34 Characteristics of the Disease 34

35 Risk of TB Infection and Disease among Exposed Immunocompetent Individuals Exposure (close contact) Infection ~30% No infection 70% Containment 90-95% Early progression 5-10% Continued containment 95% Late progression 5% 35

36 Clinical Course of HIV Infection CD4 + T-cells, cells/µl Primary infection ± Acute HIV syndrome wide dissemination of virus seeding of lymphoid organs Clinical latency Opportunistic diseases Constitutional symptoms Death Weeks Years 1/512 1/256 1/128 1/64 1/32 1/16 1/8 1/4 1/2 0 Plasma Viremia (Dilutional Titer)

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39 Effect of HIV on TB Diagnosis Increased frequency of false negative tuberculin tests Decreased sensitivity of sputum smears Atypical radiologic manifestations Huebner et al, 1992 Elliott et al, 1990 Pitchenik and Rubinson, 1985 Elliott et al,

40 Effect of HIV on Clinical Course of TB Increased likelihood of infection with TB when inhaled into the lungs Accelerated progression of new onset TB to clinically significant disease (Low Prevalence TB ) Increased likelihood of reactivation of latent tuberculosis infection (High TB Prevalence)

41 Population Dynamics of TB Latent TB Reactivation TB Primary TB Uninfected/Susceptible 41

42 Impact of HIV on Risk of TB Disease among Infected Individuals Exposure (close contact) Infection ~30% No infection 70% Containment HIV 90-95% HIV+ 60% Early progression (2 years) HIV 5 10% HIV+ 40+% 42

43 Impact of HIV on Risk of TB Disease among Infected Individuals Exposure (close contact) Infection ~30% No infection 70% Containment HIV 90-95% HIV+ 60% Early progression (2 years) HIV 5 10% HIV+ 40+% Continued containment HIV 95% HIV+??% Late progression HIV 5% HIV+ 5-10%/year 43

44 Clinical Presentation of HIV-related TB TB can occur at any point in the course of HIV infection Clinical presentation dependent on degree and extent of immunodeficiency Early stage HIV typical TB presentation Pulmonary TB is still most common form Pulmonary TB often times AFB smear negative in early stages of HIV 44

45 Clinical Presentation of HIV-related TB Late stage HIV- interstitial infiltrates common with minimal cavitary formation even with high bacillary loads of TB bacilli Late stage HIV disseminated and extrapulmonary TB more common Lymphadenopathy Pleural effusion Pericardial disease Miliary disease Meningitis 45

46 Mechanisms of Effects of HIV on TB Primarily due to depletion of CD4 cells Up-regulation of M. tuberculosis entry receptors on macrophages HIV manipulation of macrophage bactericidal pathways 46

47 Mechanisms of Effects of HIV on TB Deregulated chemotaxis and a tipped Th1/Th2 balance HIV impairs tumor necrosis factor (TNF)- mediated macrophage apoptotic response to M. tuberculosis and thus facilitates bacterial survival 47

48 Changing Incidence of HIV-Related TB Associated with HAART in Rio de Janeiro 40 TB/HIV Cases cases cases cases cases cases %TB Cases with HIV TB/HIV Linear (TB/HIV) Source: Mello et al

49 Timing of initiation of antiretroviral drugs during TB therapy Abdool Karim SS, et al. NEJM 2010;362:

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51 Effect of TB on HIV MTB increased HIV replication in vivo and in an in vitro model. This MTB-mediated viral production likely occurs through Ag-specific activation and infection of responding T cells Goletti D. et al. J Immunol Aug 1, 157(3):

52 Effect of TB on HIV Cellular markers of immune activation, CD38 and HLA-DR on CD4 and CD8 T lymphocytes, are elevated in HIV infected individuals. TB leads to further increases in immune activation and stimulate HIV viral replication Active TB correlated with increased HIV viremia in a co-infected individual Hence, presence of co-infections such as TB make the HIV+ patient more contagious Lawn SD et al. Clin Microbiol Rev Oct; 14(4):

53 Mechanisms of Effects of TB on HIV M. tuberculosis infection can up-regulate both HIV infection and replication within monocytederived macrophages (MDMs), increase the efficiency of virus transmission from infected MDMs to T cells, and favor replication of X4 HIV variants by up-regulation of CXCR4 53

54 Mechanisms of Effects of TB on HIV Monocytes from HIV + patients display an impaired response to TLR ligands Viral proteins can interfere with both MDM and DC maturation and function in vitro, including their ability to phagocytose mycobacteria and kill intracellular bacteria 54

55 Effect of TB Treatment on HIV TB therapy in HIV/TB co-infected persons with CD4 counts >350 cells/mm3 leads to significant declines in immune activation of CD8 T cells without a measurable impact on HIV load or CD4 counts Findings suggest that declines in immune activation rather than changes in HIV load or CD4 count may explain prior epidemiologic observations that TB treatment leads to survival benefits in HIV/TB coinfected patients with less advanced HIV disease. Scott Mahan et al. PLoS One. 2010; 5(2): e9138

56 Challenges to concurrent HIV and TB therapy Pill burden Overlapping drug toxicities Pharmacokinetic drug-drug interactions Increased risk of immune restoration inflammatory syndrome

57 TB Preventive Therapy and Survival in HIV Patients in Rio de Janeiro Cumulative Survival Source: Santoro-Lopes TB Preventive Therapy 0.9 Yes No Days 57

58 Risk of MDR TB in HIV Infected Persons Higher than patients without HIV HIV seropositive status is a risk factor for resistance to at least isoniazid, both isoniazid and rifampicin and rifampicin by multivariate analysis Risk also associated with higher probablity of non-adherence to TB treatment due to multiple drugs taken by patient 58

59 Attainment of MDGs for TB 59

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61 MDG targets for TB versus actual performance * Rates per 100,000 population

62 Prevalence Incidence Mortality MDG TB Burden going down Baseline Current Endpoint 100 CDR All Forms CDR New Sm + Cure Tx Success TB program indicators going up NTP Baseline Current Endpoint

63 MDR TB Cases Total MDR TB Cases = 10,600 23%

64 Attainment of MDG Targets for TB For TB related death rates, MDG targets will be achieved as long as WHO baseline indicators are followed TB prevalence based on prevalence surveys has a chance it will be halved by 2015 TB incidence rate targets may also be achieved Montoya JC. Trans Nat Acad Sci Tech (2):

65 Attainment of MDG Targets for TB For detection and cure rates under DOTS, there is sufficient evidence to support the statement that the Philippines can achieve this targets Detection rates have been reached, Success rates exceeded and Cure rates approaching targets using WHO indicators Montoya JC. Trans Nat Acad Sci Tech (2):

66 Attainment of MDGs for HIV 66

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68 Attainment of MDG Targets for HIV Many of the MDG targets seem to be far from reach for the Philippines Most of the baseline data just being generated Based on the UNGASS Report of 2009, of the program output indicators being monitored, only the blood safety program and TB/HIV programs were above the 60% benchmark for a program to make an impact Montoya JC. Trans Nat Acad Sci Tech (2):

69 Attainment of MDG Targets for HIV Regarding prevention programs reaching the most at risk populations, they did not reach the 60% benchmark for the program to be effective There is a 900% increase in prevalence among the most at risk populations from the previous UNGASS report (0.08 to 0.47%) Montoya JC. Trans Nat Acad Sci Tech (2):

70 Attainment of MDG Targets for HIV Despite an increase in resources, the Philippine HIV response can be characterized by low coverage of prevention programs which results in poor knowledge, low condom use among most at risk populations and low perception of risk among the youth Given the increase in number of cases in the last 2 years and more so in the last 5 months of the year, the likelihood of MDG targets being attained is very low Montoya JC. Trans Nat Acad Sci Tech (2):

71 Combining HIV and TB Control The Protest Initiative Community-based voluntary HIV counseling and testing HIV/AIDS education and risk reduction Referral of HIV-positive people to care INH preventive therapy Cotrimoxazole for advanced HIV Expansion of care as capacity grows Antiretroviral therapy, when available 71

72 Provider Initiated Testing and Counselling (PITC) Recommended for: All persons presenting to the health service with symptoms and signs that could be attributable to HIV infection (including persons suspected of or with TB) Symptomatic and HIV exposed children

73 Low and concentrated epidemics In addition to symptomatic patients and HIV exposed children, PITC should be considered taking into account the epidemiological and social context - in: STI services Health services for most at risk populations Antenatal, childbirth and postpartum health services TB services

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76 BCG Vaccine PRO Most used vaccine at global level Very low cost Recognized protective efficacy against infant tuberculosis (e.g. TB meningitis) CON Genetic heterogeneity of different BCG vaccines Variable efficacy against pulmonary tuberculosis 76

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78 TB Vaccines Novel vaccine development has accelerated in the past ten years At least 16 candidates entering human trials, and a few vaccines have entered into Phase 2b efficacy studies Different vaccines may be needed due to the varying disease states (naïve, latently infected, or active), the ages affected (infants, adolescents and young adults, the elderly), and patient health status (HIV and immunocompromised patients especially) 78

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85 TB Vaccines Mass vaccination of latently infected populations, especially adolescents and young adults, will likely have the largest impact on new infection rates Research and development of TB vaccine hampered by the lack of validated animal models, absence of correlates of immunity and a human challenge model, as well as by the size and cost of Proof-of-Concept clinical trials 85

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87 For HIV 87

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90 Combined HIV/TB Vaccine? Most cost-effective way of combatting both diseases One approach would be to construct a combined TB/HIV vaccine, such as a recombinant BCG vaccine as a vehicle for combinations of mycobacterial and HIV antigens Kaufmann et al. Nat Med 11: S33 S44,

91 Marco Vitoria WHO, HIV Department Geneva, August

92 Archbishop Desmond Tutu 92

93 Thank You Very Much! Maraming Salamat Po! 93

94 Acknowledgements Dr. Eric Tayag, NEC, DOH Dr. Celine Garfin, National TB Program, DOH Dr. Genesis Samonte,Unit Manager, HIV Surveillance Unit, NEC Dr. Rosanna Ditangco, HIV Group, RITM Dr. Jose Gerard Belimac, PNAC Dr. Charles Rinaldo, University of Pittsburgh Dr. Charles Yu National Academy of Science and Technology