Outline. HIV Overview. Outline. HIV history: Viral Origins 5/5/2014. Past. Present. March 25, Future. Past. Present. Future

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1 Outline HIV Overview March 25, 2014 Past History Epidemiology Present 3 Cases that demonstrate changing care paradigm Future Prevention strategies - Control Outline Past History Epidemiology Present 3 Cases that demonstrate changing care paradigm Future Prevention strategies - Control HIV history: Viral Origins Simian Immunodeficiency Virus (SIV) direct evidence of simian-to-human transmission is still missing When the jump occurred Suggest a common viral ancestor between 1884 and 1924 Methods: HIV-1 sequences preserved in human biological samples estimates of viral mutation rates Hindsight studies show clinical disease in late 1950 s early 60 s Democratic Republic of Congo preserved blood sample taken in 1959 preserved lymph node biopsy sample taken in 1960 HIV History: Discovery 1981 MMWR GRID AIDS HIV History: Discovery 1983 LAV HTLV III 1

2 HIV History: Discovery 1985 HIV History: Discovery 1987 HIV History: Discovery 1996 HIV History: Discovery s Following the introduction of HAART mortality, AIDS, AIDS-defining diagnoses, and hospitalizations all decreased 60 to 80 percent Current: HIV w/ treatment Despite the absence of a cure, the natural history of the disease has radically changed HIV Epidemiology: The Pandemic HIV Epidemiology: The Pandemic 1.3 million 230, , , million 4.0 million 800, million 22.5 million 75,000 2

3 HIV Epidemiology: Transmission Transmission risk factors Sexual intercourse Exposure to contaminated blood or body fluids Perinatal Major risk populations Heterosexual* Injection drug users Men who have sex with men (MSM) Perinatal Blood product recipients Healthcare workers with a needle-stick exposure * Despite the initial description of the disease among men who have sex with men (MSM) in the United States, more than 80 percent of infections worldwide occur through heterosexual transmission HIV Epidemiology: Transmission Other factors that increase risk for HIV transmission HIV viral load each log increment in the viral load associated with increased ratio of 2.45 for seroconversion Sexual and behavioral risks large number of sexual partners particular sexual practices IVDU w/ sharing needles Presence of other infectious diseases & STD's transmission four times higher in patients with genital ulceration Immune activation with TB, Malaria Lack of circumcision associated with risk of HIV transmission in heterosexual couples and MSM Host and genetic factors HIV Epidemiology: Transmission Risk of HIV transmission: Highest to lowest risk Sexual Receptive anal intercourse 1:30 1:100 Insertive anal intercourse 1:1000 Receptive fellatio 1:1000 Receptive vaginal intercourse 1:1000 Insertive vaginal intercourse 1:10,000 Other IVDU sharing of needles w/ HIV (+) person 1:150 HIV infected blood needlestick 1:300 Blood transfusion in US 1:2,000,000 HIV Epidemiology: Transmission Clinical Latent Period period of asymptomatic infection infected person remain healthy appearing for about a decade still highly infectious; especially early after acute HIV explains how HIV became a pandemic transmission becomes occult HIV Epidemiology: "Within each region, each country, and each community, the HIV epidemic has established its own unique character. depending upon the time of introduction of the virus, the social fabric of that community, its culture, its sexual networks, the mobility of the people and the reaction of the government to mounting an AIDS control program" HIV Epidemiology: Transmission Dominant mode of acquisition varies by period in history, by country, by gender, etc. In resource-limited areas: vaginal sex 70 to 80 percent perinatal transmission 5 to 10 percent injection drug 5 to 10 percent use In resource rich / developed areas: increasing men who have sex with men (MSM) 3/5 of new infections heterosexual declining transfusion related perinatal 3

4 HIV Epidemiology: Regional data Africa The area most affected by HIV 60% of the world s HIV-infected population Only 12% of the world's population especially Southern Africa 2% of the world's population 30% of the world s AIDS-infected population > 6 % prevalence Transmission heterosexual transmission HIV Epidemiology: Regional data Asia and the Pacific The extent of the spread of HIV in Asia is critical for the future of the pandemic half of the world s population India 2 to 3 million people living with HIV 50% of the HIV in Asia prevalence rate in India 0.36 percent below many western nations including the US Transmission 85 % of HIV transmission in India is through sexual contact often via interaction with sex workers China Between 430,000 and 1.5 million w/ HIV/AIDS fewer than one in three people living with HIV in China has been diagnosed prevalence of about 0.05% Transmission 49 % intravenous drug use 50 % by sexual transmission HIV Epidemiology: Regional data Latin America and the Caribbean Caribbean w/ some of the highest HIV seroprevalence rates in the world (after sub-saharan Africa) Transmission Primarily via heterosexual contact Europe + Central Asia Western Europe: Heterosexual transmission majority Mix of MSM, IVDU Eastern Europe/central Asia One of areas of rapid growing HIV/AIDS epidemic in the world Major risk is IVDU HIV Epidemiology: Regional Data US 1.2 million persons in the United States infected with HIV Overall, HIV prevalence is associated with poverty, less education, and drug use Men who have sex with men (MSM) 3/5 of new infections gay and bisexual men are more than 40 times as likely to have HIV as other men in US Heterosexual transmission also increasing Transfusion related and perinatal transmission almost eliminated!!! HIV Epidemiology: Demographic data / Race HIV Epidemiology: Demographic data/race In black gay American men, the HIV problem rivals the epidemic you find in South Africa, Zimbabwe or Nigeria. HIV (+) Rates > 30% reported for black MSM in Washington DC 4

5 WV HIV/AIDS Surveillance Report, Cumulative through 2010: Updated 2011 HIV total number of cases: 1640 By gender Male 1233 Female 407 By race White 1085 African American 504 Hispanic 32 Other Accessed February 23, 2012 WV HIV/AIDS Surveillance Report, Cumulative through 2012: Updated 2013 By exposure category MSM 792 Injection drug use (IDU) 287 MSM/IDU 59 Heterosexual contact 273 Perinatal 14 Other/Unknown 215 Includes hemophilia, blood transfusion, risk not reported Accessed August HIV Epidemiology: Demographic data/gender Gender Greater than 50% of persons living with HIV/AIDS globally are women Women constitute the fastest growing segment of the population with HIV infection in the United States Explanations of inequality are both biological and social HIV Epidemiology: Demographic data/gender Biologic inequity penile-vaginal intercourse transmission of HIV Receptive vaginal intercourse 1:1000 Insertive vaginal intercourse 1:10,000 transmission 10 time more efficient man to woman HIV Epidemiology: Demographic data/gender Social inequity Majority of women with HIV infection have their husbands as their only sexual contact up to 80% of HIV-positive women in long-term stable relationships infected by their stable male partner Outline Past History Epidemiology Present 3 Cases that demonstrate changing care paradigm Future Prevention strategies - Control 5

6 Cases y/o Male - MSM Presents w/ fevers and cognitive decline Diagnosed w/ Crytptococcal meningitis and PML CD4 10 treated and improved; but required long term amphotericin -B also started on Bactrim and MAI prophylaxis Initiated on NRTI monotherapy Required several re-hospitalizations refractory diarrhea, anemia/cytopenias, lactic acidosis, renal failure, retinitis Died of progressive PML 4 months after diagnosis Case 1 Themes: Patient is a member of a high risk population Tested for HIV because of presentation with an opportunistic infection (OI) Low CD4 at diagnosis Energy focused on OI treatment and prevention -- palliative approach Ineffective HIV therapies Fairly rapid decline w/ death shortly after diagnosis Case y/o male risk MSM Diagnosed after syphilis tx; had high risk partner CD4 500 at time of Dx When CD4 dropped below 350, started on complicated combination ART (anti-retrovirals) Viral load controlled to less than 400 copies/ml Develops kidney stones, neuropathy, and daily diarrhea Stops meds intermittently due to side effects Several regimen changes due to resistance Weight gain of 40lbs, mostly in abdomen Significant hyperlipidemia Died of MI at age 56 Case 2 Themes: Tested for HIV due to risk behavior Diagnosed prior to major opportunistic infections (OI) Treatment deferred until CD4 drops to guideline recommended value Therapies effective but w/ significant toxicity Development of drug resistance from poor adherence from complicated poorly tolerated med regimens Premature death from non-infectious etiology Case y/o African American female heterosexual, married, works as paralegal Diagnosed at a DMV screening program CD4 850 Treated immediately w/ 1 pill once/day regimen No subjective side effects and no adverse labs; Viral load <20 Follows w/ MD routinely no OIs Focus on medication adherence, nutrition, exercise, cancer screening, mental health/social support Becomes pregnant after physician condoned natural conception has healthy uninfected baby Continues to work; plans for retirement Case 3 Themes: Tested without regard to risk behavior True screening even in non-medical settings Treatment started immediately Regardless of CD4 count Therapies well tolerated, easy to take, and very effective Care follows chronic disease model focused on non-infectious issues, metabolic risk reduction, cancer screening, and quality of life Life is relatively normal Even unprotected sex and childbirth! 6

7 HIV Case Finding MMWR September 22, 2006 Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings HIV screening is recommended for patients in all health-care settings after the patient is notified that testing will be performed unless the patient declines (opt-out screening). Separate written consent for HIV testing should not be required; general consent for medical care should be considered sufficient to encompass consent for HIV testing. testing without the need for risk assessment and counseling screening for HIV should be performed routinely for all patients aged years Also known as Opt-Out Testing Care of HIV (+) patients Care of individual HIV (+) patients Incredible success in developed countries Paradigm shift in HIV care From palliative to chronic illness model Lifespan statistics patients recently diagnosed with HIV have an estimated median survival of more than 35 years HIV Prevalence increasing on an individual basis, means patients living longer Employment figures study: HAART increases the probability of remaining employed by HIV patients increase from 58 percent to 94 percent Currently Available Antiretroviral Drugs HIV Life Cycle and Anti-HIV Drug Targets 1. Entry Inhibitors 2. Fusion Inhibitors 3. Reverse Transcriptase Inhibitors NRTIs: 1. Didanosine: ddi, Videx 2. Emtricitabine: FTC, Emtriva 3. Lamivudine: 3TC, Epivir 4. Abacavir: ABC, Ziagen 5. Stavudine: d4t, Zerit 6. Tenofovir: TDF, Viread 7. Zalcitabine: ddc, Hivid (not used) 8. Zidovudine: ZDV, Retrovir NNRTIs: 1. Delavirdine: DLV, Rescriptor 2. Efavirenz: EFV, Sustiva 3. Etravirine: ETR, Intelence 4. Nevirapine: NVP, Viramune XR 5. Rilpivirine: RPV, Edurant Protease Inhibitors (PI): 1. Amprenavir: APV (older formulation) 2. Atazanavir: ATV, Reyataz 3. Darunavir: DRV, Prezista 4. Fosamprenavir: FPV, Lexiva 5. Indinavir: IDV, Crixivan 6. Lopinavir: LPV, (not used alone) 7. Nelfinavir: NFV, Viracept 8. Ritonavir: RTV, Norvir 9. Saquinavir: SQV, Invirase 10. Tipranavir: TPV, Aptivus 4. Integrase Inhibitors 5. Protease Inhibitors Fusion (entry) Inhibitor: 1. Enfuvirtide: T20, Fuzeon CCR5 Antagonist: 1. Maraviroc : MVC Integrase Inhibitor (INSTI): 1. Raltegravir RAL 2. Elvitegravir *- EVG *EVG available in co-formulation with cobicistat 3. Dolutegravir- Tivicay Approved August Single Tablet Regimens Antiretroviral Pill Burden Atripla: efavirenz+tenofovir+emtricitabine 1 pill every day 2 NRTIs and 1 NNRTI Complera: rilpivirine+tenofovir+emtracitibine 1 pill every day 2 NRTIs and 1 NNRTI Stribild: elvitegravir+cobicistat+tenofovir+emtracitibine 1 pill every day 2 NRTIs, 1 integrase inhibitor and 1 booster 7

8 Care of HIV (+) patients Care of HIV (+) patients From a wasting disease to obesity management Care in 2010 s in developed countries Not just effective treatments, but safe and QD Focus on: Cardiovascular and metabolic health Nutrition Tobacco / substance use cessation Bone mineral density Cancer screening Neuro-cognitive decline Care of HIV (+) patients Continuum of HIV Care Costs for care (in US dollars) Atripla $2,000 / month (>$20,000/ year) CD4+ flow cytometry $30 Ignores cost of flow equipment (about $35,000) Viral load $100-$200 per test Ignores cost of PCR equipment (about $50,000) Resistance testing Genotype $ Phenotype $ Federal funding for HIV treatment and prevention efforts in the U.S. $20.6 billion in 2011 Outline Past History Epidemiology Present 3 Cases that demonstrate changing care paradigm Future Prevention strategies - Control HIV The Problem From the 2010 National HIV/AIDS Strategy (NHAS) We have the knowledge and tools needed to slow the spread of HIV infection Despite this potential, the public s sense of urgency associated with combating the epidemic appears to be declining 1995: 44% of the general public indicated that HIV/AIDS was the most urgent health problem facing the nation 2006: compared to only 6% 8

9 HIV/AIDS How soon we forget HIV Control: Behavior Modification Paradox of the HIV message in 2010 s message to the infected individual: HIV is a treatable chronic disease message to populous: HIV is still a major public heath threat and transmission must be prevented Optimism about the effectiveness of HAART & prognosis may be contributing to: relapses in high-risk sexual behaviors decreased public concern about prevention HIV The Problem HIV Control Strategies to Control HIV Stable incidence Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines HIV Control HIV Control Strategies to Control HIV Strategies to Control HIV Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines 9

10 HIV Control Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Strategies to Control HIV Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines Anti-retrovirals: beyond the benefit to the individual Rationale HIV Transmission correlates w/ viral load The major risk factor for HIV transmission the higher the plasma viral load, the more likely HIV transmission will occur given similar exposures observational studies in Uganda among heterosexual discordant partners Anti-retrovirals lower viral load; and thus infectivity Antiretroviral therapy influences infectivity Epidemiologic / retrospective observational results antiretroviral therapy with reduction in sexual transmission of HIV among discordant heterosexual couples Mathematical models "can simply treat our way out of the epidemic utopian model universal annual HIV testing and immediate treatment optimistic assumptions about adherence and resistance HIV Prevention Trials Network (HPTN) 052 supported by National Institutes of Health A randomized controlled trial to fill in the gaps Stopped early due to 96% risk reduction Test and Treat Immediately, not CD4 based Swiss Statement Swiss Federal Commission for HIV / AIDS An HIV-infected person on antiretroviral therapy with completely suppressed viremia ( effective ART ) is not sexually infectious HIV status-discordant couples might engage in unprotected sexual intercourse with minimal risk Treatment as Prevention Role of antiretrovirals to control spread of HIV The number of new HIV infections has dropped by 20 percent worldwide since the push to expand HIV treatment worldwide began in 2002 Obstacles Case finding Modifying current approach to antiviral use Cost Adherence Efficacy Resistance 10

11 Obstacles Case finding Modifying current approach to antiviral use Cost Adherence Efficacy Resistance Obstacles Case finding Modifying current approach to antiviral use Cost Adherence Efficacy Resistance Modifying current approach to antiviral use WHO -- International AIDS Society Conference June 2013 More people should be on HIV drugs CD4 Dependent Less than 500 (rather than 350) CD4 Independent (start medications immediately) all children with HIV under 5 years of age all pregnant and breastfeeding women with HIV all HIV-positive partners where one partner in the relationship is uninfected people with HIV with active tuberculosis or with hepatitis B Modifying current approach to antiviral use Number eligible up from 16.8 million to about 26 million Now nearly 10 million people now on antiretroviral therapy worldwide Obstacles Case finding Modifying current approach to antiviral use Cost Cost of WHO's new recs? about $2.3 billion per year wait list for funded meds in USA > 5000 Adherence Efficacy Resistance Obstacles Case finding Modifying current approach to antiviral use Cost Adherence D.O.T. --- freedoms vs freedom from disease Pay 4 performance --- reward patients for undetectable viral loads Efficacy Resistance 11

12 Obstacles Case finding Modifying current approach to antiviral use Cost Adherence Efficacy Does not render an individual completely noninfectious Viral compartments suppression of HIV-RNA in blood versus genital secretions Resistance Obstacles Case finding Modifying current approach to antiviral use Cost Adherence Efficacy Resistance very concerning for future of the epidemic See next few slides HIV Drug Resistance the next global threat Tend to occur w/ sub-optimal suppression of viral load restricted access to monitoring of plasma viral load treatment interruptions when drug supplies run out suboptimal long term adherence drug-drug interactions Drug Resistance the next global threat World Health Organization ART use in resource limited countries empirical first and second line antiretroviral regimens clinical or immunological definitions of treatment failure absence of monitoring of plasma viral load Estimates that 10-24% of patients have detectable plasma viral load during first line therapy switching rates relatively low poor sensitivity of clinical and CD4 criteria to detect therapy failure HIV Control Strategies to Control HIV Drug Resistance the next global threat Increasing levels of transmitted drug resistance Ex % Uganda - Lancet Infect Dis 2011;11: mostly to non-nrtis this drug class constitutes the foundation of current first line treatment regimens and prevention of mother to Single point mutation (K103N) Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines 12

13 Pre-Exposure Prophylaxis (PrEP) Using ARVs daily or as needed on HIV uninfected individuals to prevent HIV transmission Several trials underway in at-risk groups Basis: single dose nevirapine to HIV-infected women during labor and to their newborns reduced transmission of HIV by about 50 percent Animal studies Concerns: only partially effective antiviral resistance slippery slope thinkers increased risky behavior 2499 HIV (-) MSM 100 became infected during follow-up (median, 1.2 years) 36 in the pre-exposure prophylaxis group 64 in the placebo group 44% reduction in the incidence of HIV More of PrEP N Engl J Med Jul 11 Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. conducted in heterosexual serodiscordant couples reduced the risk of acquiring HIV infection by 75% The Lancet 2013 June 15 Antiretroviral prophylaxis for HIV infection in injecting drug users 50-75% protection HIV Control Strategies to Control HIV July FDA approval of Emtricitabine/tenofovir for PrEP daily oral antiretroviral drug to reduce the risk of sexual acquisition of HIV Issues: Who to treat? MSM and Serodiscordant couples Who pays? Will it increase risk behavior? Resistance? Toxicity long term? Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines 13

14 Non-occupational Post-exposure Prophylaxis (npep) Use of anti-retroviral drugs to prevent HIV infection after unanticipated sexual exposure or IVDU Based on occupation exposure models 80 % reduction in the risk of HIV infection after occupational exposure CDC/DHHS recommendations in MMWR day course of highly active antiretroviral therapy (HAART) is recommended Less than 72 hours after exposure evaluate risks and benefits of npep on a case-by-case basis Concerns no data exist regarding the efficacy of this preventive therapy might reduce the likelihood of transmission possibility of antiretroviral drug resistance in the source partner HIV Control Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Strategies to Control HIV Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines HIV Control: MTCT Mother to Over 50 percent of HIV-infected people in the world are women Before the use of antiretrovirals one-third of babies get infected via MTCT ranging from 13% to 40% 30% to 40% Africa 15% to 20% North America or Europe Over 1,000 children become infected daily as a result of motherto-infant transmission 70% were born in sub-saharan Africa HIV Control: MTCT Prevention of Perinatal Infection Routine HIV testing Use of anti-retrovirals 1994 AIDS Clinical Trials Group Protocol 076 ZDV given to pregnant women after the first trimester and during labor and to newborns during their first 6 weeks reduces perinatal transmission 67.5% ZDV monotherapy in pregnant women has been the minimal standard of care since 1994 Longitudinal prospective study conducted in the USA HIV transmission rates 20% in women on no antiretroviral treatment during pregnancy 10% in women who received ZDV alone 3% in women on combination therapy without protease inhibitors 1% in women who received combination therapy with protease inhibitors Current guidelines: potent combination therapy (at least three drugs) for pregnant women with a viral load greater than 1000 copies/ml, regardless of CD4+ count HIV Control: MTCT Elective cesarean section Reduces the risk of perinatal HIV transmission in general, recommended when maternal HIV viral load greater than 1000 copies/ml percentage of deliveries in HIV (+) women by c- section: % % Breast feeding risk of transmission through breast-feeding is approximately 15% for children in many developing countries, the benefits from breast-feeding outweigh the risk of HIV transmission through breast-feeding HAART can reduce transmission HIV Control: MTCT Incredible success w/ optimal strategy Universal testing Antivirals ATG 076 Elective C-section Perinatal transmissions in US for 2008 : only 34! 14

15 HIV Control: MTCT HIV Control Strategies to Control HIV Challenges These optimal strategies are not applicable in the vast majority of the developing world rarely have access to reproductive health services anti-retroviral prophylaxis reaches only 10 percent of affected mothers Situation is slowly improving programs to provide antiretroviral drugs to pregnant women "3 by 5 Initiative" Global Fund President's Emergency Plan for AIDS Relief [PEPFAR] Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines Premise: need for female-controlled method of prevention Microbicide" topical agent that can be applied vaginally by women can use without the necessary consent of their partner nearly 60 potential microbicides are in the development pipeline several in phase II-III effectiveness trials Various mechanisms: physical barrier non-selective inactivation of the virus specific antiviral activity Currently available spermicides do not protect against transmission of HIV nonoxynol 9 might increase the risk for HIV sexual transmission irritative effects on the vaginal epithelium Others: P3 cellulose sulfate gel halted 2007 increased risk of HIV Carraguard microbicide trial 2008 showed safety, but no efficacy WHO s take: Evaluation of other potential microbicides should continue Finally success July, 2010 XVII International AIDS Conference Tenofovir Vaginal Gel First Microbicide to Prevent HIV Infections Application of gel or placebo before & after sex high prevalence area (pregnant women % HIV positive) 889 sexually active HIV (-) women 38 women in the tenofovir group became HIVpositive 60 women in the placebo group became HIV-positive 39% lower risk of HIV overall 54% reduction if used routinely HIV Control Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Strategies to Control HIV Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines 15

16 HIV Control Strategies to Control HIV Questions on HIV? Behavior modification safer sex campaigns / education condoms Case finding / HIV testing Blood supply testing Injecting drug users Circumcision Medical therapies HAART effect on transmission pre-exposure prophylaxis post-exposure prophylaxis prevention of mother to Treatment of co-infections and STD s HIV vaccines Past History Epidemiology Present 3 Cases that demonstrate changing care paradigm Future Prevention strategies - Control Objectives: Tuberculosis Tuberculosis Overview To review: 1. Case 2. Current Epidemiology 3. Clinical Presentation 4. New Diagnostic Techniques 5. Drug Resistance Case 1 77 year old woman from WV, previously well 8 months prior, presented with fever, chills, sweats Recurrent pneumonia 2 3 months later, received antimicrobials (quinolones) CT chest at local hospital: interstitial lung disease, cavitary lesions Sputum cultures (+) for M. tuberculosis Sensitive to all 1 st line drugs 16

17 TB Epidemiology 1/3 of the world s population is infected with M. tuberculosis In 2012, total of 9,951 new TB cases reported in US (rate of 3.2 cases/100,000) TB still persists in specific groups: foreign-born racial/ethnic minorities homeless persons affected disproportionally TB epidemiology Infected cases GLOBAL 1.7 billion (33% population) USA million (4% population) Case incidence 8 10 million/year 11,182 in 2010 Case prevalence million 20,000 Deaths 1.9 million/year ~1,000 /year HIV Co infection 1.1 million new cases/year >40% of all TB cases in Africa are HIV co infected ~700 cases 6% Estimated Tuberculosis Incidence, 2012 TB in the US 17

18 Factors Favoring Persistence of TB Poverty HIV Epidemic Need for Better Diagnostic Tools Drug Resistance Transmission of TB Clinical Presentations of Active TB TB Symptoms include: Persistent cough Chest pain Hemoptysis, blood-tinged sputum Weakness, fatigue Decreased appetite Fever, chills and/or night sweats But: Highly Variable! Risk Factors for Active TB Once infected with TB, who is more likely to develop active TB? HIV infection Recent infection (< 2 years) with Mycobacterium tuberculosis Presence of other co-morbidities such as diabetes, cancer, immunosuppressive therapy, renal disease Alcohol abuse or drug use History of incorrect treatment for TB in the past Testing for Latent Tuberculous Infection (TBI) TB skin test (TST) PPD TB blood tests Interferon Gamma Release Assays (IGRAs) Goal of Testing for Latent TBI: To identify individuals with increased risk for development of active TB and who would benefit from treatment of latent TBI Tuberculin Skin Test Criteria for Positive Test Size of Induration 5 mm Cutoff Use for immunocompromised persons and recent contacts of active TB cases 10 mm Cutoff Use for the high risk groups (Ex. Health care workers) 15 mm Cutoff Use for low risk groups 18

19 Newer Assays for Latent TB Infection Interferon Gamma Release Assays (IGRAs) Measure host cellular immune response to M. tuberculosis in whole blood samples Diagnostic tools for latent tuberculosis infection (LTBI) Should not be used for diagnosis of active TB (a microbiological diagnosis) When to Use IGRA Over Skin Test 1. People who have received BCG vaccine in past 2. When difficult for patient to return to have PPD read in 2 3 days Potential disadvantages: Cost Could still have false negative result Esp. in immunocompromised patients Diagnosis of Active Tuberculosis Traditional Methods AFB stain and culture sensitivity of AFB smear compared to culture is approx. 60% AFB cultures newer automated liquid broth systems detect growth in 1 3 weeks Newer noncommercial liquid broth assay is promising Microscopic-observation drug susceptibility (MODS) assay yields results in 7 10 days Newer Diagnostic Methods Nucleic Acid Amplification Tests (NAAT) Direct detection of M. TB in clinical specimens Complements but does not replace clinical judgment, AFB smear and culture in diagnosis PCR test available for CSF samples TB Drug Susceptibility Testing Extremely important to guide therapy AND to control/eliminate TB Agar proportion method commonly used in US Liquid broth systems also available Promising microscopic-observation drug susceptibility test (MODS assay) TB Drug Susceptibility Testing (Cont d) 2010 WHO recommended use of Xpert MTB/RIF A new diagnostic device that tests sputum for M. tuberculosis AND rifampin resistance simultaneously in less then 2 hours 19

20 Treatment of LTBI: Current Recommendations Drug Dose Duration INH 300 MG Daily 9 Months RIF 600 MG Daily 4 Months RIF/PZA 600MG/ MG/KG Daily 2 Months No Longer Recommended RBN 300 MG Daily 4 Months RPT/INH 900mg Once weekly 12 Weeks(12 doses total) Should not be used in HIV patients in general Treatment of Active TB Standard therapy for pulmonary TB isolate sensitive to all 1 st line drugs 6 months of therapy beginning with Isoniazid, Rifampin, Pyrazinamide and Ethambutol plus Pyridoxine (Vitamin B6) Use Directly-observed Therapy Multidrug Resistant TB (MDR- TB) TB isolate resistant to INH and rifampin XDR-TB (Extensively-resistant TB) Isolate resistant to INH, rifampin, plus resistant to quinolone and aminoglycoside Xpert MTB/RIF test promising Will detect rifampin resistance which is a marker for MDR-TB Need for better resistance testing for all the drugs 20

21 Multidrug Resistant TB (MDR- TB) WHO estimates half a million new cases of MDR-TB occur worldwide each year Current regimens present many challenges Treatment lasts 20 months or more More toxic drugs, more expensive Less effective drugs Globally less than half of all patients who start therapy for MDR-TB are treated successfully (WHO, 2013) MTb and HIV CD4+ cells activate macrophages to engulf MTb Alveolar macrophages undergo apoptosis to destroy MTb TB increases HIV replication, accelerating its clinical course Affects the poor, socially disadvantaged Increased mortality HIV selectively kills CD4+ cells HIV infection of macrophages prevents apoptosis HIV causes higher reactivation of MTb Affects the poor, socially disadvantaged Increased mortality TB/HIV Treatment: Basic Principles Issues of treatment Most of it is the same!! Empiric Multi-drug treatment should be initiated and continued in HIV-infected persons in whom TB is suspected until all diagnostic work-up is complete. Standard first-line therapy for TB [with a 4-drug intensive treatment phase of 2 months, followed by 4 months of treatment with a 2- drug regimen] is highly effective in patients with HIV infectionrelated TB. Early outcomes are generally very good Long-term outcomes are poor because of HIV infectionrelated mortality. Adherence the major issue Many more pills DOT is very important Side Effects Complicated TB + HIV cocktail Hepatic toxicity, peripheral neuropathy Drug Interactions Resistance IRIS Conclusions 1. TB remains a major global health problem 2. Incidence falling in US, but still a threat 3. Clinical presentation variable need high index of suspicion 4. Diagnosis of latent tuberculous infection for TB elimination Newer tests IGRAs useful Conclusions (Cont d) 5. Rapid diagnosis of active TB and Proper Therapy extremely important Newer diagnostic methods very promising 6. Management of Drug Resistance MDR-TB and XDR-TB Better assays needed New drugs needed 7. Better vaccines needed 21