Rifapentine + isoniazid to prevent TB among people living ... · Background • HIV is the...

Rifapentine + isoniazid to prevent TB

among people living with HIV:

interim data and pending issues

The PREVENT TB Study

TB Trials Consortium Study 26

AIDS Clinical Trials Group 5259

Sterling TR, Benson CA, Shang N, Miro JM,

Grinsztejn B, Chaisson RE, Lucchetti A, Sanchez J,

Benator D, Scott N, Villarino ME

Background

• HIV is the strongest risk factor for

progressing from latent M. tuberculosis

infection to active tuberculosis

• 9 months of daily INH is efficacious, but

has low completion rates, limiting its

effectiveness

– Most common adverse effect: hepatotoxicity

Background

• 3 months of once-weekly rifapentine 900 mg

+ INH 900 mg under direct observation (3HP)

(PREVENT TB study)

– At least as effective as 9 months of daily INH 300

mg self-administered (9H)

– Higher treatment completion rate than 9H

• Only 3% of study participants were HIV+

– Enrollment of HIV+ persons was extended to

adequately assess tolerability in this population

Sterling TR. N Engl J Med 2011;365:2155-66.

Overview

• Effectiveness of 3HP in the PREVENT TB

study, with focus on HIV-infected TB cases

– Risk factor analysis for TB

• Tolerability of 3HP in HIV-infected persons

• Rifampin resistance in TB cases

The PREVENT TB Study Inclusion Criteria

• Persons > 2 years old who were:

– Tuberculin skin-test (TST)-positive close contacts of a

culture-confirmed TB case

– TST-converters

• Documented negative positive within 2 years

– TST-positive, fibrosis on chest radiograph consistent

with prior untreated TB

– Children 2-4 years old with + TST or close contact

with a culture-confirmed TB case

– HIV-infected with

• Positive TST

• Close contact to TB case regardless of TST

The PREVENT TB Study Exclusion Criteria

• Confirmed or suspected TB

• TB resistant to INH or rifampin in source case

• History of treatment with

– > 14 consecutive days with a rifamycin

– > 30 days with INH

• Prior treatment of TB or M. tuberculosis infection in HIV-

uninfected persons

• Intolerance to INH or rifamycins

• Aspartate aminotransferase (AST) > 5x upper limit if AST

determined

• Pregnant or lactating females

• Weight < 10 kg

• HIV-1 antiretroviral therapy < 90 days after enrollment

The PREVENT TB Study Summary

• 8,053 persons enrolled

– United States, Canada, Brazil, Spain

– June 2001-February 2008

– 33 months of follow-up

• 7,731 in modified intention-to-treat (MITT)

– Enrolled in the study, and eligible

• Tuberculosis risk (cumulative)

– 3HP: 7 / 3,986 (0.19%)

– 9H: 15 / 3,745 (0.43%)

– Rate difference: -0.24%

– Upper limit of 95% CI of difference: 0.01%

– Pre-defined non-inferiority margin: 0.75%

.

Difference in TB rates between the 2 study arms, and non-inferiority “delta”

Modified Intention to Treat Population; A33 analysis

Cumulative TB Rate 33 months from enrollment—MITT

Log-rank P-value: 0.06

Summary of TB Cases PREVENT TB Study

3HP 9H

HIV-infected 105 100

HIV-uninfected/unknown 3,881 3,645

Primary endpoint Culture + TB in adults; culture +/- in children

N=7 N=15

HIV-infected 2 2

HIV-uninfected 2 8

HIV-unknown 3 5

Secondary endpoint Culture – TB in adults

N=2 N=2

HIV-infected 0 1

HIV-uninfected 1 1

HIV-unknown 1 0

Risk Factor Analysis-for TB Univariate

Characteristic Reference group HR (95% CI) P-value

Regimen (3RPT/INH) 9INH 0.43 (0.18, 1.07) 0.07

Age (10 years) 10 years younger 0.87 (0.65, 1.17) 0.37

Male sex Female 1.50 (0.63, 3.58) 0.36

Black race White race 1.56 (0.64, 3.81) 0.33

HIV + HIV negative 7.00 (2.19, 22.30) 0.001

BMI (1 unit) 1 unit lower 0.85 (0.78, 0.93) 0.0006

EtOH abuse No EtOH 4.84 (1.58, 14.78) 0.006

Current smoking No smoking 4.73 (1.98, 11.27) 0.0005

IDU No IDU 1.29 (0.17, 9.59) 0.80

High school Completed 1.21 (0.51, 2.85) 0.66

Jail/prison No jail/prison 3.12 (0.92, 10.54) 0.07

Unemployed Not unemployed 2.55 (0.94, 6.92) 0.07

No interaction between treatment arm and above variables.

Risk Factor Analysis-for TB Multivariate

Characteristic Reference group HR (95% CI) P-value

Regimen (3RPT/INH) 9INH 0.38 (0.15, 0.99) 0.05

Age (10 years) 10 years younger

Male sex Female

Black race White race

HIV + HIV neg/unknown 4.07 (1.26, 3.16) 0.01

BMI (1 unit) 1 unit lower 0.81 (0.73, 0.90) 0.0002

EtOH abuse EtOH use or none

Smoking-current Smoke last 5 yrs/never 4.89 (1.90, 12.58) 0.001

IDU No IDU

High school Completed

Jail/prison No jail/prison

Unemployed Not unemployed

Primary Aim of the HIV Sub-Study

• Compare the tolerability of weekly 3HP vs. daily

9H in HIV-infected persons

• Endpoints

– Treatment completion

– Permanent drug discontinuation for any reason

– Drug discontinuation due to adverse drug reaction

– Grade 3 or 4 toxicity

– Grade 5 toxicity (death)

Enrollment of HIV-infected Persons

• United States, Brazil, Spain, Peru,

Canada, Hong Kong China

• Enrolled June 2001 – December 2010

• Follow-up for TB endpoints continues

through September 2013

– Treatment effectiveness data are pending

– This analysis focuses on tolerability

Analysis Populations HIV-infected Persons

• Of 4,242 participants enrolled with known HIV

status, 403 were HIV+

• Enrolled (ITT) 403

• Eligible (MITT) 394

– 9H 193

– 3HP 201

• Received > 1 dose of study drug 393

– 9H 186

– 3HP 207

Clinical and Demographic Characteristics MITT Population

Characteristic 9H

N=193

3HP

N=201

Age (median, IQR) 36 (29-44) 36 (30-44)

Male sex 131 (68) 145 (72)

Race

White 73 (38) 75 (37)

Black 75 (39) 71 (35)

Asian/Pac. Island 3 (2) 6 (3)

Am./Can. Indian 4 (2) 5 (3)

Multiracial 38 (20) 44 (22)

Ethnicity (US/Can)

Hispanic 22 (11) 26 (13)

Non-Hispanic 74 (38) 62 (31)


Characteristic 9H

N=193

3HP

N=201

CD4 (median, IQR) 514 (404-699) 493 (379-685)

BMI (median, IQR) 25 (22-28) 25 (23-28)

Site of recruitment

U.S./Canada 96 (50) 89 (44)

Brazil/Spain/Peru 97 (50) 112 (56)

Completed high school 118 (61) 120 (60)

Jail/prison ever 24 (12) 16 (8)

Unemployed 47 (24) 38 (19)

Hx EtOH at enrollment 120 (62) 112 (56)

Hx IDU at enrollment 33 (17) 27 (13)

Current tobacco 90 (47) 81 (40)


Characteristic 9H

N=193

3HP

N=201

Indication for TLI

Close contact 25 (13) 20 (10)

Recent TST converter 5 (3) 9 (5)

HIV-infected 163 (85) 172 (86)

Fibrosis on CXR 0 (0) 0 (0)

Co-morbid liver disease

HCV 26 (14) 22 (11)

HBV 19 (10) 11 (6)

Tolerability MITT population

Outcome 9H

N=193

3HP

N=201

P-value

Treatment

completion

125 (65%) 178 (89%) < 0.0001

Permanent drug d/c-

any reason

68 (35%) 23 (11%) < 0.0001

Permanent drug d/c-

due to an adverse

event

8 (4%)

7 (4%)

0.8

Death 4 (2%) 2 (1%) 0.44

Adverse Events by Toxicity Grade Among persons receiving > 1 dose

During treatment or within 60 days of the last dose

Attributable to study drug

Toxicity 9H

N=186

3HP

N=207

P-value

Grade 1-2

51 (26) 28 (13) 0.001

Grade 3

20 (10) 16 (8) 0.39

Grade 4

10 (5) 4 (2) 0.10

Adverse Events by Category Among persons receiving > 1 dose


Toxicity 9H

N=186

3HP

N=207

P-value

SAE 21 (11%) 8 (4%) 0.006

> 1 AE 75 (40%) 45 (22%) <0.001

Related to drug 19 (10) 16 (8) 0.48

Hepatotoxicity 11 (6) 3 (2) 0.03

Possible HS 0 (0) 1(0.5) 1.0

Rash only 0 (0) 1(0.5) 1.0

Other 8 (4) 11 (5) 0.81

Not related 65 (35) 34 (16) <0.0001

HS: hypersensitivity reaction

Tolerability of 9H and 3HP by HIV Status MITT Population

9H 3HP

Toxicity HIV-pos

N=193

HIV-neg

N=1,848

P-value HIV-pos

N=201

HIV-neg

N=1,862

P-value

Perm drug d/c

any reason

68 (35) 603 (33) 0.46 23 (11) 365 (20) 0.004

Perm drug d/c

due to AE

8 (4) 63 (3) 0.54 7 (4) 99 (5) 0.32

Death

4 (2) 20 (1) 0.28 2 (1) 17 (1) 0.71

Tolerability of 9H and 3HP by HIV Status Among persons receiving > 1 dose


9H 3HP

Toxicity HIV-pos

N=186

HIV-neg

N=1,847

P-value HIV-pos

N=207

HIV-neg

N=1,888

P-value

SAE 21 (11) 60 (3) <0.001 8 (4) 41 (2) 0.14

AE related to

study drug

19 (10) 98 (5) 0.01 16 (8) 181 (10) 0.45

Hepatotoxicity 11 (6) 49 (3) 0.02 3 (2) 11 (1) 0.15

Possible HS 0 (0) 10 (0.5) 0.61 1 (0.5) 85 (5) 0.003

HS: hypersensitivity reaction

Drug Resistance Among TB cases

9H

N=12

3HP

N=7

INH

resistant

2 0

Rifampin

resistant

0 1*

* M. bovis in an HIV-infected person who had treatment interruptions

and completed therapy late. CD4 = 271 at enrollment.

Cases of Tuberculosis, Culture-Confirmed Cases, and Drug-Resistant Isolates, According to Treatment Group.

Martinson NA et al. N Engl J Med 2011;365:11-20.

Limitations

• Sample size relatively small

– Though sufficient for tolerability assessment

• Patients could not receive antiretroviral therapy

for first 90 days after enrollment

– Drug interactions with rifapentine not well-

characterized

– Limited the number of eligible participants

• Data on effectiveness pending until late 2013

– In PREVENT TB, HIV+ TB cases equally distributed

Conclusions

• Among HIV-infected persons with high CD4

counts and not on antiretroviral therapy,

3HP had higher treatment completion rates

and was better tolerated than 9H for

treatment of latent M. tuberculosis infection

• 3HP was at least as well-tolerated in HIV-

infected than HIV-uninfected persons

Conclusions

• 9H was less well-tolerated in HIV-infected

than HIV-uninfected persons

• Smoking was associated with TB risk that

was at least as high as that with HIV infection

• Insufficient number of TB cases to determine

whether risk of rifampin resistance was

increased among persons who develop TB

after 3HP

Study Sites and Investigators Agencia de Salut Publica – Barcelona, Spain and UNTHSC (70)

Joan A. Cayla, MD, PhD, Jose M. Miró, MD, PhD, Maria Antonia Sambeat, MD, PhD, Jose L.

López Colomés, MD, José A. Martinez, MD, Xavier Martinez-Lacasa MD, PhD, Angels Orcau,

MD, Paquita Sanchez, MD, Cecilia Tortajada, MD, PhD, Imma Ocana, MD, PhD, Juan P.

Millet, MD, MPH, Antonio Moreno, MD, Jeanne Nelson, MPH, Omar Sued, MD, Mª Luiza de

Souza, MD, María A. Jiménez, MD, Lucía del Baño RN, Laia Fina MSc.

IPEC Evandro Chagas (FIOCRUZ) (42)

Beatriz Grinsztejn, MD, Guilherme Calvet, MD, MSc, Sandra Wagner Cardoso, MD, Thiago

Silva Torres, R.PH., M.Sc., Ronaldo Moreira, Deise Faria, Leandro Amparo de Xouza,

Alexandre Souza, Paula Leite Cruz dos Santos, Janaina Vieira.

Johns Hopkins University (38)

Richard Chaisson, MD, Susan Dorman, MD, Jim Fisher, Gina Maltas, RN, Judith

Hackman, RN.

Impacta San Miguel, Peru (33)

Rosa Infante, MD, Aldo Lucchetti, MD, Fanny García Velarde, RN, Carmen Rosa, Yance de la

Cruz, Pharm, Carmela Ganoza, MD, Jesus Peinado, MD, Jessica Rios, Rosemery Gutierrez,

Anabeli Tataje Candiotti, MD, Mónica Isabel Sánchez Castañeda, Pharm, Melissa Meneses

Civico.

Impacta, Lima, Peru (32)

Jorge Sánchez Fernandez, MD, Alberto La Rosa, MD, Bertha Ramirez, MD, Carmela Ganoza,

Md, Esmellin, Perez, Pharm, Victor Malpartida, Oscar Cevallos lopez, Juan Hurtado, Juan

Guanira, Javier Lama, David Ruben Iglesias, Erick Ramos, Juanita Calderon, Fanny Rosas

Bonancio.

Study Sites and Investigators University of North Texas Health Science Center at Ft. Worth (UNTHSC) (30)

Stephen E. Weis, D.O., Michel Fernandez, MD, Barbara King, RN, Lee Turk, RN, Norma

Shafer, Gloria Stevenson, RN, Guadalupe Bayona, MD, Randy Dean, RN, Joseph Helal,

MS, RPh, Gerry Burgess, RN.

Emory University Department of Medicine (19)

Susan M. Ray, MD , David P. Holland, MD, Deirdre Dixon, Omar Mohamed, Kanoa Folami,

Jane Bush, MA, Cheryl D. Simpson, BS, Gibson Barika, Wenona N. Favors, Nicole Snow

Hospital Nossa Senhora do Conceicao Porto Alegre (17)

Breno Riegel Santos, MD, Rita Lira, MD, Elizabeth Magalhaes, Pharm, Rui Flores, Kelin,

Zabtoski.

University of California, San Diego Medical Center (UCSD) (15)

Antonino Catanzaro, MD, Philip LoBue, MD, Kathleen Moser, MD, Mark Tracy, MD, Peach

Francisco, RN, Judy Davis.

Hospital Universitario Clementino Fraga Filho – Rio de Janeiro, Brazil, Johns Hopkins (14)

Marcus B. Conde, MD, Fernanda C. Q. Mello, MD, Anne Efron, MSN, MPH, Carla Loredo,

RN, Millene Barty S. Fortuna, Michelle Cailleaux-Cezar, MD, Renata L. Guerra, MD, Gisele

Mota, RN, Cristina Felix, RN, Afranio Kritski, PhD, Valéria de Oliveira, Claudeci dos Santos

Sacramento.

Study Sites and Investigators

Denver Public Health Department (13)

William Burman, MD, Randall Reves, MD, Robert Belknap, MD, David Cohn, MD, Jan Tapy,

RN, Grace Sanchez, CCA, Laurie Luna, RN.

Boston University Medical Center (11)

John Bernardo, MD, Jussi Saukkonen, MD, Claire Murphy, RN, Denise Brett-Curran, RN.

University of Southern California/LA County (10)

Brenda E. Jones, MD, Patricio Escalante, MD, Peregrina Molina, RN, Claudia Silva, RN,

Angela Grbic, RN, Maria Brown, MPH, Bonifacia Oamar, RN, Ermelinda Rayos, CW, Celia

Luken.

Duke University (7)

Carol Dukes Hamilton, MD, Jason Stout, MD, MHS, Ann Mosher, RN, MPH, FNP-BC, Emily

J. Hecker, RN, MSN, Brenda Ho, RN, Elle Rich, RN, MPH.

Harlem Hospital Center (7)

Wafaa M. El-Sadr, MD, MPH, Mary Klein, RN, Cyrus Badshah, MD, John Salazar Schicchi,

MD, Yael Hirsh-Moverman, MPH.


Vanderbilt University Medical Center and Nashville Metro Public Health Department (6)

Timothy Sterling, MD, Linda R. Hammock RN, Amy Kerrigan, RN MSN, Alicia Wright, Belinda

Redd, LPN, Ingrid Montgomery, RN, Kathleen Miller, RN.

University of California, San Francisco (6)

Payam Nahid, MD, MPH, Philip Hopewell, MD, Charles Daley, MD, Robert Jasmer, MD, Cindy

Merrifield, RN, William Stanton, RN, Irina Rudoy, MD, Jill Israel, RN.

Washington DC Veterans Affairs Medical Center (4)

Fred Gordin, MD, Debra Benator, MD, Donna S. Conwell, RN.

University of Medicine and Dentistry New Jersey (UMDNJ) (4)

Bonita T. Mangura, MD, Lee B. Reichman, MD, George McSherry MD, Alfred Lardizabal, MD,

Maria Corazon Leus, RN, Marilyn Owens, RN, Eileen Napolitano, Laurie Kellert, RN, Veronica

Anokute, RN.

Montreal Chest Institute (3)

Richard I. Menzies, MD, Kevin Schwartzman, MD, MPH, Christina Greenaway, MD, Larry

Lands, MD, Sharyn Mannix, MD, Paul Brassard, MD, MSc, Bérénice Mortezai, MD, Barry

Rabinovitch, MD, Marthe Pelletier, Chantal Valiquette, Joanne Tremblay, Paul Anglade Plaisir,

Rebecca Binet, BSc.


Hospital Dos Servidores Do Estado (2)

Maria Leticia Santos Cruz, MD, MSc, Esau Joao, Leon Claude Sidi, MD, José Carlos

Cruz, Fellipe Lattanzi, Elaine Santos, Deisi Scheiner Torgecki.

TB and Chest Services of Hong Kong (2)

Chi-Chiu Leung, MBBS, Kowk-Chiu Chang, MBBS, MSc, Sik-Wai Tam, Cheuk-Ming Tam,

Sau-Yin Tam, Ida Ka-Yun, Mak, Ka-Lin Fong, Nai-Chung Lee, Kai-Man, Kam, Chi-Wai

Yip, Judy Yee-Man Lam, Chi-Wai Ng, Oi-Wah Fong, Edman Tin-Keung Lam, Michelle

Chung-Ying Wong.

Public Health – Seattle and King County Public Health (2)

Masa Narita, MD, Charles M. Nolan, MD, Stefan Goldberg, MD, Debra Schwartz, RN,

Linh Deretsky, Marcia Stone, RN, MPH, Connie Friedly, RN.

The Miriam Hospital, Providence, RI (2)

Karen Tashima, MD, Aadia Rana, MD, Awe Kwara, MD, Pamela Poethke, RN, BSN,

Deborah Good, Renee Fraatz, Pharm.D, Virginia Patrick, Deborah Perez, RN, Helen

Patterson.

University of Manitoba (2)

Wayne Kepron, MD, Earl Hershfield, MD, Marian Roth, RN, Gerry A. Izon, RN.

University of Texas Health Science Center Houston (2)

Roberto Arduino, MD, Hilda Cuervo, Grady Douglas, Maria Insignares, Maria Martinez,

Martine Diez


VA Houston Texas – Ben Taub General Hospital (2)

Elizabeth Guy, MD, Christopher Lahart, MD, Terry Scott, RN, Ruby Nickson, RN, Denise

Dunbar, Richard Hamill, MD, Michael George, Pharm D, BCPS.

VA Little Rock, Arkansas – Arkansas Department of Health (1)

Iram Bakhtawar, MD, Frank Wilson, MD, Pauline Wassler, RN, Annette Arnold, APN,

Kathy Haden, RN, Jamie Owens, HPN.

Jesse Brown VA Medical Center, Chicago (1)

Mondira Bhattacharya, MD, Susan Lippold, MD, MPH, William Clapp, MD, Julie Fabre,

RN, MPH.

Edward Hines Jr. VA Medical Center Chicago (1)

Constance T. Pachucki, MD, Anna Lee, MD, Susan Marantz MD, Mary Poly Samuel, RN,

Ana Zulaga BS, MPH.

Instituto Emilio Ribas-Sao Paolo (1)

Marinella Della Negra, MD, Gustavo Fadel, MSc, Luziane Flora Figueira, Wladimir

Queiroz, MD, Denise Pacola, Yu Ching Lian, Roberio Aves Cameiro.

Columbia University College of Physcians and Surgeons, NYC Dept of Health (1)

Neil Schluger, MD, Joseph Burzynski, MD, Vilma Lozano, RN, Magda Wolk, RN, Marta

Scotto, RPh.


Audie L. Murphy VA Hospital, San Antonio, TX (1)

Marc Weiner, MD, Melissa Engle, CRT, CCRC, Jose A. Jimenez, BS, Hipolito Pavon,

MPH, Victoria Rodriguez, RN, Col. Kevin B. West, MD, Col. David Dooley, MD, Col.

Duane Hospenthal, MD, PhD.

Universidade de Sao Paulo de Rebeirao Preto (1)

Marisa Márcia Mussi-Pinhata, MD, Marcia de Lima Isaac, MD, Hugo Lopes Gomes, MSc,

Julio Cesar Gabaldi, Pharm, Adriana Tiraboschi Barbaro, MD, Bento De Moura Negrini,

MD Fernanda Sturzbecher.

The University of British Columbia (1)

J. Mark Fitzgerald, MD, Kevin Elwood, MD, Eduardo Hernandez, MD, Banafsheh

Peyvandi, MD, Kadria Alasaly, MD.

Potential Conflicts of Interest

Analysis Populations

• Enrolled before February 15, 2008 – Completed 33 months of follow-up by September 30, 2010

• Intention-to-treat (ITT) – All persons enrolled in the study

• Modified intention-to-treat (MITT) – Enrolled in the study

– Eligible

• Per protocol (PP) – All persons enrolled in the study who were eligible

– Completed study drug within targeted time period

– Or developed TB or died but completed > 75% of expected doses prior to event

– All follow-up time counted; did not require reaching 33 months

Definitions

• Adverse Event (AE):

– As reported by local investigators

• Serious Adverse Events (SAE):

– Deaths on study drug or < 60 days after last

dose, life-threatening events, hospitalization,

disability or permanent damage, congenital

anomalies or birth defects

• Hepatotoxicity:

– As reported by local investigators, excluding

cases attributable to acute hepatitis A, B, or C

Definitions

• Possible Drug Hypersensitivity

– Hypotension, urticaria, angioedema, acute

bronchospasm, or conjunctivitis that occurred

in relation to study drug

– > 4 of the following (one of which had to be >

grade 2) that occurred in relation to study

drug: weakness, fatigue, nausea, vomiting,

headache, fever, aches, sweats, dizziness,

shortness of breath, flushing, or chills.

Reason for Ineligibility N=9 (of 403)

Reason Frequency %

Source TB case resistant to

INH or RIF

4 44.4

Source TB case culture-

negative for M. tuberculosis

3 33.3

Positive TST not confirmed 1 11.1

No susceptibility testing for

index case

0 0.0

TB at enrollment 1 11.1

Total 100%

Causes of Death

• 9H

– Hypertensive cardiovascular disease

– AIDS with dementia

– Chronic liver disease or cirrhosis

– Unknown

• 3HP

– Non-Hodgkins lymphoma

– Unknown

Population study

arms

# of

patients

# TB cases

TB per

100 p-y

Cumulative TB

rate (%)

Difference in

cumulative TB

rate

Upper bound of

95% CI of difference

in cumulative TB

rates*

MITT 9H 3,745 15 0.16 0.43 -0.24 0.01

3HP 3,986 7 0.07 0.19

Per

Protocol

9H 2,585 8 0.11 0.32 -0.19 0.06

3HP 3,273 4 0.05 0.13

Event rate estimates and the non-inferiority test for A33

33 months of follow-up from time of randomization

* non-inferiority margin (delta) = 0.75%

Once-weekly INH + rifapentine for 3 months HIV +/PPD+ Adults. Soweto, South Africa

• Rifapentine 900 mg + INH 900 mg – once-weekly for 3 months

• Rifampin 600 mg + INH 600 mg – twice-weekly for 3 months

• INH 300 mg – daily continuous

• INH 300 mg – daily for 6 months

Superiority trial—compared to 6 months of INH

All patients received B6 25 mg with each dose

Patients did not receive HAART

Martinson NA. N Engl J Med 2011.

Rates of Study End Points According to Treatment Group.

Martinson NA et al. N Engl J Med 2011;365:11-20

Adverse Events, Including Those Occurring after Discontinuation of Study Medications, and Status of Study Medications after the Adverse Events.

Martinson NA et al. N Engl J Med 2011;365:11-20

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