The Population Biology of Tuberculosis

296 Pages·2015·1.412 MB·English

by  Christopher Dye

The Population Biology of Tuberculosis
MONOGRAPHS IN POPULATION BIOLOGY
EDITED BY SIMON A. LEVIN AND HENRY S. HORN
A complete series list follows the index.
The Population Biology
of Tuberculosis
Christopher Dye
PRINCETON UNIVERSITY PRESS
Princeton and Oxford
Copyright © 2015 by Princeton University Press
Published by Princeton University Press, 41 William Street,
Princeton, New Jersey 08540
In the United Kingdom: Princeton University Press, 6 Oxford Street,
Woodstock, Oxfordshire OX20 1TW
press.princeton.edu
All Rights Reserved
Library of Congress Cataloging- in- Publication Data
Dye, Christopher, author.
The population biology of tuberculosis / Christopher Dye.
p. ; cm. — (Monographs in population biology ; 54)
Includes bibliographical references and index.
ISBN 978-0 - 691- 15462- 6 (hardcover : alk. paper)
I. Title. II. Series: Monographs in population biology ; 54.
[DNLM: 1. Mycobacterium tuberculosis—genetics. 2. Tuberculosis—epidemiology.
3. Population Dynamics. 4. Systems Biology. WF 205.1]
RA644.T7 614.5'42—dc23
2014037803
British Library Cataloging-i n- Publication Data is available
This book has been composed in Times LT Std
Printed on acid- free paper. ∞
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
Contents
Preface vii
Chapter 1 Tuberculosis Undefeated 1
Chapter 2 Concepts and Models 26
Chapter 3 Risk and Variation 64
Chapter 4 Interventions and Control 100
Chapter 5 Strains and Drug Resistance 138
Chapter 6 TB and HIV/AIDS 162
Chapter 7 Elimination and Eradication 190
Chapter 8 Populations and Social Diseases 207
Appendix 1 Derivation of the Basic Case Reproduction Number
and Epidemic Doubling Time 219
Appendix 2 Formal Description of the Standard Model 222
References 227
Index 271

Preface
O what can ail thee, knight- at- arms,
Alone and palely loitering?
—John Keats, La Belle Dame sans Merci
Is there no respect of place, persons, nor time in you?
—William Shakespeare, Twelfth Night
(Malvolio, Act 2, Scene 3)
Consumption, galloping and otherwise, asthenia, gibbus, lupus, phthisis,
scrofula, tabes, hectic and gastric fever, Pott’s and Koch’s disease: tuberculosis
in all its various guises killed more than 100 million people in the twentieth
century and uncounted numbers in the preceding millennia. Presently, there are
about 9 million new episodes of TB each year, probably a little lower than the
maximum reached around the turn of the millennium. After 90 years of vaccina-
tion and more than 60 years of drug therapy, TB is still among the top 10 causes
of human mortality. And while TB cases and deaths have fallen markedly over
the past century in the rich world, no country has yet come close to eliminating
the disease. The goal of this book is to explain why TB is so persistent and to
describe what must be done if we are to eliminate the disease during the course
of the twenty-fi rst century.
Shelves of books have been written about TB, mostly on the historical, cul-
tural, clinical and microbiological aspects of the disease. The classic exposition
of TB epidemiology in a social context is The White Plague by René and Jean
Dubos (1952). The work of Karel Styblo (1991), giant among European public
health physicians, has been brought together in a collection of papers that any TB
specialist should still keep to hand. George Comstock (1980), during a lifetime’s
work on TB in North America, succeeded in his ambition never to write a book,
but his 1980 overview of landmarks in TB epidemiology is compulsory reading.
Based on his vast experience at the International Union Against Tuberculosis
and Lung Disease, Hans Rieder (1999, 2002) has written indispensable guides
to TB epidemiology (1999) and control (2002) systematically examining the
factors that determine infection, disease, and death and reviewing the efficacy
and effectiveness of interventions based on drug treatment and vaccination.
viii PREFACE
The approach taken in this book is different. My goal is to put the key char-
acters in epidemiology—person, place and time—in the context of population
biology, that is, demography, ecology, evolution, and population genetics. Aided
by simple mathematical models, the aim is to use the insights that come from
thinking about Mycobacterium tuberculosis and its human host as dynamic,
interacting populations to describe how, within a few decades, TB cases and
deaths could be brought down to much lower levels and how a combination of
novel interventions could eventually lead to elimination. The outlook is more
strategic than tactical, exploring general patterns and principles rather than
addressing detailed epidemiological questions that apply to specific settings.
This strategic approach is different in flavor from much of the recent analytical
literature on tuberculosis, which explores detailed solutions to specific or local
problems. Although the story is told with the aid of models, this book is not
intended to be a primer on mathematical or statistical methods in epidemiology;
the particulars of the methods used can be found in the sources cited.
The conventional tools of epidemiology include cross- sectional, case-
control, and cohort studies and, the ultimate investigative method, controlled
experimental trials. With these techniques we can assess, for example, whether
drug- resistant M. tuberculosis is associated with certain genotypes, the relative
risk of TB among cigarette smokers, and whether new drugs are effective treat-
ments for individual patients. These studies tend to be static in outlook. For
instance, a new TB vaccine that is found to have, in a randomized, controlled
trial, a protective efficacy of 70% against pulmonary TB in adults would be a
breakthrough for TB control. But knowing only the protective efficacy, we could
neither predict nor retrospectively understand the community-w ide impact of a
vaccination program over 10 years. That understanding requires a knowledge
of events that happen through population interactions and across bacterial and
human generations—of processes that can be understood and measured in terms
of case reproduction numbers, heterogeneity in transmission, herd immunity,
feedback loops, equilibria, and evolutionary selective pressures. These concepts
of population biology allow us to address questions that are important for the
control of infectious diseases but which lie outside the linear, time- bound tradi-
tions of descriptive, risk- factor epidemiology.
This outlook is influenced by and shares a common aim with Infectious
Diseases of Humans by Roy Anderson and Robert May (1991) Their 1991 book
marked a new era in epidemiology, drawing widely on ideas across the population
sciences, and developing mathematical theory that was always closely linked to
data. The greatest defect of their 700-p age book, however, is that it contains just
a single mention of TB—and then only for historical background.
We are two decades into the biggest- ever attempt to scale up drug treatment
for TB control and have arrived at the United Nations 2015 deadline for reaching
PREFACE ix
the Millennium Development Goals (MDGs). The global HIV/AIDS epidemic
has peaked, and more money is now being spent on TB research and develop-
ment than ever before. And yet the number of TB cases is falling slowly, if at all,
in many low- income, high- burden countries, and new strains of drug- resistant
TB are being discovered each year. Optimists have set 2050 as the date for TB
elimination; pessimists speak of the global spread of TB strains resistant to
all antibiotics. Both outcomes are possible; this book is intended as an aid to
achieving the former and avoiding the latter.
The thread of the argument is as follows. Chapter 1 sets the scene with an
empirical account of the evolutionary and epidemiological history of TB in
populations around the world. Chapter 2 captures the key concepts underpinning
this history in a formal mathematical framework—a family of dynamic models
that are used, in this and subsequent chapters, to investigate the key questions
about TB epidemiology and control. While Chapter 2 sets out the principles by
focusing on the average characteristics of individuals in populations, a central
goal of epidemiology, and fundamental to host and pathogen evolution, is to
explain differences—why some people acquire infection and disease and not
others. Chapter 3 therefore explores the factors that affect the risk of exposure
to M. tuberculosis infection and the risk of developing TB disease. A key finding
is that the known risks are numerous but small, and each of these small risks
typically explains only a small fraction of TB cases in any chosen population.
This has implications for TB control, the subject of Chapter 4. Without a better
understanding of who is most at risk of infection and disease, the opportunities
for targeted prevention and treatment are limited. This is why dominant control
efforts today do not focus on hotspots but rather confront the disease in whole
populations. The principal approach to TB control, drug treatment of active
disease, has saved millions of lives but has been much less effective in stopping
transmission. A central conclusion of Chapter 4 is that while the mitigation of
risk factors such as diabetes, undernutrition, or tobacco smoking is helpful as
an accessory to TB control, the greater opportunity for immediate impact lies
with the early diagnosis and curative treatment of TB disease.
Chapters 5–7 deal with three specific and important topics in TB epidemiol-
ogy and control: multiple TB strains and drug resistance; the dual epidemic of
TB and HIV/AIDS; and the prospects for elimination and eradication. Resistance
to TB drugs is a threat everywhere, but the continued spread of resistance is not
inevitable. By adopting today’s best management practices, both the number and
prevalence of resistant cases can be reversed in principle and in practice, even in
settings where resistant strains have become common. The epidemic of HIV/AIDS
has increased the incidence of TB by a factor of three in southern Africa. But given
the combined potential effectiveness of preventive and curative treatments for both
infections, plus the fact that HIV epidemics have peaked in the worst-a ffected