The Changing Natural History of Tuberculosis and HIV Coinfection ...

S208 • CID 2010:50 (Suppl 3) • Bekker and Wood

S U P P L E M E N T A R T I C L E

The Changing Natural History of Tuberculosisand HIV Coinfection in an Urban Areaof Hyperendemicity

Linda-Gail Bekker1,2 and Robin Wood1,2

1The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, and 2Department of Medicine, University of Cape Town,Cape Town, South Africa

Tuberculosis (TB) has proven to be difficult to control in regions with a high prevalence of human immu-

nodeficiency virus (HIV) infection. We previously described high prevalence of HIV infection among adults

(23%) and rapidly escalating TB notification rates in a peri-urban township, Site-M in Cape Town, South

Africa. The combination of delineated boundaries, a well-characterized population, centralized TB record

keeping, and high levels of HIV testing make this population uniquely suited for TB epidemiologic and

transmission studies. The driver of the HIV and TB coepidemic appears to be a high annual risk of Myco-

bacterium tuberculosis infection in this community. A high annual risk of M. tuberculosis infection may be

the result of unrecognized infections coupled with intense social interaction and crowding. New non–facility-

based interventions will be required, with emphasis on community-based case finding and contact tracing to

decrease the infective TB pool. There is a need for better understanding of the transmission dynamics of TB

and the intensity of social interactions, which have exacerbated an HIV and TB epidemic in this community

of hyperendemicity.

Tuberculosis (TB) remains a challenge to global public

health, is a major cause of mortality, and has proven

to be particularly difficult to control in regions with a

high prevalence of human immunodeficiency virus

(HIV) infection. An estimated 1.3 million deaths due

to TB occur annually among HIV-uninfected individ-

uals, and an additional 0.5 million deaths occur among

HIV-infected persons. Of the estimated global burden

of 9.3 million new TB cases in 2007, 1.37 million

(14.8%) were associated with HIV infection and ac-

counted for almost 25% of global AIDS-related mor-

tality [1].

Sub-Saharan Africa has borne the brunt of the HIV

Reprints or correspondence: Dr Linda-Gail Bekker, The Desmond Tutu HIV Centre,The Institute of Infectious Disease and Molecular Medicine, Wernher Beit Bldg,Health Science Faculty, University of Cape Town, Anzio Rd, Observatory, 7925,Cape Town, South Africa ([email protected]).

Clinical Infectious Diseases 2010; 50(S3):S208–S214� 2010 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2010/5010S3-0019$15.00DOI: 10.1086/651493

and TB coepidemics, accounting for 79% of the global

burden of HIV infection–associated TB cases in 2007.

The 9 countries of the southern African region with

hyperendemicity have TB case notification rates that

are much higher than those for the rest of the African

continent; these 9 countries have generalized HIV ep-

idemics and report a prevalence of HIV infection of

�50% among persons with newly diagnosed TB (Figure

1). In 2007, the estimated rate of TB case notifications

in Africa was 161 cases per 100,000 population; how-

ever, in this subregion of hyperendemicity, incidence

rates of TB in South Africa and Swaziland increased to

948 cases per 100,000 population and 1198 cases per

100,000 population, respectively, with 73% and 80% of

new TB cases, respectively, involving HIV coinfection.

The Millennium Development Goals for global TB

control are to halt and start to reverse the increasing

incidence of TB and to halve the 1990 prevalence and

death rates by 2015 [2]. In countries where TB is hy-

perendemic, such as South Africa and Swaziland,

achievement of Millenium Development Goals for TB

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TB and HIV in an Area of Hyperendemicity • CID 2010:50 (Suppl 3) • S209

Figure 1. Estimated prevalence of HIV infection among persons with newly diagnosed cases of tuberculosis (TB), 2007. Reprinted with permissionfrom the World Health Organization [1].

is unlikely, because it would require a reversal of present TB

incidence trends and a 6-fold reduction in TB incidence during

the next 6 years.

Since the World Health Organization (WHO) declaration in

1993 that TB was a global emergency, the directly observed

therapy short-course (DOTS) strategy has been the key public

health intervention that has been widely used to affect global

TB control [3]. The strategy focuses on TB case management

of sputum smear–positive cases with use of short-course ri-

fampicin-containing chemotherapy. Case finding is passive and

facility based, with emphasis placed on case retention and the

achievement of a high cure rate. Although DOTS has been

effective in most regions of the world, contributing to the sus-

tained downward trend in global TB prevalence, it has been

comparatively ineffective in countries with a high prevalence

of HIV infection [1, 4–7]. During 2002–2004, the WHO and

the Stop-TB Partnership published guidelines [8], a strategic

framework [9], and an interim policy for TB and HIV infection

[10] to address the specific challenge of HIV infection–asso-

ciated TB. These interventions aim to reduce the burden of TB

in HIV-infected persons through use of TB prevention strat-

egies, including isoniazid preventive therapy (IPT), intensified

case finding, and infection control in conjunction with anti-

retroviral therapy (ART)—the so-called “3 I’s.”

However, mathematical modeling suggests that a combina-

tion of very high levels of ART coverage and early ART initi-

ation at high CD4 cell counts may be required to significantly

affect population TB control, especially in settings where TB

and HIV infection are hyperendemic [11]. Similarly, IPT is an

intervention that reduces the risk of active TB in already HIV-

infected individuals with latent TB infection rather than a pri-

mary strategy to control the public health burden of TB [12].

Although IPT is effective in decreasing the individual risk of

progression to TB [13], the modeled population impact of IPT

in areas of hyperendemicity is predicted to be small [14]. There-

fore, there is an urgent need to understand the epidemiological

factors driving the coepidemics in regions of hyperendemicity

to inform TB-control strategies.

LESSONS FROM EPIDEMIOLOGIC STUDIES INAN URBAN COMMUNITY WHERE TB ISHYPERENDEMIC

Although the global burden of HIV infection–associated TB is

concentrated in the southern African subregion, there are large

differences in disease burden even in the subregion. Specific

subpopulations, such as South African mine workers, have been

well documented to have a high TB incidence, in part because

of the multiplicative effect of HIV infection and mine work–

associated pulmonary silicosis [15]. In addition, rapid growth

of urban areas is occurring in the context of generally declining

economic performance, and the growth of urban areas includes

huge numbers of persons with low-income status [16, 17]. It

is estimated that ∼61% of South Africans are urbanized, and



Figure 2. An aerial photograph of Site-M (in Cape Town, South Africa), with superimposed property boundaries outlined. The figure was createdusing ArcGIS, version 9.2 (ESRI, 380 New York St, Redlands, CA 92373-8100).

57% of these persons live in slum conditions [18] where TB

and HIV burdens are greatest [19].

We previously described an epidemiologic study in South

Africa that found a high prevalence of HIV infection among

adults (23%) [5] and rapidly increasing TB notification rates

[20]. Specifically, annual TB notifications have now reached

2000 cases per 100,000 population in this peri-urban township

in Cape Town, designated by our study as “Site-M” [5, 20].

Regular household censuses have been performed that have

shown that the community has undergone rapid population

growth from 5000 residents in 1996 to 15,000 residents in 2008.

This population growth has occurred within well-circumscribed

boundaries (Figure 2). The community is socially deprived,

living in overcrowded, largely informal dwellings located on

demarcated plots serviced with water and sanitation. There is

a single health care facility that provides primary medical care

to community residents, and there is a primary and secondary

school. Increases in TB notification rate have occurred despite

a well-implemented national TB-control program based on the

WHO DOTS strategy [21] at the single community clinic that

manages all resident TB cases. Routine HIV testing (with con-

sent) of patients with incident TB was introduced in 2002. The

combination of delineated boundaries, a well-characterized

population, centralized TB record keeping, and high levels of

HIV testing make this population uniquely suited for studies

on TB epidemiology and transmission.

IMPACT OF HIV INFECTION ON TB CONTROL

Almost 2 decades ago, before the development of effective com-

bination ART, Styblo [6] reported that existing TB-control

strategies would be significantly undermined by HIV infection,

particularly in Africa. It was postulated that the impact of HIV

infection on the epidemiological situation of TB would depend

primarily on the following parameters: (1) the prevalence of

HIV infection in a community, (2) the prevalence of TB in the



Figure 3. The relationship between tuberculosis (TB) notification rates and seroprevalence of HIV infection in the South African population (diamonds)and the population at Site-M (triangles), with exponential regression lines for South African data during 1990–2005 (R2, 0.8461) and for Site-M dataduring 1996–2005 (R2, 0.9376).

general population aged 15–49 years, (3) the progression from

latent TB to active disease, (4) the level and trend in the annual

risk of (new) TB, and (5) the detection rate of new and relapse

cases of TB and cure rate among persons with smear-positive

cases.

Other more recently recognized factors include the obser-

vation that combination ART can significantly decrease TB in-

cidence [22] and the observation that TB incidence is very

dependent on current CD4 cell counts [23]. Taking these factors

into consideration, studies have focused on measuring the fol-

lowing likely drivers of increasing TB incidence in the study

community: prevalence of HIV infection, prevalence of un-

derlying latent TB, rates of progression from latent TB to active

TB, annual risk of TB, and case detection rates.

PREVALENCE OF HIV INFECTION

Since 1990, the South African Department of Health has per-

formed annual national surveys on the prevalence of HIV in-

fection among women attending antenatal services [24]. The

TB notification rates in South Africa from 1990 through 2005

[1] and the national antenatal seroprevalence of HIV infection

are shown in Figure 3 [24]. The corresponding adult TB no-

tification rates and prevalence of HIV infection among adults

at Site-M from 1996 through 2005 are also shown in Figure 3.

During the these periods, the seroprevalence of HIV infection

increased markedly, reaching levels of 30% and 23% among

national antenatal attendees and adults at Site-M, respectively.

TB notification rates have increased logarithmically for linear

increases in prevalence of HIV infection; an even stronger pos-

itive relationship was shown in the high-burden township. Pos-

sible explanations for this nonlinear relationship could include

changes in CD4 cell count distribution in the HIV-infected

population during the rapid-growth phase of the HIV epidemic

or increasing TB transmission between HIV-infected individ-

uals as the HIV epidemic grows rapidly.

AGE-SPECIFIC TB AND HIV INFECTION

Over the past decade the number of TB notifications has in-

creased markedly at Site-M, with the increased burden of TB

disease predominantly affecting persons aged 15–45 years (Fig-

ure 4A). The numbers of TB presentations at any age are a

function of the number of individuals in each age strata and

the TB rate specific to that age group. There have been sig-

nificant changes to age-specific TB rates over the past decade

that have been associated with increasing prevalence of HIV

infection (Figure 4B). TB rates appear to have increased in all

age groups; however, the most marked increases are among

persons aged 15–44 years, the age group most at risk of ac-

quisition of HIV infection.

POPULATION PREVALENCE OF TB

Prevalence of underlying latent TB at any age is influenced by

both the prevailing TB transmission rate and transmission rates

during the preceding years of life; therefore, prevalence of TB

increases with increasing age because of accumulated exposure.

The traditional way to measure latent TB is to measure reaction

to tuberculin antigens by tuberculin skin testing. Population

tuberculin skin testing surveys have been infrequently per-

formed in recent decades; however, a recent tuberculin skin

testing survey at Site-M township primary school reported TB

prevalences that increased from 8% at school entry to 53% by



Figure 4. A, Number of tuberculosis (TB) notifications, stratified byage, at Site-M over two 4-year periods: 1996–1999 (diamonds) and 2004–2007 (triangles). B, TB notification rates, stratified by age, at Site-M overtwo 4-year periods: 1996–1999 (diamonds) and 2004–2007 (triangles).

the age of 15 years [25]. Moreover, prevalence of latent TB

appeared to continue to increase throughout adolescence. In

2006, the HIV-uninfected control population at a similar nearby

township in Cape Town had a TB prevalence of 77% by the

age of 28 years [26]. Other similar township populations in

Cape Town have also shown equally high prevalence of adult

TB infection [27].

RATE OF PROGRESSION TO ACTIVE TBDISEASE

The temporal association between infection and risk of pro-

gression to active disease has been well recognized [28]. Pro-

gression to active disease is particularly rapid in children and

has been a marker of ongoing transmission; however, the re-

sultant TB disease is frequently sputum smear negative [29].

Childhood TB is conventionally reported internationally as a

!15 years smear positive rate [1]. In 2007, South Africa reported

a high smear positive childhood rate of 30 cases per 100,000

population. However, the high burden of childhood disease is

not adequately reflected by the !15 years smear positive rate.

In 2007, although the !15 year smear positive rate for Site-M

was 81 cases per 100,000 population, the TB notification rate

was 54 cases per 100,000 population among children !15 years

of age and reached 1390 cases per 100,000 population among

children !5 years of age.

There has been a marked change in the adult age of TB

disease presentation. During 1996–1997, a period of relatively

low prevalence of HIV infection, the incidence of TB increased

progressively with advancing age, with no case notifications for

adolescents (age, 10–19 years); however, TB notification rates

increasing steadily to 1700 cases per 100,000 population in the

fifth decade of life [5]. During 2003–2004, when the prevalence

of HIV infection among adults exceeded 20%, TB notifications

predominantly were for adolescents and young adults.

The estimated incidence of TB among HIV-uninfected and

HIV-infected adult community members in 2005 was 953 cases

per 100,000 population and 5140 cases per 100,000 population,

respectively [20], indicating a 5-fold increased risk among HIV-

infected individuals. As a consequence of these high TB inci-

dence rates, the lifetime cumulative risk of TB is extremely high

for both HIV-uninfected and HIV-infected individuals in this

community. The very high cumulative lifetime TB risk for HIV-

uninfected individuals is also much higher than the conven-

tional estimated lifetime risk of latent infection progressing to

TB disease of 10%–20% [30]. The increased lifetime risk may

result from increased rates of progression because of poor nu-

trition, exogenous reinfection, or exposure to a high initial

amount of infective TB [31]. The majority of individuals who

are coinfected with TB and HIV live in sub-Saharan Africa, an

area where hunger and malnutrition were already pressing con-

cerns before the onset of the HIV and TB epidemics.

LEVEL AND TREND OF ANNUAL RISK OF TB

Population density varies markedly among and within coun-

tries. Both the nature of the dwelling and crowding within the

dwelling will have an impact on the number of individuals

exposed to an infected person. Site-M has had an increasing

population density, reaching 15,700 persons/km2 in 2008. The

annual risk of TB among primary school children in 2008 was

estimated to be 3.8%–4.8% [25], which is unprecedented in

the current TB chemotherapeutic era. The annual risk of TB

is similar to that found in several large scale surveys performed

in western, eastern, and southern Africa from 1995 through

1960 [32]. In the prechemotherapy era, mean annual rates of

infection as high as 13% per annum were reported among

Parisian children in 1910 [33]. Lower rates of infection of 3%

per annum were recorded among children in post–World War

II Denmark [34].

A 77% prevalence of TB infection by age 28 years (during

a period of increasing TB notifications) would indicate a high

and ongoing mean risk of TB infection of 5.5% during an

individual’s preceding years of life. Childhood infection and

TB disease in Site-M have been shown to be strongly associated



with exposure to adult smear-positive TB in combined family

groups that are resident on each serviced plot [35].

In summary, the annual risk of TB in this community is

extremely high and appears to be maintained or to increase

throughout childhood and adolescence. Trends in the annual

risk of TB over time in any specific age group in this community

are less certain; however, there is little evidence for decreasing

transmission.

CASE DETECTION AND TREATMENT

Efficient case management of infective TB is the cornerstone

of the DOTS strategy [3], to which other supplementary control

strategies may be added [8–10]. The single TB facility in Site-

M implements DOTS-based, short-course, rifampicin-contain-

ing chemotherapy, administered in accordance with national

guidelines [36]. TB-associated mortality during 2002–2004, be-

fore availability of ART, among HIV-infected and HIV-unin-

fected persons with TB was 13% and 3%, respectively [20].

Treatment completion rates of persons surviving to 6 months

of age were 84% among HIV-infected persons and 86.6%

among HIV-uninfected persons [20]. In 2005, a cross-sectional

survey of a randomly selected subset of the general population

found that the existing facility-based smear-positive case find-

ing was higher for HIV-uninfected community members than

for HIV-infected community members (rates, 0.67 [95% con-

fidence interval, 0.25–0.53] and 0.37 [95% confidence interval,

0.41–1.0], respectively) [20].

TB TRANSMISSION PATTERNS

Over a 5-year period from 2001 through 2005, all acid-fast

bacilli–positive sputum samples obtained at the single clinic in

Site-M were cultured, and IS6110-based restriction fragment-

length polymorphism analysis [37] was performed [38]. A

broad diversity of ∼200 distinct circulating M. tuberculosis

strains were estimated to be circulating in this community—a

finding consistent with other studies in sub-Saharan Africa [39,

40]. This study also found an association between W-Beijing

family strains and HIV infection that may reflect ongoing trans-

mission of TB among HIV-infected persons. W-Beijing strains

have been associated with increased virulence [41] and the

development of multidrug resistance [42]. The high degree of

genotypic diversity in certain strains may indicate that they

either are endemic in this population or may be emerging and

diversifying in the community.

Another important finding was the high rate of strain clus-

tering. In this study, approximately half of the strains were

clustered, and there were close temporal associations, especially

among the paired clusters, supporting the likelihood that a

significant proportion of disease in the community is attrib-

utable to recent infections. No association was found between

HIV infection and clustering; therefore, new infections may be

occurring in both HIV-uninfected and HIV-infected patients.

DISCUSSION

This review has focused in detail on a specific, well-demarcated

population that is heavily burdened with the dual epidemics

of HIV infection and TB. Detailed analysis of the HIV and TB

epidemics in this community may reveal insight into the factors

driving the HIV and TB regional emergency in southern Africa.

The incidence of TB has increased logarithmically with growth

of the HIV epidemic and has been associated with a changed

age distribution, resulting in the TB burden transferring from

the elderly to young adults. The HIV epidemic appears to have

unmasked a previously unrecognized high prevalence of TB

and an unprecedented rate of TB in this crowded township.

Modeling studies suggest that a combination of interventions

will be required to regain TB control [12]. The present strategy

for global TB control remains the identification and effective

case management of infectious TB cases [33]. However, al-

though the facility-based program in this community appears

to have achieved standard targets for TB case management for

HIV-uninfected community members, the program has not had

an impact on the extremely high annual risk of TB.

Strategies to decrease progression from prior infection may

include ART and IPT. However, ART will need to be introduced

with high coverage and earlier in the course of HIV infection,

at higher CD4 cell counts, to significantly have an impact on

rates of TB in the population [12]. Although the effect of ART

is greater with continuing length of therapy [34], the benefits

of IPT for HIV-infected patients are time-limited, compared

with those for HIV-uninfected persons [14].

The underlying driver of the explosive HIV and TB coepi-

demic appears to be an extremely high annual risk of TB in

this community. A high annual risk of TB may be the result

of unrecognized infectious cases in the community and intense

social interaction and crowding. New interventions in addition

to the present clinic-based model of TB case management will

be required, with increased emphasis on active community-

based case finding and contact tracing to decrease the infective

TB pool. There is also an urgent need for better understanding

of the transmission dynamics of TB and intensity of social

interactions that have exacerbated the HIV and TB coepidemic

in this community of hyperendemicity.

Acknowledgments

Potential conflicts of interest. L.-G.B. and R.W.: no conflicts.Supplement sponsorship. This article is part of a supplement entitled

“Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Ep-idemics,” which was sponsored by the Center for Global Health Policy, aproject of the Infectious Diseases Society of America and the HIV MedicineAssociation, through a grant from the Bill & Melinda Gates Foundation.



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