(Commentator surprised by increased TB soon after becoming HIV
positive. He does not consider the well-documented fact that appearance

of antibodies to HIV appear as a consequence of TB. Dave)

Journal of Infectious Diseases, Jan 15, 2005 v191 i2 p147(3)

Rapid increase in tuberculosis incidence soon after infection with
HIV--a new twist in the twin epidemics. (EDITORIAL COMMENTARY) Padmini

Srikantiah; Edwin Charlebois; Diane V. Havlir.

Full Text: COPYRIGHT 2005 Published by University of Chicago Press.

Over the course of the AIDS pandemic, we have learned a considerable
amount about the intersection of HIV infection and tuberculosis (TB).
TB is a leading cause of death among people living with HIV; worldwide,

14 million people are coinfected with Mycobacterium tuberculosis and
HIV [1]. HIV infection increases the risk of reactivating latent M.
tuberculosis infection, placing HIV-positive persons at increased risk

for developing TB [2]. HIV infection also increases the risk of rapid
TB progression after primary M. tuberculosis acquisition or reinfection

[3]. TB may accelerate the progression of HIV disease via immune
activation and is associated with a higher mortality rate and shorter
survival in HIV-positive persons [4]. The risk of TB increases as CD4
cell counts decrease; similarly, the highest mortality rates associated

with TB occur in persons with the lowest CD4 cell counts [5].

It has been assumed that, very early during the natural history of HIV

disease--before a significant decrease in CD4 cell count occurs--the
risk of TB is relatively low. Hence, it is both surprising and
fascinating that, in this issue of The Journal of Infectious Diseases,

Sonnenberg et al. report evidence to the contrary. In a large cohort of

gold miners in South Africa, the authors found that the risk of TB
doubled within the first year of infection with HIV. Not unexpectedly,

this risk further increased in subsequent years.

Previous studies have suggested the possibility that TB incidence may
increase soon after infection with HIV, but these studies have lacked
the power to quantify a statistically significant risk. There were
several features of the cohort analyzed by Sonnenberg et al. that
enabled them to evaluate the temporal risk pattern of TB after HIV
seroconversion: the incidence of TB in the cohort was very high, and
the cohort had a high rate of HIV seroconversion. Sonnenberg et al.
were able to examine outcomes among 23,874 miners, including 2737
miners with documented HIV seroconversion. TB diagnostic capacity
permitted the definitive diagnosis of TB, and the cohort had consistent

access to reliable health care.

In the study, miners who were tested for HIV at sexually transmitted
disease (STD) clinics, during hospitalization, or as part of
seroprevalence surveys during the designated study period were eligible

for enrollment. Miners were followed until they developed pulmonary TB,

died, or left the mines. HIV-negative miners were also censored from
analysis at 1 year after the last negative HIV test. TB was detected
during routine annual screenings or patient-initiated visits to the
hospital or an STD clinic. Throughout the study period, repeat HIV
tests were performed primarily during patient-initiated visits to the
hospital or STD (or other) clinics, as well as during seroprevalence
surveys.

The careful and complex analytic design of Sonnenberg et al.'s study
was necessitated by the open nature of the cohort and a desire to
minimize the inclusion of incident TB among miners with unclear or
unknown HIV status. The highly variable frequency and location of HIV
tests raises the question of whether the risks of TB were different,
for example, between miners who were tested for HIV only once during a

seroprevalence survey and miners who were tested multiple times at
patient-initiated visits to an STD clinic. Sonnenberg et al. dealt with

this potential bias in sensitivity analyses by excluding HIV tests
performed at medical or TB wards, and the authors report a similar
increased incidence of TB within the first year of HIV seroconversion.

When the methods of TB diagnosis in miners are considered, which
included evaluation after patient-initiated presentation to the
hospital or medical clinics and routine annual screenings, the issue of

ascertainment bias arises. Sonnenberg et al. correctly state that
physicians at the gold mines are likely to have a high level of
suspicion of TB regardless of a miner's HIV status, because of the
incidence and prevalence of TB at the mines. Nevertheless, HIV-positive

miners may present to medical facilities more frequently because of the

development of HIV-related clinical symptoms of illness, thus
potentially biasing toward greater evaluation for, and detection of, TB

among HIV-positive miners. Another challenge that arises is the
differing rates of attrition between HIV-positive and -negative miners

in the analysis. For HIV-negative miners with only 1 HIV test, the
period of follow-up included in the analysis would be only 1 year,
whereas, for HIV-positive miners, the follow-up period included in the

analysis would likely be, on average, longer. A shorter duration of
follow-up for HIV-negative miners may translate into a decreased chance

of detecting the development of TB, potentially decreasing the
estimated incidence of TB in this population. However, a median of 1.1

years of follow-up for HIV-positive and -negative miners provides
sufficient data to reveal the most fascinating finding of Sonnenberg et

al's study: the doubling of the incidence of TB within the first year
of HIV seroconversion.

Why is the risk of developing TB increased early during the course of
HIV infection? The profound immune dysregulation that occurs soon after

infection with HIV may play a role. Immediately after acute HIV
infection, a person undergoes a period of generalized immunosuppression

that is marked by diminished responsiveness to previously exposed
antigens [6, 7]. This T cell dysfunction, which is not clearly
correlated with CD4 cell counts and may last for months [7], may be one

mechanism that would allow early progression to TB after infection with

HIV. The temporal course of the loss of response to M. tuberculosis
antigens beginning at the time of acute HIV infection bears further
investigation, for it may shed additional light on this issue.

Another possible explanation for Sonnenberg et al.'s finding of an
increased risk of TB early during the course of HIV infection is that
the miners who developed TB during the first year of infection with HIV

represent a subset of rapid progressors. In early studies of AIDS, only

2%-3% of patients progressed to a clinical diagnosis of AIDS within 2-3

years of HIV seroconversion [8]. However, coinfection with >1 strain of

HIV has been increasingly reported in African cohorts [9, 10], and the

rates of rapid HIV disease progression may be much higher in these
dually infected persons. In a recent study of 34 HIV-positive patients

with known seroconversion dates and disease-outcome data, 5 were found

to be dually infected (i.e., they either were coinfected with 2 viral
variants at the time of seroconversion or were superinfected with a
second viral variant at a later date); in all 5 of these patients, the

time to a CD4 cell count of <200 cells/[micro]L was <3.1 years, which
is much shorter than the typical time of 8-10 years [9]. In Sonnenberg

et al.'s study, of the 138 miners in the incident-HIV-infection group
(i.e., those who seroconverted during the study period) who developed
TB during the study period, 30 developed the disease during the first
year of HIV infection. It is possible that some of these miners were
infected with >1 strain of HIV, resulting in a more rapid decrease in
CD4 cell count, which led to reactivation of latent M. tuberculosis
infection.

It is interesting to contemplate whether the increased risk of TB early

during the course of HIV infection is due to reactivation or to a newly

acquired M. tuberculosis infection. To shed light on this question,
Sonnenberg et al. performed molecular fingerprinting on available
isolates. Among HIV seroconverters, the authors found that unique TB
isolates were present in 57% (8/14) of miners who developed TB within 2

years of HIV seroconversion, compared with 20% (3/15) who developed TB

later. Patients with unique isolates are more likely to have developed

TB via reactivation, whereas patients with isolates that are shared
among a cohort are thought to have been recently infected. Both
reactivation and newly acquired M. tuberculosis infection are plausible

in the context of the acute immunosuppression that is associated with
primary HIV infection and with rapidly progressive HIV disease and
decrease in CD4 cell count. The numbers in Sonnenberg et al.'s study
are too small to draw a definitive conclusion with regard to the type
of TB that predominated after HIV seroconversion. It is possible that
the risks of both new M. tuberculosis infection and reactivation
disease increased.

The increased risk of TB early during the course of HIV infection has
several important implications for predicting the impact of HIV on the

global TB epidemic. Although it is difficult to generalize the
magnitude of the increase in incidence found in this highly specialized

population of gold miners and apply it to the rest of the developing
world, it is likely that some significant increase in incidence does
occur during the first year after HIV seroconversion. Although current

models that estimate the global burden of TB acknowledge the strong
association between TB incidence and adult HIV prevalence [11, 12],
they do not account for the increased risk of TB early during the
course of HIV infection. Reframing these models in the context of these

new data is likely to affect the calculated burden of TB--and not just

for HIV-positive persons, but for the general community as well [13].

The increased risk of TB early during the course of HIV infection also

has important implications for the prevention of TB in HIV-positive
persons. Potential methods include the use of antiretroviral drugs and

chemoprophylaxis for latent TB infection. Data from South Africa
suggest that the use of highly active antiretroviral therapy is
effective in reducing the incidence of HIV-associated TB in persons
with CD4 cell counts <350 cells/[micro]L [14]. If persons who develop
TB early during the course of HIV infection represent rapid progressors

with low CD4 cell counts, then determination of CD4 cell counts may be

all that is necessary to identify the subset of persons who are at
highest risk.

Alternatively, if most persons who develop TB early during the course
of HIV infection have high CD4 cell counts and no indications for
antiretroviral therapy, then the treatment of latent M. tuberculosis
infection may be the most feasible way to reduce the risk of TB. Data
from Uganda suggest that treatment of latent M. tuberculosis infection

can provide protection against TB in HIV-positive persons; the duration

of protection was lengthened to 3 years by use of treatment regimens
that combined isoniazid with rifampicin [15]. However, defining and
implementing optimal preventive therapy for TB in Africa is a
challenging endeavor. The optimal duration of treatment and the optimal

regimens are unknown and are currently under investigation. Preventive

therapy programs also require the exclusion of active TB, which may be

difficult in resource-constrained settings.

Perhaps the most immediate and universal implication of these important

data from Sonnenberg et al.'s study is the need to expand reliable and

affordable HIV testing services in areas where TB is endemic. The
accurate identification of undiagnosed HIV infection is the necessary
first step in the implementation of prevention measures that aim to
curtail the spread of M. tuberculosis and HIV coinfection. The timely
and reliable evaluation of TB in HIV-positive persons is another key
component that needs to be further strengthened to curb the epidemic.
The ProTEST initiative that has been established in 3 sub-Saharan
African countries by the World Health Organization aims to develop a
more coherent response to TB in settings where HIV prevalence is high
by combining improved access to high-quality HIV counseling and rapid
testing services with intensified screening for TB [16]. Preliminary
reports from these sites indicate that such collaborative efforts
between HIV/AIDS and TB control programs are feasible and effective
[16]. Improvement of the links between the HIV and TB clinical and
public-health services will be critical to effectively handling the
challenges of this coepidemic.

Received 20 September 2004; accepted 22 September 2004; electronically

published 13 December 2004.

(See the article by Sonnenberg et al., on pages 150-8.)

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Padmini Srikantiah, (1,2) Edwin Charlebois, (1) and Diane V. Havlir (3)

(1) Center for AIDS Prevention Studies, (2) Division of Infectious
Diseases, and (3) HIV/AIDS Division, San Francisco General Hospital,
University of California at San Francisco, San Francisco

Reprints or correspondence: Dr. Diane V. Havlir, HIV/AIDS Div., San
Francisco General Hospital, University of California at San Francisco,

995 Potrero Ave., Bldg. 80, Ward 84, San Francisco, CA 94110
(dhavlir@php.ucsf.edu).