Slide 2
The objectives of this presentation are to:
- Describe the epidemiology and natural history of TB
- Explain the relationship between HIV and TB
- Review TB prevention and control strategies
- Discuss the impact of high HIV prevalence on TB control strategies
- Discuss key features of TB treatment
Slide 3
I'd like to start out with a description of the current global TB
situation, particularly in reference to the HIV epidemic. Throughout the
world, there are two billion people with TB infection. There are eight
million new cases of TB per year and two million deaths from TB. There are
more than 40 million people with HIV infection, most of these in
sub-Saharan Africa, and many of them are also infected with TB. TB is the
leading cause of death related to HIV throughout the world and the TB
epidemic has been made significantly worse by the HIV epidemic.
Slide 4
This map depicts the incidence of TB around the world as of 2000. As
you can see, when you look down the scale in the legend, the darker the
color the higher the incidence. Throughout sub-Saharan Africa, the
incidence of TB is very high, with more than 250 cases per 100,000
population. In some countries, there are over 500 cases per 100,000
population. In southern Asia, which is the most populous region of the
world and where the HIV epidemic is spreading rapidly, TB case rates are
also high, ranging between 100 to 250 per 100,000 people.
Slide 5
This map depicts the overlap of TB infection and HIV infection. In
sub-Saharan Africa, it is estimated that more than 1% of the population
has both infections. In South Africa, approximately 8 or 9% of the
population has both infections. This overlap has a devastating impact on
TB morbidity, mortality and control.
Slide 6
TB is contracted from exposure to an individual who is infectious. It
is transmitted when an individual with active TB infection coughs,
sneezes, spits or talks, thereby releasing small respiratory droplets that
contain tubercle bacilli into the air. These droplets are then inhaled by
another individual.
Two factors determine an individual’s risk of exposure:
- the concentration of infectious droplets in contaminated air and -
the length of time she or he breathes the air.
Slide 7
When a person is exposed to someone with active TB, the risk of
infection depends on the extent of exposure to infectious droplets and her
or his susceptibility to infection. Numerous studies over the years have
shown that about one-third of people who have close contact with someone
who has active TB acquire TB infection.
Slide 8
Specific risk factors for becoming infected include:
- Closeness of contact: people who share a bedroom are more likely to
be infected than those who just live in the same household. In turn, those
who live in the same household are more likely to be infected than those
who have casual contact outside of the household;
- Duration of infectiousness: the longer the person is infectious and
coughing TB bacteria, the more likely their contacts are to become
infected; and,
- Severity of the disease: a person who is very sick, has large
cavities in their lungs, and coughs a lot, transmits more infection than
someone who is less sick.
Slide 9
After infection is acquired, 90-95% of people contain it and do not get
sick. Five to ten percent of people who are infected progress to active
disease within 2 years.
Slide 10
There are several differences between individuals with latent infection
with TB and those with active TB disease. Both those with latent infection
and active TB will generally have a positive tuberculin skin test or TST
except in situations where they are unable to respond because of a
weakened immune system. This is called anergy and is more common in
HIV-infected individuals, especially those with more advanced HIV or AIDS.
In those who have received BCG vaccination as children, the TST may be
positive because of BCG, although with TB infection or disease, the size
of the reaction is generally larger. Other than a positive TST, however,
latently-infected individuals have no clinical signs or symptoms, no
positive laboratory or radiology findings, and they are not infectious. On
the other hand, those who have active TB disease have progressive signs
and symptoms; they will generally have an abnormal chest radiograph and a
positive sputum smear and culture, although individuals with both TB and
HIV are more likely to have negative sputum smears, as compared to HIV
negative persons. Finally, those with active TB are infectious until
treated adequately.
Slide 11
Among the people who contain their TB infection, about 5% later develop
active TB from reactivation. Overall, 85-90% of people infected with TB
never develop active disease. They live the rest of their lives with no
symptoms of TB infection. However, 10-15% of people develop disease,
become ill and infect others, beginning the cycle again.
Slide 12
What does HIV infection do to the natural history of TB? The risk of
infection after exposure to TB appears to be the same for HIV-positive and
HIV-negative people. The annual risk of progression to active TB disease
in HIV-negative individuals with latent infection is 2-5%. Therefore,
early progression to active TB within the first 2 years after infection is
5-10% for HIV-negative, but it is approximately 40% in HIV-positive
individuals. HIV completely changes the natural history of TB. Instead of
having 90-95% containment, there is 60% containment at best in
HIV-positive individuals.
Slide 13
What about people who have a contained TB infection and then acquire
HIV? Their risk of progression, instead of being 5% for their lifetime,
increases to 5-10% per year. HIV alters the natural history of TB
profoundly. It is the most important risk factor for developing TB that
has ever been described.
Slide 14
In communities, the source of TB is latent infection, those people who
are containing their TB infection, but who are at risk for developing
active disease. Every year, some proportion of these individuals with
latent TB will develop reactivation TB. When this happens, they can infect
people in their community. The newly infected individuals either develop
primary active TB themselves or become latently infected and at risk for
progression.
Slide 15
When HIV infection is added to the same population, these dynamics
change markedly. If the pool of latently infected individuals has a high
prevalence of HIV infection, those HIV-positive individuals will dominate
active TB cases because their risk of progression is several hundred-fold
larger than for HIV-negative persons. In South Africa, Botswana, and
Zambia, 60-70% of all TB patients have HIV because the prevalence of HIV
in the population is high, approximately 10% or more. These individuals
are infectious and will infect other HIV-positive persons who are their
contacts. These HIV-positive individuals in turn have a high risk for
primary TB or later reactivation. HIV quickly comes to dominate the
picture of TB in the population.
For example, throughout sub-Saharan Africa, TB case rates have been
climbing. After being fairly stable during the 1980s, the evolution of the
HIV epidemic increased case rates. Sub-Saharan Africa now has the highest
TB rates of any region in the world.
Furthermore, as HIV infection progresses and CD4 counts fall, the risk
of opportunistic diseases, including TB, increases. Therefore, once HIV
has entered a population, its effect on TB rates becomes even more
pronounced with time.
Slide 16
Traditionally, there have been three principle strategies for trying to
control TB and reduce its incidence.
The first and most important strategy is diagnosis and treatment of
cases. People throughout the world who have TB are most often identified
passively - they present with symptoms. They are treated, become
noninfectious and therefore interrupt the chain of transmission. However,
by the time they are diagnosed with TB, these individuals have already
infected approximately 8-10 other people; if they remain undiagnosed for 6
months, they may infect 100-200 people.
Prompt and accurate diagnosis of active TB cases using microscopy to
examine stained smears of infected secretions, particularly sputum, and
other body tissues can help shorten the period of time between development
of disease and treatment. Once a person with active TB is identified,
highly effective multidrug regimens are given for relatively short courses
with direct observation of therapy, as the standard of care treatment.
Surveillance and monitoring systems should be put in place to track cases
and determine outcomes. These components are part of the current WHO
strategy for TB control throughout the world, known as Directly Observed
Therapy - Short Course or DOTS. For this strategy to be effective, there
must be political commitment, adequate funding, and access to a continuous
supply of drugs.
The second principle strategy is treatment of latent cases, individuals
who are infected and at risk for progression, but who do not have active
TB. This strategy has been very effective in the U.S., but has not been
used in much of the rest of the world.
The third strategy is vaccination with BCG, the most widely used
vaccine in the world. Although BCG may help protect young children against
disseminated and severe TB, it has little or no effect in reducing the
number of adult cases of TB.
Slide 17
The clinical signs and symptoms that suggest a diagnosis of TB include
cough for longer than 3 weeks, sputum production, weight loss and systemic
symptoms such as fever and night sweats. However, all of these are
relatively unspecific and in the HIV-infected person, may be due to HIV or
other opportunistic infections related to HIV. The TST alone cannot
diagnose active TB and is of little value as an aid in diagnosis in high
prevalence populations where latent infection is common. The most
important diagnostic test is the microscopic examination of a stained
sputum smear. A chest radiograph will be abnormal in the person with
active pulmonary TB, but is not necessary for diagnosis if the sputum
smear is positive.
Slide 18
TB, unlike other opportunistic infections, can occur at any point in
the course of HIV infection. However, it may differ in clinical
presentation in the HIV-infected person, especially with late-stage HIV.
With more advanced HIV, disseminated and extra-pulmonary TB are more
common. Common disease sites or presentations include lymphadenopathy,
pleural effusion, pericardial disease, miliary disease, or meningitis.
However, pulmonary TB is still the most common form of active TB in HIV
co-infected individuals, whether they have early or more advanced HIV
infection. As we have discussed, pulmonary TB may be present with negative
sputum smears in persons with advanced HIV/AIDS. The chest radiograph with
TB in the setting of advanced HIV/AIDS often shows interstitial
infiltrates without the characteristic cavities typically seen with active
TB.
Slide 19
The management of active TB should be through the country TB control
program in order to standardize management using DOTS therapy and to
maintain adequate surveillance. Treatment regimens for HIV co-infected
patients are the same as in HIV-negative patients, with an initial 2 month
intensive phase of treatment, generally with 4 drugs, followed by a 4
month continuous phase using 2 drugs. Standard anti-TB drugs are used,
including isoniazid or INH, rifampin, pyrazinamide, ethambutol and
streptomycin. With DOTS, recurrence rates are similar in HIV-positive and
HIV-negative patients.
Slide 20
Adverse effects or toxicity from anti-TB therapy such as peripheral
neuropathy and/or hepatitis with INH, appear to be more common in
HIV-positive patients and risk increases with increasing immunosuppression.
Ideally, where possible, pyridoxine 10mg daily should be given with INH to
help prevent INH-related peripheral neuropathy. Drug interactions may also
occur. Rifampin interacts with several antiretroviral agents, potentially
decreasing the effectiveness of the antiretroviral drugs. Rifampin, also
interacts with oral contraceptives, possibly decreasing the effectiveness
of the oral contraceptives. Streptomycin should not be used to treat TB in
pregnancy because it has been associated with permanent deafness in the
baby.
Slide 21
Drug resistant TB is of great concern but can be prevented by using
effective anti-TB drug combinations and by ensuring that patients complete
their full course of treatment. Patients who previously have been treated
for TB and who remain sputum smear positive are at high risk of having
drug-resistant TB. These patients must be managed in consultation with a
specialist.
Slide 22
For more than 25 years, Botswana has used a national DOTS program that
has become a model for other countries. All of the cases are diagnosed by
microscopy. All of the therapy is supervised with the best possible
treatment available anywhere in the world. No drugs can be obtained
outside the TB control program so patients cannot walk into a pharmacy,
buy drugs and treat themselves improperly or receive improper treatment
from healthcare providers who are not TB experts. More than 90% of
patients who are treated complete a 6-month course of therapy and are
cured. Because the therapy is supervised, there is very little drug
resistance from missed doses.
After beginning this program, TB cases started to decrease; however, as
shown in this graph, they then increased dramatically throughout the
1990s. The shorter curve is the prevalence of HIV infection among pregnant
women in Francistown. Although the situation would be worse without this
program, it has not controlled TB because the incidence is going up.
When there is an HIV epidemic in the community as well as high rates of
latent TB, there is a larger number of people who progress from latent to
active TB. The DOTS strategy intervenes after this has occurred. It
reduces, but does not prevent, transmission of TB and simply reduces the
numbers of individuals who are ultimately infected. Although the DOTS
program cures over 90% of the diagnosed cases, TB remains the leading
cause of death of people with HIV in Botswana. This is because not all of
the cases are diagnosed, and if an individual has HIV, her or his risk for
death is greatly increased, even with good treatment.
Slide 23
What can we do to improve TB control in areas where HIV is common?
Expansion of DOTS is important because it does reduce transmission and,
more importantly, it improves outcomes of treatment, so fewer people die
of TB.
Another strategy is active case finding. Instead of waiting for people
who are sick to come in seeking care, often with delays of many months,
active case finding involves going out and finding people earlier so that
they will infect fewer people and will be at lower risk of dying
themselves.
Contact evaluation is a form of active case finding which targets
contacts of individuals with active TB for evaluation. These individuals
are more likely to be recently infected with early active disease and need
treatment or have latent infection with high risk for developing active
disease and need preventive therapy. Other individuals who are not
necessarily known contacts of TB patients but may be at increased risk for
other reasons such as known HIV infection, can also be evaluated for
possible latent infection and receive therapy to prevent progression to
active disease.
Finally, it is important to identify and treat persons and to use
proper respiratory infection prevention practices in institutions such as
prisons and hospital wards to reduce transmission of TB in these close
contact settings.
Slide 24
The rationale for directly observed therapy for HIV-related TB comes
from a non-randomized study conducted in Baltimore where TB clinic
patients who had received directly observed therapy were compared to those
who did not. The patients who got directly observed therapy were largely
drug users and poor and were given DOT because it was felt that they were
unlikely to adhere to their therapy regimen. The non-DOT patients were
patients who were not felt to need directly observed therapy because it
was believed that they would adhere to their therapy regimen.
At the end of analysis, more patients who did not have DOT died,
generally from TB, because they did not take their medicines as expected
and did not complete their therapy. This study was repeated in New York
City with many more patients and with the exact same finding - patients
who receive DOT, even those patients who are considered to be unreliable,
live longer and are more likely to survive treatment than those who are
left on their own to treat themselves. Beginning in 1997, the CDC
recommended that all HIV patients with TB get directly observed therapy to
improve their survival.
Slide 25
This table summarizes a pilot study of contact evaluation done as part
of a TB research program conducted throughout the 1990s at the Center for
Development and Health in Haiti. TB patients coming to the clinic were
asked to identify household contacts. A large number of contacts were
identified and about one-third of them were fully evaluated. Among those
who were evaluated, 10-15% had active TB. All of these individuals were
sick and at risk of death themselves, but were also infectious to others.
At the time of this study in Cite Soleil, approximately 40% of TB patients
also had HIV.
Slide 26
Treatment of latent TB in a high-risk population can have a dramatic
effect on TB control. In the early 1990s, a cohort of injection drug users
in Baltimore had an HIV prevalence of about 33%.
After a 5-fold increase in the incidence of active TB in this
population between 1988 and 1992, a program was begun where TST was
routinely performed and INH therapy was given to those who had a positive
TST to prevent progression to active TB whether or not they were
HIV-positive.
About 25% of these individuals had a positive TST, indicating latent
TB. After INH preventive therapy was instituted in those who had positive
TSTs, only a single case of active TB was diagnosed between 1993 and 2001.
TST can be useful in high prevalence areas to identify those at
greatest risk of developing active TB and most likely to benefit from TB
preventive therapy. However, TST is expensive, requires refrigeration and
uses needles. If not feasible for routine clinical use, TST can best be
used to estimate prevalence of infection in the population.
Slide 27
In Rio de Janeiro, Brazil, a study showed that among HIV-positive
patients who have good access to highly active antiretroviral therapy,
also called HAART, TB preventive therapy improves survival. In this cohort
of HIV-positive individuals, all patients had access to HAART, but those
who had positive TSTs and received TB preventive therapy had better
survival as indicated by the dotted line. This is because, as we shall
see, HAART can reduce the risk of TB substantially but HIV-positive
patients are still at high risk of developing active TB.
Slide 28
In developing countries where HIV and TB are both epidemic, an
important question is whether continuous TB preventive therapy is needed
for latently infected persons because of concerns about re-exposure. This
graph describes a study conducted in Zambia where patients with HIV and
positive TSTs were treated with INH for 6 months, rifampin and
pyrazinamide for 3 months, or a placebo given for 6 months. During the six
months of treatment and in the year after treatment there was a
significant decrease in TB incidence, but after that, rates of TB again
became very high and were similar whether or not treatment had been given.
This suggests that the benefit to preventive therapy may be short-lived in
these populations. A study from Uganda had slightly conflicting results.
Further study is ongoing to determine the possible benefits and risks of
continuing INH.
Slide 29
Another approach to TB control in populations with high HIV prevalence
is to improve control of HIV. Education and promotion of behavior change
have been successful in some settings and are widely used in high-risk
areas. Voluntary HIV counseling and testing has been shown to reduce high
risk behaviors in Africa. Sexually transmitted infections or STIs are
known to increase the risk of HIV transmission and therefore, appropriate
STI management may reduce HIV transmission. Finally, treating HIV with
antiretroviral drugs can reduce HIV disease consequences, as well as
transmission.
Slide 30
In Brazil, HIV-related TB has declined substantially at the major HIV
and TB treatment center in Rio de Janeiro where the number of HIV-related
TB cases declined from approximately 160 to 40 cases per year with the
introduction of HAART. The proportion of TB cases that were HIV-related
fell by almost 50%.
In Europe and the US, published studies have shown an 80-90% reduction
in the incidence of TB in patients receiving HAART when compared to
patients who do not receive HAART. In South Africa, the incidence of TB is
reduced by about 85% with HAART, although patients who get HAART still
have a 10-fold increased risk of TB compared with HIV-negative patients.
Slide 31
A combined HIV and TB control approach that is currently being
attempted is called the Protest initiative. This includes community-based
voluntary HIV counseling and testing to promote identification of people
with HIV, changing risk behaviors in HIV-positive and negative individuals
and helping get people with HIV into care. Care includes TB preventive
therapy with 6 months of INH for all HIV-positive individuals and
cotrimoxazole treatment for individuals with advanced HIV, based on
symptoms, CD4 cell count or total lymphocyte count. Routine laboratory
monitoring for toxicity is not needed for those who receive INH, unless
they have underlying liver disease.
There are now five pilot Protest projects in South Africa. As program
capacity grows and antiretroviral therapy becomes available, it will also
be part of the package of care.
The Protest initiative was first piloted 10 years ago in Haiti. Almost
11,000 people were tested for HIV and 15% were HIV-positive. Six percent
of HIV-positive individuals had active TB and 70% were TST positive.
This program proved that this combined approach can have a significant
impact on TB control in terms of active case finding, as well as
identification of latently infected individuals who are eligible for
preventive therapy.
Slide 32
To prevent spread of infection, patients with active TB should be
placed in a room with good ventilation to lower the concentration of
infectious particles in the air. Ideally, the room should receive direct
sunlight if possible since the ultraviolet rays in sunlight quickly kill
the tubercule bacilli. The patient should wear a mask over their mouth and
nose until noninfectious; however, the wearing of mouth and nose
protection only by family members, healthcare workers and other potential
contacts is not effective. Patients should be instructed to cover their
mouth when coughing and to use sputum containers with lids.
Fortunately, once effective therapy is initiated, patients become
noninfectious very quickly, within several days.
Slide 33
In summary, controlling HIV-related TB requires new approaches in
addition to traditional TB control strategies. These include:
- expansion of DOTS
- increase in active case finding, including evaluation and treatment
of contacts of cases who have active disease and latent infection
- identification of individuals who are HIV-positive and latently
infected with TB with provision of preventive therapy - increase in HIV
counseling and testing
- creation of the clinical infrastructure necessary to deliver
antiretroviral therapy and, ultimately,
- development of effective HIV and TB vaccines
