OPERATIONAL RESEARCH QUESTION

How early to start antiretroviral therapy (i.e. at what CD4 count level) among HIV-
infected TB patients, to achieve maximum reduction in the risk of developing TB?

Without treatment, most HIV-infected individuals will eventually develop progressive
immunosuppression, as evident by CD4 T lymphocyte (CD4) cell depletion, leading to AIDS-defining
illnesses and premature death. The primary goal of ART is to prevent HIV-associated morbidity and
mortality. This goal is best accomplished by using effective ART to maximally inhibit HIV replication so
that plasma HIV RNA (viral load) remains below levels detectable by commercially available assays.
Durable viral suppression improves immune function and overall quality of life, lowers the risk of both
AIDS-defining and non-AIDS-defining complications, and prolongs life.

Furthermore, high plasma HIV RNA is a major risk factor for HIV transmission, and effective antiretroviral
therapy (ART) can reduce viremia and transmission of HIV to sexual partners by more than
96%.
2
Modelling studies suggest that expanded use of ART may result in lower incidence and,
eventually, prevalence of HIV on a community or population level. Thus, a secondary goal of ART is to
reduce the risk of HIV transmission.

Historically, HIV-infected individuals have had low CD4 counts at presentation to care. However, there
have been concerted efforts to increase testing of at-risk patients and to link these patients to medical
care before they have advanced HIV disease. Deferring ART until CD4 count declines put an individual at
risk of AIDS-defining conditions has been associated with higher risk of morbidity and mortality (as
discussed below). Furthermore, the magnitude of CD4 recovery is directly correlated with CD4 count at
ART initiation. Consequently, many individuals who start treatment with CD4 counts <350
cells/mm
3
never achieve counts >500 cells/mm
3
after up to 6 years on ART.
5


The recommendation to initiate ART in individuals with high CD4 cell countswhose short-term risk for
death and development of AIDS-defining illness is low is based on growing evidence that untreated
HIV infection or uncontrolled viremia is associated with development of non-AIDS-defining diseases,
including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and
malignancies. Furthermore, newer ART regimens are more effective, more convenient, and better
tolerated than regimens used in the past.

Regardless of CD4 count, the decision to initiate ART should always include consideration of a patients
comorbid conditions, his or her willingness and readiness to initiate therapy, and available resources. In
settings where there are insufficient resources to initiate ART in all patients, treatment should be
prioritized for patients with the following clinical conditions: pregnancy; CD4 count <200 cells/mm
3
or
history of an AIDS-defining illness including HIV-associated dementia, HIV-associated nephropathy
(HIVAN), or hepatitis B virus (HBV); and acute HIV infection.

Tempering the enthusiasm to treat all patients regardless of CD4 count is the absence of randomized
trial data that demonstrate a definitive clinical benefit of ART in patients with higher CD4 counts (e.g.,
>350 cells/ mm
3
) and mixed results from observational cohort studies as to the definitive benefits of
early ART (i.e., when CD4 count >500 cells/mm
3
). For some asymptomatic patients, the potential risks of
short- or long-term drug-related complications and non-adherence to long-term therapy may offset
possible benefits of earlier initiation of therapy. An ongoing randomized controlled trial evaluating the
role of immediate versus delayed ART in patients with CD4 counts >500 cells/mm
3
(see Strategic Timing
of Antiretroviral Treatment (START); ClinicalTrials.gov identifier NCT00867048) should help to further
define the role of ART in this patient population.
HIV infection significantly increases the risk of progression from latent to active TB disease. The CD4 cell
count influences both the frequency and severity of active TB disease [1-2]. Active TB also negatively
affects HIV disease. It may be associated with a higher HIV viral load and more rapid progression of HIV
disease [3].

Active pulmonary or extrapulmonary TB disease requires prompt initiation of TB treatment. The
treatment of active TB disease in HIV-infected patients should follow the general principles guiding
treatment for individuals without HIV (AI). Treatment of drug-susceptible TB disease should include a
standard regimen that consists of isoniazid (INH) + a rifamycin (rifampin or rifabutin) + pyrazinamide +
ethambutol given for 2 months, followed by INH + a rifamycin for 4 to 7 months [4]. The Guidelines for
Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and
Adolescents [4] include a more complete discussion of the diagnosis and treatment of TB disease in HIV-
infected patients.

All patients with HIV/TB disease should be treated with ART (AI). Important issues related to the use of
ART in patients with active TB disease include: (1) when to start ART, (2) significant pharmacokinetic
drug-drug interactions between rifamycins and some antiretroviral (ARV) agents, (3) the additive
toxicities associated with concomitant ARV and TB drug use, (4) the development of TB-associated IRIS
after ART initiation, and (5) the need for treatment support including DOT and the integration of HIV and
TB care and treatment.

2. What is the optimal timing and frequency of systematic TB screening among
people living with HIV?


3. What are the barriers to care for people living with HIV, adults, children and
families, to access HIV and TB care, and antiretroviral therapy for those co-
infected with TB, from patient and health-care workers perspective, and how to
address them?
Tuberculosis (TB) and HIV infection are very closely linked, and over a million persons with both
conditions are estimated to need simultaneous treatment for both diseases each year. People
living with HIV (PLHs) have an increased risk of becoming infected and developing TB. Although
TB is curable, it is a leading cause of ill health and death among PLHs. For this reason, early
diagnosis, timely initiation of treatment for both diseases and careful monitoring are essential
to treat TB in PLHs and identify HIV infection in people with TB. The main obstacles to managing
patients with TB and HIV co-infection are weak coordination between TB and HIV programmes
and slow integration of collaborative TB-HIV services into the general health services. These
challenges may have an adverse impact on patients treatment access and outcomes. The
escalating human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have a
significant impact on public health services in resource-limited settings four potential barriers
to treatment use by comparing the reported perceptions and experiences of HIV-positive adults
(age 18+) who have never taken a prescription medicine to treat their HIV (untreated
patients) to those who had begun taking a prescription medicine to treat their HIV in the past
five years (treated patients):
Limited disease-specific knowledge. Untreated patients are less knowledgeable about HIV and
its potential effects than treated patients.
Only 38 percent of untreated patients believe that HIV attacks the immune system and
body even if the person with HIV does not feel sick, compared to 63 percent of treated
patients.
Thirty-nine percent of untreated patients believe the human body has a natural ability
to fight HIV, compared to 16 percent of treated patients.
Limited treatment-specific knowledge. Untreated patients also have limited treatment-specific
knowledge and cite reasons for not using HIV prescription medicine that are inconsistent with
available data or current treatment guidelines.
Data show that HIV-positive patients who take HIV prescription medicine reduce their
risk of transmitting the virus to someone else by 96 percent , but only 25 percent of
untreated patients are aware being on a HIV prescription medicine reduces that risk
Despite its proven efficacy, only 28 percent of untreated patients believe that HIV
prescription medicine controls the negative effects of the disease
Misperceptions regarding treatment use. The reported perceptions of HIV prescription
medicine among untreated patients were somewhat negative and inconsistent with the
reported experiences of treated patients.
Nearly one-third (30 percent) of untreated patients believe that the side effects of HIV
prescription medicine are worse than HIV itself, but only 15 percent of treated patients
report this to be the case
Eighty percent of treated patients believe that their HIV prescription medicine makes
them feel better, and they can focus on the important things in their life, and 56 percent
say that it has had a positive impact on their overall health and well-being. However,
one in five (20 percent) of untreated patients dont currently take HIV prescription
medicine because they believe once they start, theyll need to be on it for the rest of
their lives
Fewer positive perceptions of overall well-being.
Untreated patients are less likely than treated patients to agree that their disease is
well-controlled (84 percent vs. 91 percent) and less likely to agree they will live a full life
despite their HIV (72 percent vs. 83 percent)
Initial review of these parallel programs revealed barriers to optimal care of both HIV-infected
and Mycobacterium tuberculosis infected patients. These barriers are discussed below.
Strict application of ART program guidelines
Requirement of a treatment buddy to accompany the patient to a doctors appointment.
Communications barriers among providers and between providers and patients
Counselors providing ART adherence training
HIV expertise at the inpatient medical service.
Limited patient preparation for TB treatment
TB diagnosis and adherence to TB program guidelines.
Failure of DOTS in the face of human-resource shortages.
Separation from traditional healers
Need for HIV and TB support services.