Tuberculosis Clinical Trial
Official title:
Tuberculosis in HIV-infected Patients Managed in Health Centres in Ethiopia - Identification of a Screening Algorithm for Active Tuberculosis and Determination of Outcome of Combined Antituberculosis and Antiretroviral Treatment
Background: Increased access to antiretroviral therapy (ART) in Africa will require
decentralization to primary health care. For this purpose, adapted methods for management of
patients co-infected with tuberculosis (TB) and HIV are needed. Improved detection of TB in
patients starting ART, and assessment of co-administration of ART and TB treatment are
priorities in this field.
Aims: To identify clinical predictors of TB in patients starting ART, and to construct
screening algorithms for TB in this population; to assess ART outcomes in patients receiving
TB treatment at health centre level.
Work plan: The project is performed in health centres providing ART in Ethiopia. A cohort of
HIV positive patients initiating ART is prospectively followed. Baseline characteristics are
registered; blood samples for CD4 cells, HIV RNA and immunological markers are collected, as
well as sputum for TB culture and PCR. During ART, clinical data, CD4 cell counts and HIV
RNA levels are followed. Patients with TB are compared to those without TB with regard to
ART outcome. Baseline factors associated with TB will be used to construct TB screening
algorithms.
Recruitment of the cohort was completed in March 2013; follow-up for determination of long
term outcome of ART will be continued until 2016.
Significance: These studies give insight into TB-HIV co-infection at primary health care
level in a Sub-Saharan region, and may impact future guidelines for management of such
patients.
Background: Tuberculosis (TB) remains as the leading opportunistic infection and cause of
death among HIV-infected subjects in resource-limited settings (1). HIV infection is the
strongest risk factor known for developing active TB, and as a consequence, the HIV epidemic
in Sub-Saharan Africa has fuelled the incidence of TB (2). The interactions between HIV and
TB are great challenges for health care, both with regard to diagnosis and treatment. In
HIV-infected persons TB often has atypical manifestations, making correct and timely
diagnosis difficult (3, 4). Recognition of TB before starting antiretroviral therapy (ART)
is critical since a missed diagnosis of TB is associated with high early mortality after ART
initiation (1, 5). Screening for TB is recommended for HIV-positive subjects, but a method
with both satisfactory specificity and sensitivity that can be used in primary health care
settings in Africa has not yet been identified. New diagnostic techniques for TB have
recently been developed, such as the GenXpert PCR (6), but the optimal use of these
alternative methods needs to be investigated.
In settings where both TB and HIV infection are common, a high proportion of patients are in
need both of anti-tuberculosis treatment (ATT) and ART. Combined ART and ATT is associated
with risks of drug interactions, overlapping side effects, immune reconstitution disease and
poor adherence, but at least in patients with severe immunodeficiency, these risks are
outweighed by decreased mortality (7-9). Studies performed in developed countries have shown
that rates of virological suppression during ART in patients receiving concomitant ATT are
comparable to those in persons not taking ATT (10, 11), but this topic has not been
extensively investigated at primary health care level in Africa.
The number of HIV-infected subjects receiving ART in Sub-Saharan Africa has increased
dramatically during the last years. Still, it is estimated that less than half of all
patients in need of ART currently receive such treatment (12). In order to improve access,
it will become necessary to further decentralize ART and to integrate this treatment into
the primary health care system. Since many patients starting ART have unrecognized active TB
at this time point, it is important to find a practical and reliable screening algorithm for
TB among such individuals. Furthermore, the outcome of combined ATT and ART delivered in
health centres must be assessed, especially with regard to HIV RNA suppression and selection
of ART resistance.
This project aims to develop an algorithm with the potential to identify indicators of
prevalent and incident TB among patients initiating ART by correlating baseline clinical
signs and symptoms with results of culture- and PCR-based investigations for TB. Such
clinical characteristics will be compared both to TB present before starting ART, as well as
to TB presenting during the first year after ART initiation. Results from this comparison
will be used to construct an algorithm for TB screening in Ethiopian patients eligible for
ART. In addition, clinical, immunological and virological outcomes of ART in patients with
concomitant ATT will be compared to those in patients only receiving ART. Specific aims are
to study rates of virological suppression during ART, the development of antiretroviral drug
resistance, and treatment adherence.
Work plan: HIV-infected adult patients eligible to start ART will be recruited from HIV
clinics in several health centres providing integrated for HIV and TB in the Oromia region.
812 patients have been prospectively included into the cohort, and are under continued
follow-up.
At baseline, detailed demographic, socio-economic and clinical data (such as presence of
general and respiratory symptoms, body mass index, mid-upper arm circumference and various
findings on physical examination) has been collected, including information on current
medical and traditional therapies. Blood for CD4 cell count, complete blood count and HIV
RNA will be obtained. In addition, plasma, stool and urine sample for analysis of
immunological and inflammatory markers, and potential new biomarkers of active TB infection,
has been collected and stored at -80 and -20 ° C.
Participants have undergone sampling for microbiological investigations for TB before
starting ART. All patients have submitted two sputum samples for TB microscopy, culture and
PCR. From patients with peripheral lymphadenopathy, lymph node aspiration for
microbiological testing has been done. PCR has been performed using the GeneXpert technique.
The study protocol will include definitions of TB based on microbiological results and
clinical data according to WHO guidelines. Results of TB cultures are not awaited before ART
initiation. Patients in whom TB is diagnosed receive ATT as soon as the diagnosis is
established. For patients who have started ART at this time point, the recommendation will
be to continue ART; however, the responsible clinician may decide to interrupt ART if
medically indicated.
Follow up: Participants will be followed for 48 months (once monthly during the first 3
months, subsequently every 3 months for the first year of the study and then every 6
months). On follow-up visits, clinical and adherence data is collected. Incidence of death,
hospitalization, TB and other opportunistic infections, signs of immune reconstitution
inflammatory syndrome (IRIS), defaulting or treatment interruption is followed continuously,
with tracing of defaulters to ascertain rates of mortality. Blood for CD4 cell counts and
HIV RNA is obtained at 1 month after starting ART and at 3-monthly intervals for the first 6
months after study inclusion (and at 6-monthly intervals onwards). Samples obtained more
than 6 months after starting ART with detectable HIV RNA will be subjected to genotypic
testing to detect drug resistance mutations. In addition, blood samples for analysis of
immunological markers will be obtained after 1, 3, 6 and 12 months of ART. Urine samples
have been analyzed for the presence of lipoarabinomannane using a lateral flow assay.
Data analysis: Patient characteristics will be correlated with prevalent TB at baseline, to
identify indicators of TB. These results will be used to construct screening algorithms that
will be validated for sensitivity, specificity and predictive accuracy. Baseline predictors
for incident TB during ART will also be investigated. For assessment of ART outcome,
patients will be categorized according to their baseline TB status. Participants taking ATT
will be compared to controls only taking ART. Incidence and time to defined events will be
studied using survival curves (mortality, disease progression, HIV RNA suppression, loss to
follow-up). HIV RNA and CD4 cell levels during ART, treatment interruptions, adherence, new
opportunistic infections, drug side effects and TB IRIS will be compared between groups.
Predictors of death and ART failure will be assessed.
Significance: Improving the management of patients co-infected with TB and HIV in highly
endemic regions is critical for the success of continued scaling up of ART. Initiating ART
during ATT is challenging under existing conditions in Sub-Saharan Africa, where the
majority of these patients are diagnosed and treated. Case detection rates of TB remain
below estimates in Ethiopia. Active TB is frequently missed in patients eligible for ART, a
phenomenon likely to be important for mortality and medical complications following ART
initiation. A screening algorithm based on clinical data with adequate predictive accuracy
could help to identify TB in this population, and lead to improved treatment outcomes both
for TB and HIV infection. Increased detection and timely treatment of TB in HIV-infected
subjects would also reduce transmission in society. The outcome of combined ATT and ART
administered in health centres must be assessed, especially concerning the development of
drug resistance which can have serious consequences both for the infected individual and the
community. Results from this study could inform health authorities on the efficacy and
feasibility of such combined therapy, which is important for future HIV/TB policies in
Ethiopia and other Sub-Saharan countries.
The project has received ethical clearance from Lund University, Sweden, and from the
Institute of Science and Technology, Ethiopia.
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