Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01252537 |
| Other study ID # |
LU 2010/14 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
September 8, 2010 |
| Last updated |
April 21, 2014 |
| Start date |
September 2010 |
| Est. completion date |
January 2014 |
Study information
| Verified date |
April 2014 |
| Source |
Lund University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Ethiopia: Ethical Review CommitteeSweden: Institutional Review Board |
| Study type |
Observational
|
Clinical Trial Summary
Background: Tuberculosis (TB) and HIV are leading causes of disease and death in Subsaharan
Africa. Antiretroviral therapy (ART) dramatically improves prognosis in HIV infection, but
TB is still a common complication in HIV-infected subjects. Management of TB-HIV
co-infection is complex, both with regard to diagnosis and treatment. Since scaling-up of
ART requires management of most patients in primary health care, it is critical to achieve
better strategies for TB-HIV co-infection at peripheral levels of the health care system in
endemic regions. This includes development of new methods to assess the severity of HIV
disease and the need to start ART during TB treatment in this population.
Aims: To compare a scoring system for clinical signs of immunosuppression with CD4 cell
counts to assess HIV disease severity and indications for ART initiation, and to correlate
immunosuppression status with treatment outcome.
Workplan: CD4 cell levels and results of clinical scoring has been compared in 1100 patients
with TB, using HIV-negative subjects with TB treatment for control. Inclusion was closed in
February 2012, and follow-up of participants completed in August 2012. Plasma levels of
immune activation and inflammatory markers will be correlated with the degree of
immunosuppression.
Significance: TB is the most significant clinical challenge to the successful scaling-up of
ART in Africa. In order to improve management in primary health care it is necessary to find
robust and reliable techniques for determining disease severity and identification of
patients who need to start ART during TB treatment. This study may contribute to increased
knowledge in this field and help to modify guidelines for management of TB-HIV co-infection
in Ethiopia as well as in other resource-limited settings.
Description:
Tuberculosis (TB) remains as the leading opportunistic infection and cause of death among
HIV-infected subjects in resource-limited settings (1). The management of TB-HIV
co-infection constitutes a great challenge for health care systems. Often, HIV infection is
first detected when patients are diagnosed with active TB, and many such patients have
advanced immunosuppression (2, 3). However, TB can also occur in individuals with relatively
well preserved CD4 cell counts, especially in areas with high TB endemicity (4). In settings
where both TB and HIV infection are common, a high proportion of patients are in need both
of anti-TB treatment (ATT) and antiretroviral therapy (ART) at diagnosis. Combined ART and
ATT is associated with risks of drug-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 (5-7).
Although the optimal timing for when to start ART in patients receiving ATT is not
completely understood, CD4 cell count thresholds are currently often used to guide
clinicians on when to start ART in co-infected patients (8). Briefly, initiation of ART
during ATT is indicated for patients with CD4 counts lower than 350 cells/mm3, whereas it is
usually recommended to defer ART for patients without other clinical signs of
immunodeficiency and CD4 cell counts higher than 350 cells/mm3. In a recently published WHO
document, initiation of ART is proposed for all patients with active TB, but timing of ART
remains uncertain, as well as the need for ART in subjects with CD4 cell counts exceeding
350 cells/mm3 (9). Studies aiming at defining optimal time points for ART initiation in
patients receiving ATT are ongoing, and might lead to revised recommendations with regard to
co-administration of these therapies.
The number of HIV-infected subjects initiating ART has increased impressively over recent
years, especially in Subsaharan Africa. Still, it is estimated that less than half of all
patients in need of ART currently receive such treatment (10). In order to improve access,
it is necessary to decentralize treatment and integrate ART into the primary health care
system. In such settings, CD4 cell count analysis is rarely available, and patients are
usually managed by health care workers with limited knowledge and experience of HIV-TB
co-infection. Finding simple alternative tools to identify immunosuppressed patients in
these circumstances could therefore lead to significant improvements in care.
The investigators hypothesize that a structured scoring system based on clinical symptoms
and signs could be used to assess the degree of immunosuppression in HIV-infected patients
with TB, and thus help to categorize patients to determine when ART should be initiated in
settings with limited access to laboratory resources. The principal aim of the project is to
investigate how clinical scoring correlates with CD4 cell levels and specific CD4 cell
cut-off points that are used to identify patients who fulfil criteria for starting ART
during ATT (specifically for thresholds of 200, 350 and 500 cells/mm3), and to compare these
results with scoring in TB patients without HIV co-infection. The study will also evaluate
whether scoring results can predict short term mortality and treatment outcome. In addition,
the investigators aim to investigate a panel of alternative immunological surrogate markers
that could be used to measure HIV-related immunosuppression in patients co-infected with TB.
Work plan Methods: Patients diagnosed with active tuberculosis in health care facilities in
the Oromia region, Ethiopia are eligible for inclusion. The study has been performed in the
district hospital of Bishofto and in 4 health centres providing integrated care for TB and
HIV (Adama, Welenchity, Mojo and Dukam health centres). Approximately 1 112 patients have
been included. In these regions, approximately 40% of patients newly diagnosed with TB are
HIV seropositive.
Inclusion criteria are: age over 18 years, written informed consent to participate, consent
to HIV testing, residence in the catchment area of the study site, no previous treatment
with ART (except for treatment for prevention of mother-to-child transmission), and
diagnosis of active TB (either pulmonary or extrapulmonary according to current national
Ethiopian guidelines based on WHO definitions). Patients having received ATT within the
preceding 6 months and those who have received ATT for more than two weeks for their current
episode of TB have not been included.
The scoring system contains 15 items, including reported symptoms (history of dysphagia,
fever or diarrhoea of >1 month's duration) and clinical findings (anaemia, low body mass
index and mid-upper arm circumference, oral candidiasis, oral hairy leukoplakia, gingivitis,
dermatitis, Kaposi's sarcoma, herpes zoster scar).
Scoring has been performed at the time of initiation of ATT (irrespective of HIV status) by
either a trained nurse or a health officer. HIV testing has been done at the same time
according to local routine. Blood for CD4 cell counts and immunological markers have been
obtained from all consenting participants, irrespective of HIV status (in total, 10 ml of
blood). During follow-up, scoring has been repeated by study staff. CD4 cell counts as well
as haemoglobin measurements for validation of clinical evaluation of anaemia in the score
has been determined using local laboratory equipment already in place at the study sites.
Plasma for further analyses of immune activation markers is stored at -80 ° C.
Clinicians in charge of the patients determine when ART should be started following existing
national criteria (based on CD4 cell counts and WHO clinical staging). The result of the
scoring under investigation has thus not been used for determining the time point for
starting ART in this study.
Follow up: On initiation of ATT and at HIV diagnosis, patients have been evaluated according
to the clinical score. Treatment outcome according to the WHO (cure, treatment completion,
default, death, treatment failure) will be assessed for all patients. Defaulters will be
traced to ascertain rates of mortality.
All patients have been longitudinally followed up with repeated clinical scoring and CD4
count after two months of TB treatment and at the end of TB treatment, with recording of
mortality, new AIDS-defining conditions, paradoxical reactions occurring during ATT, and
start of ART.
Data analysis: Results of the scoring system has been correlated with CD4 cell counts.
Specifically, scoring results are compared with recommended CD4 cell thresholds for when ART
should be started in relation to ATT, in order to investigate whether scoring cut-offs may
be defined to identify patients correctly. Results of scoring in HIV-negative TB patients
have been used to assess how specific total results and different included items are for
HIV-related immunosuppression among co-infected individuals.
In addition, results of the scoring system will be compared to the clinician's decision with
regard to the patient's indication for starting ART or not. All data will be managed under
code for study purposes. Immune activation markers (neopterin and C-reactive protein) have
been analyzed after completion of patient inclusion in reference laboratories in Ethiopia.
For statistical evaluation, logistic and linear regression analysis of each separate item in
the scoring system will initially be performed to determine its relative importance,
existence of interactions with other variables and to define relevant cut-offs for
continuous variables. Different models of weighing separate scoring items will be evaluated
to assess positive and negative predictive values for the respective outcomes.
For comparison of inflammatory markers in the general population living in the geographical
study area, demographic data, CD4 cell counts and plasma samples for storage has been
obtained from 400 healthy adults at Mojo health centre. These persons have been recruited
from a voluntary counselling and testing service, with negative HIV test result and no
clinical signs of active TB. Persons in this comparison group have provided written consent
to participation.
Preliminary results and public health significance 1112 TB patients have been included in
this study (307 co-infected with HIV). Inclusion of new participants was terminated in
February 2012, with continued follow-up until the end of August 2012. Analysis of baseline
data for the primary outcome has been completed and the resulting scoring system has been
published in 2014. Testing of baseline samples for inflammatory markers (neopterin and
C-reactive protein) was completed in November 2012.
No similar system has been studied. It is of critical importance to improve the management
of patients co-infected with TB and HIV in resource-limited countries, especially in
settings with access to ART. Initiating ART during ATT is challenging under existing
conditions in Subsaharan Africa, where the majority of these patients are diagnosed and
treated. If the clinical scoring system can provide a reasonably reliable substitute for CD4
cell counts to estimate the degree of immunosuppression in co-infected patients, and can be
used to define cut-off points for optimal time points for initiation of ART, it could become
a robust and simple tool to be used at peripheral levels of health care systems. This would
help to identify and monitor immunosuppressed patients who need to start ART in parallel to
ATT, and could lead to improved treatment outcomes and decreased mortality.
Ethical approval from the review boards of Lund University, the Oromia Regional Health
Bureau and the National Research Ethics Review Committee of Ethiopia has been received.
References
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antiretroviral treatment programmes in sub-Saharan Africa. AIDS 2008; 22: 1897-908
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lymphocyte counts in HIV-infected persons with tuberculosis in Abidjan, Côte d'Ivoire.
Lancet 1995; 345: 607-10
3. Morris L, Martin DJ, Bredell H, et al. Human immunodeficiency virus-1 RNA levels and
CD4 lymphocyte counts, during treatment for active tuberculosis, in South African
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8. Tuberculosis care with TB-HIV co-management. WHO manual, 2007; WHO/htm/HIV/2007-01
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