Human Immunodeficiency Virus-associated Tuberculosis Research Articles

Changes in the epidemiology and clinical manifestations of human immunodeficiency virus-associated tuberculosis in Hong Kong.

Human immunodeficiency virus (HIV)-associated tuberculosis (TB) remains an important health challenge worldwide. Although TB prevalence has decreased in the general population, there is limited information regarding temporal trends in the incidence of HIV-associated TB in Hong Kong. There are also insufficient data regarding changes in clinical manifestation patterns among HIV-associated TB patients over time. This study aimed to describe temporal trends in the epidemiology and clinical manifestations of HIV-associated TB in Hong Kong. We retrospectively reviewed data regarding HIV-associated TB patients that were reported to the TB-HIV Registry of the Department of Health during the period 2007 to 2020. Trends of TB as a primary acquired immunodeficiency syndrome (AIDS)-defining illness, as well as changes in demographic features and clinical manifestations of HIV-associated TB during this period were examined using Cochran-Armitage trend test. A decreasing trend was observed in the proportion of all reported cases of AIDS in which TB was a primary AIDS-defining illness during the study period. The proportions of female patients and patients with extrapulmonary involvement significantly increased, whereas the proportions of ever-smokers and patients with sputum smear positivity significantly decreased during the same period. A decreasing trend was observed in the proportion of patients with pulmonary TB in which the lower zone was the predominant site of lung parenchymal lesions. Among patients with a diagnosis of HIV infection before TB, an increasing trend was observed in the proportion of patients receiving antiretroviral therapy. Important temporal changes were observed in the epidemiology and clinical manifestations of HIV-associated TB. These results highlight the need for continued surveillance regarding the patterns of demographic features and clinical manifestations to inform policymakers when planning control strategies for HIV-associated TB.

Advances in Antiretroviral Therapy for Patients with Human Immunodeficiency Virus-Associated Tuberculosis.

Tuberculosis is one of the most common opportunistic infections and a prominent cause of death in patients with human immunodeficiency virus (HIV) infection, in spite of near-universal access to antiretroviral therapy (ART) and tuberculosis preventive therapy. For patients with active tuberculosis but not yet receiving ART, starting ART after anti-tuberculosis treatment can complicate clinical management due to drug toxicities, drug-drug interactions and immune reconstitution inflammatory syndrome (IRIS) events. The timing of ART initiation has a crucial impact on treatment outcomes, especially for patients with tuberculous meningitis. The principles of ART in patients with HIV-associated tuberculosis are specific and relatively complex in comparison to patients with other opportunistic infections or cancers. In this review, we summarize the current progress in the timing of ART initiation, ART regimens, drug-drug interactions between anti-tuberculosis and antiretroviral agents, and IRIS.

Risk Factors for Unfavorable Treatment Outcomes among the Human Immunodeficiency Virus-Associated Tuberculosis Population in Tashkent City, Uzbekistan: 2013–2017

Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection poses a growing clinical challenge. People living with HIV have a higher chance of developing TB, and once the disease has progressed, are at greater risk of having unfavorable TB treatment outcomes. Data on TB treatment outcomes among the HIV-associated TB population in Uzbekistan are limited. Thus, we conducted a cohort study among 808 adult patients with HIV-associated TB registered at the Tashkent TB referral hospital from 2013–2017 to document baseline characteristics and evaluate risk factors for unfavorable TB treatment outcomes. The data were collected from medical records and ambulatory cards. About 79.8% of the study population had favorable treatment outcomes. Antiretroviral therapy (ART) coverage at the admission was 26.9%. Information on CD4-cell counts and viral loads were largely missing. Having extrapulmonary TB (aOR 2.21, 95% CI: 1.38–3.53, p = 0.001), positive sputum smear laboratory results on admission (aOR 1.62, 95% CI: 1.07–2.40), diabetes (aOR 5.16, 95% CI: 1.77–14.98), and hepatitis C (aOR 1.68, 95% CI: 1.14–2.46) were independent risk factors for developing unfavorable TB treatment outcomes. The study findings provide evidence for targeted clinical management in co-infected patients with risk factors. Strengthening the integration of TB/HIV services may improve availability of key data to improve co-infection management.

Early antituberculosis drug exposure in hospitalized patients with human immunodeficiency virus-associated tuberculosis.

AimsPatients hospitalized at the time of human immunodeficiency virus‐associated tuberculosis (HIV‐TB) diagnosis have high early mortality. We hypothesized that compared to outpatients, there would be lower anti‐TB drug exposure in hospitalized HIV‐TB patients, and amongst hospitalized patients exposure would be lower in patients who die or have high lactate (a sepsis marker).MethodsWe performed pharmacokinetic sampling in hospitalized HIV‐TB patients and outpatients. Plasma rifampicin, isoniazid and pyrazinamide concentrations were measured in samples collected predose and at 1, 2.5, 4, 6 and 8 hours on the third day of standard anti‐TB therapy. Twelve‐week mortality was ascertained for inpatients. Noncompartmental pharmacokinetic analysis was performed.ResultsPharmacokinetic data were collected in 59 hospitalized HIV‐TB patients and 48 outpatients. Inpatient 12‐week mortality was 11/59 (19%). Rifampicin, isoniazid and pyrazinamide exposure was similar between hospitalized and outpatients (maximum concentration [Cmax]: 7.4 vs 8.3 μg mL–1, P = .223; 3.6 vs 3.5 μg mL–1, P = .569; 50.1 vs 46.8 μg mL–1, P = .081; area under the concentration–time curve from 0 to 8 hours: 41.0 vs 43.8 mg h L–1, P = 0.290; 13.5 vs 12.4 mg h L–1, P = .630; 316.5 vs 292.2 mg h L–1, P = .164, respectively) and not lower in inpatients who died. Rifampicin and isoniazid Cmax were below recommended ranges in 61% and 39% of inpatients and 44% and 35% of outpatients. Rifampicin exposure was higher in patients with lactate >2.2 mmol L–1.ConclusionMortality in hospitalized HIV‐TB patients was high. Early anti‐TB drug exposure was similar to outpatients and not lower in inpatients who died. Rifampicin and isoniazid Cmax were suboptimal in 61% and 39% of inpatients and rifampicin exposure was higher in patients with high lactate. Treatment strategies need to be optimized to improve survival.

Human immunodeficiency virus-associated tuberculosis care in Botswana: evidence from a real-world setting

BackgroundTuberculosis (TB) is among the world’s top public health challenges and the leading killer of people with HIV, yet is a treatable disease. This study aimed to assess, in a real-world setting, the implementation of antiretroviral therapy (ART) and Cotrimoxazole preventive therapy (CPT) policy, specific interventions proven to benefit patients in HIV-associated TB care.MethodsThis retrospective cohort study was conducted in Botswana in the Serowe/Palapye district, a largely urban district with a high burden of HIV-associated TB with a high case fatality, at Segkoma and Palapye hospitals and their feeder clinics. Between 1 January 2013 and 31 December 2013, confirmed HIV-positive patients aged ≥15 years with a confirmed TB diagnosis and medical record available were included in the analysis. The Kaplan-Meier method was used to compare time to death for the group of patients on ART and the group of patients not on ART during TB treatment. Cox proportional hazard regression was undertaken to identify predictors of mortality.ResultsOf the 300 patients included in the study, 217 (72%) were ART experienced at TB diagnosis. Of these, 86 (40%) had TB within 3 months following ART initiation. Of the 83 (28%) patients who were ART-naïve at TB diagnosis, 40 (48%) were commenced on ART during TB treatment, with 24 (60%) patients commencing within 4 weeks following TB treatment initiation. The overall ART uptake was 84%, while cotrimoxazole preventive therapy uptake was 100%. There were 45 deaths (15%), ART-experienced patients during TB treatment accounted for 30 deaths (30/257; 14%), while those who were not ART-experienced during TB treatment accounted for 15 deaths (15/43; 35%). There was a significant difference in survival time between patients with no ART use during TB treatment and those with ART use during TB treatment (log rank p < 0.001). Patients with no ART use during TB treatment were more likely to die within the first 2 months.ConclusionThe implementation of CPT policy is a substantial success. Strengthening the implementation of ART policy could improve survival among HIV-associated TB patients.

Managing Human Immunodeficiency Virus-associated Tuberculosis in the Dolutegravir Era.

Managing Human Immunodeficiency Virus-associated Tuberculosis in the Dolutegravir Era.

Predictors of mortality in adults on treatment for human immunodeficiency virus-associated tuberculosis in Botswana: A retrospective cohort study.

Mortality in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly in sub-Saharan Africa. This study aimed to compare mortality and predictors of mortality in those who were antiretroviral therapy (ART) naïve to those with prior ART exposure.This retrospective cohort study was conducted in Serowe/Palapye District, Botswana, a predominantly urban district with a large burden of HIV-associated TB with a high case fatality. Between January 1, 2013 and December 31, 2013, patients confirmed with HIV-associated TB were enrolled and followed up. Kaplan–Meier and Cox proportional hazard modeling was undertaken to identify predictors of mortality, with ART initiation included as time-updated variable.Among the 300 patients enrolled in the study, 131 had started ART before TB diagnosis (44%). There were 45 deaths. There was no difference in mortality between ART-naïve patients and those with prior ART exposure. In the multivariate analysis, no ART use during TB treatment (hazard ratio [HR] = 5.6, 95% confidence interval [CI] = 2.9–11; P < .001), opportunistic infections other than TB (HR = 8.5, 95% CI = 4–18.4; P = .013), age ≥60 years (HR = 4.8, 95% CI = 1.8–13; P = .002), hemoglobin <10 g/dL (HR = 2.4, 95% CI = 1.3–4.5) and hepatotoxicity (HR = 5, 95% CI = 1.6–17; P = .007) were associated with increased mortality. In the subgroup analysis, among ART-naïve patients, no ART use during TB treatment (HR = 8.1, 95% CI = 3.4–19.4; P < .001), opportunistic infections other than TB (HR = 16, 95% CI = 6.2–42; P < .001), and hepatotoxicity (HR = 8.3, 95% CI = 2.6–27; P < .001) were associated with mortality. Among patients with prior ART exposure, opportunistic infections other than TB (HR = 6, 95% CI = 2.6–27; P < .001) were associated with mortality.Mortality in patients with HIV-associated TB is still high. To reduce mortality, close clinical monitoring of patients together with initiation of ART during TB treatment is indicated.

Effectiveness of early initiation of antiretroviral therapy in adults with HIV associated tuberculosis in Lesotho in 2012

Background:Lesotho has a huge burden of human immunodeficiency virus associated tuberculosis (HIV-TB). In this study we compared the effectiveness of early versus late commencement of antiretroviral therapy (ART) in adults living with HIV-TB in Lesotho.Methods: Three out of 17 hospitals were randomly selected and data extracted from the hospitals’ tuberculosis (TB) treatment registers for 247 adults living with HIV-TB who completed TB therapy during the first quarter of 2012.Results: Eighty (32%) commenced ART early (4 weeks), 100 (41%) were started late (≥4 weeks) and 67 (27%) received no ART. Both early and late ART initiators were more likely to have a successful TB outcome (Adjusted Odds Ratio (AOR) 10.1, 95% CI: 3.7 - 27.5 and AOR 8.4, 95% CI: 3.4 - 20.6, respectively) relative to the group who had no ART (p 0.001).Conclusions: Effective treatment exists for managing HIV-TB simultaneously. The guidelines for initiation of ART in adult HIV-TB in Lesotho have not been fully implemented, but those who commenced ART had significant clinical benefits. Health departments must address the challenges encountered in treating HIV-TB simultaneously to ensure those co-infected receive optimal care.

Effectiveness of early initiation of antiretroviral therapy in adults with HIV associated tuberculosis in Lesotho in 2012

Background: Lesotho has a huge burden of human immunodeficiency virus associated tuberculosis (HIV-TB). In this study we compared the effectiveness of early versus late commencement of antiretroviral therapy (ART) in adults living with HIV-TB in Lesotho.Methods: Three out of 17 hospitals were randomly selected and data extracted from the hospitals’ tuberculosis (TB) treatment registers for 247 adults living with HIV-TB who completed TB therapy during the first quarter of 2012.Results: Eighty (32%) commenced ART early (<4 weeks), 100 (41%) were started late (≥4 weeks) and 67 (27%) received no ART. Both early and late ART initiators were more likely to have a successful TB outcome (Adjusted Odds Ratio (AOR) 10.1, 95% CI: 3.7 - 27.5 and AOR 8.4, 95% CI: 3.4 - 20.6, respectively) relative to the group who had no ART (p < 0.001).Conclusions: Effective treatment exists for managing HIV-TB simultaneously. The guidelines for initiation of ART in adult HIV-TB in Lesotho have not been fully implemented, but those w...

The ethics of a clinical trial when the protocol clashes with international guidelines.

Due to their nature and complexity, clinical trials often take some time to launch after the protocol has been designed and ethics approval obtained. During this time, there may be changes in international treatment guidelines and recommendations that result in a conflict between study protocol and recommended international best practice. Here, we describe the situation that arose in a pharmacokinetic study on the use of two different doses of rifabutin in patients with human immunodeficiency virus-associated tuberculosis who initiated antiretroviral therapy (ART) with a lopinavir-ritonavir-based regimen in South Africa and Viet Nam. The study protocol specified that ART should be started 10 weeks after the start of anti-tuberculosis treatment. The study in South Africa was approved in June 2008, went ahead as scheduled and was completed in August 2010. The study in Viet Nam was approved in October 2008 and was started in June 2010. A few weeks later, the World Health Organization released their 2010 guidelines for adult ART; one of its strong recommendations (with moderate quality of evidence) was that ART should be started 2-8 weeks after the start of anti-tuberculosis treatment. Emerging scientific evidence also supported this recommendation. The investigators felt that the Viet Nam study protocol was in conflict with recommended international best practice, and the trial was stopped in October 2010. An amended study protocol in which ART was started at 2 weeks was developed and implemented. The ethics issues around this decision and the need to change the study protocol are discussed in this article.

Community-based multi-disease prevention campaigns for controlling human immunodeficiency virus-associated tuberculosis [Perspectives

Human immunodeficiency virus (HIV) infection increases the risk of tuberculosis (TB) 21-34 fold, and has fuelled the resurgence of TB in sub-Saharan Africa. The World Health Organization (WHO) recommends the Three I's for HIV/TB (infection control, intensified case finding [ICF] and isoniazid preventive therapy) and earlier initiation of antiretroviral therapy for preventing TB in persons with HIV. Current service delivery frameworks do not identify people early enough to maximally harness the preventive benefits of these interventions. Community-based campaigns were essential components of global efforts to control major public health threats such as polio, measles, guinea worm disease and smallpox. They were also successful in helping to control TB in resource-rich settings. There have been recent community-based efforts to identify persons who have TB and/or HIV. Multi-disease community-based frameworks have been rare. Based on findings from a WHO meta-analysis and a Cochrane review, integrating ICF into the recent multi-disease prevention campaign in Kenya may have had implications in controlling TB. Community-based multi-disease prevention campaigns represent a potentially powerful strategy to deliver prevention interventions, identify people with HIV and/or TB, and link those eligible to care and treatment.

New vaccines for the prevention of tuberculosis.

Mycobacterium bovis, bacille Calmette-Guérin (BCG) is administered widely to newborns throughout the world and has been shown to be effective in preventing childhood tuberculosis but not reactivation pulmonary disease or human immunodeficiency virus-associated tuberculosis. Development of a more effective, better standardized, affordable vaccine with durable activity and fewer side effects is a major priority. Contemporary molecular techniques have identified promising immunodominant antigens and novel immunization strategies. Vaccine development has also been informed by an improved understanding of the role of nontuberculous mycobacteria in the efficacy of BCG and in the prevention of tuberculosis. Vaccines under investigation include attenuated or enhanced whole-cell live, whole-cell inactivated, subunit, DNA, and prime-boost vaccines. Several candidate vaccines have demonstrated activity in animal models that is equal to or superior to that of BCG, and human trials are under way. Because there is no identified surrogate marker for protection, identification of an improved vaccine will require long-term efficacy trials in humans.

Tuberculosis control policies in major metropolitan health departments in the United States. VI. Standard of practice in 1996.

Since 1980, we have surveyed at 4-yr intervals the metropolitan health departments initially reporting > 250 cases of tuberculosis to determine the perceived standard of practice for tuberculosis control and the factors affecting formulation of treatment policies. Between 1992 and 1996, use of supervised short-course (6 to 9 mo) intermittent therapy with multiple drugs including isoniazid, ethambutol, pyrazinamide, and rifampin increased from 4.3% to 46% of all new patients. Pyrazinamide use for initial treatment for children has increased substantially and now predominates (74.2% of patients in 1996 versus 48.1% of patients in 1992). Duration of treatment, which was 20 +/- 2.1 mo in 1980, is now 8.00 +/- 2.29 mo in 1996. The incidence of human immunodeficiency virus-associated tuberculosis, which was virtually unrecognized in 1984, has remained the same between 1992 and 1996 (18.0%). As in previous years, there was a wide variance among health departments in the incidence (< 5% to > 40%) of HIV-associated tuberculosis. After years of funding decreases, there has been an impressive increase in resources in the past 4 yr. In 1988, mean budget allocation for health departments decreased by 7.9% versus the prior 4 yr and, in 1992, there was no overall change in budget allocation after inflation versus 1988. In 1996, however, funds for treatment increased by 84 +/- 33%. This increase in funding has been translated into the greatly expanded use of supervised intermittent therapy and aggressive screening programs, which likely have resulted in the decreased incidence of tuberculosis since the prior survey.

No increased prevalence of adrenocortical insufficiency in human immunodeficiency virus-associated tuberculosis

Setting: Acute medical wards, Kenyatta National Hospital, Nairobi, Kenya. Objective: To determine the prevalence of adrenocortical insufficiency in human immunodeficiency virus (HIV)-1 infected and non-infected patients with tuberculosis. Design: One hundred and seventy-four patients with proven tuberculosis (90 HIV-1 positive and 84 HIV-1 negative) were assessed for adrenocortical insufficiency with a 30 min synacthen stimulation test. Results: Fifty-one percent of those with pulmonary tuberculosis and 56% of those with extra-pulmonary tuberculosis had a subnormal cortisol response. However there was no statistically significant difference between the HIV-1 infected and non-infected patients in either group. Conclusion: While an impaired cortisol response is common in tuberculosis, it is no more prevalent in HIV-1 infected patients than non-infected patients with tuberculosis.

Cytokines and tuberculosis.

The evolution of Mycobacterium tuberculosis as an intracellular pathogen has led to a complex relationship between it and its host, the human mononuclear phagocyte. The products of M. tuberculosis-specific T lymphocytes are essential for macrophage activation for intracellular mycobacterial killing. However, some cytokines, including products of both lymphocytes and phagocytic cells, may contribute to enhanced mycobacterial survival and replication. In human immunodeficiency virus-associated tuberculosis, cytokine products may mediate enhanced susceptibility to tuberculosis as well as accelerated progression to AIDS. Better understanding of these interactions will allow the development of increasingly specific immune-based interventions for prevention and treatment of tuberculosis.