Articles tagged as "Avoid TB deaths"

`Real men’ do not need healthcare: men and treatment seeking in Malawi

Control, struggle, and emergent masculinities: a qualitative study of men's care-seeking determinants for chronic cough and tuberculosis symptoms in Blantyre, Malawi.

Chikovore J, Hart G, Kumwenda M, Chipungu GA, Desmond N, Corbett L.BMC Public Health. 2014 Oct 9;14:1053. doi: 10.1186/1471-2458-14-1053.

Background: Men's healthcare-seeking delay results in higher mortality while on HIV or tuberculosis (TB) treatment, and implies contribution to ongoing community-level TB transmission before initiating treatment. We investigated masculinity's role in healthcare-seeking delay for men with TB-suggestive symptoms, with a view to developing potential interventions for men.

Methods: Data were collected during March 2011 - March 2012 in three high-density suburbs in urban Blantyre. Ten focus group discussions were carried out of which eight (mixed sex = two; female only = three; male only = three) were with 74 ordinary community members, and two (both mixed sex) were with 20 health workers. Individual interviews were done with 20 TB patients (female =14) and 20 un-investigated chronic coughers (female = eight), and a three-day workshop was held with 27 health stakeholder representatives.

Results: An expectation to provide for and lead their families, and to control various aspects of their lives while facing limited employment opportunities and small incomes leaves men feeling inadequate, devoid of control, and anxious about being marginalised as men. Men were fearful about being looked at as less than men, and about their wives engaging in extramarital sex without ability to detect or monitor them. Control was a key defining feature of adequate manhood, and efforts to achieve it also led men into side-lining their health. Articulate and consistent concepts of men's bodily strength or appropriate illness responses were absent from the accounts.

Conclusions: Facilitating men to seek care early is an urgent public health imperative, given the contexts of high HIV/AIDS prevalence but increasingly available treatment, and the role of care-seeking delay in TB transmission. Men's struggles trying to achieve ideal images seem to influence their engagement with their health. Ambiguous views regarding some key masculinity representations and the embrace of less harmful masculinities raise questions about some common assumptions that guide work with men. Apparent 'emergent masculinities' might be a useful platform from which to support the transformation of harmful masculinity. Finally, the complex manifestations of masculinity indicate the need for interventions targeting men in health and TB control to assume supportive, multidimensional and long-term outlooks.

Abstract  Full-text [free] access

Editor’s notes: The differences between men and women’s willingness to seek healthcare have been described in many different settings. This paper sets out the detailed results from a cross-sectional qualitative study looking at men’s care seeking practices for tuberculosis/chronic cough in Malawi. As well as describing perceptions of how a man should behave in society, and what this means for managing health, the authors examine how masculinity influences ill-health responses. Some men delay treatment seeking, because it is not manly to give in to symptoms. Men should publicly show an ability to put up with poor health or employ alcohol or exercise to chase away sickness. While the focus of this paper is on treatment seeking for tuberculosis, the authors draw parallels with the emerging literature on masculinity and HIV-treatment access. Making treatment available will not be enough; efforts have to be made to develop programmes to support and sustain men on treatment.

Avoid TB deaths
Africa
Malawi
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Prednisolone does not reduce poor outcomes in TB pericarditis

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F, Pogue J, Thabane L, Smieja M, Francis V, Joldersma L, Thomas KM, Thomas B, Awotedu AA, Magula NP, Naidoo DP, Damasceno A, Chitsa Banda A, Brown B, Manga P, Kirenga B, Mondo C, Mntla P, Tsitsi JM, Peters F, Essop MR, Russell JB, Hakim J, Matenga J, Barasa AF, Sani MU, Olunuga T, Ogah O, Ansa V, Aje A, Danbauchi S, Ojji D, Yusuf S; IMPI Trial Investigators. N Engl J Med. 2014 Sep 18;371(12):1121-30. doi: 10.1056/NEJMoa1407380. Epub 2014 Sep 1.

Background: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis.

Methods: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

Results: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer.

Conclusions: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

Abstract  Full-text [free] access

Editor’s notes: Tuberculous pericarditis remains an important and serious complication of HIV disease. Previous studies have suggested that treatment with steroids, in addition to standard TB treatment, reduces the risk of serious complications such as constrictive pericarditis. However, previous studies have been small, and have included few HIV-positive people.

This randomised controlled trial across eight countries in Africa tested two treatments for people with either definite or probable TB pericarditis. These included high dose steroid treatment, and injections of Mycobacterium indicus pranii. Mycobacterium indicus pranii is an environmental mycobacterium suggested to have a possible effect to reduce inflammation among people with TB. Two-thirds of the 1400 study participants were HIV-positive, most of whom were not taking antiretroviral therapy at the time of enrolment. The median CD4 count at enrolment was around 150 cells/µl. The primary outcome of the study was a composite of death, cardiac tamponade requiring drainage, and constrictive pericarditis. 

The death rate overall was high at 18%, and the main causes of death were considered to be pericarditis, TB, and HIV disease. Immunotherapy with Mycobacterium indicus pranii had no beneficial effects on any outcome. There was no overall difference in the composite primary outcome among people receiving prednisolone compared to placebo. However, people receiving prednisolone were less likely to develop constrictive pericarditis or to be hospitalised. There were more cancers (primarily Kaposi’s sarcoma among HIV-positive people) in people receiving either prednisolone or Mycobacterium indicus pranii, although the absolute rate was low. This is in keeping with previous observations.

Limitations of the study include that most people did not have microbiological confirmation of their TB diagnosis, so could potentially have had other causes of pericarditis for which prednisolone would not be expected to improve outcomes.

The results of this trial suggest that guidelines concerning use of prednisolone for TB pericarditis should be reviewed, particularly for people living with HIV. The poor outcomes among this group of people with TB and advanced HIV disease highlight the need for earlier HIV diagnosis, initiation of antiretroviral therapy, and TB preventive therapy.

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
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Mefloquine not suitable as intermittent preventive treatment of malaria, in pregnant women living with HIV

Intermittent preventive treatment of malaria in pregnancy with mefloquine in HIV-infected women receiving cotrimoxazole prophylaxis: a multicenter randomized placebo-controlled trial.

Gonzalez R, Desai M, Macete E, Ouma P, Kakolwa MA, Abdulla S, Aponte JJ, Bulo H, Kabanywanyi AM, Katana A, Maculuve S, Mayor A, Nhacolo A, Otieno K, Pahlavan G, Ruperez M, Sevene E, Slutsker L, Vala A, Williamsom J, Menendez C. PLoS Med. 2014 Sep 23;11(9):e1001735. doi: 10.1371/journal.pmed.1001735. eCollection 2014.

Background: Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs).

Methods and findings: A total of 1071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p = 0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p = 0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p = 0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p = 0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p = 0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis.

Conclusions: An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs.

Abstract  Full-text [free] access

Editor’s notes: The gold standard for intermittent preventive treatment of malaria in pregnancy (IPTp) is at least three doses of sulfadoxine-pyrimethamine, along with the use of insecticide-treated nets. In resource-limited, high HIV prevalent areas, all HIV-positive pregnant women are recommended to take co-trimoxazole prophylaxis. This rules out the concomitant use of sulfadoxine-pyrimethamine because of the increased risk of drug toxicity. However, the effectiveness of co-trimoxazole alone to prevent malaria in pregnant women living with HIV has not been established.   

This article reports a randomised double-blind placebo-controlled trial. The trial compares the efficacy of three-monthly doses of mefloquine (a long-acting efficacious antimalarial, considered to be safe throughout pregnancy) with placebo, in pregnant women living with HIV taking daily co-trimoxazole. Women in the mefloquine arm had a reduced risk of maternal malarial parasitaemia, a reduced rate of placental malaria and reduced incidence of non-obstetric hospital admissions. However, mefloquine was poorly tolerated. Unexpectedly, women in the mefloquine arm had a higher HIV viral load at delivery and were more likely to transmit HIV to their child. Since this finding was based on an exploratory, rather than a pre-planned analysis, its validity is uncertain. If other data support this finding, a better understanding of the underlying mechanism (biological/immunological) will be important to inform future alternative drug regimens for pregnant women living with HIV. 

This trial suggests that an effective antimalarial drug combined with co-trimoxazole can offer additional protection against malaria in pregnant women living with HIV, but mefloquine is not the drug of choice for this purpose. 

Avoid TB deaths
Africa
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Causes of death among people with tuberculosis and low CD4 counts

Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial.

Marcy O, Laureillard D, Madec Y, Chan S, Mayaud C, Borand L, Prak N, Kim C, Lak KK, Hak C, Dim B, Sok T, Delfraissy JF, Goldfeld AE, Blanc FX, CAMELIA (ANRS 1295-CIPRA KH001) Study Team.  Clin Infect Dis. 2014 Aug;59(3):435-45. doi: 10.1093/cid/ciu283. Epub 2014 Apr 23.

Background:  Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival.

Methods: We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count ≤200 cells/µL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial.

Results: Six hundred sixty-one patients enrolled contributed to 1 366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4-10.7) in the early-ART group and 13.8 deaths per 100 person-years (95% CI, 11.2-16.9) in the late-ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis.

Conclusions: Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies.

Abstract access 

Editor’s notes: Tuberculosis (TB) remains the most important cause of death among HIV-positive people worldwide, despite increasing access to antiretroviral therapy. There is a strong emphasis on reducing TB mortality as part of the post-2015 global TB strategy. This makes it even more important to define causes of death, so that appropriate programmes can be introduced.

This analysis in Cambodia, reports causes of death among HIV-positive people with sputum smear-positive TB, and CD4 counts below 200. The participants took part in a trial of antiretroviral therapy started early, i.e. two weeks after start of TB treatment, versus late, eight weeks after TB treatment start. Causes of death were assigned by site investigators and validated by review of medical records by investigators who had not been involved in the patient’s care. Tuberculosis was the most frequently assigned cause of death (42 of 149 deaths). HIV-associated conditions accounted for 28 deaths of which diarrhoea, non-tuberculous mycobacterial disease and immune reconstitution syndrome were the most frequent. For 23 deaths, TB and HIV-associated conditions were considered equally likely. This highlights the difficulty in distinguishing between these two causes of death among people with advanced HIV-related immunosuppression. Limited autopsies based on multiple biopsies are far more acceptable to families than traditional full autopsy, and could be used to identify causes of death with greater accuracy. Further it was notable that cotrimoxazole prophylaxis was associated with a lower risk of death after 50 weeks of follow-up, underlining the importance of this programme.  

Avoid TB deaths
Comorbidity
Asia
Cambodia
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Model estimates large global burden of childhood tuberculosis infection and potentially preventable future tuberculosis disease

Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study.

Dodd PJ, Gardiner E, Coghlan R, Seddon JA. Lancet Glob Health. 2014 Aug;2(8):e453-9. doi: 10.1016/S2214-109X(14)70245-1. Epub 2014 Jul 8.

Background: Confirmation of a diagnosis of tuberculosis in children (aged <15 years) is challenging; under-reporting can result even when children do present to health services. Direct incidence estimates are unavailable, and WHO estimates build on paediatric notifications, with adjustment for incomplete surveillance by the same factor as adult notifications. We aimed to estimate the incidence of infection and disease in children, the prevalence of infection, and household exposure in the 22 countries with a high burden of the disease.

Methods: Within a mechanistic mathematical model, we combined estimates of adult tuberculosis prevalence in 2010, with aspects of the natural history of paediatric tuberculosis. In a household model, we estimated household exposure and infection. We accounted for the effects of age, BCG vaccination, and HIV infection. Additionally, we tested sensitivity to key structural assumptions by repeating all analyses without variation in BCG efficacy by latitude.

Findings: The median number of children estimated to be sharing a household with an individual with infectious tuberculosis in 2010 was 15 319 701 (IQR 13 766 297-17 061 821). In 2010, the median number of Mycobacterium tuberculosis infections in children was 7 591 759 (5 800 053-9 969 780), and 650 977 children (424 871-983 118) developed disease. Cumulative exposure meant that the median number of children with latent infection in 2010 was 53 234 854 (41 111 669-68 959 804). The model suggests that 35% (23-54) of paediatric cases of tuberculosis in the 15 countries reporting notifications by age in 2010 were detected. India is predicted to account for 27% (22-33) of the total burden of paediatric tuberculosis in the 22 countries. The predicted proportion of tuberculosis burden in children for each country correlated with incidence, varying between 4% and 21%.

Interpretation: Our model has shown that the incidence of paediatric tuberculosis is higher than the number of notifications, particularly in young children. Estimates of current household exposure and cumulative infection suggest an enormous opportunity for preventive treatment.

Abstract  Full-text [free] access 

Editor’s notes: Estimating the burden of childhood tuberculosis has been largely neglected until recently. Children with tuberculosis rarely transmit and therefore from a control perspective, childhood tuberculosis does not notably contribute to the continuation of the tuberculosis epidemic. This modelling paper attempts to estimate the global burden of childhood tuberculosis infection and disease. Incidence estimates are made by using adult tuberculosis prevalence data to tackle the known limitations of using paediatric notification data. A second model estimates the prevalence of infection in children and household exposure, ignoring exposure outside of the household.  As with all mathematical model predictions, precision of estimates are dependent on the data used as inputs in the model. Despite these limitations, the paper draws attention to the fact that the burden of childhood tuberculosis infection and disease is significant and reflects failure of tuberculosis control in the 22 high-burden countries. The paper also highlights the fact that household contact tracing and preventive therapy in tuberculosis-exposed children could substantially reduce future tuberculosis-related morbidity.

Avoid TB deaths
Comorbidity, Epidemiology
Africa, Asia, Latin America
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Water filters reduce diarrhoea among people with HIV

Water filter provision and home-based filter reinforcement reduce diarrhea in Kenyan HIV-infected adults and their household members.

Pavlinac PB, Naulikha JM, Chaba L, Kimani N, Sangare LR, Yuhas K, Singa BO, John-Stewart G, Walson JL. Am J Trop Med Hyg. 2014 Aug 6;91(2):273-80. doi: 10.4269/ajtmh.13-0552. Epub 2014 May 19.

Among human immunodeficiency virus (HIV)-infected adults and children in Africa, diarrheal disease remains a major cause of morbidity and mortality. We evaluated the effectiveness of provision and home-based reinforcement of a point-of-use water filtration device to reduce diarrhea among 361 HIV-infected adults in western Kenya by comparing prevalence of self-reported diarrhea before and after these interventions. After provision of the filter, 8.7% of participants reported diarrhea compared with 17.2% in the 3 months before filter provision (odds ratio [OR] = 0.39, 95% confidence interval [95% CI] = 0.23-0.66, P < 0.001). The association was similar among 231 participants who were already taking daily cotrimoxazole prophylaxis before being given a filter (OR = 0.47, 95% CI = 0.25-0.88, P = 0.019). Educational reinforcement was also associated with a modest reduction in self-reported diarrhea (OR = 0.50, 95% CI = 0.20-0.99, P = 0.047). Provision and reinforcement of water filters may confer significant benefit in reducing diarrhea among HIV-infected persons, even when cotrimoxazole prophylaxis is already being used.

Abstract access 

Editor’s notes: Diarrhoeal disease remains an important cause of morbidity among HIV-positive people. This analysis was part of a larger study of HIV-positive adults who were not taking antiretroviral therapy. The frequency of diarrhoea, measured by self-report, was compared before and after participants were given a water filtration device. After receiving the device, fewer people reported diarrhoea, with an odds ratio of 0.39. The beneficial effect was similar among people who were already taking cotrimoxazole prophylaxis. The benefits of water filtration or chlorination have been shown in previous studies, but this is a useful reminder of the value of clean water programmes in reducing diarrhoeal disease.  

Avoid TB deaths
Comorbidity
Africa
Kenya
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Point of care urine tests predict mortality among hospitalised HIV-positive adults

Point-of-care lateral flow assays for tuberculosis and cryptococcal antigenuria predict death in HIV infected adults in Uganda.

Manabe YC, Nonyane BA, Nakiyingi L, Mbabazi O, Lubega G, Shah M, Moulton LH, Joloba M, Ellner J, Dorman SE. PLoS One. 2014 Jul 7;9(7):e101459. doi: 10.1371/journal.pone.0101459. eCollection 2014.

Background: Mortality in hospitalized, febrile patients in Sub-Saharan Africa is high due to HIV-infected, severely immunosuppressed patients with opportunistic co-infection, particularly disseminated tuberculosis (TB) and cryptococcal disease. We sought to determine if a positive lateral flow assay (LFA) result for urine lipoarabinomannan (LAM) and cryptococcal antigenuria was associated with mortality.

Methods: 351 hospitalized, HIV-positive adults with symptoms consistent with TB and who were able to provide both urine and sputum specimens were prospectively enrolled at Mulago National Referral Hospital in Uganda as part of a prospective accuracy evaluation of the lateral flow Determine TB LAM test. Stored frozen urine was retrospectively tested for cryptococcal antigen (CRAG) using the LFA. We fitted a multinomial logistic regression model to analyze factors associated with death within 2 months after initial presentation.

Results: The median CD4 of the participants was 57 (IQR: 14-179) cells/microl and 41% (145) were microbiologically confirmed TB cases. LAM LFA was positive in 38% (134), 7% (25) were CRAG positive, and 43% (151) were positive for either test in urine. Overall, 21% (75) died within the first 2 months, and a total of 32% (114) were confirmed dead by 6 months. At 2 months, 30% of LAM or CRAG positive patients were confirmed dead compared to 15.0% of those who were negative. In an adjusted model, LAM or CRAG positive results were associated with an increased risk of death (RRR 2.29, 95% CI: 1.29, 4.05; P = 0.005).

Conclusions: In hospitalized HIV-infected patients, LAM or CRAG LFA positivity was associated with subsequent death within 2 months. Further studies are warranted to examine the impact of POC diagnostic 'test and treat' approach on patient-centered outcomes.

Abstract  Full-text [free] access 

Editor’s notes: Despite increasing coverage of antiretroviral therapy, HIV-positive people continue to experience high mortality, particularly those sick enough to require hospital admission. Tuberculosis (TB) is well-known to be one of the most important causes of death among HIV-positive people in sub-Saharan Africa. Diagnosis of TB remains difficult, particularly in the sickest people who may have low concentrations of acid-fast bacilli in sputum, or may not be able to produce sputum at all. However, most people can give a sample of urine, and point of care tests using urine specimens have great potential to accelerate diagnosis of TB, and also cryptococcal disease.

In this study of hospitalised HIV-positive adults in Uganda, mortality was extremely high; 21% had died by two months and 32% by six months, even though some 38% of people were on antiretroviral therapy at enrollment. Urine was tested using point of care assays for LAM (a component of the mycobacterial cell wall) and cryptococcal antigen. People whose urine tested positive on either test were twice as likely to have died by two months. Further studies are needed to determine to what extent clinical outcomes can be improved by early testing using these assays, followed by treatment for TB or cryptococcal disease (or both).

Avoid TB deaths
Comorbidity
Africa
Uganda
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Improved delivery of isoniazid preventive therapy with integrated HIV and TB services

Interventions to improve delivery of isoniazid preventive therapy: an overview of systematic reviews

Adams LV, Talbot EA, Odato K, Blunt H, Steingart KR. BMC Infect Dis. 2014 May 21;14(1):281. doi: 10.1186/1471-2334-14-281.

Background: Uptake of isoniazid preventive therapy (IPT) to prevent tuberculosis has been poor, particularly in the highest risk populations. Interventions to improve IPT delivery could promote implementation. The large number of existing systematic reviews on treatment adherence has made drawing conclusions a challenge. To provide decision makers with the evidence they need, we performed an overview of systematic reviews to compare different organizational interventions to improve IPT delivery as measured by treatment completion among those at highest risk for the development of TB disease, namely child contacts or HIV-infected individuals.

Methods: We searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (DARE), and MEDLINE up to August 15, 2012. Two authors used a standardized data extraction form and the AMSTAR instrument to independently assess each review.

Results: Six reviews met inclusion criteria. Interventions included changes in the setting/site of IPT delivery, use of quality monitoring mechanisms (e.g., directly observed therapy), IPT delivery integration into other healthcare services, and use of lay health workers. Most reviews reported a combination of outcomes related to IPT adherence and treatment completion rate but without a baseline or comparison rate. Generally, we found limited evidence to demonstrate that the studied interventions improved treatment completion.

Conclusions: While most of the interventions were not shown to improve IPT completion, integration of tuberculosis and HIV services yielded high treatment completion rates in some settings. The lack of data from high burden TB settings limits applicability. Further research to assess different IPT delivery interventions, including those that address barriers to care in at-risk populations, is urgently needed to identify the most effective practices for IPT delivery and TB control in high TB burden settings.

Abstract  Full-text [free] access

Editor’s notes: Isoniazid preventive therapy (IPT) is a key component of the “3 Is” strategy to reduce tuberculosis among people living with HIV. Despite evidence of efficacy, initiation of IPT among eligible people in HIV care programmes has been disappointing. When IPT has been delivered as a stand-alone activity, treatment completion has often been poor. This overview of systematic reviews brings together evidence concerning organisational programmes to improve IPT delivery, using treatment completion as the main outcome. Three of the six included reviews, specifically included HIV-positive people.

When IPT delivery was integrated into other services, such as HIV care, good IPT completion rates were reported. A common weakness in the studies reviewed, was the lack of a suitable comparison group. This made it difficult to be sure that the good outcomes were due to the service integration. HIV This Month reported in June 2014 a trial from South Africa, showing that IPT reduces TB incidence among people taking antiretroviral therapy. Viewed together, these studies provide additional evidence supporting IPT delivery as part of the package of care for people in HIV care. More research is needed to guide implementers on how to deliver TB preventive therapy most effectively for people living with HIV.

Avoid TB deaths
Africa, Asia, Europe, Northern America
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Simple but effective management of raised intracranial pressure in cryptococcal meningitis

Cryptococcal meningitis management in Tanzania with strict schedule of serial lumbar punctures using intravenous tubing sets: an operational research study.

Meda J, Kalluvya S, Downs JA, Chofle AA, Seni J, Kidenya B, Fitzgerald DW, Peck RN. J Acquir Immune Defic Syndr. 2014 Jun 1;66(2):e31-6. doi: 10.1097/QAI.0000000000000147.

Background: Cryptococcal meningitis (CM) has a mortality rate of approximately 70% among HIV-infected adults in low-income countries. Controlling intracranial pressure (ICP) is essential in CM, but it is difficult in low-income countries because manometers and practical ICP management protocols are lacking.

Methods: As part of a continuous quality improvement project, our Tanzanian hospital initiated a new protocol for ICP management for CM. All adult inpatients with CM are included in a prospective patient registry. At the time of analysis, this registry included data from 2 years before the initiation of this new ICP management protocol and for a 9-month period after. ICP was measured at baseline and at days 3, 7, and 14 by both manometer and intravenous (IV) tubing set. All patients were given IV fluconazole according to Tanzanian treatment guidelines and were followed until 30 days after admission.

Results: Among adult inpatients with CM, 32 of 35 patients (91%) had elevated ICP on admission. Cerebrospinal fluid pressure measurements using the improvised IV tubing set demonstrated excellent agreement (r = 0.96) with manometer measurements. Compared with historical controls, the new ICP management protocol was associated with a significant reduction in 30-day mortality (16/35 [46%] vs. 48/64 [75%] in historical controls; hazard ratio = 2.1 [95% CI: 1.1 to 3.8]; P = 0.018].

Conclusions: Increased ICP is almost universal among HIV-infected adults admitted with CM in Tanzania. Intensive ICP management with a strict schedule of serial lumbar punctures reduced in-hospital mortality compared with historical controls. ICP measurement with IV tubing sets may be a good alternative in resource-limited health facilities where manometers are not available.

Abstract access 

Editor’s notes: Cryptococcal meningitis remains an important cause of morbidity and mortality among people with advanced HIV disease. Management is difficult in resource-limited settings. This is in part because optimal drug treatments are often not accessible, but also because of increased intracranial pressure, which may require repeated lumbar puncture. This should be done ideally using specialist equipment to measure intracranial pressure. This operational research study from United Republic of Tanzania illustrates the effectiveness of a standardised management protocol to manage intracranial pressure, using equipment which is widely available in resource-constrained settings. The simplified equipment produced pressure measurements which agreed well with measures from the “gold standard” manometer, and people managed according to this protocol experienced lower mortality than historical controls. However, mortality was still higher than would be expected in industrialised countries, illustrating the need for improved access to more effective antifungal drugs. 

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
United Republic of Tanzania
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Isoniazid prevents TB among people taking antiretroviral therapy

Isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial.  

Rangaka MX, Wilkinson RJ, Boulle A, Glynn JR, Fielding K, van Cutsem G, Wilkinson KA, Goliath R, Mathee S, Goemaere E, Maartens G. Lancet. 2014 May 13. pii: S0140-6736(14)60162-8. doi: 10.1016/S0140-6736(14)60162-8. [Epub ahead of print]

Background: Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy.

Methods: For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis.

Findings: 1 329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3 227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2.3 per 100 person-years, 95% CI 1.6-3.1), and 58 in the placebo group (3.6 per 100 person-years, 2.8-4.7; hazard ratio [HR] 0.63, 95% CI 0.41-0.94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1.9, 95% CI 0.90-4.09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0.43 [0.21-0.86] and 0.43 [0.20-0.96]; for positive tests 0.86 [0.37-2.00] and 0.55 [0.26-1.24], respectively).

Interpretation: Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status.

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Editor’s notes:  In the pre-antiretroviral therapy (ART) era, trials demonstrated that isoniazid prevented tuberculosis among people living with HIV. Antiretroviral therapy also reduces the risk of tuberculosis. Observational studies suggested that adding isoniazid to antiretroviral therapy would further reduce the risk of tuberculosis. This study from South Africa is the first randomised trial confirming, with a more robust study design, that isoniazid preventive therapy reduces the risk of tuberculosis among people taking ART. The main results of this trial are therefore not surprising. Less expected, however, are the findings of the trial among subgroups who had negative baseline tests for tuberculosis infection. The subgroups were measured both by tuberculin skin test (TST) and by interferon gamma release assay (IGRA). Previous studies have consistently shown little benefit from isoniazid preventive therapy among people with negative TST results. By contrast, in this trial isoniazid was no less effective among people with negative compared to positive results on either TST or IGRA. The reason for this is not clear, but the implication is that isoniazid preventive therapy should be offered to people taking ART in tuberculosis-prevalent settings who do not have active tuberculosis, regardless of TST or IGRA result.

Reassuringly, isoniazid was well tolerated among study participants who were also taking ART.

The protective effect of isoniazid waned over time after the end of the 12-month treatment period, consistent with other studies in settings where tuberculosis is prevalent. This supports prolonged use of isoniazid in people with HIV in such settings, and the need to evaluate shorter, potentially more curative regimens.

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
South Africa
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