Articles tagged as "Health systems and services"

Changing norms: lessons from HIV advocacy for NCDs prevention

Ability of HIV advocacy to modify behavioral norms and treatment impact: a systematic review.

Sunguya BF, Munisamy M, Pongpanich S, Yasuoka J, Jimba M. Am J Public Health. 2016 Aug;106(8):e1-e8. Epub 2016 Jun 16.

Background: HIV advocacy programs are partly responsible for the global community's success in reducing the burden of HIV. The rising wave of the global burden of noncommunicable diseases (NCDs) has prompted the World Health Organization to espouse NCD advocacy efforts as a possible preventive strategy. HIV and NCDs share some similarities in their chronicity and risky behaviors, which are their associated etiology. Therefore, pooled evidence on the effectiveness of HIV advocacy programs and ideas shared could be replicated and applied during the conceptualization of NCD advocacy programs. Such evidence, however, has not been systematically reviewed to address the effectiveness of HIV advocacy programs, particularly programs that aimed at changing public behaviors deemed as risk factors.

Objectives: To determine the effectiveness of HIV advocacy programs and draw lessons from those that are effective to strengthen future noncommunicable disease advocacy programs.

Search methods: We searched for evidence regarding the effectiveness of HIV advocacy programs in medical databases: PubMed, The Cumulative Index to Nursing and Allied Health Literature Plus, Educational Resources and Information Center, and Web of Science, with articles dated from 1994 to 2014.

Search criteria. The review protocol was registered before this review. The inclusion criteria were studies on advocacy programs or interventions. We selected studies with the following designs: randomized controlled design studies, pre-post intervention studies, cohorts and other longitudinal studies, quasi-experimental design studies, and cross-sectional studies that reported changes in outcome variables of interest following advocacy programs. We constructed Boolean search terms and used them in PubMed as well as other databases, in line with a population, intervention, comparator, and outcome question. The flow of evidence search and reporting followed the standard Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Data collection and analysis: We selected 2 outcome variables (i.e., changing social norms and a change in impact) out of 6 key outcomes of advocacy interventions. We assessed the risk of bias for all selected studies by using the Cochrane risk-of-bias tool for randomized studies and using the Risk of Bias for Nonrandomized Observational Studies for observational studies. We did not grade the collective quality of evidence because of differences between the studies, with regard to methods, study designs, and context. Moreover, we could not carry out meta-analyses because of heterogeneity and the diverse study designs; thus, we used a narrative synthesis to report the findings.

Main results: A total of 25 studies were eligible, of the 1463 studies retrieved from selected databases. Twenty-two of the studies indicated a shift in social norms as a result of HIV advocacy programs, and 3 indicated a change in impact. We drew 6 lessons from these programs that may be useful for noncommunicable disease advocacy: (1) involving at-risk populations in advocacy programs, (2) working with laypersons and community members, (3) working with peer advocates and activists, (4) targeting specific age groups and asking support from celebrities, (5) targeting several, but specific, risk factors, and (6) using an evidence-based approach through formative research.

Author conclusions: HIV advocacy programs have been effective in shifting social norms and facilitating a change in impact.

Public health implications: The lessons learned from these effective programs could be used to improve the design and implementation of future noncommunicable disease advocacy programs.

Abstract access

Editor’s notes: This article presents the results of a systematic review to answer a question about the effectiveness of HIV advocacy in changing social norms and changing impact among key populations. The review was conducted to learn from effective HIV advocacy and apply similar strategies for the prevention and reduction of the global burden of non-communicable diseases. The review included quantitative research only. After searching 3320 articles, 25 articles met the inclusion criteria. The HIV advocacy activities reviewed ranged from local and mass campaigns using a variety of media, to social marketing, celebrities, drama, promotional activities and counselling. Changes in social norms were assessed using six specific variables, for example testing behaviour change or HIV-associated stigma. Changes in impact were analysed in two aspects, changes in HIV transmission and in adherence to antiretroviral therapy. The review has found significant evidence of the effect of HIV advocacy on the outcomes of interest. The authors highlight lessons from HIV advocacy that might be useful for future non-communicable diseases advocacy. These included the vital role of peer-educator and of lay members of the community and the involvement of key populations in programmes that focus on them.  In addition, there is a need to tailor programmes to specific (rather than multiple) risks using local and salient evidence. 

Africa, Northern America, Oceania
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Role for LAM test in TB diagnosis among the sickest people living with HIV

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in HIV-positive adults.

Shah M, Hanrahan C, Wang ZY, Dendukuri N, Lawn SD, Denkinger CM, Steingart KR. Cochrane Database Syst Rev. 2016 May 10;5:CD011420. doi: 10.1002/14651858.CD011420.pub2.

Background: Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease.

Objectives: To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis). To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening).

Search methods: We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861).

Selection criteria: Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older.

Data collection and analysis: Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert(R) MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert(R) MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert(R) MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert(R) MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB). LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses. The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution.

Authors' conclusions: We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

Abstract  Full-text [free] access

Editor’s notes: Tuberculosis (TB) remains a leading cause of death among people living with HIV. Diagnostic tests for TB are suboptimal, and a test for TB with adequate performance which could be used by nurses in primary care clinics would be a great advance. Lipoarabinomannam (LAM) is a component of mycobacterial cell wall which can be found in urine. A lateral flow assay to detect LAM in urine is commercially available at low cost, and can be used in primary care settings without the need for laboratory equipment. However the test is insensitive, such that it has no useful role among HIV-negative people, but has better sensitivity among people living with HIV, leading to questions concerning its role in TB diagnostic pathways.

This systematic review puts together data concerning the performance of the LAM lateral flow assay when used either as a screening test or for diagnosis of TB among people living with HIV. Assessment is made more complicated because the recommended reference cut-off for the test has been changed, with relatively few studies performed after the recommended cut off became what is referred to here as the “higher quality” reference standard (grade two test band intensity, rather than grade one as was previously recommended). Based on the grade two cut–off, the pooled estimate of sensitivity of the test was 45%. As expected, sensitivity was better for individuals with low CD4 counts.

This review informed WHO recommendations on the use of the LAM assay, suggesting that its use should be restricted to assisting with TB diagnosis in people living with HIV with low CD4 counts who are seriously ill. This is consistent with the results of the recent trial (PMID: 26970721) comparing management of hospitalised HIV-positive people reporting one or more TB symptoms with routine testing of urine for LAM compared to standard diagnostic tests, which found that the addition of LAM testing resulted in a small reduction in eight-week mortality.

Overall, LAM is inadequate as a single test for TB, and an accurate diagnostic test that could be used in-session for TB diagnosis in primary care clinics remains a pressing priority.

Comorbidity, HIV testing
Africa
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Antiretroviral choice may affect malaria outcomes in children

Antiretroviral choice for HIV impacts antimalarial exposure and treatment outcomes in Ugandan children.

Parikh S, Kajubi R, Huang L, Ssebuliba J, Kiconco S, Gao Q, Li F, Were M, Kakuru A, Achan J, Mwebaza N, Aweeka FT. Clin Infect Dis. 2016 May 3. pii: ciw291. [Epub ahead of print]

Background: The optimal treatment of malaria in HIV-infected children requires consideration of critical drug-drug interactions in co-infected children, as these may significantly impact drug exposure and clinical outcomes.

Methods: We conducted an intensive and sparse pharmacokinetic and pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on three different first-line antiretroviral therapies (ART) were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin (DHA) and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated.

Results: 145 and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared to no ART, efavirenz reduced exposure to all antimalarial components by 2.1 to 3.4-fold; lopinavir/ritonavir increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on efavirenz versus lopinavir/ritonavir-based ART, changes that were associated with an approximately 4-fold higher odds of recurrent malaria by day 28 in those on efavirenz versus lopinavir/ritonavir-based ART.

Conclusions: The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. Efavirenz-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on efavirenz, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure is warranted.

Abstract access

Editor’s notes: This study looks at the pharmacokinetic (PK) and clinical outcomes for artemether/lumefantrine therapy of falciparum malaria in Ugandan children aged 1-8 years living without HIV and with HIV on antiretroviral therapy (ART) regimes containing efavirenz, nevirapine or lopinavir. The stand-out result is that malaria outcomes were better in children who were taking lopinavir-based ART, without any significant drug adverse effects. 

The most commonly-used ART combinations have extensive interactions with other classes of drugs.  The effects of these interactions on clinical outcomes cannot always be accurately predicted from PK studies in healthy adults. This is especially so for sick children whose drug handling may be different. Large PK studies of unwell children are difficult to do, so this study is a rare gem. In fact the PK results are largely as expected. Exposure to artemether and its active metabolite are reduced by efavirenz and nevirapine; and exposure to lumefantrine is reduced by efavirenz and increased by lopinavir with ritonavir. Lumefantrine is the component of the combination malaria therapy with a longer effect and is intended to provide protection from recurrence.

The big question is, what is the impact of these PK differences on clinical outcomes? This is where it gets complicated. In total some 370 malaria episodes were studied. The authors illustrate that the efavirenz group had substantially higher malaria recurrence than the lopinavir group. The lopinavir group had the highest levels of lumefantrine. The efavirenz group had similar outcomes to the HIV-negative group, despite having lower levels of lumefantrine.

The recurrence rate in this study, in an area of intense malaria transmission, is dominated by early reinfection rather than recrudesence. The great majority of children taking ART were also taking co-trimoxazole, which provides protection against malaria infection, giving all children taking ART additional protection versus malaria compared to HIV-negative children. The difference between the efavirenz and lopinavir groups is likely to be due to lumefantrine levels. Higher levels of lumefantrine persist in combination with lopinavir / ritonavir – an effect that might also apply to other protease inhibitors. WHO guidelines recommend lopinavir/ritonavir as part of first-line ART for children under three years old. Whether this effect is large enough to influence ART choices in older children will depend on local circumstances, particularly the malaria transmission rate 

Africa
Uganda
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Near-patient TB test reduces hospital deaths in HIV-positive adults

Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. 

Peter JG, Zijenah LS, Chanda D, Clowes P, Lesosky M, Gina P, Mehta N, Calligaro G, Lombard CJ, Kadzirange G, Bandason T, Chansa A, Liusha N, Mangu C, Mtafya B, Msila H, Rachow A, Hoelscher M, Mwaba P, Theron G, Dheda K. Lancet. 2016 Mar 19;387(10024):1187-97. doi: 10.1016/S0140-6736(15)01092-2. Epub 2016 Mar 10.

Background: HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.

Methods: We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weight loss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730.

Findings: Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0.83 (95% CI 0.73-0.96), p=0.012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0.82 [95% CI 0.70-0.96], p=0.015). No adverse events were associated with LAM testing.

Interpretation: Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital in-patients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum.

Abstract access  

Editor’s notes: TB is a leading cause of hospitalization and in-hospital death among people living with HIV worldwide. This randomised controlled trial in southern Africa provides strong evidence of the impact of a simple, urine-based test in HIV-positive adults admitted to hospital with symptoms of TB. Use of the lateral flow lipoarabinomannan (LAM) test, in addition to a package of routine TB diagnostic tests, led to a modest reduction in all-cause mortality. This reduction in mortality occurred despite only a small increase in the proportion starting TB treatment, suggesting that LAM testing might have enabled more precision in the identification of people with TB.

Half of all deaths occurred in people with CD4 cell count ≤50 cells/µL and the impact of the urinary LAM test was greatest in this group, as suggested by previous studies. This may lead to strengthening of WHO policy recommendations to use the lateral flow LAM test to assist with TB diagnosis in people admitted to hospital with advanced HIV and with symptoms and signs of TB. There is still no strong evidence to suggest a role for LAM testing at more peripheral levels of the health system or in people who are not seriously ill.

The heterogeneity in effect between countries is notable, although the trial was not powered to detect mortality differences at each site. The availability and use of other diagnostics (which could include sputum smear microscopy, Xpert®, chest X-ray, ultrasound and computed tomography), and the level of physician input in clinical management, differed substantially across sites and could have modified the effect of LAM testing. Additional exploration of data from this trial and from other ongoing studies should help to further define the role of urine LAM in the TB diagnostic bundle in different health care settings.

Africa
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Empirical TB treatment no better than isoniazid among people with low CD4 counts and negative TB tests

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial. 

Hosseinipour MC, Bisson GP, Miyahara S, Sun X, Moses A, Riviere C, Kirui FK, Badal-Faesen S, Lagat D, Nyirenda M, Naidoo K, Hakim J, Mugyenyi P, Henostroza G, Leger PD, Lama JR, Mohapi L, Alave J, Mave V, Veloso VG, Pillay S, Kumarasamy N, Bao J, Hogg E, Jones L, Zolopa A, Kumwenda J, Gupta A, Adult ACTGAST. Lancet. 2016 Mar 19;387(10024):1198-209. doi: 10.1016/S0140-6736(16)00546-8.

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert® MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2.5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5-7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4-7.8); absolute risk difference of -0.06% (95% CI -3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Abstract access

Editor’s notes: Tuberculosis (TB) remains the leading cause of death among HIV-positive people worldwide. Existing diagnostic tests for TB lack sensitivity, particularly among HIV-positive people, and autopsy studies consistently illustrate that TB is common at death, but often not identified prior to death. This has led to questions about whether empirical TB treatment, meaning treatment for TB in the absence of bacteriological confirmation, should be more widely used among HIV-positive people.

This trial compared empirical TB treatment to isoniazid preventive therapy among adult outpatients with very low CD4 counts starting antiretroviral therapy (ART). People could be enrolled in the study if they did not have confirmed or suspected TB based on symptoms, locally-accessible diagnostic tests (including chest radiography and sputum smear) and, when available, testing with Xpert® MTB/RIF. There was no difference in mortality at six months between participants given empirical TB treatment compared to isoniazid preventive therapy. Mortality was remarkably low overall, particularly considering that participants had very low CD4 counts. It seems likely that the enrolment criteria excluded people at highest risk of death from participating in the study.

Screening for TB at the time of starting ART could reduce mortality if the tests are sufficiently sensitive, and if people identified to have TB receive effective treatment. However, this study was not designed to address how best to do this in resource-limited settings, where chest radiography and Xpert® MTB/RIF are often not accessible. This study does suggest that isoniazid preventive therapy can be given at the time of ART initiation among people who have been effectively screened for TB. The results of other studies of empirical TB treatment, with different designs in different populations, are awaited. Data from all these studies together may provide evidence to guide the optimal package of care for people presenting with advanced HIV disease. 

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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High TB mortality among people living with HIV in eastern Europe: a growing concern

Tuberculosis-related mortality in people living with HIV in Europe and Latin America: an international cohort study. 

Podlekareva DN, Efsen AM, Schultze A, Post FA, Skrahina AM, Panteleev A, Furrer H, Miller RF, Losso MH, Toibaro J, Miro JM, Vassilenko A, Girardi E, Bruyand M, Obel N, Lundgren JD, Mocroft A, Kirk O, TB:HIV study group in EuroCoord. Lancet HIV. 2016 Mar;3(3):e120-31. doi: 10.1016/S2352-3018(15)00252-0. Epub 2016 Feb 2.

Background: Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study.

Methods: Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models.

Findings: Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0.0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0.0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0.23 (95% CI 0.16-0.31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3.17; 95% CI 1.83-5.49) as were those who did not have baseline drug-susceptibility tests (2.24; 1.31-3.83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0.0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0.0001).

Interpretation: Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe.

Abstract access

Editor’s notes: Eastern Europe is experiencing one of the fastest growing HIV epidemics globally. Within this, the number of HIV-positive people with tuberculosis (TB) is also rising rapidly, posing a significant public health challenge. The authors have previously reported retrospective data illustrating 30% mortality at one year among HIV-positive people with TB in eastern Europe. This was noted to be at least three times higher than mortality among people from western Europe and Argentina. Within this study they go further to provide prospective data with comparison across multiple regions. They also highlight prognostic markers associated with death.

The study spans across eastern Europe, western Europe and Latin America with a cohort of 1406 people. It robustly demonstrates a significant excess of TB-associated mortality in HIV-positive people with TB receiving care in eastern Europe. The cumulative probability of TB-associated death at 12 months in eastern Europe was 23% (95% confidence interval [CI] 20 – 26), versus 1% (95% CI 0 - 3) in western Europe and 4% (95% CI 2-8) in Latin America. Prognostic markers associated with an increased risk of death included multidrug-resistant TB, disseminated TB and modifiable factors such as choice of initial anti-TB regimen and a lack of baseline drug susceptibility tests.

These findings highlight the hugely detrimental impact of the fragmented system of HIV and TB services within eastern Europe. Such inequality in outcomes emphasises the need for urgent strategic change. Co-ordinated care across HIV and TB services, alongside timely and appropriate diagnostics and treatment, is of paramount importance.

Europe, Latin America
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ART reduces fertility differences by HIV status among women living in sub-Saharan Africa

Measuring the impact of antiretroviral therapy roll-out on population level fertility in three African countries. 

Marston M, Nakiyingi-Miiro J, Hosegood V, Lutalo T, Mtenga B, Zaba B, and on behalf of the ALPHA network. PLoS One. 2016 Mar 25;11(3):e0151877. doi: 10.1371/journal.pone.0151877. eCollection 2016.

Background: UNAIDS official estimates of national HIV prevalence are based on trends observed in antenatal clinic surveillance, after adjustment for the reduced fertility of HIV positive women. Uptake of ART may impact on the fertility of HIV positive women, implying a need to re-estimate the adjustment factors used in these calculations. We analyse the effect of antiretroviral therapy (ART) provision on population-level fertility in Southern and East Africa, comparing trends in HIV infected women against the secular trends observed in uninfected women.

Methods: We used fertility data from four community-based demographic and HIV surveillance sites: Kisesa (Tanzania), Masaka and Rakai (Uganda) and uMkhanyakude (South Africa). All births to women aged 15-44 years old were included in the analysis, classified by mother's age and HIV status at time of birth, and ART availability in the community. Calendar time period of data availability relative to ART introduction varied across the sites, from 5 years prior to ART roll-out, to 9 years after. Calendar time was classified according to ART availability, grouped into pre ART, ART introduction (available in at least one health facility serving study site) and ART available (available in all designated health facilities serving study site). We used Poisson regression to calculate age adjusted fertility rate ratios over time by HIV status, and investigated the interaction between ART period and HIV status to ascertain whether trends over time were different for HIV positive and negative women.

Results: Age-adjusted fertility rates declined significantly over time for HIV negative women in all four studies. However HIV positives either had no change in fertility (Masaka, Rakai) or experienced a significant increase over the same period (Kisesa, uMkhanyakude). HIV positive fertility was significantly lower than negative in both the pre ART period (age adjusted fertility rate ratio (FRR) range 0.51 95%CI 0.42-0.61 to 0.73 95%CI 0.64-0.83) and when ART was widely available (FRR range 0.57 95%CI 0.52-0.62 to 0.83 95%CI 0.78-0.87), but the difference has narrowed. The interaction terms describing the difference in trends between HIV positives and negatives are generally significant.

Conclusions: Differences in fertility between HIV positive and HIV negative women are narrowing over time as ART becomes more widely available in these communities. Routine adjustment of ANC data for estimating national HIV prevalence will need to allow for the impact of treatment.

Abstract  Full-text [free] access 

Editor’s notes: Antenatal care (ANC) clinics records on demographic characteristics and HIV status of attenders are a major component of primary data used to estimate HIV prevalence in sub-Saharan Africa. Prior to scale-up of antiretroviral therapy (ART), the fertility of women living with HIV was lower than that for people without HIV. This means that prevalence estimates from ANC data were adjusted to avoid underestimating the true population fertility rates.

This paper analyses the changing fertility patterns in four longitudinal community-based cohorts in eastern and southern Africa. The study finds that differences in fertility rates between women living with HIV and women without HIV are narrowing as ART is scaled-up, although substantial differences still exist. There was considerable variation in the patterns between the sites reflecting the differing local epidemic profiles. The authors explain this variation as being due to various factors including biological (increased fertility associated with viral suppression), or behavioural (increased fertility among women experiencing widowhood and then forming new partnerships). The impact of treatment on fertility needs to be incorporated into models of HIV prevalence estimated from ANC data, to inform national policy makers measuring their progress towards HIV elimination targets.

Africa
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Shorter treatment for latent TB infection?

Three months of weekly rifapentine plus isoniazid for treatment of M. tuberculosis infection in HIV co-infected persons. 

Sterling TR, Scott NA, Miro JM, Calvet G, La Rosa A, Infante R, Chen MP, Benator DA, Gordin F, Benson CA, Chaisson RE, Villarino ME, Tuberculosis Trials Consortium, the AIDS Clinical Trials Group for the PREVENT TB Trial (TBTC Study 26 ACTG 5259). AIDS. 2016 Mar 17. [Epub ahead of print]

Objective: Compare the effectiveness, tolerability, and safety of three months of weekly rifapentine plus isoniazid under direct observation (3HP) vs. 9 months of daily isoniazid (9H) in HIV-infected persons.

Design: prospective, randomized, open-label non-inferiority trial.

Setting: U.S., Brazil, Spain, Peru, Canada, and Hong Kong.

Participants: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.

Intervention: 3HP vs. 9H.

Main outcome measures: The effectiveness endpoint was tuberculosis; the non-inferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation due to adverse drug reaction.

Results: Median baseline CD4+ counts were 495 (IQR: 389-675) and 538 (IQR: 418-729) cells/mm3 in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention to treat analysis, there were two tuberculosis cases among 206 persons (517 person-years (p-y) of follow-up) in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01% vs. 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval (CI) of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation due to an adverse drug reaction was similar (3% vs. 4%; P = 0.79) in 3HP and 9H, respectively.

Conclusions: Among HIV-infected persons with median CD4+ count of approximately 500 cells/mm3, 3HP was as effective and safe for treatment of latent M. tuberculosis infection as 9H, and better tolerated.

Abstract access 

Editor’s notes: People with HIV are at higher risk of reactivation of latent tuberculosis (TB). The standard treatment for latent TB, with six to nine months of daily isoniazid, is effective, but treatment completion rates are typically low, and implementation has been poor. Shorter, effective regimens to treat latent TB are therefore necessary, and rifapentine and isoniazid, given weekly for 12 weeks, is one such candidate regimen. The analysis reported in this paper is a sub-study of a larger trial which was reported in 2011 (Sterling et al, NEJM 2011;365:2155). The main trial was open to people regardless of HIV status, but few HIV-positive people were enrolled. Trial enrolment was therefore continued for HIV-positive people, and this paper reports outcomes among this group.

Although the number of tuberculosis events was very small in this sub-study (two versus six people developed tuberculosis in the rifapentine-isoniazid versus isoniazid only arms), the rifapentine-isoniazid regimen, given directly-observed, was non-inferior to self-administered isoniazid, similar to the results of the main trial. Treatment completion was substantially better with the rifapentine-isoniazid regimen, as expected for a shorter regimen given under direct observation. The rifapentine-isoniazid regimen was equally well-tolerated to the isoniazid-only regimen.

This study provides evidence that rifapentine-isoniazid has potential as an alternative to isoniazid for the treatment of latent tuberculosis among HIV-positive people. Several questions remain. Weekly directly-observed therapy could be difficult to implement in resource-limited settings, especially if people are required to travel to health centres to receive their weekly dose, and the effectiveness of this regimen is uncertain when self-administered. The weekly dose represents a substantial pill burden unless combination tablets are available, and there are potential drug interactions between rifapentine and some antiretroviral agents. Further research is necessary to establish whether, in settings where the risk of tuberculosis reinfection is high, a single 12-week course of rifapentine-isoniazid has a long-lasting effect.

Comorbidity, HIV Treatment
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Routine use of steroids harmful in cryptococcal meningitis

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.

Beardsley J, Wolbers M, Kibengo FM, Ggayi AB, Kamali A, Cuc NT, Binh TQ, Chau NV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN, CryptoDex Investigations. N Engl J Med. 2016 Feb 11;374(6):542-54. doi: 10.1056/NEJMoa1509024.

Background: Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600 000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis.

Methods: In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole.

Results: The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.

Conclusions: Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo.

Abstract  Full-text [free] access 

Editor’s notes: Outcomes from cryptococcal meningitis in people living with HIV are very poor. This was highlighted here. Three out of five people overall had died or were severely disabled ten weeks after enrolment. This clinical trial provides strong evidence that steroids cause more harm than good and therefore routine use should not be recommended. Dexamethasone was not only associated with higher risk of death or disability but also with higher risk of significant adverse events, particularly bacterial sepsis.

The majority of deaths occurred early, in the first three weeks. Most participants were ART naïve and severely immunosuppressed (CD4+ cell count <50 cells/µL) and most deaths look to have occurred prior to the scheduled start of antiretroviral therapy. This may also partly explain the low frequency of immune reconstitution inflammatory syndrome (IRIS) and the lack of any observed benefit of dexamethasone in reducing IRIS.

Although dexamethasone was associated with greater decline in intracranial pressure, this did not translate into improved neurological outcomes. All participants had regular lumbar punctures for pressure monitoring. This might have limited the potential to observe a benefit from dexamethasone. Some explanation for the adverse outcomes might come from the impaired fungal clearance in cerebrospinal fluid – a marker of poor outcomes in previous studies. It should be noted that antifungal treatment in this trial was suboptimal. The combination of amphotericin and flucytosine was not used, despite evidence of improved outcomes and more rapid fungal clearance with this regimen.

While the search should go on for better treatment strategies, the findings in this study emphasise the importance of prevention, focused firmly, on earlier HIV diagnosis and treatment.  

Comorbidity, HIV Treatment
Indonesia, Laos, Malawi, Thailand, Uganda, Viet Nam
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Novel specimens feasible and sensitive for Xpert® MTB/RIF diagnosis in children

Performance of Xpert® MTB/RIF and alternative specimen collection methods for the diagnosis of tuberculosis in HIV-infected children.

Marcy O, Ung V, Goyet S, Borand L, Msellati P, Tejiokem M, Nguyen Thi NL, Nacro B, Cheng S, Eyangoh S, Pham TH, Ouedraogo AS, Tarantola A, Godreuil S, Blanche S, Delacourt C, PAANTHER study group. Clin Infect Dis. 2016 Feb 7. pii: ciw036. [Epub ahead of print]

Methods: HIV-infected children aged 13 years with suspected intrathoracic tuberculosis were enrolled in 8 hospitals in Burkina Faso, Cambodia, Cameroon, and Vietnam. Gastric aspirates were taken for children aged <10 years and expectorated sputum samples were taken for children aged 10 years (standard samples); nasopharyngeal aspirate and stool were taken for all children, and a string test was performed if the child was aged 4 years (alternative samples). All samples were tested with Xpert®. The diagnostic accuracy of Xpert® for culture-confirmed tuberculosis was analyzed in intention-to-diagnose and per-protocol approaches.

Results: Of 281 children enrolled, 272 (96.8%) had ≥1 specimen tested with Xpert® (intention-to-diagnose population), and 179 (63.5%) had all samples tested with Xpert® (per-protocol population). Tuberculosis was culture-confirmed in 29/272 (10.7%) children. Intention-to-diagnose sensitivities of Xpert® performed on all, standard, and alternative samples were 79.3% (95% confidence interval [CI], 60.3-92.0), 72.4% (95% CI, 52.8-87.3), and 75.9% (95% CI, 56.5-89.7), respectively. Specificities were 97.5%. Xpert® combined on nasopharyngeal aspirate and stool had intention-to-diagnose and per-protocol sensitivities of 75.9% (95% CI, 56.5-89.7) and 75.0% (95% CI, 47.6-92.7), respectively.

Conclusions: The combination of nasopharyngeal aspirate and stool sample is a promising alternative to methods usually recommended by national programs. Xpert® performed on respiratory and stools samples enables rapid confirmation of tuberculosis diagnosis in HIV-infected children.

Abstract access  

Editor’s notes: This article reports on a prospective cohort study of HIV-positive children (≤ 13 years) with suspected intrathoracic tuberculosis in eight hospitals in Burkina Faso, Cambodia, Cameroon, and Viet Nam. Diagnosis of tuberculosis among children is challenging because it is more difficult to obtain sputum, and their sputum often has fewer bacilli, requiring more sensitive tests. In 2014, WHO recommended scaling-up the use of Xpert® MTB/RIF among children. However, any test which is dependent on obtaining a sputum specimen will be suboptimal for diagnosis of tuberculosis in children.

In this study the investigators examined the feasibility of using alternative specimens with Xpert® MTB/ RIF for the diagnosis of tuberculosis in HIV-positive children. Using an intention-to-diagnose and a per-protocol analysis, they also assessed the diagnostic accuracy of Xpert® on nasopharyngeal aspirate and stool samples, using culture-confirmed tuberculosis as the reference standard.

The authors found that the performance of Xpert® in alternative samples was comparable to that of standard samples. They found excellent feasibility of obtaining samples of nasopharyngeal aspirates and stool, and a good sensitivity of Xpert® (~76%) when using that combination of samples. The authors suggested more research to simplify the processing of the stool samples for Xpert®, which would make the combination of both samples an attractive collection method for children unable to produce sputum.

Although Xpert® produces results relatively rapidly, some testing was done retrospectively, and only half of the Xpert® results were immediately available. As many children in this study had features of severe disease, it is not surprising that clinicians often started TB treatment immediately without waiting for results. Thus in practice the Xpert® result often provided bacteriological confirmation of a clinical diagnosis for children who had already started TB treatment, although it did also lead to some TB treatment initiations.

Despite conducting this study over more than two years in eight hospitals, the final number of enrolled children with culture-confirmed tuberculosis was only 29. It would be interesting to know whether using Xpert® on alternative specimens from children had an impact on patient-important outcomes, particularly mortality, though this would have required a much larger study. Studies of Xpert® implementation among adults have found increased yield in terms of bacteriological diagnoses. However, most have not found an impact on patient-important outcomes. Several children died before all the protocol-required specimens could be obtained, emphasizing the importance of rapid and more sensitive TB diagnostic tests for severely-ill children.

Africa, Asia
Burkina Faso, Cambodia, Cameroon, Viet Nam
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