Articles tagged as "Avoid TB deaths"

High TB incidence in children in Mozambique

Incidence of tuberculosis among young children in rural Mozambique.

López-Varela E, Augusto OJ, Gondo K, Garcia-Basteiro AL, Fraile O, Ira T, Ribo Aristizabal JL, Bulo H, Munoz Gutierrez J, Aponte J, Macete E, Sacarlal J, Alonso PL. Pediatr Infect Dis J. 2015 Jul;34(7):686-92. doi: 10.1097/INF.0000000000000710.

Background: Tuberculosis (TB) contributes significantly to child morbidity and mortality. This study aimed to estimate the minimum community-based incidence rate of TB among children <3 years of age in Southern Mozambique.

Methods: Between October 2011 and October 2012, in the Manhica District Health and Demographic Surveillance System, we enrolled prospectively all presumptive TB cases younger than 3 years of age through passive and active case finding. Participants included all children who were either symptomatic or were close contacts of a notified adult smear-positive pulmonary TB. Children were clinically evaluated at baseline and follow-up visits. Investigation for TB disease included chest radiography, HIV and tuberculin skin testing as well as gastric aspirate and induced sputum sampling, which were processed for smear, culture and mycobacterial molecular identification.

Results: During the study period, 13 764 children <3 years contributed to a total of 9575 person-years. Out of the 789 presumptive TB cases enrolled, 13 had TB culture confirmation and 32 were probable TB cases. The minimum community-based incidence rate of TB (confirmed plus probable cases) was 470 of 100 000 person-years (95% confidence interval: 343-629 of 100 000). HIV co-infection was present in 44% of the TB cases.

Conclusion: These data highlight the huge burden of pediatric TB. This study provides one of the first prospective population-based incidence data of childhood tuberculosis and adds valuable information to the global effort of producing better estimates, a critical step to inform public health policy.

Abstract access 

Editor’s notes: Mozambique is one of the few high HIV/TB burden countries where TB prevalence and incidence has not improved in recent years. This prospective cohort study nested within a rural demographic surveillance site brings to light the immense burden of paediatric tuberculosis in the southern part of the country. The findings of an estimated minimum community-based TB incidence rate in children aged < 3 years of 470 per 100 000 person years (nearly double the number of cases notified) emphasise the gross under-detection of paediatric tuberculosis in this region. 

Children are unlikely to contribute to onward transmission of Mycobacterium tuberculosis (Mtb) because they rarely have large numbers of bacilli in respiratory secretions. Thus, from a public health point of view, childhood tuberculosis has not until recently been considered a priority in high burden settings. One of the study’s strengths is the huge effort made to confirm TB diagnoses, which, due to low numbers of bacilli in sputum and inability to produce sputum samples, is notoriously difficult in young children.  Accurate estimates of paediatric TB (especially in the very young, e.g. ≤3 years), as attempted by this population-based study, act as a critical indicator of the effectiveness of programmes to curtail community transmission. These findings therefore signal an extremely high level of on-going Mtb transmission and the urgent need for effective public health programmes to halt the TB/HIV epidemic in Mozambique.

Avoid TB deaths
Comorbidity
Africa
Mozambique
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Diminished immunity despite MMR immunisation in children with perinatally-acquired HIV

Immunity to measles, mumps and rubella in US children with perinatal HIV infection or perinatal HIV exposure without infection.

Siberry GK, Patel K, Bellini W, Karalius B, Purswani M, Burchett SK, Meyer WA, 3rd, Sowers SB, Ellis A, Van Dyke RB, Pediatric HIVACS, Pediatric  HIV AIDS Cohort Study PHACS. Clin Infect Dis. 2015 Jun 9. pii: civ440. [Epub ahead of print]

Background: Children with perinatal HIV infection (PHIV) may not be protected against measles, mumps and rubella because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort.

Methods: PHIV and HEU were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007-2009. At annual visits, demographic, laboratory, immunization and clinical data were abstracted and serologic specimens were collected. Most recent serologic specimen was used to determine measles seroprotection by plaque-reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained cART was defined as taking cART for at least 3 months.

Results: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57%[95% CI: 52-62%] vs. 99% [95% CI: 96-100%]), rubella seroprotection (65% [95% CI: 60-70%] vs. 98% [95% CI: 95-100%]), and mumps seropositivity (59% [95% CI: 55-64%] vs. 97% [95% CI: 94-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar.

Conclusions: High proportions of PHIV children, but not HEU children, lack serologic evidence of immunity to measles, mumps and rubella, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity.

Abstract access 

Editor’s notes: Administration of combination measles, mumps and rubella (MMR) vaccine has resulted in dramatic declines in these diseases. Children with HIV, however, may be susceptible to vaccine-preventable diseases despite immunisation, due to weaker or short-lived immunological responses following immunisation. Children living with HIV may be at higher risk of more severe disease. In addition, children who are susceptible to these diseases may contribute to community risk of outbreaks as control of measles, mumps and rubella depends upon a high proportion of the population being immune.

This study demonstrates that sero-protection to rubella and measles and sero-positivity to mumps was substantially lower among children with HIV aged seven to 15 years than among HIV-exposed but HIV-negative children. Notably, nearly all children with HIV in this study had received the full two-dose series of MMR vaccines, in contrast to previous studies where HIV infection has been a risk factor for failure to receive recommended immunisations. Also, despite concerns that HIV-exposed, but HIV-negative children may have subtle immunological abnormalities that could impair their responses to vaccines, the rates of sero-protection and sero-immunity in this group were high, and comparable to rates in the general population.

Previous studies have illustrated that immunosuppression, lack of antiretroviral therapy (ART) or incomplete HIV virologic suppression are associated with a poor response to vaccines. This study demonstrates that a high proportion of older children and youth (all infected perinatally) may not be protected against MMR despite achieving virologic suppression and good immune status with ART.  Timing of receipt of MMR immunisation in relation to ART, but not overall number of vaccine doses, was independently associated with seropositivity to MMR vaccine. Children who received MMR doses after being on sustained ART had significantly higher levels of sero-positivity and sero-protection than children who received MMR vaccine before ART was instituted.    

This study has important policy implications. ART coverage in children globally is still less than coverage in adults. Many children with HIV start ART only in older childhood. Early ART for children followed by the standard MMR schedule as well as repeating MMR vaccine dosing for older children, particularly children who received MMR vaccine prior to starting ART, will be important to avert the risk of these vaccine-preventable infections in this vulnerable population.     

Avoid TB deaths
Northern America
United States of America
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Xpert testing - rationalise with chest X-ray or HIV pre-screening?

Implementation research to inform the use of Xpert MTB/RIF in primary health care facilities in high TB and HIV settings in resource constrained settings.

Muyoyeta M, Moyo M, Kasese N, Ndhlovu M, Milimo D, Mwanza W, Kapata N, Schaap A, Godfrey Faussett P, Ayles H. PLoS One. 2015 Jun 1;10(6):e0126376. doi: 10.1371/journal.pone.0126376. eCollection 2015.

Background: The current cost of Xpert MTB RIF (Xpert) consumables is such that algorithms are needed to select which patients to prioritise for testing with Xpert.

Objective: To evaluate two algorithms for prioritisation of Xpert in primary health care settings in a high TB and HIV burden setting.

Method: Consecutive, presumptive TB patients with a cough of any duration were offered either Xpert or Fluorescence microscopy (FM) test depending on their CXR score or HIV status. In one facility, sputa from patients with an abnormal CXR were tested with Xpert and those with a normal CXR were tested with FM ("CXR algorithm"). CXR was scored automatically using a Computer Aided Diagnosis (CAD) program. In the other facility, patients who were HIV positive were tested using Xpert and those who were HIV negative were tested with FM ("HIV algorithm").

Results: Of 9482 individuals pre-screened with CXR, Xpert detected TB in 2090/6568 (31.8%) with an abnormal CXR, and FM was AFB positive in 8/2455 (0.3%) with a normal CXR. Of 4444 pre-screened with HIV, Xpert detected TB in 508/2265 (22.4%) HIV positive and FM was AFB positive in 212/1920 (11.0%) in HIV negative individuals. The notification rate of new bacteriologically confirmed TB increased; from 366 to 620/100 000/yr and from 145 to 261/100 000/yr at the CXR and HIV algorithm sites respectively. The median time to starting TB treatment at the CXR site compared to the HIV algorithm site was: 1(IQR 1-3 days) and 3 (2-5 days) (p<0.0001) respectively.

Conclusion: Use of Xpert in a resource-limited setting at primary care level in conjunction with pre-screening tests reduced the number of Xpert tests performed. The routine use of Xpert resulted in additional cases of confirmed TB patients starting treatment. However, there was no increase in absolute numbers of patients starting TB treatment. Same day diagnosis and treatment commencement was achieved for both bacteriologically confirmed and empirically diagnosed patients where Xpert was used in conjunction with CXR.

Abstract  Full-text [free] access

Editor’s notes: Although many countries have begun to deploy molecular TB diagnostics, the cost of these technologies remains prohibitive for widespread use in low- and middle-income countries. This study in Zambian primary health care clinics aimed to explore whether the use of Xpert® MTB/RIF could be rationalised by pre-screening individuals with cough, either by chest X-ray (CXR) or by HIV testing. CXR screening only marginally reduced the use of Xpert® (as three-quarters of people screened had an abnormal CXR, using digital X-ray and computerised interpretation). Restricting use of Xpert® to those known to be HIV-positive reduced the number of Xpert® tests by around half. Under both algorithms, the proportion testing Xpert® positive was very high (22-32%), suggesting that too few people were being identified as needing TB investigation. Similar to other studies of Xpert® implementation, the overall number of people starting TB treatment did not increase with the introduction of Xpert®. However, the proportion of people starting TB treatment who had microbiological confirmation did increase substantially under both algorithms. Empirical TB treatment (meaning initiation of treatment without microbiological confirmation) remained common, in the X-ray algorithm particularly where a third of people with an abnormal CXR but a negative Xpert® were started on TB treatment. This study was not designed to determine how many people who genuinely had TB were missed by each algorithm. Also this paper did not include cost-effectiveness analyses. Based on this evidence, neither of these algorithms can be clearly recommended. Further evaluation of different screening and testing strategies will be important to inform the scale-up of molecular diagnostics.   

Avoid TB deaths
Africa
Zambia
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Timing of ART for HIV-associated TB – still room to improve and to save lives

The impact of implementation fidelity on mortality under a CD4-stratified timing strategy for antiretroviral therapy in patients with tuberculosis.

Patel MR, Westreich D, Yotebieng M, Nana M, Eron JJ, Behets F, Van Rie A. Am J Epidemiol. 2015 May 1;181(9):714-22. doi: 10.1093/aje/kwu338. Epub 2015 Mar 18.

Among patients with tuberculosis and human immunodeficiency virus type 1, CD4-stratified initiation of antiretroviral therapy (ART) is recommended, with earlier ART in those with low CD4 counts. However, the impact of implementation fidelity to this recommendation is unknown. We examined a prospective cohort study of 395 adult patients diagnosed with tuberculosis and human immunodeficiency virus between August 2007 and November 2009 in Kinshasa, Democratic Republic of the Congo. ART was to be initiated after 1 month of tuberculosis treatment at a CD4 count of <100 cells/mm3 or World Health Organization stage 4 (other than extrapulmonary tuberculosis) and after 2 months of tuberculosis treatment at a CD4 count of 100-350 cells/mm3. We used the parametric g-formula to estimate the impact of implementation fidelity on 6-month mortality. Observed implementation fidelity was low (46%); 54% of patients either experienced delays in ART initiation or did not initiate ART, which could be avoided under perfect implementation fidelity. The observed mortality risk was 12.0% (95% confidence interval (CI): 8.2, 15.7); under complete (counterfactual) implementation fidelity, the mortality risk was 7.8% (95% CI: 2.4, 12.3), corresponding to a risk reduction of 4.2% (95% CI: 0.3, 8.1) and a preventable fraction of 35.1% (95% CI: 2.9, 67.9). Strategies to achieve high implementation fidelity to CD4-stratified ART timing are needed to maximize survival benefit.

Abstract access 

Editor’s notes: There is clear evidence from randomised controlled trials that the early initiation of antiretroviral therapy (ART) during TB treatment reduces mortality in HIV/TB co-infected people. That evidence has translated to policy and most countries now follow WHO guidelines which recommend treatment within eight weeks of starting TB treatment, and within two weeks in people with the most advanced immunodeficiency (CD4+ T-cell count <50cells/µL).

This paper presents a post hoc analysis from an intervention study evaluating integrated, nurse-delivered TB/HIV care in primary health care clinics in the Democratic Republic of the Congo. The parent study illustrated that integrated care led to better uptake of ART and lower mortality, in comparison to a historical cohort prior to integration. However, mortality was still substantial - around one in 10 participants died within six months - and under half of all participants failed to start ART on time. The definition of fidelity was quite tight, only five days allowed beyond the one-month or two-month timing threshold.

Analysis suggested that around a third of the mortality could have been prevented if ART had been started within the defined time periods. As in most studies, mortality was strongly associated with low CD4+ T-cell count (<50cells/µL) and this group were responsible for much of what was considered to be unavoidable mortality. Additional strategies are clearly necessary to improve outcomes in this group alongside broader strategies to promote earlier diagnosis of HIV and TB. 

Avoid TB deaths
Africa
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High early mortality after ART initiation despite screening for TB and cryptococcal disease

Implementation and operational research: Integrated pre-antiretroviral therapy screening and treatment for tuberculosis and cryptococcal antigenemia.

Pac L, Horwitz MM, Namutebi AM, Auerbach BJ, Semeere A, Namulema T, Schwarz M, Bbosa R, Muruta A, Meya DB, Manabe YC. J Acquir Immune Defic Syndr. 2015 Apr 15;68(5):e69-76. doi: 10.1097/QAI.0000000000000527.

Objective: To demonstrate the feasibility of integrated screening for cryptococcal antigenemia and tuberculosis (TB) before antiretroviral therapy (ART) initiation and to assess disease specific and all-cause mortality in the first 6 months of follow-up.

Methods: We enrolled a cohort of HIV-infected, ART-naive adults with CD4 counts ≤250 cells per microliter in rural Uganda who were followed for 6 months after ART initiation. All subjects underwent screening for TB; those with CD4 ≤100 cells per microliter also had cryptococcal antigen (CrAg) screening. For those who screened positive, standard treatment for TB or preemptive treatment for cryptococcal infection was initiated, followed by ART 2 weeks later.

Results: Of 540 participants enrolled, pre-ART screening detected 10.6% (57/540) with prevalent TB and 6.8% (12/177 with CD4 count ≤100 cells/muL) with positive serum CrAg. After ART initiation, 13 (2.4%) patients were diagnosed with TB and 1 patient developed cryptococcal meningitis. Overall 7.2% of participants died (incidence rate 15.6 per 100 person-years at risk). Death rates were significantly higher among subjects with TB and cryptococcal antigenemia compared with subjects without these diagnoses. In multivariate analysis, significant risk factors for mortality were male sex, baseline anemia of hemoglobin ≤10 mg/dL, wasting defined as body mass index ≤15.5 kg/m, and opportunistic infections (TB, positive serum CrAg).

Conclusions: Pre-ART screening for opportunistic infections detects many prevalent cases of TB and cryptococcal infection. However, severely immunosuppressed and symptomatic HIV patients continue to experience high mortality after ART initiation.

Abstract access 

Editor’s notes: Early mortality remains high among people starting antiretroviral therapy (ART) in resource-constrained settings. The risk of death is strongly associated with low baseline CD4 count. Leading causes of death in this population include tuberculosis (TB) and cryptococcal disease.

ART-naïve people with CD4 counts of 250 cells/µl or less were included in this study at a district hospital in Uganda. All were offered screening for TB, and people with CD4 counts below 100 cells/µl also had screening for cryptococcal antigen with follow-on management for people screening positive. The TB screening protocol comprised symptom screening plus an initial sputum for smear microscopy and culture, and a second sputum for smear was taken if the first was negative. Further investigations appear to have been according to clinical presentation rather than standardised. Overall, 13.3% of participants were diagnosed with TB. Some 6.8% of people with CD4 below 100 cells/µl had a positive serum cryptococcal antigen test. One was diagnosed with and treated for cryptococcal meningitis and the other 11 were treated with high dose fluconazole.

Despite the high prevalence of TB and cryptococcal disease detected and treated, the overall mortality was 7.2% (39/540) by six months. This is a minimum estimate, since it assumes that the 33 additional people who were lost to follow-up, transferred or withdrawn were all alive at six months. The mortality rate was higher among people diagnosed with TB, and was very high among people who were cryptococcal antigen positive, despite fluconazole treatment. The article does not describe the care pathways in detail, so it is not clear whether there were delays in treatment initiation which could be reduced, for example if point-of-care diagnostic testing with immediate results had been available at enrolment. In addition there is no comparison group and so the effect of this package of care on mortality is not clear. However the results suggest that early mortality may remain substantial among people presenting with advanced HIV disease in the absence of even more intensive management.

Several trials are in progress to evaluate programmes aiming to reduce early mortality among people starting ART, including trials of empirical TB treatment (i.e. without bacteriological confirmation). In last month’s HIV This Month we featured a trial of a cryptococcal screen and treat programme plus community support which reduced 12-month mortality from 18% to 13%. The results of these trials will inform the optimal package of care for people presenting with low CD4 counts. Ultimately, earlier HIV testing and linkage to care would be the ideal way to reduce the high mortality among people starting ART with very low CD4 counts.

Avoid TB deaths
Africa
Uganda
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Screening for and treating cryptococcal infection – better evidence of impact necessary

Cryptococcal antigen screening and early antifungal treatment to prevent cryptococcal meningitis: a review of the literature.

Kaplan JE, Vallabhaneni S, Smith RM, Chideya-Chihota S, Chehab J, Park B. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S331-9. doi: 10.1097/QAI.0000000000000484.

Background: Screening individuals with AIDS for serum cryptococcal antigen (CrAg), followed by treatment of CrAg positives with antifungals, may prevent cryptococcal meningitis. This review examined data on CrAg screening and treatment in resource-limited settings.

Methods: We searched articles published during 2007-2014 on the effectiveness and cost-effectiveness of CrAg screening and treatment on the outcomes of mortality, morbidity, retention in care, quality of life, and/or prevention of ongoing HIV transmission. We rated overall quality of individual articles, summarized the body of evidence, the expected impact, and cost-effectiveness for each outcome.

Results: We identified 2613 articles. Eight met all inclusion criteria. Five studies addressed mortality and/or morbidity outcomes; all were observational and had small sample sizes; 3 lacked a comparison group. Ratings of study quality ranged from "medium" to "weak," and the quality of the overall body of evidence for mortality and morbidity outcomes was rated as "fair." The intervention's expected impact on mortality and morbidity was rated as "moderate." The 4 cost-effectiveness studies included in the analysis showed that CrAg screening and treatment interventions are highly cost-effective. No studies addressed retention in care, quality of life, or HIV transmission.

Conclusions: Although limited, the body of evidence regarding CrAg screening and treatment suggests that the intervention may have an impact on preventing cryptococcal meningitis and death in persons with AIDS. Additional research is needed to quantify the intervention's effectiveness and identify optimal treatment dosing and implementation best practices.

Abstract access 

Editor’s notes: This systematic review was one of a series aimed at evaluating the impact of services supported by the US President’s Emergency Plan for AIDS Relief (PEPFAR). The review set out to assess the evidence around the impact of targeted cryptococcal antigen (CrAg) testing and antifungal treatment for people with advanced HIV disease. In 2011 World Health Organization (WHO) gave a conditional recommendation, based on low quality evidence, that adults with CD4 count <100 cells per μL, in populations where the CrAg prevalence is above 3%, should undergo CrAg screening and be provided with antifungal treatment if CrAg positive.

The quality of the evidence was rated using a system adapted from the US Preventive Services Task Force. Five observational studies that evaluated the impact of the CrAg screening and antifungal treatment approach on mortality were included. Most of these did not have a comparator. One study used a historical control group from the same facility and another study compared mortality in people who received fluconazole following a positive CrAg, to people who did not. All studies had a very small number of deaths. In the five studies, mortality in people testing CrAg positive and receiving fluconazole varied between 0 and 29%. Based on these studies it would be difficult to evaluate the true impact of the strategy on mortality.

Four cost-effectiveness studies from different settings were also reviewed. All four studies suggested that a strategy with CrAg screening and antifungal treatment would be cost-effective. However, the cost-effectiveness modelling was based on data from the observational studies mentioned above and required other assumptions based on low quality evidence, leading to substantial uncertainty around the cost-effectiveness estimates.

Although a few countries have already implemented CrAg screening and antifungal treatment strategies, better quality evidence is necessary to inform management more broadly in countries with a high burden of cryptococcal disease. Some evidence has already appeared, with a randomised controlled trial in Tanzania and Zambia demonstrating a reduction in mortality with a CrAg screening strategy combined with a community support package during the early phase of antiretroviral therapy (see HIV This Month Issue 4). In addition there are three other randomised controlled trials exploring the impact of CrAg screening, ongoing or planned in Uganda, Zimbabwe and Viet Nam (NCT01535469, NCT02434172, and NCT02334670). It is hoped that the evidence generated by these studies will improve our understanding of the impact of a CrAg screening strategy and also give further insight into how best to implement this in different health care settings.   

Avoid TB deaths
Africa, Asia
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Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors from concluding that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools - rapid tests for hepatitis B surface antigen - are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

Avoid TB deaths
Africa
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Hepatitis B virus co-infection: a challenge to successful ART in sub-Saharan Africa?

Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.

Stabinski L, OʼConnor S, Barnhart M, Kahn RJ, Hamm TE. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S274-85. doi: 10.1097/QAI.0000000000000496.

Background: Screening people living with HIV for hepatitis B virus (HBV) co-infection is recommended in resource-rich settings to optimize HIV antiretroviral therapy (ART) and mitigate HBV-related liver disease. This review examines the need, feasibility, and impact of screening for HBV in resource-limited settings (RLS).

Methods: We searched 6 databases to identify peer-reviewed publications between 2007 and 2013 addressing (1) HIV/HBV co-infection frequency in sub-Saharan Africa (SSA); (2) performance of hepatitis B surface antigen (HBsAg) rapid strip assays (RSAs) in RLS; (3) impact of HBV co-infection on morbidity, mortality, or liver disease progression; and/or (4) impact of HBV-suppressive antiretroviral medications as part of ART on at least one of 5 outcomes (mortality, morbidity, HIV transmission, retention in HIV care, or quality of life). We rated the quality of individual articles and summarized the body of evidence and expected impact of each intervention per outcome addressed.

Results: Of 3940 identified studies, 85 were included in the review: 55 addressed HIV/HBV co-infection frequency; 6 described HBsAg RSA performance; and 24 addressed the impact of HIV/HBV co-infection and ART. HIV/HBV frequency in sub-Saharan Africa varied from 0% to >28.4%. RSA performance in RLS showed good, although variable, sensitivity and specificity. Quality of studies ranged from strong to weak. Overall quality of evidence for the impact of HIV/HBV co-infection and ART on morbidity and mortality was fair and good to fair, respectively.

Conclusions: Combined, the body of evidence reviewed suggests that HBsAg screening among people living with HIV could have substantial impact on preventing morbidity and mortality among HIV/HBV co-infected individuals in RLS.

Abstract access 

Editor’s notes: The routes of transmission for hepatitis B virus (HBV) and HIV are the same, and they frequently co-infect individuals in high HIV prevalence settings. HIV has also been shown to accelerate the progression of HBV. This has important implications for ART programmes, given also the potential for hepatotoxicity of ART. The response of both infections to certain antivirals gives an opportunity to treat both infections simultaneously, but also the potential to engender resistant strains of virus if treatment is optimised for one and not the other.

This paper reviews the evidence that might support inclusion of HBV screening as part of HIV care programmes. No clinical trials have been done in this area, so the review is based on observational studies. The data are incomplete and geographically patchy, largely from Nigeria and South Africa. However, this does not prevent the authors to conclude that the co-infection risk is sufficiently high and the consequences of lack of treatment sufficiently severe to consider allocation of scarce resources to identify and manage HBV co-infection in HIV programmes. Appropriate validated screening tools such as rapid tests for hepatitis B surface antigen are available. The potential benefit warrants consideration of this issue in sub-Saharan Africa, and inclusion of HBV surveillance alongside HIV to resolve the paucity of data in most countries. This should be rapidly followed by further consideration of the cost- and risk-benefit of introduction of an HBV screening and treatment programme.

Interested readers might also refer to a review by Matthews et al. (J Clin Virol 2014;6:20-33) which considers similar questions and also discusses hepatitis C co-infection.

Avoid TB deaths
Africa
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Cryptococcal antigen screening plus home visits reduces early mortality

Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial.

Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, Chijoka C, Masasi A, Kimaro G, Ngowi B, Kahwa A, Mwaba P, Harrison TS, Egwaga S, Jaffar S, REMSTART trial team. Lancet. 2015 Mar 9. pii: S0140-6736(15)60164-7. doi: 10.1016/S0140-6736(15)60164-7. [Epub ahead of print]

Background: Mortality in people in Africa with HIV infection starting antiretroviral therapy (ART) is high, particularly in those with advanced disease. We assessed the effect of a short period of community support to supplement clinic-based services combined with serum cryptococcal antigen screening.

Methods: We did an open-label, randomised controlled trial in six urban clinics in Dar es Salaam, Tanzania, and Lusaka, Zambia. From February, 2012, we enrolled eligible individuals with HIV infection (age ≥18 years, CD4 count of <200 cells per uL, ART naive) and randomly assigned them to either the standard clinic-based care supplemented with community support or standard clinic-based care alone, stratified by country and clinic, in permuted block sizes of ten. Clinic plus community support consisted of screening for serum cryptococcal antigen combined with antifungal therapy for patients testing antigen positive, weekly home visits for the first 4 weeks on ART by lay workers to provide support, and in Tanzania alone, re-screening for tuberculosis at 6-8 weeks after ART initiation. The primary endpoint was all-cause mortality at 12 months, analysed by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISCRTN 20410413.

Findings: Between Feb 9, 2012, and Sept 30, 2013, 1001 patients were randomly assigned to clinic plus community support and 998 to standard care. 89 (9%) of 1001 participants in the clinic plus community support group did not receive their assigned intervention, and 11 (1%) of 998 participants in the standard care group received a home visit or a cryptococcal antigen screen rather than only standard care. At 12 months, 25 (2%) of 1001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10-43) lower in the clinic plus community support group than in standard care group (p=0.004).

Interpretation: Screening and pre-emptive treatment for cryptococcal infection combined with a short initial period of adherence support after initiation of ART could substantially reduce mortality in HIV programmes in Africa.

Abstract access 

Editor’s notes: Despite the huge success of antiretroviral programme roll-out, early mortality among people initiating antiretroviral therapy (ART) in low- and middle-income countries remains high, and reducing early mortality is a priority. The risk of early mortality is highest among people with low CD4 counts. Although there has been an increase over calendar time in the median CD4 count at ART start, many people still start ART with low CD4 counts, and continue to be at high risk of death.

Cryptococcal disease is consistently identified at autopsy among HIV-positive people, although less commonly than tuberculosis and other lung infections. Cryptococcal disease is typically seen among individuals with very low CD4 counts, and has high case-fatality, for reasons including late presentation and suboptimal treatment and care. Among people with low CD4 counts, cryptococcal antigen can be detected in blood several weeks before cryptococcal disease becomes symptomatic. In 2011, the World Health Organization (WHO) issued rapid advice concerning prevention and treatment of cryptococcal meningitis in resource-constrained settings. This included a conditional recommendation (based on low-quality evidence) to screen individuals with CD4 counts below 100 cells per µl for cryptococcal antigen, followed by treatment either for cryptococcal meningitis, or with fluconazole for asymptomatic cryptococcal antigenaemia, as appropriate.

This trial is the first to provide evidence that this strategy can save lives. This was a pragmatic, individually randomised trial enrolling HIV-positive, ART-naïve people initially with CD4 counts below 100 cells per µl. Because of slow enrolment, inclusion criteria were later expanded to include people with CD4 counts below 200 cells per µl. The programme had two components. The first involved screening for cryptococcal antigen with a point-of-care test using a finger prick blood sample, followed by management in line with WHO guidelines. The second was adherence support, with trained lay workers visiting participants at or near their homes weekly for the first four weeks. The lay workers delivered ART, provided adherence support and monitored for adverse events.

The reduction of mortality from 18% to 13% in the intervention arm is clearly important, but also intriguing in terms of identifying the “active ingredient”. This may be difficult in a pragmatic trial of a programme with more than one component. For example, there was no cryptococcal antigen testing in control arm participants. Thus we cannot assess precisely the reduction in mortality attributable to this component of the programme. The authors estimate that cryptococcal antigen screening and treatment contributed about half of the observed effect. This component is also interesting because in practice, implementation of the cryptococcal antigen “screen and treat” pathway in the trial was not exactly as per WHO guidelines. WHO guidelines recommend lumbar puncture for people who screen positive for cryptococcal antigen and have symptoms suggesting meningitis. However, in this trial 76% of people testing cryptococcal antigen positive refused lumbar puncture, similar to experience elsewhere. Despite the programme, 32% of people in the intervention arm who were cryptococcal antigen positive died. This suggests that the fluconazole that most people received may have been inadequate, and that alternatives to lumbar puncture are necessary to identify people at highest risk who would benefit from full treatment for cryptococcal meningitis with amphotericin B. Quantifying the cryptococcal antigen titre in blood might serve this purpose, and needs further investigation.

In a previous trial in Uganda, home-based ART care (monthly delivery of ART by lay workers) was as effective as clinic-based care, in terms of virologic failure. However, other programmes similarly aiming to provide support for individuals starting ART have been less successful. For example a recently-presented trial of health “navigators” who used mobile phones and text messages to help people living with HIV link to ART and, where relevant, TB treatment, did not reduce mortality at nine months. Supporting adherence and retention is clearly critical to the long-term success of ART programmes. The challenge is defining how to do this most effectively and sustainably.

As part of this trial, in both arms ART was intended to be started within four to seven days of the first visit where possible, substantially faster than was previously routine. All participants were asked to provide sputum for testing for tuberculosis with Xpert MTB/RIF, regardless of reported symptoms. Some 16% of participants were already on tuberculosis treatment at enrolment. A further 11% were newly-diagnosed with tuberculosis at enrolment, roughly half based on sputum smear or clinical features and half based on the Xpert MTB/RIF result. This emphasises the importance of routine investigation for tuberculosis among people presenting to start ART. In the United Republic of Tanzania, people not on tuberculosis treatment were rescreened with Xpert MTB/RIF six weeks after enrolment. A further 5% were found to have tuberculosis, highlighting the inadequate sensitivity of Xpert MTB/RIF on sputum in this group of people.

Overall this trial provides encouragement that early on-ART mortality among people with low CD4 counts can be reduced. This is achieved with targeted treatment of cryptococcal disease and home-based early adherence support, in the context of universal screening for tuberculosis and rapid ART initiation. Ongoing studies are investigating whether empirical treatment for tuberculosis will reduce early mortality among similar patient populations. These results together will help define the optimum package of care to minimise mortality among individuals presenting with low CD4 cell counts. At the same time, HIV testing needs to be promoted so that people living with HIV can start ART before reaching the stage of advanced disease where mortality is such a risk.

Avoid TB deaths
Africa
United Republic of Tanzania, Zambia
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TB common at post-mortem among medical inpatients in Zambia

Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study.  

Bates M, Mudenda V, Shibemba A, Kaluwaji J, Tembo J, Kabwe M, Chimoga C, Chilukutu L, Chilufya M, Kapata N, Hoelscher M, Maeurer M, Mwaba P, Zumla A. Lancet Infect Dis. 2015 Mar 9. pii: S1473-3099(15)70058-7. doi: 10.1016/S1473-3099(15)70058-7. [Epub ahead of print]

Background: Patients with subclinical tuberculosis, smear-negative tuberculosis, extrapulmonary tuberculosis, multidrug-resistant tuberculosis, and asymptomatic tuberculosis are difficult to diagnose and may be missed at all points of health care. We did an autopsy study to ascertain the burden of tuberculosis at post mortem in medical inpatients at a tertiary care hospital in Lusaka, Zambia.

Methods: Between April 5, 2012, and May 22, 2013, we did whole-body autopsies on inpatients aged at least 16 years who died in the adult inpatient wards at University Teaching Hospital, Lusaka, Zambia. We did gross pathological and histopathological analysis and processed lung tissues from patients with tuberculosis through the GeneXpert MTB/RIF assay to identify patients with multidrug-resistant tuberculosis. The primary outcome measure was specific disease or diseases stratified by HIV status. Secondary outcomes were missed tuberculosis, multidrug-resistant tuberculosis, and comorbidities with tuberculosis. Data were analysed using Pearson chi2, the Mann-Whitney U test, and binary logistic regression.

Findings: The median age of the 125 included patients was 35 years (IQR 29-43), 80 (64%) were men, and 101 (81%) were HIV positive. 78 (62%) patients had tuberculosis, of whom 66 (85%) were infected with HIV. 35 (45%) of these 78 patients had extrapulmonary tuberculosis. The risk of extrapulmonary tuberculosis was higher among HIV-infected patients than among uninfected patients (adjusted odds ratio 5.14, 95% CI 1.04-24.5; p=0.045). 20 (26%) of 78 patients with tuberculosis were not diagnosed during their life and 13 (17%) had undiagnosed multidrug-resistant tuberculosis. Common comorbidities with tuberculosis were pyogenic pneumonia in 26 patients (33%) and anaemia in 15 (19%).

Interpretation: Increased clinical awareness and more proactive screening for tuberculosis and multidrug-resistant tuberculosis in inpatient settings are needed. Further autopsy studies are needed to ascertain the generalisability of the findings.

Abstract access 

Editor’s notes: This paper adds to the growing body of literature documenting a very high burden of tuberculosis (TB) in young adults, the majority of whom are HIV-positive, dying in hospitals in sub-Saharan Africa. Accurate knowledge of causes of death among people living with HIV is critical to developing strategies to reduce mortality. Although autopsies are the gold standard for identifying specific causes of death, autopsy data are sparse. In this study the authors undertook whole-body autopsies in medical inpatient deaths to describe the burden of TB. The GeneXpert MTB/RIF assay was used to assess the prevalence of multidrug-resistant tuberculosis.

The study achieved only 9% coverage of all deaths during the study period, similar to most other studies attempting full autopsy, which has poor acceptability to families. Among 125 included inpatients, the median time from admission to death was seven days. The majority of included people were HIV-positive, all diagnosed before death. The authors report a substantial burden of TB at autopsy, of which 26% (20/78) was only diagnosed after death and 17% (13/78) had undiagnosed multidrug-resistant (MDR) TB. None of the people with MDR-TB was on appropriate treatment. Bacterial pneumonia, found in over one-third of autopsies, was the next most common autopsy finding after TB.

The high burden of undiagnosed TB and MDR-TB at autopsy reported in this study highlights the need for routine screening for TB and MDR-TB among inpatients in TB endemic settings, and for measures to prevent in-hospital TB transmission. Rapid point-of-care diagnostics are necessary to enable early initiation of appropriate treatment. The study also highlights the key role of autopsy in identifying TB at death. This is consistently underestimated by physicians. Less invasive autopsy techniques based on multiple tissue biopsies are more acceptable to families and could have an important role in surveillance for TB as a cause of death. 

Avoid TB deaths
Africa
Zambia
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