Articles tagged as "Comorbidity"

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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People living with HIV at higher risk of developing disabilities in sub-Saharan Africa

The relationship between HIV and prevalence of disabilities in sub-Saharan Africa: systematic review.

Banks LM, Zuurmond M, Ferrand R, Kuper H. Trop Med Int Health. 2015 Apr;20(4):411-29. doi: 10.1111/tmi.12449. Epub 2015 Jan 14.

Objective: To systematically review evidence on the prevalence and risk of disabilities among children and adults living with HIV in sub-Saharan Africa.

Methods: Articles were identified from 1980 to June 2013 through searching seven electronic databases. Epidemiological studies conducted in sub-Saharan Africa that explored the association between HIV status and general disability or specific impairments, with or without an HIV-uninfected comparison group, were eligible for inclusion.

Results: Of 12 867 records initially identified, 61 papers were deemed eligible for inclusion. The prevalence of disability was high across age groups, impairment types and study locations. Furthermore, 73% of studies using an HIV- comparator found significantly lower levels of functioning in people living with HIV (PLHIV). By disability type, the results were as follows: (i) for studies measuring physical impairments (n = 14), median prevalence of limitations in mobility and motor function among PLHIV was 25.0% (95% CI: 21.8-28.2%). Five of eight comparator studies found significantly reduced functioning among PLHIV; for arthritis, two of three studies which used an HIV- comparison group found significantly increased prevalence among PLHIV; (ii) for sensory impairment studies (n = 17), median prevalence of visual impairment was 11.2% (95%CI: 9.5-13.1%) and hearing impairment was 24.1% (95%CI: 19.2-29.0%) in PLHIV. Significantly increased prevalence among PLHIV was found in one of four (vision) and three of three studies (hearing) with comparators; (iii) for cognitive impairment in adults (n = 30), median prevalence for dementia was 25.3% (95% CI: 22.0-28.6%) and 40.9% (95% CI: 37.7-44.1%) for general cognitive impairment. Across all types of cognitive impairment, twelve of fourteen studies found a significant detrimental effect of HIV infection; (iv) for developmental delay in children with HIV (n = 20), median prevalence of motor delay was 67.7% (95% CI: 62.2-73.2%). All nine studies that included a comparator found a significant difference between PLHIV and controls; for cognitive development and global delay, a significant detrimental effect of HIV was found in five of six and one of two studies, respectively. In the nine cohort studies comparing vertically infected and uninfected children, eight showed a significant gap in development over time in children with HIV. Finally, fifteen of thirty-one (48%) studies found a statistically significant dose-response relationship between indicators of disease progression (CD4 or WHO stage) and disability.

Conclusions: HIV is widespread in sub-Saharan Africa and the evidence suggests that it is linked to disabilities, affecting a range of body structures and functions. More research is needed to better understand the implications of HIV-related disability for individuals, their families as well as those working in the fields of disability and HIV so that appropriate interventions can be developed.

Abstract  Full-text [free] access

Editor’s notes: As ART is scaled-up, and people living with HIV live longer, an increasing number of people will face challenges of HIV-associated disability. Disability may be partly a direct effect of living with HIV, but may also be an indirect effect, for example due to side effects of treatment. There has been relatively little research on this topic, particularly in low and middle-income countries and this is the first systematic review of the prevalence of disability among people living with HIV in sub-Saharan Africa. The review found a high prevalence of all categories of disability. The majority of studies had an HIV-negative comparison group among whom levels of disability were lower than among people living with HIV. Developmental delay was the impairment most strongly linked to HIV, with prevalence as high as 78% in children living with HIV. To minimize the chance that the observed association was due to reverse causality, the review excluded studies which clearly focused on disability as a risk factor for HIV, although it is likely that some studies still included individuals in whom disability preceded HIV infection. There was also relatively little data on ART status and duration in many studies, which may impact on the association of HIV and disability.  Despite these limitations, this study highlights the need to focus on prevention and management of HIV-associated disability in sub-Saharan Africa and development of effective, low-cost evidence-informed activities.

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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Need for further water, sanitation and hygiene programmes among people living with HIV

The impact of water, sanitation, and hygiene interventions on the health and well-being of people living with HIV: a systematic review.

Yates T, Lantagne D, Mintz E, Quick R. J Acquir Immune Defic Syndr. 2015 Apr 15;68 Suppl 3:S318-30. doi: 10.1097/QAI.0000000000000487.

Background: Access to improved water supply and sanitation is poor in low-income and middle-income countries. Persons living with HIV/AIDS (PLHIV) experience more severe diarrhea, hospitalizations, and deaths from diarrhea because of waterborne pathogens than immunocompetent populations, even when on antiretroviral therapy (ART).

Methods: We examined the existing literature on the impact of water, sanitation, and hygiene (WASH) interventions on PLHIV for these outcomes: (1) mortality, (2) morbidity, (3) retention in HIV care, (4) quality of life, and (5) prevention of ongoing HIV transmission. Cost-effectiveness was also assessed. Relevant abstracts and articles were gathered, reviewed, and prioritized by thematic outcomes of interest. Articles meeting inclusion criteria were summarized in a grid for comparison.

Results: We reviewed 3355 citations, evaluated 132 abstracts, and read 33 articles. The majority of the 16 included articles focused on morbidity, with less emphasis on mortality. Contaminated water, lack of sanitation, and poor hygienic practices in homes of PLHIV increase the risk of diarrhea, which can result in increased viral load, decreased CD4 counts, and reduced absorption of nutrients and antiretroviral medication. We found WASH programming, particularly water supply, household water treatment, and hygiene interventions, reduced morbidity. Data were inconclusive on mortality. Research gaps remain in retention in care, quality of life, and prevention of ongoing HIV transmission. Compared with the standard threshold of 3 times GDP per capita, WASH interventions were cost-effective, particularly when incorporated into complementary programs.

Conclusions: Although research is required to address behavioral aspects, evidence supports that WASH programming is beneficial for PLHIV.

Abstract access 

Editor’s notes: Researchers, implementers, and policy makers have been examining how to better integrate programmes with overlapping burdens of morbidity and mortality. This paper illustrates how access to clean water and good sanitation practices, or lack thereof, can impact the health of people living with HIV. Water, sanitation, and hygiene (WASH) programmes can improve the negative effects poor water quality and bad sanitation have on people living with HIV. They reduce or even eliminate diarrheal infections, which allow for better absorption of HIV treatment medication that leads to a reduction in viral load and increased CD4 counts. While this systematic review revealed evidence on the reduced burden of morbidity that WASH programmes can confer, little has been done in the way of research linking WASH programmes to mortality in people living with HIV, nor how they may affect adherence or retention in care. Side effects of HIV treatment is a common reason why people stop taking medications, and common side effects are nausea and diarrhoea. It is possible that intestinal issues caused by unsafe drinking water could exacerbate the impact of side effects on people already experiencing them, therefore reducing motivation to continue taking their ARVs. This paper also suggests that synergies in cost sharing and increasing cost effectiveness could be achieved by integrating programmes. However further research is necessary to fully understand the logistical and cost implications.

 

Africa, Asia
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Can a simple risk score predict chronic kidney disease among people living with HIV?

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Mocroft A, Lundgren JD, Ross M, Law M, Reiss P, Kirk O, Smith C, Wentworth D, Neuhaus J, Fux CA, Moranne O, Morlat P, Johnson MA, Ryom L, D:A:D study group, the Royal Free Hospital Clinic Cohort, and the INSIGHT, SMART, and ESPRIT study groups. PLoS Med. 2015 Mar 31;12(3):e1001809. doi: 10.1371/journal.pmed.1001809. eCollection 2015.

Background: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.

Methods and findings: A total of 17 954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR >60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103 185 person-years of follow-up (PYFU; incidence 6.2/1000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score <0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1702 (95% CI 1166-3367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2548 individuals, of whom 94 individuals developed CKD (3.7%) during 18 376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria.

Conclusions: Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

Abstract  Full-text [free] access

Editor’s notes: The nephrotoxicity of antiretroviral drugs, particularly tenofovir, is of concern, particularly where there is limited access to laboratory monitoring of kidney function. The development of kidney impairment among people with HIV is associated with poor outcomes, and in low resource settings where dialysis is not available this can be catastrophic.

This study, like previous work, attempts to address this problem by developing a risk score for the development of chronic kidney disease (CKD). The strength of this study is the availability of data for over 17 000 men and women living with HIV enrolled in cohort studies for many years, and in over 40 countries globally. The resulting risk score uses nine simple clinical variables which predict CKD both overall, and after starting potentially nephrotoxic antiretrovirals. A short risk score, not including cardiovascular risk factors, which may be more suitable for low resource settings, shows almost as good a prediction of CKD.

So will this risk score become widely used in clinical decision making? For high income countries this tool may be useful to identify people where strategies to prevent cardiovascular and renal disease are best focussed. It may also be useful to identify people at high risk of developing CKD for whom use of tenofovir may be unacceptable, especially when monitoring of kidney function is limited. However, few of the enrolled people were from low and middle income countries, and there was limited information on the race of participants. Therefore, the risk score may need to be validated in low resource settings before it can be widely used. Whether the use of the tool would help to improve clinical outcomes where kidney function is frequently monitored is unclear.

Meanwhile, a new drug formulation, tenofovir alafenamide (TAF), is currently in clinical trials. This appears to be associated with less renal toxicity, and to be safe and well tolerated among adults with decreased kidney function. If future trial results support this evidence, and tenofovir alafenamide becomes widely available, concern about drug nephrotoxicity may become a less pressing clinical issue.

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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.

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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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TB protection from 36 months of isoniazid preventive therapy wanes after IPT stopped in Botswana

Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis.

Samandari T, Agizew TB, Nyirenda S, Tedla Z, Sibanda T, Mosimaneotsile B, Motsamai OI, Shang N, Rose CE, Shepherd J. AIDS. 2015 Jan 28;29(3):351-9. doi: 10.1097/QAD.0000000000000535.

Objective: Thirty-six months of isoniazid preventive therapy (36IPT) was superior to 6 months of IPT (6IPT) in preventing tuberculosis (TB) among HIV-infected adults in Botswana. We assessed the posttrial durability of this benefit.

Design: A 36-month double-blind placebo controlled trial (1:1 randomization) with recruitment between November 2004 and July 2006 and observation until June 2011.

Methods: One thousand, nine hundred and ninety-five participants were followed in eight public health clinics. Twenty-four percent had a tuberculin skin test ≥5 mm (TST-positive). A minimum CD4 lymphocyte count was not required for enrolment. Antiretroviral therapy (ART) was provided in accordance with Botswana guidelines; 72% of participants retained by June 2011 had initiated ART. Multivariable analysis using Cox regression analysis included treatment arm, TST status, ART as a time-dependent variable and CD4 cell count at baseline and updated at 36 months.

Results: In the posttrial period, 2.13 and 2.14 per 100 person-years accumulated, whereas 0.93 and 1.13% TB incidence rates were observed in the 36IPT and 6IPT arms, respectively (P = 0.52). The crude hazard ratio of TB during the trial and posttrial was 0.57 [95% confidence intervals (CI) 0.33, 0.99] and 0.82 (95% CI 0.46, 1.49), and when restricted to TST-positive participants was 0.26 (95% CI 0.08, 0.80) and 0.40 (95% CI 0.15, 1.08), respectively. Multivariable analysis showed that ART use was associated with reduced death (adjusted hazard ratio 0.36, 95% CI 0.17-0.75) but not TB (0.92, 95% CI 0.55-1.53) in the posttrial period.

Conclusion: The benefit of 36IPT for TB prevention declined posttrial in this cohort. Adjunctive measures are warranted to prevent TB among HIV-infected persons receiving long-term ART in TB-endemic settings.

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Editor’s notes: Randomised controlled trials have illustrated that isoniazid preventive therapy (IPT) prevents TB among people living with HIV. Limited data from early trials suggested that the protective effect of a six month course of IPT waned over time after the end of the IPT course. The authors conducted a clinical trial among people living with HIV in Botswana, comparing 36 with six months of IPT. They found that TB incidence was lower in the group receiving 36 months of IPT, but this effect was limited to people whose baseline tuberculin skin test (TST) was positive.

In this paper, the authors present additional data from that trial, illustrating TB incidence during extended follow-up of participants after the end of the study. Participants started antiretroviral therapy (ART) according to national guidelines. By the end of follow up in 2011, 72% had started ART. In the post-trial period, i.e. from 36 months after enrolment, TB incidence was around 1%, similar in both arms of the trial. During the 36 months of the trial, the unadjusted hazard of TB was reduced by nearly half in the group taking 36 months of IPT. However, after the end of the trial, this protective effect waned to around 20%. Among participants who were TST positive at enrolment, the protective effect of prolonged IPT was greater during the trial, nearly a 75% reduction in TB. This effect waned to 60% after the end of the trial.

Several recent papers have discussed possible mechanisms for waning protection after a limited course of IPT in settings where TB transmission is common. An obvious explanation would be reinfection with TB, followed by rapid progression to active disease. An alternative could be that IPT does not effectively “sterilise” latent TB infection, resulting in reactivation disease after IPT is stopped. Since diagnostic tests for latent infection are unsatisfactory, it is difficult to distinguish between these possibilities. Whatever the mechanism, HIV-positive people remain at higher risk of TB despite ART. In settings where TB is common, a limited course of IPT does not give lasting protection. The data from this study provide further evidence in support of continuous IPT, particularly for people living with HIV who are TST-positive. Studies are in progress to evaluate alternative preventive therapy regimens which have greater potential to sterilise latent TB infection. Such regimens might be effective in shorter courses, which would be an advantage. But this would need to be balanced against the risk of disease due to reinfection with TB. How best to ensure lasting protection against TB for HIV-positive people remains a critically important question.

Avoid TB deaths
Comorbidity
Africa
Botswana
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