Articles tagged as "Comorbidity"

Invasive cervical cancers preventable by HPV vaccines: a comparison of HIV-positive and negative women

Effect of HIV infection on human papillomavirus types causing invasive cervical cancer in Africa.

Clifford GM, de Vuyst H, Tenet V, Plummer M, Tully S, Franceschi S. J Acquir Immune Defic Syndr. 2016 Nov 1;73(3):332-339.

Objectives: HIV infection is known to worsen the outcome of cervical human papillomavirus (HPV) infection and may do so differentially by HPV type.

Design: Twenty-one studies were included in a meta-analysis of invasive cervical cancers (ICC) among women infected with HIV in Africa.

Method: Type-specific HPV DNA prevalence was compared with data from a similar meta-analysis of HIV-negative ICC using prevalence ratios (PR).

Results: HPV detection was similar in 770 HIV-positive (91.2%) and 3846 HIV-negative (89.6%) ICC, but HIV-positive ICC harbored significantly more multiple HPV infections (PR = 1.75, 95% confidence intervals: 1.18 to 2.58), which were significantly more prevalent in ICC tested from cells than from biopsies. HPV16 was the most frequently detected type in HIV-positive ICC (42.5%), followed by HPV18 (22.2%), HPV45 (14.4%), and HPV35 (7.1%). Nevertheless, HIV-positive ICC were significantly less frequently infected with HPV16 than HIV-negative ICC (PR = 0.88, 95% confidence intervals: 0.79 to 0.99). Other high-risk types were significantly more prevalent in HIV-positive ICC, but only for HPV18 was there a significantly higher prevalence of both single and multiple infections in HIV-positive ICC. Increases for other high-risk types were primarily accounted for by multiple infections. The proportion of HPV-positive ICC estimated attributable to HPV16/18 (71.8% in HIV positive, 73.4% in HIV negative) or HPV16/18/31/33/45/52/58 (88.8%, 89.5%) was not affected by HIV.

Conclusions: HIV alters the relative carcinogenicity of HPV types, but prophylactic HPV16/18 vaccines may nevertheless prevent a similar proportion of ICC, irrespective of HIV infection.

Abstract access  

Editor’s notes: Invasive cervical cancer (ICC) is one of the most common cancers in low and middle income countries. In the African region the prevalence of both ICC and HIV are high. Compared to HIV-negative women, HIV-positive women are at increased risk of oncogenic high-risk (HR) human papillomavirus (HPV) incidence and persistence, and cervical lesion incidence and progression. Current HPV vaccines offer potential for cervical cancer prevention by targeting the HR-HPV types associated with ICC. Although there is no data yet available on HPV vaccine efficacy among HIV-positive persons, HPV vaccines have been reported to be safe and immunogenic in HIV-positive children, female adolescents and adults. 

This systematic review compared the HPV type distribution and the HPV vaccine type distribution in ICC biopsy and cervical cell specimens of 770 HIV-positive and 3846 HIV-negative women from 21 studies in 12 African countries.

The authors report that the fraction of ICC attributable to the HPV types included in the current bivalent (HPV16/18) and nonavalent (HPV16/18/31/33/45/52/58) vaccines was similar among HIV-positive and HIV-negative women (bivalent: 61.7% and 67.3%; nonavalent: 88.9% and 89.5%, respectively). However, a non-negligible proportion of ICC from both HIV-positive and HIV-negative women were infected with non-vaccine types in the absence of any of the vaccine types (7.0% and 7.9% of ICC from HIV-positive and HIV-negative women, respectively), and this was highest for HPV35.

These findings confirm that the currently available HPV vaccines could prevent a similar proportion of ICC cases in HIV-positive as in HIV-negative women. ICC remains an important co-morbidity among HIV-positive women even in the antiretroviral era. Given that HIV-positive women are at greater risk of HR-HPV persistence and cervical lesion incidence and faster progression to high-grade cervical lesions, primary prevention of HPV infection through vaccination could reduce HPV infection and HPV-associated disease in Africa. However, cervical cancer screening will continue to remain important for both HIV-positive and HIV-negative women as there remain a proportion of ICC cases that may not be preventable by currently available vaccines. 

Comorbidity, Epidemiology
Africa
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‘I wish I could have a life like others’: mental health challenges for young people living with HIV in Tanzania

A qualitative exploration of the mental health and psychosocial contexts of HIV-positive adolescents in Tanzania.

Ramaiya MK, Sullivan KA, K OD, Cunningham CK, Shayo AM, Mmbaga BT, Dow DE. PLoS One. 2016 Nov 16;11(11):e0165936. doi: 10.1371/journal.pone.0165936. eCollection 2016.

Although 85% of HIV-positive adolescents reside in sub-Saharan Africa, little is known about the psychosocial and mental health factors affecting their daily well-being. Identifying these contextual variables is key to development of culturally appropriate and effective interventions for this understudied and high-risk population. The purpose of this study was to identify salient psychosocial and mental health challenges confronted by HIV-positive youth in a resource-poor Tanzanian setting. A total of 24 qualitative interviews were conducted with a convenience sample of adolescents aged 12-24 receiving outpatient HIV care at a medical center in Moshi, Tanzania. All interviews were audio-recorded, transcribed, and coded using thematic analysis. Psychosocial challenges identified included loss of one or more parents, chronic domestic abuse, financial stressors restricting access to medical care and education, and high levels of internalized and community stigma among peers and other social contacts. Over half of youth (56%) reported difficulties coming to terms with their HIV diagnosis and espoused related feelings of self-blame. These findings highlight the urgent need to develop culturally proficient programs aimed at helping adolescents cope with these manifold challenges. Results from this study guided the development of Sauti ya Vijana (The Voice of Youth), a 10-session group mental health intervention designed to address the psychosocial and mental health needs of HIV-positive Tanzanian youth.

Abstract  Full-text [free] access 

Editor’s notes: This article presents the findings of a mixed-methods study with young people living with HIV and accessing care in Moshi, Tanzania. The study was conducted as part of a larger study assessing mental health needs in this population. The article reports on themes from individual qualitative interviews with 24 young people (aged 13-23) who had mental health difficulties that were previously assessed with the scales used in the larger project. Young people reported a wide range of psychosocial issues leading to ongoing mental health challenges.  These were challenges for which they had received little or no psychological support. Issues included internalized, feared and experienced HIV stigma, loss and bereavement from being orphaned.  Additional challenges were stress from poverty and insecurity in the household, isolation and difficulties with disclosure of their HIV status, and direct and vicarious experiences of violence and abuse. Young people also discussed finding strength in spirituality, friendships and especially peer-support from other young people living with HIV. Findings from the overall study are being used to inform the development of a mental health activity model that, if effective, could be scaled up in other low-income settings. 

Africa
United Republic of Tanzania
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Health care navigators do not improve early outcomes on ART in South Africa

Sizanani: a randomized trial of health system navigators to improve linkage to HIV and TB care in South Africa.

Bassett IV, Coleman SM, Giddy J, Bogart LM, Chaisson CE, Ross D, Jacobsen MM, Robine M, Govender T, Freedberg KA, Katz JN, Walensky RP, Losina E. J Acquir Immune Defic Syndr. 2016 Oct 1;73(2):154-60. doi: 10.1097/QAI.0000000000001025.

Background: A fraction of HIV-diagnosed individuals promptly initiate antiretroviral therapy (ART). We evaluated the efficacy of health system navigators for improving linkage to HIV and tuberculosis (TB) care among newly diagnosed HIV-infected outpatients in Durban, South Africa.

Methods: We conducted a randomized controlled trial (Sizanani Trial, NCT01188941) among adults (≥18 years) at 4 sites. Participants underwent TB screening and randomization into a health system navigator intervention or usual care. Intervention participants had an in-person interview at enrollment and received phone calls and text messages over 4 months. We assessed 9-month outcomes via medical records and the National Population Registry. Primary outcome was completion of at least 3 months of ART or 6 months of TB treatment for coinfected participants.

Results: Four thousand nine hundred three participants were enrolled and randomized; 1899 (39%) were HIV-infected, with 1146 (60%) ART-eligible and 523 (28%) TB coinfected at baseline. In the intervention, 212 (39% of outcome-eligible) reached primary outcome compared to 197 (42%) in usual care (RR 0.93, 95% CI: 0.80 to 1.08). One hundred thirty-one (14%) HIV-infected intervention participants died compared to 119 (13%) in usual care; death rates did not differ between arms (RR 1.06, 95% CI: 0.84 to 1.34). In the as-treated analysis, participants reached for ≥5 navigator calls were more likely to achieve study outcome.

Conclusions: approximately 40% of ART-eligible participants in both study arms reached the primary outcome 9 months after HIV diagnosis. Low rates of engagement in care, high death rates, and lack of navigator efficacy highlight the urgency of identifying more effective strategies for improving HIV and TB care outcomes.

Abstract access  

Editor’s notes: Early mortality remains high among people starting antiretroviral therapy (ART) in low- and middle-income countries, and tuberculosis is consistently identified as a leading cause. In KwaZulu-Natal province, South Africa, where this study was conducted, tuberculosis incidence is very high, and around two-thirds of people starting tuberculosis treatment are HIV-positive. Previous studies have illustrated gaps between positive test results and linkage to HIV and tuberculosis care. For HIV-positive people with tuberculosis, accessing treatment for both HIV and tuberculosis is made more difficult by a lack of integrated care in many settings. Health care navigators have helped people with HIV link to care in the United States.

This study tested a programme whereby health care navigators helped newly-diagnosed HIV-positive people to link to HIV care, and if necessary also to tuberculosis treatment. The navigators had a counselling role, and also contacted patients by phone or text message reminders. Disappointingly, the programme did not improve outcomes at nine months after enrolment. All-cause mortality was high at around 14% by nine months, and was not reduced by the programme. This is an important result, contrasting with findings from other studies. The SEARCH trial in Uganda illustrated more rapid ART initiation resulting from a complex programme, primarily targeting health system rather than individual barriers. However, the primary outcome of the SEARCH analysis was ART initiation; there was no detectable effect on mortality, which was very low, suggesting a lower-risk study population. In the REMSTART study, a programme including point-of-care testing for cryptococcal antigen plus adherence support from community counsellors (along with routine tuberculosis investigation in both arms) was associated with a reduction in early mortality; the “active ingredient” of this programme was not clearly defined. Ideally, people with HIV need to start ART before they reach the stage of advanced disease. However, given the reality that many people do present with advanced disease, more work is necessary to define which programme could reduce their risk of mortality.

Africa
South Africa
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Worms and HIV – time to end the debate?

Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study.

Kroidl I, Saathoff E, Maganga L, Makunde WH, Hoerauf A, Geldmacher C, Clowes P, Maboko L, Hoelscher M. Lancet. 2016 Oct 15;388(10054):1912-1920. doi: 10.1016/S0140-6736(16)31252-1. Epub 2016 Aug 3.

Background: The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania.

Methods: In this population-based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis.

Findings: Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly      18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1.91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0.80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2.17 (95% CI 1.08-4.37, p=0.0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors.

Interpretation: To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented.

Abstract access    

Editor’s notes: The interest in the link between helminth infections and HIV is based on our understanding of how helminth infections affect the human immune system. One core hypothesis has been that the shift to a predominantly T-helper type 2 (Th2) immune response associated with helminth infection might increase the risk of HIV acquisition. Until now, there has been no compelling evidence to support this. Observational studies looking at co-prevalence of HIV and filarial infection have not consistently illustrated an association between filarial infection and prevalent HIV infection. This relatively large population-based cohort study allowed a different approach, exploring the association between helminth infection and incident HIV infection over an average of three years follow-up. The presence of circulating filarial antigens doubled the risk of HIV acquisition.

So do the findings of this study end the debate? Perhaps not. The analysis did not account for the presence or absence of other helminth infections around the time of HIV acquisition. Also, although the analysis controlled for some socio-economic and behavioural factors known to be associated with HIV acquisition, this was incomplete so there is the possibility of residual confounding.

The findings from this study have led to renewed calls for clinical trials to evaluate the effect of antihelminthic treatment on HIV acquisition, but it may be too late. Elimination of neglected tropical diseases (including filariasis) is a global health priority in its own right, as is scale-up of combination HIV prevention strategies, including universal test and treat and pre-exposure prophylaxis. Clinical trials might therefore require unfeasibly large sample sizes to demonstrate an independent effect of antihelminthic treatment.

Africa
United Republic of Tanzania
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Young people living with HIV, stigma and its mental health effects

HIV-related stigma, shame, and avoidant coping: risk factors for internalizing symptoms among youth living with HIV?

Bennett DS, Hersh J, Herres J, Foster J. Child Psychiatry Hum Dev. 2016 Aug;47(4):657-64. doi: 10.1007/s10578-015-0599-y.

Youth living with HIV (YLH) are at elevated risk of internalizing symptoms, although there is substantial individual variability in adjustment. We examined perceived HIV-related stigma, shame-proneness, and avoidant coping as risk factors of internalizing symptoms among YLH. Participants (N = 88; ages 12-24) completed self-report measures of these potential risk factors and three domains of internalizing symptoms (depressive, anxiety, and PTSD) during a regularly scheduled HIV clinic visit. Hierarchical regressions were conducted for each internalizing symptoms domain, examining the effects of age, gender, and maternal education (step 1), HIV-related stigma (step 2), shame- and guilt-proneness (step 3), and avoidant coping (step 4). HIV-related stigma, shame-proneness, and avoidant coping were each correlated with greater depressive, anxiety, and PTSD symptoms. Specificity was observed in that shame-proneness, but not guilt-proneness, was associated with greater internalizing symptoms. In multivariable analyses, HIV-related stigma and shame-proneness were each related to greater depressive and PTSD symptoms. Controlling for the effects of HIV-related stigma and shame-proneness, avoidant coping was associated with PTSD symptoms. The current findings highlight the potential importance of HIV-related stigma, shame, and avoidant coping on the adjustment of YLH, as interventions addressing these risk factors could lead to decreased internalizing symptoms among YLH.

Abstract access

Editor’s notes: This study examined the relationship between stigma, shame and avoidant coping strategies and the development of internalizing symptoms, such as anxiety and depression, in young people living with HIV. It is based on researcher-administered questionnaires with 88 young people living with HIV attending an HIV clinic in Philadelphia, USA. The questionnaire included multiple scales to assess. These included young people’s self-reported issues with HIV stigma; tendency to feel shame; tendency to feel guilt; avoidant coping strategies; depressive symptoms; anxiety symptoms; and post-traumatic stress disorder symptoms. Multiple statistical analyses were performed, controlling for the effects of gender, age and maternal education. The study found that HIV-associated stigma, shame and avoidant strategies are risk-factors for the development of depression, anxiety and post-traumatic stress disorder in young people living with HIV. The study provides evidence for the development of psychosocial support that focuses on shame reduction as a way to mediate the impact of stigma on mental health outcomes for young people living with HIV.

Northern America
United States of America
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Real-world barriers to active TB case detection in HIV clinics

Implementation and operational research: use of symptom screening and sputum microscopy testing for active tuberculosis case detection among HIV-infected patients in real-world clinical practice in Uganda.

Roy M, Muyindike W, Vijayan T, Kanyesigye M, Bwana M, Wenger M, Martin J, Geng E. J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):e86-91. doi: 10.1097/QAI.0000000000001067.

Background: The uptake of intensified active TB case-finding among HIV-infected patients using symptom screening is not well understood. We evaluated the rate and completeness of each interim step in the TB pulmonary "diagnostic cascade" to understand real-world barriers to active TB case detection.

Methods: We conducted a cohort analysis of new, antiretroviral therapy-naive, HIV-infected patients who attended a large HIV clinic in Mbarara, Uganda (March 1, 2012-September 30, 2013). We used medical records to extract date of completion of each step in the diagnostic cascade: symptom screen, order, collection, processing, and result. Factors associated with lack of sputum order were evaluated using multivariate Poisson regression and chart review of 50 screen-positive patients.

Results: Of 2613 patients, 2439 (93%) were screened for TB and 682 (28%) screened positive. Only 90 (13.2%) had a sputum order. Of this group, 83% completed the diagnostic cascade, 13% were diagnosed with TB, and 50% had a sputum result within 1 day of their visit. Sputum ordering was associated with WHO stage 3 or 4 HIV disease and greater number of symptoms. The main identifiable reasons for lack of sputum order in chart review were treatment of presumed malaria (51%) or bacterial infection (43%).

Conclusions: The majority of newly enrolled HIV-infected patients who screened positive for suspected TB did not have a sputum order, and those who did were more likely to have more symptoms and advanced HIV disease. Further evaluation of provider behavior in the management of screen-positive patients could improve active TB case detection rates.

Abstract access  

Editor’s notes: This cohort analysis of people enrolling for HIV care at a President’s Emergency Plan for AIDS Relief (PEPFAR) clinic in Uganda used medical record review to identify barriers to active TB case finding in a programmatic setting. This study is unique in evaluating each step along the entire TB diagnostic cascade, from the WHO screening tool, which asks about four symptoms, through to sputum result, in a setting where TB diagnosis was based on sputum microscopy, prior to availability of Xpert ® MTB/RIF.

The authors found high uptake of TB symptom screening at enrolment to HIV care, with cough being the most commonly reported symptom. However, most people with symptoms suggestive of TB were not documented to have had sputum investigation ordered, this being the major point of loss from the TB diagnostic pathway. Given that the prevalence of active TB among people newly testing HIV positive is consistently high in African countries, this represents a substantial missed opportunity for prompt identification and treatment of TB. The study design did not allow in-depth evaluation of the reasons for lack of sputum order since this may not be clearly documented in medical records. Factors such as a person’s inability to produce sputum should also be considered. Ultimately, a high sensitivity, affordable, non-sputum based, point-of-care diagnostic test for TB is necessary to overcome the barriers inherent in the current complex TB diagnostic pathway.

Africa
Uganda
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Improved survival with lymphoma in the antiretroviral therapy era

Evolution of HIV-associated lymphoma over 3 decades.

Ramaswami R, Chia G, Dalla Pria A, Pinato DJ, Parker K, Nelson M, Bower M. J Acquir Immune Defic Syndr. 2016 Jun 1;72(2):177-83. doi: 10.1097/QAI.0000000000000946.

Introduction: The emergence of combined antiretroviral therapy (cART) and improvements in the management of opportunistic infections have altered the HIV epidemic over the last 30 years. We aimed to assess changes to the biology and outcomes of HIV-associated lymphomas over this period at the national center for HIV oncology in the United Kingdom.

Methods: Clinical characteristics at lymphoma diagnosis have been prospectively collected since 1986, along with details of lymphoma treatment and outcomes. The clinical features and outcomes were compared between 3 decades: pre-cART decade (1986-1995), early-cART decade (1996-2005), and late-cART decade (2006-2015).

Results: A total of 615 patients with HIV-associated lymphoma were included in the study: 158 patients in the pre-cART era, 200 patients in the early-cART era, and 257 patients in the late-cART era. In more recent decades, patients were older (P < 0.0001) and had higher CD4 cell counts (P < 0.0001) at lymphoma diagnosis. Over time, there has also been a shift in lymphoma histological subtypes, with an increase in lymphoma subtypes associated with moderate immunosuppression. The overall survival for patients with HIV-associated lymphoma has dramatically improved over the 3 decades (P < 0.0001).

Conclusion: Over the last 30 years, the clinical demographic of HIV-associated lymphomas has evolved, and the outcomes have improved.

Abstract access

Editor’s notes: Lymphomas are the second most common malignancy after Kaposi’s sarcoma among people living with HIV in Europe, Australia and northern America. This study examined how the biology and rates of survival have changed since combination antiretroviral therapy (cART) became available.

People living with HIV and diagnosed with lymphoma over the past thirty years in a specialist oncology centre in the United Kingdom were included in the study. The mean age at diagnosis of lymphoma increased over time, most likely reflecting improvement in life expectancy with cART. As would be expected, the mean CD4 count and the proportion of people with a suppressed viral load at lymphoma diagnosis increased, while proportion with an AIDS-defining illness before lymphoma diagnosis declined significantly.  

This study demonstrated a shift of the histological subtypes of lymphoma that are associated with less severe immunosuppression, for example the proportion of primary CNS lymphoma (PCNSL) and diffuse large B-cell lymphoma (DLBCL), which are associated with severe immunosuppression, declined, while the proportion of Burkitt’s lymphoma and Hodgkin’s lymphoma (associated with less profound immunosuppression) increased.

A key finding of this study was the significantly improved overall survival of people with lymphoma. The improved survival is not explained by changes in histological subtypes of lymphoma over time, as improvement in prognosis was observed for each histological subtype. The substantial improvement in overall survival is attributable to a number of factors. They include the availability of cART, attention to opportunistic infection prophylaxis, improved supportive care for people undergoing lymphoma treatment as well as improved modalities of lymphoma treatment. Such modalities include efficacious drugs that can be safely co-administered with cART, e.g., rituximab, novel agents and use of autologous stem cell transplants.  

Europe
United Kingdom
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Ending deaths in people with TB and HIV – still some way to go

High mortality in tuberculosis patients despite HIV interventions in Swaziland.

Mchunu G, van Griensven J, Hinderaker SG, Kizito W, Sikhondze W, Manzi M, Dlamini T, Harries AD. Public Health Action. 2016 Jun 21;6(2):105-10. doi: 10.5588/pha.15.0081.

Setting: All health facilities providing tuberculosis (TB) care in Swaziland.

Objective: To describe the impact of human immunodeficiency virus (HIV) interventions on the trend of TB treatment outcomes during 2010-2013 in Swaziland; and to describe the evolution in TB case notification, the uptake of HIV testing, antiretroviral therapy (ART) and cotrimoxazole preventive therapy (CPT), and the proportion of TB-HIV co-infected patients with adverse treatment outcomes, including mortality, loss to follow-up and treatment failure.

Design: A retrospective descriptive study using aggregated national TB programme data.

Results: Between 2010 and 2013, TB case notifications in Swaziland decreased by 40%, HIV testing increased from 86% to 96%, CPT uptake increased from 93% to 99% and ART uptake among TB patients increased from 35% to 75%. The TB-HIV co-infection rate remained around 70% and the proportion of TB-HIV cases with adverse outcomes decreased from 36% to 30%. Mortality remained high, at 14-16%, over the study period, and anti-tuberculosis treatment failure rates were stable over time (<5%).

Conclusion: Despite high CPT and ART uptake in TB-HIV patients, mortality remained high. Further studies are required to better define high-risk patient groups, understand the reasons for death and design appropriate interventions.

Abstract  Full-text [free] access 

Editor’s notes: This article adds to the body of evidence describing a reduction in TB case notifications at national level at a time of increasing coverage of antiretroviral therapy. Despite the apparent strengthening of the HIV treatment cascade in people with TB, mortality remained high. Around one in seven people with TB and HIV died during TB treatment, and additional deaths may have occurred in people lost to follow-up or with no outcome evaluation.

This analysis using aggregated data does not allow for detailed understanding of why people with TB and HIV died. The authors raise a number of important questions arising from these results. To achieve World Health Organization End TB target of reducing TB deaths by 90% by 2030, we need to understand where to focus resources for maximum impact.

Although not the focus of this paper, it is notable that there appeared to be a relatively stable TB case notification rate in HIV negative people across the four-year study period. This is a reminder that although TB/HIV programmes may be the key to reducing TB mortality, broader population-level programmes to interrupt TB transmission will be required to drive down TB incidence rates.           

Africa
Swaziland
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Role for LAM test in TB diagnosis among the sickest people living with HIV

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

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

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

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Africa
Uganda
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