Articles tagged as "Zambia"

Updated evidence that DMPA increases HIV risk among women

Update on hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence, 2016.

Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN, Westreich DJ, Steyn PS. AIDS. 2016 Aug 5. [Epub ahead of print]

Objective and design: Some studies suggest that specific hormonal contraceptive (HC) methods (particularly depot medroxyprogesterone acetate [DMPA]) may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data.

Methods: We searched for articles published between 1/15/2014-1/15/2016, and hand-searched reference lists. We identified longitudinal studies comparing users of a specific HC method against either (1) non-users of HC, or (2) users of another specific HC method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus no HC.

Results: We identified ten new reports: five were considered "unlikely to inform the primary question". We focus on the other five reports, along with 9 from the previous review, considered "informative but with important limitations". The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate (NET-EN), and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher-quality studies on DMPA (or non-disaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios (HR) between 1.2 and 1.7, consistent with our meta-analytic estimate for all higher-quality studies of HR 1.4.

Conclusions: While confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely ≤HR 1.5. Data for other hormonal contraceptive methods, including NET-EN, are largely reassuring.

Abstract access

Editor’s notes: For several years there has been debate about whether the risk of HIV acquisition in women may be increased by the use of hormonal contraception. A systematic review published in 2014 included a meta-analysis of data from 22 studies, and this paper adds 10 new studies to the analysis. While these new papers carried some of the previous review’s limitations which cannot be ignored, the new data also lends further strength to the evidence and renewed analysis. The authors found some encouraging results which suggest that there is no significant increased risk of HIV with the use of oral contraceptives and the NET-EN injectable. However, this analysis does suggest that there is an increased risk of 1.4-1.5 of HIV with the use of DMPA. This is particularly concerning given the widespread use of this product throughout the world, and especially in areas where high rates of new HIV infections continue to persist, such as sub-Saharan Africa. Studies continue to explore this association of risk, and will hopefully produce evidence in the near future to definitively provide guidance as to how clinicians should direct the use of DMPA in women at risk of HIV. 

Africa, Northern America
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Demand-side activities are essential for achieving population level impact of HIV prevention tools

Interventions to strengthen the HIV prevention cascade: a systematic review of reviews.

Krishnaratne S, Hensen B, Cordes J, Enstone J, Hargreaves JR. Lancet HIV. 2016 Jul;3(7):e307-17. doi: 10.1016/S2352-3018(16)30038-8.

Background: Much progress has been made in interventions to prevent HIV infection. However, development of evidence-informed prevention programmes that translate the efficacy of these strategies into population effect remain a challenge. In this systematic review, we map current evidence for HIV prevention against a new classification system, the HIV prevention cascade.

Methods: We searched for systematic reviews on the effectiveness of HIV prevention interventions published in English from Jan 1, 1995, to July, 2015. From eligible reviews, we identified primary studies that assessed at least one of: HIV incidence, HIV prevalence, condom use, and uptake of HIV testing. We categorised interventions as those seeking to increase demand for HIV prevention, improve supply of HIV prevention methods, support adherence to prevention behaviours, or directly prevent HIV. For each specific intervention, we assigned a rating based on the number of randomised trials and the strength of evidence.

Findings: From 88 eligible reviews, we identified 1964 primary studies, of which 292 were eligible for inclusion. Primary studies of direct prevention mechanisms showed strong evidence for the efficacy of pre-exposure prophylaxis (PrEP) and voluntary medical male circumcision. Evidence suggests that interventions to increase supply of prevention methods such as condoms or clean needles can be effective. Evidence arising from demand-side interventions and interventions to promote use of or adherence to prevention tools was less clear, with some strategies likely to be effective and others showing no effect. The quality of the evidence varied across categories.

Interpretation: There is growing evidence to support a number of efficacious HIV prevention behaviours, products, and procedures. Translating this evidence into population impact will require interventions that strengthen demand for HIV prevention, supply of HIV prevention technologies, and use of and adherence to HIV prevention methods.

Abstract  Full-text [free] access

Editor’s notes: Demand, supply and use of programmes are crucial for the uptake and effective use of HIV prevention strategies. This paper presents an impressive undertaking in which the authors conducted a review of systematic reviews on the evidence for the effectiveness of HIV prevention programmes across the multiple steps in an HIV prevention cascade. This particular prevention cascade allocates programmes into demand-side, supply-side, adherence, and direct HIV prevention technologies. This was published in a separate paper in conjunction with this review. The review found that there is strong evidence with regards to which direct HIV prevention technologies are efficacious, as well as maps where adherence and supply-side programmes have been effective. A primary gap was noted on the demand-side of the cascade (e.g. information, education and communication, and peer-based activities to increase demand for medical male circumcision) where studies have not resulted in reducing HIV incidence or prevalence. There remains a need to understand why, despite supply, there is low uptake of some HIV prevention strategies, and for evaluation of novel activities to increase demand.  

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The negative health impacts of HIV-associated stigma

Examining the associations between HIV-related stigma and health outcomes in people living with HIV/AIDS: a series of meta-analyses.

Rueda S, Mitra S, Chen S, Gogolishvili D, Globerman J, Chambers L, Wilson M, Logie CH, Shi Q, Morassaei S, Rourke SB. BMJ Open. 2016 Jul 13;6(7):e011453. doi: 10.1136/bmjopen-2016-011453.

Objective: To conduct a systematic review and series of meta-analyses on the association between HIV-related stigma and health among people living with HIV.

Data sources: A structured search was conducted on 6 electronic databases for journal articles reporting associations between HIV-related stigma and health-related outcomes published between 1996 and 2013.

Study eligibility criteria: Controlled studies, cohort studies, case-control studies and cross-sectional studies in people living with HIV were considered for inclusion.

Outcome measures: Mental health (depressive symptoms, emotional and mental distress, anxiety), quality of life, physical health, social support, adherence to antiretroviral therapy, access to and usage of health/social services and risk behaviours.

Results: 64 studies were included in our meta-analyses. We found significant associations between HIV-related stigma and higher rates of depression, lower social support and lower levels of adherence to antiretroviral medications and access to and usage of health and social services. Weaker relationships were observed between HIV-related stigma and anxiety, quality of life, physical health, emotional and mental distress and sexual risk practices. While risk of bias assessments revealed overall good quality related to how HIV stigma and health outcomes were measured on the included studies, high risk of bias among individual studies was observed in terms of appropriate control for potential confounders. Additional research should focus on elucidating the mechanisms behind the negative relationship between stigma and health to better inform interventions to reduce the impact of stigma on the health and well-being of people with HIV.

Conclusions: This systematic review and series of meta-analyses support the notion that HIV-related stigma has a detrimental impact on a variety of health-related outcomes in people with HIV. This review can inform the development of multifaceted, intersectoral interventions to reduce the impact of HIV-related stigma on the health and well-being of people living with HIV.

Abstract  Full-text [free] access 

Editor’s notes: There is a growing body of research documenting the negative impact of stigma and discrimination on the health of people living with HIV. Stigma is associated with poorer mental health, including emotional distress, depression and reduced psychological functioning. It has also been linked to intermediate health outcomes such as seeking healthcare and adherence to antiretroviral therapy. This paper reports a comprehensive systematic review and meta-analyses summarising the published evidence on the relationship between HIV-associated stigma and a wide range of health outcomes, including intermediate health outcomes. Results illustrate associations between HIV-associated stigma and depressive symptoms, lower levels of social support, ART adherence and use of health services. However, the majority of studies in the review were cross-sectional and longitudinal studies are necessary to explore the complex relationship between these factors, including the role of moderating factors, such as coping strategies. In addition, more research is necessary from low- and middle-income countries given that much of the published research is from North America. Further, there is also a need to better understand the intersection of HIV-associated stigma with other types of stigma experienced by people living with HIV, including homophobia, racism and gender discrimination. 

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Immediate initiation of HIV treatment is cost-effective, but needs a large portion of health system spending

Changing HIV treatment eligibility under health system constraints in sub-Saharan Africa: Investment needs, population health gains, and cost-effectiveness.

Hontelez JA, Chang AY, Ogbuoji O, Vlas SJ, Barnighausen T, Atun R. AIDS. 2016 Jun 29. [Epub ahead of print]

Objective: We estimated the investment need, population health gains, and cost-effectiveness of different policy options for scaling-up prevention and treatment of HIV in the 10 countries that currently comprise 80% of all people living with HIV in sub-Saharan Africa (Ethiopia, Kenya, Malawi, Mozambique, Nigeria, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe).

Design: We adapted the established STDSIM model, to capture the health system dynamics: demand-side and supply-side constraints in the delivery of antiretroviral treatment (ART).

Methods: We compared different scenarios of supply-side (i.e. health system capacity) and demand-side (i.e. health seeking behavior) constraints, and determined the impact of changing guidelines to ART eligibility at any CD4 cell count within these constraints.

Results: Continuing current scale-up would require US$178 billion by 2050. Changing guidelines to ART at any CD4 cell count is cost-effective under all constraints tested in the model, especially in demand-side constrained health systems because earlier initiation prevents loss to follow-up of patients not yet eligible. Changing guidelines under current demand-side constraints would avert 1.8 million infections at US$208 per life-year saved.

Conclusions: Treatment eligibility at any CD4 cell count would be cost-effective, even under health system constraints. Excessive loss to follow up and mortality in patients not eligible for treatment can be avoided by changing guidelines in demand-side constrained systems. The financial obligation for sustaining the AIDS response in sub-Saharan Africa over the next 35 years is substantial, and requires strong, long-term commitment of policy makers and donors to continue to allocate substantial parts of their budgets.

Abstract access

Editor’s notes: Recent WHO guidelines recommend that everyone who is diagnosed as HIV positive should be allowed to start treatment immediately, a change to the former guideline where their CD4 count (a measure of disease progression) was the main criteria for starting treatment. This paper uses a model to look at the costs and benefits of changing to this immediate treatment regimen in the sub-Saharan African countries most affected by the epidemic. The authors find that allowing all HIV people living with HIV to access treatment is cost-effective, and this finding does not change when the model assumptions are varied. However, the impact of this change on the health system budgets in these countries is very substantial, and the authors suggest that a large commitment is necessary from policymakers and donors to sustain this response as short-term spending will not be enough to make an impact.

Africa
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Changing norms: lessons from HIV advocacy for NCDs prevention

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

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

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

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

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

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

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

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

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

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

Abstract access

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

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

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

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

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

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

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

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

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

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

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

Abstract  Full-text [free] access

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

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

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

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

Comorbidity, HIV testing
Africa
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Profound effect of ART on mortality through reduction of opportunistic infections

Incidence of opportunistic infections and the impact of antiretroviral therapy among HIV-infected adults in low and middle income countries: a systematic review and meta-analysis. 

Low A, Gavriilidis G, Larke N, Lajoie MR, Drouin O, Stover J, Muhe L, Easterbrook P. Clin Infect Dis. 2016 Mar 6. pii: ciw125. [Epub ahead of print]

Background: To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in HIV-infected adults in low and middle-income countries (LMIC).

Methods: Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at CD4 ≥200 cells/µl was estimated using UNAIDS country estimates and global average OI treatment cost per case.

Results: We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range 57-91%) except for tuberculosis, and was largest for oral candidiasis, PCP and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, 43.8-49.4).

Conclusions: There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

Abstract  Full-text [free] access

Editor’s notes: Opportunistic infections (OIs) remain the major cause of HIV-associated mortality. OIs account for substantially higher mortality in low and middle income countries (LMICs) compared to high income countries (HICs).

This paper describes the results of a systematic review and meta-analysis including about 500 000 people on ART in LMICs across three regions (sub-Saharan Africa, Asia, and Latin America). These large numbers enabled the investigators to look at the effect of ART on the incidence of key OIs during and after the first year of treatment.

Not surprisingly they found that the effect of ART reduced the risk of all OIs during the first year after ART initiation, although the reduction was less for tuberculosis. The authors attribute this to the occurrence of tuberculosis across a wide range of CD4 cell counts, a smaller effect of early immune restoration and the contribution of TB as a manifestation of immune reconstitution syndrome during the first months after ART initiation. Beyond one year after ART initiation, the reduction in tuberculosis was greater.

They conclude that the effect of ART on the incidence of most HIV-associated OIs is the key reason for the global decline in HIV-associated mortality. However, a significant proportion of HIV-positive persons still continue to present with advanced disease. Besides timely ART initiation, additional measures such as CTX prophylaxis, screening for TB and cryptococcal disease, and the use of isoniazid and fluconazole prophylaxis should be considered for late presenters. 

Africa, Asia, Latin America
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The conundrum of future funding for HIV – who pays and how?

Long-term financing needs for HIV control in sub-Saharan Africa in 2015-2050: a modelling study. 

Atun R, Chang AY, Ogbuoji O, Silva S, Resch S, Hontelez J, Barnighausen T. BMJ Open. 2016 Mar 6;6(3):e009656. doi: 10.1136/bmjopen-2015-009656.

Objectives: To estimate the present value of current and future funding needed for HIV treatment and prevention in 9 sub-Saharan African (SSA) countries that account for 70% of HIV burden in Africa under different scenarios of intervention scale-up. To analyse the gaps between current expenditures and funding obligation, and discuss the policy implications of future financing needs.

Design: We used the Goals module from Spectrum, and applied the most up-to-date cost and coverage data to provide a range of estimates for future financing obligations. The four different scale-up scenarios vary by treatment initiation threshold and service coverage level. We compared the model projections to current domestic and international financial sources available in selected SSA countries.

Results: In the 9 SSA countries, the estimated resources required for HIV prevention and treatment in 2015-2050 range from US$98 billion to maintain current coverage levels for treatment and prevention with eligibility for treatment initiation at CD4 count of <500/mm3 to US$261 billion if treatment were to be extended to all HIV-positive individuals and prevention scaled up. With the addition of new funding obligations for HIV–which arise implicitly through commitment to achieve higher than current treatment coverage levels–overall financial obligations (sum of debt levels and the present value of the stock of future HIV funding obligations) would rise substantially.

Conclusions: Investing upfront in scale-up of HIV services to achieve high coverage levels will reduce HIV incidence, prevention and future treatment expenditures by realising long-term preventive effects of ART to reduce HIV transmission. Future obligations are too substantial for most SSA countries to be met from domestic sources alone. New sources of funding, in addition to domestic sources, include innovative financing. Debt sustainability for sustained HIV response is an urgent imperative for affected countries and donors

Abstract  Full-text [free] access 

Editor’s notes: The authors of this interesting paper use the most up-to-date cost and coverage data to provide a range of estimates for future treatment financing obligations. Epidemiological parameters are included to fit the Goals model and key prevention services such as ‘prevention of mother-to-child HIV transmission’ and ‘voluntary medical male circumcision’ are also included.

Financing needs for the nine countries are estimated by varying treatment initiation threshold (everyone initiated on treatment versus initiation at CD4 of <500cells/mm3) and/or coverage level for prevention and treatment (‘current’ levels and a ‘scale up’ scenario). The authors also attempt to assess both the ethics and the cost of different approaches.

For all scenarios, there is a steady decline in proportion of treatment costs and an increase in the proportion of prevention costs. This apparent contradiction is largely because there will be fewer individuals on treatment over time but prevention costs rise because they are mostly invested in non-infected populations, which increases with population growth.

In the nine countries, estimated resources required for HIV prevention and treatment from 2015-2050 will be large. This is increased further when human resources and supplies increase at the rate of GDP per capita.

However, there is undoubtedly an ethical responsibility to not only continue financing people receiving ART, but, that the responsibility extends to people in equal need who are not on treatment. The ethics is underpinned by the evidence. This illustrates how ‘front-loading’ investments in HIV scale-up now to ensure high levels of coverage, will significantly reduce future HIV incidence and prevalence. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract access

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

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

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

Comorbidity, HIV Treatment
Africa, Asia, Latin America
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