Articles tagged as "Taiwan"

Despite better access to HIV treatment we need stronger evidence based guidance on treating people with serious complications of advanced HIV infection

Editor’s notes: The emphasis for scaling up HIV treatment usually focuses on outpatient and primary care clinics with increasing decentralization to the community.  It is therefore sobering to see the results of a randomized trial conducted at a national referral hospital in Zambia.  Andrews and colleagues report on 209 adults admitted to hospital with sepsis and hypotension, a combination referred to as septic shock.  Several important points emerge.  Almost 90% of patients admitted with this serious condition were HIV-positive.  Most had only been diagnosed with HIV infection in the last three months, and approximately half were taking ART.  The median CD4 count was only 70 cells per microlitre. Almost half had a history of having tuberculosis and one quarter were currently on anti-tuberculosis treatment at the time of admission to hospital. Most were also anaemic, with an average haemoglobin of 7.8 g/dl. Mortality from septic shock has been falling in Europe and the United States of America largely due to more intensive management of intravenous fluids and blood pressure.  The focus has been on strict protocols to ensure that all patients get the best treatment. However, there has been debate about the best approach to take when less sophisticated monitoring and supportive technology such as artificial ventilation is not available. In this Zambian tertiary hospital setting, only one patient was able to be managed in the intensive care unit due to resource constraints.  Patients were randomized to receive a protocolized intensive fluid and blood pressure resuscitation or to receive the more standard care with the responsible physicians making the decisions.  The death rate from this severe condition was very high.  85 of the 209 patients randomized died.  However, despite receiving more intravenous fluids, more blood transfusions and more drugs to raise blood pressure, the outcomes were worse in the group treated according to the protocol with 48% mortality compared to 33% in the standard care arm.  As always, the lesson is that many of these deaths could have been avoided if we were able to diagnose, link and treat people living with HIV much earlier in the course of their infection.  However, there is also an important caution that treatments that make good sense and seem the best course of action may in fact make the situation worse, even if the same treatments have been shown in other contexts to be beneficial.  Such information will only come from randomized trials, and the authors should be congratulated for being bold enough to conduct a high-quality study that should make us reflect on our preconceptions about how best to treat seriously ill patients in resource poor settings.

Andrade and colleagues have reviewed the literature in order to determine the best approach to treating critically unwell people living with HIV who are admitted to intensive care units.  They examined whether starting ARVs while the person was already critically ill was associated with better outcomes.  Patients in intensive care may already have many different medicines, as well as altered metabolism.  In addition, ARVs can provoke immune reconstitution inflammatory syndromes that have been shown to make outcomes worse in some serious conditions such as cryptococcal meningitis.  On the other hand, the evidence from patients with tuberculosis is clear – starting ARVs as soon as possible is associated with better outcomes.  In this review and meta-analysis, there was a clear short-term advantage to starting ARVs while the patient was still in intensive care.  The data were not sufficient to tell whether the longer-term outcome as also improved by the earlier start of ART.  One limitation is that all the studies reviewed were observational, and the decision to start ARVs was not randomized, so that it is plausible that clinicians may have started ARVs more willingly in those patients who were most likely to survive.  Nonetheless, in the absence of randomized trials, this study makes a strong case for starting ARVs promptly even in the sickest patients.

Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial.

Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR. JAMA. 2017 Oct 3;318(13):1233-1240. doi: 10.1001/jama.2017.10913.

Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown.

Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care.

Design, setting, and participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013.

Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management.

Main outcomes and measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors.

Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001).

Conclusions and relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations.

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Highly active antiretroviral therapy for critically ill HIV patients: a systematic review and meta-analysis.

Andrade HB, Shinotsuka CR, da Silva IRF, Donini CS, Yeh Li H, de Carvalho FB, Americano do Brasil PEA, Bozza FA, Miguel Japiassu A. PLoS One. 2017 Oct 24;12(10):e0186968. doi:10.1371/journal.pone.0186968. eCollection 2017

Introduction: It is unclear whether the treatment of an HIV infection with highly active antiretroviral therapy (HAART) affects intensive care unit (ICU) outcomes. In this paper, we report the results of a systematic review and meta-analysis performed to summarize the effects of HAART on the prognosis of critically ill HIV positive patients.

Materials and methods: A bibliographic search was performed in 3 databases (PubMed, Web of Science and Scopus) to identify articles that investigated the use of HAART during ICU admissions for short- and long-term mortality or survival. Eligible articles were selected in a staged process and were independently assessed by two investigators. The methodological quality of the selected articles was evaluated using the Methodological Index for Non-Randomized Studies (MINORS) tool.

Results: Twelve articles met the systematic review inclusion criteria and examined short-term mortality. Six of them also examined long-term mortality (≥90 days) after ICU discharge. The short-term mortality meta-analysis showed a significant beneficial effect of initiating or maintaining HAART during the ICU stay (random effects odds ratio 0.53, p = 0.02). The data analysis of long-term outcomes also suggested a reduced mortality when HAART was used, but the effect of HAART on long-term mortality of HIV positive critically ill patients remains uncertain.

Conclusions: This meta-analysis suggests improved survival rates for HIV positive patients who were treated with HAART during their ICU admission.

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Technology for tuberculosis, but why can’t we simply prevent it with proven tools that save lives?

Editor’s notes: Advances in diagnostic test technology have transformed the management of HIV and related infections.  For HIV, we have seen the introduction of self-administered test kits as well as new approaches to HIV viral load testing and nucleic acid based infant diagnosis.  Cryptococcal antigen screening can make prophylaxis and treatment more focused and potentially cost-effective.  For tuberculosis the biggest revolution has been the widespread introduction of the geneXpert® system.  The newest version, the Xpert® Ultra, is more sensitive than the original cartridge and is now being scaled up in countries including South Africa.  Agizew and colleagues conducted a study in Botswana to compare how the Xpert® MTB/RIF cartridge performed when used in centralized or peripheral health facilities.  Encouragingly there were few differences between the two levels, suggesting that the systems can be used close to the point of care.  However, the authors did note a surprisingly high level of unsuccessful tests (15%) both at the central lab and at the peripheral clinic.  Many of these test failures seem to have been because the sample was not processed correctly, and so should be amenable to better training for the health care workers performing the test.  The yield of testing varied greatly between the 13 sites. Between 1% and 23% of samples were positive for tuberculosis, with an average of 14%.  This may be because some sites were receiving specialized referrals.  Of the 447 positive samples, 8% were shown to be rifampicin resistant.  This figure is hard to interpret without more detail of the sample of patients in whom the test was performed.  Resistance is always higher among those who have been treated previously and may be higher in those referred to specialized centres.  Nonetheless, it demonstrates that there are a significant number of people with tuberculosis in Botswana who are very likely to have multi-drug resistant disease and need effective second line treatment.  Technology comes with a price tag.  In this study, the team bought test kits for $18 each, which makes it an expensive choice.  However, if it leads to prompt treatment of multi-drug resistant disease and more accurate diagnosis of tuberculosis, including among those living with HIV, this might still be cost-effective.

A small implementation research study from a single provincial referral centre in Zambia also examined the use and results of geneXpert® screening.  Masenga and colleagues found that 6.6% of 2374 samples tested by geneXpert® over the course of a year were positive for tuberculosis.  An additional 1301 samples were tested by sputum microscopy.  Their results suggest that geneXpert® was used mainly on people who were living with HIV, given that more than 90% of the positive samples came from people living with HIV.  5.9% of the 152 positive samples that were tested in the system were resistant to rifampicin, with no difference by gender.  This study leaves many questions unanswered, such as the sampling strategy, the history of previous treatment and the outcomes of the diagnosis in terms of treatment regimen and success.  However, it shines a light on the ways that new technology is now routine in some settings.  We need more research from diverse settings to paint the full picture of implementation outside traditional research centres.

Zenner and colleagues revisit the question of the risks and benefits of treatment for latent tuberculosis infection.  In a systematic review and network meta-analysis, they demonstrate once more that we have several effective ways to prevent tuberculosis among people living with HIV and that the harms are much smaller than the risks.  The question remains why we have failed so badly to scale up preventive therapy for tuberculosis alongside the success in scale up of antiretrovirals.


Peripheral clinic versus centralized laboratory-based XPERT® MTB/RIF performance: experience gained from a pragmatic, stepped-wedge trial in Botswana

Agizew T, Boyd R, Ndwapi N, Auld A, Basotli J, Nyirenda S, Tedla Z, Mathoma A, Mathebula U, Lesedi C, Pals S, Date A, Alexander H, Kuebrich T, Finlay A. PLoS One. 2017 Aug 17;12(8):e0183237. doi: 10.1371/journal.pone.0183237. eCollection 2017.

Background: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert® MTB/RIF (Xpert®) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert® scale-up.

Methods: Xpert® was implemented from August 2012 through November 2014 with 13 GeneXpert® instruments (GeneXpert®) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert® testing. We documented our experience with staff training and GeneXpert® performance. Test results were extracted from GeneXpert® software; unsuccessful tests were analysed in relation to testing sites and trends over time.

Results: During 276 instrument-months of operation a total of 3630 tests were performed, of which 3102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3630 Xpert® tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert® instruments (14%, 95% CI: 11-17%; p = 0.140).

Conclusions: Xpert® introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert® location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert® testing staff is essential to minimize errors.

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Rifampicin resistance in mycobacterium tuberculosis patients using GeneXpert® at Livingstone Central Hospital for the year 2015: a cross sectional explorative study

Masenga SK, Mubila H, Hamooya BM. BMC Infect Dis. 2017 Sep 22;17(1):640. doi: 10.1186/s12879-017-2750-9

Background: Since the recent introduction of GeneXpert® for the detection of Tuberculosis (TB) drug resistance mutations in both primary resistance and acquired resistance in Zambia, little has been documented in literature on the issue of rifampicin resistance especially in the face of a high National TB burden. The study aimed to determine the prevalence of rifampicin resistance in tuberculosis patients at Livingstone Central Hospital for the year 2015.

Methods: This was a cross sectional study conducted at Livingstone Central Hospital where we reviewed 152 records (from January 1, 2015 to 31st December 2015) involving patients who presented with clinically suspected TB or documented TB, whose samples were sent to the laboratory for GeneXpert® Mycobacterium tuberculosis/rifampicin testing. Statistical evaluations used a one-sample test of proportion and Fisher's exact test.

Results: The age of participants ranged from 8 months to 73 years old (median = 34). Of the participants with complete data on gender, 99 (66%) and 52 (34%) were males and females respectively. The TB co-infection with HIV prevalence was 98.3% (p < 0.001). Prevalence of rifampicin resistance was 5.9% and there was no statistical significant difference between being male or female (p = 0.721).

Conclusion: We were able to show from our study, evidence of rifampicin resistance at Livingstone Central Hospital. Hence, there was need for further in-depth research and appropriate interventions (i.e. close follow-up and patient care for drug resistance positive patients).

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Treatment of latent tuberculosis infection: an updated network meta-analysis

Zenner D, Beer N, Harris RJ, Lipman MC, Stagg HR, van der Werf MJ.  Ann Intern Med. 2017 Aug 15;167(4):248-255. doi: 10.7326/M17-0609. Epub 2017 Aug 1.

Background: Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.

Purpose: To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.

Data sources: PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.

Study selection: Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).

Data extraction: 2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.

Data synthesis: The network meta-analysis of 8 new and 53 previously included studies showed that isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.

Limitation: Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.

Conclusion: Evidence exists for the efficacy and safety of 6-month isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of isoniazid and rifampicin.

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H*V – can we do better for HIV, HBV and HCV if we all work together?

Editor’s notes: The Sustainable Development Goals (SDGs) signal a major shift in the way that the United Nations and her development partners aim to shape the next decades.  Whereas the Millennium Development Goals reinforced specific programmes for HIV, tuberculosis and malaria, the SDGs call for a more integrated approach to health and well-being and encourage integration and synergy wherever it makes sense.  Hepatitis is one obvious area in which better collaboration and coordination could yield benefits.  Hepatitis B (HBV) and C (HCV) viruses are both more common in some of the populations most affected by HIV.  HCV can now be cured with drugs that derive directly from the HIV portfolio, while some ARVs have a direct effect on HBV.

Rwanda is one of the first countries in sub-Saharan Africa to set up a control programme for viral hepatitis, building on the infrastructure established for HIV. Umutesi and colleagues report on results of screening almost 120 000 people living with HIV who entered care for markers of HBV and HCV.  Around 5000 people (4.3%) were identified with a positive Hepatitis B surface antigen and a similar number (4.6%) were found to have antibodies against HCV.  There was marked variation geographically with a range by district from 2%-11% for HBV, higher in more urban areas and in men.  For HCV the range was from 3%-8% and was higher in more rural areas, and also in men.  This study provides a good platform to estimate numbers of people who might need treatment and to plan the next steps in an integrated programme.

People who inject drugs are particularly severely affected by HCV, and so co-infection with both HIV and HCV is common in areas where both viruses circulate.  Some estimates from Ho Chi Minh City in Viet Nam suggest that more than 40% of people who inject drugs are living with HIV and that essentially all of these people are also co-infected with HCV.  Birger R and colleagues developed a mathematical model to explore the likely impact of interventions aimed at HIV, HCV or broad harm reduction [with methadone maintenance treatment (MMT)] on future mortality and incidence of both infections.  While ART scale up reduces HIV incidence and mortality, it has no effect on HCV.  MMT is effective at reducing incidence of both HIV and HCV (and has morbidity and mortality benefits beyond these viruses).  However, MMT does not help the many people already living with HCV and so has little effect on HCV related mortality. So the model is clear that treatment for HCV needs to be an important part of a combined programme and that we urgently need to find ways to reduce the price of directly acting antivirals if we are to save more Vietnamese lives.

Haldane and colleagues have also focused on this intersection between HIV and substance use services.  They carried out a systematic review to understand the models and implications of integration of service delivery.  The authors expand their typology of integration models considering the point of entry of the client, and the degree to which services are co-located and delivered.  Integration can be considered as “clinical”, “service” or “systems”.  The first two can operate at the micro or meso level meaning that individual staff can deal with both situations, or that staff are trained to provide appropriate referrals.  Systems level integration operates at a macro level and implies that programmes for each service make collaborations and coordinate in ways that may affect staffing, funding and fragmentation of services. Although there are theoretical advantages to coordination and integration (as shown by the mathematical model above), there are few good empirical studies of integrated service delivery reported outside the USA.  The authors considered that most of the intervention studies had a risk of bias in the interpretation of their impact, although all demonstrated positive changes in outcomes.  Furthermore, almost all the studies focussed on integration at the clinic or individual provider level (meso or micro) rather than addressing the larger systemic challenges that we need to consider.  If we are to achieve the ideals laid out in the Sustainable Development Goals, we will need to overcome some of these systemic challenges, particularly for populations that are criminalized and marginalized by many of the public services.

Prevalence of hepatitis B and C infection in persons living with HIV enrolled in care in Rwanda.

Umutesi J, Simmons B, Makuza JD, Dushimiyimana D, Mbituyumuremyi A, Uwimana JM, Ford N, Mills EJ, Nsanzimana S. BMC Infect Dis. 2017 May 2;17(1):315. doi: 10.1186/s12879-017-2422-9.

Background: Hepatitis B (HBV) and C (HCV) are important causes of morbidity and mortality in people living with human immunodeficiency virus (HIV). The burden of these co-infections in sub-Saharan Africa is still unclear. We estimated the prevalence of the hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCVAb) among HIV-infected individuals in Rwanda and identified factors associated with infection.

Methods: Between January 2016 and June 2016, we performed systematic screening for HBsAg and HCVAb among HIV-positive individuals enrolled at public and private HIV facilities across Rwanda. Results were analyzed to determine marker prevalence and variability by demographic factors.

Results: Overall, among 117 258 individuals tested, the prevalence of HBsAg and HCVAb was 4.3% (95% confidence interval [CI] (4.2-4.4) and 4.6% (95% CI 4.5-4.7) respectively; 182 (0.2%) HIV+ individuals were co-infected with HBsAg and HCVAb. Prevalence was higher in males (HBsAg, 5.4% [5.1-5.6] vs. 3.7% [3.5-3.8]; HCVAb, 5.0% [4.8-5.2] vs. 4.4% [4.3-4.6]) and increased with age; HCVAb prevalence was significantly higher in people aged ≥65 years (17.8% [16.4-19.2]). Prevalence varied geographically.

Conclusion: HBV and HCV co-infections are common among HIV-infected individuals in Rwanda. It is important that viral hepatitis prevention and treatment activities are scaled-up to control further transmission and reduce the burden in this population. Particular efforts should be made to conduct targeted screening of males and the older population. Further assessment is required to determine rates of HBV and HCV chronicity among HIV-infected individuals and identify effective strategies to link individuals to care and treatment.

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The impact of HCV therapy in a high HIV-HCV prevalence population: A modeling study on people who inject drugs in Ho Chi Minh City, Vietnam.

Birger RB, Le T, Kouyos RD, Grenfell BT, Hallett TB. PLoS One. 2017 May 11;12(5):e0177195. doi: 10.1371/journal.pone.0177195. eCollection 2017.

Background: Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) coinfection is a major global health problem especially among people who inject drugs (PWID), with significant clinical implications. Mathematical models have been used to great effect to shape HIV care, but few have been proposed for HIV/HCV.

Methods: We constructed a deterministic compartmental ODE model that incorporated layers for HIV disease progression, HCV disease progression and PWID demography. Antiretroviral therapy (ART) and Methadone Maintenance Therapy (MMT) scale-ups were modeled as from 2016 and projected forward 10 years. HCV treatment roll-out was modeled beginning in 2026, after a variety of MMT scale-up scenarios, and projected forward 10 years.

Results: Our results indicate that scale-up of ART has a major impact on HIV though not on HCV burden. MMT scale-up has an impact on incidence of both infections. HCV treatment roll-out has a measurable impact on reductions of deaths, increasing multifold the mortality reductions afforded by just ART/MMT scale-ups.

Conclusion: HCV treatment roll-out can have major and long-lasting effects on averting PWID deaths on top of those averted by ART/MMT scale-up. Efficient intervention scale-up of HCV alongside HIV interventions is critical in Vietnam.

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Integrating HIV and substance use services: a systematic review

Haldane V, Cervero-Liceras F, Chuah FL, Ong SE, Murphy G, Sigfrid L, Watt N, Balabanova D, Hogarth S, Maimaris W, Buse K, Piot P, McKee M, Perel P, Legido-Quigley H. Journal of the International AIDS Society. 2017 May 30;20(1).

Introduction: Substance use is an important risk factor for HIV, with both concentrated in certain vulnerable and marginalized populations. Although their management differs, there may be opportunities to integrate services for substance use and HIV. In this paper we systematically review evidence from studies that sought to integrate care for people living with HIV and substance use problems.

Methods: Studies were included if they evaluated service integration for substance use and HIV. We searched multiple databases from inception until October 2015. Articles were screened independently by two reviewers and assessed for risk of bias.

Results and discussion: 11 057 records were identified, with 7616 after removal of duplicates. After screening titles and abstracts, 51 met the inclusion criteria. Integration models were categorized by location (HIV, substance use and other facilities), level of integration from micro (integrated care delivered to individuals) to macro (system level integrations) and degree of integration from least (screening and counselling only) to most (care for HIV, substance use and/or other illnesses at the same facility). Most reported descriptive or cohort studies; in four randomized control trials integrated activities improved patient outcomes. There is potential for integrating services at all facility types, including mobile health services. While services offering screening only can achieve synergies, there are benefits from delivering integrated treatment for HIV and substance use, including ease of referral to other mental health and social services.

Conclusions: Our review used a wide range of databases and conference archives to increase representation of papers from low- and middle-income countries. Limitations include the overrepresentation of studies from the United States, and the descriptive nature of the majority of papers. The evidence reviewed shows that greater integration offers important benefits in both patient and service outcomes but further research and outcome reporting is needed to better understand innovative and holistic care models at the complex intersection of substance use and HIV services.

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Africa, Asia, Europe, Northern America
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AIDS and bacterial disease remain leading causes of hospital admission

Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis.

Ford N, Shubber Z, Meintjes G, Grinsztejn B, Eholie S, Mills EJ, Davies MA, Vitoria M, Penazzato M, Nsanzimana S, Frigati L, O'Brien D, Ellman T, Ajose O, Calmy A, Doherty M. Lancet HIV. 2015 Oct;2(10):e438-44. doi: 10.1016/S2352-3018(15)00137-X. Epub 2015 Aug 11.

Background: Morbidity associated with HIV infection is poorly characterised, so we aimed to investigate the contribution of different comorbidities to hospital admission and in-hospital mortality in adults and children living with HIV worldwide.

Methods: Using a broad search strategy combining terms for hospital admission and HIV infection, we searched MEDLINE via PubMed, Embase, Web of Science, LILACS, AIM, IMEMR and WPIMR from inception to Jan 31, 2015, to identify studies reporting cause of hospital admission in people living with HIV. We focused on data reported after 2007, the period in which access to antiretroviral therapy started to become widespread. We estimated pooled proportions of hospital admissions and deaths per disease category by use of random-effects models. We stratified data by geographical region and age.

Findings: We obtained data from 106 cohorts, with reported causes of hospital admission for  313 006 adults and 6182 children living with HIV. For adults, AIDS-related illnesses (25 119 patients, 46%, 95% CI 40-53) and bacterial infections (14 034 patients, 31%, 20-42) were the leading causes of hospital admission. These two categories were the most common causes of hospital admission for adults in all geographical regions and the most common causes of mortality. Common region-specific causes of hospital admission included malnutrition and wasting, parasitic infections, and haematological disorders in the Africa region; respiratory disease, psychiatric disorders, renal disorders, cardiovascular disorders, and liver disease in Europe; haematological disorders in North America; and respiratory, neurological, digestive and liver-related conditions, viral infections, and drug toxicity in South and Central America. For children, AIDS-related illnesses (783 patients, 27%, 95% CI 19-34) and bacterial infections (1190 patients, 41%, 26-56) were the leading causes of hospital admission, followed by malnutrition and wasting, haematological disorders, and, in the African region, malaria. Mortality in individuals admitted to hospital was 20% (95% CI 18-23, 12 902 deaths) for adults and 14% (10-19, 643 deaths) for children.

Interpretation: This review shows the importance of prompt HIV diagnosis and treatment, and the need to reinforce existing recommendations to provide chemoprophylaxis and vaccination against major preventable infectious diseases to people living with HIV to reduce serious AIDS and non-AIDS morbidity.

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Editor’s notes: Despite the widening availability of antiretroviral therapy (ART), HIV-associated disease remains an important cause of illness and death. In this systematic review the authors summarise published data concerning causes of hospital admission among HIV-positive people since 2007. This date was selected on the basis that access to ART was limited prior to 2007.

Overall the most common causes of admission among adults, across all geographical regions, were AIDS-associated illness and bacterial infections. Tuberculosis was the most common cause among adults, accounting for 18% of all admissions, followed by bacterial pneumonia (15%). Among children, similarly AIDS-associated illnesses (particularly tuberculosis and Pneumocystis pneumonia) and bacterial infections were the most common causes of admission. Among the 20% of adults who died during their admission, the most common causes of death were tuberculosis, bacterial infections, cerebral toxoplasmosis and cryptococcal meningitis. Among children the most common causes of death were tuberculosis, bacterial infections and Pneumocystis pneumonia. Tuberculosis is likely to have been underestimated in these studies. Autopsy studies consistently illustrate that around half of HIV-positive people who have tuberculosis identified at autopsy had not been diagnosed prior to death.

The review highlights that the majority of severe HIV-associated disease remains attributable to advanced immunosuppression. This is reflected by a median CD4 count at admission among adults of 168 cells per µl. Some 30% of people first tested HIV positive at the time of the admission. The review underlines the need to promote HIV testing so that HIV-positive people can access ART, and prevent the complications of advanced HIV disease. It also underscores the need for better coverage of screening for tuberculosis and preventive therapy for people without active disease.  

Avoid TB deaths
Comorbidity, Epidemiology
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Increasing transmitted resistance to antiretroviral therapy in low/middle-income countries - highest prevalence in MSM

Global burden of transmitted HIV drug resistance and HIV-exposure categories: a systematic review and meta-analysis.

Pham QD, Wilson DP, Law MG, Kelleher AD, Zhang L. AIDS. 2014 Nov 28;28(18):2751-62. doi: 10.1097/QAD.0000000000000494.

Objectives: Our aim was to review the global disparities of transmitted HIV drug resistance (TDR) in antiretroviral-naive MSM, people who inject drugs (PWID) and heterosexual populations in both high-income and low/middle-income countries.

Design/methods: We undertook a systematic review of the peer-reviewed English literature on TDR (1999-2013). Random-effects meta-analyses were performed to pool TDR prevalence and compare the odds of TDR across at-risk groups.

Results: A total of 212 studies were included in this review. Areas with greatest TDR prevalence were North America (MSM: 13.7%, PWID: 9.1%, heterosexuals: 10.5%); followed by western Europe (MSM: 11.0%, PWID: 5.7%, heterosexuals: 6.9%) and South America (MSM: 8.3%, PWID: 13.5%, heterosexuals: 7.5%). Our data indicated disproportionately high TDR burdens in MSM in Oceania (Australia 15.5%), eastern Europe/central Asia (10.2%) and east Asia (7.8%). TDR epidemics have stabilized in high-income countries, with a higher prevalence (range 10.9-12.6%) in MSM than in PWID (5.2-8.3%) and heterosexuals (6.4-9.0%) over 1999-2013. In low/middle-income countries, TDR prevalence in all at-risk groups in 2009-2013 almost doubled than that in 2004-2008 (MSM: 7.8 vs. 4.2%, P = 0.011; heterosexuals: 4.1 vs. 2.6%, P < 0.001; PWID: 4.8 vs. 2.4%, P = 0.265, respectively). The risk of TDR infection was significantly greater in MSM than that in heterosexuals and PWID. We observed increasing trends of resistance to non-nucleoside reverse transcriptase and protease inhibitors among MSM.

Conclusion: TDR prevalence is stabilizing in high-income countries, but increasing in low/middle-income countries. This is likely due to the low, but increasing, coverage of antiretroviral therapy in these settings. Transmission of TDR is most prevalent among MSM worldwide.

Abstract access 

Editor’s notes: HIV mutates very rapidly, and many early antiretroviral agents had a low genetic barrier to the development of resistance. Thus the emergence of virus resistant to antiretroviral agents, particularly to early drug classes, was inevitable. Surveillance for drug-resistant virus among people with no prior history of taking antiretroviral drugs (transmitted drug resistance) is essential to monitor the spread of drug resistance at population level.

This systematic review aimed to compare transmitted drug resistance in different geographical regions and between subpopulations of HIV-positive people by likely route of transmission. Transmitted resistance was most prevalent in high income settings. This is not surprising given wide use of suboptimal drug regimens before effective triple therapy was available. Reassuringly, the prevalence of transmitted resistance seems to have stabilised in high-income settings. The increase in transmitted resistance in low and middle income countries is of more concern. It is not surprising, given that first-line regimens comprising two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor are vulnerable to the development of resistance if the drug supply is interrupted or adherence is suboptimal. In addition, if viral load monitoring is not available, people remain on failing drug regimens for longer, and thus have more risk of transmitting resistant virus.

Within the subpopulations examined in this review, transmitted resistance was consistently higher in men who have sex with men, suggesting that resistance testing prior to treatment is particularly valuable for this population.

Limitations of the review include exclusion of studies that did not compare transmitted resistance between the specified subpopulations, and small sample size in many subgroups.

Continued surveillance for transmitted drug resistance is critical. This is most important in settings where individualised resistance testing is not available. This will ensure that people starting antiretroviral therapy receive treatment that will suppress their viral load effectively. Wider use of viral load monitoring, combined with access to effective second and third line regimens, will also help limit spread of drug resistance.

HIV Treatment
Angola, Argentina, Australia, Austria, Belgium, Benin, Botswana, Brazil, Burkina Faso, Cambodia, Cameroon, Canada, Central African Republic, Chad, China, Côte d'Ivoire, Croatia, Cuba, Cyprus, Denmark, Dominican Republic, El Salvador, Estonia, Ethiopia, France, Gabon, Georgia, Germany, Greece, Guatemala, Honduras, Hong Kong Special Administrative Region of China, Hungary, India, Indonesia, Ireland, Israel, Italy, Japan, Kazakhstan, Kenya, Latvia, Malawi, Malaysia, Moldova, Mozambique, Netherlands, Peru, Philippines, Poland, Portugal, Republic of Korea, Romania, Russia, Rwanda, Slovenia, South Africa, Spain, Swaziland, Sweden, Switzerland, Taiwan, Thailand, Uganda, United Kingdom of Great Britain and Northern Ireland, United Republic of Tanzania, United States of America, Viet Nam, Zambia, Zimbabwe
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Antiretroviral therapy alone not enough to reduce TB incidence where HIV- and TB- prevalence is high

Incidence of HIV-associated tuberculosis among individuals taking combination antiretroviral therapy: a systematic review and meta-analysis.

Kufa T, Mabuto T, Muchiri E, Charalambous S, Rosillon D, Churchyard G, Harris RC. PLoS One. 2014 Nov 13;9(11):e111209. doi: 10.1371/journal.pone.0111209. eCollection 2014.

Background: Knowledge of tuberculosis incidence and associated factors is required for the development and evaluation of strategies to reduce the burden of HIV-associated tuberculosis.

Methods: Systematic literature review and meta-analysis of tuberculosis incidence rates among HIV-infected individuals taking combination antiretroviral therapy.

Results: From PubMed, EMBASE and Global Index Medicus databases, 42 papers describing 43 cohorts (32 from high/intermediate and 11 from low tuberculosis burden settings) were included in the qualitative review and 33 in the quantitative review. Cohorts from high/intermediate burden settings were smaller in size, had lower median CD4 cell counts at study entry and fewer person-years of follow up. Tuberculosis incidence rates were higher in studies from sub-Saharan Africa and from World Bank low/middle income countries. Tuberculosis incidence rates decreased with increasing CD4 count at study entry and duration on combination antiretroviral therapy. Summary estimates of tuberculosis incidence among individuals on combination antiretroviral therapy were higher for cohorts from high/intermediate burden settings compared to those from the low tuberculosis burden settings (4.17 per 100 person-years [95% Confidence Interval (CI) 3.39-5.14 per 100 person-years] vs. 0.4 per 100 person-years [95% CI 0.23-0.69 per 100 person-years]) with significant heterogeneity observed between the studies.

Conclusions: Tuberculosis incidence rates were high among individuals on combination antiretroviral therapy in high/intermediate burden settings. Interventions to prevent tuberculosis in this population should address geographical, socioeconomic and individual factors such as low CD4 counts and prior history of tuberculosis.

Abstract Full-text [free] access

Editor’s notes: This systematic review and meta-analysis looks at tuberculosis (TB) incidence rates among adults living with HIV on antiretroviral treatment (ART). The review reinforces and quantifies what we already know about the disparities between low-burden and high-burden settings. TB incidence rates in high and intermediate burden settings are ten times higher than those in low burden settings.

The authors draw attention to the need for implementation of programmes that address the social determinants of TB. Low socio-economic conditions are associated with higher TB incidence rates in individuals on ART. Interestingly, the meta-analysis found that TB incidence rates were higher among individuals on ART who had a previous history of TB, than individuals who did not have a history of previous TB. The epidemiological association between previous TB treatment and active TB was one of the foundations for the emphasis on case retention and cure rates with the Directly Observed Treatment, Short-Course (DOTS) strategy. Yet prevalence surveys conducted in Zimbabwe, South Africa and Zambia in the pre-ART and early ART era did not find an association between a history of previous TB and prevalent active undiagnosed TB in individuals living with HIV. The finding from this meta-analysis suggests that individuals on ART are now surviving long enough to develop recurrent TB disease.

The overall message of the study is that ART alone is not sufficient to reduce TB incidence in high HIV prevalence settings. Additional strategies are required to prevent TB focussing on individuals with low CD4 counts, a history of previous TB disease and people who have recently initiated ART.

Avoid TB deaths
Africa, Asia, Europe, Northern America
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Counting and classifying global deaths

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Murray CJ, Ortblad KF, Guinovart C, et al. Lancet. 2014 Sep 13;384(9947):1005-70. doi: 10.1016/S0140-6736(14)60844-8. Epub 2014 Jul 22.

Background: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occurred since the Millennium Declaration.

Methods: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

Findings: Globally in 2013, there were 1.8 million new HIV infections (95% uncertainty interval 1.7 million to 2.1 million), 29.2 million prevalent HIV cases (28.1 to 31.7), and 1.3 million HIV deaths (1.3 to 1.5). At the peak of the epidemic in 2005, HIV caused 1.7 million deaths (1.6 million to 1.9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19.1 million life-years (16.6 million to 21.5 million) have been saved, 70.3% (65.4 to 76.1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$ 4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7.5 million (7.4 million to 7.7 million), prevalence was 11.9 million (11.6 million to 12.2 million), and number of deaths was 1.4 million (1.3 million to 1.5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7.1 million (6.9 million to 7.3 million), prevalence was 11.2 million (10.8 million to 11.6 million), and number of deaths was 1.3 million (1.2 million to 1.4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64.0% of cases (63.6 to 64.3) and 64.7% of deaths (60.8 to 70.3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1.2 million deaths (1.1 million to 1.4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31.5% (15.7 to 44.1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

Interpretation: Our estimates of the number of people living with HIV are 18.7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

Abstract  Full-text [free] access

Editor’s notes: The Global Burden of Disease (GBD) study uses standard methods to compare and track over time national distributions of deaths by cause, and the prevalence of disease and disability.  This detailed report focuses on HIV, TB and Malaria. It presents regional summaries of incidence, prevalence and mortality rates, and national estimates of the number of male and female deaths and new infections. Point estimates are shown for 2013, and annualised rates of change for 1990-2000 and 2000-2013. These highlight the contrasting trends in disease impact before and after the formulation of the Millennium Development Goal to combat these diseases.  The global peak of HIV mortality occurred in 2005, but regional annualised rates of change for 2000-2013 indicate that HIV deaths are still increasing significantly in east Asia, southern Africa, and most rapidly in eastern Europe.

The GBD 2013 global estimates of new infections and deaths agree closely with the corresponding estimates made by UNAIDS. But there are significant differences in the respective estimates of the number of people currently living with HIV (UNAIDS estimates are some 18% higher), and historical trends in AIDS deaths, with UNAIDS judging that the recent fall has been steeper. These differences are attributed primarily to methods used in the GBD study to ensure that the sum of deaths from specific causes fits the estimated all cause total, and to varying assumptions about historical survival patterns following HIV infection. 

It may be worthwhile to look at a comment by Michel Sidibé, Mark Dybul, and Deborah Birx in the Lancet on MDG 6 and beyond: from halting and reversing AIDS to ending the epidemic which refers to this study.

Afghanistan, Albania, Algeria, Andorra, Angola, Antigua and Barbuda, Argentina, Australia, Austria, Bahamas, Bahrain, Bangladesh, Barbados, Belarus, Belgium, Belize, Benin, Bhutan, Bolivia, Bosnia and Herzegovina, Botswana, Brazil, Bulgaria, Burkina Faso, Burundi, Cambodia, Cameroon, Canada, Cape Verde, Central African Republic, Chad, Chile, China, Colombia, Comoros, Congo, Costa Rica, Côte d'Ivoire, Croatia, Cuba, Cyprus, Czech Republic, Democratic People's Republic of Korea, Democratic Republic of the Congo, Democratic Republic of Timor-Leste, Denmark, Djibouti, Dominica, Dominican Republic, Ecuador, Egypt, El Salvador, Equatorial Guinea, Eritrea, Estonia, Ethiopia, Fiji, Finland, France, Gabon, Gambia, Germany, Ghana, Greece, Grenada, Guatemala, Guinea, Guinea-Bissau, Guyana, Haiti, Honduras, Hungary, Iceland, India, Indonesia, Iran (Islamic Republic of), Iraq, Ireland, Israel, Italy, Jamaica, Jordan, Kazakhstan, Kenya, Kiribati, Kuwait, Kyrgyzstan, Lao People's Democratic Republic, Latvia, Lebanon, Lesotho, Liberia, Libyan Arab Jamahiriya, Lithuania, Luxembourg, Madagascar, Malawi, Malaysia, Maldives, Mali, Malta, Marshall Islands, Mauritania, Mauritius, Mexico, Micronesia (Federated States of), Monaco, Mongolia, Morocco, Mozambique, Myanmar, Namibia, Nepal, Netherlands, New Zealand, Nicaragua, Niger, Nigeria, Norway, Oman, Pakistan, Palestinian Territory, Occupied, Panama, Papua New Guinea, Paraguay, Peru, Philippines, Poland, Portugal, Qatar, Romania, Russian Federation, Rwanda, Saint Lucia, Saint Vincent and the Grenadines, Samoa, Sao Tome and Principe, Saudi Arabia, Senegal, Serbia and Montenegro, Seychelles, Sierra Leone, Slovakia, Slovenia, Solomon Islands, Somalia, South Africa, Spain, Sri Lanka, Sudan, Suriname, Swaziland, Sweden, Switzerland, Syrian Arab Republic, Taiwan, Tajikistan, Thailand, Togo, Tonga, Trinidad and Tobago, Tunisia, Turkey, Turkmenistan, Uganda, Ukraine, United States of America, Uruguay, Uzbekistan, Vanuatu, Venezuela, Viet Nam, Yemen, Zimbabwe
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No evidence that antiretroviral therapy increases risk taking behaviour

Effects of HIV antiretroviral therapy on sexual and injecting risk-taking behaviour: a systematic review and meta-analysis.

Doyle JS, Degenhardt L, Pedrana AE, McBryde ES, Guy R, Stoove MA, Weaver E, Grulich AE, Lo YR, Hellard ME. Clin Infect Dis. 2014 Aug 4. pii: ciu602. [Epub ahead of print]

Background:  Increased global access and use of HIV antiretroviral therapy (ART) has been postulated to undermine HIV prevention efforts by changing individual risk-taking behaviour. This review aims to determine whether ART use is associated with changes in sexual or injecting risk-taking behaviour or diagnosis of sexually transmitted infections (STIs).

Methods: A systematic review and meta-analysis was conducted of HIV-seropositive participants receiving ART compared to no ART use in experimental or observational studies. Primary outcomes included: (1) any unprotected sexual intercourse; (2) STI diagnoses; and (3) any unsafe injecting behaviour.

Results: Fifty-eight studies met the selection criteria. Fifty-six studies containing 32 857 participants reported unprotected sex; eleven studies containing 16 138 participants reported STI diagnoses; and four studies containing 1 600 participants reported unsafe injecting behaviour. All included studies were observational. Unprotected sex was lower in those receiving ART than those not receiving ART (odds ratio (OR) 0.73, 95%CI 0.64-0.83, p<0.001; heterogeneity I2=79%) in both high-income (n=38) and low-/middle-income country (n=18) settings, without any evidence of publication bias. STI diagnoses were also lower among individuals on ART (OR 0.58, 95%CI 0.33-1.01, p=0.053; I2=92%), however there was no difference in injecting risk-taking behaviour with antiretroviral use (OR 0.90, 95%CI 0.60-1.35, p=0.6; I2=0%).

Conclusions: Despite concerns that use of ART might increase sexual or injecting risk-taking, available research suggests unprotected sex is reduced among HIV-infected individuals on treatment. The reasons for this are not yet clear, though self-selection and mutually reinforcing effects of HIV treatment and prevention messages among people on ART are likely.

Abstract access 

Editor’s notes: Use of antiretroviral therapy (ART) may modify risk perception, leading to increases in risk-taking behaviour and HIV transmission. This has important implications for HIV prevention. In particular in low and middle-income countries, where the global burden of HIV is greatest and where access to, and use of, ART is rapidly increasing. This systematic review identified observational studies comparing risk-taking behaviour in people living with HIV using ART, compared with people not using ART. The review found that ART does not appear to increase reported unprotected anal or vaginal intercourse, newly diagnosed sexually transmitted infections, or unsafe injecting behaviour among people on treatment. The observation that reductions in unprotected sex are associated with ART use should be interpreted cautiously as limited data are available to accurately assess a causal relationship. The current practice of providing ART with counselling, education and ongoing clinical care probably offers the optimal strategy of ensuring that individuals on ART minimise risks associated with unsafe sex. 

Africa, Asia, Europe, Northern America, Oceania
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