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Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis
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HCV/HIV Coinfection Study Published: IDUs, prevention, screening, treatment access
"Our study corroborates other evidence showing the importance of injecting drug use in driving the HCV epidemic in PWID and HIV-infected individuals, and that the highest burden of HCV in PWID is in Russia and China....We reported a six-times increase in odds of HCV infection in HIV-positive compared with HIV-negative PWID population groups......These findings emphasise the urgent need to scale up HIV and HCV prevention interventions in PWID including needle or syringe exchange programmes, opiate substitution therapy, and provision of ART, both worldwide and especially in eastern Europe and southeast Asia.34 Additionally, the new era of highly curative short-course direct-acting antiviral therapies for HCV offer the potential to not only improve individual clinical outcomes but also reduce transmission,35 and therefore emphasises the importance of ensuring equitable access of PWID to HCV testing and direct-acting antiviral treatment.....Overall, there was moderate HCV co-infection in HIV-positive MSM samples with an eight-times increase in odds of HCV infection in HIV-infected MSM compared with HIV-uninfected MSM. These data align well with growing evidence suggesting that MSM are increasingly susceptible to HCV transmission, in part fuelled by the use of new psychoactive substances, increased sexual and drug-injecting risk, and sero-sorting within this risk group.36, 37 Evidence also suggests high rates of HCV re-infection after spontaneous clearance or treatment in HIV-positive MSM, emphasising the need for repeated testing and targeted interventions in this population.38".......International guidelines recommend HCV screening for HIV-infected individuals in many settings, and provision of appropriate HCV care and access to direct-acting antiviral treatment for those with chronic active infection......However, this approach is poorly implemented, particularly in low-income and middle-income settings, and in populations such as PWID, prisoners, sex workers, and MSM, where access to care and treatment are already challenging"
"2 278 400 HIV-HCV co-infections......82⋅4% (55⋅2-88⋅5) in people who inject drugs (PWID).......4⋅0% (1⋅2-8⋅4) within pregnant or heterosexually exposed samples, 6⋅4% (3⋅2-10⋅0) in men who have sex with men (MSM), ......study highlights the importance of routine HCV testing in all HIV-infected individuals, but especially in PWID. There is also a need to improve country-level surveillance of HCV prevalence across different population groups in all regions.
To our knowledge, this is the first global systematic review and meta-analysis of the prevalence and burden of HCV in HIV-infected people. We estimate that there are 2⋅3 million (IQR 1⋅3-4⋅4 million) cases of HCV co-infection in HIV-infected individuals worldwide, making a global prevalence of 6⋅2%, of whom 59% are PWID. The greatest burden is in eastern Europe and central Asia, because of the large HIV-infected population of PWID, where an estimated 607 700 HIV-infected people are co-infected with HCV infection, followed by 429 600 in sub-Saharan Africa. Prevalence of HCV co-infection in HIV-infected populations varies widely and is highest in PWID, then MSM, and pregnant or heterosexually exposed populations, and lowest in general population samples."
"Our findings corroborate previously published evidence that south Asia, east Asia, and eastern Europe constitute the largest populations of anti-HCV infections.3, 4 We reported clear geographical differences in estimated HIV-HCV co-infection prevalence across population groups. In general population samples, prevalence was highest in South America and west and central Africa and lowest in east Africa. In HIV-positive pregnant women or individuals with heterosexual exposure, prevalence was again highest in west and central Africa, but lower in the rest of sub-Saharan Africa. Previous reviews16, 17 of HIV-HCV co-infection in sub-Saharan Africa showed a prevalence of between 5⋅7% and 7% in HIV-positive cohorts, which is within the range of our estimates. One of these reviews also reported similarly high rates of HCV co-infection in west Africa, but far higher rates in southern and east Africa than in our study. An absence of data for risk behaviours made comparison of these regional differences challenging.17 In PWID, HIV-HCV co-infection prevalence is more than 80% in six regions, particularly in regions where there are large populations of PWID with concentrated HIV epidemics, including central and eastern Europe, south and southeast Asia, and North America.31"
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Prevalence and burden of HCV co-infection in people living with HIV: a global systematic review and meta-analysis
full text below following WHO press release
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More than 2 million people coinfected with HIV and hepatitis C
http://www.who.int/hiv/mediacentre/news/hep-hiv-coinfected/en/
"An estimated 2.3 million people living with HIV are coinfected with hepatitis C virus (HCV) globally, a new study sponsored by the World Health Organization (WHO) has reported. Of these, more than half, or 1.3 million, are people who inject drugs (PWID)........The study also found that HIV-infected people are on average 6 times more likely than HIV-uninfected people to have HCV infection, pointing to a need to improve integrated HIV/HCV services.
The study shows the greatest burden of HIV/HCV coinfection in eastern Europe and central Asia, where there are an estimated 607,700 cases (27% of all cases), particularly among PWID. The sub-Saharan African region accounts for 19% of all cases, with 429,600 cases, due to high burdens of HIV.
Dr Philippa Easterbrook, from WHO's Global Hepatitis Programme explains, "The study shows that not only are people with HIV at much higher risk of HCV infection, groups such as people who inject drugs have extremely high prevalence of HCV infection - over 80%. There is a need to scale-up routine testing to diagnose HCV infection in HIV programmes worldwide, especially among high-risk groups, as the first step towards accessing the new, highly curative HCV treatments."
Improvement in the surveillance of HCV and HIV is imperative to help define the epidemiology of coinfection and inform appropriate policies for testing, prevention, care and treatment to those in need. This is especially the case in countries with growing populations of PWID and also in sub-Saharan Africa where the burden of coinfection is large due to high burden of HIV"
7 March 2016 - An estimated 2.3 million people living with HIV are coinfected with hepatitis C virus (HCV) globally, a new study sponsored by the World Health Organization (WHO) has reported. Of these, more than half, or 1.3 million, are people who inject drugs (PWID). The study also found that HIV-infected people are on average 6 times more likely than HIV-uninfected people to have HCV infection, pointing to a need to improve integrated HIV/HCV services.
HIV and HCV infections are major global public health problems, with overlapping modes of transmission and affected populations. Globally, there are 37 million people infected with HIV, and around 115 million people with chronic HCV infection. However, very little was known about the extent of HIV/HCV coinfection prior to this study, which was the first global study of its kind.
Sponsored by WHO, and conducted in collaboration with the London School of Hygiene & Tropical Medicine (Dr Lucy Platt and others) and the University of Bristol (Professor Peter Vickerman), the study was published online in The Lancet Infectious Diseases on 24 February. WHO commissioned the study to inform an update of its guidelines on screening of coinfections and initiation of antiretroviral therapy, and to inform regional and national strategies for HCV screening and management.
The study systematically reviewed 783 medical studies from worldwide sources, to build the first global estimates on the prevalence of HIV/HCV co-infection (measured by HCV antibody) as a public health problem.
Dr Philippa Easterbrook, from WHO's Global Hepatitis Programme explains, "The study shows that not only are people with HIV at much higher risk of HCV infection, groups such as people who inject drugs have extremely high prevalence of HCV infection - over 80%. There is a need to scale-up routine testing to diagnose HCV infection in HIV programmes worldwide, especially among high-risk groups, as the first step towards accessing the new, highly curative HCV treatments."
Dr Lucy Platt, lead author and Senior Lecturer from the London School of Hygiene & Tropical Medicine adds, "Despite a systematic search of published and unpublished literature, estimates were identified in only 45% of countries and the study quality was variable. Improvement in the surveillance of HCV and HIV is imperative to help define the epidemiology of coinfection and inform appropriate policies for testing, prevention, care and treatment to those in need. This is especially the case in countries with growing populations of PWID and also in sub-Saharan Africa where the burden of coinfection is large due to high burden of HIV."
According to Professor Vickerman, from the University of Bristol's School of Social and Community Medicine, "This study shows how important injecting drug use is in driving the epidemic of HCV in people with HIV infection, especially in eastern European and central Asian countries. It also shows the need to scale up prevention interventions, such as needle and syringe programmes and opioid substitution therapy, as well as access to HIV and HCV treatment, to reduce morbidity and new infections."
The study focusses on prevalence of HCV antibodies that measures exposure to HCV but not active infection. Measuring the presence of active virus and the need for treatment, requires an additional more costly viral test, which very few of the reviewed studies had done. Around 20-30% of people exposed to HCV and found positive with antibody will clear the virus.
The study shows the greatest burden of HIV/HCV coinfection in eastern Europe and central Asia, where there are an estimated 607,700 cases (27% of all cases), particularly among PWID. The sub-Saharan African region accounts for 19% of all cases, with 429,600 cases, due to high burdens of HIV.
The researchers included studies with estimates of HCV coinfection in the main HIV population, as well as sub-groups of PWID, men who have sex with men, heterosexually exposed and pregnant women, other high-risk groups and the general population. Studies were eligible if they included a minimum of 50 individuals.
The search focused on published medical literature, and excluded samples drawn from populations with other comorbidities, or undergoing interventions that put them at increased risk of coinfection.
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Prevalence and burden of HCV co-infection in people living
with HIV: a global systematic review and meta-analysis
The Lancet Infectious Diseases Feb 24 2016
Lucy Platt, Philippa Easterbrook, Erin Gower, Bethan McDonald, Keith Sabin, Catherine McGowan, Irini Yanny, Homie Razavi, Peter Vickerman
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Summary
Background
At global level, there are 37 million people infected with HIV and 115 million people with antibodies to hepatitis C virus (HCV). Little is known about the extent of HIV-HCV co-infection. We sought to characterise the epidemiology and burden of HCV co-infection in people living with HIV.
Methods
In this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL+, POPLINE, Africa-wide Information, Global Health, Web of Science, and the Cochrane Library and WHO databases for studies measuring prevalence of HCV and HIV, published between Jan 1, 2002, and Jan 28, 2015. We included studies in HIV population samples of more than 50 individuals and recruited patients based on HIV infection status or other behavioural characteristics. We excluded editorials or reviews containing no primary data, samples of HCV or HIV-HCV co-infected individuals, or samples relying on self-reported infection status. We also excluded samples drawn from populations with other comorbidities or undergoing interventions that put them at increased risk of co-infection. Populations were categorised according to HIV exposure, with the regional burden of co-infection being derived by applying co-infection prevalence estimates to published numbers of HIV-infected individuals. We did a meta-analysis to estimate the odds of HCV in HIV-infected individuals compared with their HIV-negative counterparts.
Findings
From 31 767 citations identified, 783 studies met the inclusion criteria, resulting in 902 estimates of the prevalence of HIV-HCV co-infection. In HIV-infected individuals, HIV-HCV co-infection was 2⋅4% (IQR 0⋅8-5⋅8) within general population samples, 4⋅0% (1⋅2-8⋅4) within pregnant or heterosexually exposed samples, 6⋅4% (3⋅2-10⋅0) in men who have sex with men (MSM), and 82⋅4% (55⋅2-88⋅5) in people who inject drugs (PWID). Odds of HCV infection were six times higher in people living with HIV (5⋅8, 95% CI 4⋅5-7⋅4) than their HIV-negative counterparts. Worldwide, there are approximately 2 278 400 HIV-HCV co-infections (IQR 1 271 300-4 417 000) of which 1 362 700 (847 700-1 381 800) are in PWID, equalling an overall co-infection prevalence in HIV-infected individuals of 6⋅2% (3⋅4-11⋅9).
Interpretation
We noted a consistently higher HCV prevalence in HIV-infected individuals than HIV-negative individuals across all risk groups and regions, but especially in PWID. This study highlights the importance of routine HCV testing in all HIV-infected individuals, but especially in PWID. There is also a need to improve country-level surveillance of HCV prevalence across different population groups in all regions.
Introduction
HIV and hepatitis C virus (HCV) infection are major global public health concerns, with overlapping modes of transmission and affected populations. As of December, 2014, an estimated 36⋅9 million people were living with HIV, 2 million were newly infected, and 1⋅6 million died.1 Although HIV transmission has declined since 2001, with improved survival due to the scale-up of antiretroviral therapies (ART), more people are living with HIV than ever before.2 In 2005, more than 184 million people were estimated to be HCV antibody positive.3 Data from 2014 suggest that this number has declined to 115 million (range 92-149)4 as a result of improved screening of blood supply, decreases in injecting risk behaviours, and differences in prevalence reported from southeast Asia. However, other evidence5, 6 suggests that the disease burden is high, with 3-4 million new infections and 704 000 deaths in 2013.3, 7 HCV treatment has been transformed with the advent of direct-acting antivirals, which offer high cure rates within 12-24 weeks.8
The interaction between HIV and HCV co-infection affects the transmission and natural history of HCV infection. The transmission efficiency of HCV increases in the presence of HIV infection, with the perinatal transmission risk doubling in HIV-infected mothers.9, 10 People living with HIV without treatment are less likely to spontaneously clear HCV infection, have higher HCV viral loads, and experience more rapid HCV disease progression than those without HIV infection.11 Although ART improves outcomes in HCV co-infected patients, with decreased HCV-related mortality,12 HCV co-infection might also complicate HIV treatment, with some evidence suggesting an increased risk of drug-related hepatoxicity in those receiving ART.12 An absence of consistent data remains for the effect of HCV co-infection on HIV progression.9, 12, 13
Research in context
Evidence before this study
In this systematic review and meta-analysis we searched eight databases for studies that reported the prevalence of HCV and HIV, published between Jan 01, 2002, and Jan 28, 2015, following PRISMA guidelines. The searches were done with no language restrictions on Jan 28, 2015, in MEDLINE, Embase, CINAHL+, POPLINE, Africa-wide Information, Global Health, Web of Science, and the Cochrane Library, Index Medicus of the Eastern Mediterranean Region, Index Medicus of the South-East Asian Region, LILACS, and Western Pacific Region Index Medicus. Search terms included "HIV OR Human immunodeficiency virus", "OR Hepatitis-C OR HCV", and "prevalen* OR inciden* OR seroprevalen* OR screening OR surveillance OR population* OR survey* OR epidem* OR data collection OR population sample* OR community survey* OR cohort OR cross-sectional OR longitude* OR follow-up". Searches were tailored to each database. Reference lists were screened for additional sources.
We included studies with estimates of HCV co-infection in HIV population samples of more than 50 individuals recruited based on HIV infection status or other behavioural characteristic. We excluded editorials or reviews containing no primary data, no samples of HCV or HIV-HCV-infected individuals, or samples relying on self-reported infection status. We excluded samples drawn from populations with other comorbidities or undergoing interventions that put them at increased risk of co-infection. The search focused on published medical literature and did not include an exhaustive review of grey literature.
Previous reviews of HIV-HCV co-infection have focused on specific regions or sub-populations or have not used systematic review methods to extract and synthesise data. Data are needed to establish the global burden of HCV co-infection in HIV-infected individuals and to identify the populations at risk and the key geographical regions most affected. These data are essential to inform normative guidance and service delivery for testing and care and treatment services.
Added value of study
We estimate a midpoint of roughly 2⋅3 million (IQR 1⋅3-4⋅3 million) cases of HIV-HCV co-infection worldwide, of whom more than half (an estimated 1⋅3 million [0⋅89-1⋅4 million]) are PWID. This number equates to a worldwide HCV co-infection prevalence of 6⋅2% (3⋅4-11⋅9) in HIV-infected individuals. The greatest burden of HIV-HCV co-infection is in eastern Europe, where an estimated 607 700 HIV-infected people are co-infected with HCV, followed by 429 600 people in sub-Saharan Africa. Prevalence of HCV co-infection in HIV-infected people is highest in PWID (82⋅4%, 55⋅2-88⋅5), followed by MSM (6⋅4%, 3⋅2-10⋅0) and pregnant or heterosexually exposed populations (4⋅0%, 1⋅2-8⋅4), and lowest in general population samples (2⋅4%, 0⋅8-5⋅8). Odds of HCV infection are six times higher in HIV-infected people than in HIV-negative populations ranging from 1⋅6 times higher in the general population, 1⋅4-6⋅8 times higher in sex workers, and 4-13 times higher in MSM, PWID, and high-risk populations.
Implications of all the available evidence
Our findings clearly show that HIV-infected individuals are at high risk of HCV infection, particularly PWID who constitute 58% of the global burden of HCV co-infections in HIV-infected individuals. Routine testing of HCV in HIV-infected individuals is needed, including good linkage to care and treatment in PWID and MSM especially.
There is also a need to improve surveillance and country-level data on prevalence of HCV in all populations to help countries define their epidemiology and inform policies for hepatitis C testing, prevention, and care and treatment services.
As people living with HIV live longer, HCV-related liver disease in co-infected patients is becoming a major cause of morbidity and mortality. However, the burden of HIV-HCV co-infection is poorly understood. One review14 suggested that 4-5 million HIV-infected individuals are infected with HCV, but it relied on a small number of studies and unclear methods, whereas a second review15 reported prevalence from selected studies only. Other reviews have provided estimates for sub-Saharan Africa only16, 17 or in people who inject drugs (PWID),18 but there have been no reviews documenting the global burden of HCV co-infection in HIV-infected individuals. Reliable estimates are needed to establish the scale of the public health problem posed by HCV co-infection and to inform regional and national strategies for hepatitis screening and management.19, 20, 21, 22, 23 We therefore undertook a systematic review to estimate the prevalence and global burden of HCV antibody seropositivity in HIV-infected individuals.
Methods
Data extraction and quality assessment
We searched eight databases for studies that reported the prevalence of HCV and HIV, published between Jan 01, 2002, and Jan 28, 2015, following PRISMA guidelines.24
Two authors (CM, BM) screened all sources for inclusion, with a third reviewer (LP) consulted when necessary. Data extracted by BM, IY, EG, and LP included study methods, field-work dates, population sampled, recruitment site, sample size, diagnostic assays used, and prevalence of co-infection. For 10% of included studies, data were double extracted by a second author (EG) to check for accuracy.
Studies were rated according to their study design and assay quality (appendix). Studies with larger sample sizes, recruited from several sites, recording age, sex, or HIV risk factors were scored higher, and lower scores were given if no HIV risk factors were reported. HCV antibody assay methods were rated from 0, when no assay type was specified in the study, up to 3, when a second or third generation HCV antibody assay was used with confirmatory testing. Best estimates were selected for each population group per country based on the highest study design and assay score. Where several estimates existed, we applied decision rules to select the best estimate (appendix). We used HCV antibody seropositivity as a measure of overall burden of HCV infection, even though between 20% and 30% of people initially infected and who are HCV-antibody positive will subsequently clear the virus, they will remain antibody positive.
Classification of countries and definition of population groups
Countries were grouped according to the 21 Global Burden of Disease regions, consistent with previous published reviews on HCV burden and further summarised into 12 sub-regions.3, 25
Populations were classified according to their main HIV exposure categories. General population samples were regarded as low risk, and included samples of blood donors (unpaid), antenatal clinic attendees, or general population surveys, not recruited based on HIV-positive status. Samples of HIV-infected individuals reporting heterosexual transmission as the main risk factor or pregnant women were grouped together. We classified samples as PWID when more than 75% of individuals had experience of injecting drugs, and as men who have sex with men (MSM) when more than 75% of individuals reported their main HIV exposure to be sex with men. These two groups included studies of HIV-infected individuals and populations recruited based on risk behaviour. Other population groups included HIV-infected individuals reporting any injecting drug use (but <75% had experience of injecting), sex workers, prison inmates, drug users (non-injecting), and high-risk populations (recruited from sexually transmitted infection clinics or a mixed population participating in sexual or drug-injecting risk behaviours, but in which <75% had experience of injecting).
Data analysis
We reported HIV-HCV co-infection prevalence in four population groups by country and region, reporting the best estimate and range for each country. Global and regional prevalence estimates were derived from the median of the best estimates for that region with the IQR. Data were entered into ArcGIS 10.2 to generate maps presenting country-level HIV-HCV co-infection prevalence estimates.
We also synthesised estimates across six independent population groups (general population, PWID, MSM, sex workers, prison inmates, and high-risk populations) on overall HCV co-infection and mono-infection prevalence, and did a meta-analysis across the best estimates of the odds of being HCV-positive in HIV-positive populations compared with HIV-negative populations, stratified by population group. A standard correction of 0⋅5 was added to all zero prevalence estimates using Stata (version 13.1). Odds ratios were calculated through a Mantel-Haenszel method with a random effects model. Meta-analyses are presented as forest plots.
We report global and regional estimates of burden of HCV co-infection in HIV-infected individuals. Using the number of HIV-infected individuals by country and region estimated by the Joint United Nations Programmes on HIV/AIDS (UNAIDS),1 we applied median best estimate of HCV co-infection prevalence in HIV-infected individuals for non-PWID samples from the literature search for MSM, general population, and HIV-positive samples of pregnant women or those heterosexually exposed by sub-regions and then applied the median HCV co-infection prevalence overall. The median best estimate of HCV prevalence in HIV-positive PWID was also applied to the distribution of HIV-positive PWID across subregions, as estimated by UNAIDS.26 The median of best estimates was applied to generate burden of disease to minimise heterogeneity across the studies. The process of quality assessment used to define best estimates was described earlier (appendix).
Role of the funding source
WHO commissioned this review to inform the update of the WHO guidelines on screening of co-infections and initiation of ART. The funder contributed to the data collection, analysis, interpretation, and writing of the review. All authors had full access to the study data and share final responsibility for the findings submitted for publication.
Results
From 31 767 citations, 783 studies met the inclusion criteria resulting in 902 estimates of the prevalence of HIV-HCV co-infection (figure 1).
Co-infection estimates were identified for 88 of the 194 (45%) countries identified in the study (for all population groups, not just the groups summarised in table 1). In sub-Saharan Africa, the most estimates were identified in east Africa (11/15 countries), then southern Africa (four of six), and the fewest were in central and west Africa (nine of 24). Seven estimates were identified in north Africa and the Middle East (seven of 21). Estimates were recorded in every country in North America (two of two), but estimates were recorded for only a minority of countries in South America (eight of 21) and the Caribbean (three of 15). Estimates were identified in eight countries in south and southeast Asia (eight of 18), three countries in Asia Pacific and Australasia (three of 17), and one in east Asia (one of two). Nine estimates were identified in eastern European and central Asian countries (nine of 17), 17 in western European countries (17 of 24), and six in central European countries (six of 12).
The midpoint prevalence of HCV co-infection in 30 HIV-infected general population samples was 2⋅4% (IQR 0⋅8-5⋅8). The highest prevalence was in north Africa and the Middle East and the lowest prevalence was in east Africa (table 1, figure 2). Within these general population samples, prevalence was highest in blood donors at more than 10% in India and Nepal, and 7% in Brazil.27, 28, 29, 30
The midpoint prevalence of HCV co-infection in 95 studies in HIV-infected individuals (heterosexual people or pregnant women) was 4⋅0% (IQR 1⋅2-8⋅4). Prevalence was highest in west and central Africa and lowest in southern Africa (table 1).
The midpoint prevalence in 80 MSM samples was 6⋅4% (IQR 3⋅2-10⋅0). Prevalence was highest in North America and lowest in east Asia and south and south-east Asia (table 1).
The midpoint prevalence in 123 studies of PWID (≥75% of sample had a history of injecting drug use) was 82⋅4% (IQR 55⋅2-84⋅5) with little regional variation. The highest prevalence was in north Africa and the Middle East and lowest was in western and central Europe. A further 333 estimates were obtained from samples of HIV-infected individuals, for whom injecting drug use was a key exposure, but less than 75% of the sample injected drugs. In these estimates, the median prevalence of injecting drug use was 29⋅0% (IQR 13⋅9-46⋅0). There was a clear association between the prevalence of self-reported injecting drug use and HIV-HCV co-infection prevalence (correlation coefficient 0⋅89, p<0⋅001; figure 3).
Across all population groups, there was a 5⋅8-times (95% CI 4⋅5-7⋅5) increased odds of HCV antibody positivity in HIV-positive people compared with HIV-negative people, but with high heterogeneity (I2 95⋅7%, p<0⋅001). Odds of HCV were highest in HIV-positive prison inmates (OR 17⋅4, 95% CI 7⋅6-39⋅5), but similar in MSM (7⋅5, 4⋅4-12⋅7), PWID (6⋅0, 4⋅2-8⋅7), and other high-risk populations (6⋅8, 4⋅0-11⋅5), then lower in sex workers (3⋅1, 1⋅4-6⋅8) and general population samples (1⋅6, 1⋅0-2⋅5). Within-study heterogeneity was high for all population groups except for general population and sex-worker samples for which it was moderate (figure 4).
We estimate that there are 2 278 400 (IQR 1 271 300-4 417 000) cases of HCV co-infection in HIV-infected individuals worldwide, of which 1 362 700 (847 700-1 381 800) are among HIV-positive PWID. This gives a global prevalence of HCV co-infection in HIV-infected individuals of 6⋅2% (3⋅4-11⋅9). Eastern Europe and central Asia has the largest burden, representing 27% of the total burden, which shows the large population of PWID (table 2).
Discussion
To our knowledge, this is the first global systematic review and meta-analysis of the prevalence and burden of HCV in HIV-infected people. We estimate that there are 2⋅3 million (IQR 1⋅3-4⋅4 million) cases of HCV co-infection in HIV-infected individuals worldwide, making a global prevalence of 6⋅2%, of whom 59% are PWID. The greatest burden is in eastern Europe and central Asia, because of the large HIV-infected population of PWID, where an estimated 607 700 HIV-infected people are co-infected with HCV infection, followed by 429 600 in sub-Saharan Africa. Prevalence of HCV co-infection in HIV-infected populations varies widely and is highest in PWID, then MSM, and pregnant or heterosexually exposed populations, and lowest in general population samples.
Our findings corroborate previously published evidence that south Asia, east Asia, and eastern Europe constitute the largest populations of anti-HCV infections.3, 4 We reported clear geographical differences in estimated HIV-HCV co-infection prevalence across population groups. In general population samples, prevalence was highest in South America and west and central Africa and lowest in east Africa. In HIV-positive pregnant women or individuals with heterosexual exposure, prevalence was again highest in west and central Africa, but lower in the rest of sub-Saharan Africa. Previous reviews16, 17 of HIV-HCV co-infection in sub-Saharan Africa showed a prevalence of between 5⋅7% and 7% in HIV-positive cohorts, which is within the range of our estimates. One of these reviews also reported similarly high rates of HCV co-infection in west Africa, but far higher rates in southern and east Africa than in our study. An absence of data for risk behaviours made comparison of these regional differences challenging.17 In PWID, HIV-HCV co-infection prevalence is more than 80% in six regions, particularly in regions where there are large populations of PWID with concentrated HIV epidemics, including central and eastern Europe, south and southeast Asia, and North America.31
Our study corroborates other evidence showing the importance of injecting drug use in driving the HCV epidemic in PWID and HIV-infected individuals, and that the highest burden of HCV in PWID is in Russia and China.25, 32 We reported a six-times increase in odds of HCV infection in HIV-positive compared with HIV-negative PWID population groups. This finding is consistent with parenteral transmission being the primary method of HIV and HCV acquisition in PWID, and HCV being much more easily transmitted than HIV.33 These findings emphasise the urgent need to scale up HIV and HCV prevention interventions in PWID including needle or syringe exchange programmes, opiate substitution therapy, and provision of ART, both worldwide and especially in eastern Europe and southeast Asia.34 Additionally, the new era of highly curative short-course direct-acting antiviral therapies for HCV offer the potential to not only improve individual clinical outcomes but also reduce transmission,35 and therefore emphasises the importance of ensuring equitable access of PWID to HCV testing and direct-acting antiviral treatment.32, 35
Overall, there was moderate HCV co-infection in HIV-positive MSM samples with an eight-times increase in odds of HCV infection in HIV-infected MSM compared with HIV-uninfected MSM. These data align well with growing evidence suggesting that MSM are increasingly susceptible to HCV transmission, in part fuelled by the use of new psychoactive substances, increased sexual and drug-injecting risk, and sero-sorting within this risk group.36, 37 Evidence also suggests high rates of HCV re-infection after spontaneous clearance or treatment in HIV-positive MSM, emphasising the need for repeated testing and targeted interventions in this population.38
Despite a systematic search of published and unpublished scientific literature, estimates were identified in only 45% of countries worldwide, with few country-level estimates in general population samples. The study quality was variable, emphasising the need for more robust surveillance of HCV in HIV-infected individuals, increased transparency in the methods used, and availability of estimates to help monitoring of worldwide trends. The higher co-infection prevalence in blood donors clearly shows the continued need for careful screening of blood donations for HCV and emphasises the difficulties in inferring general population prevalence from this population.27, 28, 29, 30 In view of this potential bias, our general population estimate for co-infection could be an over-estimate, although it falls within the range of previously published, regionally focused reviews, and estimates are consistently lower than for other groups engaging in higher-risk behaviours. Prevalence in blood donors was higher in studies done before 2008 than in more recent studies, indicative of improved screening of donors.17, 28, 39, 40, 41 The high level of within-study heterogeneity within our meta-analysis urges some caution in our interpretation of the effect of HIV positivity on odds of HCV infection, particularly for prison inmates where the confidence intervals are wide, PWID, and high-risk populations.
Our global study focused on published literature and did not include an exhaustive review of grey literature, as applied in other systematic reviews of this kind,42 although the inclusion of WHO and Global Health databases captured some unpublished grey literature. We lastly acknowledge that our focus on HCV antibody prevalence fails to fully establish the burden of active HCV infections in HIV-infected individuals (determined by HCV RNA positivity). Only 92 (10%) of our estimates contained data for HCV RNA, most of which (47%) were derived from studies in North America or western Europe. An estimated 20-30% of those exposed to HCV antibodies will spontaneously clear the virus and be HCV RNA negative but remain antibody positive and this might differ across populations.43, 44 In view of the paucity of data and diversity in geographical regions, populations, and risk groups covered in our study we deemed that a focus on antibody prevalence is better for showing the epidemiology of exposure and infection.
International guidelines recommend HCV screening for HIV-infected individuals in many settings, and provision of appropriate HCV care and access to direct-acting antiviral treatment for those with chronic active infection.19, 20, 21, 22, 23 However, this approach is poorly implemented, particularly in low-income and middle-income settings, and in populations such as PWID, prisoners, sex workers, and MSM, where access to care and treatment are already challenging.32, 45 Countries should ensure implementation of existing recommendations for screening of all blood donors and promote routine testing of HCV in all HIV-infected individuals. Targeted and outreach approaches are needed for PWID and MSM because stigmatisation and other factors might limit their access to services for testing and treatment. Improvement of country-level data for prevalence of HCV in all populations is needed to help them to define their epidemiology and inform policies for hepatitis C testing, prevention, care, and treatment. This is particularly important in countries with growing populations of PWID and concentrated HIV epidemics in PWID and MSM, but also in sub-Saharan Africa where the burden of co-infection is large owing to the high burden of HIV. This approach will need investment in building HCV surveillance and care and treatment capacity.
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