Download HCV in Sub-Saharan Africa: a systematic review

Hepatitis C seroprevalence and HIV co-infection in subSaharan Africa: a systematic review and meta-analysis
**Bhargavi V Rao1,2, MRCP, Nur Johari2, BSc, Phillip du Cros1,
MRCP, Janey Messina4, PhD, Nathan Ford2,3*, PhD Graham S
Cooke2* PhD
1 Manson Unit, Médecins Sans Frontières (MSF), London, UK
2 Division of Infectious Diseases, Imperial College London, UK
3 Médecins Sans Frontières (MSF), Geneva, Switzerland
4 Spatial Epidemiology and Ecology Group, Department of
Zoology, University of Oxford, UK
*contributed equally to this work
Total word count: 2998
**Corresponding authors: [email protected] and
[email protected]
Address: Manson Unit, MSF-UK, 67-74 Saffron Hill, London EC1N
8QX, UK
Tel: +44 (0)2074046600
Fax: +44 (0)2074044466
Oxford
1
Abstract
Background
An estimated 150 million people worldwide have been infected
with hepatitis C virus (HCV). HIV co-infection accelerates the
progression of HCV and represents a major public health
challenge. In a systematic review and meta-analysis, we aimed to
determine the epidemiology of HCV and the prevalence of coinfection with HIV in sub-Saharan Africa.
Methods
We included HCV seroprevalence data from 2002 to end of 2014
relating to the WHO defined regions of sub-Saharan Africa. We
estimated pooled regional prevalence estimates using a
DerSimonian-Laird random effects model. Data were further
stratified by risk factor and HIV status.
Findings
From 213 studies, we identified 287 separate cohorts with a total
of 1,198,167 individuals. The mean pooled HCV seroprevalence
from all cohorts was 3% (95%CI: 2.9-3.1). The pooled HCV
seroprevalence was 2.7% (95%CI: 2.5-2.8) across all 185 low risk
cohorts; 3% (95%CI: 2.2-3.8) in antenatal groups, 2% (95%CI: 1.92
2.1) among blood donors but 6.9% (95%CI: 6.1-7.5) in other
general population cohorts. The pooled seroprevalence of HCV
across all high-risk groups was 11.9% (95%CI: 7.1-16.7) and 10%
(95%CI: 6.8-13.1) in patients with liver disease. 101 cohorts
included HIV-positive samples tested for HCV (42,648 individuals)
with pooled seroprevalence of 5.7% (95%CI: 4.9-6.6).
Interpretation
We found a high seroprevalence of HCV across populations of
sub-Saharan Africa including within HIV-positive adults, with
evidence of regional variation in the general population. Monitoring
antenatal HCV prevalence may be a helpful indicator of population
trends in HCV infection. There are limitations to available data with
a need for larger survey studies. Access to prevention and
treatment needs to be improved for both mono-infected and coinfected individuals.
Funding
None.
3
Introduction
Hepatitis C virus (HCV) is estimated to have infected 130-150
1,2
million individuals worldwide
Global Burden of Disease
and contributes significantly to the
3,4
. There is no vaccine close to market
for HCV, hence control of the epidemic rests on preventative
measures - including the screening of blood products, opiate
substitution, and needle exchange - and treatment to prevent
progression to cirrhosis and hepatocellular carcinoma. Until
recently, the complexity of HCV therapy was a barrier to
widespread treatment; standard therapy involved injectable
pegylated interferon and ribavirin tablets, in a long and complex
regimen dependant on viral genotype and requiring frequent
monitoring
5,6
. HCV management has been revolutionised by
recently licensed directly acting antiviral agents (DAAs), including
protease inhibitors, NS5B inhibitors (e.g. sofosbuvir
7,8
) and NS5A
inhibitors (e.g. ledipasvir and daclatasvir), which allow shortened
treatment with improved success rates without the use of
interferon
9,10
. The new treatments have the potential to reduce
substantially the clinical and operational barriers to treatment
throughout the world, provided they are accessible and affordable
6,11
.
4
Accurate epidemiological information is essential to inform
treatment and control priorities at national and regional levels. In
particular, data are needed on the burden of co-infection with HIV
given the poorer outcomes for HCV in this population 12.
There is paucity of such data in many regions, particularly parts of
sub-Saharan Africa, to some extent due to the relative public
health importance of HCV infection being only recently recognised
3
. A review of HCV epidemiology in sub-Saharan Africa published
in 2002 estimated the overall prevalence of HCV to be 3%, with
significant regional variation
13
. A further review of the association
of HIV and hepatitis B and C showed a relative risk of HIV coinfection of 1.6 (95%CI: 1.05-2.45)
14
. However, both analyses
found little data on the prevalence of HIV-HCV co-infection, which
is critical to the current policy debate surrounding expansion of
HCV treatment.
In a systematic review and meta-analysis of studies published
since 200213, we aimed to determine the seroprevalence of HCV
and the prevalence of HCV/HIV co-infection across sub-Saharan
Africa, addressing the availability and type of data included and
categorising cohorts by risk.
5
Methods
Inclusion criteria
Countries included in the study were limited to countries in subSaharan Africa grouped according to WHO Africa regions. In order
to directly compare results with earlier published analyses, six
countries were excluded (Algeria, Cape Verde, Comoros,
Mauritius, Sao Tome & Principe, and Seychelles). Three countries
not listed in the WHO regional list – Sudan (and South Sudan after
2012), Djibouti, and Somalia were included in the study.
Studies published in English and French were included. Studies
were not rejected on the basis on sample size or design (including
both retrospective and prospective studies), and included crosssectional national surveys, as well as surveys from screening
programmes, antenatal clinics (ANC), blood donations, hospitals,
and other institutions such as prisons. Papers that did not state
sample size or HCV seroprevalence or identify the HCV diagnostic
assays used were excluded. No study was discounted on the basis
of HCV diagnostic assay; this review includes studies using both
non-confirmatory (ELISA, EIA, screening assays) and confirmatory
6
(RIBA, Western blots, PCR) assays. The prevalence of detectable
HCV RNA prevalence was included where available.
Search strategy
References were identified from Medline and EMBASE (via Ovid).
We searched for all papers that may contain HCV seroprevalence
data in different population groups, the search strategy is shown in
detail in Supplementary Table 1 and includes terms to assess the
availability of data on HIV/HCV co-infection. Papers were included
if published between 1st January 2002 and 31st December 2014 13.
Data were extracted by one author (NJ) and verified in full by
another (VBR) on the following: country, year of publication, year
of collection; study type, study design, HCV assay used, study
population,
sample
size,
proportion
male,
age,
HCV
seroprevalence, PCR prevalence, genotype (including percentage
of each genotype where available), subtypes, and HIV co-infection
prevalence.
Cohort classification
Cohorts were separated by either time of collection (if this was
defined by the paper) or by collection site i.e. ANC or Blood donor.
We also separated out control cohorts from intervention cohorts in
7
case control studies. If there was a separate HIV sub-analysis
within a study, this was included as a separate cohort within the
HIV pooled prevalence but not counted overall as a separate
cohort. Cohort studies were initially categorised as either low risk
or high risk using definitions comparable with previous work 13. The
low-risk category followed the definition from Madhava et al
13
,
namely according to the setting from which the samples were
obtained and tested. The aggregated low risk group included (1)
pregnant women at Antenatal Care (ANC), (2) blood donors and
(3) other samples that were collected from the general population randomly selected communities whether rural or urban, students,
and samples from inpatients or outpatients seeking care for nonhepatic illnesses or who had not had multiple blood transfusions .
The high-risk group was divided into two groups: (1) patients
suffering from known liver disease, whether acute or chronic; and
(2) patients who had not been documented to have liver disease
but who had high risk exposures such as multiple blood
transfusions, haemodialysis, renal transplants, sickle-cell disease,
or injecting drug use. HIV-infected cohorts were grouped
separately to assess the prevalence of HIV and HCV co-infection.
Data analysis
8
Point estimates and 95% confidence intervals (CI) were calculated
for the proportion of people with HCV in each study. Prevalence of
HCV by WHO region was estimated through pooling data from
each study. Data were pooled using a DerSimonian-Laird random
effects model
15
which incorporates an estimate of between-study
variance, allowing that the true effect size may vary from study to
study. 16
To
assess
between-study
heterogeneity
for
the
estimates of pooled prevalence by region, the 2 statistic was
calculated. The variance of raw proportions was stabilised using a
Freeman-Tukey type arcsine square-root transformation.
17
Several methods of pooling proportions exist; the Freeman-Tukey
method works well with both fixed-effects and random-effects
meta-analysis.
18,19
Data were further stratified by risk group and
HIV status. Analyses were conducted using STATA (v12,
www.stata.com).
Role of the funding source
There was no specific funding for this article. The corresponding
author had full access to all the data and had final responsibility for
the decision to submit for publication.
Results
9
Search results
213 studies met eligibility criteria for inclusion identified from 33
countries in sub-Saharan Africa (Supplementary Figure 1; for all
papers and references see Supplemental Table 6). These 213
studies included data on 287 cohorts comprising 1,198,167
individuals; 241 cohorts had sample sizes greater than 100.
Most studies (177/213) were cross-sectional surveys; 15, were
retrospective cohort studies and 19 were case-control studies.
Testing methodology
Of the 287 cohorts, 81 (28%) used confirmatory assays to screen
for the presence of anti-HCV antibodies and HCV RNA. Less than
20% of the cohorts (55 of 287) described testing for HCV RNA (i.e.
reported HCV prevalence based on PCR testing). 39 cohorts
presented data on HCV genotyping.
Pooled seroprevalence
The estimated pooled HCV seroprevalence across all 287 cohorts
identified was 3% (95%CI: 2.9-3.1; 2 0.06), varying widely
between 7.8% (70 cohorts; 95%CI: 6.6-9.0; 2 0.05) in the Central
region to 4.5% (142 cohorts; 95%CI: 4.1-4.9; 2 0.05) in West
10
Africa and 0.8% (75 cohorts; 95%CI: 0.6-0.8; 2 0.02) in Southern
and Eastern (SE) Africa. 142/287 (49%) cohorts were collected in
the West Africa region, but the majority of individuals included
were from SE Africa skewed by a single survey from the South
African Blood Service (732,250 samples) 20.
Low-risk groups
185 cohorts studies (including 1,151,337 individuals) were
identified as low-risk populations (Supplementary information
Table
2)
representing
30/33 countries.
The pooled
HCV
seroprevalence among all low risk groups aggregated (defined
above), across all regions of sub-Saharan Africa was 2.7%
(95%CI: 2.5-2.8), Figure 1). This was higher than the pooled
seroprevalence among all blood donor cohorts of 2% (95%CI: 1.92,1) but lower than the 6.9% (95%CI: 6.1-7.5) observed in other
general population cohorts (1.8%, 95%CI: 1.6–1.8).
There was considerable regional variation among the low risk
cohorts (Figure 1) with pooled HCV seroprevalence highest in the
central African region (6.9%; 50 cohorts; 95% CI: 6-7.8) and lowest
in SE Africa (0.7%; 35 cohorts; 95%CI: 0.7-0.78). West Africa
11
contributed the largest number of cohorts (100) and most closely
approaches the overall estimate.
The pooled prevalence in aggregated low risk populations was a
little higher than among blood donors (overall 2%, 76 cohorts;
95%CI: 1.9–2.1%), but this difference was most marked in the
Central region with a seroprevalence amongst blood donors of
2.6% (19 cohorts; 95% CI: 1.7-3.6).
The HCV pooled
seroprevalence in the West Africa region among blood donors was
3.2% (95%CI: 2.8-3.6; 45 cohorts), and 0.4% (12 cohorts; 95%CI:
0.3-0.5) in SE Africa. The highest HCV seroprevalence estimate in
a blood donor cohort included in this analysis was 14.6% from a
study that sampled blood donated at teaching hospitals and
privately owned blood banks in Nigeria (n=624)21.
Among ANC populations, overall pooled HCV seroprevalence was
3% (21 cohorts; 95%CI: 2.2–3.8%), similar to the aggregated low
risk cohort pooled estimate (Figure 1;). However, regional subanalysis, despite low cohort numbers, showed the ANC pooled
HCV seroprevalence in Central Africa was again markedly lower
(1.71; 95% CI: 1.3-2.2) than the overall Central region estimate in
low risk populations. Pooled ANC seroprevalence in the West
Africa (4.3%; 95%CI: 3-5.6) was higher than the Central Africa
12
region SE Africa (pooled HCV seroprevalence of 0.4% (95%CI: 00.8).
Finally a sub-analysis of the other 88 cohorts that were included in
the low risk category, namely samples from the “general
population” as well as inpatients and outpatients, not deemed to be
a high risk of HCV, showed an overall pooled seroprevalence of
6.9% (95% CI: 6.1-7.7), i.e. higher than the estimates for ANC and
Blood Donor populations. Regional variation was marked with a
pooled seroprevalence estimate in Central Africa of 12.1% (26
cohorts; 9.4-14.8) compared with 2.4% (21 cohorts; 96% CI: 1.83.1) in SE region and 5.7% (41 cohorts; 95% CI: 4.7-6.8) in West
Africa. In all regions, pooled estimates in these “other” low risk
cohorts was higher than in ANC and Blood donor populations..
High-risk groups
41 cohorts across 15 countries were categorised as high risk for
HCV infection (20 from individuals with known liver disease, 21
from
individuals
transfusions,
with
injecting
high-risk
drug
use,
exposures,
e.g.
haemodialysis,
multiple
healthcare
workers, and prisoners), see Figure 2. The studies are detailed in
Supplementary information table 3.
13
Pooled HCV seroprevalence estimates across all 21 high-risk
exposure cohorts were higher than those for low risk cohorts at
11.9% (95%CI: 7.1-16.7), with similar values across all regions
(Figure 2). The estimates for high-risk cohorts in the Central region
(8.4; 95% CI: 5.1-11.8) was lower than the pooled seroprevalence
estimate amongst “other” low risk cohorts for the same region,
although
cohort
numbers
are
low.
The
highest
HCV
seroprevalence estimate identified through the literature review
was recorded in Kenya in a sample population of 145 injecting
drug users (46.2% HCV infected)22.
In contrast, analysis of the 20 liver disease cohorts (Figure 2 ;
Supplementary information table 3) found an overall pooled HCV
seroprevalence estimate of 10% (95%CI: 6.8-13.1). Although
similar levels of infection were estimated in West and SE regions,
in the Central region the mean pooled seroprevalence of HCV
among liver disease cohorts sampled was 2.5% (4 cohorts;
95%CI: 1.0-4.0). This is lower than estimates in this region for the
aggregated low risk cohorts and in line with estimates for blood
donor and ANC populations in the Central region.
14
Our results suggest that whilst high-risk exposures may result in a
similar level of HCV infection across the regions of Africa, the
proportion of liver disease caused by HCV varies significantly.
HIV co-infection prevalence
Seroprevalence of HCV/HIV co-infection was reported in 101
cohorts from 27 countries; some of which were recruited as HIV
positive cohorts (61) and some identified as a sub-group within the
primary analysis of each study. (A total of 42,648 HIV-positive
individuals were included (Supplementary information table 3).
74% of cohorts (75/101) included more than 50 individuals.
The overall pooled seroprevalence of HCV co-infection among
HIV-infected individuals was estimated at 5.7% (95%CI: 4.9 - .6.6,
Figure 3;). The majority of co-prevalence studies were from
countries in the West Africa region (42 cohorts), with a pooled
HCV seroprevalence of 6.7% (95%CI: 4.8-8.5 and SE Africa (43
cohorts) with a pooled HCV seroprevalence of 4.6% (95%CI: 3.75.4). Estimates of co-infection in HIV-positive cohorts in all regions
lie between those for blood donor/ANC cohorts and high-risk
cohorts.
15
Some countries, e.g. Senegal, Rwanda, Djibouti, and Gambia
report relatively low HIV prevalence and low levels of co-infection
(Figure 4). Some areas of high HIV prevalence, e.g. Malawi,
Zimbabwe, and Zambia in southern Africa are estimated to have
low HCV co-prevalence levels. The highest levels of co-prevalence
are seen in East and South-East Africa (Tanzania, Mozambique,
and Kenya) and Central Africa (Cameroon, Burundi, and Angola)
of which only Mozambique reports HIV prevalence above 10%.
Considering only countries with either a sample size greater than
500 HIV-positive patients or more than four HIV-positive cohorts,
co-infection with HCV was estimated to be greater than mean
seroprevalence
of
10%
in
Burundi,
Cameroon,
Kenya,
Mozambique, Tanzania, and Burkina Faso, and less than 5% in
Uganda, Malawi, South Africa, and Côte d’Ivoire.
40 cohorts with 3422 HCV-infected individuals were included, with
pooled HIV prevalence of 15.9% (95%CI: 12.5-19.2). Regional
breakdown revealed the highest rates of HIV co-infection in those
with known HCV were in SE Africa (33.4%, 14 cohorts; 95%CI:
17.5-49.4) by contrast with West Africa (10%, 18 cohorts; 95%CI:
6.1-14) and Central Africa (5.9%, 8 cohorts; 95%CI: 2.5-9.3).
Confirmatory and molecular testing
16
Only 52/185 low risk cohorts employed confirmatory assays to
screen for the presence of anti-HCV antibodies. The mean
estimates for pooled HCV seroprevalence overall and in each of
the regions were not significantly different to those found from all
general population cohorts when restricted to those with
confirmatory assays.
Analysis of the 35 low risk cohorts that also reported PCR testing
revealed the pooled mean proportion of positive serology samples
that were PCR positive was 49.5% (95%CI: 40.3.-58.9). (Figure 5)
Data for the genotype distribution of HCV was reported for only 39
cohorts in 19 countries.
Discussion
We have estimated the pooled seroprevalence of HCV infection in
sub-Saharan Africa to be 3% (95%CI: 2.9-3.1) when all samples
were analysed collectively, and 2.7% (95%CI: 2.5-2.8) when
limited to ‘low risk” samples in line with previous definitions. We
identified regional variation among groups considered “low risk”,
with the highest pooled seroprevalence calculated within the
Central Africa region. In all regions, the estimates of HCV
17
seroprevalence were lower among blood donor cohorts and ANC
groups than within aggregated low risk cohorts.
However the
regional and overall pooled seroprevalences in the “other” low risk
groups were higher. These cohorts included individuals in
healthcare settings as part of case control studies or convenience
sampling. Such settings are known to be associated with
transmission of HCV due to potential nosocomial transmission
through fomites or non-exposure prone procedures including
venepuncture and cannulation14,24-26 and may explain why
observed prevalences are higher than in population surveys.
The overall estimates for HCV seroprevalence are very similar to
those described previously, despite the estimates being based on
different studies and different time periods [13] {Madhava, 2002
#396}. This gives more confidence on the robustness of these
estimates and suggests no major change in HCV prevalence
between the periods of study. However, larger population surveys,
repeated over time, are required to monitor these trends. Given
that population surveys are time consuming and expensive, other
complementary methods are required to monitor changes in
prevalence. The observation that HCV prevalences in antenatal
cohorts are similar to those in the overall population suggests
18
antenatal surveillance may represent a useful population for
monitoring, particularly as there are many existing programmes
testing for HIV in this group.
Earlier analyses conducted as the HIV epidemic took hold in subSaharan Africa found little evidence of association between the
prevalence of HIV and HCV infections13. More recently, an
increased relative risk of HBV and HCV infection has been
reported in HIV-positive compared with HIV-negative populations
14
. We found the overall the seroprevalence of HCV infection in
HIV-infected individuals was significantly higher than in blood
donor or ANC groups and similar to defined general population
cohorts (6.2%), a finding consistent across all regions.
The highest estimates of HCV/HIV co-infection occurred in
countries (Tanzania, Burkina Faso, Cameroon, and Kenya) with
moderate reported adult HIV prevalence (all, except Mozambique,
less than 6%). By contrast, countries with the highest HIV
prevalence
(South
Africa,
Botswana,
Zimbabwe,
Zambia,
Mozambique, and Malawi) were all estimated to have low to
moderate levels of HCV co-infection (less than 5%), again
excepting Mozambique. Conversely, we found an increased
seroprevalence of HIV co-infection in those identified as HCV
19
seropositive, except in the Central region although, again, our
analysis included fewer cohorts and samples from the Central
region than from SE or West Africa.
These differences suggest that risk behaviours responsible for
HCV transmission might be quite dissociated from those
associated with HIV transmission in some regions, for example
Central Africa. It is also possible that regional differences are in
part explained by risk behaviours that are specific to one area (e.g.
scarification or specific medical practices) but we did not find large
studies that were able to explore this hypothesis further.
Although our meta-analysis of HIV/HCV co-infection is the largest
to date, it is limited by the geographic distribution of the papers
identified through the systematic review. While the majority of
reported studies were from the West Africa region, most samples
were from SE Africa, especially South Africa (including one large
population survey). Nonetheless, the data here support the need
for provision of HCV testing and care in all HIV programmes and
developing programmes for HCV infection. Despite retrieving a
large number of studies, we limited our review to published articles
retrieved from searching two databases and published in two
languages; it is possible that an expanded search including grey
20
literature
and
additional
languages
(notably
Arabic
and
Portuguese) would have contributed additional studies.
The quality of studies included was variable since the great
majority were not cross-sectional population-based surveys, but
instead targeted specific groups in limited geographic regions. All
the studies assessed HCV infection through serology, a proportion
going on to perform confirmatory testing. The results of the PCR
testing suggest the numbers of seropositive patients who have
active disease, and hence require treatment, is around half. The
extent to which this is a result of false-positive serology, a wellrecognised challenge, is hard to quantify. However, a sub-analysis
restricted to those general population samples with confirmed
serology found prevalence similar to that in all general population
samples, suggesting this was not a major issue. It is important to
recognise that a large proportion of seropositive individuals will not
require treatment and this data reinforces the need for larger
community surveys with high quality diagnostic methodology
including HIV and HCV nucleic acid testing for more robust
prevalence estimates to inform development of prevention and
treatment programmes.
Conclusions
21
Our systematic review and meta-analysis found a high
seroprevalence of HCV across populations of sub-Saharan Africa
including within HIV-positive adults, with evidence of regional
variation in the general population. There are limitations to
available data with a need for larger survey studies, but monitoring
antenatal HCV prevalence may be a helpful indicator of trends in
HCV infection. Regardless, there is clear unmet need for
prevention and treatment, access to which needs to be improved
for both mono-infected and co-infected individuals.
Contributors
The study was designed by GC and NF. Analysis was done by NJ,
BR, JM, NF, and GC. The first draft was written by BR and GC; all
authors contributed to the final manuscript and approved the final
version of the manuscript before submission.
Declaration of interests
GC has been an investigator on trials of HCV therapy sponsored
by Boeringher-Ingelheim, Gilead, Merck and Bristol-Myers Squibb.
GC has acted in an advisory role to Merck, Boeringher-Ingelheim,
Gilead, Janssen and WHO in relation to viral hepatitis.
22
Acknowledgements
GC is supported in part by the Biomedical Research Centre of
Imperial College NHS Trust and the MRC STOP HCV consortium.
Sarah Venis of MSF UK provided editing assistance, Theo Cooke
and Fred Cooke assistance with data collection.
23
24
Figure Legends
Figure 1: Forest plot of estimated HCV pooled seroprevalence in low risk populations (i) All low risk cohorts
aggregated (ii) Blood donor cohorts (iii) Antenatal clinic cohorts and (iv) All Other low risk cohorts – general
population, inpatients and outpatients
Figure 2: Forest plot of estimated HCV pooled seroprevalence in high risk populations (i) All high risk cohorts
aggregated (ii) Patients presenting with liver disease
Figure 3 (i) Seroprevalence of HCV in HIV positive cohorts and (ii) Seroprevalence of HIV in HCV positive cohorts ,
both separated by region
Figure 4: Estimated HCV seroprevalence in HIV positive cohorts in relation to HIV prevalence in 15-49 year olds [HIV
data from WHO/UNAIDS 2013)
Figure 5: Forest plot of estimated HCV seroprevalence in 35 low risk cohorts using confirmatory assays and pooled
regional HCV seroprevalence
25
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