Some may say that the COVID-19 pandemic has highlighted the importance of scientific research and global collaboration. Some may even take to the extreme to say that COVID-19 pandemic is the most significant health issue affecting the world right now. Shiny headlines and reverberating health messages promulgated by official sources, pervade the world as COVID-19 tightens its grip on the masses. However, while the world is focusing on COVID-19 and torrents of research papers concerning COVID-19 gush into the pages of prestigious journals, we are forgetting something. In fact, we have never noticed the 'hidden pandemics' in the first place. Contrary to popular belief, we have never been dealing with just one pandemic. COVID-19 is a newcomer. A total newbie in this world dominated by giants. AIDS (Acquired Immunodeficiency Syndrome) caused by HIV (Human Immunodeficiency Virus), Hepatitis B caused by Hepatitis B Virus (HBV), Hepatitis C caused by Hepatitis C Virus (HCV), Tuberculosis caused by Mycobacterium tuberculosis and HPV (Human Papilloma Virus) infections all carry significant global burden and lead to clinical manifestations which involve high mortality and morbidity rates. Not only do we need to avoid the gradual shift of conversation from general health to merely COVID-19, we also need to improve the conversation. The first step of so is to acknowledge the fact that not everyone is born the same.
Political correctness and virtue signalling aside, men who have sex with men (MSM) are still discriminated and are subjected to more health issues. I deliberately avoid the use of words such as homosexuality and gay since they add nothing to the medical conversation. These terms concern one's sexual orientation, which are unrelated to one's sexual activity - the key factor affecting one's risk of exposure to deadly infections such as HIV and HCV. In a study published by Lancet HIV, 31 per cent of MSM respondents described living with HIV as burdensome, where 82 per cent stated they would be relieved if they could be cured. Predominant personal feelings incurred when living with HIV were shame (26 per cent) and stress (18 per cent). [1] At the same time, MSM with Hepatitis C experience greater stigmatisation. [2] It is postulated that this originates from the normalisation of HIV due to more widespread acceptance, while Hepatitis C is inadvertently bundled up with intravenous drug use. [3] Lack of awareness is still an issue. As with any medical discussion, to improve patient care and management, we need to first improve the quality of the conversation. To do so, we need to understand more about the correlation between Hepatitis C and MSM. More importantly, it is necessary for us to dissect the relationships between Hepatitis C prevalence (the proportion of population being afflicted the disease at a given time) and incidence (number of new cases at a given time), and multiple factors which are associated with MSM. The most paramount of which are HIV status and the use of pre-exposure prophylaxis (PrEP; usually emtricitabine plus tenefovir) for HIV.
Figure of Facts of Hepatitis C, extracted from URL: http://www.hep-c-alert.org/wp-content/uploads/2017/11/global-stats.jpg.
Figure showing the global distribution and prevalence of Hepatitis C (WHO Statistics). As we can see, the Eastern Mediterranean has the highest number of cases.
Schematic Diagram showing the progression of Hepatitis C infection to Hepatocellular Carcinoma (extracted from Nature Reviews- Immunology on URL: https://labiotech.eu/wp-content/uploads/2016/05/hcv_infection_genotype_cirrhosis_hepatocellular_carcinoma_epistem.jpg)
A recent study published on Lancet Gastroenterology and Hepatology has given a general overview of the 'hidden pandemic' - the pandemic that nobody really talks about daily, one that is also tucked in the shadows since it concerns a marginalised society. [4] Global Hepatitis C prevalence in 2015 was found to be at 1.0 per cent, amounting to 71.1 million individuals who were positive for HCV in blood (also known as viraemic individuals). [5] What about MSM? What about those with HIV co-infection, which by the way, is more of a possibility in MSM?
The Study:
This is not a research article in the traditional sense - it is a systematic review and meta-analysis which involves the analysis of a huge pool of studies to synthesise an evidence-based answer to a research question. They are carried out by a group of researchers who have taken interest in the research done in a particular field. The PRISMA method is then adopted to weed out unsuitable studies, so that only studies falling into the pre-defined inclusion criteria (which also do not fit into the exclusion criteria) are analysed. These studies have to be directly related to the research question and of substantially high quality. The question of quality is determined by the cohort size and methodology. It is common for researchers to only select studies written in English (or at least with the abstract written in English). Unfair it may seem, but let's face it - English is the language of science.
PRISMA Method for doing Systematic Reviews (extracted from Wikipedia). Common databases used include MEDLINE, Embase and PubMed. Personally, I like using Science Direct when looking for papers. However, it only returns studies published by journals owned by Elsevier.
Key Words used in Systematic Review: (1) Gay / Homosexuality, Male / Men who have sex with men / Men having sex with men, AND (2) HCV / Hepatitis C, AND (3) Prevalence / Incidence / Risk Factors;
Databases Used: MEDLINE and Embase.
Number of Studies Included: 194
This study, commissioned by WHO, removes studies which rely on self-reported Hepatitis C status. The information must be confirmed by testing - this can be through serological testing (proving seroconversion, meaning that there are anti-HCV antibodies present in the serum) or viraemia testing (HCV RNA PCR technique).
5 studies are removed from pool estimates to avoid skewing of data since over 70 per cent of their cohorts engage in injecting drug use (history of, or current use). They are only included in data stratification by the type of injecting drug use
Aims of the Study: To assess the prevalence and incidence of Hepatitis C in MSM, as well as stratifying the risk according to HIV status, HIV PrEP, history of and current injecting drug use**. Comparisons are made between MSM and the general population.
Comparisons are also made between different geographical regions defined by the WHO, and the wealth category of nations (low-income, lower-middle-income, and so forth).
This scoping exercise is extremely important since it highlights the importance of the hidden pandemic and provides us with extra information regarding the scale and severity of the problem. By gathering more data, we can generate a clearer picture of what's going on and design appropriate interventions for this population subgroup.
Just as a point, the word 'range' below means 95% Confidence Interval - just don't want to type this over and over again.
Results on MSM Seroprevalence by Geography:
Overall MSM HCV Seroprevalence (Global): 3.4 per cent;
Top three regions of highest seroprevalence: Africa-5.8 per cent (range: 2.5-10.4), Southeast Asia- 5.0 per cent (range: 0.0-16.6), Eastern Mediterranean***- 4.1 per cent (range: 3.1-5.2);
Seroprevalence according to Income Status: Lower-middle income countries-10.3 per cent (range: 3.0-21.0), Low-income countries-5.8 per cent (range: 1.1-13.4), High-income countries- 3.7 per cent (range: 3.1-4.4), Upper-middle income countries- 1.6 per cent (range: 1.1-2.1).
As we can see from the above data, health inequality is still a living and breathing issue. Lower-middle and low-income countries account for the highest seroprevalence in the globe and Africa, where most countries fall into the two aforementioned wealth categories, accommodates the highest number of HCV-seropositive cases. Any future public health initiatives and interventions must take this into account. This can involve cross-border ventures and ameliorating the provision of healthcare services in these regions. Vaccination programmes, provided that we can find an appropriate HCV vaccine (not a remote, yet also not a close possibility, due to the heterogeneity of the viral genome - there are 8 discovered genotypes of HCV), should be promulgated. This can be complemented by the increase in direct-acting antiviral (DAA) medication provision (and possibly supervision of patients taking the medication- something similar to DOTS for tuberculosis) and enhanced diagnostic support, such as the import of PCR technology to developing countries for faster HCV diagnosis.
Results on MSM Seroprevalence & HIV Status:
HIV-positive: 6.3 per cent (range: 5.3-7.5);
HIV-negative: 1.5 per cent (range: 1.0-2.1);
Regardless of HIV status, low-income and lower-middle income countries have the highest seroprevalence;
There is an estimated annual increase of 10.9 per cent in pooled HCV incidence in HIV-positive MSM; however, this statistic is not significant (p>0.05).
There is also higher HCV incidence found in HIV-negative MSM undertaking PrEP;
The greatest difference in seroprevalence in terms of wealth category is found in high-income countries;
Europe features the greatest difference in seroprevalence between HIV-positive and HIV-negative MSM populations.
A greater difference means that the baseline risk of contracting HCV for MSM in general is not very high. Moreover, it stresses on the importance of administering anti-retroviral therapy (ART) promptly.
Prevalence ratios (PRs) are also calculated to compare the prevalence between HIV-positive and HIV-negative MSM. The highest prevalence ratios (implying the greatest difference between the two groups) are in Eastern Mediterranean (46.09; 95% CI: 0.27-7795.22), Spain (41.02; 95% CI: 9.15-184.00) and Germany (20.76; 95% CI: 0.11-3902.77). The prevalence ratio for the UK is 8.98 (95% CI: 2.01-40.24).
HIV is another chronic disease which carries high disease burden, morbidity and mortality. HIV is also more prevalent in MSM since it can be spread quicker through anal sexual intercourse. The resultant immunodeficiency can explain why HIV-positive MSM also experience higher rates of HCV seroprevalence. Behaviour-wise, HIV-positive MSM may also be more inclined to engage in high-risk sexual activities. This includes fisting (which can lead to greater rectal trauma; mucosal epithelium is easily torn if done wrongly) and group sex. The adoption of such sexual practices encourages the transmission of HCV. A study done by UCL showed that unprotected anal intercourse, having more than 30 sexual partners in the past year, higher numbers of new anal sex partners, rimming, fisting and the use of sex toys were associated with HCV. Amidst all these factors, fisting carries the highest incidence rate ratio of 9.39 (95% CI: 2.87-30.77) [6] This highlights the fact that we are not dealing with a single hidden pandemic, but multiple, mutually-interacting ones.
In terms of observed differences in PrEP, this can be due to multiple factors. The investigators postulated that this might not be directly attributable to behavioural factors. Other factors are more significant, including serosorting and the greater predisposition of MSM taking PrEP to begin with. PrEP is usually given to those experiencing high risk of contracting HIV. This can be due to the nature of their occupation (e.g. prostitution), or the presence of comorbidities, including other sexually-transmitted infections and diabetes mellitus, which leads to immunodeficiency. The higher prevalence in this case is got to do with the people who take the prophylaxis, not the prophylaxis itself. Moreover, serosorting means the practice of having sexual intercourse based on the person's HIV serological status. From this, a seronegative person is more likely to be chosen as a sexual partner. Serosorting enables the mixing between HIV-positive and HIV-negative individuals taking PrEP. However, the prophylaxis only works for HIV, not HCV. As HIV-positive individuals are more likely to have HCV, Hepatitis C can be disseminated through sexual activity. At this stage, I think we cannot completely rule out the possibility of behavioural factors playing a role. As I mentioned in the introduction, HIV is gradually normalised due to more widespread public education as to what it is and what it entails. HIV is less stigmatised than HCV owing to the rise of public campaigns and popularisation of anti-retroviral therapy (ART). However, HCV is still bundled with stigmatising circumstances such as male homosexuality and injecting drug use. The public also know less about this enigmatic malady. This is likely to feed into the myth that HIV is the only infection one should be caring about when having male same-sex sexual activity. Following this line of reasoning, taking PrEP eliminates this risk and justifies the adoption of more high-risk sex acts. This behavioural shift is logical and should be verified in subsequent studies.
Results on MSM Seroprevalence & Injecting Drug Use:
Yes (History): 30.2 per cent (range: 22.0-39.0);
Yes (Current): 45.6 per cent (range: 21.6-70.7);
Overall No: 2.7 per cent (range: 2.0-3.6).
Mixing this with geographical regions, the following three countries have the highest MSM HCV seroprevalence when coupled with current injecting drug use: Mexico (97.4 per cent, 95% CI: 92.6-99.5), Vietnam (48.9 per cent, 95% CI: 33.7-64.2), and Canada (47.6 per cent, 95% CI: 32.0-63.6). I don't think we should draw too many conclusions from this because only one study has been included in each country. This might be due to the scarcity of research in this field done nationally. However, regarding the high rates of injecting drug use recorded in all three countries, this might be a nationwide matter rather than a purely MSM issue.
The much higher rates of seroprevalence in MSM with the history of, or even current injecting drug use, confirm the long-held belief that HCV is a blood-borne infection and injecting drug use is a major risk factor. This has wider implications. If we transpose injecting drug use to other contexts, we know that needle-stick injury, blood transfusions and other medical procedures and risks also carry higher risk of HCV transmission. This sends out a strong message that healthcare workers should follow infectious control guidelines laid down by the hospital at all times, especially procedures for handling needles. Patients with conditions that require regular blood transfusions, such as haemophilia A (fresh frozen plasma transfusion) also have to be wary of the risks involved.
There is also the issue of resources and prison health. In the healthcare setting, it is established protocol that all needles are to be used once only. This minimises the risk of disease transmission (not just HCV, but other blood-borne infections including HIV). However, what about other locations where there is frequent needle use? I am talking about prisons here. Prison health is a frequently neglected area of care. The public might not care about prisons that much, considering that mostly prisoners are locked behind bars. A sense of corrective and retributive justice renders us cold and heartless when commencing any discourse regarding improvement in prison health. Emotion-fuelled assertions such as 'they deserve it' and 'if they don't want to be treated that way, they should never have committed the crime in the first place' are ubiquitous. However, we also need to realise that prisoners are human and they should be proffered a chance to repent and reflect. Incarcerated persons were found to be 9 to 13 times more likely to suffer from Hepatitis C. Moreover, corresponding public health measures are deemed inadequate. Only 10 out of 29 (34 per cent) surveyed Western European countries reported HCV screening programmes for prisoners. Chronic HCV treatment is also under-provided, due to the high costs involved. [7] The HCV seroprevalence among prisoners was found by a systematic review of 30 studies done by 14 countries to be around 30 to 40 per cent. In the US, HCV seroprevalence rates among different states linger in the zone of 23 to 34 per cent. [8]
More importantly, lying within the walls of prisons is the very severe problem of needle-sharing and illicit drug use. In the UK, the rate of positive random tests for traditional drugs (those contained in the Misuse of Drugs Act 1971, including opiates and cannabis) from 2012/2013 to 2017/2018 rose from 7 per cent to 10.6 per cent. The prevalence of drug use is even higher in male prisoners and category C prisons. [9] Instead of mere criminalisation, the criminal justice system needs to recognise that prisoners won't stop taking illicit drugs just because it's illegal. They are going to do it anyway, might as well reduce the risk of disease transmission and seize this opportunity to improve general prison health. This can be done by providing inmates with clean needles of one-off use. They can also be educated regarding the techniques of injection which pose the least risk (comparatively) of HCV transmission. Accompanied by widespread testing and possible prophylaxis (subject to cost), it is expected that general levels of prison health can be improved. Moreover, we should change our thinking. Prison health is not just health for an unwelcome subgroup of the population. It affects us all. Most prisoners will eventually find their way back to the community. Efforts of reintegration can never be complete without their receiving adequate medical care. Moreover, mistreating prisoners leads to a gap in the public healthcare system. With higher rates of disease transmission within prisons, once they are released, they can spread it more widely in the community. In public health, we leave no stone unturned. Every person matters because even one ill person impugns the efficacy of a public health intervention.
Results on MSM vs General Population Seroprevalence:
Overall PR: 3.04 (range: 2.55-3.53);
MSM HIV-negative vs General Population PR: 1.58 (range: 1.14-2.01);
MSM HIV-positive vs General Population PR: 6.22 (range: 5.14-7.29).
As we can see, there is not much difference between MSM HIV-negative people and the general population, indicating that the variance in sexual practices might not contribute to that much of a difference. Of course, this deduction has to take into account the factors behind the HIV-negative status of these MSM. This might be due to greater health awareness and the use of protection during sexual intercourse. By adhering to the tenets of safe sex, the sexual practice itself does not cause as great an impact on public health as expected.
Results on MSM & HCV Viraemia:
Overall Viraemia Prevalence: 1.6 per cent (range: 0.8-2.8);
HIV-negative MSM viraemia prevalence: 0.5 per cent (range: 0.1-1.1);
HIV-positive MSM viraemia prevalence: 2.4 per cent (range: 1.4-3.6);
As a recap, HCV viraemia and seroprevalence are different. Viraemia refers to virulent presence in the blood, while seroprevalence refers to the presence of anti-HCV antibodies. An infection can be cleared, but antibodies still remain. HCV Viraemia is indicative of active disease.
Summary & Comments:
From the result above, we can make several conclusions:
MSM status results in greater likelihood of contracting HCV relative to the general population. However, the likelihood is small;
MSM of HIV-positive status leads to greater HCV incidence than those of HIV-negative status;
Injecting drug use contributes to much higher risk of contracting HCV;
MSM HCV prevalence is higher in countries of lower income. Africa also has the highest MSM HCV prevalence in all reported WHO geographical regions.
This study has provided us with an insight of the hidden pandemic. However, there remain certain unresolved issues. By answering additional research questions, not only can we acquire a more comprehensive picture, we can also improve clinical outcomes for those afflicted by Hepatitis C.
(a) The systematic review analysed 194 studies. However, most studies were performed in Europe (n=58) and the Americas (n=45). Although Africa, East Mediterranean and Southeast Asia have high rates of Hepatitis C prevalence, research in these regions is scarce. This can also be traced back to the language limitation. Only studies published in English or with abstracts written in English are included in the analysis. This may have contributed to the geographical skewing of results.
(b) The systematic review can, in later analyses, incorporate data regarding regional genotypic prevalence. Currently, 8 genotypes of HCV are identified. Genotype 1 is the most common in high-income countries. Genotypes 2 and 6 are the most common in East Asia. Genotype 4 is the most common in the Middle East and North Africa. Genotype 3 is the most common in lower-income countries including South Asia, while genotypes 5, 7 and 8 are not as common as the others. Genotypic differences can lead to varying treatment responses. The Y93H genetic mutation in HCV genotype 3 is found to lead to greater treatment resistance in conventional regimens, such as sofosbuvir-ledipasvir and sofosbuvir-velpatasvir. [5] There may be genotypic differences between the general population of a certain geographical designation and MSM, in virtue of the variant sexual practices adopted. By unearthing these differences, we can improve treatment options which can result in higher rates of sustained virologic response (SVR), meaning that the viral load is reduced to undetectable levels (therefore minimal disease effects).
(c) The association between HIV and HCV is significant in MSM. This brings us to therapeutic concerns. Is it sensible for us to commence both ART and DAA at the same time? There may be drug-drug interactions which justifies starting either first and not both together. Then, the question migrates to which we should start first. For MSM taking PrEP, there is higher incidence of HCV. These patients are likely to benefit from DAA in the long-term. It is efficacious for us to see what modifications can be made to the DAA in those cases so that it does not conflict with the PrEP.
(d) I think there is also one glaring gap which can be followed up in subsequent analyses: HBV and HCV co-infection. It has been reported that the co-infection rate ranges from 1 to 15 per cent. The rate in the US was also found to be 1.4 per cent. [10] However, these figures are prone to underestimation since any co-infection would involve HCV being the predominant microbe. It means that once DAA exerts its effect and HCV is suppressed, HBV assumes preponderance and can lead to hepatocellular carcinoma. Co-infection is also not a remote possibility in MSM. HBV is traditionally known to be transmitted through sexual contact and blood. The HBV seroprevalence rate in MSM was found to be 23-61.5 per cent. [11] Knowing about the prevalence of co-infection across different geographical regions and countries according to wealth status allows us to plan treatment accordingly - both whether to administer Hepatitis B nucleoside analogue therapy (e.g. entecavir) and what modifications should be done to DAA to avoid drug-drug interactions, as well as the timing (tandem or simultaneous) of therapeutic interventions.
Figure showing the SVRs for the two regimens, (a) sofosbuvir-velpatasvir (respectively non-structured proteins 5B and 5A inhibitors), and (b) sofosbuvir-ribavirin (where ribavirin is a guanosine analogue). It is evident that treatment-naive patients report higher SVRs and regimen (a) has the highest SVRs across all categories. Non-cirrhotic patients also report higher SVRs. [12]
Concluding Remarks:
The WHO-commissioned study gives us a much clearer picture of the current state of the 'hidden pandemic'. I know COVID-19 has been under the spotlight for the majority of this year. It has been the talk of the town and the reason why many people are becoming more aware of health issues. However, we must not forget that we are fighting multiple pandemics. This includes Hepatitis C. The fight is harder for some of us due to stigmatisation of both the disease and their sexual preferences. Rather than perpetuating stereotypes and prejudice, we should gather more information regarding how sexual preference influences one's risk of disease. By generating a clearer picture of the pandemic, it is no longer hidden - we can tailor public health interventions and treatment modalities according to the results garnered. Of course, this study can be improved by studying more correlates, including genotypic considerations and HBV-HCV co-infection in MSM. It can also include more studies (possibly by dropping the language requirement) so as to reduce the likelihood of geographical skewing of data. By holding on together, we can make this world a better place.
*The cover image is extracted from: https://www.pharmacist.com/sites/default/files/HCV-graphic.png.
**Originally, I was tempted to use the term 'intravenous drug use'. However, I realised the deliberate use of the term 'injecting drug use' in the study. It intended to include cases where patients injected drugs via a different conduit, i.e. arteries and capillaries. Any contact between foreign bodies and blood constitutes to higher risk of HCV transmission and this should not differ too much by the type of conduit utilised.
***As a reminder, East Mediterranean refers to countries in the Middle East and North Africa.
References and Further Reading:
[1] van Bilsen W, Zimmermann H, Boyd A, Davidovich U. Burden of living with HIV among men who have sex with men: a mixed-methods study. The Lancet HIV. 2020;7(12):e835-e843. doi:10.1016/s2352-3018(20)30197-1.
[2] Owen G. An 'elephant in the room'? Stigma and hepatitis C transmission among HIV-positive 'serosorting' gay men. Cult Health Sex. 2008;10(6):601-610. doi:10.1080/13691050802061673.
[3] Schroeder SE, Higgs P, Winter R, et al. Hepatitis C risk perceptions and attitudes towards reinfection among HIV-diagnosed gay and bisexual men in Melbourne, Australia. J Int AIDS Soc. 2019;22(5):e25288. doi:10.1002/jia2.25288.
[4] Jin F, Dore GJ, Matthews G, et al. Prevalence and incidence of hepatitis C virus infection in men who have sex with men: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021;6(1):39-56. doi:10.1016/S2468-1253(20)30303-4.
[5] Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Lancet. 2019;394(10207):1451-1466. doi:10.1016/S0140-6736(19)32320-7.
[6] Turner J. Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men. Sex Transm Infect. 2006;82(4):298-300. doi:10.1136/sti.2005.018366.
[7] Rich JD, Beckwith CG, Macmadu A, et al. Clinical care of incarcerated people with HIV, viral hepatitis, or tuberculosis. Lancet. 2016;388(10049):1103-1114. doi:10.1016/S0140-6736(16)30379-8.
[8] Fazel S, Baillargeon J. The health of prisoners. Lancet. 2011;377(9769):956-965. doi:10.1016/S0140-6736(10)61053-7.
[9] HM Prison & Probation Service. Prison Drugs Strategy. 3 April 2019. Accessed on 31 December 2020. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/792125/prison-drugs-strategy.pdf.
[10] Mavilia MG, Wu GY. HBV-HCV Coinfection: Viral Interactions, Management, and Viral Reactivation. J Clin Transl Hepatol. 2018;6(3):296-305. doi:10.14218/JCTH.2018.00016.
[11] Kahn J. Preventing Hepatitis A and Hepatitis B Virus Infections among Men Who Have Sex with Men. Clinical Infectious Diseases. 2002;35(11):1382-1387. doi:10.1086/343044.
[12] Foster G, Afdhal N, Roberts S et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. New England Journal of Medicine. 2015;373(27):2608-2617. doi:10.1056/nejmoa1512612.
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