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Global View Series: Sub-Saharan Africa

The deck is stacked against patients with HCV in sub-Saharan Africa. Health care infrastructure is lacking, the level of awareness of the disease is low and many populations are plagued by HIV and other health concerns that detract from efforts to deal with viral hepatitis. All of this contributes to some of the highest rates of HCV infection in the world.

Jennifer Layden, MD, PhD, of the Department of Infectious Diseases at Loyola University Medical Center in Chicago, painted a stark picture of HCV in the region. “In sub-Saharan Africa, the burden of HCV is quite high,” she said. “Roughly 20% of all global cases occur in this region of the world. In some parts of this region, the number of HCV cases is as high as, or higher than, the number of HIV cases. Liver cancer is the most common cause of cancer-related death in sub-Saharan Africa, and liver cirrhosis is increasing. Unfortunately, most people with HCV are not aware that they are infected, and of those who are, very few can afford or obtain HCV therapy.”

For Camilla S. Graham, MD, MPH, of the Division of Infectious Disease, Beth Israel Deaconess Medical Center and Harvard Medical School and vice president of medical and government affairs at Trek Therapeutics, Public Benefits Corporation, tackling all of these issues has to start small. “The most critical step is to develop low-cost diagnostics — around $1 a test, if we can manage it — that directly detect HCV RNA,” she said. “These tests should be available across sub-Saharan Africa. If patients aren’t diagnosed, nothing else can happen to keep them healthy with HCV.”

But we should not lose sight of the fact that the problems are myriad, according to Graham S. Cooke, MD, a clinician scientist based within the Division of Infectious Diseases at the Wright-Fleming Institute, Imperial College London. “We see many problems, ranging from the cost of the drugs to a lack of public health engagement,” he said. “Until recently, it was the ability to deliver the drugs, but that has now improved.”

There is a whole host of unknown factors about prevalence, natural history and antiviral treatment outcomes, according to Graham. “A good start would be to develop a number of pilot projects in countries like Nigeria, Ghana and Cameroon that study the entire continuum of care from diagnosis of a population, training of health workers, counseling on reduction of transmission and antiviral treatment,” she said. “Other pilots are needed to determine how much of the liver disease burden in each country is attributed to HCV infection. Each country can then develop cost-effectiveness analyses and budget impact models that allow them to determine how to prioritize HCV relative to other diseases and what resources need to be allocated.”

But the clinical community is not close to attaining these goals. In the meantime, it may be helpful to simply categorize the many obstacles in the region.

Starting with Epidemiology

Because of limited resources and a potential patient population that is spread throughout large, hard-to-reach areas, comprehensive demographic studies in sub-Saharan Africa are few and far between. However, Rao and colleagues undertook this challenge in an extensive seroprevalence study published in 2015. They reviewed 213 studies from 33 countries in sub-Saharan Africa in search of data sets containing HCV seroprevalence information. The analysis comprised data from 2002 to 2014 involving 1,198,167 individuals from 287 cohorts. Results indicated an overall pooled HCV seroprevalence of 2.98% (95% CI, 2.86-3.1). Among 185 low-risk cohorts, the seroprevalence was 2.65% (95% CI, 2.53-2.78), while a rate of 3.04% (2.23-3.84) was reported in antenatal clinics and a rate of 1.99% (1.86-2.12) was reported among blood donors. However, seroprevalence was 6.9% (6.1-7.5) in other general population cohorts.

In high-risk cohorts, Rao and colleagues observed a seroprevalence of 11.87% (95% CI, 7.05-16.7). The rate was 9.95% (6.79-13.11) among patients with liver disease and 5.73% (95% CI, 4.9-6.56) in a cohort of 42,648 individuals from 101 studies involving HIV-positive samples.

“We recorded a high seroprevalence of HCV across populations of sub-Saharan Africa, including in HIV-positive adults, with evidence of regional variation in the general population,” the researchers concluded. “Monitoring of antenatal HCV prevalence might be a helpful indicator of population trends in HCV infection; however, larger population surveys are needed to monitor these trends.”

Studies like these are instrumental in shining a light on where to begin dealing with HCV in the region, according to Layden. “First, a full understanding of who is infected or at risk for infection, as well as understanding the predominant transmission modes, is lacking,” she said. “This limits the ability to implement targeted screening and effective prevention efforts. Limited screening and prevention efforts hinder the ability to identify cases. This could be due to limited resources as well as the general lack of knowledge to guide policies on screening.”

Once the research community has obtained more of this broad population data, treatment and prevention strategies can get underway. But Layden suggested that even patients who have been diagnosed are still in a difficult position. “Access to care and treatment are profoundly limited due to geographical barriers, limited access to appropriate care settings, as well as limited financial resources to afford therapy,” she said.

For Graham, a significant challenge comes in the form of the many competing health issues that vie for limited health resources. “A country needs to be able to survey its population in order to understand the country-specific disease burden and costs attributable to HCV in order to determine what resources should be allocated to address it,” she said. “It becomes a chicken and egg problem because countries need to prioritize the need for HCV surveillance in order to determine the disease burden. Even end-stage complications of HCV are often blamed on hepatitis B or alcohol instead of HCV.”

Diagnosis and Treatment

A further complication is that in many countries, approximately 25% of people who have detectable anti-HCV antibodies will have undetectable HCV RNA because of immune-mediated spontaneous clearance, according to Graham. “A further complication in sub-Saharan Africa is that in many countries a much higher percentage of anti-HCV antibody-positive patients have no detectable HCV RNA,” she said. “It is unknown why there is such a high discrepancy between serology and molecular testing, but most people believe this is not spontaneous clearance after true exposure, but rather an antibody cross-reactivity with an unknown infectious agent. Serological tests are much less expensive and easier to perform than molecular testing, but can be misleading to useless in various regions of sub-Saharan Africa.”

Unfortunately, the sample collection and preservation, instruments for detecting HCV RNA, and skilled health care personnel required to perform the tests are scarce across the region. “HCV RNA tests are much more expensive than serological tests,” Graham added. “This provides an additional barrier to doing diagnostic work.”

That said, developing a stand-alone point-of-care diagnostic test may be even more difficult than implementing a point-of-care serological test, according to Graham. “Several companies such as Cepheid and Alere have developed single-test cartridges that can be run using a relatively inexpensive bench top instrument,” she said. “An up-front investment is required to buy the bench top analyzer, but individual tests are much less than what is typically charged for real-time PCR tests. These analyzers can test a number of other infections important in sub-Saharan Africa and may help with the management of HIV, HBV, HCV, TB, and other infections common in the region.”

With an inexpensive test to directly identify the presence of HCV RNA, which is necessary to confirm active infection in all patients who have HCV antibodies, it may be possible to skip the antibody step and directly test for presence of virus, according to Graham.

In spite of these obstacles, efforts are being made. Ntagirabiri and colleagues tested 179 samples of anti-HCV antibodies for HCV RNA, genotype and subtype. Their aim was to determine the nature of HCV in Burundi and to highlight the difficulties associated with the LiPA Method, which is commonly used in many areas in Africa. Results indicated that 92.7% of the samples were genotype 4, while 5.6% were genotype 1 and 1.7% were genotype 3.

Subtype analysis results indicated that 49.1% of genotype 4 patients had 4h-infection disease, while 21.6% were 4e, 3.9% were 4k and 25.5% had 4a/4c/4d. The LiPA method was unable to subtype 69.3% of the genotype 4 infections. This method also failed to separate 4a, 4c and 4d.

“These tests need to be validated in sub-Saharan Africa to make sure the sensitivity and specificity are high,” Graham said. “A project that involved FIND and HIV Forum developed a target product profile for diagnostics that would be adequate to confirm active infection and confirm cure after treatment.”

Cooke suggested that one of the key challenges in getting patients tested is the simple fact that little is known about HCV. “There is a lack of awareness about screening and routine diagnosis,” he said. “Once diagnosed, there are few services established to deliver care. The challenges of treatment are probably similar to TB.”

Modes of Transmission

Another important challenge for the research community is to classify the modes of HCV transmission. “We believe that the risk factors and transmission modes vary by age groups,” Layden said. “Older individuals may have been infected years ago before more routine screening of blood products was implemented.”

She suggested that there are many more potential transmission modes in the present day. “This includes the sharing of or exposure to items such as razors and needles that are contaminated with blood, and sexually-related transmission,” she said. “We have observed very few cases of HCV among children younger than 15 years, and believe that potential exposures to, and subsequently transmission of, HCV begins in the early adult age range. With so many potential transmission routes, it is difficult to imagine one effective mechanism to prevent transmission.”

Graham cited iatrogenic transmission as a key focus area. “She said that it continues to occur even in wealthy countries like the United States, which have had rigorous infection control practices in place since the push to reduce iatrogenic HIV transmission, we have iatrogenic transmission of HCV from breaks in infection control or drug diversion. We have sophisticated molecular testing that can trace an outbreak and define the source.”

However, because few people are even being tested in sub-Saharan Africa, Graham believes it is likely that faults in infection control practices may go unrecognized. “When health care resources are limited and patients have to pay cash for medicine and medical equipment, the possibility of re-using or inadequately sterilizing materials is high,” she said. “It is vitally important that countries are supported to obtain single-use needles and infusion equipment, that testing of the blood supply is done on every blood donation, and surveillance of health care settings is performed.”

Interventions should also be undertaken to reduce transmission among people who inject drugs, according to Graham. “Like in many areas of the world, there is denial and stigma associated with drug use in sub-Saharan Africa,” she said. “Drug treatment, including opiate replacement therapy, and harm reduction interventions like needle exchange programs, are rare. The flow of the drug trade has led to more drugs in the region, so this is likely a bigger problem than countries have acknowledged.”

Cooke summed up the modes of transmission. “There are likely to be different factors in different countries,” he said. “But it’s likely that health care associated infection plays a significant role. For example, we recognize issues with contaminated blood products and needles. Injection drug use is a problem in some parts of sub-Saharan Africa, but this tends to be focused in urban centers.”

Potential Impact of DAAs

In a recent paper, Layden and colleagues expressed tepid optimism that novel therapies could begin to make a dent in the HCV burden in sub-Saharan Africa. “With the advent of highly effective anti-HCV agents, there exists great potential to at least curb the global epidemic,” they wrote. “For regions such as sub-Saharan Africa, however, this will require a thorough understanding of the regional population-level epidemiology, risk factors and transmission mechanisms.”

A supplementary beneficial effect of these drugs could be reductions in liver cancer and other hepatic comorbidities, according to Layden. “This would require appropriate diagnosis and confirmation of active infection, addressing financial and other limitations that prevent access to therapy, as well as education about prevention,” she said. “HCV therapies can lead to cure. However, individuals can become re-infected. Thus, public health campaigns are needed to educate the public about how HCV is transmitted and provide guidance on how to reduce the risk of infection and re-infection.”

For Graham, it’s a matter of economics. As with any discussion of HCV today, cost of therapy remains a barrier. Graham and Swan plainly addressed this issue in a paper in 2015. “Soon the main barrier to curing hepatitis C, even in wealthy countries, will be the high price of these all-oral regimens,” they wrote. “The gulf between the advances in HCV drug development and access to treatment for individual patients will be even greater in low- and middle-income countries where 80% of the global burden of HCV infection and mortality exists.” They recommend improving low-cost diagnostic tests in regions such as sub-Saharan Africa, largely due to high rates of false-positive tests, and ongoing efforts to reduce transmission in all of its forms.

But it always comes back to money, and the deals countries can make with pharma to bring the drugs in. All countries in sub-Saharan Africa are on the list of 111 countries that have access to voluntary licensing and generic sofosbuvir and daclatasvir, according to Graham. “Each country needs to undergo regulatory/marketing approval and negotiate prices with the generics companies,” she said. “Countries like Egypt, with very large populations of patients with HCV infection, have been able to negotiate generic sofosbuvir plus daclatasvir for about $300 per 12-week course. Some countries have so little health care expenditure that even this low price may be unaffordable.”

Cooke is hopeful that there may be a sea change in terms of the cost of DAA therapies. “Cost will still probably be a limiting factor in the short term,” he said. “But as costs come down, the nature of DAAs and how they can be delivered means they should be able to offer cure to many more people in the region.”

Graham added, however, that organizations that helped purchase medications for HIV, TB and malaria — including PEPFAR, Global Fund, and the Clinton Health Initiative — are not purchasing drugs for HCV. “There needs to be a certain volume of treatment in order to optimize bulk pricing and this may be a barrier for some countries,” she said. “The World Health Organization has added direct-acting antiviral medications to its list of essential medications and has issued guidelines for HCV treatment. It does not have the budget to purchase drugs for low-income countries, but it could help facilitate collective negotiations across multiple countries to help achieve the best price possible for these drugs and help ensure the quality of the drug supply.”

Dealing with Specific Countries

The data coming out of the region are sparse, so it is sometimes difficult to discern whether there are few patients, or just few patients that can be identified. While widespread studies like the one conducted by Rao and colleagues are helpful, country-specific data are crucial.

In Cameroon, Noubiap and colleagues noted that patients with HIV are living longer due to widespread use of antiretroviral therapies to treat HIV. As a result, they are becoming increasingly at risk for other complications, including HCV. They screened 531 individuals from Cameroon with HIV for HBV surface antigen and antibodies to HCV. The HCV seroprevalence was 7.2%.

Purdy and colleagues found that HCV genotype 2 is not only the most common genotype in the West African region, but also that genotype originated there, possibly in Ghana. Evaluation of NS5B sequences of samples obtained from Côte d’Ivoire, Ghana and Nigeria revealed that Ghana was mostly the site where genotype 2 originated. “Spread of HCV genotype 2 from Ghana did not appear to be through diffusion to adjacent countries along the coast,” they wrote. “Rather, it was transmitted from Ghana to many distant countries in Africa, suggesting that certain routes of geographical dissemination were historically more efficient than mere proximity and that the HCV genotype 2 epidemic history in West Africa is extremely complex.”

In another study by Layden and colleagues, 363 previous blood donors were recalled to identify the level of active infection and risk factors for HCV. Eligible participants were recruited at a single teaching hospital in Kumasi, Ghana. The researchers observed active HCV infection in as few as 74.4% of participants, and as many as 88%, depending on the criteria used to define a case. Liver inflammation was present in those with active disease, along with a mean viral load of 5.7 log copies/mL. HCV risk was higher in the northern and upper regions of Ghana, according to the results. Traditional circumcision, home birth, tribal scarring and HBV co-infection were other risk factors for active HCV disease. “Viremic infection was common among serologically confirmed cases,” the researchers concluded. “Attention to testing algorithms is needed in order to define the true HCV burden in [sub-Saharan Africa]. These data also suggest that several transmission modes are likely contributing to the current HCV epidemic in Ghana and that the distribution of these practices may result in substantial regional variation in prevalence.”

In Nigeria, it has been reported that there is a low HCV prevalence. However, the study involved small numbers. Onyekwere and Hameed agreed that small, select population studies are insufficient to determine the burden of disease in a country like Nigeria. They conducted a screening exercise in 5,558 individuals from 2010 to 2012. HBV prevalence was 6.7%, while HCV was relatively low, at 0.9%. “Overall our findings suggest that hepatitis B is endemic in Nigeria, much less than previously reported, while the prevalence for HCV is low, although reports of pockets of high prevalence exist in select populations (hospital patients including those living with HIV),” they wrote.

“West Africa, especially Ghana, has a high prevalence of genotype 2 infection, central Africa has predominantly genotype 4 infection, South Africa has a high rate of genotype 5 infection, and other regions have a mix with mostly genotype 1 infection,” Graham said. “A pangenotypic regimen would obviate the need for genotype testing, with its additional cost and complexity.” - by Rob Volansky

• References:
• Graham CS and Swan T. Antiviral Res. 2015;doi:10.1016/j.antiviral.2015.01.004.
• Layden JE, et al. Clin Infect Dis. 2015;doi:10.1093/cid/ciu965.
• Layden JE, et al. Open Forum Infect Dis. 2014;doi:10.1093/ofid/ofu065.
• Ntagirabiri R, et al. Pan Afr Med J. 2014;doi:10.11604/pamj.2014.19.69.4580.
• Noubiap JJ, et al. PLoS One. 2015;doi:10.1371/journal.pone.0137375.
• Onyekwere CA, Hameed L. Trop Doct. 2015;doi:10.1177/0049475514560211.
• Purdy MA, et al. J Gen Virol. 2015;doi:10.1099/vir.0.000153.
• Rao VB, et al. Lancet Infect Dis. 2015;doi:10.1016/S1473-3099(15)00006-7.

• For more information:
• Graham S. Cooke, MD, PhD, can be reached at Imperial College London, South Kensington Campus, London SW7 2AZ; email: g.cooke@imperial.ac.uk.
• Camilla S. Graham, MD, MPH, can be reached at BIDMC Division of Infectious Disease, 110 Francis St., Suite GB, Boston, MA 02215; email: cgraham@bidmc.harvard.edu.
• Jennifer Layden, MD, PhD, can be reached at Media Relations, Loyola University Health System, 2160 S. First Ave, Maywood, IL 60153; email: THOMS@lumc.edu.

Disclosures: Cooke reports consulting for Gilead Sciences and WHO. Layden reports no relevant financial disclosures. Graham reports working part-time with Trek Therapeutics.