Special SeriesPublication Exclusive

Global View Series: HCV in Southeast Asia

In many parts of the world, the fast-moving clinical environment of hepatitis C virus today is a reason for hope. However, certain countries and regions still face more significant obstacles than others in managing the disease. With that in mind, HCV Next undertook the Global View Series, a four-part investigation of HCV in places that face unique and appreciable hurdles. In this installment, we look at Southeast Asia.

Island nations in the region include Brunei, Christmas Island, East Malaysia, East Timor, Indonesia, the Philippines and Singapore. On the mainland, Cambodia, Laos, Myanmar, Thailand, Vietnam and West Malaysia are included. However, few data sets exist for the more developed countries such as Thailand and Vietnam, and virtually nothing exists farther afield.

The primary issues in the region are lack of resources and poor epidemiology, according to most experts, including Kimberly Page, PhD, MPH, professor in the departments of Epidemiology and Biostatistics at the University of California San Francisco School of Medicine. “There just isn’t that much there in terms of surveillance,” she said. “We have very little baseline data, and that is largely because resources are so constrained.”

Nick Walsh, the Focal Point for Viral Hepatitis at the WHO Regional Office for the Western Pacific, based in Manila, Philippines, agreed. “The two main issues are lack of data on the number of people living with HCV and HCV-related liver disease and lack of access to treatment,” he said. “Price is a major barrier. These issues occur across all countries.”

What is known is that genotypes 3 and 6 are prevalent in Southeast Asia. The clinical community is rapidly arriving at effective therapies for these patient populations, but they remain somewhat difficult to tackle, particularly in the hard-to-reach places of Southeast Asia. Co-infection with HIV also poses a problem, along with injection drug use, as those two issues frequently go hand-in-hand.

While these obstacles are not being addressed as effectively as experts would like, it may be helpful to focus first on the initial strides clinicians are making in the direct-acting antiviral era.

Regional Action Plan

Walsh called attention to the 66th Regional Committee Meeting for the Western Pacific, which occurred in October 2015, and the associated Regional Action Plan for Viral Hepatitis in the Western Pacific 2016 to 2020. “From Southeast Asia, this means Vietnam, Cambodia and the People’s Democratic Republic of Laos have now committed to addressing viral hepatitis, including HCV, over the next 5 years,” he said. “The plan involves screening, care and treatment.”

The strategy provides priority areas for action by countries in addressing the national burden of viral hepatitis. “One key component is that countries pledged to develop national action plans based on the local epidemiological context,” Walsh said. This entails building on existing human resources and health systems infrastructure. “Another component is to address the high prices and lack of availability of hepatitis medicines as a specific priority to improve access to treatment. The third component is to mobilize and invest in technical and financial resources for addressing viral hepatitis.”

This is the first concrete step toward understanding the epidemic in Southeast Asia and putting into place a response effort. Walsh stressed access to care and treatment as focal points. “The millions of people living with chronic HCV infection in the whole region will ultimately benefit,” he said.

In other comprehensive efforts, Lim and colleagues published a paper with a roadmap to dealing with HCV infection in Southeast Asia. They noted that HCV prevalence in all of Asia may range from 0.5% to 4.7%. Their data indicated that genotype 1b predominates in East Asia, while South and Southeast Asia are dealing primarily with genotype 3 and Indochina has a significant number of genotype 6 infections. “Official approval for DAAs in Asia lags significantly behind that in the West, such that in most countries the mainstay of therapy is still pegylated interferon and ribavirin,” they wrote.

However, they suggested that PEG–IFN-based therapies carry high SVR because the interleukin-28B genetic variant is commonly found in Asian patient populations.

“A roadmap for HCV therapy that starts with [PEG-IFN and ribavirin] and takes into account those DAAs already approved in some Asian countries can provide guidance as to the best strategies for management, particularly of genotype 1 and 3 infections, based on SVR rates,” they wrote, and added that increasing use of sofosbuvir (Sovaldi, Gilead) has fortified the armamentarium.

Poor Epidemiology

“The number of people living with chronic HCV varies from country to country and by age — lower in younger populations, higher in older,” Walsh said. He suggested that improvements in infection prevention and control in the health care arena has yielded lower rates of new infections. The screening of blood products and awareness in the public sector also have been contributing factors to these improvements. “Nevertheless, we are left with a large burden of infections through transmission over the past decades, and it is unknown how much transmission is occurring through informal injections such as tattooing, in private medical settings through poor infection prevention and control, and in prisons,” he said.

Page is deeply concerned about the epidemiology. “There is just not that much there in terms of surveillance,” she said. “It’s a patchwork quilt. The first data I saw on HCV was in 2002 at a blood bank, where the primary donor groups are volunteers, monks and paid donors. The rate was 5% among paid donors, which tend to have the highest prevalence. Keeping an eye on these blood banks is a first step. It’s a good surveillance group.”

Infections in the Health Care Setting

Beyond epidemiology, Page highlighted risks associated with outpatient medical care. “There is a huge need to scale up prevention of unsafe medical exposures,” she said. “In an outbreak of HIV in Cambodia last January, there were a number of unlicensed practitioners involved and a large number of HCV infections. But you didn’t hear about the HCV, and relief efforts to combat this kind of thing are low.”

 

“Most HCV cases in Southeast Asia were acquired during the 20th century, and the main routes were by unsafe medical and nonmedical injections, through poor infection prevention and control in health and para-health settings and through unscreened blood products,” Walsh said. He added that there are few doctors and clinics in Southeast Asia who have the expertise to treat. “Knowledge is limited in the general population and among clinicians. Traditional medicines are commonly used to treat HCV-related liver disease.”

Breakdown by Country

Wasitthankasem and colleagues investigated the distribution of HCV genotypes in Thailand and Southeast Asia using 588 HCV-positive samples. From the samples in Thailand, they found that genotype 3a was most common in that country, along with 1a, 1b, 3b and 2a. Various strains of genotype 6 — including 6f, at 7.8% — also were found, particularly in the north and northeast of the country.

Findings from outside of Thailand indicated that northern countries such as Laos, Myanmar and Vietnam had a higher prevalence of genotype 6 disease, while genotype 3 was common in the island nations of Indonesia, the Philippines and Singapore.

“Thailand has been a leader, in my opinion,” Walsh said. “They have incorporated HCV treatment into their national insurance program, and this was a major step forward.

“Vietnam has a small, funded treatment program for HCV in two hospitals,” Walsh continued. “But patient numbers are very low compared with the burden, which is around 1% to 2% of Vietnam’s population, or about 1.6 million people. There’s very limited treatment available in the public sector outside those two countries, to my knowledge. As a result, treatment is limited to the private sector. Consequently, it is very expensive (around $10,000 U.S.). The new DAAs are not yet available in Southeast Asia apart from individual importation from other countries.”

Page agreed. “The new drugs are not getting in,” she said. “Even the Gilead plan to provide generics didn’t include Cambodia on the list.”

Infrastructure constraints pose a big problem outside of Thailand and Vietnam, according to Page.

“Vietnam or Thailand is where people used to go to when they had liver disease,” she said. “Cambodia is looking to scale up its efforts against HCV, but it’s difficult. Cambodia is a really excellent example of what’s not happening in those kinds of developing areas. There is a complete lack of awareness. People there often have so many conflicting medical issues that they are trying to deal with at small provincial health centers.”

HIV, Injection Drug Use

Injection drug use is problematic in a number of Southeast Asian countries. “The prevalence of HCV among people who inject drugs is very high, over 80%,” Walsh said.

Ye and colleagues aimed to investigate HIV and HCV co-infections in the region by reviewing 13 papers from 2012 and 2013. Findings indicated wide variability, from 1.2% to 98.5% rates of HCV among HIV-positive people in South and Southeast Asia. Injection drug use was the most common factor, with HCV observed in 89.8% and 98.5% of HIV-positive injecting drug users in Vietnam, according to the results.

“There are some opiate substitution programs in the region, but not enough,” Page said. “There is very little money and what money there is goes to HIV.”

In other HIV-related data, Juniastuti and colleagues looked at 187 plasma samples from patients with HIV in Indonesia. They aimed to determine where HCV was detectable or not detectable. Anti-HCV antibodies were found in 63.6% of the cohort, while 61.3% of those patients had detectable HCV RNA levels. Clinicians detected HCV RNA in 38.2% of the 68 samples that were negative for anti-HCV antibodies. Patients who were HCV-seropositive were more likely to have high HCV viral loads.

Among HCV-seropositive samples, detectable HCV RNA was most likely to be found in patients with HIV who had acquired the disease via parenteral transmission, at 76.7%. However, patients who were HCV seronegative, but with detectable RNA levels, acquired HCV via heterosexual transmission at a rate of 61.5%.

“HIV-positive patients were at high risk of becoming co-infected with HCV,” the researchers concluded. “Several remained HCV-seronegative.”

Moving Forward

Walsh lamented that novel therapies are not available at affordable prices in Southeast Asia. “Some countries outside the region, such as Egypt and Mongolia, have negotiated relatively inexpensive prices for these DAAs, but in Southeast Asia, there has been little movement on price so far,” he said.

He stressed, though, that WHO is working with a number of countries in the area to estimate the burden of HCV infection, including related liver disease and mortality, to inform a response. “We are working with countries to identify and overcome the barriers to accessing new direct-acting antivirals which are highly effective in treating HCV,” he said.

Acquiring population-level data can be done inexpensively, according to Page. “It is possible to get information not only in the general population but also in high-risk groups, including IDUs and people with HIV,” she said.

For Page, it comes down to a matter of desire. “WHO is committed to progress,” she said. “They instituted hepatitis B vaccination and reduced chronic HBV in children. There is political and community will. We want to capitalize on this. Now we have to bring awareness, surveillance and prevention to HCV.”

Disclosures: Page and Walsh report no relevant financial disclosures.

In many parts of the world, the fast-moving clinical environment of hepatitis C virus today is a reason for hope. However, certain countries and regions still face more significant obstacles than others in managing the disease. With that in mind, HCV Next undertook the Global View Series, a four-part investigation of HCV in places that face unique and appreciable hurdles. In this installment, we look at Southeast Asia.

Island nations in the region include Brunei, Christmas Island, East Malaysia, East Timor, Indonesia, the Philippines and Singapore. On the mainland, Cambodia, Laos, Myanmar, Thailand, Vietnam and West Malaysia are included. However, few data sets exist for the more developed countries such as Thailand and Vietnam, and virtually nothing exists farther afield.

The primary issues in the region are lack of resources and poor epidemiology, according to most experts, including Kimberly Page, PhD, MPH, professor in the departments of Epidemiology and Biostatistics at the University of California San Francisco School of Medicine. “There just isn’t that much there in terms of surveillance,” she said. “We have very little baseline data, and that is largely because resources are so constrained.”

Nick Walsh, the Focal Point for Viral Hepatitis at the WHO Regional Office for the Western Pacific, based in Manila, Philippines, agreed. “The two main issues are lack of data on the number of people living with HCV and HCV-related liver disease and lack of access to treatment,” he said. “Price is a major barrier. These issues occur across all countries.”

What is known is that genotypes 3 and 6 are prevalent in Southeast Asia. The clinical community is rapidly arriving at effective therapies for these patient populations, but they remain somewhat difficult to tackle, particularly in the hard-to-reach places of Southeast Asia. Co-infection with HIV also poses a problem, along with injection drug use, as those two issues frequently go hand-in-hand.

While these obstacles are not being addressed as effectively as experts would like, it may be helpful to focus first on the initial strides clinicians are making in the direct-acting antiviral era.

Regional Action Plan

Walsh called attention to the 66th Regional Committee Meeting for the Western Pacific, which occurred in October 2015, and the associated Regional Action Plan for Viral Hepatitis in the Western Pacific 2016 to 2020. “From Southeast Asia, this means Vietnam, Cambodia and the People’s Democratic Republic of Laos have now committed to addressing viral hepatitis, including HCV, over the next 5 years,” he said. “The plan involves screening, care and treatment.”

The strategy provides priority areas for action by countries in addressing the national burden of viral hepatitis. “One key component is that countries pledged to develop national action plans based on the local epidemiological context,” Walsh said. This entails building on existing human resources and health systems infrastructure. “Another component is to address the high prices and lack of availability of hepatitis medicines as a specific priority to improve access to treatment. The third component is to mobilize and invest in technical and financial resources for addressing viral hepatitis.”

This is the first concrete step toward understanding the epidemic in Southeast Asia and putting into place a response effort. Walsh stressed access to care and treatment as focal points. “The millions of people living with chronic HCV infection in the whole region will ultimately benefit,” he said.

In other comprehensive efforts, Lim and colleagues published a paper with a roadmap to dealing with HCV infection in Southeast Asia. They noted that HCV prevalence in all of Asia may range from 0.5% to 4.7%. Their data indicated that genotype 1b predominates in East Asia, while South and Southeast Asia are dealing primarily with genotype 3 and Indochina has a significant number of genotype 6 infections. “Official approval for DAAs in Asia lags significantly behind that in the West, such that in most countries the mainstay of therapy is still pegylated interferon and ribavirin,” they wrote.

PAGE BREAK

However, they suggested that PEG–IFN-based therapies carry high SVR because the interleukin-28B genetic variant is commonly found in Asian patient populations.

“A roadmap for HCV therapy that starts with [PEG-IFN and ribavirin] and takes into account those DAAs already approved in some Asian countries can provide guidance as to the best strategies for management, particularly of genotype 1 and 3 infections, based on SVR rates,” they wrote, and added that increasing use of sofosbuvir (Sovaldi, Gilead) has fortified the armamentarium.

Poor Epidemiology

“The number of people living with chronic HCV varies from country to country and by age — lower in younger populations, higher in older,” Walsh said. He suggested that improvements in infection prevention and control in the health care arena has yielded lower rates of new infections. The screening of blood products and awareness in the public sector also have been contributing factors to these improvements. “Nevertheless, we are left with a large burden of infections through transmission over the past decades, and it is unknown how much transmission is occurring through informal injections such as tattooing, in private medical settings through poor infection prevention and control, and in prisons,” he said.

Page is deeply concerned about the epidemiology. “There is just not that much there in terms of surveillance,” she said. “It’s a patchwork quilt. The first data I saw on HCV was in 2002 at a blood bank, where the primary donor groups are volunteers, monks and paid donors. The rate was 5% among paid donors, which tend to have the highest prevalence. Keeping an eye on these blood banks is a first step. It’s a good surveillance group.”

Infections in the Health Care Setting

Beyond epidemiology, Page highlighted risks associated with outpatient medical care. “There is a huge need to scale up prevention of unsafe medical exposures,” she said. “In an outbreak of HIV in Cambodia last January, there were a number of unlicensed practitioners involved and a large number of HCV infections. But you didn’t hear about the HCV, and relief efforts to combat this kind of thing are low.”

 

“Most HCV cases in Southeast Asia were acquired during the 20th century, and the main routes were by unsafe medical and nonmedical injections, through poor infection prevention and control in health and para-health settings and through unscreened blood products,” Walsh said. He added that there are few doctors and clinics in Southeast Asia who have the expertise to treat. “Knowledge is limited in the general population and among clinicians. Traditional medicines are commonly used to treat HCV-related liver disease.”

Breakdown by Country

Wasitthankasem and colleagues investigated the distribution of HCV genotypes in Thailand and Southeast Asia using 588 HCV-positive samples. From the samples in Thailand, they found that genotype 3a was most common in that country, along with 1a, 1b, 3b and 2a. Various strains of genotype 6 — including 6f, at 7.8% — also were found, particularly in the north and northeast of the country.

Findings from outside of Thailand indicated that northern countries such as Laos, Myanmar and Vietnam had a higher prevalence of genotype 6 disease, while genotype 3 was common in the island nations of Indonesia, the Philippines and Singapore.

“Thailand has been a leader, in my opinion,” Walsh said. “They have incorporated HCV treatment into their national insurance program, and this was a major step forward.

“Vietnam has a small, funded treatment program for HCV in two hospitals,” Walsh continued. “But patient numbers are very low compared with the burden, which is around 1% to 2% of Vietnam’s population, or about 1.6 million people. There’s very limited treatment available in the public sector outside those two countries, to my knowledge. As a result, treatment is limited to the private sector. Consequently, it is very expensive (around $10,000 U.S.). The new DAAs are not yet available in Southeast Asia apart from individual importation from other countries.”

PAGE BREAK

Page agreed. “The new drugs are not getting in,” she said. “Even the Gilead plan to provide generics didn’t include Cambodia on the list.”

Infrastructure constraints pose a big problem outside of Thailand and Vietnam, according to Page.

“Vietnam or Thailand is where people used to go to when they had liver disease,” she said. “Cambodia is looking to scale up its efforts against HCV, but it’s difficult. Cambodia is a really excellent example of what’s not happening in those kinds of developing areas. There is a complete lack of awareness. People there often have so many conflicting medical issues that they are trying to deal with at small provincial health centers.”

HIV, Injection Drug Use

Injection drug use is problematic in a number of Southeast Asian countries. “The prevalence of HCV among people who inject drugs is very high, over 80%,” Walsh said.

Ye and colleagues aimed to investigate HIV and HCV co-infections in the region by reviewing 13 papers from 2012 and 2013. Findings indicated wide variability, from 1.2% to 98.5% rates of HCV among HIV-positive people in South and Southeast Asia. Injection drug use was the most common factor, with HCV observed in 89.8% and 98.5% of HIV-positive injecting drug users in Vietnam, according to the results.

“There are some opiate substitution programs in the region, but not enough,” Page said. “There is very little money and what money there is goes to HIV.”

In other HIV-related data, Juniastuti and colleagues looked at 187 plasma samples from patients with HIV in Indonesia. They aimed to determine where HCV was detectable or not detectable. Anti-HCV antibodies were found in 63.6% of the cohort, while 61.3% of those patients had detectable HCV RNA levels. Clinicians detected HCV RNA in 38.2% of the 68 samples that were negative for anti-HCV antibodies. Patients who were HCV-seropositive were more likely to have high HCV viral loads.

Among HCV-seropositive samples, detectable HCV RNA was most likely to be found in patients with HIV who had acquired the disease via parenteral transmission, at 76.7%. However, patients who were HCV seronegative, but with detectable RNA levels, acquired HCV via heterosexual transmission at a rate of 61.5%.

“HIV-positive patients were at high risk of becoming co-infected with HCV,” the researchers concluded. “Several remained HCV-seronegative.”

Moving Forward

Walsh lamented that novel therapies are not available at affordable prices in Southeast Asia. “Some countries outside the region, such as Egypt and Mongolia, have negotiated relatively inexpensive prices for these DAAs, but in Southeast Asia, there has been little movement on price so far,” he said.

He stressed, though, that WHO is working with a number of countries in the area to estimate the burden of HCV infection, including related liver disease and mortality, to inform a response. “We are working with countries to identify and overcome the barriers to accessing new direct-acting antivirals which are highly effective in treating HCV,” he said.

Acquiring population-level data can be done inexpensively, according to Page. “It is possible to get information not only in the general population but also in high-risk groups, including IDUs and people with HIV,” she said.

For Page, it comes down to a matter of desire. “WHO is committed to progress,” she said. “They instituted hepatitis B vaccination and reduced chronic HBV in children. There is political and community will. We want to capitalize on this. Now we have to bring awareness, surveillance and prevention to HCV.”

Disclosures: Page and Walsh report no relevant financial disclosures.