Cover Story

Vertical Transmission of HCV: The Next Big Treatment Frontier

Novel antiviral therapies with overwhelmingly positive sustained virologic response rates have dominated headlines in hepatitis C virus for the past few years, but many experts said eradication efforts may never completely succeed until the clinical community deals with vertical transmission of the disease.

A recent study conducted by Lenka Benova, MSc, a research fellow at the London School of Hygiene and Tropical Medicine in London, along with Laith Abu-Raddad, PhD, associate professor of public health at Weill Cornell Medical College in Qatar, and colleagues highlighted some of the key issues in the discussion. They systematically reviewed 109 papers on vertical transmission risk of hepatitis C virus and found that more than one in 20 infants delivered by women with chronic HCV becomes infected, making vertical transmission the primary transmission route among children. The overall risk for vertical transmission of HCV antibody-positive and RNA-positive women was 5.8% (95% CI, 4.2-7.8) for children of HIV-negative women and 10.8% (95% CI, 7.6-15.2) among those born to women with HIV, according to the study findings.

Lenka Benova

Lenka Benova

Beyond the HIV association, some data show stark disparities between infection rates in the developed world compared with those in the developing world, a problem that continues to confound both the research and clinical communities. There are gaps in knowledge surrounding pregnancy and breast-feeding as they pertain to vertical transmission, and there is currently insufficient information available about the role of revolutionary direct-acting antiviral therapies as a solution to this problem.

However, the Center for Disease Control states that HCV antibody and HCV RNA-positive women should be encouraged to breast feed their infants as there is no evidence to support breast feeding as a mode of transmission of HCV from mother to infant. Mothers with cracked or bleeding nipples should temporarily discontinue breast feeding until the problem has resolved, the CDC suggests.

Benova said not enough attention is being paid to any of these concerns. “Vertical transmission is sometimes neglected in the debates on HCV,” she said in an interview with HCV Next.

By the Numbers

There may be as many as 11 million children with HCV in the world, according to Kathleen B. Schwarz, MD, professor of pediatrics, director of the Pediatric Liver Center at Johns Hopkins and president of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition.

“Because of this, vertical transmission should be the most important area of research,” she said in an interview. “It is the only source of HCV for which we have no solution.”

In a study by Yeung and colleagues cited WHO estimates indicating that between 1% and 8% of pregnant women in the world have HCV. They added that for children worldwide, HCV prevalence rates range between 0.05% and 5%. In the developing world, pediatric infection rates are estimated to be between 0.05% and 0.36%, whereas the estimates creep up to between 1.8% and 5% in the developing world.

Benova suggested that the data are not complete. “Our systematic review summarized the last 2 decades of evidence on the risk of HCV transmission,” she said. “There is large variability in HCV prevalence across countries. For the majority of countries globally, HCV prevalence among pregnant women is closer to the 1% limit, and among children, depending on age, closer to 0.5% or even smaller.”

In another study, Cottrell and colleagues found that as many as 4,000 new cases of vertical transmission occur in the United States each year. They reviewed data as far back as 1947 to determine how mode of delivery, labor management strategies and breast-feeding affect this risk.

Philip Rosenthal, MD, professor of pediatrics and surgery, director of pediatric clinical research, pediatric hepatology and liver transplant research and pediatric hepatology at the University of California, San Francisco, pushed that number higher, suggesting that as many as 7,500 new cases occur from vertical transmission each year in the United States. “Spontaneous clearance of the virus can be seen in up to 40% of infants infected by vertical transmission, but only in 6% to 12% of older children with HCV,” he told HCV Next. “A small subset of children — between 20% and 25% — can have more aggressive disease with evidence of cirrhosis or hepatocellular carcinoma.”

There is a hint of consolation behind these sobering numbers, according to Rosenthal. “Obviously, and thankfully, the number of children with HCV is small relative to the numbers in adults,” he said.

Coinfection with HIV

Other findings from Benova and colleagues indicated that maternal HIV coinfection was the main predictor of vertical transmission risk (adjusted OR=2.56; 95% CI, 1.5-4.43). Rosenthal estimates that women who are coinfected with HIV and not being treated for HIV are approximately six times more likely to transmit HCV to their infant than monoinfected women. It is generally accepted that high HIV viral load increases the likelihood of transmission.

Philip Rosenthal

Philip Rosenthal

“Numerous studies, including ours, have found that children born to HCV/HIV coinfected mothers are more likely to be vertically infected with HCV than children born to women with HCV infection only,” Benova said. “The primary biological mechanism of this association seems to be related to higher HCV viral load among women with HIV coinfection.”

Schwarz agreed, but added that the problem may be manageable. “HIV treatments are sufficiently effective now that they have lowered HCV transmission rate of coinfected women to those similar to the rates we see for women monoinfected with HCV,” she said. “If the HIV drugs are so good that we are doing liver transplant in people with HIV, then they are good enough to lower maternal-fetal transmission.”

HCV transmission rates to infants born to women with untreated HIV can range as high as 30%, according to Schwarz “but are about 5% in women with treated HIV, equivalent to HCV transmission rates for women monoinfected with HCV.”

But with rates of HIV so much higher in the developing world, this raises the ever-present issues of disparity and access.

Disparity in the Developing World

Benova said there may not be a biological reason for increased vertical transmission in the developing world. It may simply be a matter of volume. “In a minority of countries such as Egypt and Pakistan, the prevalence of HCV reaches much higher levels,” she said. “In Egypt, for example, HCV antibody prevalence among women of reproductive age exceeds 10%. The importance of vertical transmission is higher in countries with higher prevalence among women in reproductive age.”

Schwarz built on this point. “I don’t think this has been studied carefully enough,” she said. “The only places where you would see different rates of transmission are in Africa, where there are large cohorts of women with untreated HIV, but I don’t think we have enough information.”

Yeung and colleagues recommended that children of women with anti-HCV antibodies should be screened. However, access issues may prevent such basic interventions from being performed.

“Access to therapy and monitoring during pregnancy likely are the factors contributing to differences between the US rates and other countries,” Rosenthal said.

Modifiable and Non-modifiable Factors

Injection drug use may be associated with increased vertical transmission risk, according to Benova. “However, because IV drug users have a higher prevalence of HCV/HIV coinfection than nonusers, the independent effects of HIV and injection drug use are difficult to disentangle,” she said.

Breast-feeding and HCV genotype are likely not associated with increased vertical transmission rates, according to the findings from Yeung and colleagues.

“We also know that cesarean section will not prevent transmission,” Schwarz added.

“At present, no clinical intervention has been clearly studied and proved to reduce the HCV vertical transmission risk,” Yeung and colleagues wrote. “The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to reduce the burden of chronic liver disease.”

Working with Novel Therapies

Although most clinicians agree that interrupting transmission is the goal, the way to reach that goal remains undefined. Rosenthal said lowering the HCV viral load before pregnancy is the most important intervention, but Schwarz noted that because this is not always possible, the clinical community should be exploring other options.

“We still don’t know when HCV is transmitted during gestation,” Schwarz said. “That is a really important question for which we don’t have an answer.”

Once this question is answered, novel DAA therapies must be tested for safety.

“The regimens for treating HCV up to now — pegylated interferon, ribavirin, telaprevir and boceprevir — could not be utilized during pregnancy because of the teratogenicity of ribavirin,” Rosenthal said. “The newer drugs all have warnings about their use in pregnancy, but there are no human data to make recommendations.”

Although experts explained that there are no controlled data for sofosbuvir (Sovaldi, Gilead Sciences) in pregnant women, animal studies have demonstrated conflicting evidence of fetal harm. However, sofosbuvir monotherapy is contraindicated. Women undergoing combination therapy with sofosbuvir — and the female partners of men receiving combination therapy — should avoid pregnancy.

According to prescribing information, ribavirin is contraindicated in women of reproductive potential and their partners unless two reliable forms of contraception are being used during treatment and for at least 6 months after discontinuation of ribavirin. Women should have a negative pregnancy test before initiating therapy. Clinicians are encouraged to monitor all maternal-fetal outcomes as closely as possible.

There are no data from the use of daclatasvir (Bristol-Myers Squibb) in pregnant women, according to Rosenthal. However, he noted that daclatasvir is not recommended during pregnancy or in women of childbearing potential not using contraception.

Similarly, although garnering a pregnancy category B designation in its package insert, there are insufficient data on ledipasvir-sofosbuvir (Harvoni, Gilead Sciences) in pregnant women. However, clinicians are encouraged to weigh the risk–benefit ratio before using this drug in pregnant women.

“Clinicians currently have very little to offer women diagnosed with HCV while pregnant,” Benova said.

Schwarz said she is cautiously optimistic that, with time, these drugs will be proved as safe as those found in the HIV armamentarium. “If you look at the new agents that are highly effective and seem to be quite safe, why can’t we give them in the third trimester?” she said. “It is a fairly short course.”

Kathleen Schwarz

Kathleen B Schwarz

More understanding of the timing of transmission during gestation could lead to real progress, according to Schwarz. “If HCV is transmitted, for example, at week 37 of gestation, it may be safe to lower the viral load therapeutically at that time,” she said. “Lowering the viral load around the time of delivery will be markedly better than what we are doing now.”

Clinical Challenges

“Vertical transmission is an important concern and an issue where options are limited,” Benova said. “It contributes to new HCV infections every year. Having said that, relative to other current pressing issues, it is not the major priority. Dealing with vertical transmission in the context of access to treatment offers an opportunity to synergistically and cost-effectively address the current disease burden and prevent new infections.”

Benova laid out a roadmap for future research. “First, feasibility and cost-effectiveness of pre-conception screening and treatment needs to be established in contexts with varying prevalence,” she said. “Second, assessment of safety and efficacy of new HCV treatments during pregnancy and early childhood is crucial to clinicians’ ability to offer proven interventions to women diagnosed during pregnancy.”

No current studies are assessing whether antiretroviral treatment provided for prevention of mother-to-child transmission of HIV can also reduce HCV viral load and thereby lower risk for HCV vertical transmission, according to Benova. “Our study highlighted that more rigorous primary research on vertical transmission of HCV is needed from low- and middle-income countries,” she said. “Such research could contribute to our understanding of whether factors such as delay in HIV diagnosis and treatment play a role in HCV vertical transmission.”

Neutralizing HCV antibodies may be a viable approach and should be a target for research, according to Schwarz. “We have seen this in chimpanzee studies, but no human studies have been conducted as yet,” she said.

Rosenthal highlighted another clinical challenge in vertical transmission. “In children, the long-expected lifespan makes HCV a huge burden from a time perspective,” Rosenthal said. “As a pediatric hepatologist, HCV remains to me just as big a problem as it does for my adult colleagues.”

Despite these challenges, Schwarz said there may be a light at the end of the tunnel, albeit far in the distance.

“We have highly effective treatments,” she said. “These treatments are just beginning to be tested in pediatric trials, so we have a ways to go. Figuring out how to interrupt transmission from mother to child is a difficult task. But pharma is thinking about this. This is the most important next frontier.”

References:
Benova L. Clin Infect Dis. 2014;59:765-773.
Cottrell EB. Ann Intern Med. 2013;158:109-113.
Cuadros DF. Hepatology. 2014; 60:1150-1159.
Mohamoud YA. BMC Infect Dis. 2013;13:288.
Resti M. J Infect Dis. 2002;185:567-572.
Yeung CY. World J Hepatol. 2014;6:643-651.

For more info:
Lenka Benova, MSc, and Laith Abu-Raddad, PhD, can be reached at Weill Cornell Medical College in Qatar; Qatar Foundation - Education City; P.O. Box 24144; Doha, Qatar; email: lenka.benova@lshtm.ac.uk.
Philip Rosenthal, MD, can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143; email: prosenth@peds.ucsf.edu.
Kathleen B. Schwarz, MD, can be reached at CSMC 2-125, 600 North Wolfe St., Baltimore, MD 21287; email: kschwarz@jhmi.edu.
Disclosures: Abu-Raddad, Benova and Schwarz report no relevant financial disclosures. Rosenthal reports associations with AbbVie, Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck and Vertex.

Novel antiviral therapies with overwhelmingly positive sustained virologic response rates have dominated headlines in hepatitis C virus for the past few years, but many experts said eradication efforts may never completely succeed until the clinical community deals with vertical transmission of the disease.

A recent study conducted by Lenka Benova, MSc, a research fellow at the London School of Hygiene and Tropical Medicine in London, along with Laith Abu-Raddad, PhD, associate professor of public health at Weill Cornell Medical College in Qatar, and colleagues highlighted some of the key issues in the discussion. They systematically reviewed 109 papers on vertical transmission risk of hepatitis C virus and found that more than one in 20 infants delivered by women with chronic HCV becomes infected, making vertical transmission the primary transmission route among children. The overall risk for vertical transmission of HCV antibody-positive and RNA-positive women was 5.8% (95% CI, 4.2-7.8) for children of HIV-negative women and 10.8% (95% CI, 7.6-15.2) among those born to women with HIV, according to the study findings.

Lenka Benova

Lenka Benova

Beyond the HIV association, some data show stark disparities between infection rates in the developed world compared with those in the developing world, a problem that continues to confound both the research and clinical communities. There are gaps in knowledge surrounding pregnancy and breast-feeding as they pertain to vertical transmission, and there is currently insufficient information available about the role of revolutionary direct-acting antiviral therapies as a solution to this problem.

However, the Center for Disease Control states that HCV antibody and HCV RNA-positive women should be encouraged to breast feed their infants as there is no evidence to support breast feeding as a mode of transmission of HCV from mother to infant. Mothers with cracked or bleeding nipples should temporarily discontinue breast feeding until the problem has resolved, the CDC suggests.

Benova said not enough attention is being paid to any of these concerns. “Vertical transmission is sometimes neglected in the debates on HCV,” she said in an interview with HCV Next.

By the Numbers

There may be as many as 11 million children with HCV in the world, according to Kathleen B. Schwarz, MD, professor of pediatrics, director of the Pediatric Liver Center at Johns Hopkins and president of the Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition.

“Because of this, vertical transmission should be the most important area of research,” she said in an interview. “It is the only source of HCV for which we have no solution.”

In a study by Yeung and colleagues cited WHO estimates indicating that between 1% and 8% of pregnant women in the world have HCV. They added that for children worldwide, HCV prevalence rates range between 0.05% and 5%. In the developing world, pediatric infection rates are estimated to be between 0.05% and 0.36%, whereas the estimates creep up to between 1.8% and 5% in the developing world.

Benova suggested that the data are not complete. “Our systematic review summarized the last 2 decades of evidence on the risk of HCV transmission,” she said. “There is large variability in HCV prevalence across countries. For the majority of countries globally, HCV prevalence among pregnant women is closer to the 1% limit, and among children, depending on age, closer to 0.5% or even smaller.”

In another study, Cottrell and colleagues found that as many as 4,000 new cases of vertical transmission occur in the United States each year. They reviewed data as far back as 1947 to determine how mode of delivery, labor management strategies and breast-feeding affect this risk.

Philip Rosenthal, MD, professor of pediatrics and surgery, director of pediatric clinical research, pediatric hepatology and liver transplant research and pediatric hepatology at the University of California, San Francisco, pushed that number higher, suggesting that as many as 7,500 new cases occur from vertical transmission each year in the United States. “Spontaneous clearance of the virus can be seen in up to 40% of infants infected by vertical transmission, but only in 6% to 12% of older children with HCV,” he told HCV Next. “A small subset of children — between 20% and 25% — can have more aggressive disease with evidence of cirrhosis or hepatocellular carcinoma.”

PAGE BREAK

There is a hint of consolation behind these sobering numbers, according to Rosenthal. “Obviously, and thankfully, the number of children with HCV is small relative to the numbers in adults,” he said.

Coinfection with HIV

Other findings from Benova and colleagues indicated that maternal HIV coinfection was the main predictor of vertical transmission risk (adjusted OR=2.56; 95% CI, 1.5-4.43). Rosenthal estimates that women who are coinfected with HIV and not being treated for HIV are approximately six times more likely to transmit HCV to their infant than monoinfected women. It is generally accepted that high HIV viral load increases the likelihood of transmission.

Philip Rosenthal

Philip Rosenthal

“Numerous studies, including ours, have found that children born to HCV/HIV coinfected mothers are more likely to be vertically infected with HCV than children born to women with HCV infection only,” Benova said. “The primary biological mechanism of this association seems to be related to higher HCV viral load among women with HIV coinfection.”

Schwarz agreed, but added that the problem may be manageable. “HIV treatments are sufficiently effective now that they have lowered HCV transmission rate of coinfected women to those similar to the rates we see for women monoinfected with HCV,” she said. “If the HIV drugs are so good that we are doing liver transplant in people with HIV, then they are good enough to lower maternal-fetal transmission.”

HCV transmission rates to infants born to women with untreated HIV can range as high as 30%, according to Schwarz “but are about 5% in women with treated HIV, equivalent to HCV transmission rates for women monoinfected with HCV.”

But with rates of HIV so much higher in the developing world, this raises the ever-present issues of disparity and access.

Disparity in the Developing World

Benova said there may not be a biological reason for increased vertical transmission in the developing world. It may simply be a matter of volume. “In a minority of countries such as Egypt and Pakistan, the prevalence of HCV reaches much higher levels,” she said. “In Egypt, for example, HCV antibody prevalence among women of reproductive age exceeds 10%. The importance of vertical transmission is higher in countries with higher prevalence among women in reproductive age.”

Schwarz built on this point. “I don’t think this has been studied carefully enough,” she said. “The only places where you would see different rates of transmission are in Africa, where there are large cohorts of women with untreated HIV, but I don’t think we have enough information.”

Yeung and colleagues recommended that children of women with anti-HCV antibodies should be screened. However, access issues may prevent such basic interventions from being performed.

“Access to therapy and monitoring during pregnancy likely are the factors contributing to differences between the US rates and other countries,” Rosenthal said.

Modifiable and Non-modifiable Factors

Injection drug use may be associated with increased vertical transmission risk, according to Benova. “However, because IV drug users have a higher prevalence of HCV/HIV coinfection than nonusers, the independent effects of HIV and injection drug use are difficult to disentangle,” she said.

Breast-feeding and HCV genotype are likely not associated with increased vertical transmission rates, according to the findings from Yeung and colleagues.

“We also know that cesarean section will not prevent transmission,” Schwarz added.

“At present, no clinical intervention has been clearly studied and proved to reduce the HCV vertical transmission risk,” Yeung and colleagues wrote. “The high prevalence of global HCV infection necessitates renewed efforts in primary prevention, including vaccine development, as well as new approaches to reduce the burden of chronic liver disease.”

Working with Novel Therapies

Although most clinicians agree that interrupting transmission is the goal, the way to reach that goal remains undefined. Rosenthal said lowering the HCV viral load before pregnancy is the most important intervention, but Schwarz noted that because this is not always possible, the clinical community should be exploring other options.

PAGE BREAK

“We still don’t know when HCV is transmitted during gestation,” Schwarz said. “That is a really important question for which we don’t have an answer.”

Once this question is answered, novel DAA therapies must be tested for safety.

“The regimens for treating HCV up to now — pegylated interferon, ribavirin, telaprevir and boceprevir — could not be utilized during pregnancy because of the teratogenicity of ribavirin,” Rosenthal said. “The newer drugs all have warnings about their use in pregnancy, but there are no human data to make recommendations.”

Although experts explained that there are no controlled data for sofosbuvir (Sovaldi, Gilead Sciences) in pregnant women, animal studies have demonstrated conflicting evidence of fetal harm. However, sofosbuvir monotherapy is contraindicated. Women undergoing combination therapy with sofosbuvir — and the female partners of men receiving combination therapy — should avoid pregnancy.

According to prescribing information, ribavirin is contraindicated in women of reproductive potential and their partners unless two reliable forms of contraception are being used during treatment and for at least 6 months after discontinuation of ribavirin. Women should have a negative pregnancy test before initiating therapy. Clinicians are encouraged to monitor all maternal-fetal outcomes as closely as possible.

There are no data from the use of daclatasvir (Bristol-Myers Squibb) in pregnant women, according to Rosenthal. However, he noted that daclatasvir is not recommended during pregnancy or in women of childbearing potential not using contraception.

Similarly, although garnering a pregnancy category B designation in its package insert, there are insufficient data on ledipasvir-sofosbuvir (Harvoni, Gilead Sciences) in pregnant women. However, clinicians are encouraged to weigh the risk–benefit ratio before using this drug in pregnant women.

“Clinicians currently have very little to offer women diagnosed with HCV while pregnant,” Benova said.

Schwarz said she is cautiously optimistic that, with time, these drugs will be proved as safe as those found in the HIV armamentarium. “If you look at the new agents that are highly effective and seem to be quite safe, why can’t we give them in the third trimester?” she said. “It is a fairly short course.”

Kathleen Schwarz

Kathleen B Schwarz

More understanding of the timing of transmission during gestation could lead to real progress, according to Schwarz. “If HCV is transmitted, for example, at week 37 of gestation, it may be safe to lower the viral load therapeutically at that time,” she said. “Lowering the viral load around the time of delivery will be markedly better than what we are doing now.”

Clinical Challenges

“Vertical transmission is an important concern and an issue where options are limited,” Benova said. “It contributes to new HCV infections every year. Having said that, relative to other current pressing issues, it is not the major priority. Dealing with vertical transmission in the context of access to treatment offers an opportunity to synergistically and cost-effectively address the current disease burden and prevent new infections.”

Benova laid out a roadmap for future research. “First, feasibility and cost-effectiveness of pre-conception screening and treatment needs to be established in contexts with varying prevalence,” she said. “Second, assessment of safety and efficacy of new HCV treatments during pregnancy and early childhood is crucial to clinicians’ ability to offer proven interventions to women diagnosed during pregnancy.”

No current studies are assessing whether antiretroviral treatment provided for prevention of mother-to-child transmission of HIV can also reduce HCV viral load and thereby lower risk for HCV vertical transmission, according to Benova. “Our study highlighted that more rigorous primary research on vertical transmission of HCV is needed from low- and middle-income countries,” she said. “Such research could contribute to our understanding of whether factors such as delay in HIV diagnosis and treatment play a role in HCV vertical transmission.”

PAGE BREAK

Neutralizing HCV antibodies may be a viable approach and should be a target for research, according to Schwarz. “We have seen this in chimpanzee studies, but no human studies have been conducted as yet,” she said.

Rosenthal highlighted another clinical challenge in vertical transmission. “In children, the long-expected lifespan makes HCV a huge burden from a time perspective,” Rosenthal said. “As a pediatric hepatologist, HCV remains to me just as big a problem as it does for my adult colleagues.”

Despite these challenges, Schwarz said there may be a light at the end of the tunnel, albeit far in the distance.

“We have highly effective treatments,” she said. “These treatments are just beginning to be tested in pediatric trials, so we have a ways to go. Figuring out how to interrupt transmission from mother to child is a difficult task. But pharma is thinking about this. This is the most important next frontier.”

References:
Benova L. Clin Infect Dis. 2014;59:765-773.
Cottrell EB. Ann Intern Med. 2013;158:109-113.
Cuadros DF. Hepatology. 2014; 60:1150-1159.
Mohamoud YA. BMC Infect Dis. 2013;13:288.
Resti M. J Infect Dis. 2002;185:567-572.
Yeung CY. World J Hepatol. 2014;6:643-651.

For more info:
Lenka Benova, MSc, and Laith Abu-Raddad, PhD, can be reached at Weill Cornell Medical College in Qatar; Qatar Foundation - Education City; P.O. Box 24144; Doha, Qatar; email: lenka.benova@lshtm.ac.uk.
Philip Rosenthal, MD, can be reached at the University of California, San Francisco, 500 Parnassus Ave., Box 0136, MU 4-East, San Francisco, CA 94143; email: prosenth@peds.ucsf.edu.
Kathleen B. Schwarz, MD, can be reached at CSMC 2-125, 600 North Wolfe St., Baltimore, MD 21287; email: kschwarz@jhmi.edu.
Disclosures: Abu-Raddad, Benova and Schwarz report no relevant financial disclosures. Rosenthal reports associations with AbbVie, Bristol-Myers Squibb, Genentech/Roche, Gilead, Merck and Vertex.