Hepatitis Delta

Executive summary

Overall summary

This is a shallow investigation of hepatitis delta (“hepatitis D”). My goal was to estimate the disease burden attributable to the condition, learn about barriers to addressing the burden, and identify any promising opportunities that Coefficient Giving can fund. My investigation included a survey of the existing literature and a number of conversations with experts on hepatitis D and related matters.

There are several promising approaches that could allow for significant progress toward addressing hepatitis D, like developing better diagnostics or facilitating access to newer and more effective treatments. While I don’t think any of those approaches are strong enough for Coefficient to investigate further, other funders with different goals might find them interesting.

What is hepatitis D?

All of the hepatitis viruses (A, B, C, D, and E) cause liver inflammation. Hepatitis D, caused by hepatitis delta virus (HDV), is the most aggressive form of liver disease. It can only infect people who have already been infected with hepatitis B virus (HBV), because it requires the presence of HBV to infect liver cells and replicate within them.

As a blood-borne virus, HDV can be transmitted through the use of contaminated needles, syringes, or other injection equipment, as well as through sexual contact. In rare cases, it can also be transmitted “vertically” — from mother to child during pregnancy, delivery, or breastfeeding.

Compared to HBV infection alone, having both HBV and HDV is associated with:

• A nearly fourfold risk of liver cirrhosis (scarring of the liver from repeated damage).
• A 28% increase in the risk of hepatocellular carcinoma (HCC — a type of cancer that affects liver cells).
• A reduced lifespan (since both conditions progress faster in people infected with HDV).

The WHO recommends HDV testing in all individuals who test positive for HBV. Following a positive HBV test, HDV can be diagnosed through a two-step process:

1. Antibody screening that detects whether someone has been exposed to HDV (“anti-HDV testing”). Not all cases of HDV exposure progress to a chronic hepatitis D infection.
2. RNA testing to confirm whether someone is actually infected, and to measure the viral load (as long as it falls within the range of levels the test can accurately measure).

The global prevalence of hepatitis D among those with HBV infection is estimated to be 4.5%. Globally, about 257 to 291 million people are chronically infected with HBV; of these, roughly 12 million are affected by HDV.

What is the problem?

Several factors are responsible for the continued prevalence of HDV:

Uncertain estimates of the burden: All experts we spoke with noted the paucity of epidemiological data on the burden of hepatitis D across various geographies. This lack of data typically leads health officials to underestimate the impact of HDV, which in turn leads to delayed or underfunded public health interventions.

Efficacy and cost of existing treatments: Existing treatments for HDV are not suited for a public health approach to treatment in low- and middle-income countries (LMICs), where most health care costs are paid out-of-pocket. Treatments include:

Importance

While the Global Burden of Disease study (“GBD”) publishes estimates for the DALY burden of HBV, it doesn’t do so for HDV. However, we can use the former to estimate the latter. Below, I explain several approaches I used to create my estimate:

Neglectedness

In my research and conversations with experts, I found that HDV is highly neglected, especially in terms of philanthropic funding (as distinct from government spending or private investment). One expert described HDV as relatively neglected even within the neglected field of hepatitis. HDV funding is largely integrated into broader hepatitis initiatives (which typically prioritize other forms that are easier to diagnose, prevent, and treat). Without dedicated funding, hepatitis D will likely continue to be overlooked — slowing down targeted research and policy attention.

Public health work to address the burden of HDV also seems to be highly neglected. I could not find any organization working specifically on HDV; most organizations focus on HBV and/or HCV. That said, some funding goes toward efforts to eliminate hepatitis generally. Organizations in that space include The Hepatitis Fund, the Coalition for Global Hepatitis Elimination, the CDA Foundation, the Hepatitis B Foundation, the John C. Martin Foundation, and Wellcome Trust. Multilateral organizations include the D-SOLVE Consortium, Unitaid, and Gavi.

Tractability

Despite the challenges I’ve highlighted for HDV prevention, diagnosis, and treatment, I think there are opportunities for cost-effective spending in this area. I ran BOTECs (back-of-the-envelope calculations) on several potential opportunities; below, I list a few that were sufficiently promising to merit further exploration. In most cases, ideas that weren’t listed seemed likely to be much less cost-effective than our bar for grantmaking requires and/or very difficult to estimate.

All names of organizations have been anonymized. As of the publication of this research, we target a ~2000x “bar” for SROI (social return on investment).

While vertical transmission (mother-to-child) is rare for HDV, it is how most new HBV infections occur. Therefore, improved coverage of the hepatitis B vaccine in infancy and early childhood, beginning with the hepatitis B birth dose vaccine, will significantly reduce new HBV infections and consequently prevent new HDV infections. This, however, will not improve morbidity or mortality outcomes for those already chronically infected with HBV and HDV.

For this group, I am most excited about opportunities that could improve access to testing via the development and distribution of rapid diagnostic tests (RDTs) and point-of-care tests. These tests would enable clinic-based and possibly community-based testing for HBV and HDV. However, I think this approach would be more impactful if we simultaneously supported efforts to make an improved treatment option available — one cheap enough to be accessible to patients in LMICs.

I am skeptical that this area is promising enough to merit further investigation from Coefficient; the highest impact levels I estimated are below our bar. However, governments and other funders with different goals might want to pay more attention to HDV; they could easily look at the same data I did and reach a different conclusion.

Background

The term “hepatitis” can refer to any inflammation of the liver. The most common form is viral hepatitis, which is caused by five distinct viruses (A, B, C, D, and E). Other forms have non-viral causes, from metabolic and autoimmune conditions to heavy alcohol consumption.

Individuals with concurrent HBV and HDV infection are at risk of the most severe form of chronic viral hepatitis. Compared to HBV infection alone, the accelerated liver damage from concurrent infection with both viruses causes a faster progression to liver fibrosis, liver cirrhosis, and HCC. Miao et al. (2020) quantified the risk of liver cirrhosis progression as 3.8x higher in HBV/HDV coinfection compared to HBV mono-infection.

There are two possible patterns of HDV transmission:

How HDV is diagnosed

Following a positive HBsAg test (indicating active HBV infection), HDV can be diagnosed through a two-step process:

1. Antibody screening that detects whether someone has been exposed to HDV (“anti-HDV testing”). Not all cases of exposure progress to a chronic hepatitis D infection.
2. If the anti-HDV test is positive (indicating exposure), proceed to RNA testing to confirm whether someone is actually infected, and to assess viral replication.

Figure 1: Reflex testing for HDV diagnosis following positive HBsAg result (source: Hep B Foundation).

What is the problem?

Multiple factors contribute to the burden of HBV/HDV coinfection, ranging from the difficulty of even estimating the burden to gaps in prevention, diagnosis, and treatment.

Uncertain estimates of the burden of HDV

Several experts I interviewed acknowledged the lack of proper epidemiological estimates of the prevalence or impact of HDV infection.

Good data is hard to find for several reasons:

1. The other four variants are easier to test for; there are affordable, standardized tests for them (but not for HDV — see “diagnostic challenges”).
2. Many studies that include anti-HDV testing don’t proceed to RNA testing (making it impossible to confirm which subjects were actually infected).
3. Few national serosurveys have been conducted to measure HDV prevalence; existing estimates are based on testing among members of high-risk groups, which could make them overestimates for the general population. However, my best guess is that prevalence is still underestimated in most contexts: the experts I spoke with believe this, and I think the lack of available testing typically leads governments to assume infection isn’t a widespread problem (despite what the available data implies).

The image below shows the GBD 2021 death and DALY burden estimates for hepatitis A, B, C, and E. GBD does not publish death or DALY estimates for HDV, but its impact is likely reflected under HBV.

Figure 2: Global Burden of Disease (GBD) 2021 estimates for the number of deaths associated with hepatitis A, B, C, and E.

Figure 3: Global Burden of Disease (GBD) 2021 estimates for the number of DALYs associated with hepatitis A, B, C, and E.

The most commonly referenced estimates for the prevalence of HDV come from a systematic review and meta-analysis conducted in collaboration with the WHO (Stockdale et al. 2020).

Key findings from the research:

According to the WHO, the WHO Western Pacific and African Regions have the highest HBV burden, with 97 million and 65 million people chronically infected.

Figure 4: Global prevalence of hepatitis D (source: Stockdale et al. (2020))

Obstacles to prevention

HDV can be prevented in multiple ways:

1. While there is no HDV-specific vaccine, people can be vaccinated against HBV, either as infants beginning at birth or adults. Infant vaccination is more effective.
2. Health care and harm reduction services can adopt safer practices around blood transfusions, injections, and sexual health to reduce the risk that patients with HBV also contract HDV — similar to efforts aimed at preventing blood-borne viral infections and sexual transmission.

However, there are several obstacles to widespread prevention efforts:

Diagnostic challenges

Few people are actually tested for HDV. This contributes to the aforementioned challenge: it’s hard to estimate the burden of HDV without widespread testing.

Barriers to HDV testing include:

In summary, the following strategies should serve to increase HDV diagnosis rates:

• Creating better diagnostics for HDV and making them more widely available and affordable.
• Scaling up HBV testing and more reliably testing for HDV in people found to be HBV-positive.

Efficacy and affordability of available treatment options

Treatment for HDV aims to prevent the progression of liver damage, cirrhosis, liver cancer, and death from liver disease. As these outcomes require long-term follow-up, they are hard to assess in clinical trials. Alternative ways to monitor response to treatment include:

1. Checking for HBsAg clearance (which indicates suppression of HBV).
2. Checking whether HDV RNA has been suppressed (reduced to below measurable levels).
3. Checking for an HDV RNA decline of more than 2 log IU/mL from baseline (which indicates that a treatment is working even though suppression hasn’t yet been achieved).

Unfortunately, current methods for treating HBV, even if they sharply reduce HBsAg levels, do not affect HDV viral load or outcomes. HBV integrates its own DNA into human cellular DNA, leading that cellular DNA to produce HBsAg. Fully stopping HBsAg production is impossible with current methods, and even a small amount of HBsAg enables HDV to keep reproducing. However, if a method were found to completely clear HBsAg, HDV would also eventually be cleared.

Current treatment options

For decades, pegylated interferon-alfa (PegIFNα) has been used in the treatment of HDV despite the absence of any regulatory approval for this usage (its use is off-label). It is administered as a subcutaneous injection once weekly, and treatment typically lasts for 48 weeks. However, its use has been limited by contraindications, poor side effect profile, and poor virologic response rates.

The response rates (defined by HDV RNA negativity) for treatment with PegIFNα range from 17% to 48%, and with long-term follow-up of 5 years, 50% of these cases had a relapse.

Despite these limitations, PegIFNα is still recommended by the WHO for HDV infection, as treatment reduces the risk of disease progression.

Figure 5: Virologic and biochemical responses from the MYR301 Phase 3 trial of bulevirtide in patients with chronic HDV (source: Wedemeyer et al. (2025))

In 2022, the U.S. FDA rejected an application for approval of bulevirtide to treat HDV, due to issues with “manufacturing and delivery.” So for now, Gilead isn’t able to market the drug in the U.S. Gilead is yet to refile an application with the FDA.

Treatment costs

In LMICs, where most health care costs are paid out of pocket, medication prices are a major determinant of access to treatment.

Pegasys (PegIFNα-2a), manufactured by Roche, is sold as a prefilled injection of 180mcg/mL (which constitutes a weekly dose). I found that private pharmacies in Nigeria sell Pegasys at a price of 40,000 Nigerian Naira (~$26) per dose, which translates to ~$1,250 for a 48-week treatment course (slightly below Nigeria’s per capita GDP).

There are other reports of efforts by governments to reduce the cost of interferon-based treatment for hepatitis. For example, in Egypt, local manufacture of a version of PegIFNα enabled negotiations with Roche and Merck to drive down the price to $2,000 for a treatment course in 2013.

While market shaping efforts have historically driven down prices, it is not clear what the route to improved access to affordable treatment in LMICs will be, or how quickly that can happen given the high current prices.

Complicating factors

Before HDV treatment can commence, patients are required to undergo further liver tests (e.g. transient elastography to check for kidney scarring/fibrosis) to assess the severity of the disease and ensure that treatment can be safely tolerated.

Additionally, both PegIFNα and bulevirtide are administered via weekly and daily injections respectively, and require cold chain storage. While they can be administered in outpatient settings, patients need to attend the clinic for the first couple of doses for training on self-administration, and regularly thereafter for monitoring.

The required testing and clinic attendance add further cost and complication to the treatment process, posing a considerable challenge in resource-limited settings.

Importance

In this section, I estimate the DALY burden of HDV using information from GBD, the Stockdale paper, and the WHO global hepatitis report.

Population attributable fraction (PAF) estimates of HDV

Since IHME/GBD does not publish data for HDV, I roughly estimate the burden using published data on HBV mortality and DALY burden. Globally and in LMICs, GBD’s estimate for the total DALY burden from hepatitis B is largely accounted for by chronic hepatitis B, including cirrhosis (~65%) and liver cancer (~25%). Less than 10% is due to acute hepatitis.

Figure 6: Contributions to total DALY burden related to hepatitis B in LMICs

Population attributable fraction (PAF) estimates suggest that HDV accounts for 18% of cirrhosis cases and 20% of hepatocellular carcinoma (HCC) cases among HBsAg-positive individuals.

Using these estimates, HDV is responsible for:

• 18% of the DALYs from chronic hepatitis B, including cirrhosis: that’s 2.4 million DALYs.
• 20% of the DALYs from liver cancer due to hepatitis B: that’s 1 million DALYs.

According to the Stockdale paper, HDV is estimated to affect ~4.5% of individuals with chronic HBV infection, yet it accounts for 17% (3.4M/20.5M) of all HBV-related DALYs.

HDV risk multipliers

Multiple studies compare health outcomes from patients with HBV/HDV coinfection, relative to those with HBV monoinfection. In a meta-analysis, Miao et al. (2020) report a 3.8x higher risk of developing cirrhosis; Alfaiate et al. (2020) report a 1.28x higher risk of developing hepatocellular carcinoma (HCC).

Based on these numbers and the table above:

Correlation between HBV DALY rate and anti-HDV prevalence for selected countries

Using data from GBD, I created a scatter plot to check for correlation in selected countries between HBV DALY rates (for 2020) and published estimates of anti-HDV prevalence from Stockdale et al. (2020).

This chart reflects the regression equation 928x + 204, where:

1. x represents the % of HBV-infected individuals coinfected with HDV (i.e. HDV prevalence among HBsAg-positive individuals).
2. For every additional 1% of the population with hepatitis D (given that they have hepatitis B), the DALY burden increases by 9.28.
3. How to think about these figures:
   1. If hepatitis D didn’t exist (x = 0), the DALY burden would be 204 DALYs per 100,000.
   2. If every person with hepatitis B also had hepatitis D (x = 1), the DALY burden would be 204+928 = 1,132 DALYs per 100,000.
   3. That suggests that a case of hepatitis D (coinfected with hepatitis B) is 1,132/204 = ~5.6x the DALY burden of hepatitis B.
4. This implies that hepatitis D is (5.6*0.045)/((5.6*0.045) + (1*0.955)) = ~0.21, or ~21% of the hepatitis B burden = ~4.3 million DALYs.

Note that this is a very rough estimate: confounders could include access to better health care and antiviral treatment, higher HBV vaccination coverage rates, higher GDP, or higher literacy rates. There is also the possibility of “reverse causation” — a higher rate of hepatitis B cases could cause a higher rate of hepatitis D among the hepatitis B population (e.g. if hepatitis D is more likely to develop in areas with a higher concentration of hepatitis B, perhaps because that high concentration could imply a higher rate of risky behavior like needle sharing). One could investigate this further by running a series of country regressions with more controls.

Overall, these three estimates imply that hepatitis D accounts for between 11% and 21% of the total burden from hepatitis D.

The chart below shows how hepatitis D compares to other disease areas, taking the average of the three estimates above (3.4M, 2.34M, and 4.3M) to get a DALY burden of 3.35 million:

Figure 7: LMIC DALYs per disease area (GBD 2021 estimates)

WHO estimates on mortality from viral hepatitis

Additional data from the WHO’s global hepatitis report (2024):

• An estimated 254 million people are living with hepatitis B globally.
• This implies that ~11.4 million people are living with HDV: ~4.5% of 254 million.
• Data from 187 countries show an estimated 1.3 million deaths from viral hepatitis in 2022 — an increase from 1.1 million in 2019.
• 83% of these 1.3 million deaths from viral hepatitis in 2022 (~1.1 million deaths) were caused by hepatitis B.
• When CG creates BOTECs, we estimate that premature death (for people over 5 years of age) accounts for an average of 32 DALYs.
• ~1.1 million * 32 = ~35.2 million DALYs.
• If we assume that HDV burden accounts for 16.3% of HBV burden (the average from the three estimates above), it would account for ~5.7 million DALYs.

Ways these estimates could be wrong

Some other studies suggest that HDV prevalence may be higher:

• A systematic review and meta-analysis by Chen et al. (2019) found an HDV prevalence of 14.57% among HBsAg-positive individuals.
• Miao et al. (2020) reported an HDV prevalence of 13.02% among HBsAg-positive individuals.

A more recent study by the Polaris Observatory Collaborators provided an adjusted estimate of the prevalence of HDV in 25 countries and territories. They found lower estimates than previously reported for 18 countries.

Neglectedness

Global R&D funding

Funding for HDV-specific public health interventions, such as market shaping or implementation science, is extremely limited in LMICs.

While G-FINDER does not publish funding data for R&D spending toward HDV, we can use HBV as a proxy. For each DALY of global burden from HBV, G-FINDER reports $1.20 in R&D spending. This is quite low compared to spending for tuberculosis ($17/DALY), HIV/AIDS ($32/DALY), and malaria ($13/DALY). Total funding for HBV R&D in 2023 was $25 million, comprising $16 million from public funds, $8.3 million from industry funds, and $0.3 million from philanthropic funding (specifically from Wellcome Trust).

Figure 9: Trends in HBV R&D funding from 2018 to 2023 (source: G-FINDER)

Compared to disease areas like tuberculosis, HIV/AIDS, and malaria, R&D funding for hepatitis B and C is neglected — as seen in the Total $/DALY column in the table below.

Figure 10: R&D funding by disease area vs. DALY burden (source: G-FINDER)

Philanthropic funding

Below, I list organizations that fund work on HBV and/or HCV (mostly for implementation science, public health awareness, and modeling), which could serve to indirectly address the burden of HDV.

The Task Force for Global Health is a U.S.-based nonprofit organization that supports large-scale public health programs globally, and includes viral hepatitis as one of its focus areas. The Coalition for Global Hepatitis Elimination (CGHE) was established by the task force in 2019, and works on viral hepatitis prevention, testing, and treatment via provision of technical assistance, knowledge generation and sharing, and advocacy.

The Center for Disease Analysis (CDA) Foundation is a nonprofit organization focused on eliminating hepatitis B and C globally by 2030. It founded the Polaris Observatory, which provides modeling data on the impact of HBV and HCV disease progression and supports governments to use that data to inform elimination strategies. The foundation disbursed $5.9 million between 2017 and 2024, comprising $2 million in international grants and $3.9 million in U.S. grants (all for cross-cutting activities, none specific to HDV).

The John C. Martin Foundation funds some work on viral hepatitis, including a grant to understand the epidemiology of HDV across China (amount not specified).

Bilateral and multilateral agencies

Unitaid’s Eliminating Vertical Transmission portfolio (~$25 million) covers HIV, HBV, syphilis, and Chagas disease under a new project with PATH and partners: SAFEStart+.

Gavi, as part of its vaccine investment strategy, provides funding to some countries to introduce the hepatitis B birth dose vaccination.

The Global Fund to fight AIDS, TB and Malaria (GFATM) policies have been expanded to include support to reduce the impact of HBV and HCV within HIV programs.

Governments

Mongolia has one of the highest HDV burdens globally, with a prevalence of ~40% amongst those with HBV. In 2024, the government of Mongolia stated that it would cover the cost of HDV treatment, though the funding amount was not specified.

Other funding

In 2022, the D-SOLVE Consortium — a team of experts in HDV research from several European institutions (Germany, France, Sweden, Italy, Romania) — received a €6.75 million grant from the European Union to study and develop tailored treatment approaches for hepatitis D. This will involve research to understand the variation in viral suppression across individuals, mechanisms of disease progression, and response to antiviral treatment.

Gilead Sciences launched the ALL4LIVER grant program in 2021 and has awarded >$1 million in grant funding directed at initiatives to combat hepatitis B, C, and D. The initial 2021 launch was specific to the Asia-Pacific region, but in 2023, Gilead expanded the program to support countries around the world excluding the United States. 71 projects were funded in 2023. About half of the funded projects focused on either HBV or HCV, and five projects addressed gaps in HBV, HCV, and HDV.

Similarly, Gilead’s SPEARHEAD program, launched in 2022 in the U.S. and relaunched globally in 2024, will provide grants of up to $200K for programs aimed at understanding and addressing barriers to HDV screening and linkage to care.

Tractability

In this section, I suggest ways philanthropic funds could address the burden of HDV by addressing the challenges I described earlier.

Run a study in a high-burden LMIC to improve HDV prevalence estimates

John W. Ward, director of the Coalition for Global Hepatitis Elimination (CGHE), said that improved prevalence data would draw the needed attention to HDV and motivate policy change. Proper estimates of the HDV burden and its contribution to liver disease, both globally and across countries, would provide a clearer picture of its true impact, and help direct attention and resources. While higher estimates could drive urgency, government and other donor efforts, and policy action, lower estimates could refine priorities and ensure proper allocation of resources.

Summary of BOTEC methodology (full calculation here):

This gives a final SROI of 301x — very far below our bar of roughly 2000x.

Develop better HDV diagnostics

A rapid diagnostic test for anti-HDV screening was highlighted by experts as an area that would significantly and positively impact the HDV space. Current diagnostic methods for HDV are laboratory-based, as mentioned in the “diagnostic challenges” section. This limits the scale-up of HDV diagnosis in LMICs, and an expert from CGHE mentioned that improved access to diagnostics would be an important first step in addressing the burden of HDV in LMICs.

One argument against making this grant would be that improved testing without addressing barriers to treatment will not reduce the burden of HDV. However, a small fraction of those diagnosed may be able to access treatment. Others who test positive for HDV might adopt other positive health behaviors. Better epidemiological data on the burden of the disease could improve impact modeling and lead to stronger advocacy for access to treatment, which could in turn spur action from governments and other donors.

The current WHO guidelines stipulate HBV/HDV coinfection as an indication for commencement of HBV treatment (without the requirement of other tests like HBV viral load or liver function tests). Improved access to HDV testing could simplify the process of treatment initiation for hepatitis B.

Summary of BOTEC methodology (full calculation here):

This results in an estimated ~20K DALYs averted and an SROI of 789x.

Facilitate access to improved HDV treatment (alongside improvement in diagnostics)

It might be possible to make grants to market shaping organizations to expand access to promising treatments that are currently under testing. One example is lonafarnib: a Phase 3 D-LIVR study tested the efficacy of lonafarnib combined with ritonavir, with or without PegIFNα, for 48 weeks among 407 patients. The combination therapy had higher efficacy — 19.2% of patients reached the primary endpoint of ≥2 log reduction in HDV RNA and ALT normalization, compared to 10.1% for lonafarnib + ritonavir and 9.6% for PegIFNα alone.

The LOWR-6 study, which also evaluates the efficacy of lonafarnib + ritonavir, is ongoing. If it is shown to be effective and gets regulatory approval, we could fund an organization to engage with the innovator and facilitate generic access for LMICs.

Summary of BOTEC methodology (full calculation here):

This gives ~46K DALYs averted and an SROI of 1,773x.

Fund expansion of hepatitis B birth dose vaccine uptake

Challenges to HBV vaccine uptake include poor awareness, out-of-facility births, supply chain issues, a shortage of trained health care workers, absent or poorly implemented strategies for national coverage, and a lack of access to health care facilities.

The grant would pay for technical support to the government to expand access to HBV vaccines.

Summary of BOTEC methodology (full calculation here):

This results in an SROI of 1,833x.

Other opportunities in this space

1. Support R&D to develop a cure for hepatitis B. Since HDV requires hepatitis B for replication even after infection, complete clearance of HBV will eventually clear HDV.
2. Support the launch of a fund for hepatitis broadly: the field is neglected, there are tractable opportunities for existing interventions, and future products (like a cure for HBV or vaccine for HCV) could be hugely impactful.
3. Awareness campaigns calling for health care workers to screen for hepatitis D, similar to the work of Hepatitis Delta Connect. This seems relatively unpromising: even if awareness is raised, barriers to diagnosis and treatment still exist.
4. Market shaping to drive down the costs of current diagnostics and treatments for HDV. This is also not very promising, because the current price points are quite high and it will take a long time for prices to reach affordable levels in LMICs.

Conclusion

Overall, hepatitis D appears to be highly neglected. Arguably, the most tractable approach would be to improve HBV vaccination rates, especially birth dose vaccination. This, coupled with other HBV prevention interventions such as maternal prophylaxis and wider testing and treatment, will reduce the prevalence of HBV and in turn HDV.

These strategies, however, will not address the mortality and morbidity associated with those already coinfected with HBV and HDV. Despite the existence of barriers to prevention, testing, and treatment, there are tractable opportunities in this space. Additionally, since promising treatments could become available in the near future, it seems valuable to lay the groundwork for access to those treatments by improving diagnostics, and by using market shaping to ensure these treatment(s) will be affordable when they become available.

I am most excited about funding directed at accelerating the commercialization of RDTs for HDV (or better, a combined RDT for HBV and HDV) and LMIC access for the most suitable treatment options. Since two RDTs for HDV are in advanced stages, a philanthropist could engage with the developers to understand what it will take to bring the test to market.

From our conversations with experts, it seems unlikely that additional funding will speed up the process to get lonafarnib approved if the Phase 3 trial results are promising. Market analysis and preparation for accessing the product when available will help improve outcomes, in combination with the development of an RDT, and point-of-care testing for HDV RNA. I did not spend much time investigating other promising treatments in the pipeline, such as Pegylated Interferon Lambda and Nucleic Acid Polymers (NAPs). This is because issues with pricing and administration will likely make them unsuitable for LMICs for at least the next decade.

One obstacle to progress is that multiple changes need to happen at or around the same time to produce impactful reductions in the DALY burden from HDV. If, for instance, RDTs are developed successfully and priced comparably to existing RDTs, development of effective treatment may lag behind. This would result in a situation where individuals with HDV are successfully diagnosed but have no clear path to obtain treatment.

Additionally, despite the availability of rapid diagnostics for HBV, and relatively affordable treatment, testing and treatment coverage remain sub-optimal in LMICs. It could be more beneficial to first address the barriers to HBV diagnosis, as testing for HDV begins with an initial screening for HBV (though an RDT could also be developed that tests for both HBV and HDV).

Increased testing for HDV has the potential to draw more attention to HDV by showing that prevalence is higher than previously estimated. On the other hand, if it shows that the burden is much lower than previously estimated, that would still be valuable — it could help donors decide to focus attention on other, more promising areas.

Appendices

Resources

• WHO global hepatitis report (2024): pages 42 to 48 contain guidance on testing and treatment for HBV and HDV
• WHO guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection, March 2024
• 2024 study by the Polaris Observatory Collaborators which provides an adjusted estimate of the prevalence of HDV
• Global HDV Elimination: Challenges and Opportunities: July 2023 webinar hosted by the CGHE (Coalition for Global Hepatitis Elimination) and ICE-HBV (International Coalition to Eliminate HBV)
• 2024 Update on Chronic Hepatitis D: from Disease Awareness to Therapeutic Opportunities: July 2024 webinar hosted by the CGHE (Coalition for Global Hepatitis Elimination) and ICE-HBV (International Coalition to Eliminate HBV)

Interviews conducted