Estimated global cost of treating COVID-19, HIV, Hepatitis B and Hepatitis C with approved effective oral medications

doi:10.21203/rs.3.rs-1606136/v1

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Research Article

Estimated global cost of treating COVID-19, HIV, Hepatitis B and Hepatitis C with approved effective oral medications

https://doi.org/10.21203/rs.3.rs-1606136/v1

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Background

High drug prices can limit treatment access. Patented drugs can be sold for prices far higher than the costs of production. This analysis aimed to determine prices currently feasible to treat COVID-19, HIV, and Hepatitis B or C, with WHO/FDA/NICE approved oral medications assuming competitive generic manufacture.

Methods

Data on Active Pharmaceutical Ingredients (API) exported from India were collected from the Panjiva database ( www.panjiva.com ) – an online database of global exports – and were used to calculate current weighted mean cost/kg of API. Target prices were calculated based on the per-pill cost of API, plus costs of manufacture ($0.01/pill), 10% profit margin, and assumed 27% tax on profit. We selected a range of the most commonly used oral treatments based on WHO guidelines for treatment of COVID-19, HIV, HBV and HCV. Current lowest global prices were obtained from public reports and the Pan American Health Organization Antiretroviral Report. Our target prices were compared with national pricing data from a range of low, middle, and high-income countries.

Results

The main results table shows current prices of antiretrovirals for SARS-CoV-2 (5–14-day course), HIV or HBV (per 365-day course), and HCV treatments (per 12-week course). COVID-19 can be treated with molnupiravir for $12.40, baricitinib for $0.60, or dexamethasone for $0.19 per course. HIV can be treated with DRV/r for $286 per year, ATV/r for $140 per year, TDF/3TC/DTG for $74 per year, TAF/FTC/DTG for $89 and TDF/FTC for $59. HBV can be treated with TDF for $23 per year and TAF for $38 per year. HCV could be cured with sofosbuvir/daclatasvir for $35 per patient and sofosbuvir/velpatasvir for $79 per patient. Maximum list prices (typically from US) were up to 600 times higher than costs of production (e.g. for TDF).

Conclusions

Key viral infections can be treated or cured with generic drugs at prices far below those of branded equivalents. Use of branded drugs at high prices can limit the potential for countries to achieve the UNAIDS 95-95-95 targets.

COVID-19

HIV

HBV

HCV

Four viral infectious diseases are responsible for a significant collective global burden of disease; SARS-CoV-2, HIV/AIDS, HBV, and HCV. The estimated average burden of disease of these four infectious viruses totals 3.6 million deaths and 877.4 million individuals living with infections, per year. Table 1 shows the epidemic size and deaths attributed to each. Although these are reported statistics, the World Health Organization (WHO) estimates the death toll from SAR-CoV-2 to be much higher, with approximately 1.2 million deaths missing from the total estimates [1]. For each viral infection, effective treatments are currently available to mitigate and counter this global burden.

SARS-CoV-2

Treatment of SARS-CoV-2 with antiviral drugs and immunomodulators remains a key approach alongside a successful vaccine rollout [2]. For treatment of mild disease, the antiviral molnupiravir has been approved by UK Medicines and Healthcare Products Regulatory Agency (MHRA) for treatment of patients either over 60 years old, or with risk factors for severe disease. For mild disease, nirmatrelvir plus ritonavir (Paxlovid) has shown an 89% reduction in hospitalization or death when taken within 3 days of symptom onset, compared to placebo [3,4]. This has led to a recommendation for treatment from the World Health Organization, but only for patients at the highest risk of hospitalization [5].

Dexamethasone is a glucocorticoid which has been shown to reduce mortality from SARS-CoV-2 in hospitalized patients [6]. For severe COVID-19, baracitinib, a Janus kinase (JAK) inhibitor, is currently recommended by the WHO for treatment in combination with corticosteroids, based on evidence of improved survival and decreased need for mechanical ventilation [7,8,9]. Monoclonal antibodies have also received NICE and FDA approval for patients who are seronegative, however these are not included in our analysis [10,11].

HIV/AIDS

Treatment recommendations for HIV include a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase inhibitor (INI), typically dolutegravir [12]. A combination dose of Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC), and dolutegravir has demonstrated its safety and efficacy against HIV infection in several randomized clinical trials [13,14,15]. Dolutegravir has shown to be effective as a first line and second-line treatment [16]. Typically, dolutegravir is taken with the combination of TDF and FTC [13, 17]. A combination dose of tenofovir alafenamide (TAF), emtricitabine (FTC), and dolutegravir also has demonstrated promising results in maintaining virologic suppression of HIV [18, 19, 20]. Additionally, TDF/FTC (PrEP) has also been approved for treatment of HIV infection [21].

Protease inhibitors (PI), such as darunavir or atazanavir, are typically used as a second line of defense, in combination with the pharmacokinetic booster ritonavir [22, 23]. As a result of ART, the additional life expectancy for individuals with HIV has increased from 11.8 years to 54.9 years [24].

Hepatitis B

For Hepatitis B, a severe liver infection caused by the HBV virus, a vaccine is available which offers 98% to 100% protection and has been estimated to have averted 7 million deaths [25]. If HBV is contracted however, a range of antiviral medications are available to slow its progression and assure long term survival.

Used on its own, TDF has been proven to be a safe and effective treatment for Hepatitis B [26]. TAF alone can be used interchangeably with TDF, where available, as this is recently used as a subsequent pro-drug formulation [27].

Hepatitis C

Hepatitis C, an inflammation of the liver caused by the HCV virus, can cause both acute and chronic infection. A combination dose of direct-acting antivirals (DAAs) such as sofosbuvir with either daclatasvir or velpatasvir are widely available for chronic infection and have the ability to cure over 90% of those infected with HCV [28, 29]. There are other combinations of direct acting antivirals (DAAs) available

Treatment impacts and study aim

Although available treatments have been proven to be effective, the combined global mortality estimate of 3.6 million deaths per year from COVID-19, HIV/AIDS, and viral hepatitis indicates a large percentage of the infected population are not accessing treatment. HIV treatments have proven a successful global reach with 75% of HIV-diagnosed positive individuals being on antiretroviral therapy [30, 31]. With successful treatments available, there is a potential to extend this achievement to COVID-19 and viral hepatitis. However, significant challenges remain. HBV and HCV treatment programs have been estimated to reach only 22% and 62% of infected individuals, respectively, with costs being a main barrier [32, 33].

This study aims to systematically analyze reported cost of active pharmaceutical ingredients (API) of various drugs for each infectious disease to calculate the potential cost of generic production. We also compared the calculated minimum costs of production to current list of prices of these medications in a variety of countries. The purpose of our analysis is to apply established methods of calculating minimum cost of production for safe and effective drugs for SAR-CoV-2, HIV/AIDS, HBV, and HCV. Through this analysis, we aim to highlight the potential impact reduced pricing may have on the 3.6 million deaths per year cause by the large treatment discrepancy of these four infectious diseases.

We analyzed the cost of production and available national price data for a selection of approved and widely used first line oral medications for SARS-CoV-2, HIV, HBV, and HCV. The Panjiva database and national drug price sources listed in Appendix 1 were searched for available data. In April 2020, we published analyses of the costs of production for a wide range of repurposed drugs for COVID-19 in April 2020 [34] for drugs being evaluated in clinical trials, and in October 2021 [35], and December 2021 [36] for drugs which received regulatory approval.

We only included oral treatments and did include approved injectable medications such as the intramuscular long-acting integrase inhibitor cabotegravir for HIV nor intravenous infusions of monoclonal antibodies for COVID-19 in this analysis. We excluded experimental treatments that have not approved by WHO/NICE/FDA from our analysis. The methods in this analysis are only reliable for calculated production costs of simple molecules.

Minimum Cost Estimation

Methodologies for estimating minimum costs of oral medication production have been previously published [37]. Using the online database Panjiva which shows API shipment details including quantities and costs per kilogram, the costs of Indian API exports were analyzed (LE) and independently reviewed (JW). All available API data from January-December 2021 were included. Shipments <1kg in volume were excluded and the 15% highest and lowest priced shipments were removed to exclude outliers.

For each drug, profit margins of 10% and Indian taxation of 27% on profit were added. For each drug, a 5% API loss during tableting process, and a conversion cost based on the frequency of dosing were factored into calculations alongside a multiplier based on API mass to account for the expense of excipients (additional substances needed to convert API into the finished pharmaceutical product). Indian production was assumed given the country’s leading role in global generic medicine manufacturing, especially for oral anti-viral medications [38].

Cost estimation patterns over time throughout 2021 were also evaluated using available data from the Panjiva database.

International list price comparison

Estimated minimum production costs were compared with published list prices in a range of countries across the economic development spectrum to give a representative sample of prices globally. Country sources are detailed in Appendix 1. As the prices for molnupiravir and nirmatrelvir were not available on any country database site, prices for this drug were extracted from various news outlets, detailed in Appendix 2. For reference pricing of HIV and Hepatitis B medications, the Pan American Health Organization (PAHO) antiretroviral costing data was used [39]. Data was collected by LE and independently reviewed by JW.

Key assumptions

The costs of regulatory filings and approvals are often significant add-ons to the initial use of drugs in any specific country. All drugs analyzed in this study have been approved for treatment for some indications already. We have not included the cost or timing associated with regulatory approvals for the use of these drugs. We assume that the WHO and other influential regulatory agencies will cooperate to define a pathway for use of these drugs which does not include additional financial outlays or filing for marketing approvals. Furthermore, research and development costs are not factored in, but the majority of funding for this has been shown to come from public funds such as the WHO, University laboratories, and global fund.

COVID-19 Treatments

Table 2 shows the calculated cost of production, as well as the minimum and maximum available price for each drug. Pricing trends of export data for each medication throughout 2021, where available, are presented as bubble plots in the Appendix.

Molnupiravir

Our analysis used a 5-day, 800mg twice a day course, as reflected in the MOVe-Out trial [40]. The weighted mean API cost in 2021 was $1,293/kg. After factoring in the costs of excipients, formulation, tax, and profit, a 5-day oral course could be manufactured for an estimated $12.40 per patient (Figure 1a).

International list prices per single dose of molnupiravir ranged between $750 per course in Japan to $20 in India (Figure 1b).

Figure 1c shows the cost per kg of molnupiravir throughout 2021 as reported by Panjiva. The price of molnupiravir API stayed relatively constant throughout the year.

Nirmatrelvir/ritonavir

Our analysis of nirmatrelvir used a dose of 300mg twice daily for 5 days, in combination with 100mg of ritonavir, consistent with NIH recommendations [5]. The weighted mean API cost was $16,614/kg for nirmatrelvir and $221/kg for ritonavir. This corresponds to the estimated cost of a combined 5-day oral treatment of nirmatrelvir/ritonavir of $59 per patient (Appendix 1a).

International list prices per course of nirmatrelvir/ritonavir are limited in availability and ranged between $530 in the United States to $93 per course in Bangladesh (Figure 2a).

Baricitinib

Our analysis of baracitinib used a dose of 4mg once daily for 14 days, consistent with WHO recommendations [7]. The API cost of imports from 2021 was $6,624/kg. After including costs of formulation, a 14-day oral course could be manufactured for $0.60 per patient (Appendix 2a).

International list prices per course of baricitinib ranged between $2,422 in the US and $544 in the UK to $4.22 in India (Figure 2b). The United States price was slightly lower through the Veterans affairs system compared to standard pharmacy prices, at $2,045 per course.

Dexamethasone:
For dexamethasone, the dose of 6mg once daily for 10 days used in our analysis, is the same dose used in the RECOVERY trials [6]. The weighted average API cost of available export data was $1,068/kg. After the addition of costs, a 10-day oral course could be manufactured for $0.19 per patient (Appendix 3a).

International list prices per single dose of dexamethasone ranged between $21 per course in US pharmacies to $0.02 in Vietnam (Figure 2c).

HIV Treatments:

Tenofovir disoproxil fumarate (TDF)/Emtricitabine (FTC)/Dolutegravir (DTG):

Our analysis used a 300mg/200mg/50mg once daily dosage for TDF/FTC and dolutegravir, as per FDA guidelines [41]. The weighted mean API cost was $141/kg for TDF, $361/kg for FTC, and $668/kg for Dolutegravir. This corresponds to the estimated cost of TDF/FTC/dolutegravir of $74 per patient per year (Appendix 4a).

Current international list prices for a combined dose ranged from $36,374 per course in US pharmacies to $605 per course in India (Figure 2d). The PAHO price list shows a minimum pricing of $61 per patient per year [39]. Prices extracted for the US, UK, and India used a combination dose of TDF/3TC plus dolutegravir. As FTC and 3TC can be used interchangeably, availability of FTC varies upon region [42].

Tenofovir alafenamide (TAF)/Emtricitabine (FTC)/Dolutegravir (DTG):

The weighted mean API cost of the available TAF export data was $3,114/kg. After the addition of costs, this TAF could be manufactured for $38 per patient per year. The combined treatment of TAF/FTC is prescribed with a 50mg dose of dolutegravir [13].

As a combined dose the production cost of TAF/FTC/Dolutegravir is estimated at $89 per patient (Appendix 5a)

International list prices for a combined dose of TAF/FTC/DTG ranged from $50,473 in US pharmacies, to $14,043 in the United Kingdom. The price of TAF/FTC/dolutegravir in the US was only slightly lower through the Veterans affairs system at $38,963 per course. The PAHO database shows price of $60 per patient per year [39] (Figure 2e).

Tenofovir disoproxil fumarate (TDF)/ Emtricitabine (FTC) (PrEP):

TDF is used with FTC (PrEP) at a dose of 300mg/200mg one daily for 365 days [43]. Using the weighted mean calculated above, the combined estimated cost of PrEP per patient per year is $59 (Appendix 6a).

International list prices of PrEP range from $21,402 in US pharmacies to $16 in Vietnam (Figure 2f).

Darunavir/Ritonavir:

Darunavir 800mg is used with ritonavir 100mg once daily [23] as reflected by NICE recommendations [44]. The weighted API costs of darunavir and ritonavir were $774/kg and $221/kg, respectively. As a combined dose, the production cost of darunavir/ritonavir is estimated at $286 per patient (Appendix 7a).

Current list prices for oral darunavir/ritonavir ranged from $24,773 per course in the US to $945 in Turkey (Figure 2g). The PAHO database shows a minimum price of $702 per year. [39].

Atazanavir/Ritonavir

The weighted mean API cost of atazanavir export data was $702/kg. After factoring in costs, a combined dose of atazanavir/ritonavir could be manufactured for $109 per patient per year (Appendix 8a). The atazanavir/ritonavir dose of 300/100 mg once daily is reflective of EMA and UK BNF regulations [45]. International list prices of atazanavir/ritonavir ranged between $4,995 per year in US pharmacies to $363 in India (Figure 2h). The PAHO database shows a minimum available price of $324 per patient per year for atazanavir [39].

Hepatitis B Treatments

Tenofovir disoproxil fumarate (TDF) and Tenofovir alafenamide (TAF)

The above analysis shows that TDF and TAF could be manufactured for $23 and $38 per patient, per year, respectively (Appendix 4a, 5a).

International list prices for oral courses of TDF ranged from $13,204 per course in US pharmacies to $4.36 per course in Vietnam (Figure 2i). The PAHO database showed a minimum price for TDF of $39 per year [39]. Annual prices of TAF ranged from $16,471 in the United States to $190 in India. The price of TAF in the US was slightly lower through the Veterans affairs system compared to standard pharmacy prices, at $11,052 per course (Figure 2j).

Hepatitis C Treatments

Sofosbuvir/daclatasvir

Our analysis used an 84-day, 400mg/60mg once daily course of treatment, as per FDA guidelines [46, 47]. The weighted mean API cost of the shipments for SOF and DAC in 2021 were $756/kg and $494/kg, respectively. This corresponds to an 84-day course of this combined dose at $35 per patient (Appendix 9a).

Limited international list prices for an oral combined dose of SOF/DAC ranged from $983 per course in Bangladesh to $704 in India (Figure 2k). SOF/DAC is not available for routine sale in the US.

Sofosbuvir/velpatasvir:

The combined dose of SOF/VEL uses a dose of 400mg/100mg once daily, for 84 days [48].

The weighted average API cost of velpatasvir was $4,704/kg. After factoring in costs, an 84-day oral course could be manufactured for $48 per patient (Appendix 10a). Using this price, and the above calculated price for SOF, a combined dose production cost of SOF/VEL is estimated at $79 per patient.

International list prices for an oral combined dose of SOF/VEL ranged from $52,676 in the UK, to $565 in India (Figure 2l).

Repurposed drugs for SARS-CoV-2, HIV, HBV, and HCV have the potential for generic production at low costs. Treatment for SARS-CoV-2 could be treated very cheaply: combination treatment with dexamethasone and baracitinib could be manufactured for under $2 per treatment course, respectively. Treatment for HIV can be manufactured for $74 per year, using TDF/FTC/DTG. Hepatitis B could be treated with TDF for $23 per year. Hepatitis C could be cured with Direct Acting Antivirals such as SOF/DCV for $35 per patient.

In developed economies such as the United States, the available prices for these medications stand at an average of 600 times higher than their potential cost of production based on available API data. The extreme variations in prices between countries further illustrate the necessity of strategies to reduce pricing of live-saving medications.

Our analysis is based on previously published methodology for estimating minimum costs of oral medication production [37]. Cost reduction mechanisms have been applied to HIV antiretrovirals, which have been successful in the reduction of global prices. The Global Fund has been successful in developing innovative finance mechanisms to reduce the price of HIV, tuberculosis, and malaria drugs which has been directly responsible for saving 44 million lives [49]. As SARS-CoV-2, HIV, HBV, and HCV are responsible for a total average of 3.6 million deaths per year, this success provides a clear illustration of the potential of price reduction methods for relieving this burden of disease for SARS-CoV-2 and viral hepatitis.

Voluntary and compulsory licensing has shown success in the past in allowing for generic manufacturers to produce patented life-saving medications, which has ultimately allowed for wider access at low cost [50, 51, 52]. Pharmaceutical companies have agreed non-exclusive voluntary licensing for HIV and viral hepatitis medications which has resulted in nine out of ten individuals affected by HIV/AIDS in low-income settings to be provided medication under this licensing [53]. Allowing for 14 generic manufacturers to produce their medications for viral hepatitis allowed for the production of these life-saving medications in 105 countries [53]. Although there has been extreme resistance for compulsory licensing of the COVID-19 vaccine, the application of these methods has proven successful in the past and should be applied to life-saving treatments for SARS-CoV-2 [54].

Our analysis has several limitations. We have not included costs of product development, bioequivalence studies, registration costs and costs of litigation in our methodology due to a lack of published data. This, however, is balanced against a possible overestimation of API costs and ultimate excess in generic price calculation [37]. Our estimated cost prices of treatments for HIV are very close to the current minimum prices for the same drugs when sold in low- or middle-income countries [39].

Additionally, we did not include exports from other country sources in our analysis. This analysis concentrated on export data from India only due to its successful history with generic manufacturing and experience with the WHO prequalification program [55]. The range of API data observed illustrates trends from 2021 alone. As API prices can change over time as demand rise and falls, a subsequent analysis should be produced to monitor changes in API prices over time.

In terms of medication inclusion criteria, we have only analyzed key drugs to treat the SARS-CoV-2, HIV, and viral hepatitis. These were chosen based on regulatory approvals and main international recommendations for each infection. Monoclonal antibodies to treat SARS-CoV-2 such as tocilizumab, sarilumab, and sotrovimab were also not included in our scope of study due to the inability to apply our methodology to these types of complex molecules.

Additionally, when comparing country pricing, list prices may not reflect the actual prices paid by governments. Further treatments may become available for future analysis based on promising preliminary results of large, randomized control trials. For example, we have included Nirmatrelvir (PF-073201332 + ritonavir), or Paxlovid, based on results from unvaccinated high-risk adult patients in the EPIC-HR trial [56]. As limited data was available on this novel medication, our analysis must be re-run based on prospective data which may become available, including vaccinated patients, as well as for other therapies which may emerge. Long-acting antiretroviral treatments should also be analyzed, as they can be administered via injections every 2 to 3 months, rather than a daily oral medication regimen for HIV and viral hepatitis [57].

These low costs of production support the feasibility of mass test and treat campaigns to eliminate key viral diseases worldwide.

Funding:

International Treatment Preparedness Coalition/Make Medicines Affordable Campaign

Potential conflicts of interest:

All authors: No reported conflicts of interest.

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Table 1: Burden of Disease for COVID-19, HIV, HBV, and HCV

Disease	Epidemic Size (Current Infections)	Deaths Per Year (2019-2021)	Treatments
SARS-CoV-2	58M* [58]	1,884,000 [59]	Nirmatrelvir/r
			Molnupiravir
			Baracitinib
			Dexamethasone
HIV/AIDS	33.7M***	680,000*** [60]	TDF/FTC/DTG
			TAF/FTC/DTG
			TDF/FTC (PrEP)
			DRV/r
			ATV/r
Hepatitis B	296M** [61]	820,000** [61]	TDF
			TAF
Hepatitis C	58M**	290,000** [62]	SOF/DAC
			SOF/VEL

*As of 7 April 2022, however this fluctuates more than the other more stable epidemics

**Estimate from 2019

***Estimates from 2020

Treatment Abbreviations: TDF = tenofovir disoproxil fumarate; FTC = Emtricitabine; DTG = Dolutegravir; TAF = Tenofovir alafenamide; DRV = Darunavir; r= Ritonavir; ATV = Atazanavir; SOF = Sofosbuvir; DAC = Daclatasvir; VEL = Velpatasvir

Table 2: Drugs for COVID-19, HIV, HBV, and HCV

Drugs	Dose	API cost/kg	Production Cost (USD)	Minimum Price (USD)	Maximum Price (USD)
COVID-19
Molnupiravir (MOL)	800 mg BID	$1,293	$12.40 (5 days)	$20	$750
Nirmatrelvir/r	300/100 BID	$16,614/$221	$59 (5 days)	$93	$530
Baricitinib (BCB)	4mg OD	$6,624	$0.60 (14 days)	$4.22	$2,422
Dexamethasone (DEX)	6mg OD	$1,068	$0.19 (10 days)	$0.02	$21
HIV
TDF/FTC/DTG	300/200/50 OD	$141/$361/$668	$74 (365 days)	$61	$36,374
TAF/FTC/DTG	25/200/50 OD	$3,114/$361/$668	$89 (365 days)	$60	$50,473
TDF/FTC (PrEP)	300/200 OD	$141/$361	$59 (365 days)	$16	$21,402
Darunavir/ritonavir (DRV/r)	800/100 OD	$774/$221	$286 (365 days)	$702	$24,773
Atazanavir/ritonavir (ATV/r)	300/100 OD	$702/$221	$109 (365 days)	$324	$4,995
Hepatitis B
TDF	300mg OD	$141	$23 (365 days)	$4.36	$13,204
TAF	25 mg OD	$3,114	$38 (365 days)	$190	$16,741
Hepatitis C
Sofosbuvir/daclatasvir (SOF/DAC)	400/60 OD	$756/$494	$35 (84 days)	$704	$983
Sofosbuvir/velpatasvir (SOF/VEL)	400/100 OD	$756/$4,705	$79 (84 days)	$565	$52,676

BID = twice daily

OD = Once daily

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Estimated global cost of treating COVID-19, HIV, Hepatitis B and Hepatitis C with approved effective oral medications

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