Hepatitis C virus (HCV) infection is a global public health problem associated with significant morbidity and mortality. According to estimates made in 2022 by the World Health Organization (WHO), around 58 million persons have chronic HCV infection worldwide, with an approximate incidence of 1.5 million new infections each year.1

In Mexico, according to the National Statistics and Geography Registry (INEGI, for the Spanish acronym),2 cirrhosis of the liver was the fifth cause of death in men and the seventh in women in 2022, and the only available cure at present is orthotopic liver transplant (OLT). There are different challenges in Mexico for organ transplantation, which include a low donation rate, donors with marginal organs, and the prevalence of fatty liver among donors. In addition, there is a significant discrepancy between organ demand and supply, for which the use of organs from HCV-infected donors could be of help.3 The use of organs with HCV infection requires universal access to direct-acting antivirals (DAAs). Said strategy could be implemented in Mexico, given that DDAs are required for the transplantation of organs from HCV-positive donors, in HCV-negative recipients.3 The results with this approach are similar to those of transplants performed with organs from donors that are negative for HCV.

On the other hand, the opioid epidemic is of great importance because it leads to a high mortality rate. Within the time frame of 1996 to 2019, approximately 500,000 deaths secondary to opioid overdose were reported.4 This epidemic has mainly affected North America, especially the United States, and more recently, Canada.4

In Mexico, the estimated prevalence of opioid use in the general population is under 1%. The most affected individuals are men under 45 years of age, particularly in the Mexican states bordering the United States. Given that intravenous drug use and abuse leads to the risk for infection, transmission, and development of HCV, it should be contemplated that these patients, in the long term, could be possible organ donors (due to the deaths associated with abuse). It must also be remembered that during the progression of opioid use, more than one out of every 3 drug users negative for HCV before their drug use, will develop HCV infection in the following year.5

Our aim was to carry out a review of the current evidence on the impact of the transplantation of organs from HCV-positive donors in HCV-negative recipients.

With respect to solid organ transplantation, demand continues to exceed supply, resulting in a considerable mortality rate in the patients on the waiting list, given that 25% of these patients are removed from the list or die, annually.6 This situation has made it necessary to look for alternatives other than the exclusive use of the brain-dead donor, resulting in the options of donors in controlled asystole (Maastricht III and IV), living donors, split organs, and organs from donors with chronic viral infections, especially hepatitis C. This last group accounted for 9.7% of the livers donated in 2019 and has recently increased.7

The arrival of the DAAs produced a revolution in the management prospects of hepatitis C,8 because they have been shown to be highly effective, achieving a sustained virologic response (SVR) above 95%, regardless of fibrosis grade and viral genotype. This had led to the worldwide development of HCV eradication programs.

It is well known that HCV recurrence after OLT is practically inevitable in infected patients, and if not treated, can lead to graft loss. However, DAAs have had a significant impact at all stages of liver disease. The achievement of SVR in patients with advanced liver disease stabilizes the disease and can delay transplantation. A considerable reduction in the number of patients with cirrhosis due to HCV on the waiting list for liver transplantation has also been observed.9

The high level of efficacy and tolerability of the currently available antivirals makes it possible to consider the use of organs from HCV-positive donors that previously would not have been considered viable. As a result, there is a higher percentage of this type of donor, increasing from 7 to 17% since 2015,10 posing new challenges and ethical considerations.11

The opioid epidemic is extremely concerning, with a notable concentration in the United States and Canada in recent years. There has been a third wave of this problem since 2013 due to synthetic opioid use. In 2009, death due to drug use surpassed the automobile accident mortality rate, and between 1996 and 2019, more than 500,000 opioid-related deaths were registered. Importantly, since 2012, the number of opioid users has increased to approximately 225 million, with mortality at 11,000 persons per year, regardless of age, sex, race, or ethnicity.4

A study conducted during 2017 in the United States revealed that approximately 11.4 million persons stated that they had used drugs in the past year. Strikingly, 4.2% of that study population was only 12 years of age and the related mortality was 47,000 persons.12

Historically, Mexico has been considered a country with a low prevalence of drug use. However, in recent years, data have shown an increase in opioid use, associated with production. According to the National Survey on Drug, Alcohol, and Tobacco Use (ENCODAT, the Spanish acronym) conducted in 2016-2017, the prevalence of opioid use was below 1%, with a greater risk in men than in women; the most affected age group was 18 to 34 years.13

The opioid epidemic has been associated with an increase in parenterally transmitted infections, including hepatitis C. More than 30% of initially uninfected persons are known to end up positive for HCV after one year of being intravenous drug users (IDUs)4 and the development of the infection leads to a greater risk for death. Likewise, in 2017, the number of infected donors was observed to increase from 1.1 to 13.7%.14 These donors tend to be young and previously healthy, enabling the procurement of organs in excellent conditions.15

The phenomenon of opioid abuse is occurring in Mexico, which could lead to problems similar to those described in the United States and Canada.12 A study conducted on IDUs at Mexico’s border zones with the United States (Tijuana and Ciudad Juárez) found a general prevalence of antibodies against HCV of 94.6% and against human immunodeficiency virus (HIV) of 2.8%.16

To understand the reach of the use of organs from HCV-positive donors, the fact that there are 2 groups of infected patients must be underlined. The first group is made up of persons with positive antibodies and positive RNA for HCV (Ab+/RNA+) or with positive antibodies and a positive nucleic acid test (NAT) (Ab+/NAT+). The second group is made up of persons with positive antibodies and negative RNA (Ab+/RNA–).17 The relevance of this is in the fact that the group of donors with Ab+/RNA– has negative viremia and the risk for disease transmission is null.11 However, the majority of studies conducted before 2013 report “positive donors” as those with only a positive antibody test, and so the number of patients with viremia is unknown.

The use of organs from Ab+/RNA+ donors has been considered for many years in solid organ transplantation. However, given all the adverse effects caused by interferon (IFN), as well as a low SVR (under 50%), the implementation of this therapy has had suboptimal results. With the current increase in the need for OLT and the high cure rate with DAAs, the possibility of utilizing organs from IDUs and HCV-positive persons offers a great opportunity for increasing the number of donors.

The high prevalence of Ab+ individuals in Mexican border cities, such as Tijuana and Ciudad Juárez, should be considered an option for increasing the number of solid organ transplants in the different programs of our country.17 Given that the IDUs that die from a drug overdose are often young and with few comorbidities or none at all, they could be considered ideal candidates for organ donation.17

The criteria utilized in different studies that evaluate organs from HCV-positive donors vary. Some depend solely on the experience of the surgeon, given that an organ can be considered viable simply through its macroscopic appearance. However, there are also studies that employ stricter criteria, performing a baseline liver biopsy in organs from potential donors; the organs are considered adequate for donation if they have a fibrosis grade under 2 (18–20

The advantages in using organs from HCV-positive donors are not only reflected in OLT programs. Kidney transplantation provides the clearest example, taking into account that the time from starting dialysis to transplantation can be on average 4 years in developed countries, such as Canada and the United States, whereas in Mexico the interval can be even longer. Utilizing organs from donors that have HCV and are Ab+/RNA+can increase access to transplantation, as well as significantly reduce the time on the waiting list (years), with excellent results in graft function, converting this therapy into a cost-effective strategy in the medium and long terms. In Mexico, studies analyzing costs have been conducted on populations with chronic kidney disease, comparing renal replacement therapy with kidney transplantation. The result at follow-up year 3 was a significant cost reduction of more than 60%, in favor of transplantation.21 Another study analyzed the cost-benefit at follow-up year 5, evaluating the strategy of accepting an Ab+/RNA+ graft in HCV-negative recipients, who after the procedure, received a DAA regimen. Said intervention was effective and less costly ($138,000.00 USD), with 4.8 years of life, compared with the strategy of continuing on dialysis and staying on the waiting list until receiving a no-risk organ, with a cost that was over 200% higher ($329,000.00 USD) and 4.7 years of life.22

In patients with cirrhosis of the liver, the grade of decompensation is known to be proportional to the costs of medical care. In a study that analyzed mean yearly costs in USD per type of care at the Instituto Mexicano de Seguridad Social (IMSS), the costs were $4,269.00, $16,949.63, and $30,249.25 for patients classified as Child-Pugh A, Child-Pugh B, and Child-Pugh C, respectively. The estimated lifetime cost for a patient with cirrhosis was $65,520.19.23 The increase in the number of donors, and consequently, the number of OLTs, not only impacts survival and time on the waiting list, but also can significantly reduce the reported high costs of medical care for advanced liver disease in the Mexican public health systems.

As described above, DAAs confer a high rate of HCV eradication in the general population, as well as in the transplanted population. Because side effects and medication interactions are minimal, treatment with DAAs after transplantation is considered safe.24 As a result, broad experience in OLT with Ab+/RNA+donors has been accumulated in recent years. For example, in the study conducted by Cotter et al. that analyzed a cohort of patients that underwent transplantation within the time frame of January 2008 and January 2018, overall survival and graft survival at one and 2 years in recipients with Ab+/RNA+ donors were similar to results with non-viremic donors.25

In addition, in a systematic review that included 15 studies conducted in the United States and Europe, with a sample size of more than 1,900 patients, there was no difference in overall survival and graft survival. Despite the fact that infected grafts can have a lower SVR and higher costs due to additional treatments, survival is known to improve in critically ill patients on the waiting list, especially in those that have a MELD score above 20 or even > 28 points.26Table 1 summarizes the impact of DAAs on OLTs from positive donors (D+)/negative recipients (R-) for HCV.

Significantly, due to the wave of treatments with DAAs, the infected population that received treatment and achieved SVR is going to be Ab+for HCV. However, viremia or NAT will always be negative. This distinction is important, given that transmission of the virus is unusual in donors with a negative NAT test. Even though cases of transmission are rare, if they do occur, it is most likely due to an acute infection in patients that were in the “window period”.37

Currently, overall survival and graft survival in recipients of HCV-infected organs have been shown to improve with DAA use, even resulting in survival comparable to that of patients transplanted with organs from HCV-negative donors. Nevertheless, it is essential to always inform the potential recipient about the risks and benefits of this strategy.17,38 This should be done through informed consent, with the information provided by trained personnel in a clear and simple manner, with no coercion, and letting the recipient exercise his/her autonomy, given that all patients may not wish to accept this type of organ donation. A study conducted in the United States showed that, despite the abovementioned advantages, only 46% of patients accepted an organ from an HCV-positive donor, and of those patients only 60% were aware that HCV was curable.39

Since 2010, the World Health Assembly has recognized the hepatitis viruses as a public health problem, which is why the World Health Organization (WHO) established a global hepatitis C program, for the purpose of its eradication through different strategies.

In the same context, Mexico created the Specific Action for the Prevention, Diagnosis, and Treatment of Hepatitis C Program, 2016-2018, to achieve those goals in the medium term. Thanks to this program, Mexico has had universal access to effective treatments against HCV, making it possible to consider the strategy of organ donation from infected patients.40 However, there is currently no solid public policy in the country for accepting the use of infected organs, representing a challenge, not only for the National Transplant Center (CENATRA, the Spanish acronym), but also for every authorized transplant center and committee.

Not only are there advantages with respect to OLT, but the efficacy of using HCV-positive donors in HCV-negative recipients in the transplantation of organs, such as the kidney, heart, and lung, among others, has also been shown.

The different DAA treatment regimens for HCV have numerous advantages, including a short period of duration (12 weeks), few adverse effects, and a high eradication rate. With the great disparity between patients that need an organ transplant and organ availability, many transplantation programs worldwide have opted for using organs from HCV-positive donors, given the high response rate to DAAs.38

In the posttransplant patient population, it is important to be aware of possible drug interactions when choosing the treatment regimen. The majority of DAAs are metabolized by cytochrome P450 3A (CYP3A), which can give rise to interactions with immunosuppressants.

Caution must be taken, with respect to the glecaprevir-pibrentasvir regimen, due to possible interactions with the calcineurin inhibitors, especially cyclosporine. At high doses of 400 mg or more, cyclosporine can increase the serum level of glecaprevir by up to 5 times. Therefore, that combination is not recommended in patients that require stable doses of cyclosporine above 100 mg per day. With respect to tacrolimus, serum levels can be increased by a factor of 1.45, but adjusting the dose is not recommended. When given concomitantly, the patient should be monitored frequently, adjusting the dose, when necessary (Table 4).57,62

Interactions are not limited to immunosuppressants and they should also be verified with other drugs used in the transplanted population, and the corresponding adjustments or changes should be made.

We provide here a link where all interactions of DAAs with other drugs can be consulted: (https://hep-druginteractions.org/checker).

In Mexico, there are currently no centers that perform or have performed transplants from HCV-positive donors. With the accumulated experience available at present, transplants utilizing HCV-positive organs in HCV-negative recipients, followed by DAA therapy, provides excellent overall survival and graft survival, taking into account that evidence is limited in some areas.5 In very well selected cases, it appears to be an efficacious and well tolerated strategy. However, the safety of posttransplant DAA therapy is essential and patients must be made aware of the potential risks, including treatment failure, albeit that risk is lower than the risk of dying while on the waiting list.

On January 6, 2023, the CENATRA registry documented 160,406 patients on the waiting list for a kidney transplant, 241 for a liver transplant, and 40 for a heart transplant.63 We believe that the use of organs from HCV Ab+/RNA+donors in Mexico could be a feasible option in one of the Latin American countries with the lowest donation and transplant rates in general,3 keeping in mind that more studies need to be conducted.

We understand that there are many obstacles to utilizing organs from HCV-positive that are not limited only to ethical concepts and certain controversial points. Even though access to DAAs is universal in Mexico and they offer the advantage of having few side effects and interactions with immunosuppressants, the best moment for starting treatment after transplant is not yet clear. With the currently available evidence, we conclude that the advantages outweigh the risks, and therefore, the use of these organs should not be limited in a country, such as Mexico, where the number of organ donations and transplants performed annually do not meet the needs of the population.

The use of organs from HCV-positive donors provides a great opportunity for increasing the number of solid organ transplants. With the present accumulated experience, the high eradication rate with DAAs, and the excellent 6 and 12-month overall survival and graft survival, the use of these organs is a real option in Mexico and other countries, where, in general, the mortality rate due to cirrhosis exceeds the organ donation rate.

No financial support was received in relation to this article.

The authors declare that there is no conflict of interest.