INTRODUCTION:

Orthopoxviruses are a genus of viruses in the Poxviridae family, which includes significant human and zoonotic pathogens like variola (smallpox), monkeypox, cowpox, and vaccinia viruses, are estimated to have diverged from a common ancestor around 10,000 years ago. The original orthopoxvirus ancestor likely spread across continents with global climate changes and migrations. The most well-known orthopoxvirus is the variola virus, which caused smallpox. This marked the first and only disease eradication through vaccination, following Edward Jenner’s pioneering use of cowpox for immunization in 1796. Smallpox eradication in 1980 was a historic public health victory. After smallpox eradication, monkeypox emerged as a notable orthopoxvirus infection, primarily in Africa. In the 1970s, human-to-human transmission was documented, especially in non-vaccinated individuals due to the cessation of smallpox vaccination. With the cessation of smallpox vaccination, immunity to orthopoxviruses in the human population has declined, leading to an increase in zoonotic orthopoxvirus outbreaks, including monkeypox in Africa and cowpox in Europe. Emerging infections like the Alaskapox virus and Akhmeta virus highlight the evolutionary potential of these viruses and their risk for human spillover. The lack of immunity in younger populations, post-smallpox vaccination cessation, raises the risk of spread and underscores the need for vigilant surveillance and preparedness for potential bioterrorism threats¹.

Smallpox primarily spreads through inhalation of respiratory droplets, with an incubation period of 7-17 days. It starts with high fever, severe body pain, and malaise, followed by a distinctive rash that progresses from macules to pustules and eventually scabs, leaving pitted scars. Mortality rates were around 30% for the major form, variola major. The smallpox vaccine, originally based on the vaccinia virus, remains the most effective preventive measure, although vaccination now occurs only in high-risk groups due to eradication. Immediate vaccination post-exposure can help mitigate outbreaks if accidental or intentional release occurs².

Cowpox virus is endemic to Eurasia and has a wide host range. Most human cases occur through contact with infected animals, especially domestic cats and, occasionally, exotic pets like rats. An outbreak in Munich involved transmission from pet rats to humans. Symptoms include painful, hemorrhagic pustules, often accompanied by fever and lymphadenopathy. CPXV has extensive genetic coding for immune evasion proteins, such as those inhibiting antigen processing and inflammatory cytokine activation, making it more virulent and adaptable to multiple hosts. Recent genomic studies have revealed significant genetic diversity within cowpox strains, suggesting that cowpox virus may be a composite of multiple species. This diversity raises challenges for classification and understanding host-specific adaptations³.

Monkeypox has historically been limited to rural areas of Central and West Africa, particularly in countries like the DRC, Nigeria, and Cameroon, where sporadic outbreaks have been reported. The disease was first identified in laboratory monkeys during an outbreak in Copenhagen, Denmark. It was named "monkeypox" due to its initial association with these primates, although its primary reservoirs are rodents, found in Central and West Africa as shown in (figure 1 & 2). The first human case was reported in the Democratic Republic of the Congo (DRC). A 9-month-old boy contracted the virus, marking the recognition of monkeypox as a zoonotic disease. Following this case, additional infections were documented in rural regions of Central and West Africa. Throughout the 1970s and 1980s, monkeypox cases were mainly reported in Africa, particularly in the DRC, where outbreaks occurred sporadically. The disease was typically linked to contact with infected animals, often during hunting or handling bushmeat. There was a rise in reported cases in Africa, prompting increased research and awareness about the virus during the period of 1990s-2000s. There has been a notable increase in human cases, partly attributed to diminishing population immunity due to the cessation of routine smallpox vaccination. The first outbreak outside Africa occurred in the United States, linked to the importation of African rodents and has a report or myth that it was spreaded due to priorie dogs. This outbreak involved 47 confirmed cases and demonstrated the potential for monkeypox to spread beyond endemic regions. Nigeria experienced a significant outbreak in 2017, with over 200 suspected cases, indicating the persistence of monkeypox in endemic regions. As the world recovering from pandemic again on 2022, again a global outbreak emerged, with cases reported in multiple countries outside of Africa, including the U.S., Europe, and parts of Asia, marking a significant public health concern. Many infections were in individuals without recent travel to endemic areas, suggesting community transmission. This led the World Health Organization (WHO) to declare monkeypox a Public Health Emergency of International Concern (PHEIC)⁴.

Figure 1. Transmission between human to monkey

Figure 2. Transmission of monkeypox

SYMPTOMS OF MONKEYPOX:

Monkeypox symptoms typically appear 5 to 21 days after exposure and progress through two phases. In the initial phase, prodromal symptoms include fever, severe headache, muscle aches, fatigue, and swollen lymph nodes, a key feature distinguishing monkeypox from smallpox. In the secondary phase, a rash emerges 1 to 3 days after fever, starting as flat spots (macules) and progressing to papules, vesicles, pustules, and eventually crusts that shed within 2 to 4 weeks. Other symptoms may include chills, mild respiratory issues like cough, and sore throat⁵. Severity varies, with immunocompromised individuals and children at higher risk of complications.

PATHOGENESIS OF MONKEYPOX:

The pathogenesis of monkeypox involves several key steps, from the initial infection to the manifestation of symptoms.

Entry and Initial Infection of monkeypox begins with viral entry through broken skin, mucous membranes, or the respiratory tract, followed by local replication in tissues and lymph nodes. The innate immune response activates immune cells and releases cytokines, causing inflammation, fever, and swollen lymph nodes. The virus spreads systemically via the bloodstream (viremia), leading to symptoms like fever, headache, and muscle aches. Within 1-3 days of fever, a characteristic rash develops, progressing through stages from macules to pustules and crusts, which contain infectious fluid. Most cases resolve within 2-4 weeks as the immune system controls the infection, often resulting in immunity.

In most cases, the immune response effectively controls the infection, and individuals begin to recover after 2 to 4 weeks. The lesions crust over and fall off as the skin heals⁶. Surviving an infection typically results in the development of immunity, although the duration and robustness of this immunity are still under investigation.

PHARMACOLOGICAL THERAPY FOR ORTHOPOX VIRUSES (MONKEYPOX, SMALLPOX AND COWPOX):

Tecovirimat:

Tecovirimat is an antiviral drug specifically developed for the treatment of orthopoxvirus infections, including smallpox and monkeypox.

Mechanism of action:

Tecovirimat inhibits the VP37 envelope wrapping protein, essential for the dissemination of orthopoxviruses like smallpox and monkeypox, preventing the formation of virions that can spread within the host.During the 2022 monkeypox outbreak, tecovirimat was prescribed through the Expanded Access Investigational New Drug (EA-IND) protocol. It showed promise in alleviating symptoms of monkeypox infection, with patients often reporting improvement within 3 days of treatment. However, formal trials are ongoing to establish its efficacy definitively⁷.

The dosage of Tecovirimat (TPOXX®):

Oral dosage:

For adults and pediatric patients weighing ≥13 kg, tecovirimat is typically administered in 600 mg doses, twice daily for 14 days. This regimen has been recommended for severe cases of monkeypox and smallpox. In some severe monkeypox cases, rapid symptom improvement was observed within 3 days of treatment initiation.

Intravenous dosage:

In patients unable to take oral medication, intravenous tecovirimat may be administered at 200 mg every 12 hours for 4 days, followed by the remainder of the 14-day course being completed with oral medication⁸.

General tolerability:

Most patients tolerate tecovirimat well. In a U.S. study treating monkeypox, only 3.5% of patients reported adverse events, and nearly all were non-serious. Commonly reported mild side effects included gastrointestinal issues such as diarrhea.

Non-severe side effects:

Some patients reported mild gastrointestinal discomfort, headaches, and fatigue. These non-severe adverse effects were seen in about 22% of patients treated for monkeypox.

Serious adverse events:

In rare cases, there were serious adverse events, though they were not definitively linked to tecovirimat. Some patients with HIV and low CD4 counts reported more serious health concerns, but these were likely due to underlying conditions⁹.

Off-target effects:

Studies suggest tecovirimat may interact with off-target human proteins, potentially affecting other biological processes. However, these interactions are not fully understood and require more research.

Contraindications:

Tecovirimat can be used in immunosuppressed individuals (such as those undergoing chemotherapy) with close monitoring. For example, it was used in a patient with acute myeloid leukemia after smallpox vaccination to prevent progressive vaccinia. Interaction with antiretrovirals: In patients with HIV, particularly those taking antiretroviral medications metabolized by cytochrome P450 enzymes (CYP3A4), tecovirimat may affect drug levels, though no dose adjustment is usually required. Lack of data in certain populations: Though tecovirimat is generally safe, more research is needed to establish its safety profile in populations like pediatric patients under 13 kg and pregnant women.

Drug interactions:

Cytochrome P450 interactions: Tecovirimat is metabolized via UDP-glucuronosyltransferase (UDG) and inhibits CYP2C8/2C19, with weak induction of CYP3A4. This can affect drugs metabolized through these pathways. For example, it has been shown to reduce the concentration of midazolam, a CYP3A4 substrate, by 32-39%. Therefore, dose adjustments may be necessary when combining tecovirimat with drugs metabolized by CYP3A4. HIV Antiretrovirals: Tecovirimat can potentially reduce the efficacy of some antiretrovirals such as rilpivirine, doravirine, and maraviroc. These are also metabolized via CYP pathways, and dose adjustments or alternative treatments like dolutegravir may be needed for patients on prolonged tecovirimat treatment. Vaccine interactions: Tecovirimat, when co-administered with the ACAM2000 smallpox vaccine, may reduce the vaccine’s immune response, as shown in animal studies. This suggests tecovirimat could slightly impair the immunogenicity of live viral vaccines when used concurrently¹⁰.

Cidofovir:

Cidofovir is primarily approved for treating cytomegalovirus (CMV) retinitis in patients with AIDS, significantly delaying the progression of this sight-threatening condition. Cidofovir has demonstrated in vitro and in vivo activity against a variety of viruses, including herpesviruses, adenoviruses, papillomaviruses, and poxviruses such as smallpox and monkeypox. This makes it a potential treatment for multiple viral infections, especially in immunocompromised patients.

Mechanism of action:

DNA polymerase inhibition: Cidofovir is an acyclic nucleoside phosphonate that, after being phosphorylated within infected cells, forms cidofovir diphosphate (CDVpp), a structural analogue of deoxycytidine triphosphate. CDVpp selectively inhibits viral DNA polymerases by incorporating itself into the viral DNA chain during replication. This causes chain termination or slows down further extension, disrupting viral DNA synthesis. Error-prone DNA synthesis: In viruses like vaccinia, cidofovir can be incorporated into the viral genome but makes the viral DNA polymerase less efficient, promoting error-prone DNA synthesis. This is compounded by the fact that the drug-resistant viral DNA can escape exonuclease proofreading, further impairing accurate viral replication⁴⁶. Broad-spectrum antiviral activity: Cidofovir’s mechanism is effective against a broad range of DNA viruses, including herpesviruses, adenoviruses, papillomaviruses, and poxviruses. It has been used both for direct viral inhibition and for its antiproliferative properties in viral-related tumors.

Adverse effects:

Nephrotoxicity: The most common and dose-limiting side effect of cidofovir is kidney toxicity. It can cause acute kidney injury, characterized by elevated serum creatinine and proteinuria, which can be managed with probenecid and hydration.

Ocular complications:

Cidofovir use in treating cytomegalovirus (CMV) retinitis has led to ocular issues such as chronic ocular hypotension, uveitis, and in rare cases, retinal detachment. These complications can result in permanent vision loss if not monitored carefully.

Bone marrow suppression: Cidofovir may cause neutropenia (low white blood cell counts), which raises the risk of infections in immunocompromised patients.

Gastrointestinal symptoms and probenecid reactions: Cidofovir is often administered with probenecid to reduce nephrotoxicity. Probenecid can cause side effects such as nausea, vomiting, and headaches, which may compound the side effects of cidofovir¹¹.

Contraindications:

Nephrotoxicity: The primary concern with cidofovir use is its potential for severe nephrotoxicity, which limits its use, particularly in patients with pre-existing kidney disease. Cidofovir is contraindicated in patients with baseline serum creatinine greater than 1.5 mg/dL or creatinine clearance less than 55 mL/min.

Concomitant nephrotoxic drugs: Cidofovir is contraindicated in patients receiving other nephrotoxic agents, including aminoglycosides, amphotericin B, or non-steroidal anti-inflammatory drugs (NSAIDs), due to the increased risk of renal damage.

Probenecid hypersensitivity: Since cidofovir is administered with probenecid to reduce nephrotoxicity, it is contraindicated in individuals with known hypersensitivity to probenecid.

Severe pulmonary conditions: The aggressive hydration required for cidofovir therapy may precipitate respiratory compromise in patients with pre-existing severe pulmonary disease, necessitating careful management.

Drug interactions:

Probenecid: Cidofovir is administered with probenecid to reduce nephrotoxicity by blocking active tubular secretion in the kidneys. This combination reduces renal clearance, which can help prevent kidney damage. However, probenecid itself may cause gastrointestinal side effects, so patients are advised to hydrate well.

Other nephrotoxic agents: Cidofovir is contraindicated for concurrent use with aminoglycosides, amphotericin B, and nonsteroidal anti-inflammatory drugs (NSAIDs) because these can increase the risk of nephrotoxicity.

Antiviral agents: In vitro studies suggest that combining cidofovir with ganciclovir (GCV) results in a synergistic antiviral effect against human cytomegalovirus (HCMV), making this combination potentially effective for difficult-to-treat cases. However, combinations with other antivirals like AZT or ddC have shown little additional benefit.

Immunosuppressants:

Common immunosuppressive agents, such as cyclosporine A or methotrexate, do not alter the antiviral activity of cidofovir when used in transplant patients, making it compatible with these drugs in managing viral infections post-transplant.

Brincidofovir (BCV) is an oral antiviral prodrug derived from cidofovir, designed to improve bioavailability and reduce nephrotoxicity. It has been primarily developed for the treatment of double-stranded DNA (dsDNA) viruses, including smallpox, cytomegalovirus (CMV), adenovirus, and variola virus.

Mechanism of action:

Brincidofovir is a lipid conjugate of cidofovir. Upon administration, it is cleaved to cidofovir, which is then phosphorylated to its active form, cidofovir diphosphate. This metabolite competes with deoxycytidine triphosphate (dCTP) for viral DNA polymerase, leading to termination of viral DNA synthesis and prevention of viral replication¹².

Efficacy:

Brincidofovir has demonstrated broad-spectrum antiviral activity against multiple dsDNA viruses. Studies have shown its effectiveness in treating smallpox and other infections, such as adenovirus, in immunocompromised patients.

Safety and adverse effects:

Brincidofovir offers a favourable safety profile compared to cidofovir, with lower rates of nephrotoxicity. However, gastrointestinal side effects like diarrhoea are common, especially in high doses or prolonged use.

Uses:

Brincidofovir has been studied for smallpox treatment under the FDA's Animal Rule, with promising results in animal models. It has shown strong antiviral potency against orthopoxviruses, including variola virus, and could be crucial in the event of a bioterrorism outbreak.

Dosing:

In smallpox treatment, the proposed dosing regimen is 200mg weekly for 3 consecutive weeks, administered orally.

Contraindications:

Nephrotoxicity Risk in Solid Organ Transplant Patients, Gastrointestinal Toxicity, Hepatotoxicity, Immunocompromised Patients.

Drug interactions that should be carefully managed, especially when used in immunocompromised patients.

Probenecid and Nephrotoxicity, Immunosuppressants, Antivirals, Gastrointestinal Interactions.

The Vaccinia virus vaccine, often referred to as the smallpox vaccine, is derived from the vaccinia virus, which is a member of the Orthopoxvirus genus. Here are some key points about the vaccine:

Background:

Smallpox Eradication:

The vaccine was crucial in the global effort to eradicate smallpox, a highly contagious and deadly disease caused by the variola virus. The World Health Organization (WHO) declared smallpox eradicated in 1980 due to successful vaccination campaigns.

Vaccine Characteristics:

Live Attenuated Virus:

The vaccinia vaccine is a live vaccine, meaning it uses a live but attenuated (weakened) virus. It does not cause smallpox but can produce mild symptoms and a localized skin reaction at the injection site.

Administration:

The vaccine is typically administered via a bifurcated needle, which pricks the skin and introduces the virus.

Efficacy:

Immunity:

One vaccination provides immunity for several years, and a booster is recommended for individuals at high risk of exposure (e.g., healthcare workers in contact with orthopoxviruses).

Cross-Protective:

The vaccine offers some cross-protection against related viruses, including monkeypox and cowpox.

Safety and Side Effects:

Common Reactions:

Mild side effects may include redness, swelling, and a sore arm at the injection site. Some individuals may experience fever, fatigue, or rash.

Serious Risks:

Although rare, serious side effects can occur, such as progressive vaccinia or eczema vaccinatum, particularly in individuals with weakened immune systems or certain skin conditions.

Current Use:

Bioterrorism Concerns: Due to concerns about the potential use of smallpox as a bioweapon, the U.S. and some other countries maintain stockpiles of the vaccine and have protocols for vaccination in case of an outbreak¹³.

Vaccinia Immune Globulin (VIG) is a product derived from the plasma of individuals who have been vaccinated against the vaccinia virus. It is primarily used for the treatment of complications related to vaccinia vaccination.

Purpose and Indications:

Treatment of Complications: VIG is used to treat serious side effects that can arise from vaccinia vaccination, particularly in individuals who are immunocompromised or have certain skin conditions.

Indications: Specific indications for VIG include:

Progressive Vaccinia: A rare but serious condition characterized by the progressive growth of the vaccinia virus in vaccinated individuals.

Eczema Vaccinatum: A serious complication that can occur in individuals with eczema or other atopic dermatitis when exposed to the vaccinia virus.

Other Orthopoxvirus Infections: It may also be used for other related viral infections¹⁴.

Composition:

Immunoglobulin: VIG is made up of a concentrated solution of immunoglobulins (antibodies) that neutralize the vaccinia virus. The antibodies in VIG are derived from the blood plasma of vaccinated individuals, which contains high levels of antibodies against the virus.

Administration:

Route: VIG is typically administered intravenously (IV), and the dosage may vary based on the severity of the condition and the clinical judgment of the healthcare provider.

Efficacy:

Neutralization of Virus: VIG works by providing passive immunity to individuals who may not have adequate immune responses due to underlying health conditions, helping to neutralize the vaccinia virus and control its effects.

Side Effects:

Common Reactions:

Side effects of VIG may include headache, fever, and allergic reactions, though serious side effects are rare.

Monitoring:

Patients receiving VIG should be monitored for any adverse reactions, especially given the potential for allergic responses.

Preventive Measures for Monkeypox:

Preventing monkeypox involves avoiding contact with wild animals, especially in endemic regions, and practicing good hygiene, such as frequent handwashing and using alcohol-based sanitizers. Protective gear is essential for those handling animals or caring for infected individuals. Vaccination, particularly for high-risk groups like healthcare workers, offers significant protection, as does pre-exposure prophylaxis in outbreak scenarios. Community education, surveillance, and early detection are crucial for controlling outbreaks. Travelers should follow advisories, avoid direct wildlife contact, and monitor symptoms post-travel. Infected individuals should be isolated, and close contacts may require monitoring or quarantine to limit transmission as shown in (figure 3).

Figure 3. Prevention of monkeypox

CONCLUSION:

Orthopoxviruses, adaptable pathogens with historic and ongoing public health impacts, pose modern challenges through zoonotic transmission risks. The global rise in monkeypox cases, including its emergence in non-endemic regions like India, underscores the need for heightened awareness, improved diagnostic resources, and preventive strategies. Overall, orthopoxvirus pharmacology combines vaccination, immune globulin therapies, and antiviral agents to manage and prevent infections effectively. Ongoing research and increased awareness are essential for both prevention and control efforts. Public health efforts must prioritize outbreak control in Africa, address social determinants of health, and strengthen global preparedness through collaboration. Managing monkeypox highlights the interconnectedness of human, animal, and environmental health, emphasizing that global safety depends on equitable healthcare access and disease prevention.

REFERENCES:

1. Castro R, Casanas B. Orthopoxviruses and human disease. In Global Virology II-HIV and NeuroAIDS 2017 (pp. 689-697). Springer, New York, NY.

2. Walsh M. Smallpox: the disease and strategies for its control. Nursing times. 2002; Dec 1; 98(51): 26-7.

3. Diaz-Cánova D, Mavian C, Brinkmann A, Nitsche A, Moens U, Okeke MI. Genomic sequencing and phylogenomics of cowpox virus. Viruses. 2022; Sep 28; 14(10): 2134.

4. Ferdous J, Barek MA, Hossen MS, Bhowmik KK, Islam MS. A review on monkeypox virus outbreak: New challenge for world. Health science reports. 2023; Jan;6(1): e1007.

5. Sharma A, Prasad H, Kaeley N, Bondalapati A, Edara L, Kumar YA. Monkeypox epidemiology, clinical presentation, and transmission: a systematic review. International Journal of Emergency Medicine. 2023; Mar 17; 16(1): 20.

6. Tiecco G, Degli Antoni M, Storti S, Tomasoni LR, Castelli F, Quiros-Roldan E. Monkeypox, a literature review: what is new and where does this concerning virus come from?. Viruses. 2022 Aug 27;14(9):1894.

7. Nyame J, Punniyakotti S, Khera K, Pal RS, Varadarajan N, Sharma P. Challenges in the treatment and prevention of Monkeypox infection; a comprehensive review. Acta Tropica. 2023; Sep 1; 245: 106960.

8. Harapan H, Ophinni Y, Megawati D, Frediansyah A, Mamada SS, Salampe M, Bin Emran T, Winardi W, Fathima R, Sirinam S, Sittikul P. Monkeypox: a comprehensive review. Viruses. 2022; Sep 29; 14(10): 2155.

9. Di Gennaro F, Veronese N, Marotta C, Shin JI, Koyanagi A, Silenzi A, Antunes M, Saracino A, Bavaro DF, Soysal P, Segala FV. Human monkeypox: a comprehensive narrative review and analysis of the public health implications. Microorganisms. 2022; Aug 12;10(8): 1633.

10. McLean J, Stoeckle K, Huang S, Berardi J, Gray B, Glesby MJ, Zucker J. Tecovirimat treatment of people with HIV during the 2022 mpox outbreak: a retrospective cohort study. Annals of internal medicine. 2023; May;176(5): 642-8.

11. Magee WC, Hostetler KY, Evans DH. Mechanism of inhibition of vaccinia virus DNA polymerase by cidofovir diphosphate. Antimicrobial Agents and Chemotherapy. 2005; Aug; 49(8): 3153-62.

12. Mercer J. Vaccinia Virus. Springer New York; 2019.

13. El-Haddad D, El Chaer F, Vanichanan J, Shah DP, Ariza-Heredia EJ, Mulanovich VE, Gulbis AM, Shpall EJ, Chemaly RF. Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience. Antiviral Research. 2016 Oct 1; 134:58-62.

14. Detweiler CJ, Mueller SB, Sung AD, Saullo JL, Prasad VK, Cardona DM. Brincidofovir (CMX001) toxicity associated with epithelial apoptosis and crypt drop out in a hematopoietic cell transplant patient: challenges in distinguishing drug toxicity from GVHD. Journal of Pediatric Hematology/Oncology. 2018; Aug 1; 40(6): e364-8.

Received on 21.11.2024 Revised on 20.12.2024

Accepted on 11.01.2025 Published on 08.03.2025

Available online from March 12, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(1):52-58.

DOI: 10.52711/2321-5836.2025.00009

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.