Acyclovir is broadly used for the treatment of herpes virus infections particularly those caused by herpes simplex virus (HSV) and varicella zoster virus (VZV). It is prescribed to treat the symptoms of herpes virus infections (infections of sex organs, skin, brain, and mucous membranes), shingles, and chickenpox. Acyclovir also treats the widespread herpes virus infections in newborns and prevents recurrent genital herpes infections.
Acyclovir Overview
Acyclovir treats and prevents herpes infections, chickenpox, and shingles. This drug does not cure herpes infections but effectively treats pain and other symptoms, allowing the infection to clear up rapidly. In the case of chickenpox and shingles, Acyclovir reduces the infection-associated pain and heals the sores and blisters faster.
In this article, we will shed light on the mechanism of action and resistance of Acyclovir, so keep reading.
Overview of Viral Resistance and its Significance
Viral resistance is when a virus modifies and becomes resistant to an antiviral drug making it difficult to treat. It happens when a virus obtains a gene mutation that modifies the viral DNA polymerase or diminishes the activity of thymidine kinase (TK).
How it happens?
The process of virus replication involves a high mutation rate and random mutation takes place in the viral genome as it infects cells. When these mutations gather, the original virus can be destroyed through antiviral methods however mutated forms of the virus can survive.
How does viral resistance affect treatment?
Resistant viruses can still cause major diseases, however, they are usually not as infectious as wild-type viruses. Treatments fail when the resistant virus replicates more proficiently and turns out to be the predominant virus in the host’s body.
Diagnosis and treatment
Antiviral resistance testing can diagnose genetic mutations that lead to resistance. Treatment of resistant viruses necessitates an alternate agent with a different mechanism of action.
It is extremely important to be aware of viral resistance because it can have both pros and cons. The purpose of this article is to explain the viral resistance thoroughly. Now, you must be thinking about why is it important to understand viral resistance. So let us tell you why:
Treatment failure
Viral resistance can lead to treatment failure allowing the disease to progress and even make the symptoms worse and difficult to treat.
Medical expenses
Due to viral resistance, your healthcare provider needs to extend the course of treatment which could be more expensive.
Mechanism of Action of Acyclovir
Acyclovir triphosphate obstructs viral DNA polymerase by behaving as an analog to deoxyguanosine triphosphate (dGTP). Integrating Acyclovir triphosphate into DNA leads to chain termination since the absence of a 3’hydroxyl group stops the attachment of additional nucleosides.
How Acyclovir Works Against Viral Infections (HSV, HZV)
Acyclovir is a nucleoside analog that impedes the replication of herpes simplex virus type 1 and type 2 and varicella zoster virus. It is converted to Acyclovir monophosphate by virally-encoded thymidine kinase after intracellular uptake.
This process does not take place at any significant level in uninfected cells, which is why it offers specificity to the drug’s activity. Subsequently, the monophosphate derivate is converted to Acyclovir triphosphate by cellular enzymes.
Acyclovir triphosphate holds a much higher attraction for viral DNA polymerase than for the cellular homolog yielding an enhanced therapeutic ratio.
Understanding Acyclovir Resistance
Acyclovir resistance happens in the case of herpes simplex virus infection when the virus develops mutations in its DNA polymerase or thymidine-kinase genes. The resistance can be recognized through genotyping, phenotyping, or clinical observation.
Mechanisms of Resistance in Viruses
Acyclovir resistance occurs due to the procurement of mutations in the UL23 genes encoding for the viral TK and the UL30 gene encoding for the DNA pol. Usually, Acyclovir-resistant HSV infections are associated with mutations in the TK gene.
Antiviral drug-resistant strains have specific mutations in the reverse transcriptase domains of the viral polymerase gene with most replacements happening in domains B, C, and D. Resistant mutations modify the communication between HBV polymerase and antiviral drug.
Resistance prevalence
Acyclovir resistance is uncommon in immunocompetent patients but very common in immunocompromised patients. For instance, the prevalence of Acyclovir resistance is usually less than 1% in immunocompetent patients however it can range from 3.5 to 10% in immunocompromised patients.
Treatment
Alternative medications such as Cidofovir can be prescribed to treat Acyclovir-resistant HSV infections. These medicines work in a different manner than Acyclovir thus they are effective against Acyclovir-resistant strains.
Clinical impact of resistance
Acyclovir-resistant herpes virus infection can give rise to several mucosal diseases and visceral dissemination.
Factors contributing to resistance
Acyclovir resistance is common in immunocompromised patients who usually necessitate long-term anti-HSV treatment. Acyclovir resistance in herpes infections can be caused by mutations in the viral TK and DNA polymerase genes:
TK mutations
These mutations can cause a loss of TK activity (TK-deficient) or modification in TK substrate specificity (TK-altered).
DNA polymerase mutations
These mutations can extract HSV strains resistant to Acyclovir even when maintaining a TK-positive phenotype.
Clinical Implications of Acyclovir Resistance
Acyclovir resistance is a significant problem with herpes simplex virus. Although acyclovir is a common treatment option for herpes virus infections, certain patients may develop resistance to this drug. Resistance can happen due to mutations in the viral thymidine (TK) or DNA polymerase genes, as mentioned above.
Impact on Treatment Outcomes
Acyclovir resistance is more common in immunocompromised patients including those who received a transplant or infected with HIV. Some common risk factors for Acyclovir resistance include ongoing viral replication, immunosuppression, suboptimal Acyclovir dosing, and Long-term Acyclovir prophylaxis.
Associated Complications and Morbidity
Acyclovir resistance may lead to severe complications including debilitating mucosal disease and visceral dissemination. Patients who develop antiviral resistance to a virus can transmit it to other people through direct contact with blood, saliva, and semen.
Pregnant females can also pass antiviral-resistant viruses to their babies during childbirth. In case of transmitted resistance, a virus is already resistant to certain antivirals even if you have never taken those drugs. Your healthcare provider needs to prescribe other antiviral drugs.
Acyclovir Resistance can have many clinical implications such as:
Disease obstinate to antiviral treatment. In the case of immunocompromised patients, Acyclovir resistance can cause disease that does not respond to antiviral therapy.
Adverse effects of alternative medications. Alternative medications including Foscarnet sodium and Cidofovir can have adverse effects (eg. kidney function compromise).
Cross-resistance to other antiviral medicines. Acyclovir-resistant strains of the virus can also be resistant to other antiviral drugs which can complicate the treatment process.
Importance of Susceptibility Testing for Acyclovir Resistance
Susceptibility testing is vital as it can improve the management of patients suffering from herpes virus infections who are not responding to Acyclovir therapy.
- It can help guide therapy by recognizing alternative antiviral medicines that might work effectively.
- Quick detection of Acyclovir resistance allows medical professionals to offer better individualized antiviral treatment.
- Acyclovir resistance may cause severe disease, particularly in immunocompromised patients and susceptibility testing can prevent these serious diseases.
Some well-known tests for detecting HSV susceptibility to Acclovir include:
- Plaque reduction assay (PRA)
- Viral cytopathic effect reduction assay (CRA)
- Dye uptake method (DUA)
- DNA hybridization assay
Typically Acyclovir-resistant isolates are susceptible to an Acyclovir concentration of greater than or equal to 2-3 µg/mL. However, there is no clear compromise on in vitro susceptibility that signifies a drug-resistant virus. Real-time cell analysis (RTCA) based methods could be a less labor-intensive alternative for phenotypic testing in the case of Acyclovir resistance.
Identifying Resistance
If your symptoms do not improve or you are not feeling better after you finish the prescribed course of Acyclovir, talk to your doctor. In case your symptoms become severe during the treatment, it’s time to seek your doctor. Acyclovir-resistant herpes infection is more common among HIV-infected patients.
Role of Laboratory Testing
For HIV-infected patients, a blood test can detect antiviral resistance. Genotypic antiretroviral resistance test finds drug-resistant alterations in HIV genes. Phenotypic antiretroviral resistance test recognizes how HIV strains act to various concentrations of antiviral medicines.
Diagnostic methods for detecting resistance
Acyclovir resistance in HSV can be diagnosed by:
Clinical observation:
A lack of clinical response to Acyclovir therapy within a week of beginning therapy may signify drug resistance.
Phenotyping:
The phenotyping test measures the amount of Acyclovir concentration that constrains the growth of the virus in cell culture. The test detects the inhibitory drug dose concentration. Acyclovir sensitivity is defined as IC50 < 2µg/mL and resistance as IC50 ≥ 2µg/mL.
Genotyping:
Acyclovir resistance can be due to mutation in the viral TK gene or DNA polymerase gene. Genotyping test identifies certain mutations associated with drug resistance.
Sanger sequencing:
It detects mutations in the Thymidine Kinase gene of herpes simplex virus that may be responsible for a reduced or no response to Acyclovir.
HSV resistance testing:
It determines if cultured herpes simplex virus isolates are susceptible to Acyclovir medication.
Management of Acyclovir Resistance
Acyclovir resistance can be managed and treated with various treatment strategies.
Treatment strategies for resistant infections
When a virus indicates signs of developing resistance to the antiviral, your doctor may increase the dose or prescribe a different antiviral drug. Your healthcare provider may also administer high-dose IV Acyclovir. Some viruses have a limited number of approved antiviral treatments available.
Alternative Antiviral Therapies
Once the Acyclovir resistance is detected, alternative medications can be prescribed to treat the infection. Antiviral medications to treat acyclovir-resistant HSV include:
- Foscarnet (a direct inhibitor of virus DNA polymerases)
- Cidofovir (Alternative drug to guanosine-analog drugs)
- Brincidofovir (viral polymerase inhibitor)
- Valomaciclovir (viral polymerase inhibitor)
- N-methanocarbathymidine (a viral polymerase inhibitor)
- Pritelivir (inhibitor of helicase primase complex)
- Amenamevir (inhibitor of helicase primase complex)
Importance of Combination Therapy
Combination therapy involves combining two or more medications into a single treatment. It is considered a significant treatment because it can effectively improve patients’ health and provide other benefits. Combination therapy is used to treat various diseases, such as hypertension, cancer, and many fungal and bacterial infections.
Better patient outcomes:
Combination therapy can synergistically target multiple condition pathways, improving outcomes. For instance, combining anti-cancer medications can improve efficacy compared to using a single medication.
Reduced disease resistance:
Combination therapy can significantly reduce disease resistance to drugs, meaning the medicines may work longer.
More effective than a single drug:
Combination therapy can be more effective than using a single medicine. For instance, hypertension treatment using a combination of two different classes of antihypertensive agents can target blood pressure in more than 70% of patients.
Enhanced compliance:
Combination therapy can improve patient amenability. For instance, a single-pill combination may ease the psychological and financial distress of taking multiple pills a day.
Improved tolerability:
Combination therapy can be better tolerated than using a single medicine. For instance, combining small doses of two medicines can have fewer side effects than using large doses of one medicine.
Prevention of Resistance
Make sure you follow the guidelines for the appropriate use of Acyclovir as provided by your doctor or healthcare professional. Do not miss or skip any doses during the treatment. Never use this drug more often or for longer than the prescribed period until your doctor advises.
If your doctor has prescribed you Acyclovir tablets, capsules, or oral suspension, do not forget to drink plenty of water throughout the treatment to prevent dehydration. If you have any questions or confusion concerning the proper use of Acyclovir, talk to your healthcare provider for the best advice.
Importance of adherence to prescribed regimens
It is highly important to adhere to the prescribed regimens as it can save you from developing drug resistance. Inappropriate use of Acyclovir can be the reason for developing Acyclovir resistance.
To prevent Acyclovir resistance you should:
- Take the correct dose of your medicine exactly as directed by your healthcare provider.
- Use an adequately high dose of Acyclovir to prevent resistance.
- Take antiviral prophylaxis (oral Acyclovir or Valacyclovir) as a prophylactic to prevent the reactivation of herpes simplex virus.
Monitoring and follow-up strategies
It is advised to check your U&E, LFT, and FBC at baseline. If found normal, no further monitoring is required. If considerable low eGFR, leucopenia, or elevated LFTs are diagnosed, either reduce the dose or stop using Acyclovir and let the medical professional investigate.
Future Directions and Research
Acyclovir resistance-based studies have been performed to evaluate the prevalence of resistance in herpes virus infections and to find out the ways for the treatment of Acyclovir-resistant HSV. Studies signify that Acyclovir resistance is infrequent in immunocompetent patients which is 0.1 to 0.6%. On the other hand, in immunocompromised patients, the prevalence is much higher which is around 4-7%. Infections of immune-privileged sites including cornea are more likely to develop Acyclovir resistance.
Recent research findings on viral resistance mechanisms:
Viruses become drug-resistant through random point mutations. These mutations alter the interaction between the viral polymerase and the drug or cause downstream structural alterations that meddle with the inhibitory effect of the drug.
Viruses with segmented genomes can also become resistant through genetic reassortment. Genetic barrier enhancement can delay the resistance to antiviral drugs. It can be done using drug combinations that target various major virus enzymes.
Using antivirals that target host proteins instead of viral proteins can help prevent resistance. Nevertheless, this approach may also lead to undesirable toxicity.
Conclusions
Antiviral resistance develops when a virus stops responding to an antiviral drug. The virus modifies making the drug less effective or even completely ineffective. When a virus develops antiviral resistance it is difficult to treat. Patients who take antiviral drugs for the treatment of chronic viral infections such as herpes and HIV are at risk of experiencing antiviral resistance. The resistance can be prevented by taking the antiviral medications exactly as guided.
Awareness of drug resistance can help patients understand the importance of taking their medications as prescribed. Antiviral resistance can be a serious problem if you are not aware of it. When you are aware you can prevent or manage the resistance more efficiently.
