|Year : 2019 | Volume
| Issue : 2 | Page : 101-104
Drug–drug interaction analysis: Antituberculosis drugs versus antiretroviral drugs
Won Sriwijitalai1, Viroj Wiwanitkit2
1 RVT Medical Center, Bangkok, Thailand
2 Department of Biological Science, Joseph Ayobabalola University, Ikeji-Arakeji, Nigeria
|Date of Submission||19-Mar-2019|
|Date of Decision||05-May-2019|
|Date of Acceptance||10-May-2019|
|Date of Web Publication||17-Jun-2019|
Dr. Won Sriwijitalai
RVT Medical Center, Bangkok
Source of Support: None, Conflict of Interest: None
Background: Human immunodeficiency virus (HIV) infection is an important public health globally. An important concomitant medical disorder among HIV-infected patients is tuberculosis. The management of concurrent infection between HIV and tuberculosis is usually difficult. The concomitant use of antituberculosis drug and antiretroviral drug is required. The important clinical pharmacological concern is on the possible drug–drug interaction. Methods: Here, the authors performed an informatics study. The standard drug–drug interaction analysis was done. The possible interaction between antituberculosis drug and antiretroviral drug is accessed, and the degree of severity is also predicted using a standard bioinformatics tool, drug interaction checker. Results: Several possible drug–drug interactions can be predicted through the bioinformatics analysis tool. The different degrees of interactions can be observed for different combinations between antituberculosis drug and antiretroviral drug. Conclusion: The drug–drug interaction between antituberculosis drug and antiretroviral drug is possible and can occur at various degrees. The monitoring of the concomitant use of drugs in each specific HIV-infected individual is necessary.
Keywords: Analysis, drug, human immunodeficiency virus, interaction, tuberculosis
|How to cite this article:|
Sriwijitalai W, Wiwanitkit V. Drug–drug interaction analysis: Antituberculosis drugs versus antiretroviral drugs. Biomed Biotechnol Res J 2019;3:101-4
|How to cite this URL:|
Sriwijitalai W, Wiwanitkit V. Drug–drug interaction analysis: Antituberculosis drugs versus antiretroviral drugs. Biomed Biotechnol Res J [serial online] 2019 [cited 2021 Jul 23];3:101-4. Available from: https://www.bmbtrj.org/text.asp?2019/3/2/101/260484
| Introduction|| |
Tuberculosis is a common infectious disease worldwide. Tuberculosis is caused by a pathogenic bacterium, namely Mycobacterium tuberculosis. This infection can result in chronic unexplained clinical problems of chronic cough and weight loss. The pathogen, M. tuberculosis, can cause a long-term clinical problem. The infected patients might be wasted and might finally die. As an important public health problem, the good management of tuberculosis by medical therapy is needed. At present, the gold standard for the treatment of tuberculosis is antituberculosis drug treatment.,
Tuberculosis is common among the groups of people with poor sanitation and low immunity. Of several groups of people, the patients with human immunodeficiency virus (HIV) infection become an important group affecting by tuberculosis. The tuberculosis is accepted as an important concomitant infection from HIV-infected patients. Tuberculosis is also an important leading cause of death for the HIV-infected patients., Due to the immune defect in HIV-infected patients, a patient can easily get concomitant infection including tuberculosis. At present, there is still no curative treatment for HIV infection. Nevertheless, the standard effective management of HIV infection is the antiretroviral therapy. At present, several antiretroviral drugs are available and proven effective in control of HIV infection. It is suggested that all HIV-infected patients should receive antiretroviral drug treatment for stabilizing of the disease. It is proven that the combined therapy by both antituberculosis and antiretroviral drugs is useful in the management of coinfection.
Since there is a change that there might be a concurrence between tuberculosis and HIV infections, it is required to search for the possible co-occurrence.,,,,,,,,, If there is a proof of coinfection, treatment for both medical problems is needed. Routinely, the use of both antituberculosis drug and antiretroviral drug treatments is required. Since the combination therapy means the use of several drugs, the chance of drug–drug interaction becomes an important consideration in clinical pharmacology. For HIV-infected patients with tuberculosis, the adverse effect due to the use of both antituberculosis drug and antiretroviral drug treatments is possible. It is no doubt that there might be an interaction. It is recommended for good drug section and closed monitoring for any patient requiring concomitant antituberculosis drug and antiretroviral drug therapies. However, there is no systematic analysis on the severity degree of possible interaction. Here, the authors performed a bioinformatics analysis for analyzing the possible interactions among antituberculosis and antiretroviral drugs.
| Methods|| |
Here, the authors performed an informatics study. As an informatics study, which does not deal with any human or animal subjects and clinical specimens, there is no requirement for written informed consent or ethical approval. The main of the present work is to clarify the interactions between antituberculosis drug and antiretroviral drug. The studied antituberculosis drugs include rifampicin, isoniazid, pyrazinamide, and ethambutol. The studied antiretroviral drugs include nevirapine, efavirenz, lamivudine, tenofovir, zidovudine, rilpivirine, stavudine, atazanavir, lopinavir, ritonavir, abacavir, darunavir, and raltegravir [Table 1]. All drugs are separately analyzed in the present study. No combination of drugs is analyzed. This is not a study on human or animal subjects and required no ethical approval.
The standard drug–drug interaction analysis was performed. The possible interaction between antituberculosis drug and antiretroviral drug was accessed accompanied with prediction of degree of severity of possible interaction. The work is based on standard bioinformatics tool, drug interaction checker, which is freely available online at https://www.webmd.com/interaction-checker. The tool is an informatics tool using computational approach for analysis, and the technique is purely in silico and not involves any patient, animal, or clinical specimen. The tool can help predict and clarify interaction between two drugs. The predicted results are (a) whether there is any interaction or not and (b) in case that there is an interaction, the interaction occurs at which degree (degrees of possible drug–drug interaction include 1 = minor, 2 = monitor closely, 3 = serious, and 4 = don't use together. N/A means no predicted interaction).
| Results|| |
The predicted drug–drug interaction between antituberculosis drug and antiretroviral drug is shown in [Table 2]. There are many possible drug–drug interactions, and there are also various degrees of identified interactions. For all studied antituberculosis drug, there is no predicted drug–drug interaction for ethambutol.
|Table 2: Predicted drug–drug interaction due to the concomitant use of antituberculosis drug and antiretroviral drug|
Click here to view
| Discussion|| |
Globally, HIV infection is still an important public health threaten. Several millions of HIV-seropositive patients reside around the world. HIV is still an exact public health burden presently. The management of HIV infection becomes important public health strategies for public health management in any country. The use of antiretroviral drug therapy is a basic important clinical practice. In addition, the management of concurrent medical disorder among HIV-infected cases is needed. Due to impaired immune status, there are several possible concurrent medical problems among HIV-infected patients. A possible important concurrent problem is tuberculosis infection. The tuberculosis is an important comorbidity among HIV-infected patients, and there is a requirement for good clinical management.,
The use of both antituberculosis and antiretroviral drugs is the basic clinical management of the patients with both HIV infection and tuberculosis. The advantage of disease control by the simultaneous therapy is confirmed., However, an important clinical issue that is widely discussed is the possible unwanted clinical problem due to the combining usage of both antituberculosis drug and antiretroviral drugs. The great concern is usually on the possible drug–drug interaction between antituberculosis drug and antiretroviral drug. In fact, the adverse effect of drugs usually increases when there are many drugs used at the same time for the management of the same patient. Conceptually, polydrug use is not recommended if there is no exact requirement. For the case of a patient with both HIV infection and tuberculosis, there is a need for the use of several drugs. Manosuthi et al. noted that adverse reactions to either antituberculous or antiretroviral drugs, as well as immune reconstitution inflammatory syndrome, are common in patients receiving integrated therapy by both antituberculosis and antiretroviral drugs. Manosuthi et al. suggested that “Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with tuberculosis.” The provision of enhanced monitoring of drug–drug interactions and adverse side effects are important concepts in the present integrated therapy by both antituberculosis and antiretroviral drugs for the patients with both infections.
In the present study, the interaction can be seen in many drugs, in both antituberculosis drug and antiretroviral drug groups. For example, many interactions are predicted for rifampicin. In fact, drug–drug interaction is well known in rifampicin use. Semvua et al. noted that “Rifampicin is a very potent enzyme inducer, which can result in subtherapeutic antiretroviral drug concentrations.” In addition, the hepatotoxicity due to the combination of rifampicin with other drugs is the common concern in clinical pharmacology. In a recent report from Nigeria, the rifampicin-related hepatotoxicity is strongly related with concomitant antiretroviral drug use. On the other hand, the drug–drug interaction induced by rifampicin also results in the requirement for antiretroviral drug dosage adjustment in efavirenz use. The result in the present informatics study is also concordant with the previous observation among the trials in real patients. According to a recent study, Naidoo et al. found that individual drug switched for toxicity occurred at incidence rate 2.1 per 100 person-years in HIV–tuberculosis coinfection receiving integrated therapy. Regarding antiretroviral drugs, several drugs can cause drug–drug interactions according to the present prediction. In a recent study from Malawi, the patients with concurrent HIV and tuberculosis receiving different antiretroviral drugs did not show a significant different in adverse effect rate, but there was an observation on a nonstatistical different rate among different drugs.
Based on the present study, the possible drug–drug interactions can be demonstrated. Several drugs might involve in possible interactions. Furthermore, some interactions are considered serious. Nevertheless, some drugs are considered safe. The selection of the proper concomitant therapy with antituberculosis and antiretroviral drugs is necessary. A more complex situation can be expected in case that there are other additional medical problems in the patients such as hepatitis virus infection. In case of concurrent HIV and tuberculosis infection plus hepatitis virus infection, additional drugs for the management of viral hepatitis might cause additional drug–drug interaction complicating the integrated therapy. Further researches on the more complex situations of combined HIV, tuberculosis, and other medical problems are recommended.
| Conclusion|| |
There is a possibility for drug–drug interaction between antituberculosis drug and antiretroviral drug. The interaction might occur at various severity degrees. The monitoring of concomitant use of drugs in each specific HIV-infected individual is necessary, and the specific concerns should be given in many cases receiving the combination with possible high severe drug–drug interaction. Several drug–drug interactions are predicted for rifampicin and isoniazid. The most severe interactions are predicted for rifampicin. Regarding antiretroviral drugs, lamivudine, tenofovir, zidovudine, rilpivirine, abacavir, stavudine, nevirapine, and stavudine have not predicted interaction.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Morrison JB. Natural history of segmental lesions in primary pulmonary tuberculosis: Long-term review of 383 patients. Arch Dis Child 1973;48:90-8.
Pai M, Behr MA, Dowdy D, Dheda K, Divangahi M, Boehme CC, et al.
Tuberculosis. Nat Rev Dis Primers 2016;2:16076.
Diedrich CR, O'Hern J, Wilkinson RJ. HIV-1 and the Mycobacterium tuberculosis
granuloma: A systematic review and meta-analysis. Tuberculosis (Edinb) 2016;98:62-76.
Diedrich CR, Flynn JL. HIV-1/Mycobacterium tuberculosis
coinfection immunology: How does HIV-1 exacerbate tuberculosis? Infect Immun 2011;79:1407-17.
Pau AK, George JM. Antiretroviral therapy: Current drugs. Infect Dis Clin North Am 2014;28:371-402.
Venturini E, Turkova A, Chiappini E, Galli L, de Martino M, Thorne C. Tuberculosis and HIV co-infection in children. BMC Infect Dis 2014;14 Suppl 1:S5.
Shankar EM, Vignesh R, Ellegård R, Barathan M, Chong YK, Bador MK, et al.
co-infection: A 'danger-couple model' of disease pathogenesis. Pathog Dis 2014;70:110-8.
Trinh QM, Nguyen HL, Nguyen VN, Nguyen TV, Sintchenko V, Marais BJ. Tuberculosis and HIV co-infection-focus on the Asia-pacific region. Int J Infect Dis 2015;32:170-8.
Frasca K, Cohn J. Integration of HIV and tuberculosis in the community. J Int Assoc Provid AIDS Care 2014;13:534-8.
Scott L, da Silva P, Boehme CC, Stevens W, Gilpin CM. Diagnosis of opportunistic infections: HIV co-infections – Tuberculosis. Curr Opin HIV AIDS 2017;12:129-38.
Gray JM, Cohn DL. Tuberculosis and HIV coinfection. Semin Respir Crit Care Med 2013;34:32-43.
Lessells RJ, Swaminathan S, Godfrey-Faussett P. HIV treatment cascade in tuberculosis patients. Curr Opin HIV AIDS 2015;10:439-46.
Tornheim JA, Dooley KE. Tuberculosis associated with HIV infection. Microbiol Spectr 2017;5. doi: 10.1128/microbiolspec.TNMI7-0028-2016. [Epub ahead of print].
Tiberi S, Carvalho AC, Sulis G, Vaghela D, Rendon A, Mello FC, et al.
The cursed duet today: Tuberculosis and HIV-coinfection. Presse Med 2017;46:e23-39.
Bruchfeld J, Correia-Neves M, Källenius G. Tuberculosis and HIV coinfection. Cold Spring Harb Perspect Med 2015;5:a017871.
Rabie H, Decloedt EH, Garcia-Prats AJ, Cotton MF, Frigati L, Lallemant M, et al.
Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis. Expert Opin Pharmacother 2017;18:589-98.
Manosuthi W, Wiboonchutikul S, Sungkanuparph S. Integrated therapy for HIV and tuberculosis. AIDS Res Ther 2016;13:22.
Sylla L, Bruce RD, Kamarulzaman A, Altice FL. Integration and co-location of HIV/AIDS, tuberculosis and drug treatment services. Int J Drug Policy 2007;18:306-12.
Semvua HH, Kibiki GS, Kisanga ER, Boeree MJ, Burger DM, Aarnoutse R, et al.
Pharmacological interactions between rifampicin and antiretroviral drugs: Challenges and research priorities for resource-limited settings. Ther Drug Monit 2015;37:22-32.
Isa SE, Ebonyi AO, Shehu NY, Idoko P, Anejo-Okopi JA, Simji G, et al.
Antituberculosis drugs and hepatotoxicity among hospitalized patients in Jos, Nigeria. Int J Mycobacteriol 2016;5:21-6. [Full text]
Maartens G, Boffito M, Flexner CW. Compatibility of next-generation first-line antiretrovirals with rifampicin-based antituberculosis therapy in resource limited settings. Curr Opin HIV AIDS 2017;12:355-8.
Naidoo A, Naidoo K, Yende-Zuma N, Gengiah TN, Padayatchi N, Gray AL, et al.
Changes to antiretroviral drug regimens during integrated TB-HIV treatment: Results of the SAPiT trial. Antivir Ther 2014;19:161-9.
Tweya H, Ben-Smith A, Kalulu M, Jahn A, Ng'ambi W, Mkandawire E, et al.
Timing of antiretroviral therapy and regimen for HIV-infected patients with tuberculosis: The effect of revised HIV guidelines in Malawi. BMC Public Health 2014;14:183.
[Table 1], [Table 2]
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