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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 95-100

Coinfection between human immunodeficiency virus and tuberculosis: A consideration on ritonavir-related heme Oxygenase-1 pathway

1 TWS Medical Center, Bangkok, Thailand
2 Department of Biological Science, Joseph Ayobabalola University, Ikejo-Arakeji, Nigeria

Date of Submission07-Mar-2019
Date of Decision05-May-2019
Date of Acceptance10-May-2019
Date of Web Publication17-Jun-2019

Correspondence Address:
Dr. Won Sriwijitalai
TWS Medical Center, Bangkok
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_50_19

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Background: Human immunodeficiency virus (HIV) infection is an important infection seen worldwide. HIV-infected patients usually have impaired immune function and get infected with other concurrent infections. Tuberculosis is a common concurrent infection in HIV-infected cases. The effect of coinfection and the response to the standard antiretroviral therapy in HIV-infected patients with concurrent tuberculosis infection is interesting. Methods: The aim of this study is to assess the effect of pharmacological pathway of ritonavir on tuberculosis treatment in HIV-infected patients with concurrent tuberculosis infection. The standard network pharmacology analysis is performed. Results: According to the network pharmacology analysis, the identified linkage is heme oxygenase-1. The ritonavir can result in increased expression of heme oxygenase-1 that further possible induces tuberculosis treatment failure in HIV-infected patients with concurrent tuberculosis infection. Conclusion: Ritonavir-related heme oxygenase-1 pathway is an important pathway that might affect the treatment of tuberculosis. Ritonavir dosage adjustment for tuberculosis treatment in HIV-infected patients with concurrent tuberculosis infection is necessary.

Keywords: Heme oxygenase-1, human immunodeficiency virus, ritonavir, tuberculosis

How to cite this article:
Sriwijitalai W, Wiwanitkit V. Coinfection between human immunodeficiency virus and tuberculosis: A consideration on ritonavir-related heme Oxygenase-1 pathway. Biomed Biotechnol Res J 2019;3:95-100

How to cite this URL:
Sriwijitalai W, Wiwanitkit V. Coinfection between human immunodeficiency virus and tuberculosis: A consideration on ritonavir-related heme Oxygenase-1 pathway. Biomed Biotechnol Res J [serial online] 2019 [cited 2022 Sep 27];3:95-100. Available from: https://www.bmbtrj.org/text.asp?2019/3/2/95/260482

  Introduction Top

Immune system is an important system of human beings. This system is a specific defensive mechanism of the human body against foreign body.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13] The immune system plays an important role for maintenance of normal physiological function and normal daily life. The disease of the immune system is also observable in clinical medicine, and this specific group of disease is called immune disease.[14],[15],[16],[17],[18],[19],[20] The immune disease is a specific kind of medical problem that requires good clinical management. Some diseases might be congenital, whereas others are considered acquired problems.[14],[15],[16],[17],[18],[19],[20] Since the immune system usually plays a role in disease defense, the disease of the immune system is usually difficult for management and becomes a big problem in clinical practice.

Human immunodeficiency virus (HIV) infection is an important infection seen worldwide. This infection is caused by a retrovirus which is known as HIV.[21] This viral infection is the present problem in clinical medicine. Due to the direct lymphocyte attack of the virus, the infection can result in immunodeficiency problem.[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] It is an important cause of acquired immunodeficiency disease. The infection has been detected for a few decades, but HIV infection becomes a very big public health problem of the world at present. Millions of HIV-infected patients are registered in several countries worldwide.

It is an important retrovirus infection that mainly affects the immune system of the patients and results in immunodeficiency. HIV can be transmitted through several modes including sexual contact, vertical transmission, and blood contact. Due to no curative therapy, HIV infection is still an important disease to be focused in global public health.[40] Rutstein et al. noted that implementation of antiviral treatment into existing health systems is essential for prospective management of HIV infection.[41] Rutstein et al. also noted that effective first-line regimens were very important.[41]

HIV-infected patients usually have impaired immune function and get infected with other concurrent infections. A common coinfection in HIV-infected patients is tuberculosis. Tuberculosis is a common concurrent infection in HIV-infected cases.[42] The effect of coinfection and the response to the standard antiretroviral therapy in HIV-infected patients with concurrent tuberculosis infection is interesting. Here, the authors focus interest on an important antiretroviral drug, ritonavir.[43]

  Methods Top

Aim of the study

The aim of this study is to assess the effect of pharmacological pathway of ritonavir on tuberculosis treatment in HIV-infected patients with concurrent tuberculosis infection. The standard network pharmacology analysis[44],[45],[46] is performed. Basically, the standard network pharmacology is a novel approach in pharmacology. This new approach in pharmacology is based on the advanced concept of biochemioinformatics. As a biochemioinformatic approach, the network pharmacology approach is an approach based on informatic manipulation aiming at clarifying or predicting for a complete question, which is hereby in the specific field of pharmacology.[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60] The approach is based on the concept of network analysis. Regarding network analysis, it is an informatic approach for grouping and rearranging of informatic data on pathways, which might be the cellular pathway or biochemical process. The mapping of the pathway data and searching for interrelationship for final construction of the web-linkage network for all included pathway data is the main process. This technique is accepted as a new useful for clinical pharmacology study. The technique was used in several previous international publications.[61],[62],[63],[64],[65],[66],[67],[68],[69]

Study design

Based on the already mentioned of network pharmacology analysis, the present study was performed. First, the authors identified the pharmacological pathway of ritonavir. Then, the interrelationship with pathophysiological pathway of tuberculosis was done. All identified pathways were from direct literature searching for standard international databases (PubMed and Scopus). Briefly, the network mapping was done to represent the interrelationship. At first, the authors firstly performed data mining by searching on mentioned international databases. The focus of the search is to identify the information regarding pharmacological pathway of ritonavir and the pathophysiological pathway. From the search, the reports with complete available data were included for further informatic analysis. From all recruited publications derived from searching, the data on pathways were extracted for usage in further step in network pharmacology analysis. Regarding the next step, the derived pathways were identified and rearranged. Clarification on all included pathways was done to identify the possible common linkage among the pharmacological pathways of ritonavir and the pathophysiological pathways. The identification of common node at the linkage for common position between pharmacological pathways of ritonavir and the pathophysiological pathways was finally done. Then, the finalized new network representing the common pathway was constructed to represent identified final interrelationship between pharmacological pathways of ritonavir and the pathophysiological pathways and written in the final diagram format in the last step.

Ethical issue

This study is a pure clinical pharmacoinformatic study that does not deal with human or animal subjects. It also does not involve a clinical specimen. Therefore, no written informed consent or ethical approval is required.

  Results Top

According to the network pharmacology analysis, the main identified pathways for pharmacological reaction of ritonavir involve heme oxygenase-1, interleukin-8, tumor necrosis factor-alpha, chemokine ligand 5, and monocyte chemotactic protein 1.[70],[71] From interrelation analysis with tuberculosis, the identified linkage is heme oxygenase-1 [Figure 1]. The ritonavir can result in increased expression of heme oxygenase-1 that further possible induces tuberculosis treatment failure in HIV-infected patients with concurrent tuberculosis infection.
Figure 1: Pharmacology network showing interrelationship between ritonavir pharmacological action and tuberculosis treatment

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  Discussion Top

At present, there are many important viral infections in clinical medicine. HIV is one of the most important clinical problems in the present day. HIV infection is a big public health problem.[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40] It is still highly endemic in several countries worldwide. As noted by Paraskevis et al.,[72] HIV is responsible for one of the largest pandemic diseases in human history and it is still the present global problem. Despite a concerted global response for prevention and treatment, HIV infection is still the problem in many countries. HIV medicine research is required for the prevention of future transmission events.[72] It is also a critical point for successful eliminating HIV.[72] In the present day, HIV infection is still a big medical disease to be further studied. HIV medicine is an important issue in medicine that deals with HIV. The complex immunodeficiency status is the main clinical problem that has never been successfully managed until present. The diagnosis, treatment, and prevention of HIV are all the important issues in clinical medicine.

Due to the impairment of the immune system, there are several clinical problems due to the defect. Several diseases are seen in HIV-infected patients with defective immune status and those diseases are usually hard to manage.[40] The possible diseases in HIV-infected patients might be diseases caused by several kinds of pathogens including bacteria, virus, fungus, and parasite.[32],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86] Furthermore, the abnormal immune system might result in uncontrolled tumorigenesis and cancer.[88],[89],[90],[91] Regarding infectious diseases, both opportunistic and nonopportunistic infections are observable in HIV-infected cases. The linkage to the immunodeficiency status is usually mentioned in clinical literature. In routine clinical management of HIV-infected patients, the medical practitioner has to concern about the coinfection problem.[32],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91]

A good example of coinfection seen in HIV-infected patients is the coinfection between HIV and tuberculosis. Basically, tuberculosis is a bacterial infection. The causative agent of tuberculosis is a mycobacterial pathogen, Mycobacterium tuberculosis. The tuberculosis is still an important public health problem globally. The infection can cause chronic lung infection. The patients with pulmonary tuberculosis might have some chronic pulmonary problems such as chronic cough and hemoptysis. The chronic fatigue and weight loss are also common clinical presentations in the patients infected with M. tuberculosis. At present, tuberculosis is still an important public health problem in several countries around the world, and there are numerous patients with tuberculosis. Tuberculosis can be seen in both immunocompromised and immunocompetent hosts. However, the problem usually exists in immunocompromised host such as HIV-infected patients.

The coinfection between HIV and tuberculosis is common.[40],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101] HIV infection and tuberculosis can affect the health of the patients. The concurrence of the two diseases might cause an increased clinical problem, and there might be additional pathology contributing as an effect of one another.[102],[103],[104],[105] Regarding this concurrent infection problem, Tabarsi et al. studied the treatment outcome and mortality among HIV/tuberculosis-coinfected patients from Iran and concluded that the administration of antiretroviral therapy led to a better outcome.[106] Indeed, antiretroviral therapy is the standard clinical management for HIV-infected patients.[107],[108],[109],[110],[111],[112],[113],[114],[115] The antiretroviral therapy is aimed at the reduction of viral load that can be useful in control of immune impairment in the patients. It is usually difficult to manage these patients. Parallel treatment for both diseases is required, and the problem might be sometimes seen. Decloedt et al. recently studied the safety, effectiveness, and concentrations of adjusted lopinavir/ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy and found that several factors including pregnancy, productive age group, gender, contraception, and comorbidity diseases were associated with treatment outcome.[116] Mirsaeidi and Sadikot noted that host-specific factors play an important role in determining treatment outcome.[117] Hence, it is necessary to have in-depth studies on the biological pathways involving in treatment process.

At present, there are several antiretroviral drugs that can be used in the management of HIV-infected patients. Ritonavir is a drug that is widely used at present. It is also proposed as an effective safe drug for the management of HIV-infected cases with concurrent tuberculosis.[118] Amani-Bosse et al. noted that ritonavir antiretroviral therapy could result in effective virological response, but the important problem was adherence of HIV-infected patients to the antiretroviral drug use.[119] Simpson et al. also showed the cost-effectiveness of using ritonavir antiretroviral therapy.[120] Nevertheless, the important problem on the use of ritonavir in HIV-infected patients with tuberculosis is also observable. In the previous report, it can be observed that rifampin in tuberculosis treatment can alter the effectiveness of ritonavir antiviral therapy and it results in requirement for double dosing.[70] In the present study, the network pharmacology analysis can show an opposite finding. It can show that the ritonavir treatment might also result in difficulty in tuberculosis treatment. According to the common pathway search, a common node at heme oxygenase-1 pathway can be observed.

The increased heme oxygenase-1 expression due to ritonavir use can further affect the tuberculosis treatment.[69] Increased heme oxygenase-1 expression is related with tuberculosis treatment failure.[71] On the other hand, the inhibition of heme oxygenase-1 expression results in suppression of the tuberculosis pathogen.[121] The inhibition directly affects survival in human macrophage during pathogenic mycobacterial infection.[122] As noted by Rockwood et al., M. tuberculosis induction of heme oxygenase-1 expression is dependent on oxidative stress.[71] The heme oxygenase-1 expression is also accepted as a good biomarker for successful therapy in tuberculosis[123] or HIV–tuberculosis infection.[71] Indeed, the finding in the present study can confirm the statement proposed by Singh et al. that heme oxygenase-1 plays an important role in pathophysiology of several infections including HIV and tuberculosis.[124]

This observation that ritonavir should be carefully used in the management of HIV-infected patients with concurrent tuberculosis infection. Adding to the already known inference effect of antituberculosis treatment on the effectiveness of antiretroviral therapy,[107],[108],[109],[110],[111],[112],[113],[114],[115] the antiretroviral therapy can also affect the tuberculosis treatment on another side of the coin.

In case with HIV-infected patients with concurrent tuberculosis infection, the other antiretroviral drug rather than ritonavir might be more appropriate.

  Conclusion Top

According to the present study, it reveals that ritonavir-related heme oxygenase-1 pathway is an important pathway that might counteract the effectiveness of tuberculosis treatment. This is a reason for requirement for adjustment for tuberculosis treatment in HIV-infected patients with concurrent tuberculosis infection.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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1 Biochemical value dynamics in patients with multidrug-resistant tuberculosis/hiv with CD4+ lymphocyte cells below 50 cells/µCL and its variability in the application of adjuvant immunoglobulin therapy
NinaA Matsegora,AntoninaV Kaprosh,PetroB Antonenko
International Journal of Mycobacteriology. 2019; 8(4): 374
[Pubmed] | [DOI]


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