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www.wjpps.com Vol 9, Issue 9, 2020. 913

HUMAN IMMUNODEFICIENCY VIRUS ASSOCIATED

TUBERCULOSIS

Sereena Saju1, PharmD*, A.S. Ezhilarasi1, PharmD, Mancy Jose Mattam1, PharmD, Mehnaaz Anjum. H1, PharmD, M. Vani2, M. Pharm., Ph.D., Meena3, M. Pharm., Ph.D.

1

PharmD Interns, the Tamil Nadu Dr. M.G.R. Medical University, Chennai – 600122.

2

Professor, the Tamil Nadu Dr. M.G.R. Medical University, Chennai – 600122.

3

Principal, K.K. College of Pharmacy, the Tamil Nadu Dr. M.G.R. Medical University, Chennai – 600122.

ABSTRACT

The association of tuberculosis (TB) with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) over the past many years has become a rising syndemic. Co-infection with HIV provokes challenges in identification and treatment of tuberculosis. Further, there has been a rise in rates of drug resistant TB, including multi-drug resistant TB (MDR-TB) and extensively drug resistant TB (XDRTB), which poses a troublesome in treatment thus, contributing to increased mortality. HIV complicates every aspects of TB including presentation, diagnosis and treatment. HIV-TB coinfected patients encounters distinctive issues like drug–drug

interactions, additive toxicity, lower plasma drug levels, suboptimal adherence and emergence of drug resistance, particularly immune reconstitution inflammatory syndrome (IRIS). Moreover, poor performance of sputum smear microscopy resulted in inadequate diagnosis of HIV-infected patients, newer diagnostic measures are urgently needed that not only seem to be solely sensitive and specific, however, easy to use in remote and resource-constrained settings. Linkage of co-infected patients to antiretroviral treatment centres is crucial if early mortality is to be prevented. This review focuses on the epidemiology, etiology, pathophysiology, clinical aspects, diagnosis of HIV-associated TB and summarizes World Health Organisation (WHO) recommendations for treatment.

Volume 9, Issue 9, 913-929 Review Article ISSN 2278 – 4357

Article Received on 30 June 2020, Revised on 20 July 2020, Accepted on 10 August 2020 DOI: 10.20959/wjpps20209-17062 *Corresponding Author

Sereena Saju, PharmD

PharmD Interns, the Tamil Nadu Dr. M.G.R. Medical University, Chennai – 600122.

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www.wjpps.com Vol 9, Issue 9, 2020. 914 KEYWORDS: Co-infection, Xpert MTB Rif, tuberculous granulomas, antiretroviral therapy, drug resistance, infection control.

INTRODUCTION

Tuberculosis (TB) is the most common cause of death among individuals living with HIV, accounting for about one in three AIDS-related deaths globally.[1] The risk of eventually developing active TB from latent TB infection is about 10% per year in HIV‑positive patients in contrast to 10% lifetime risk in HIV‑negative patients. HIV‑positive patients with TB are more likely to have extra‑pulmonary, atypical, and unique clinical and radiological presentations. Furthermore, TB is harder to diagnose and, therefore, progresses more rapidly in the HIV‑positive population.[2,3]

Although the initiation rates of HIV-positive TB patients to Antiretroviral therapy (ART) are improving case fatality continues to be steep compared to HIV-negative TB patients. The chief rationale for this difference may include delays in bacteriological detection of HIV-associated TB, enrolment into ART care or immediacy of ART initiation. Diverse population poses group-specific challenges in response to detection and treatment. Other challenges exist in overcrowded settings such as mines, prisons, homeless shelters, and opioid substitution therapy centres. Social issues, including poverty, are warped into the fabric of clinical course of HIV–MTB coinfection.[4]

According to WHO, initiation of Highly Active Antiretroviral Therapy (HAART) at CD4 T-cell count ≤ 350/μL should be followed strictly to prevent TB or other opportunistic infections.[5] Nonetheless, coadministration of ART along with anti-TB therapy presents several management challenges including drug-drug interactions, overlapping drug toxicities and Immune Reconstitution Syndrome (IRS).

Epidemology

HIV stands out as the most potent risk factor for TB. HIV-infection increases the risk of TB 20-fold as compared to HIV infected patients, resulting in public health emergencies. According to the WHO, in 2015, there were an estimated 10.4 million people infected with TB globally, out of which, 1.2 million [11%] people are infected with HIV. While, 60% [57%] of TB cases among HIV-infected people were not diagnosed or treated, resulting in 3,90,000 TB-related deaths among people living with HIV in 2015.[6]

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www.wjpps.com Vol 9, Issue 9, 2020. 915 India has a very high burden of TB and ranks foremost among opportunistic infections i.e. 2.5 million people infected with HIV. Of these, 40% suffer coinfection with TB as per WHO datas. Preliminary datas from five southern African countries of Zimbabwe, South Africa, Lesotho, Swaziland, and Botswana, annual TB incidence and resultant caseloads have increased enormously from past 20 years, shifting TB from a relatively stable public health problem to a crisis.[7] In 2015 WHO report, out of 47 African countries, 30 countries reported ≥75% of TB patients had documented HIV test in which 23 achieved levels of ≥90% (Fig.1).[8]

The 2016 United Nations Political Declaration on Ending AIDS, targeted to reduce TB-related deaths among people living with HIV by 75% by 2020. Moreover, all countries belonging to WHO and the United Nations have united to end TB as a public health problem by 2030. To achieve this goal, the rate of deaths associated with TB must reduce by 90% and incidence of active TB by 80% from 2015 levels. However, progress towards ending TB is slow, and persistent gaps in preventing, diagnosing and treating TB still remains.[9]

These epidemiological datas have led to a heightened concern about the revival of TB as a major public health problem, posing a serious threat to control programmes worldwide.

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www.wjpps.com Vol 9, Issue 9, 2020. 916

(Reproduced from Who’s global tuberculosis report 2015 by permission of the World Health Organization)

Etiology of hiv-tb coinfection

Most cases of human TB are caused by the human tubercle bacillus, Mycobacterium tuberculosis (M. tuberculosis), but in countries where cattle tuberculosis persists, human tuberculosis is also caused by M bovis. Infection usually develops by inhaling small droplets of cough aerosol, about 5µ in diameter, containing tubercle bacilli and can also be acquired by drinking infected milk resulting in occurrence of primary lesions in the pharynx or intestine. Rarely, infection occurs by traumatic inoculation of bacilli into the skin, particularly in butchers and others handling the carcasses of tuberculous animals.[10]

TB in high-burden countries parallels the HIV epidemic, with young women and men bearing the brunt. Several sociodemographic and clinical factors, including smoking, have been linked to TB (Table 1).[11] Male gender is reported to be positively correlated with TB infection than females at a ratio of 2:1. HIV–TB coinfection is more common in adults with an average age of 33–45 years. Other demographic factors such as single status, low socioeconomic and income status, compromised sanitation, poor access to healthcare and lack of education negatively impact outcomes with higher incidence of mortality in such patients.[12]

Moreover, immunocompromised states, such as those receiving anti-tumor necrosis factor treatment, corticosteroids, dialysis, organ, or hematologic transplantation or those with silicosis, may be more predisposed to HIV–MTB coinfection due to activation of latent TB infection.[13]

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www.wjpps.com Vol 9, Issue 9, 2020. 917 Table 1: Factors associated with tuberculosis in hiv-infected individuals.

Characteristics Associated with Increased Risk of Tuberculosis

Characteristics Associated with Decreased Risk of Tuberculosis

1. Sociodemographic factors 1. Clinical factors

 High body mass index

 Higher CD4 cell count

 Low or undetectable viral load 2. Residence in high prevalence area

3. Work or residence in institutions with high prevalence

4. Recent exposure to infectious case 2. Treatment factors

 Isoniazid or other preventive therapy

 Antiretroviral therapy 5. Tobacco Smoking*

6. Clinical factors

 Lower body mass index

 Latent tuberculosis infection

 Silicosis

 Lower CD4 cell count

 High HIV viral load

* Putative risk extrapolated from HIV-seronegative populations Clinical manifestations

Pulmonary disease: The most common manifestation of TB is pulmonary (Koch‘s) disease exhibiting as prolonged cough for more than 2 weeks, haemoptysis, fever, weight loss and night sweats. In addition, HIV-infected patients with TB (advanced) and low CD4+ T lymphocyte counts are less likely to have cavitary pulmonary disease than are HIV-uninfected patients with TB, and approximately 22% of HIV co-infected persons with pulmonary TB, presents with normal chest radiograph findings.

Smear-negative pulmonary disease: As sputum smear is the principal means of detecting TB in much of the world, smear-negative patients often do not receive a diagnosis and are often not treated promptly, if at all. The mortality rate is higher among such patients than among HIV-infected patients with smear-positive TB (because of delays in TB diagnosis in the former) and higher than among HIV-infected persons with smear-negative TB (because of HIV infection).

Subclinical disease: The history of subclinical TB in HIV infected persons is not well understood. Unlike individuals without HIV infection, in whom TB may be a chronic, low grade condition, persons with HIV infection almost always experience progression of TB disease, ultimately leading to death in the absence of effective treatment. Thereby, subclinical TB may represent the early stages of the disease that will inevitably progress to overt illness.

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www.wjpps.com Vol 9, Issue 9, 2020. 918 Extrapulmonary disease: The liability of extrapulmonary TB increases with lower CD4+ T lymphocyte count. The most common forms of extrapulmonary disease includes lymphatic and pleural, but almost any site can be involved, including the bone and/or joint (particularly the thoracic spine), soft tissue (e.g., psoas muscle, which may be associated with spinal disease), central nervous system, and pericardium.[14]

Pathophysiology of hiv-tb coinfection

TB infection is a result of coaction of bacterial virulence and host resistance. The infection emerges through inhalation of air droplets containing approximately 1–200 bacilli from an individual with active Mycobacterium Tuberculosis (MTB), thus provoking cascade of inflammatory events followed by tuberculous granulomas (in particular TNFα) as depicted in (Fig. 2).[15] This process occurs with increased HIV viral load in the blood, which aids in severe immunosuppression. Therefore, the risk of death in HIV-infected patients with TB is twice that in HIV-infected patients without TB with comparable CD4 cell counts.

TB is caused by Mycobacterium tuberculosis complex, primarily M. tuberculosis (Koch‘s bacilli) & rarely, M. bovis or M. africanum. After penetration into respiratory tract, these bacilli infect macrophages

CD4+ T-lymphocytes & Tϒ8-lymphocytes produce Interferon-ϒ (INF-ϒ), Interleukin-2 (IL-2), Tumor Necrosis Factor (TNF-ꭤ) & Macrophage Colony Stimulating Factor

Activation of macrophages & cytotoxic cells to inhibit their intracellular growth

TB appears when immune response inducing granuloma is insufficient to limit the growth of mycobacteria. INF-ϒ plays a crucial role at this stage.

People with decreased IFN-ϒ develops severe & fatal TB

During HIV infection, INF-ϒ production gets reduced in association with decreased CD4+ T-lymphocytes.

Increased risk of developing reactivation or reinfection by M. tuberculosis in HIV patients Fig. 2: Pathophysiology of hiv-tb Co-infection.

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www.wjpps.com Vol 9, Issue 9, 2020. 919 Diagnosis of tb in hiv- infected patients

In view of the problems encountered in the clinical diagnosis of tuberculosis, various efforts have been forwarded in the development of rapid and sensitive diagnostic tests as mentioned in the following.

Clinical screening algorithms: In 2007, WHO International Expert Committee issued new guidelines to improve the diagnosis of TB in HIV infected individuals. It was advocated that screening for TB should not only include asking questions about a combination of symptoms rather than only about chronic cough. A recent meta-analysis depicts that the presence of any one of current cough, fever, night sweats or weight loss was best performing rule. The reversal of chronic cough with current cough is the only change to existing practice as a screening question and the addition of other symptoms to ideal screening.

Radiographic features: In the initial stage of HIV disease, when individuals are not immunosuppressed, the classic pattern of pulmonary reactivation occurs with the chest x-ray depicting cavitary apical disease of the upper lobes. With advancing immunosuppression, extra pulmonary involvement, intra-thoracic/mediastinal lymphadenopathy, lower lobe infiltrate and miliary TB becomes more common. Chest X-ray can still drop a substantial proportion of individuals with sub-clinical disease, often seen in advanced HIV immunosuppression. However, this sub-population of co-infected individuals is likely to be aided from sputum culture or nucleic acid amplification tests for TB diagnosis.

Sputum smear microscopy: The most conventional method of pulmonary TB detection in HIV co-infected persons involves examination of at least two sputum specimens, including one early-morning specimen, for acid-fast bacilli (AFB). Although the sensitivity of sputum microscopy in HIV infection is low, i.e. ranging from 43 to 51 per cent. Fluorescence microscopy, light emitting diode microscopy, alternative specimen processing methods, such as concentration, bleach sedimentation and same-day sputum collection (front loading) strategies increase the sensitivity of sputum microscopy from 59 to 93 % in the detection of pulmonary TB in HIV co-infected persons.

Culture-based detection: Culture of MTB is much more sensitive than smear microscopy and has been recommended in the diagnosis of TB in HIV-infected individuals. The process of replication of M. tuberculosis via solid media cultures is slow, requiring 2-8 weeks for the growth of millions of organisms to generate visible colonies, which can be accelerated by

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www.wjpps.com Vol 9, Issue 9, 2020. 920 automated liquid culture systems, revealing the growth of mycobacteria within 1-2 weeks by bacterial carbon dioxide production or oxygen consumption with various sensors such as radiometric sensors, fluorescent sensors, colorimetric sensors, pressure sensors, or redox reagents, such as Alamar blue.

The Microscopic Observation Drug-Susceptibility (MODS) assay is a simple, rapid, low-cost method for diagnosis of TB and MDR-TB; MODS provided high sensitivity and specificity for rapid diagnosis of TB and MDR-TB, endorsed by WHO in 2009 for use as an interim solution in resource constrained settings. There are currently multiple rapid diagnostic technologies in progress, such as recombinant mycobacteriophages, and colorimetric culture system using TK medium culture system.

Molecular detection: Commercially available and several ‗in house‘ nucleic acid amplification (NAAT) tests have a high specificity and sensitivity in smear-positive sputum for M. tuberculosis. Moreover, sensitivity in smear-negative TB and disseminated TB has tended to be moderate, which limits their diagnostic role. A few modified or simplified versions of NAAT kit includes loop-mediated isothermal amplification (LAMP), fluorescence in-situ hybridization (FISH) and line probe assays (LPA).

Gene Xpert-Rif: Recently, the use of Gene Xpert-Rif accounts for the rapid diagnosis of TB as well as rifampicin resistance among HIV-infected individuals, providing the results within 2 h. Xpert—Ultra is an improved version that has been equated to a liquid culture in its ability to detect TB with an improvised specificity to detect MTB. In addition to the current reference standard of TB diagnostics, this test implies to complement by increasing its overall sensitivity and speed.

Serological diagnosis of TB

1. Detection of antibodies: Based on suggested datas, the WHO has recently made a negative recommendation regarding the use of serological tests for TB, stating that these tests could neither replace sputum microscopy nor be used as an add-on test to rule out TB.

2. Detection of antigen: Assays such as lipoarabinomannan (LAM) in urine, antigenic target 6 in the cerebrospinal fluid, MPB-64 (TAUNS) antigens in peripheral blood, tend to perform better in HIV infected compared to HIV uninfected TB patients.

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www.wjpps.com Vol 9, Issue 9, 2020. 921 Tuberculin skin test (TST): Studies have shown that TST-positive patients benefit more from Isoniazid Preventive Therapy (IPT) than those who are TST negative. Anergy, improper cold chain maintenance can give rise to pseudo-negative results in HIV. Considering these limitations in resource limited set-ups, WHO Guidelines Group strongly recommends IPT irrespective of TST for people living with HIV.[16]

Treatment

The basic principles of treatment for HIV coinfected TB are the same as for the TB infected individuals. Other than antiretroviral therapy (ART) during anti-TB therapy (ATT), there are variations in treatment of HIV associated TB because of overlapping drug toxicities, pill burden and suboptimal adherence, drug-drug interactions between ART and ATT as well as timing of ART. [17]

Anti-tuberculous therapy

Irrespective of HIV status, the standard recommendation for the treatment of TB is a 6-month regimen of four drugs in the intensive phase i.e. for 2 months: Isoniazid (H), Rifampicin (R), Pyrazinamide (Z) and Ethambutol (E), followed by E, H and R in the continuation phase of 4 months while only Z will be stopped. In India, under Revised National Tuberculosis Control Programme (RNTCP), for newly diagnosed TB, a daily fixed dose regimen of category I (2EHRZ3/4EHR3) is recommended whereas for previously treated TB cases, category II (2EHRSZ3/1EHRZ3/5EHR3) is recommended with the total duration increased to eight months. However, the American Thoracic Society (ATS), Centres for Disease Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) guidelines recommend to lengthen treatment beyond 6 months to 9 months in HIV-infected patients, especially when there is delayed sputum conversion or evidence of dissemination and low CD4+ cell count. The WHO recommends daily TB regimens for the treatment of HIV infected patients, rather than intermittent dosing, used in some patients but ART has to be administered daily.[16] Anti-retroviral therapy

The WHO guidelines, recommends a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) along with one non-nucleoside reverse transcriptase inhibitor (NNRTI) as a first line therapy for the management of HIV-infected TB patients in resource-limited settings (Table 2).[18]

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www.wjpps.com Vol 9, Issue 9, 2020. 922 Rifampicin is a potent inducer of many genes controlling drug metabolism and transport, including cytochrome P450 isoenzymes (CYP3A4) and the drug efflux pump p-glycoprotein, thereby increasing the metabolism of protease inhibitors (PIs) and NNRTIs. Therefore, rifa-mpicin may reduce plasma concentrations of concomitantly administered NNRTIs and protease inhibitors (PIs), potentially resulting in therapeutic failure.

Table 2: Recommendations for individuals with TB and HIV coinfection. CD4 cell count, Cells/mm3 Recommended regimen Comments

< 200 Start TB treatment; start ART as soon as TB treatment is tolerated (between 2 weeks and 2 months) a use EFV-containing regimens b, c, d

Recommend ART; EFV is

contraindicated in pregnant women or women of childbearing age without effective contraception 200—350 Start TB treatment; start one of the

following regimens after the initiation phase (start earlier if patient is severely compromised): EFV-containing regimens b or NVP-containing regimens in case of a rifampin-free continuation phase TB treatment regimen

Consider ART

>350 Start TB treatment Defer ART e

Note: Adapted from WHO’s global tuberculosis report 2003 by permission of the World

Health Organization: ART, antiretroviral therapy; EFV, efavirenz; NVP, nevirapine.

a

Timing of ART initiation should be based on clinical judgement in relation to other signs of immunodeficiency. For patients with extrapulmonary TB, ART should be started as soon as TB treatment is tolerated, irrespective of CD4 cell count.

b

Alternatives to the EFV regimen includes saquinavir (SQV)/ritonavir (RTV) (400/400 mg twice daily), SQV/low-dose ritonavir (SQV/r) (1600/200 mg daily in soft gel capsule), lopinavir/RTV (400/400 mg twice daily), and abacavir.

c

NVP (200 mg daily for 2 weeks, followed by 200 mg twice daily) may be used in place of EFV in the absence of other options. NVP-containing regimens include stavudine (d4T)/lamivudine (3TC)/NVP or zidovudine (ZDV)/3TC/NVP.

d

EFV-containing regimens include d4T/3TC/EFV and ZDV/3TC/EFV.

e

Unless non-TB stage IV conditions are present; otherwise, initiate ART on completion of TB treatment.

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www.wjpps.com Vol 9, Issue 9, 2020. 923 However, Efavirenz is the preferred NNRTI of choice for patients with TB and HIV co-infection at the recommended dose of 600mg, which achieves adequate blood levels and is associated with good outcomes, despite high intra/inter-individual variability. In patients who cannot tolerate or have contraindications to efavirenz (e.g. psychiatric disturbances, pregnancy), either a triple NRTI regimen or a combination of two NRTIs and nevirapine can be employed. Although the efavirenz dose (600 vs 800 mg) and concurrent rifampicin administration have less impact, a polymorphism in the CYP2B6 gene (G-to-T mutation) results in significantly higher blood levels of the drug and may be associated with an increased risk of neurotoxicity.

The use of nevirapine is not recommended routinely with rifampicin, unless there is a contraindication to efavirenz, such as pregnancy or psychiatric illness. Triple NRTI regimens containing abacavir or tenofovir can be used alternatively but have been associated with worse outcomes in patients with a high viral load. Currently, several countries are incorporating Protease Inhibitors (PI) as second line regimens in case of failure of first line therapy. The recommended doses of PIs: lopinavir/ritonavir at 400/400mg or saquinavir/ritonavir at 1000/100 mg BID along with rifampicin. Alternatively, rifabutin with dose modifications can be used as it has less interaction with PIs. Usually, rifabutin is given at a dose of 300 mg daily, while the dose needs to be increased to 450-600 mg daily with EFV and decreased to 150 mg thrice-weekly with amprenavir, ritonavir and lopinavir/ritonavir. Rifabutin is contraindicated in leukopenia and thrombocytopenia while high doses are known to cause uveitis.[16]

Prophylaxis of TB in HIV patients

The Development of Antiretroviral Therapy in Africa (DART) trial, indicated that the prophylactic use of cotrimoxazole shortens mortality in patients with HIV infection on ART for up to 72 weeks regardless of CD4 count status, with mortality similarly reduced in patients with CD4 cell counts above and below 200 cells/μL. The definite mode of activity is not clear but the prophylactic therapy of co-trimoxazole seems to prevent Pneumocystis jirovecii pneumonia and malaria and is likely to have an impact on a wide range of other bacterial infections in HIV-positive TB patients. Hence, it is suggested that co-infected patients should be administered co-trimoxazole 960 mg daily or thrice weekly while ATT is being given as a standard regimen.[19]

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www.wjpps.com Vol 9, Issue 9, 2020. 924 As part of core HIV and TB prevention, the WHO recommends provision of combination of ART and the Three I‘s strategy for HIV/TB—Intensified case-finding (ICF), Infection control (IC) and Isoniazid preventive therapy (IPT) for TB.

Intensified case finding: It is recommended that HIV infected people who live with or are in close contact with active TB patients should undergo clinical evaluation of TB. After proper evaluation, if the patient found not to have active TB should be treated with IPT for presumed latent TB.

Isoniazid preventive therapy: It has been shown to have an additive action in combination with ART as a prophylactic therapy in HIV infected patients.

Infection control: WHO highly suggests that TB infection control practices should be undertaken in all health care facilities as HIV patients are vulnerable to M. tuberculosis if exposed. TB infection control practices includes: administrative, personal and environmental controls detailed below.

The major challenges to uptake of IPT in TB/HIV programs have been the issue of lack of resources to identify and exclude active TB, high dropout rate and side effects especially hepatotoxicity and the risk for INH-resistant TB after IPT.[9]

Tb-associated immune reconstitution inflammatory syndrome (iris)

The immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART). This condition arises from rapid restoration of pathogen-specific immune responses to opportunistic infections, causing either worsening of a treated infection or the new presentation of a previous subclinical infection. IRIS typically occurs within the initial months of ART and can manifest as fever, nodal enlargement, and worsening pulmonary infiltrates observed on a chest radiograph, with or without recurrent respiratory symptoms.

It can present as one of the two main syndromes: (1) a paradoxical reaction after the start of ART in patients receiving TB treatment (paradoxical TB-associated IRIS), or (2) a new presentation of TB that is ―unmasked‖ in the weeks following initiation of ART with an exaggerated inflammatory clinical presentation or complicated by a paradoxical reaction (unmasking TB-associated IRIS).

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www.wjpps.com Vol 9, Issue 9, 2020. 925 In resource-constrained settings where diagnostic capacity is limited, a definition of TB-IRIS is suggested based on 3 criteria as recommended by the International Network for the Study of HIV-associated IRIS (INSHI) in 2006:

1. An initial clinical response to ATT, based on a combination of some of the following factors: Cessation of fever, relief of pulmonary symptoms, decrease in lymph node size, termination of meningeal signs.

2. New insistent fevers with unidentifiable source or reason (e.g., an allergic reaction, malaria) and/or worsening or emergence of dyspnoea and/or stridor and/or increase in lymph node size and/or development of abscesses and/or development of abdominal pain with ultrasound evidence of abdominal adenopathies and/or unexplained CNS symptoms. 3. Adequate compliance to ART and ATT

Despite of the fact that it is associated with an elated production of cytokines, its pathophysiology is incompletely understood. The phenomena of drug resistance, malignancies, drug reactions and other opportunistic infections needs to be rolled out. TB-IRIS can be managed by anti-inflammatory drugs and steroids which have been found to reduce the need for hospitalization and accelerates improvements in quality of life.[19,20] Multidrug-resistant (mdr-tb) and extensively drug-resistant tuberculosis (xdr-tb)

MDR-TB appears not to cause infection or disease more readily than drug-susceptible TB in HIV infected persons, delayed diagnosis, inadequate initial treatment, and prolonged infectiousness contributes to increased attack rates and fatality rates. As per WHO, there are four drugs having efficacy—including a fluoroquinolone, an injectable agent (capreomycin, kanamycin, or amikacin), and at least 2 agents from the second-line anti-tuberculosis drug classes (cycloserine, thioamides [ethionamide or prothionamide], and p-aminosalicyclic acid)—in addition to pyrazinamide and ethambutol, if still sensitive, should be used. Therapy may be individualized on the basis of drug susceptibility test results; however, many countries use standardized regimens that are based on surveillance of antituberculosis drug resistance in the community.[19] According to United States Centres for Disease Control and Prevention (CDC) and WHO, bedaquiline should be added to a conventional MDR or XDR regimen designed as above. Extremely drug-resistant tuberculosis (XDR-TB) is defined as multidrug-resistant tuberculosis plus resistance to any fluoroquinolone and 1 of the second-line antituberculosis injectable agents (kanamycin, amikacin, or capreomycin). Treatment

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www.wjpps.com Vol 9, Issue 9, 2020. 926 options are extremely limited and challenging, with high frequencies of adverse events and death.[21]

Enhancing infection control for tb in arv(antiretroviral) clinics

In 2007, approximately 5 per cent of all diagnosed TB cases in India came from integrated counselling and testing centres (ICTCs), demonstrating that these are the excellent sites for active TB case finding. TB clinics, therefore, forms an important entry point not only for HIV diagnosis, care and support but are also crucial to improve the outcome of HIV-infected TB patients by undertaking following controls to regulate the burden of TB in India.

Administrative controls

1. Early identification and separation of infectious patients

2. Regulating infectiousness by educating patients on proper cough etiquette and respiratory hygiene.

3. Limiting time patients spend in health care facilities through reducing hospital stays and potentiating outpatient TB treatment.

4. Use of rapid diagnostics with Xpert TB. Environmental controls

1. Encouraging natural and mechanical ventilation. 2. Use of upper-room ultraviolet germicidal irradiation.

Natural ventilation could be as simple as opening a window and a door to create cross ventilation. However, mechanical ventilation is quite complex and expensive as the installation of split vent cooling and air exchange systems. UV light, if installed properly, has been shown to destroy the MTB organism without posing harm to patients.

Health workers and carers controls 1. Surveillance and information.

2. Package of care for HIV positive workers (ART and IPT).

3. Providing protective equipment- (particulate respirator masks which meet or exceed N95 standards).

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www.wjpps.com Vol 9, Issue 9, 2020. 927 Personal controls

1. Use of particulate respirators for staffs, such as N95 respirator, although effectiveness is dependent on staff compliance to it, additional training, as well as fit testing should be done to ensure its proper use.

2. Distribution of surgical masks for patients to create a mechanical barrier to prevent the spread of infectious droplet nuclei.[18]

CONCLUSION

The prevalence of TB among patients with HIV infection proves that TB diagnosis, treatment, and prevention are essential for all the health care providers, caring for persons infected with HIV. The integration of HIV and TB services to reduce the mortality is enhancing day by day with substantial gains at the individual and population level, despite HIV still remains to be a massive challenge to global TB control. The control of HIV-TB co-infection requires efforts made at strengthening national control programs by optimizing the directly observed therapy strategy (DOTS) and improving or integrating TB-HIV alliances including the 3I‘S, anti-retroviral therapy and co-trimoxazole preventive therapy. This must be matched by huge political commitment to provide adequate funding to ensure that the aims of the WHO Global Plan to stop TB are achieved.

ACKNOWLEDGEMENTS

The authors wish to thank Dr. M. Vani, Professor, K.K. College of Pharmacy, for the guidance and an exceptional support in assisting the review paper. The authors are also highly grateful to Dr. A. Meena, Principal, K.K. College of Pharmacy, for the insightful comments and generous support.

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References

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