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In This Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 » Acknowledgments
 »  References
 »  Article Figures
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 Table of Contents    
RESEARCH ARTICLE
Year : 2013  |  Volume : 45  |  Issue : 5  |  Page : 447-452
 

Efficacy and safety of anti-tuberculosis drugs in HIV-positive patients: A prospective study


1 Department of Pharmacology, B. J. Medical College, Civil Hospital, Ahmedabad, Gujarat, India
2 Department of Medicine, Civil Hospital, Ahmedabad, Gujarat, India

Date of Submission18-Feb-2013
Date of Decision23-Apr-2013
Date of Acceptance08-Aug-2013
Date of Web Publication6-Sep-2013

Correspondence Address:
Chetna K Desai
Department of Pharmacology, B. J. Medical College, Civil Hospital, Ahmedabad, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.117723

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 » Abstract 

Objectives: To assess the efficacy and safety of anti-tuberculosis drugs in HIV-positive patients at a tertiary care teaching hospital. Materials and Methods: As a part of an ongoing study of opportunistic infections (OIs) in HIV-positive patients, drug treatment in patients suffering from tuberculosis was assessed to determine its efficacy and safety. Based on prevalence data for last three years, a purposive sampling of study population was carried out in this observational, prospective, single centre study. Tuberculosis (TB) was the most common OI observed. The selected patients were followed up for a period of one year to evaluate the clinical course and outcome of OIs, and the efficacy and safety of drugs used was checked. Results: Tuberculosis was observed in 89 out of 134 enrolled patients. These included 79 adults and 10 children. Males (66.2%) were commonly affected. Extra pulmonary TB (73%) was the most common manifestation with abdominal TB observed in 55 (61.7%) patients. All patients were treated in accordance with the Revised National Tuberculosis Control Programme (RNTCP) guidelines as recommended by National AIDS Control Organization (NACO), India. Outcome of TB was assessable in 70 patients. Majority (82.8%) of the patients were cured, while 12 patients (17.1%) died during the course of treatment. A total of 149 ADRs were observed in 67 (75.2%) patients. Majority of ADRs (n = 147) were non-serious and did not warrant a change in therapy. Discoloration of urine was the most common ADR observed. Conclusion: TB is the most common opportunistic infection in HIV-positive patients with abdominal TB being the most common manifestation. RNTCP and NACO guidelines are adhered to in these patients. Anti-tuberculosis drugs are well tolerated and effective in majority of the patients.


Keywords: Adverse drug reactions, anti-tuberculosis drugs, efficacy, HIV, safety, tuberculosis


How to cite this article:
Kapadia JD, Desai CK, Solanki MN, Shah AN, Dikshit R K. Efficacy and safety of anti-tuberculosis drugs in HIV-positive patients: A prospective study. Indian J Pharmacol 2013;45:447-52

How to cite this URL:
Kapadia JD, Desai CK, Solanki MN, Shah AN, Dikshit R K. Efficacy and safety of anti-tuberculosis drugs in HIV-positive patients: A prospective study. Indian J Pharmacol [serial online] 2013 [cited 2019 Jun 27];45:447-52. Available from: http://www.ijp-online.com/text.asp?2013/45/5/447/117723



 » Introduction Top


Once believed to be on the verge of extinction in United States,  Mycobacterium tuberculosis Scientific Name Search owed a resurgence with the onset of Human Immunodeficiency Virus (HIV) epidemic. [1] HIV infection is the strongest risk factor for developing tuberculosis (TB). [2] HIV-positive persons have a more than 20-fold increased risk of developing tuberculosis (TB) as compared to HIV-negative individuals. [3] HIV infection has contributed significantly to the global increase in the incidence of TB [4] and active TB is one of the most common opportunistic infections (OI) in HIV-positive patients in endemic areas of tuberculosis. [5] India has a significant burden of HIV infection and TB with an estimated 2.5 million People Living With HIV and AIDS (PLWHA) at the end of the year 2007 and an estimated 1.8 million cases of TB are detected every year. [4] Tuberculosis also accounted for approximately 20% of 1.8 million AIDS-related deaths worldwide in the year 2009. [6] Active TB is also an independent risk factor increasing the progression of HIV-AIDS. [7]

The National AIDS Control Organization (NACO), India, has classified the OIs in HIV-positive patients into 12 categories and provided guidelines for their prevention and treatment. The use of Revised National Tuberculosis Control Programme (RNTCP) guidelines is recommended for treatment of TB in these patients. [8] However, currently, data regarding efficacy and safety of these drugs in these patients is limited. Hence, the present study was undertaken to evaluate the efficacy and safety of anti-tuberculosis drugs in these patients.


 » Materials and Methods Top


The study was a part of a drug utilization study carried out to evaluate the utilization pattern and safety of drugs used for treatment of OIs in outdoor and hospitalized HIV-positive patients. It was an observational, prospective, single centre study carried out at the Anti Retroviral Therapy (ART) Centre of a tertiary care hospital in Ahmedabad, for a period of 21 months from September 2010 to June 2012. The approval to conduct the study was obtained from the Nodal officer, ART Centre, Gujarat State AIDS Control Society (GSACS) and the Institutional Ethics Committee (ref No. EC/A/93/10/25.10.10).

The investigator attended the outpatient department (OPD) of ART centre daily. All HIV-positive patients reporting to the centre were screened for the presence of OIs. Patients (either ART naive or those receiving ART), registered with the parent ART Centre at Civil Hospital, who were newly diagnosed to be suffering from OI were included in the study after a written informed consent. A purposive sampling of the study population was carried out based on the previous data about the prevalence of different OIs in these patients. Patients were enrolled during the first nine months of study period and followed up for a period of one year to monitor any new or recurrent OI. The data was collected in a pre-tested case record form. Demographic characteristics (age and gender), mode of HIV transmission and details of OIs (clinical features, laboratory investigations, and outcome) were noted. Details of drugs used in the treatment of OIs and adverse reactions due to these drugs were also recorded. The data obtained from patients suffering from tuberculosis were analyzed for demographic and other characteristics, mode of HIV transmission, type of tuberculosis, baseline CD4 count, efficacy, safety, and adherence to NACO guidelines. ADRs were evaluated for severity using modified Hartwig and Seigel scale [9] and a causality assessment was done using the WHO-UMC criteria [10] and Naranjo's scale. [11] Fischer's Exact test was used to assess the gender differences in mortality rate due to TB.


 » Results Top


A total of 222 OIs were observed in 134 enrolled patients. Tuberculosis (TB) was the most common OI detected in 89 (66.4%) patients [Figure 1]. Of the 89 patients, 79 were adults (54 males and 25 females) with a mean age of 39.05 ± 11.7 years and a mean baseline CD4 count of 144.53 ± 93.78 cells/microliter. The CD4 count was less than 500 cells/ microliter in all adults [Table 1]. The mean age and baseline CD4 count of 10 children (five males and five females) was 9.4 ± 3.63 years and 726.5 ± 649.80 cells/microliter, respectively. The modes of HIV transmission among adult patients were heterosexual (50 patients) and blood transfusion (14 patients). Mode of transmission was unknown in 15 patients. The modes of HIV transmission among pediatric patients were vertical (7 patients) and blood transfusion (one patient), while the mode of transmission was unknown in two children. A total of 78 patients were ART naive. Of 89 patients, hospitalization was required in 17 patients.
Figure 1: Opportunistic infections (OIs) observed in HIV positive patients (n = 134) in a tertiary care hospital

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Table 1: Outcome in HIV-positive patients suffering from tuberculosis

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Different manifestations of TB included abdominal TB (n = 55, 61.7%), pulmonary TB (n = 18, 20.2%), combined form of pulmonary and extra pulmonary TB (n = 6, 6.7%), pleural effusion (n = 5, 5.6%), lymphadenitis (cervical) (n = 3, 3.3%) and meningitis (n = 2, 2.2%) [Figure 2].
Figure 2: Manifestations of tuberculosis in HIV positive patients at a tertiary care hospital (n = 89)

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Anti-tuberculosis drugs were prescribed to these patients according to the RNTCP guidelines as recommended by NACO. [8] Accordingly, patients suffering from TB for the first time (n = 65) received category I drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol in the usual recommended doses), while patients having relapse or failure of treatment and the defaulters (n = 23) were prescribed category II drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin in the usual recommended doses). One patient preferred to receive treatment from a private practitioner because of less pill burden due to prescription of fixed drug combinations. Noncompliance was observed in one case, where patient defaulted category I treatment and was later switched to category II treatment. Pyridoxine was prescribed to all patients in the usual recommended doses. Of the 89 patients, outcome was not assessable in 19 cases since these patients were either lost to follow up, transferred out, or the treatment was continuing at the end of study period. Of the remaining 70 patients, 58 (82.8%) were cured while 12 (17.1%) died. Mortality was more in females (n = 7, 31.8%) as compared to males (n = 5, 12.8%) (P = 0.0978).

The mean baseline CD4 count, drug treatment and outcome in these patients are mentioned in [Table 1]. Of the 55 cases of abdominal TB, 49 were observed in adults and six in children. Among them, one patient attended a private clinic and was prescribed Forcox (fixed drug combination of isoniazid, rifampicin, pyrazinamide and ethambutol) and AKT-3 (fixed drug combination of isoniazid, rifampicin and ethambutol). Outcome was assessable in 44 cases, of which 38 were cured. Abdominal TB was associated with six of the total 12 deaths observed [Table 1].

Of the total 18 cases of pulmonary TB observed in adults, eight were sputum positive for acid fast bacilli (AFB), five were sputum negative and in five cases, sputum examination reports were not available. Of the eight cases of sputum positive pulmonary TB, outcome was assessable in seven cases; five recovered and two died. Of the five sputum negative pulmonary TB cases, outcome was assessable in two cases and both patients were cured. In the remaining five cases where report of sputum examination was not available, outcome was assessable in three. Of these, one patient recovered while two patients died. It was observed that the mean CD4 count of patients suffering from pulmonary TB was lower as compared to those suffering from extrapulmonary TB. Patients with sputum negative pulmonary TB had lower mean CD4 count as compared to sputum positive pulmonary TB [Table 1].

Six cases of pulmonary with extra pulmonary TB were observed. Five of these were detected in adults and one in a7-year-old child. Outcome was assessable in five cases, all of whom were cured. Of the five cases of tuberculous pleural effusion, four were detected in adults and one in a 14-year-old child. Outcome was assessable in four cases, of which three were cured and one patient died. Tuberculous meningitis was observed in two patients (one adult and one child), both of whom were cured with the prescribed treatment. Of the three cases of TB lymphadenitis (cervical), two were observed in adults and one in a six year old child. Of these, two patients were cured while one patient died.

A modification in ART was required in few cases. Nevirapine was substituted with efavirenz in ten patients on nevirapine based regime developing TB due to the risk of interaction between nevirapine and rifampicin. Efavirenz was substituted with nevirapine after completion of AKT in 47 patients.

The ADRs due to the prescribed drugs were observed. A total of 149 ADRs were observed [Table 2]. The most common ADR was discoloration of urine associated with rifampicin (58 cases). Majority of ADRs (n = 147, 98.6%) were mild in nature with a severity of level 1 as per the Modified Hartwig and Siegel scale. Two severe ADRs were detected (severity level 2 and 3 in one case each). One patient developed severe generalized skin rash progressing to peeling of skin. Rifampicin was suspected to be the causal drug. The drug was stopped, patient was treated symptomatically, and the ADR subsided thereafter. Hepatitis with elevated SGPT level (216 IU/L) was observed in one patient, which required withdrawal of isoniazid and rifampicin. The ADR subsided after this.
Table 2: Adverse drug reactions to anti-tuberculosis drugs in HIV-positive patients (n=89)

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The causality of ADRs as assessed by WHO-UMC scale showed that the suspected drug had a possible causal association in 90 cases, probable association in 58 cases, while the drug was the certain cause of ADR in one case. As per the Naranjo score, the causality of ADR was possible in 90 cases and probable in 59 cases.


 » Discussion Top


HIV and TB have been closely associated since the onset of HIV epidemic. [4] HIV has contributed significantly to a global increase in the incidence of TB. TB is one of the important causes of death in these patients. [3] Tuberculosis was the commonest OI in the present study, in accordance with the fact that in endemic zones, TB is one of the most frequent OIs in HIV-positive patients. [5] A study carried out in Pune, India showed that TB was the most common diagnosis (55%) among hospitalized HIV-positive patients. [12] It is important to assess the efficacy and safety of anti-tuberculosis therapy as TB is one of the most common OI in these patients. [5] Hence, the present study was conducted to evaluate the efficacy and safety of anti-tuberculosis drugs in HIV-positive patients.

In our study, majority of the cases were observed in adults. This might be attributed to higher mean baseline CD4 count observed in pediatric patients as compared to adults and hence an overall lesser risk of OIs. Majority of the patients suffering from TB were ART naive. ART restores the immune response of the patient and protects the patient from the risk of OIs and accordingly, TB was less common in HIV-positive patients receiving ART. A study conducted in south India also showed that the incidence of OIs among HIV-positive patients receiving HAART was much lower than that in patients not receiving HAART. [13] ART was initiated in majority of ART naive patients subsequently and it was prescribed in accordance with the NACO guidelines. Decreased mortality has been observed in HIV-TB co-infected patients receiving ART as compared to those who do not receive ART [14] and early initiation of ART in HIV TB co-infected patients helps reduce the mortality.

In the present study, extra-pulmonary TB (73%) was more common than pulmonary TB (20.2%) in contrast to another study. [15] Similarly, the mean baseline CD4 count of patients suffering from pulmonary TB was lower than that of patients of extra-pulmonary TB which is contrary to the available literature [16] and needs further evaluation. The mean CD4 count of patients suffering from sputum negative pulmonary TB was lower than that of sputum positive cases, in accordance with the fact that sputum negative TB is more common in patients with advanced immunosuppression. [3]

All patients were treated in accordance with RNTCP guidelines as recommended by NACO. Under the RNTCP programme, patients are dispensed AKT during the intensive phase in a blister pack containing multiple drugs per pack to be taken thrice a week. This can significantly increase the pill burden in these patients who also receive ART and other medications like cotrimoxazole for prophylaxis of PCP, nutritional supplements etc. Increased pill burden is known to affect the compliance adversely [17] and may lead to the development of drug resistance in both HIV infection and TB. However, in spite of increased pill burden, non-compliance to AKT was uncommon in the present study. Yet, inclusion of FDCs in treatment of TB can help reduce the pill burden and improve compliance to therapy.

Treatment outcome was not assessable in nearly 21% patients due to a variety of reasons. In the remaining, treatment was curative in nearly 82.8% of patients. Mortality rate (17.1%) in these patients was comparable to that reported globally due to TB in AIDS patients (12% in the year 2000 [18] and 20% in the year 2009 [6] ) indicating that the RNTCP regimes are effective in treating TB in these patients. These figures are higher than the mortality rate reported in HIV negative patients suffering from TB (0.024%) in India in 2011. [19] Multiple factors such as presence of concomitant diseases, poor general health in HIV positive patients and non-initiation of ART [20] are associated with increased mortality in these patients. Gender differences in mortality observed in our study could not be explained based from the available data and further studies are required to substantiate or negate this finding.

ART was altered in some of these patients. Nevirapine was substituted with efavirenz in all patients receiving nevirapine based ART to avoid the potential interaction between rifampicin and nevirapine. Rifampicin induces the metabolism of nevirapine, leading to a reduction in the plasma level of nevirapine, although some studies have shown that it does not significantly affect the antiviral effect of nevirapine. [21] Ribera et al. have also observed that the dose modification of nevirapine is not required in patients receiving both nevirapine and rifampicin, and there is no significant change in plasma level of rifampicin in these patients. [22] The risk of combined toxicities like liver damage or skin rash is also not significantly increased in patients receiving both nevirapine and rifampicin. [21] Hence, consequences of co administration of nevirapine and rifampicin need to be further evaluated to help simplify the choice of ART regime in these patients.

Adverse Drug Reactions

The number of ADRs associated with anti-tuberculosis drugs per patient in this study was higher than the reported incidence worldwide. [23] This can be attributed to multi-drug therapy, coexisting HIV infection and prolonged treatment. Majority of ADRs were non-serious in nature and did not warrant a change in treatment, suggesting that the drugs were well tolerated. Most common ADR observed was discoloration of urine associated with rifampicin. Gastrointestinal ADRs were also frequent, which is explained by the fact that most of these drugs were administered by oral route. Dermatological ADRs, more frequent in HIV-positive patients, [1] were, however, less common in the present study and majority of these were non-serious. As these patients were also receiving concomitant drugs like ART, cotrimoxazole, and nutritional supplements, a "possible" causal association was attributed to suspected drugs in nearly 60% cases.

Strengths of the Study

The study was conducted at the ART Center of a tertiary care hospital for 21 months. It was prospective in nature and all patients visiting the center were enrolled according to the selection criteria and followed up regularly. Majority of the studies previously conducted in India have focussed on the pattern of OI in hospitalized HIV positive patients, while the present study included both indoor and outdoor patients. The long duration of follow up (one year) allowed us to assess the recurrence and outcome in these patients.

Limitations of the Study

The pattern of TB and the efficacy and safety of anti-tuberculosis drugs in pediatric patients could not be assessed adequately because of the small number of patients enrolled. Majority of the patients were followed up every month. Hence, the possibility of recall bias in ADR reporting could not be ruled out.


 » Conclusion Top


Tuberculosis (TB) is the most common opportunistic infection (OI) in HIV-positive patients with a preponderance of extrapulmonary over pulmonary TB. A rational approach in prescribing the medication is observed. Patients are treated in accordance with the national guidelines. Anti-tuberculosis drugs are effective in majority of the patients and are well tolerated with only a few serious ADRs. Further studies are recommended to determine the pattern of TB in HIV-positive children, the relation between CD4 count and the type of TB in adults and to determine the consequences of co-administration of nevirapine and rifampicin in these patients.


 » Acknowledgments Top


We gratefully acknowledge Gujarat State AIDS Control Society (GSACS) for granting us the permission to conduct the study in ART Center, Civil Hospital Ahmedabad.

 
 » References Top

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2.Bucher HC, Griffith LE, Guyatt GH, Sudre P, Naef M, Sendi P, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: A meta-analysis of randomized controlled trials. AIDS 1999;13:501-7.  Back to cited text no. 2
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8.National AIDS Control Organization, Ministry of Health and Family Welfare, Government of India. Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV-Infected Adult and Adolescent. New Delhi; 2007. p. 88.  Back to cited text no. 8
    
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11.Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 11
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22.Ribera E, Pou L, Lopez RM, Crespo M, Falco V, Ocaña I, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001;28:450-3.  Back to cited text no. 22
    
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    Figures

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    Tables

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