|Year : 2006 | Volume
| Issue : 2 | Page : 64-69
A study on comparative efficacy of anti tubercular chemoprophylaxis with 2 different regimens: 2 months of rifampicin and pyrazinamide and 6 months of daily isoniazid and rifampicin in HIV infected tuberculin reactors
Senior Advisor (Medicine & Pulmonology) Army Hospital (R&R), Delhi Cantt-110010, India
Senior Advisor (Medicine & Pulmonology) Army Hospital (R&R), Delhi Cantt-110010
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Human immune-virus (HIV) infection is the most significant risk factor for progression of latent mycobacterium tuberculosis (MTB) infection to active tuberculosis. Tuberculosis reactivation among human immunodeficiency virus (HIV) infected cases can be prevented by anti tubercular chemoprophylaxis. This randomized controlled study compared the efficacy of 2 months of daily rifampicin and pyrazinamide and 6 months of daily rifampicin and isoniazid drug regimes in preventing active tuberculosis in HIV seropositives. It is observed that 2 months of daily rifampicin in combination with pyrazinamide is not only efficacious as that of 6 months of daily rifampicin and isoniazid combination in preventing active tuberculosis in HIV seropositives but has the advantage of better compliance, lesser side effects and prolonged post prophylactic preventive effect.
Keywords: Chemoprophylaxis; Tuberculosis; HIV.
|How to cite this article:|
Prasad B. A study on comparative efficacy of anti tubercular chemoprophylaxis with 2 different regimens: 2 months of rifampicin and pyrazinamide and 6 months of daily isoniazid and rifampicin in HIV infected tuberculin reactors. Lung India 2006;23:64-9
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Prasad B. A study on comparative efficacy of anti tubercular chemoprophylaxis with 2 different regimens: 2 months of rifampicin and pyrazinamide and 6 months of daily isoniazid and rifampicin in HIV infected tuberculin reactors. Lung India [serial online] 2006 [cited 2020 Oct 25];23:64-9. Available from: https://www.lungindia.com/text.asp?2006/23/2/64/44411
| Introduction|| |
HIV infection is the most significant risk factor for progression of latent Mycobacterium tuberculosis TB) infection to active tuberculosis ,, . Although only about 10% of persons infected with MTB will develop active tuberculosis during their lifetime, when compromised by human immunodeficiency virus (HIV) infection as many as 50% to 100% of persons infected with MTB will develop active tuberculosis during shortened life span. ,,,
Tuberculosis reactivation among HIV infected persons may be preventable by identifying and prescribing preventive therapy to individuals infected with MTB and HIV (5,23). Data from several uncontrolled studies suggest that preventive therapy with isoniazid for 6-12 months is effective, at least in the short term in preventing the development of active tuberculosis. However, duration of tuberculosis prevention is not exactly known in HIV infected cases. In an ongoing control study of self-administered isoniazid prophylaxis for 6 months, a significant reduction of tuberculosis was seen among HIV infected persons receiving isoniazid as compared with placebo. However among patients receiving isoniazid the incidence of tuberculosis began to increase during post prophylaxis period . ,, Isoniazid preventive therapy here to fore has been deemed impractical in the third world for several reasons: the relatively high prevalence of isoniazid resistance, the extended duration of treatment required and the probability of non compliance with self administered medicine.  A short course preventive therapy using rifampicin and pyrazinamide- a regimen with high sterilizing activity was found to be more effective than 6 months of therapy with isoniazid alone in murine experimental model.  There is paucity of data on feasibility and efficacy of preventive therapy in dual infections of HIV and MTB particularly in Indian context, where a large pool of such dual infections exists. This study was undertaken to compare the efficacy of chemoprophylaxis regimens: 2 months of rifampicin (R) and pyrazinamide (Z) and 6 months of isoniazid (H) and rifampicin (R) in cases with dual infections with MTB and HIV
| Material and Methods|| |
The study was done at Military Hospital Cardio Thoracic Center Pune, a premier thoracic center of armed forces that offers sanatorium treatment to cases of pulmonary tuberculosis including those cases with HIV infection among Armed Forces personnel. The study groups consisted of asymptomatic confirmed HIV cases with positive tuberculin reaction that were referred to this center for screening out active tuberculosis from regional Armed Forces surveillance centers. Also included in the study were those HIV seropositive cases with active tuberculosis who did not receive prior chemprophylaxis. The end point of this study was the development of active tuberculosis confirmed by clinical, radiological and bacteriological methods in those with dual infections of HIV and tuberculosis who had received chemoprophylaxis.
All eligible candidates who were asymptotic HIV and tuberculin positives were enrolled in the study for the chemoprophylaxis. They were randomized in to 2 groups. One received 2 months of rifampicin 600 mg and pyrazinamide 1.5 gms while the other received 6 months of rifampicin 600 mg and isoniazid 300 mg per oral once daily under supervision. The eligibility criteria for chemoprophylaxis included the following.
(a) Serving soldiers weighing over 50 kgs.
(b) Asymptomatic HIV seropositives confirmed by ELISA, rapid test and western blot method with a positive tuberculin reaction. The tuberculin reaction is considered positive when 5 mm or more indurations occurred to 5 tuberculin units (TU) of purified protein derivative (PPD) given intradermally. Those with tuberculin reaction less than 5 mm indurations and reaction to other recall antigens such as tetanus toxoid 1:10 dilution were considered to be tuberculin negative anergic cases.
(c) No evidence of active tuberculosis, excluded by clinical examination, ESR, sputum examination for acid-fast bacillus (AFB) and chest X-ray examination.
Follow up: Cases were followed up every month while on chemoprophylaxis and once in every 6 months till next 2 years on completion of chemoprophylaxis. During therapy and follow up, cases were assessed for evidence of active tuberculosis, hepatitis, peripheral neuropathy, hyperurecaemia or new HIV related diseases.
Data analysis : Data on efficacy and toxicity of chemoprophylaxis were reviewed periodically during follow up and treatment groups were compared.
| Results|| |
Between 01 Jul 1996 to 01 Jan 1999, 160 cases that fulfilled eligibility criteria received chemoprophylaxis. Among these 80 cases each that were matched in terms of age received 2 months of once daily 600 mg rifampicin and 1.5 gm pyrazinamide and 6 months of once daily 300 mg isoniazid and 600 mg rifampicin respectively. There was one case of active pleural tuberculosis confirmed by pleural biopsy occurring 6 months after completion of chemoprophylaxis with isoniazid and rifampicin. This case had a tuberculin reaction of 10 mm to 5 TU PPD prior to institution of chemoprophylaxis, while the tuberculin test carried out during development of active tuberculosis showed a reaction of 6mm indurations. In the other group who received chemoprophylaxis with rifampicin and pyrazinamide, none developed active tuberculosis at the end of 2 years follow up.
The third group consisted of 25 cases of confirmed active tuberculosis with HIV seropositivity that was hospitalized for the treatment. None of them had received prior chemoprophylaxis. On analysis of past medical record of these cases, 10 among them were detected to be HIV positive when screened for blood donation. 8 among them were also tuberculin positive with mean indurations of 10 mm to 5 TU PPD. The mean duration of HIV seropositivity prior to development of active tuberculosis was 2.6 years among 10 HIV seropositives in this group. When tuberculin test was repeated on those 8 cases with active tuberculosis who were tuberculin reactors previously it was observed that 4 of them had developed energy while remaining 4 had a lesser reaction with mean indurations of 6.8 mm to 5 TU PPD. 2 of these cases with energy had CD 4 counts of 82 and 76 per cubic mm respectively. 20 cases among this group received ATT regimen- 2 months of once daily administered ethambutol, isoniazed, rifampicin and pyrazinamide and 4 months of once daily administered isoniazid and rifampicin (2EHRZ+4HR), with clinical radiological and bacteriological recovery. Remaining 5 cases received chemotherapy with once daily administered 3 months of EHRZ and 6 months of HR Among them 3 cases recovered while remaining 2 cases developed pneumocystis carinii pneumonia while on therapy. Between these 2 cases, one responded to therapy while the other died while on therapy. This case with a fatal outcome had severe reactions to rifampicin in the form of Steven Johnson syndrome at the end of 2 months, necessitating discontinuation of the drug. The characteristics of study group are summarized in [Table 1].
Among the chemoprophylaxis group adverse reactions to rifampicin in the form ofmaculo-papular rashes were observed in 4 cases, 3 from rifampicin and isoniazid group and 1 from rifampicin and pyrazinamide group. This did not warrant discontinuation of therapy since these cases responded to antihistamines. There was no major adverse reaction to anti tubercular drugs in both chemoprophylaxis groups.
| Discussion|| |
Synergistic relationship exists between tuberculosis and HIV infection." In a person with dual infections of HIV and MTB, there is not only an enhanced risk of active and progressive tuberculosis but also accelerated HIV replications, there-by adversely affecting the clinical outcome.
This synergistic interaction between HIV infection and tuberculosis has implications for the epidemiology, clinical manifestations, treatment and prevention of both diseases. Globally in the year 2000 there were an estimated 200 million tuberculosis infected persons, 40 million HIV infected persons and 15 million persons with dual infections of HIV and tuberculosis. In India by Dec 2000, there were an estimated 44-million tuberculin positive cases, 4 million HIV infected cases and 1.8 million cases with dual infections of HIV and tuberculosis. , India has total prevalence of approximately 15 million active tuberculosis cases, of which approximately 3% have HIV infection. With such a large pool of dual infections existing in country like India, there is an imminent threat of devastating AIDS epidemic, unless the synergistic interactions between the deadly duo of tuberculosis and HIV are prevented. Treating both latent and active tuberculosis among HIV infected is critically important to prevent further transmission. As a public health measure prophylaxis with isoniazid alone for 12 months in those with dual infections of MTB and HIV has been recommended. , However use of isoniazed prophylaxis in eligible person in a community with high degree of drug resistance, may not be effective. The incidence of multiple drug resistance (MDR) tuberculosis in HIV infected individuals is much higher than those who are HIV sero-negatives.  There are also problems of poor compliance and adverse drug reactions with prolonged chemoprophylaxis. This study was undertaken to analyze the outcome of short-term chemoprophylaxis regimens as regard to their efficacy & safety in preventing development of active tuberculosis among HIV infected individuals. In this present study, strict entry criteria for chemoprophylaxis was adopted and only those having latent tuberculosis infection without any evidence of acquired immunodeficiency syndrome were eligible for chemoprophylaxis. Those with energy, were also excluded since some of them may be having advanced immunodeficiency not confirmed otherwise by CD 4 counts (which were not done in all cases). Though some of these anergic individuals due to advanced immunodeficiency may be having latent tuberculosis infection with high risk of development active tuberculosis, yet treating all anergic HIV infected individuals with isoniazid prophylaxis did not find favor.  Moreover majority of HIV infected cases with latent tuberculosis infection react with 5mm indurations or more to 5TU intradermal PPD and hence are eligible for chemoprophylaxis. In the present study none of the anergic HIV seropositive cases on follow up developed active tuberculosis. Some of the studies have shown that results of anergic testing are not reproducible in HIV infected individual. 
Given these findings, anergic testing is no longer recommended to assess the risk. However those anergic HIV seropositives can be considered for tuberculosis chemoprophylaxis if there is strong history of close contact with cases with active tuberculosis in the recent past. In the present study, the presence of energy in 4 of the cases with active tuberculosis who were previously tuberculin reactors is indicative of underlying progressive immunodeficiency as evidenced by low CD 4 counts in 2 of them. The conversion of tuberculin reactors to non-reactors and the decrease in the size of tuberculin reaction in those with active tuberculosis with HIV seropositivity as was observed in the present study, is an ominous sign reflecting the synergistic interactions of HIV and MTB infections on cell mediated immunity.
This study has shown that daily administered 2 months regimen of rifampicin and pyrazinamide is as efficacious as that of 6 months of daily regimen of isoniazed and rifampicin in preventing development of active tuberculosis in those with dual infections of HIV and MTB. Though one of the case on chemoprophylaxis with isoniazed and rifampicin, developed breakthrough tubercular pleural effusion after 3 months of stopping chemoprophylaxis, this finding is not statistically significant. During follow up period of 2 years, none of the other cases in both groups who received chemoprophylaxis developed breakthrough tuberculosis. A trial by Pape and colleagues  , compared 12 months of daily isoniazid and pyridoxine with pyridoxine alone in HIV seropostive Haitian adults. The rate of tuberculosis in tuberculin positive cases treated with isoniazid was 1.7 per 100 persons years follow-up as compared to 10 per 100 persons years in pyridoxine group. In another study by Halsey NA et al  , twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar over all protection against tuberculosis in HIV infected PPD positive adults. However at the end of the 4 years follow-up, tuberculosis developed in 3.8% in isoniazid group and in 5% of rifampicin and pyrazinamide group. Slightly better protection seen in isoniazid group on follow-up by the authors was attributed to longer duration of chemoprophylaxis in isoniazid group.
The protective role of chemoprophylaxis is further substantiated in the present study. 10 of 25 cases in the third group with active TB (who were HIV seropositive and tuberculin positive for a mean duration 2.6 years but never had prior chemo prophylaxis), had advanced disease and 4 of them had energy. The absence of breakthrough tuberculosis on follow up at the end of 2 years in pyrazinamide and rifamipicin chemoprophylaxis group in the present study seems to be due to higher effectiveness of daily regimen over intermittent regimen. Some of the animal studies have suggested that intermittently administered rifiampicin is less active in chronic tuberculosis infection than rifampicin given daily  . The use of rifampicin and pyrazinamide as a short course chemoprophylaxis in HIV seropositives with latent tuberculosis infection has a theoretical advantage over 6 months of isoniazid alone or in combination with rifampicin prophylaxis.
Use of pyrazinamide being the drug of choice for killing bacillary population in the acidic intercellular milieu not only shortens duration of chemotherapy but also enhances the sterilizing activity of rifampicin as suggested by experimental studies by Lecoeur et al 10 In the same study Lecoeur et al, observed that a combination of rifampicin and pyrazinamide was even more active than a combination of rifampicin, pyrazinamide and isoniazid, thereby suggesting that addition of isoniazid to combination of rifampicin and pyrazinamide did not offer benefit. Isoniazid alone or in combination with rifampicin is not effective against persisters and addition of pyrazianamide eliminates persisters.
The antagonism between isoniazid with rifampicin and pyrazinamide combination observed by Lecoeur etal. was speculated to be due to weak bactericidal or only bacterostatic activity against persisting MTB. With high degree isoniazid mono resistance reported in non HIV population and reported more common occurrence of rifampicin monoresistant tuberculosis in HIV seropositives, use of monotherapy for chemo prophylaxis is not advisable. Though isoniazid alone given for 12 months, reduced incidence of tuberculosis in HIV seropositives with latent tuberculosis in some of the studies  , frequent development of active tuberculosis in these cases on follow up period on completion of chemoprophylaxis, was a worrisome factor. Some clinicians would favor life long chemoprophylaxis in patients with HIV infection because of inevitable progressive deterioration of cellular immune function in this population  . Currently there are no reliable data as to the optimal duration of chemoprophylaxis. Elimination of only active extra cellular organisms by isoniazid or in combination with rifampicin threatens the development of active tuberculosis due to the presence of persisters. This could be responsible for the development of active tuberculosis during post chemoprophylaxis period that occurred in some of the cases that received chemoprophylaxis with isoniazid alone or along with rifampicin. Only long term follow up of HIV seropositives with latent tuberculosis who received short term chemoprophylaxis with rifampicin and pyrazinamide can substantiate its superiority over isoniazid alone / isoniazid and rifampicin combination in preventing the development of active tuberculosis during post chemoprophylaxis period. The potent combination of rifampicin and pyrazinamide appears promising since it has the advantage of eliminating persisters, thereby shortening the duration of chemoprophylaxis and prolonging post chemoprophylaxis protection.
In the present study no significant side effects were observed with antitubercular chemoprophylaxis. Therefore drug toxicity should not be a major consideration for deciding the right combination of chemoprophylaxis in asymptomatic cases with dual infection of MTB & HIV. Rashes, hepatitis and gastrointestinal distress are common side effects that are seen in HIV seropositives with active tuberculosis on standard antitubercular treatment as was observed in this study. Rifampicin appears to be the most common culprit and its discontinuation is required in about 10% of such cases  . In those cases of acquired immunno deficiency syndrome, multiple factors including advanced immunodeficiency and concurrent therapy for other opportunistic infections play a significant role for adverse reactions to anti tubercular drugs.
| Conclusions|| |
Tuberculosis being the common cause of death among HIV seropositive cases, the only effective way of reducing tuberculosis related morbidity in HIV seropositives with latent tuberculosis, is by effective antitubercular chemoprophylaxis. Ideal antitubercular chemprophylactic therapy and its optimal duration is not yet established. The combination of rifampicin and pyrazinamide given daily for 2 months in HIV sepositives with latent tuberculosis has the advantage of better compliance, lesser side effects due to shortened duration and prolonged preventive benefits during post chemoprophylaxis period. 6 months of chemoprophylaxis with rifampicin and isoniazid has no added advantage over 2 months of chemoprophylaxis with rifampicin and pyrazinamide combination in HIV seropositives with positive tuberculin reaction. This has been validated in the present study. In this study it is further observed that with the advancement of HIV infection the size of tuberculin reaction shows decline.
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