Abstract
Tuberculosis (TB) is one of the most common opportunistic infections that affects patients with HIV. HIV and TB coinfection have a synergistic effect on each other, with one disease worsening the effects and treatment of the other. In the recent past, varying levels of drug resistance are also found in patients coinfected with HIV and TB, but rarely is it reported in children in India. The present case documents partial extensively drug-resistant TB in an 8-year-old child.
Introduction
Tuberculosis (TB) is one of the most common opportunistic infections in HIV. 1 The lifetime risk of TB in the general public is found to be 5% to 10%, while in HIV-positive people it is estimated to be 5% to 15% every year. 2 In India and worldwide, very few studies have been done with regard to drug-resistant (DR) TB among children. One study in South Africa found multi-DR TB (MDR-TB) to be prevalent in 6.55% of children <13 years of age, in 2003 to 2005. 3 In another study in South Africa, the prevalence of MDR-TB was found to be 22.2% and isoniazid monoresistance 5.6% among culture-confirmed, HIV-exposed and infected children. 4 In a study conducted in Mumbai, India, between 2007 and 2010, of 500 children with TB, 34 (6.8%) were found to have DR-TB and 3 (10.3%) of them were coinfected with HIV. 5 Among adults with HIV, DR-TB was seen in 7.4% of patients in Africa, with even extensive DR (XDR) TB being reported. 6,7 In India, MDR-TB has ranged from 14.2% to 22.2%, with 33.3% XDR-TB reported among HIV-infected adults having MDR-TB. 8,9
Case Report
An 8-year-old, HIV-infected girl presented with cough and fever for 1 month and loss of weight. She had been treated for TB 1 year ago for 6 months. Both her parents were infected with HIV and her father had died 7 years ago. The child’s chest x-ray showed left lower lobe consolidation, and sputum smear showed acid-fast bacilli (AFB). She was started on a 5-drug antituberculous therapy (ATT) consisting of isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) pending TB culture report. Her CD4 count was 863 cells/mm3. Echocardiography showed mild left ventricular dilatation with left ventricular hypertrophy and early diastolic dysfunction. On examination, her weight was 14.5 kg (<5th centile) and height was 104 cm (<5th centile). She had insignificant cervical lymphadenopathy, pallor, and crepts in the left mammary region. Her other systems were normal. Her sputum culture showed Mycobacterium tuberculosis resistant to HRZES, ethionamide, ofloxacin, and moxifloxacin. Sensitivity to kanamycin, amikacin, clofazimine, capreomycin, and para-amino salicylic acid (PAS) was documented. Drug-susceptibility testing (DST) was done in Hinduja Hospital, Mumbai, India, which is a Revised National Tuberculosis Control Program (RNTCP)-certified laboratory. The child was then shifted to amikacin, PAS, clofazimine, and linezolid 6 weeks after starting ATT per her DST report. She had a weight gain of 3 kg in the next 5 months; however, the chest x-ray did not show any change. Also, hearing assessment showed a mild to moderate mixed hearing loss. She was then started on antiretroviral therapy (ART) consisting of stavudine (d4T), lamivudine (3TC), and nevirapine (NVP). Amikacin was stopped after 1 year of therapy and the remaining ATT was continued along with the ART. She now weighed 20 kg. Her sputum smear was negative for AFB. She is on a regular follow-up schedule.
Discussion
HIV-positive individuals are 20 to 40 times more likely to develop active TB when compared to those not infected with HIV. 10 The DR-TB is on the rise not only among HIV-positive people but also in the general population. Several factors contribute to increased preponderance of DR-TB in HIV-positive patients. It is inferred that HIV causes malabsorption of anti-TB drugs and can lead to acquired rifamycin resistance. 11 Studies have also shown that another frequent cause for MDR-TB in HIV-infected people is increased exogenous transmission. A systematic review published in 2009 showed a statistically significant association between HIV status and the direct transmission of an MDR strain of M tuberculosis. 12 Rifampicin monoresistance is often encountered. It may arise independently due to mutations in drug-susceptible strains. 13 Certain observational studies in adults have documented that the risk of acquired rifamycin resistance is higher if intermittent regimens are used in advanced HIV disease. 14 Similarly, rates of relapse and mortality have been attributed to severe immunosuppression, thrice weekly dose of rifampicin, lack of rifampicin in the treatment regimen, and less than 6 months of treatment duration in adults. 15 -17 The literature is limited with regard to ART and ATT drug interactions in children. Studies on adults published in the 1980s and 1990s showed interactions between ethionamide and ART. 18,19 Jenner et al in 1981 showed that coadministration of ethionamide and protease inhibitors increases the serum concentration of ethionamide, therefore increasing its toxicity. 19 Another commonly observed side effect of starting ART in patients being treated for TB is immune reconstitution inflammatory syndrome (IRIS). In a study by Narita et al, the incidence of IRIS in TB alone was 2%, with HIV coinfection, it was 7% and in those started on HAART, it was 36%. 20
Treatment of TB in HIV coinfected patients is the same as HIV-negative individuals. First-line drugs in the standard regimens are to be used unless drug resistance is proven. Daily dosing is recommended over thrice weekly therapy. However, due to the nature of the illness, drug resistance is more common in patients coinfected with HIV and TB than it is in the general population, and it should be actively investigated for. A pilot study in adults by the Tuberculosis Research Centre found a favorable response in 72% of the patients with advanced HIV and TB and an unfavorable response in 28% of these patients, when RNTCP Category I regimen was used. 13 The outcome of treatment of MDR-TB with HIV coinfection is poor. In 2003, a study conducted in South Africa showed 41% mortality among HIV-positive patients with MDR-TB. 21 Earlier, a study in New York in 1996 showed 72% mortality among HIV-positive patients with MDR-TB. 22 Similar data in children are lacking.
Thus, HIV-infected children should be screened for TB, especially DR-TB in the current era. Treatment with second-line ATT along with ART needs intense monitoring to ensure good outcome.