C. Padmapriyadarsini

Decreased Bioavailability of Rifampin and Other Antituberculosis Drugs in Patients with Advanced Human Immunodeficiency Virus Disease

ABSTRACT We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.

Diagnosis & treatment of tuberculosis in HIV co-infected patients

Human immunodeficiency virus (HIV) associated tuberculosis (TB) remains a major global public health challenge, with an estimated 1.4 million patients worldwide. Co-infection with HIV leads to challenges in both the diagnosis and treatment of tuberculosis. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDR-TB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Because of the poor performance of sputum smear microscopy in HIV-infected patients, newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-constrained settings. The treatment of co-infected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution inflammatory syndrome. Also important questions about the duration and schedule of anti-TB drug regimens and timing of antiretroviral therapy remain unanswered. From a programmatic point of view, screening of all HIV-infected persons for TB and vice-versa requires good co-ordination and communication between the TB and AIDS control programmes. Linkage of co-infected patients to antiretroviral treatment centres is critical if early mortality is to be prevented. We present here an overview of existing diagnostic strategies, new tests in the pipeline and recommendations for treatment of patients with HIV-TB dual infection.

Malabsorption of Rifampin and Isoniazid in HIV-Infected Patients With and Without Tuberculosis

The absorption of rifampin, isoniazid, and D-xylose in patients with human immunodeficiency virus (HIV) infection and diarrhea, in patients with HIV infection and tuberculosis (TB), in patients with pulmonary TB alone, and in healthy subjects was studied. Percentage of dose of the drugs, their metabolites, and D-xylose excreted in urine were calculated. A significant reduction in the absorption of drugs and D-xylose in both the HIV infection/diarrhea and HIV infection/TB groups was observed (P<.05), and the correlation between them was significant. Our results indicate that patients with HIV infection and diarrhea and those with HIV infection and TB have malabsorption of rifampin and isoniazid.

HIV-Associated Tuberculosis: Clinical Update

The human immunodeficiency virus (HIV) epidemic has led to an increase in the incidence of tuberculosis globally, particularly in sub-Saharan Africa. Coinfection with HIV leads to difficulties in both the diagnosis and treatment of tuberculosis. Because of the poor performance of sputum smear microscopy in HIV-infected patients, more sensitive tests-such as liquid culture systems, nucleic acid amplification assays, and detection of mycobacterial products in various body fluids-are being investigated. The treatment of coinfected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution syndrome. Both multidrug-resistant and extensively drug-resistant tuberculosis can spread rapidly among an immunocompromised population, with resulting high mortality rates. Current guidelines recommend starting antiretroviral treatment within a few weeks of antituberculosis therapy for patients with CD4 cell counts <350 cells/microL; however, important questions about the drug regimens and timing of antiretroviral therapy remain. Ongoing trials may answer many of these unresolved questions.

Nutritional Status of Persons with HIV Infection, Persons with HIV Infection and Tuberculosis, and HIV-Negative Individuals from Southern India

We compared the nutritional status of individuals with human immunodeficiency virus (HIV) infection alone, individuals with HIV infection and tuberculosis (after completion of antituberculosis treatment), and HIV-negative individuals and found that malnutrition, anemia, and hypoalbuminemia were most pronounced among HIV-positive patients with tuberculosis. Weight loss was associated with loss of fat in female patients and with loss of body cell mass in male patients.

Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration

Summary: We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 &mgr;g/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 &mgr;g/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

Efficacy and Safety of Once-Daily Nevirapine- or Efavirenz-Based Antiretroviral Therapy in HIV-Associated Tuberculosis: A Randomized Clinical Trial

BACKGROUND Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. METHODS An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ(3)/4RH(3); [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide / 4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. RESULTS A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm(3), and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058). CONCLUSIONS Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Clinical Trials Registration. NCT00332306.

Association of high T allele frequency of CYP2B6 G516T polymorphism among ethnic south Indian HIV-infected patients with elevated plasma efavirenz and nevirapine

location and similar symptoms after 35 months of follow-up, but refused further diagnostic or therapeutic attempts. Another four patients experienced local infectious complications probably related to the former actinomycosis at 4, 25, 27 and 30 months after the end of treatment, respectively. Treatment duration in 5 of these 6 patients had a length of ,3 months and was significantly shorter than that of the 35 patients with an uneventful follow-up (P1⁄40.001, two-sided Mann–Whitney U-test). According to reviews, the recommended treatment length consists of several weeks of intravenous therapy followed by 6–12 months of oral treatment. Recently, the concept of shorter treatment courses has been introduced, especially for cervicofacial actinomycosis. Case series involving patients with pulmonary actinomycosis, treated exclusively medically with short course regimens, are sparse: a few series with a maximum number of 15 patients showed treatment successes after antibiotic regimens shortened to a median duration of 4–20 weeks; however, follow-up data were often missing or incomplete. – 6 In our series, 24 patients (56%) were treated for ,6 months without prior surgical debulking and with a clinical cure rate of 100%. On the other hand, 10 of 13 patients with evidence of abscess formation or chest wall involvement were treated for .6–14 months because of slow resolution of the radiographic lesions. Six of 41 patients (15%) with complete follow-up data developed either documented or possible recurrence or local complications. These patients received significantly shorter antibiotic courses when compared with the other patients, and duration was below 3 months in five of them. We suggest that antibiotic treatment duration should be individualized, and termination of treatment can probably be considered 1 or 2 months after complete clinical and radiological disease resolution in most patients. However, treatment durations below 3 months in medically treated patients without prior surgical debulking should probably be avoided, as they might be associated with an increased risk of complications. The main limitations of our study are those generally inherent in retrospective analyses. We were not able to calculate the diagnostic accuracy of the applied procedures in detail, and we cannot provide a prospective comparison between different antibiotics and treatment durations. However, due to the sporadic occurrence of actinomycosis, prospective trials might be nearly impossible to perform, and our case series represents the largest report on pulmonary actinomycosis in the recent literature. We conclude that (i) surgical diagnostic procedures can be avoided in the majority of patients by performing transbronchial catheter biopsies and/or transthoracic needle aspiration, (ii) antibiotic treatment with penicillin and alternatively doxycycline is associated with an excellent clinical cure rate despite high rates of penicillin intolerance, and (iii) individual treatment duration can be shortened below the recommended 6–12 months; however, treatment below 3 months in exclusively medically treated patients might be associated with complications during follow-up.

Nutritional supplementation in HIV-infected individuals in South India: a prospective interventional study.

BACKGROUND Malnutrition in human immunodeficiency virus (HIV)-infected individuals is associated with faster disease progression, higher mortality rates, and suboptimal response to antiretroviral therapy (ART). METHODS We conducted a prospective interventional study to evaluate the effects of an oral macronutrient supplement among HIV-infected adults in South India. Patients attending Tuberculosis Research Centre clinics from June 2005 through December 2007 had baseline nutritional assessment and laboratory investigations performed. Patients at 1 center received nutritional counseling and standard care, whereas patients at 2 centers additionally received a macronutrient providing 400 cal and 15 g of protein daily. Study outcomes were changes in anthropometry, body composition, blood chemistry, and immune status at 6 months. RESULTS In total, 636 ART-naive patients were enrolled in the study; 361 completed 6 months of follow-up (282 received supplements and 79 received standard care). Mean age +/- standard deviation (SD) was 31 +/- 7 years, mean weight +/- SD was 50 +/- 10 kg, and 42% were male. Significant increases in body weight, body mass index, midarm circumference, fat-free mass, and body cell mass were observed in the supplement group but not in the control group at 6 months; gains were greater in patients with CD4 cell counts <200 cells/microL. No changes were observed in lipid levels, whereas the CD4 cell count decreased in the control group. However, after adjusting for baseline differences, these changes were not statistically significantly different between the groups. CONCLUSIONS Macronutrient supplementation did not result in significantly increased weight gain compared with standard care (including nutritional counseling) among patients with moderately advanced HIV disease. The effect of supplementation on specific subsets of patients and on preserving immune function needs further research.

Prevalence of Underweight, Stunting, and Wasting among Children Infected with Human Immunodeficiency Virus in South India

Background. Growth failure is a common feature of children with human immunodeficiency virus (HIV) infection. Malnutrition increases mortality and may impair the response to antiretroviral treatment. Objective. Our objective was to describe the prevalence of stunting, underweight, and wasting in HIV-infected children in south India and to assess the utility of these parameters in predicting immune status. Methodology. In this cross-sectional study, anthropometric measurements and CD4 counts were performed on 231 HIV-infected children. Z scores for height for age, weight for age, and weight for height were correlated with CD4 cell counts and receiver operating characteristic curves plotted. Results. Prevalence of underweight was 63%, stunting 58%, and wasting 16%, respectively. 33–45% of children were moderately or severely malnourished even at CD4 >25%; sensitivity and specificity of stunting or underweight to predict HIV disease severity was low. Conclusions. Undernutrition and stunting are common among HIV-infected children at all stages of the disease in India. Early and aggressive nutritional intervention is required, if long-term outcomes are to be improved.