Nadim Salomon

Evaluation of an Intensive Intermittent-Induction Regimen and Duration of Short-Course Treatment for Human Immunodeficiency Virus-Related Pulmonary Tuberculosis

This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates.

The Clinical Pharmacokinetics of Rifampin and Ethambutol in HIV-Infected Persons with Tuberculosis

BACKGROUNDnThe pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States.nnnMETHODSnSerum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data.nnnRESULTSnWith daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL).nnnCONCLUSIONSnIn HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.

Modified Directly Observed Antiretroviral Therapy Compared with Self-Administered Therapy in Treatment-Naïve HIV-1 Infected Patients: A Randomized Trial

BACKGROUNDnSuccess of antiretroviral therapy depends on high rates of adherence, but few interventions are effective. Our objective was to determine if modified directly observed therapy (mDOT) improves initial antiretroviral success.nnnMETHODSnIn an open-label, randomized trial comparing mDOT (Monday-Friday for 24 weeks) and self-administered therapy with lopinavir/ritonavir soft gel capsules (800 mg/200 mg), emtricitabine (200 mg), and either extended-release stavudine (100 mg) or tenofovir (300 mg), all taken once daily, 82 participants received mDOT and 161, self-administered therapy. Participant eligibility included a plasma human immunodeficiency virus RNA level higher than 2000 copies/mL and being naïve to antiretroviral therapy. A total of 243 participants were predominantly male (79%) (median age, 38 years), with 84 Latinos (35%), 74 non-Latino blacks (30%), and 79 non-Latino whites (33%). The study was conducted at 23 AIDS Clinical Trials Group (ACTG) sites in the United States and 1 site in South Africa between October 2002 and January 2006. The primary outcome was virologic success at week 24 and secondary outcomes were virologic success, clinical progression, and adherence at week 48.nnnRESULTSnOver 24 weeks, mDOT had greater virologic success (0.91; 95% confidence interval [CI], 0.81 to 0.95) than self-administered therapy (0.84; 95% CI, 0.77 to 0.89), but the difference (0.07; lower bound 95% CI, -0.01) did not reach the prespecified threshold of 0.075. Over 48 weeks, virologic success was not significantly different between mDOT (0.72; 95% CI, 0.61 to 0.81) and self-administered therapy (0.78; 95% CI, 0.70 to 0.84) (difference, -0.06; 95% CI, -0.18 to 0.07 [P = .19]).nnnCONCLUSIONSnThe potential benefit of mDOT was marginal and not sustained after discontinuation. Modified DOT should not be incorporated routinely for care of treatment-naïve human immunodeficiency virus type 1-infected patients.

Clinical features and outcome of HIV-related cytomegalovirus pneumonia

Objective:To describe the characteristics and outcomes of HIV-infected patients with biopsy-proven cytomegalovirus (CMV) pneumonia. Design:Retrospective study. Setting:A 900-bed acute care facility in New York City. Patients:Eighteen HIV-infected patients with pathologically confirmed CMV inclusions in lung tissue without other pathogens and 36 control patients with biopsy-proven Pneumocystis carinii pneumonia (PCP) selected for comparisons by computer-generated random sequential numbers. Main outcome measures:Demographic, clinical, laboratory, radiological findings, and in-hospital mortality. Results:Eighteen HIV-infected patients were found to have CMV lung infection alone. Pathologic findings were pneumonitis (n = 11); pneumonitis and pulmonary vasculitis (n = 1); and CMV inclusions alone (n = 6). All presented with respiratory symptoms (cough or dyspnea), 89% had fever, 83% had radiological abnormalities, and 56% had severe hypoxemia. The pulmonary presentation was similar except for higher lactate dehydrogenase (median, 449 versus 329 IU/l; P = 0.03) and presence of pleural effusions (33 versus 0%; P = 0.001) in CMV patients. Multivariate analysis showed that CD4 counts ≤ 12 × 106/l (odds ratio, 9.2; P = 0.029) and extrapulmonary CMV (odds ratio, 20.4; P = 0.039) were independently associated with CMV pneumonia. Seventeen patients received specific anti-CMV therapy for a mean of 22 ± 13 days. In-hospital mortality was higher in patients with CMV pneumonia (odds ratio, 11.9; P = 0.002). The median time from admission to death was 31 days. Conclusions:CMV lung infection was seen in severely immunosuppressed HIV-positive patients and was associated with clinical pneumonitis with high early mortality. Although the clinical features resemble PCP, the presence of extrapulmonary CMV disease should suggest the diagnosis of CMV pneumonia.

The Clinical Pharmacokinetics of Pyrazinamide in HIV-Infected Persons with Tuberculosis

The pharmacokinetics of pyrazinamide (PZA) in patients with human immunodeficiency virus (HIV)-related tuberculosis are incompletely characterized. Serum PZA concentrations were determined at 2, 6, and 10 h after dosing in 48 subjects with HIV-related tuberculosis. Estimates of drug exposure using 2-h concentrations and 2- and 3-time point estimates of area under time-concentration curves (AUCs) were compared. For daily dosing, 2-h concentrations less than low and very low literature-defined cut points (i.e., 20 and 10 mg/L) were noted for 2 subjects (4%) and 1 subject (2%), respectively. For intermittent PZA dosing, 1 subject (4%) had a 2-h concentration that was less than the low cut point (25 mg/L). Correlations between 2-h concentration and AUC estimates based on 2- or 3-time point concentration determinations were strong. In HIV-infected persons receiving antituberculosis regimens containing PZA, lower-than-expected 2-h concentrations are uncommon. For therapeutic monitoring of PZA drug exposure, determination of a 2-h postdose concentration appears as reliable as 2- or 3-time point estimates of the AUC for PZA.