Changes to antiretroviral drug regimens during integrated TB-HIV treatment: results of the SAPiT trial.

Background—Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and human immunodeficiency virus (HIV) therapy, as a result of treatment-limiting toxicity or virological failure, is not well established. Methods—Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients. Results—A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs used, were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate: 2.1 per 100 person-years; 95% (CI): 1.1 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (n= 3; 0.6%), and peripheral neuropathy (n=2; 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study. Conclusion—Both drug switches and complete regimen change were uncommon in patients cotreated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change

The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.

Background: Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients. Objective: To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis. Design: Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996) Setting: An outpatient clinic in Durban, South Africa. Patients: 642 patients co-infected with HIV and tuberculosis. Measurements: In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored. Results: Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 10.9 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups. Limitations: It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis. Conclusion: Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 10.9 cells/L, given the increased survival benefit of early ART initiation in this group

Timing of Initiation of Antiretroviral Drugs during Tuberculosis Therapy

The rates of death are high among patients with coinfection with tuberculosis and the human immunodeficiency virus (HIV). The optimal timing for the initiation of antiretroviral therapy in relation to tuberculosis therapy remains controversial

Culture Conversion Among HIV Co-Infected Multidrug-Resistant Tuberculosis Patients in Tugela Ferry, South Africa

Little is known about the time to sputum culture conversion in MDR-TB patients co-infected with HIV, although such patients have, historically, had poor outcomes. We describe culture conversion rates among MDR-TB patients with and without HIV-co-infection in a TB-endemic, high-HIV prevalent, resource-limited setting.Patients with culture-proven MDR-TB were treated with a standardized second-line regimen. Sputum cultures were taken monthly and conversion was defined as two negative cultures taken at least one month apart. Time-to-conversion was measured from the day of initiation of MDR-TB therapy. Subjects with HIV received antiretroviral therapy (ART) regardless of CD4 count.Among 45 MDR-TB patients, 36 (80%) were HIV-co-infected. Overall, 40 (89%) of the 45 patients culture-converted within the first six months and there was no difference in the proportion who converted based on HIV status. Median time-to-conversion was 62 days (IQR 48-111). Among the five patients who did not culture convert, three died, one was transferred to another facility, and one refused further treatment before completing 6 months of therapy. Thus, no patients remained persistently culture-positive at 6 months of therapy.With concurrent second-line TB and ART medications, MDR-TB/HIV co-infected patients can achieve culture conversion rates and times similar to those reported from HIV-negative patients worldwide. Future studies are needed to examine whether similar cure rates are achieved at the end of MDR-TB treatment and to determine the optimal use and timing of ART in the setting of MDR-TB treatment

Chest radiograph findings and time to culture conversion in patients with multidrug-resistant tuberculosis and HIV in Tugela Ferry, South Africa.

BACKGROUND: The majority of patients with multidrug-resistant tuberculosis (MDR-TB) in South Africa are co-infected with HIV, but the radiographic features of MDR-TB and their relationship with time to sputum culture conversion in the antiretroviral therapy era have not been described. METHODS: We reviewed baseline chest radiographs for 56 patients with MDR-TB from a rural area of South Africa. We analyzed the association of cavities, consolidation, pleural effusion and hilar lymphadenopathy with time to sputum culture conversion, adjusting for HIV status, baseline sputum smear and CD4 count. RESULTS: Of the 56 subjects, 49 (88%) were HIV-positive, with a median CD4 count of 136 cells/mm(3) (IQR 65-249). Thirty-two (57%) patients were sputum smear positive. Twenty-two (39%) patients had a cavity and 37 (66%) patients had consolidations. Cavitary disease and consolidations were each associated with longer time to culture conversion on bivariate analysis but not after adjusting for sputum smear status (aORs 1.79 [0.94-3.42] and 1.09 [0.67-1.78], respectively). Positive baseline sputum smear remained independently associated with longer time to conversion (aOR 3.45 [1.39-8.59]). We found no association between pleural effusion or hilar lymphadenopathy and time to conversion. Seventy-nine percent of patients were cured at the end of treatment. CONCLUSIONS: Despite high rates of HIV co-infection and advanced immunodeficiency, the majority of patients had severe pathology on baseline chest radiograph. Nevertheless, culture conversion rates were high and treatment outcomes were favorable. Cavitation and consolidation do not appear to have an independent association with time to culture conversion beyond that of baseline sputum smear status

Chest radiograph showing left-sided pleural effusion, consolidation and both hilar and mediastinal lymphadenopathy.

<p>Chest radiograph showing left-sided pleural effusion, consolidation and both hilar and mediastinal lymphadenopathy.</p

Kaplan-Meier plot of time to sputum culture conversion, by HIV-status.

<p>Kaplan-Meier plot of time to sputum culture conversion, by HIV-status.</p

Baseline characteristics by HIV status.

<p>IQR: interquartile range; MDR-TB: multidrug-resistant tuberculosis; ART: antiretroviral therapy;</p><p>BMI: body mass index.</p