Anushka. Naidoo

Integration of antiretroviral therapy with tuberculosis treatment.

BACKGROUND We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. METHODS We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. RESULTS At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). CONCLUSIONS Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. Presidents Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.).

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 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 (ART) 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 >1,000 copies/ml on two occasions, taken ≥4 weeks apart) were assessed in these patients. RESULTS A total of 501 TB-HIV-coinfected patients were followed for a mean of 16.0 months (95% CI 15.5, 16.6) after ART initiation. The standard first-line antiretrovirals 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, 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate 3.7 per 100 person-years, 95% CI 2.4, 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4, 0.8%), elevated transaminase levels and hyperlactataemia (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(+) T-cell count <50 cells/mm(3) (P<0.001) at ART initiation and body mass index >25 kg/m(2) (P=0.01) at entry into the study. CONCLUSIONS 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.

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB

Objectives We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

Moxifloxacin, an 8‐methoxy quinolone, is an important drug in the treatment of multidrug‐resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug‐susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment‐shortening regimens for drug‐susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first‐line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400‐mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug‐susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug‐susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first‐line tuberculosis drug regimens.

Efficacy and safety of tenofovir-containing antiretroviral therapy in women who acquired HIV while enrolled in tenofovir gel prophylaxis trials.

BACKGROUND We assessed whether women who acquired HIV during tenofovir gel prophylaxis trials can be safely and effectively treated with tenofovir-containing antiretroviral therapy (ART). METHODS Between May 2011 and October 2014, HIV seroconvertors from two tenofovir gel trials were recruited when eligible for ART (CD4+ T-cell count <350 cells/μl, pregnancy or AIDS-defining illness). Women were randomized to tenofovir-containing (tenofovir + lamivudine/emtricitabine + efavirenz) or tenofovir-sparing (zidovudine + lamivudine/emtricitabine + efavirenz) antiretroviral treatment regimens. The proportion with virological suppression, adverse events and drug switches were compared. RESULTS Fifty-nine women were enrolled and followed-up for median 18 months (IQR 6-24). Twenty-nine women (7 tenofovir gel exposed, 22 tenofovir gel unexposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed, 21 tenofovir gel unexposed) to a tenofovir-sparing regimen. Median baseline CD4+ T-cell count and viral load (VL) were 345 cells/μl (IQR 280-423) and 4.5 log copies/ml (sd 0.79), and did not differ by ART assignment. Overall VL suppression rates were 88.0% and 78.3% at 6 months (P=0.454) and 85.7% and 79.0% at 12 months (P=0.689) in women on the tenofovir-containing and tenofovir-sparing regimens, respectively. Toxicity-related drug switches were more frequent in women on the tenofovir-sparing than tenofovir-containing regimen (36.7% versus 0.0%, P<0.001). CONCLUSIONS Preliminary data show that tenofovir-containing ART was effective and more tolerable in HIV seroconvertors from tenofovir gel prophylaxis trials and may be considered for use in women with prior tenofovir gel exposure. Clinical trials.gov NCT01387022.

Hyperbilirubinemia in atazanavir-treated human immunodeficiency virus-infected patients: the impact of the UGT1A1*28 allele

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Implementing isoniazid preventive therapy in a tuberculosis treatment-experienced cohort on ART.

SETTING Urban clinical research site in Durban, South Africa. OBJECTIVE To describe outcomes associated with the implementation of isoniazid preventive therapy (IPT) in a cohort of tuberculosis (TB) treatment-experienced human immunodeficiency virus (HIV) infected patients on antiretroviral therapy (ART). DESIGN We conducted a secondary analysis of data collected between October 2009 and October 2013 from patients enrolled in a prospective cohort study conducted in Durban, South Africa. RESULTS Of the 402 patients enrolled in the parent study, 344 (85.6%) were eligible for IPT, 212 of whom (61.6%) initiated IPT. Of those who initiated IPT, 184 (86.8%) completed the 6-month course, while 24 (11.3%) permanently discontinued IPT, 3.8% of whom due to side effects. More women than men initiated IPT (n = 130, 61.3% vs. n = 82, 38.7%, P = 0.001). Overall median adherence to IPT was 97.6% (interquartile range 94.2-99.4). There were 22 cases of incident TB in this cohort: 13 occurred before IPT and 9 after (incidence rate ratio 0.67, 95%CI 0.29-1.58, P = 0.362). CONCLUSIONS IPT implementation among ART and TB treatment-experienced patients was well tolerated, with good completion rates and fewer TB cases diagnosed after IPT.