Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TBcoinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4. Rifampin is a key drug in the treatment of tuberculosis (TB), and the World Health Organization (WHO) currently recommends weight-adjusted doses of 8 to 12 mg/kg daily. Despite its being used in the treatment of TB for nearly 50 years, there is evidence that current rifampin exposures may be suboptimal. Rifampin's efficacy is exposure dependent (1-3); therefore, the efficacy and toxicity of higher doses are under investigation. Recent reports show that larger doses of rifampin are well tolerated by humans (4) and may improve treatment outcomes, as well as reduce the treatment duration from the current 6 months (5, 6).Rifampin is mainly hepatically cleared, and it undergoes extensive first-pass metabolism (7), whose saturation with higher doses has been reported since early pharmacokinetic (PK) studies (8). Thus, when the rifampin dose is increased above a certain level, a more-than-proportional increase in the plasma rifampin concentration results. Rifampin also induces its own metabolism via the pregnane X receptor (9), a phenomenon known as clearance autoinduction, resulting in less exposure at steady state than after a single dose.Previous studies have proposed rifampin PK models (10), but those trying to characterize clearance autoinduction have done so mostly by relying on only two PK sampling occasions (11), which limited their ability to characterize the process. Nonlinearity in a dose-exposure relationship suggesting saturation of rifampin clearance has been reported (8). However, a population PK model has not jointly described the autoinduction and hepatic extraction (E H ) of rifampin. In this study, we analyzed rich data from an intensive sampling scheme to develop a rifampin PK model for TB patients that accounts for both clearance autoinduction and saturation of E H . This model was then employed to explore changes in rifampin exposure when doses are incr...

Introduction. GeneXpert® MTB/RIF (Xpert) is now widely distributed in high human immunodeficiency virus (HIV)/tuberculosis (TB)-burden countries. Yet, whether the test improves patient-important outcomes within HIV treatment programs in limited resource settings is unknown.Methods. To investigate whether use of Xpert for TB screening prior to initiation of antiretroviral treatment (ART) improves patient-important outcomes, in a pragmatic randomized controlled trial we assigned 424 patients to Xpert or fluorescence sputum smear microscopy (FM) at ART initiation. The primary endpoint was a composite of 3-month mortality and ART-associated TB.Results. There was no difference in overall TB diagnosis at ART initiation (20% [n = 43] Xpert vs 21% [n = 45] FM; P = .80), with most patients in both groups treated empirically. There was no difference in time to TB treatment initiation {5 days (interquartile range [IQR], 3–13) vs 8 days [IQR, 3–23; P = .26]} or loss to follow-up (32 [15%] vs 38 [18%]; P = 0.38). Although a nonsignificant reduction in mortality occurred in the Xpert group (11 [6%] vs 17 [10%]; 95% CI, −9% to 2%; P = .19), there was no difference in the composite outcome (9% [n = 17] Xpert vs 12% [n = 21] FM; difference −3%; 95% CI, −9% to 4%).Conclusions. Among HIV-infected initiating ART, centralized TB screening with Xpert did not reduce the rate of ART-associated TB and mortality, compared with fluorescence microscopy.

Background Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART). Methods We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm. Results There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype. Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin. Materials & methods: Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan R Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics. Results: Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3-and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes. Conclusion: Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

Universal access to renal replacement therapy is beyond the economic capability of most low and middle-income countries due to large patient numbers and the high recurrent cost of treating end stage kidney disease. In countries where limited access is available, no systems exist that allow for optimal use of the scarce dialysis facilities. We previously reported that using national guidelines to select patients for renal replacement therapy resulted in biased allocation. We reengineered selection guidelines using the ‘Accountability for Reasonableness’ (procedural fairness) framework in collaboration with relevant stakeholders, applying these in a novel way to categorize and prioritize patients in a unique hierarchical fashion. The guidelines were primarily premised on patients being transplantable. We examined whether the revised guidelines enhanced fairness of dialysis resource allocation. This is a descriptive study of 1101 end stage kidney failure patients presenting to a tertiary renal unit in a middle-income country, evaluated for dialysis treatment over a seven-year period. The Assessment Committee used the accountability for reasonableness-based guidelines to allocate patients to one of three assessment groups. Category 1 patients were guaranteed renal replacement therapy, Category 3 patients were palliated, and Category 2 were offered treatment if resources allowed. Only 25.2% of all end stage kidney disease patients assessed were accepted for renal replacement treatment. The majority of patients (48%) were allocated to Category 2. Of 134 Category 1 patients, 98% were accepted for treatment while 438 (99.5%) Category 3 patients were excluded. Compared with those palliated, patients accepted for dialysis treatment were almost 10 years younger, employed, married with children and not diabetic. Compared with our previous selection process our current method of priority setting based on procedural fairness arguably resulted in more equitable allocation of treatment but, more importantly, it is a model that is morally, legally and ethically more defensible.