Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF)

Abstract Background Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients. Methods This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid. Discussion This study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort. Trial registration ClinicalTrials.gov, ID: NCT03982277. Registered retrospectively on 11 June 2019

Understanding the Role of Past Health Care Discrimination in Help-Seeking and Shared Decision-Making for Depression Treatment Preferences

As a part of a larger, mixed-methods research study, we conducted semi-structured interviews with 21 adults with depressive symptoms to understand the role that past health care discrimination plays in shaping help-seeking for depression treatment and receiving preferred treatment modalities. We recruited to achieve heterogeneity of racial/ethnic backgrounds and history of health care discrimination in our participant sample. Participants were Hispanic/Latino (n = 4), non-Hispanic/Latino Black (n = 8), or non-Hispanic/Latino White (n = 9). Twelve reported health care discrimination due to race/ethnicity, language, perceived social class, and/or mental health diagnosis. Health care discrimination exacerbated barriers to initiating and continuing depression treatment among patients from diverse backgrounds or with stigmatized mental health conditions. Treatment preferences emerged as fluid and shaped by shared decisions made within a trustworthy patient–provider relationship. However, patients who had experienced health care discrimination faced greater challenges to forming trusting relationships with providers and thus engaging in shared decision-making processes

Incidence of HIV disclosure among HIV affected heterosexual partners using a community health worker led mechanism in rural Uganda; a quasi-experimental study

Abstract Background HIV disclosure is vital in HIV management. Community Health Workers (CHW) were reported to support partner disclosure among HIV affected heterosexual partners with disclosure difficulties. However, time to disclosure attributed to use of CHW led disclosure support mechanism was not documented. This study compared the incidence of sexual partner disclosure among adults living with HIV (ALHIV) with CHW support and those without in the greater Luwero region, Uganda. Methods We conducted a quasi-experimental study with two arms allocated by geographically determined clusters and adjusted for between-group differences; among ALHIV in the greater Luwero region of Uganda who had never disclosed to their current primary sexual partners. We allocated study clusters to either a CHW-led intervention or control arm. In both arms, we consecutively recruited participants; those in the intervention arm received CHW disclosure support in addition to routine care. The overall follow-up was six months, and the primary outcome was disclosure to the partner. We used survival analysis with proportional hazard ratios to determine the time to partner disclosure in both arms. Results A total of 245 participants were enrolled, and 230 (93.9%) completed the study; of these, 112 (48.7%) were in the intervention and 118 (51.3%) in the control arm. The mean age was 31 ± 8 years with a range of 18 to 55 years; the majority were females, 176 (76.5%). The cumulative incidence of disclosure was higher in the intervention arm, 8.76 [95% CI: 7.20–10.67] per 1,000 person-days versus 5.15 [95%CI: 4.85–6.48] per 1,000 person-days in the control arm, log-rank test, X2 = 12.93, P  six months, aHR = 1.19 predicted disclosure. Prior disclosure to a relative, aHR = 0.55, and having more than one sexual partner in the past three months, aHR = 0.74, predicted non-disclosure. Conclusion CHW-led support mechanism increased the rate of sexual partner disclosure among ALHIV with disclosure difficulties. Therefore, to achieve the global targets of ending HIV, near location CHW-led disclosure support mechanism may be used to hasten HIV disclosure in rural settings

Community Health Workers Improve HIV Disclosure Among HIV-Affected Sexual Partners in Rural Uganda : A Quasi-Experimental Study

Background: We evaluated the efficacy of a community health worker (CHW)–led intervention in supporting disclosure among adults living with HIV in heterosexual relationships. Methods: We conducted a quasi-experimental study with 2 arms allocated by geographically determined clusters and adjusted for between-group differences among adults living with HIV in the greater Luwero region of Uganda who had never disclosed their status to their current primary sexual partners. Clusters were allocated to either a CHW-led intervention or a control arm. In both arms, participants were consecutively recruited. As opposed to receiving routine care for the control arm, participants in the intervention arm received additional CHW disclosure support. The overall follow-up was 6 months, and the primary outcome was disclosure to the sexual partner. Data were analyzed using a clustered modified Poisson regression model with robust standard errors to determine independent factors associated with disclosure. Results: Of the 245 participants who enrolled, 230 (93.9%) completed the study, and 112 (48.7%) of those were in the intervention arm. The median age was 30 (interquartile range=25–37) years, the majority were women (76.5%), and most (80%) did not know their partners’ HIV status at study entry. At the end of follow-up, the overall disclosure prevalence was 74.4% (95% confidence interval [CI]=68.2, 79.9) and participants in the intervention arm were 51% more likely to disclose compared to those in the control (adjusted relative ratio [aRR]=1.51; 95% CI=1.28, 1.77). Men were 24% (aRR=1.24; 95% CI=1.07, 1.44) more likely to disclose compared to women, and membership in an HIV/AIDS association increased disclosure by 18% (aRR=1.18; 95% CI=1.01, 1.39). Conclusion: CHW support improved disclosure among adults living with HIV in heterosexual relationships when compared to routine care. Therefore, CHW-led mechanisms may be utilized in increasing disclosure among adults living with HIV in heterosexual relationships in rural settings

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination

Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7–36.7) and 153 (138−175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h−1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1–1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen

“It is not easy”:experiences of people living with HIV and tuberculosis on Tuberculosis treatment in Uganda

This study was funded by the Global Challenges Research Fund through the Scottish Funding Council administered via the University of St Andrews reference SFC/AN/18/2020, and the EDCTP2 programme supported by the European Union (grant number TMA2016CDF-1580). Additional research support was provided by the Fogarty Interntional Centre, National Institutes of Health (grant # 2D43TW009771-06 "HIV and co-infections in Uganda."Background Completion of tuberculosis (TB) treatment presents several challenges to patients, including long treatment duration, medication adverse-effects and heavy pill burden. WHO emphasize the need for patient-centered TB care, but such approaches require understanding of patient experiences and perceptions. Methods In 2020, we nested a qualitative study within a clinical trial that recruited 128 HIV-TB co-infected adults in Kampala receiving rifampicin-based TB treatment, alongside anti-retroviral therapy. A purposively selected sub-sample of 46 trial participants contributed to nine gender segregated focus group discussions. Of these, 12 also participated in in-depth interviews. Sessions were recorded, transcribed verbatim and translated from local languages into English. Thematic analysis focused on drug adverse-effects, use of self-prescribed medications and barriers to treatment adherence. Results Patients seemed more concerned about adverse effects that clinicians sometimes overlook such as change in urine color. Those who remembered pre-treatment counselling advice were disinclined to manage adverse-effects by self-prescription. Difficulty in accessing a medical practitioner was reported as a reason for self-medication. Obstacles to adherence included stigma (especially from visible adverse-effects like “red urine”), difficulties with pill size and number, discomfort with formulation and medication adverse effects. Conclusion Tailored pre-treatment counselling, improved access to clinical services, and simpler drug administration will deliver more patient-centered care.Publisher PDFPeer reviewe

Decreased dolutegravir and efavirenz concentrations with preserved virological suppression in patients with TB and HIV receiving high-dose rifampicin

Background Higher doses of rifampicin may improve treatment outcomes and reduce the duration of TB therapy, but drug-drug interactions with anti-retroviral therapy (ART) and safety in people living with HIV have not been evaluated.  Methods This was a randomized open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily dose rifampicin. ART treatment naïve patients were randomized to dolutegravir- or efavirenz-based ART, whilst those already on ART continued existing medications. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. Sputum was collected for mycobacterial culture collected at week 8, and plasma for HIV viral load at Week 24.  Results Among 128 patients randomized, the median CD4 count was 191cells/mm3. Geometric mean ratio (GMR) for trough dolutegravir concentrations on higher vs. standard-dose rifampicin was 0.57 [95% CI, 0.34-0.97, p = 0.039] and GMR for mid-dose efavirenz was 0.63 [95% CI, 0.38-1.07, p = 0.083]. There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs. 14.0%, p = 0.901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs. 37.0%, p = 0.063).  Conclusions Compared to standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well-tolerated among people living with HIV, and associated with a trend towards faster sputum culture conversion.</div