Long-Term Hepatitis B Virus (HBV) Response to Lamivudine-Containing Highly Active Antiretroviral Therapy in HIV-HBV Co-Infected Patients in Thailand

Background: Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known. Methodology/Principal Finding: HIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 $log_{10}$ IU/mL and 4.47 $log_{10}$ copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L. Conclusions: All HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC

The association of functional status with mortality and dialysis modality change : results from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS)

BACKGROUND: Little is known about the prevalence of functional impairment in peritoneal dialysis (PD) patients, its variation by country, and its association with mortality or transfer to hemodialysis. METHODS: A prospective cohort study was conducted in PD patients from 7 countries in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) (2014 - 2017). Functional status (FS) was assessed by combining self-reports of 8 instrumental and 5 basic activities of daily living, using the Lawton-Brody and the Katz questionnaires. Summary FS scores, ranging from 1.25 (most dependent) to 13 (independent), were based on the patient's ability to perform each activity with or without assistance. Logistic regression was used to estimate the odds ratio (OR; 95% confidence interval [CI]) of a FS score < 11 comparing each country with the United States (US). Cox regression was used to estimate the hazard ratio (HR; 95% CI) for the effect of a low FS score on mortality and transfer to hemodialysis, adjusting for case mix. RESULTS: Of 2,593 patients with complete data on FS, 48% were fully independent (FS = 13), 32% had a FS score 11 to < 13, 14% had a FS score 8 to < 11, and 6% had a FS score < 8. Relative to the US, low FS scores (< 11; more dependent) were more frequent in Thailand (OR = 10.48, 5.90 - 18.60) and the United Kingdom (UK) (OR = 3.29, 1.77 - 6.08), but similar in other PDOPPS countries. The FS score was inversely and monotonically associated with mortality but not with transfer to hemodialysis; the HR, comparing a FS score < 8 vs 13, was 4.01 (2.44 - 6.61) for mortality and 0.91 (0.58 - 1.43) for transfer to hemodialysis. CONCLUSION: Regional differences in FS scores observed across PDOPPS countries may have been partly due to differences in regional patient selection for PD. Functional impairment was associated with mortality but not with permanent transfer to hemodialysis

Influence of body weight on achieving indinavir concentrations within its therapeutic window in HIV-infected Thai patients receiving indinavir boosted with ritonavir

Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity

HIV RNA measurement in dried blood spots of HIV-infected patients in Thailand using Abbott m2000 system.

World Health Organization recommends using dried blood spots (DBS) for HIV RNA viral load (VL) measurement whenever plasma processing is not convenient or feasible. DBS collected from 80 treatment-naïve HIV-infected patients presenting in three hospitals of two different regions of Thailand were shipped to a central laboratory along with corresponding plasma specimens. Viral load was measured in both DBS and plasma using the Abbott m2000 system. HIV RNA levels were strongly correlated (r = 0.94) with a mean of differences of 0.23 log10 copies/mL. Using the 1,000 copies/mL cut-off, the sensitivity of DBS was 97% (95%CI, 91-100%) and specificity was 75% (95%CI, 19-99%). DBS are useful to scale-up HIV RNA VL testing in settings with limited access to VL testing

Intraperitoneal cefepime monotherapy versus combination therapy of cefazolin plus ceftazidime for empirical treatment of CAPD-associated peritonitis: A multicenter, open-label, noninferiority, randomized, controlled trial

Rationale & Objective: Compared to combination therapy, intraperitoneal (IP) cefepime monotherapy for continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis may provide potential benefits in lowering staff burden, shortening time-consuming antibiotic preparation, and reducing bag contamination risk. This study sought to evaluate whether cefepime monotherapy is noninferior to combination regimens. Study Design: Multicenter, open-label, noninferiority, randomized, controlled trial. Setting & Participants: Adult incident peritoneal dialysis (PD) patients with CAPD-associated peritonitis in 8 PD centers in Thailand. Interventions: Random assignment to either IP monotherapy of cefepime, 1 g/d, or IP combination of cefazolin and ceftazidime, 1 g/d, both given as continuous dosing. Outcomes: Primary end point: resolution of peritonitis at day 10 (primary treatment response). Secondary outcomes: initial response (day 5), complete cure (relapse/recurrence-free response 28 days after treatment completion), relapsing/recurrent peritonitis, and death from any cause. Noninferiority would be confirmed for the primary outcome if the lower margin of the 1-sided 95% CI was not less than −10% for difference in the primary response rate. A 2-sided 90% CI was used to demonstrate the upper or lower border of the 1-sided 95% CI. Results: There were 144 eligible patients with CAPD-associated peritonitis, of whom 70 and 74 patients were in the monotherapy and combination-therapy groups, respectively. Baseline demographic and clinical characteristics were not different between the groups. The primary response was 82.6% in the monotherapy group and 81.1% in the combination-therapy group (treatment difference, 1.5%; 90% CI, −9.1% to 12.1%; P = 0.04). There was no significant difference in the monotherapy group compared with the combination-therapy group in terms of initial response rate (65.7% vs 60.8%; treatment difference, 4.9%; 95% CI, −10.8% to 20.6%; P = 0.5) and complete cure rate (80.0% vs 80.6%; treatment difference, −0.6%; 95% CI, −13.9% to 12.8%; P = 0.7). Relapsing and recurrent peritonitis occurred in 4.6% and 4.6% of the monotherapy group and 4.2% and 5.6% of the combination-therapy group (P = 0.9 and P = 0.8, respectively). There was nominally higher all-cause mortality in the monotherapy group (7.1% vs 2.7%; treatment difference, 4.4%; 95% CI, −2.6% to 11.5%), but this difference was not statistically significant (P = 0.2). Limitation: Not double blind. Conclusions: IP cefepime monotherapy was noninferior to conventional combination therapy for resolution of CAPD-associated peritonitis at day 10 and may be a reasonable alternative first-line treatment. Funding: This study is supported by The Kidney Foundation of Thailand (R5879), Thailand; Rachadaphiseksompotch Fund (RA56/006) and Rachadaphicseksompotch Endorsement Fund (CU-GRS_61_06_30_01), Chulalongkorn University, Thailand; National Research Council of Thailand (156/2560), Thailand; and Thailand Research Foundation (IRG5780017), Thailand. Trial Registration: Registered at ClinicalTrials.gov with study number NCT02872038

Long-term hepatitis B virus (HBV) response to lamivudine-containing highly active antiretroviral therapy in HIV-HBV co-infected patients in Thailand.

Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known.HIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 log(10) IU/mL and 4.47 log(10) copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L.All HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC