Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B.

BACKGROUND & AIMS: Lamivudine resistance occurs in patients with chronic hepatitis B at rates of 16%-32% after 1 year and 49% after 3 years. Adefovir dipivoxil, a nucleotide analogue recently approved by the Food and Drug Administration for the treatment of chronic hepatitis B, is effective against hepatitis B virus (HBV) but has been associated with renal toxicity at high doses. Tenofovir disoproxil fumarate is another nucleotide analogue with demonstrated antiviral activity against both wild-type and lamivudine-resistant HBV. Tenofovir, at its licensed dose, has not been associated with renal dysfunction. METHODS: We describe a series of 9 patients with lamivudine-resistant hepatitis B treated with tenofovir, 300 mg, once daily before the availability of adefovir. Levels of HBV DNA, alanine aminotransferase (ALT), hepatitis B e antigen (HBeAg), and antibody to HBeAg (anti-HBe) were monitored. RESULTS: The addition of tenofovir to the existing regimen of lamivudine resulted in a median decline of 4.5 log(10) copies/mL in HBV DNA levels (range, 3.2-6.3 log(10) copies/mL) after a median treatment duration of 12 months (range, 6-16 mo). HBeAg seroconversion was observed in 2 patients, with a third patient undergoing HBeAg loss while remaining anti-HBe negative. In 4 of 7 patients with elevated ALT levels at baseline, ALT levels normalized. No significant adverse events were encountered during treatment. CONCLUSIONS: In patients with lamivudine-resistant hepatitis B, treatment with tenofovir is well tolerated and results in significant virological, serological, and biochemical improvements on par with those seen with high-dose adefovir (30 mg/day) therapy, without the complication of renal toxicity.     

Durability of serologic response after lamivudine treatment of chronic hepatitis B

Forty subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following lamivudine therapy in previous trials were monitored after treatment to assess the durability of serologic responses. Patient follow-up began a median of 4.3 months after completion of therapy in previous trials. At months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter, we tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT). After a median (range) of 36.6 (4.8-45.6) months of follow-up monitoring, HBeAg seroconversion was demonstrated at the last visit by 77% (30 of 39) of patients. In a post hoc analysis of a slightly different population of all 65 patients with HBeAg seroconversion in previous trials, the 3-year durability of HBeAg seroconversion measured from the time immediately after discontinuing lamivudine therapy was 64%. Nine (9 of 40, 23%) patients were HBsAg negative at the last assessment. Seventy-four percent (17 of 23) of patients with baseline undetectable HBV DNA and normal ALT maintained these responses at the last visit. Eight patients (8 of 40, 20%) initiated retreatment for reappearance of HBV markers, and 7 showed biochemical and/or virologic improvement (including regained HBeAg seroconversion in 2). No safety issues of concern emerged. In conclusion, most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression.     

Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B

Elevated alanine transaminase (ALT) levels and low serum hepatitis B virus (HBV) DNA predict a higher likelihood of hepatitis B e antigen (HBeAg) loss in patients with chronic hepatitis B treated with interferon. Predictors of HBeAg loss in patients treated with lamivudine are not known. The objective of this analysis of 4 lamivudine-controlled Phase III trials was to determine patient-dependent or laboratory variables that predict HBeAg loss. Predictors of HBeAg loss in patients treated with interferon, lamivudine plus interferon, or placebo are also described. A total of 805 adults with chronic hepatitis B were treated either with lamivudine (n = 406), matching placebo (n = 196), interferon (n = 68), or the combination of lamivudine plus interferon (n = 135). Demographic and baseline disease characteristics were used in stepwise multivariate analyses to identify features that were predictive of lamivudine-induced HBeAg loss. HBeAg loss correlated with increased pretreatment ALT levels in all groups. The rate of HBeAg loss was highest among patients with pretreatment ALT levels greater than 5 times the upper limit of normal (ULN) and was most pronounced in the lamivudine group (56%). Multivariate modeling indicated that elevated baseline ALT levels (P <.001) and histologic activity index (HAI) score (P <.001) were important predictors of HBeAg loss in response to lamivudine. The effect of pretreatment ALT levels on HBeAg loss was similar for Asians and Caucasians. In conclusion, elevated pretreatment ALT levels and/or active histologic disease were the most important predictors of lamivudine-induced HBeAg loss. Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels.     

A C-Peptide-Based Model of Pancreatic Insulin Secretion in Extremely Preterm Neonates in Intensive Care

Background:

Model-based glycemic control relies on sufficiency of underlying models to describe underlying patient physiology. In particular, very preterm infant glucose-insulin metabolism can differ significantly from adults, and is relatively unstudied. In this study, C-peptide concentrations are used to develop insulin-secretion models for the purposes of glycemic control in neonatal intensive care.

Methods:

Plasma C-peptide, insulin, and blood glucose concentrations (BGC) were retrospectively analyzed from a cohort of 41 hyperglycemic very preterm (median age 27.2 [26.2-28.7] weeks) and very low birth-weight infants (median birth weight 839 [735-1000] g). A 2-compartment model of C-peptide kinetics was used to estimate insulin secretion. Insulin secretion was examined with respect to nutritional intake, exogenous and plasma insulin concentration, and BGC.

Results:

Insulin secretion was found to be highly variable between patients and over time, and could not be modeled with respect to age, weight, or protein or dextrose intake. In 13 of 54 samples exogenous insulin was being administered, and insulin secretion was lower. However, low data numbers make this result inconclusive. Insulin secretion was found to increase with BG, with a stronger association in female infants than males (R² = .51 vs R² = .13, and R² = .26 for the combined cohort).

Conclusions:

A sex-based insulin secretion model was created and incorporated into a model-based glycemic control framework. Nutritional intake did not predict insulin secretion, indicating that insulin secretion is a complex function of a number of metabolic factors.     

Introduction of Monkeypox into a Community and Household: Risk Factors and Zoonotic Reservoirs in the Democratic Republic of the Congo

An increased incidence of monkeypox (MPX) infections in the Democratic Republic of the Congo was noted by the regional surveillance system in October 2013. Little information exists regarding how MPX is introduced into the community and the factors associated with transmission within the household. Sixty-eight wild animals were collected and tested for Orthopoxvirus. Two of three rope squirrels (Funisciurus sp.) were positive for antibodies to Orthopoxviruses; however, no increased risk was associated with the consumption or preparation of rope squirrels. A retrospective cohort investigation and a case–control investigation were performed to identify risk factors affecting the introduction of monkeypox virus (MPXV) into the community and transmission within the home. School-age males were the individuals most frequently identified as the first person infected in the household and were the group most frequently affected overall. Risk factors of acquiring MPXV in a household included sleeping in the same room or bed, or using the same plate or cup as the primary case. There was no significant risk associated with eating or processing of wild animals. Activities associated with an increased risk of MPXV transmission all have potential for virus exposure to the mucosa.