Home Hepatitis Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

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Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Viral-host kinetics during REP 2139-Ca monotherapy

The kinetics of HBV DNA, anti-HBs, ALT, HBsAg and HDV for individual participants are described in Fig. 1. The pre-treatment HBV DNA was <3 log10 IU/mL in all 12 participants and it was <LLoQ in 5 cases (Table 1). HBV DNA levels varied by <1 log10 over the course of treatment and did not correlate with observed responses in HBsAg and HDV RNA levels.

Figure 1

HDV RNA (triangles), HBV DNA (circles), HBsAg (squares), and ALT (x) kinetics during 15-week REP 2139-Ca monotherapy. Point markers with no fill indicate a measurement below the LLoQ, markers with gray fill indicate TND, and an asterisk below a week number indicates the point at which the given patient’s level of Anti-HBs surpassed the LLoQ (i.e., 10 mIU/mL) if at all. LLoQ is HBsAg: 0.05 IU/mL, HDV RNA: 1800 U/mL, HBV DNA: 10 IU/mL.

Pre-treatment ALT had a median value of 97 U/L [interquartile range:85.5–128]. Half of the cases experienced transient ALT increases and the highest ALT flare was 281 U/L. The median pre-treatment HBsAg titer was 4.15 [3.96–4.31] log10 IU/mL. Two patients (Pt 20 and Pt 22) experienced HBsAg decline <1 log10 IU/mL from baseline and were classified as non-responders. A third patient, Pt 9, was a borderline responder, who had a minimal HBsAg decrease and HDV decreased only towards the end of treatment. Nonetheless, due to the magnitude of HDV decline, we chose to include Pt 9 in our modeling analysis. After a delay of 3–7 weeks during which HBsAg remained at pre-treatment levels, all responding patients exhibited a biphasic decrease in HBsAg, except for Pt 9 who had a monophasic HBsAg decline (Fig. 1). The median anti-HBs titers at week 15 post initiation of monotherapy in the 6 patients who experienced seroconversion (Fig. 1) was 25 [IQR: 23–30] mIU/mL.

The median pre-treatment HDV level was 6.7 [6.1–7.1] log10 U/mL. In the 2 HBsAg non-responders, HDV decline was either 0.83 log10 U/mL from baseline (Pt20) or transiently increased but eventually declined to 2.48 (Pt22) log10 U/mL from baseline. After a 3–7 week delay during which HDV remained at pre-treatment levels, 5 of 10 responding patients experienced a rapid monophasic decline in HDV either reaching LLoQ or TND and 5 had a biphasic pattern with a slower 2nd phase HDV decline (Fig. 1). By the end of therapy, the 10 responding patients experienced median HDV declines of 4.4 [3.5–5.8] log10 U/mL. HDV was undetectable in 4 cases and below LLoQ in 3 additional patients at week 15 (Fig. 1).

Following monotherapy, patients underwent combination therapy with REP 2139-Ca and pegIFN. A total of 9 patients were HDV RNA negative at the end of the full treatment course and 7 of these 9 patients remained HDV RNA negative 2.5 years later8,12.

Overall, the kinetic analysis suggests that: (i) there was no association between changes in HBV DNA and HBsAg levels or between HBV DNA and HDV RNA levels, (ii) anti-HBs sero-conversion occurred in half of responding patients and took place several weeks after HBsAg and HDV started to decline from pre-treatment levels and typically occurred towards the end of treatment, (iii) reminiscent of our previous findings in mono-infected HBV patients10, ALT elevations (with the exception of patient 1) did not correlate with changes in HBsAg or HDV levels, and (iv) after apparently similar delays HBsAg and HDV kinetics were highly correlated. Thus, we chose to model only the kinetics of HDV RNA and HBsAg in Eq. 1 (Fig. 2).

Modeling results

The model (Fig. 2 and Eq. 1) reproduces well the HDV RNA and HBsAg kinetics in the 10 responding patients (Fig. 3) and provides estimates of unknown model parameters (Table 2). Modeling calibration with measured data estimates median baseline HDV RNA V0 of 6.7 [6.1–7.0] log10 U/mL and median baseline HBsAg H0 of 4.2 [4.1–4.3] log10 IU/mL. The median time delay before blockage of HBsAg and HDV RNA production tb was 25.3 [20.3–32.8] days. The median clearance rate of HBsAg c, was found to be 0.53 [0.38–0.79] days−1 corresponding to a HBsAg t1/2 = 1.3 days. The estimated HBsAg t1/2 implies a median production and clearance of 108 [107.7–108.3] copies/day. The median efficacy of blocking HBsAg production εH was 0.982 [0.945–0.999] and the median efficacy of blocking HDV RNA production εV was found to be 0.997 [0.959–0.998]. The median estimated loss rate of infected cells δ, was 0.052 [0.035–0.074] cells/day. We note that model fits for Pt 9, who was a border-line responder were included in our analysis of the median and IQR, however as these are nonparametric measures, removing this Pt 9 from the analysis had a minimal effect on these values.

Figure 2
figure2

A schematic description of the model (Eq.1). Target cells, T0, are infected with rate β, and become infectious cells I. Infectious cells loss at a rate 𝛿, and produce virions, V, at rate p. After treatment the production rate of virions is reduced by a factor (1-εv). Virions are cleared at rate c. Infectious cells also produce HBsAg, H, at rate PH. This rate is reduced by a factor (1-εH) after treatment. HBsAg is cleared at rate cH. As was done previously13, we assume that T0 was constant during the 15 weeks of treatment at its pre-treatment steady-state value.

Table 1 Patient baseline characteristics.

We did not find any association between the individual fit parameter values tb, εH, εV, and δ and baseline characteristics including duration of infection, ALT, gender, liver stiffness, V0, and H0. We found that p > 0.1 for all tested associations. In particular, the lack of association with ALT further justifies excluding ALT dynamics from our model.

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