Modeling of patient virus titers suggests that availability of a vaccine could reduce hepatitis C virus transmission among injecting drug users

Abstract

The major route of hepatitis C virus (HCV) transmission in the United States is injection drug use. We hypothesized that if an HCV vaccine were available, vaccination could affect HCV transmission among people who inject drugs by reducing HCV titers after viral exposure without necessarily achieving sterilizing immunity. To investigate this possibility, we developed a mathematical model to determine transmission probabilities relative to the HCV RNA titers of needle/syringe-sharing donors. We simulated sharing of two types of syringes fitted with needles that retain either large or small amounts of fluid after expulsion. Using previously published viral kinetics data from both naïve subjects infected with HCV and reinfected individuals who had previously cleared an HCV infection, we estimated transmission risk between pairs of serodiscordant injecting drug users, accounting for syringe type, rinsing, and sharing frequency. We calculated that the risk of HCV transmission through syringe sharing increased ~10-fold as viral titers (log₁₀ IU/ml) increased ~25-fold. Cumulative analyses showed that, assuming sharing episodes every 7 days, the mean transmission risk over the first 6 months was >90% between two people sharing syringes when one had an HCV RNA titer >5 log₁₀ IU/ml. For those with preexisting immunity that rapidly controlled HCV, the cumulative risk decreased to 1 to 25% depending on HCV titer and syringe type. Our modeling approach demonstrates that, even with transient viral replication after exposure during injection drug use, HCV transmission among people sharing syringes could be reduced through vaccination if an HCV vaccine were available.

Fig. 1.

Study design, equation parameters and sources of data. The goals of each analysis are shown together with corresponding figures relating to data generated.

Fig. 2.. RNA carry-over of HCV Positive Human Plasma in two different syringe types with attached needles.

Mean RNA titers and percentage carry-over for HCV-positive human plasma samples (diluted 1:10) after being carried over in (A) low dead space syringes (LDSS) and (B) high dead space syringes (HDSS) (mean of 3 independent experiments). Mean RNA titers and percentage carry-over for human plasma samples (diluted 1:100) after being carried over in (C) low dead space syringes and (D) high dead space syringes (mean of 3 independent experiments). Bars represent s.e.m. Means were calculated using log-transformed data. HCV+ pre= HCV-positive plasma before uptake into a syringe; HCV+ post= HCV-positive plasma after expulsion from the syringe; HCV- pre= HCV-negative plasma before uptake into a syringe; HCV- post= HCV-negative plasma after uptake and expulsion from a contaminated syringe; HCV- post H₂O= HCV-negative plasma after uptake and expulsion from a contaminated syringe rinsed in tap water.

Fig. 3.. Carry-over of HCV cell culture virus (HCVcc) positive samples in two different syringe types with attached needles.

Shown are mean titers and percentage carry-over of HCVcc before uptake into (A) a low dead space syringe (LDSS) (B) a high dead space syringe (HDSS). HCVcc+ pre= HCVcc-positive sample before uptake into a syringe; HCVcc+ post= HCVcc-positive sample after expulsion from the syringe; HCVcc- post= HCVcc-negative plasma after uptake and expulsion from a contaminated syringe; HCVcc- post H₂O= HCVcc-negative plasma after uptake and expulsion from a contaminated syringe rinsed in tap water. Data represent the mean values of 2 independent experiments. Percentages were calculated as described for Figure 2 using HCVcc titers instead of HCV RNA titers. Means were calculated using log transformed data. Ranges taken from all experiments are reported in the text.

Fig. 4.. Probability of HCV Transmission Based on HCV RNA titer.

Probability of transmission (P_trans) was calculated using Eq.1, described in Materials and Methods, for increasing viral load as a function of syringe type, with and without rinsing. Set viral loads were taken and combined with randomly chosen ranges and frequencies for RNA carry-over and relative volume of donor blood in the drug mixture (ranges for these parameters are shown in Table 1). (A) Calculated values for P_trans as a function of viral load using rinsed and unrinsed low dead space syringes (LDSS). (B) Calculated values for P_trans as a function of viral load using rinsed and unrinsed high dead space syringes (HDSS). Grey bands show the interquartile range based on Monte Carlo sensitivity analyses.

Fig. 5.. Probability of HCV transmission via a rinsed LDSS during acute phase infection and reinfection.

Probability of transmission (P_trans) (solid red) and syringe donors’ median viral titers (dotted black) following different HCV infection outcomes in naïve patients (A, B and C) and patients who had cleared primary infections and experienced reinfection (D, E and F). Data are presented as the median HCV RNA titer for patients grouped by outcome: (A) naïve acute phase, self-clearing (B) naïve acute phase, incomplete control (C) naïve acute phase, persistence (D) reinfection acute phase, low titer with rapid clearance (E) reinfection acute phase, high titer with rapid clearance (F) reinfection acute phase, chronic infection. Gray cross-hatched bands represent the interquartile range of measured data points of all individuals in the group at the given time points. Pink bands show the interquartile range of transmission probability based on Monte Carlo sensitivity analyses.

Fig. 6.. Cumulative probability of transmission (P_trans) via shared syringes over 6 months for the reinfected low titer group based on frequency of sharing.

This patient group corresponds to that shown in Fig. 5A. (A) LDSS, low dead space syringe; (B) HDSS, high dead space syringe. Data are shown for rinsed (blue line) or unrinsed (red line) syringes. Bands show the interquartile range of cumulative transmission probability based on Monte Carlo sensitivity analyses. Of note, all viral kinetic profiles for other groups, either following primary infection or re-infection, resulted in a cumulative transmission probability of >99.9% over a 6-month period.