Research ArticleHepatitis C Virus

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

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Science Translational Medicine  11 Jul 2018:
Vol. 10, Issue 449, eaao4496
DOI: 10.1126/scitranslmed.aao4496
  • 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 three independent experiments). Mean RNA titers and percentage carry-over for human plasma samples (diluted 1:100) after being carried over in (C) LDSS and (D) HDSS (mean of three independent experiments). Bars represent SEM. Means were calculated using log-transformed data. HCV+ pre is the HCV-positive plasma before uptake into a syringe; HCV+ post is the HCV-positive plasma after expulsion from the syringe; HCV− pre is the HCV-negative plasma before uptake into a syringe; HCV− post is the HCV-negative plasma after uptake and expulsion from a contaminated syringe; and HCV− post H2O is the HCV-negative plasma after uptake and expulsion from a contaminated syringe rinsed in tap water.

  • Fig. 3 Carry-over of 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) an LDSS (B) an HDSS. HCVcc+ pre is the HCVcc-positive sample before uptake into a syringe; HCVcc+ post is the HCVcc-positive sample after expulsion from the syringe; HCVcc− post is the HCVcc-negative plasma after uptake and expulsion from a contaminated syringe; HCVcc− post H2O is the HCVcc-negative plasma after uptake and expulsion from a contaminated syringe rinsed in tap water. Data represent the mean values of two independent experiments. Percentages were calculated as described for Fig. 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 (Ptrans) was calculated using Eq. 1, as 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 Ptrans as a function of viral load using rinsed and unrinsed LDSS. (B) Calculated values for Ptrans as a function of viral load using rinsed and unrinsed HDSS. Gray 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 (Ptrans) (solid red lines) and syringe donors’ median viral titers (dashed black lines) after different HCV infection outcomes in naïve patients (A to C) and patients who had cleared primary infections and experienced reinfection (D to F). Data are presented as the median HCV RNA titer for patients grouped by outcome: (A) naïve acute phase and self-clearing, (B) naïve acute phase and incomplete control, (C) naïve acute phase and persistence, (D) reinfection acute phase and low titer with rapid clearance, (E) reinfection acute phase and high titer with rapid clearance, and (F) reinfection acute phase and 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 (Ptrans) 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 and (B) HDSS. 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. Notably, all viral kinetic profiles for other groups, either after primary infection or reinfection, resulted in a cumulative transmission probability of >99.9% over a 6-month period.

  • Table 1 Equation 1 parameters, values, and sources.

    Transmission probability was calculated on the basis of Eq. 1. The parameters VL, s, ρ, and q used in Eq. 1 are described together with values and their ranges. Sources are identified, whether calculated in this study, taken from previously published data, or estimated from experts familiar with practices used by injecting drug users. IQR, interquartile range (Q1 to Q3).

    ParameterDescription (units)Value (range)ScenarioSource
    nNumber (#) of transferred HCV RNA
    IUs by contaminated syringe
    VL · ρ · sCalculated as described in
    text and in Fig. 1
    VLDonor’s viral load in blood
    (RNA IU/ml)
    Variable (0 to 6 log10 IU/ml)ExperimentalValues input for testing
    (Fig. 4 and Table 1)
    Time-dependent:
    three primary acute-phase
    viral kinetic patterns
    Self-limiting, transient, and chronic
    outcome (Fig. 5, A to C)
    InC3 Study (1720)
    Time-dependent:
    three reinfection viral
    kinetic patterns
    Self-limiting (low and high titer) and
    chronic outcome (Fig. 5, D to F)
    sDonor blood as a fraction of the
    mixture with illicit drugs (%)
    25% (5–50%)Expert view
    ρHCV RNA carry-over0.6% (0.02 to 2.6%)LDSSEstimated in the current
    study (Fig. 2)
    3.1% (1.4 to 7.2%)HDSS
    0.12% (0.003 to 0.8%)LDSS + rinse
    0.38% (0.03 to 0.77%)HDSS + rinse
    qRatio of infectious doses to
    HCV RNA IU
    17% (IQR, 7–33%)Table S2 based on published
    studies (8, 9, 11, 21, 30)
  • Table 2 Probability (means ± SD) of HCV transmission as a function of viral load.

    To estimate the probability of HCV transmission (Eq. 1), means were calculated using a Monte Carlo procedure. For parameter ρ (Eq. 1), samples were generated using the truncated normal distribution with the SD equal to one-quarter of the experimentally determined range. For parameter s, values were chosen from a uniform distribution between 0.05 and 0.5, and q values were chosen from a gamma distribution with calculated median and Q1 to Q3 as 17% and 7 to 33%, respectively (table S2).

    Mean HCV transmission probability (±SD)
    LDSSHDSS
    HCV titer
    (log10 IU/ml)
    UnrinsedRinsedUnrinsedRinsed
    1.00.57 (±1.25)0.16 (±0.30)2.58 (±4.16)0.30 (±0.55)
    1.51.78 (±3.53)0.51 (±0.96)7.58 (±10.36)0.97 (±1.72)
    2.05.43 (±8.60)1.67 (±3.00)19.97 (±20.84)3.09 (±5.10)
    2.514.12 (±17.34)4.89 (±7.85)40.81 (±30.08)8.66 (±12.00)
    3.031.00 (±28.03)12.95 (±16.67)65.67 (±31.68)21.18 (±22.10)
    3.554.04 (±33.41)28.73 (±27.39)84.54 (±25.09)42.25 (±30.94)
    4.075.50 (±30.68)50.95 (±33.81)94.26 (±16.41)66.45 (±32.01)
    4.588.90 (±23.29)72.52 (±31.79)98.04 (±9.78)84.66 (±25.26)
    5.095.31 (±15.79)87.22 (±24.31)99.37 (±5.73)94.12 (±16.89)
    5.598.13 (±10.09)94.79 (±16.41)99.78 (±3.29)97.89 (±10.19)
    6.099.30 (±6.03)97.91 (±11.36)99.94 (±1.25)99.31 (±6.11)

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/449/eaao4496/DC1

    Fig. S1. Illustration of HCV transmission via a shared syringe.

    Fig. S2. Sensitivity analysis of Eq. 2 (Hill function) as a function of viral load.

    Fig. S3. Ptrans generated by Eqs. 1 and 2.

    Fig. S4. Probability of HCV transmission via a rinsed low dead space syringe during reinfection using Eq. 2.

    Fig. S5. Cumulative probability of transmission via shared needles over 6 months for the reinfected low-titer group based on frequency of sharing using Eq. 2.

    Table S1. Carry-over titers obtained for in vitro syringe studies.

    Table S2. Estimated q distribution calculated from chimpanzee reverse-titration experiments.

    Table S3. Critical probabilities of HCV transmission and corresponding viral log10 international units per milliliter titers.

  • The PDF file includes:

    • Fig. S1. Illustration of HCV transmission via a shared syringe.
    • Fig. S2. Sensitivity analysis of Eq. 2 (Hill function) as a function of viral load.
    • Fig. S3. Ptrans generated by Eqs. 1 and 2.
    • Fig. S4. Probability of HCV transmission via a rinsed low dead space syringe during reinfection using Eq. 2.
    • Fig. S5. Cumulative probability of transmission via shared needles over 6 months for the reinfected low-titer group based on frequency of sharing using Eq. 2.
    • Table S2. Estimated q distribution calculated from chimpanzee reverse-titration experiments.
    • Table S3. Critical probabilities of HCV transmission and corresponding viral log10 international units per milliliter titers.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S1 (Microsoft Excel format). Carry-over titers obtained for in vitro syringe studies.

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