**1. Introduction**

Over the years, global electric energy consumption has increased from 440 Mtoe in 1973 to 1737 Mtoe in 2015 [1]. This has resulted in electricity becoming a specific product that is subject to market regulation in both quantitative and qualitative terms. Quantitative analysis is mainly focused on the balance between energy that is produced, transmitted, stored, consumed or lost. The current issues connected to quantitative aspects of energy consumption are related to demand-side

response, the integration of renewable energy sources, and energy storage systems with electrical power systems [2–5]. The qualitative approach mainly uses power quality analysis. The issues related to power quality (PQ) include definitions of the parameters, and the methods of measurements and assessment, which are already standardized, among others [6–8]. The methods described in the standards of power quality analysis are based on power quality parameters measured during a representative period of time, normally one week, which corresponds to the normal working conditions of the observed network [9]. The parameters which characterize power quality include: frequency variation, voltage variation, voltage fluctuation, voltage asymmetry, and voltage waveform distortion. These parameters are collected during the period of observation, with the aggregation time interval usually equal to 10 min; however, 1 min aggregation intervals are also currently studied [10]. Using these parameters creates a significant number of data to be considered in the analysis. Moreover, PQ data depends on the network conditions, load changes, generation level, or configurations of the network. For this reason, a rational approach is to search for data mining techniques able to extract and classify vectors of the power quality data that represent different features. This would allow the range of qualitative analyses to be extended by correlating the information of the network, environment or market condition.

There are many works dedicated to power quality disturbance extraction, PQ events recognition, and the classification of PQ events and disturbances, which are all directly focused on the measured voltage and current signals. Most of the works propose wavelet transforms, S-transforms, empirical mode decomposition, and other different decomposition techniques, which are supported by artificial neural networks in order to find valuable methods for PQ disturbance extraction and recognition [11–13]. However, a different problem can be formulated when there is a need for identifying and extracting some of the data that represent different features from the long-term aggregated power quality data. This necessitates a comprehensive method for the automatic classification of long-term power quality data into groups that represent similar features. This task is essentially a data mining area of interest. One of the data mining techniques that can meet these requirements is cluster analysis (clustering). The general application of data mining techniques in power systems is presented in [14]. Specific applications of cluster analysis to electrical power networks include:

This article extends the cluster analysis (CA) proposed by the authors in [9]. Jasi ´nski et al. [9] present the results of the application of CA in order to achieve a desirable division of the long-term 10-min aggregated power quality data into groups of data representing similar features. The collection of the PQ data comes from four real points of measurement in the supply network of a copper mine. The significant elements of the investigated power network are combined heat and power (CHP) plants with gas-steam turbines working as a local distributed generation (DG), and also a welding machine (WM) as the main time-varying load. Time-varying PQ conditions were intentionally created. The distributed generation was switched on and off for a period of time, and a network reconfiguration was also performed. The results discussed in [9] confirm the possibility of using cluster analysis for the extraction of power quality data into groups related to the different working conditions of an electrical network, including the influence of DG, reconfiguration of the network, working days, and holiday time. In [9], the methodology of application of the cluster analysis, including the preparation of the database structure, was also described. The idea presented in [9] leads to efficient classification of the power quality data, but it does not provide a suitable method for the assessment of collected clusters of the data. Searching for (1) a comprehensive solution that provides automatic classification of the multipoint measurement data, and (2) a method for comparative evaluation of the collected data, remains a desirable aim for wide-area monitoring systems and smart grids. Thus this article

is an extension of the previously obtained classification [9] in order to a achieve quality assessment of obtained clusters using global power quality indices. This leads to an automatic classification of working conditions of an electrical power network (EPN), and the possibility of an easy comparison using global values, that incorporate the impact of different PQ elements.

Both cluster analysis of PQ data and global power quality index (GPQI) application may be found in the literature:

The aspect that distinguishes the solution proposed in this paper from the methods described in quoted works is the area-based approach to the PQ assessment, involving all measurement points for the cluster analysis, as well as development of a new synthetic power quality index. Novel aspects of the method proposed in this article include:

The remaining structure of this paper is as follows: Section 2 reviews the present application of global power quality indices in the electrical power network, and also proposes a new definition of the GPQIs proposed in our assessment of clustered PQ data. Section 3 describes the proposed algorithm methodology for the comparative assessment of the power quality conditions using a combination of clustering and global power quality indices. The first step of the algorithm is the identification and allocation of the power quality data into groups that represent similar features. This part is based on previous experience with CA application described in [9]. The second step is the assessment of the collected data using the proposed GPQI. The results of the assessment are presented using real multipoint power quality measurements in a medium voltage electrical network supplying the mining industry. Additionally, this section also contains a sensitivity analysis of the proposed GPQI in terms of the selection of the power quality parameters used to construct the GPQI. The presented results are towered to realize one of the article's aims—to highlight the impact of DG on PQ in the industry network. The obtained clusters represent different conditions of PQ indices which are directly associated with impact of the DG. Qualitative assessment of the PQ data collected in the identified clusters using the proposed global power quality indices allows us to confirm several relations between DG impact on PQ condition. Section 4 contains the discussion of the obtained results. Section 5 formulates the conclusions, interpretations in perspective studies, and implications for the future.

## **2. Global Power Quality Indices**

Classical power quality assessment is a multi-criteria analysis approach that is independently applied to particular power quality parameters. The idea of a simplified and generalized assessment of the power quality condition uses a single index, known as a global, unified, total or synthetic index. In this paper, we decided to use global power quality indices (GPQIs) as a unified name. Before new definitions of GPQIs are introduced, it is relevant to have a review of the knowledge concerning the development of GPQIs. Singh et al. [43] present the application of a unified power quality index that uses the matrix method. The index, corresponding to voltage sag severity, was highlighted as a suitable proposition for power quality assessment, and is carried out in a three-stage approach. The first stage requires the preparation of a graphical system model (attribute digraph). The second step is the conversion into an attribute matrix. The next step is the presentation of the matrix as a variable permanent function. Ignatova and Villard [44] define green-yellow-red indicators for all PQ problems. The proposed algorithm obtains the green-yellow-red indicators for both events and disturbances. The index consists of all individual PQ parameters, which are expressed as a percentage in a range from 0% to 100%, where 0% denotes the worst PQ and 100% the optimal PQ. The index may be defined for each single point or for the whole facility. The benefit of the proposed generalization is the possibility to easily understand the interpretation of the PQ condition in the monitoring systems. Nourollah and Moallem [45] present the application of data mining to determine the unified power quality index which corresponds to all power quality parameters, with further classification, normalization, and incorporation. The proposed fast independent component analysis algorithm was proposed to determine the power quality level of each distribution site. The mentioned article proposes two indexes: the Supply-side Power Performance Index, which expresses the impact of six voltage indices; and the Load-side Power Performance Index. The second index corresponds to three current PQ indices. Raptis et al. [46] present artificial neural networks as a sufficient tool to support PQ assessment using an index called Total Power Quality Index. The index is the artificial neural network combination of eight power quality values used as input variables. The presented method uses a multilayer perceptron artificial neural network. Lee et al. [47] propose another power quality index. This index includes the power distortion, which concerns non-linear loads. The indicated aim of the proposed PQI is to support harmonic pollution determination in a distributed power system. The work [47] proposes a new distortion power quality index. The application of this index is a determination of the harmonic pollution ranking for different non-linear loads. It is realized by multiplication of the load composition rate and the load currents' total harmonic distortion. Hanzelka et al. [48] propose the idea of a synthetic PQ index. This index is based on the maximum values of traditional PQ parameters. These parameters are slow voltage change, harmonic content in voltage (represented by total harmonic distortion in voltage, and a particular harmonic from 2nd to 40th), unbalance, and voltage fluctuation

(represented by long-term flicker severity). The proposed assessment provided only satisfactory or unsatisfactory results.

In the present work, two definitions of GPQIs are proposed—one for 10-min aggregated data, and the other for the events. The proposed indices are inspired by the synthetic approach described in [48,49]. Some elements of the GPQI definitions, in terms of the multipoint measurements, were also proposed by the authors in [50]. Typical for the generalization process is that global indices are usually less sensitive due to synthetization. In order to enhance the sensitivity, the global indices proposed in this work are not only based on classical 10-min aggregated power quality parameters, but they are also extended by other parameters like an envelope of voltage changes based on 200-ms values. In order to demonstrate the proposed approach, we also present an analysis of how selected parameters comprising the global index influence its sensitivity.

The first proposed global power quality index is called the aggregated data index (*ADI*), and is expressed in (1).

$$ADI = \sum\_{i=-1}^{7} k\_i \cdot \mathcal{W}\_i \tag{1}$$

*ADI*—aggregated data index;

*i*—number of the factor ranging from 1 to 7;

*Wi*—the particular power quality factors which create a synthetic aggregated data index;

*ki*—the importance rate (weighted factors) of the particular power quality factor constituting the synthetic aggregated data index, range of [0, 1], where 7 *i* = 1 *ki* = 1.

The *ADI* utilizes five classical 10-min aggregated PQ parameters, including: frequency (*f*), voltage (*U*), short-term flicker severity (*P*st), asymmetry factor (*ku*2), total harmonic distortion in voltage (*THDu)*, and also two additional parameters which are responsible for the enhancement of the sensitivity of the proposed global index. The first additional parameter is represented by an envelope of voltage deviation obtained by the difference between the maximum and minimum of 200-ms voltage values identified during the 10-min aggregation interval. The second is a maximum of the 200-ms value of the total harmonic distortion in voltage, similarly identified in the 10-min aggregation interval. The mentioned parameters are calculated and refer to standard IEC 61000-4-30 [7]. Three phase values, like *U*, *P*st, and *THDu* are reduced to one using the mean value of the three phase values. To be more specific, particular factors that create the proposed *ADI* index are based on the differences between the measured 10-min aggregated power quality data and the recommended limits stated in the standards. The differences are expressed as a percentage in relation to the limits. The final values of the factors taken in the *ADI* calculation are the mean values of the time-varying factors during the time period of observation. Additionally, the contribution of the particular power quality factors in global indices can be controlled by the importance factors, which serve as the weight of the contribution of particular parameters. The values of weighting factors are normalized to one. Selection of importance factors makes it possible to check the impact of single parameters as well as groups of parameters. The selection of parameters may be defined by a priori analysis of EPN problems (e.g., harmonics, voltage variations). No a priori statements were conducted in this work, so the weight of all parameters is the same and the priorities of particular parameters were the same. The aim of the introduced weighted factors is to open the possibility to make the analysis more focused on particular PQ parameters and neglect others—in other words, to obtain an analysis that is more sensitive for selected PQ phenomena controlled by weighted factors. For example, to justify adding 200-ms values, analyses with and without them were conducted.

Particular factors which create the global *ADI* index are defined as follows [50]:

$$\mathcal{W}\_1 = \mathcal{W}\_f = \frac{mean(\left| f\_{\rm m} - f\_{\rm nom} \right|)}{\Delta f\_{\rm limit}} \tag{2}$$

*W*1 = *Wf*—factor of frequency change;

*f*m—10-min measured value of frequency;

*f*nom—nominal value of frequency;

*mean f*m − *f*nom —mean of frequency deviations in the observation time period; Δ*f*limit—limit value of frequency change as a %.

$$\mathcal{W}\_2 = \mathcal{W}\_{\mathcal{U}} = \frac{\text{mean}(|\mathcal{U}\_\mathbf{m} - \mathcal{U}\_\mathbf{c}|)}{\Delta \mathcal{U}\_{\text{limit}}} \tag{3}$$

*W*2 = *WU*—factor of the voltage level;

*U*m—mean of 10-min measured values of voltage from three phases;

*U*c—declared voltage;

*mean*(|*U*m − *U*c|)—mean of voltage deviations in the observation period of time; Δ*U*limit—limit value of voltage change in volts.

$$\mathcal{W}\_{\text{3\\_}} = \mathcal{W}\_{\text{Pst}} = \frac{\text{mean}(\text{Pst}\_{\text{m}})}{\text{Pst}\_{\text{limit}}} \tag{4}$$

*W*3 = *WPst*—factor of voltage variation;

*Pst*m—mean of 10-min measurement value of the short-term flicker severity index from three phases;

*mean*(*Pst*m)—mean of voltage variations in the observation time period;

*Pst*limit—limit value of short-term flicker severity.

$$\mathcal{W}\_{\mathsf{4}} = \mathcal{W}\_{\mathsf{ku2}} = \frac{mean(\mathsf{ku2}\_{\mathsf{m}})}{\mathsf{ku2}\_{\mathsf{limit}}} \tag{5}$$

*W*4 = *Wku*2—factor of voltage unbalance;

*ku*2m—10-min measured values of voltage unbalance;

*mean*(*ku*2m)—mean value of voltage unbalance in the observation time period;

*ku*2limit—limit level of voltage unbalance.

$$\mathcal{W}\_5 = \mathcal{W}\_{THDu} = \frac{mean(THDu\_\text{m})}{THDu\_\text{limit}} \tag{6}$$

*W*5 = *WTHDu*—factor of total harmonic distortion factor of voltage supply;

*THDu*m—mean of 10-min measurement values of the total harmonic distortion factor of the voltage supply from three phases;

*mean*(*THDu*m)—mean value of the total harmonic distortion factor in the observation time period; *THDu*limit—limit level of the total harmonic distortion factor of the voltage supply.

$$\mathcal{W}\_6 = \mathcal{W}\_{llemv} = \frac{\frac{m \text{cen} (|lL\_{\text{max}} - lL\_{\text{min}}| )}{\mathcal{U}\_c}}{2 \times \Delta l I\_{lrmit}} \tag{7}$$

*W*6 = *WUenv*—factor of voltage deviation envelope;

*U*max—mean value of 200-ms voltage maximum values from three phases allocated in 10-min data; *U*min—mean value of 200-ms voltage minimum values from three phases allocated in 10-min data; *U*c—declared voltage;

*mean*(|*U*max − *U*min|)—mean of voltage envelope width in the observation time period; Δ*U*limit—limit level of voltage change.

$$\mathcal{W}\tau = \mathcal{W}\_{THD\text{unmax}} = \frac{\text{mean}(THD u\_{\text{max}})}{THD u\_{\text{limit}}} \tag{8}$$

*W*7 = *WTHDu*max—factor of the maximum 200 ms value of the total harmonic distortion factor of voltage supply;

*THDu*max—mean value of 200-ms maximum values of the total harmonic distortion factor of voltage supply from three phases;

*mean*(*THDu*max)—mean of the total harmonic distortion factor in the observation time period;

*THDu*limit—limit level of the total harmonic distortion factor of the voltage supply.

Then, the preparation of the particular factors *W*1 ÷ *W*7 and the selection of its important rates, the aggregated data index factor expresses the PQ level in a global range. The interpretation of the obtained index values are as natural. A value of "0" represents the ideal PQ; "0–1" represents possible power quality deterioration, but in compliance with the requirements defined in the standards; and finally, a value greater than 1 indicates the permissible parameters level defined in the standard is exceeded.

The second proposed global index relates to events. The classical approach to power quality assessment utilizes a flagging concept, which generally prescribes the extraction of the aggregated values that are affected by events like dips, swells and interruptions. The authors propose to use the information about the number of data which are not considered in classical PQ analysis due to the flagging concept. This is used as the base for a global index called the flagged data index (*FDI*), defined as follows [50]:

$$FDI = \frac{f}{n} \times 100\% \tag{9}$$

*FDI*—flagged data index;

*f*—number of 10-min data, which were flagged in the observation time period;

*n*—number of all 10-min data in the observation time period.

Interpretation of the obtained *FDI* values can be formulated such that "0%" represents the ideal PQ without any event disturbances, and "100%" expresses measurement data where each averaged value is contaminated by voltage events.

The proposed concepts for the generalization of the power quality assessment using GPQIs can be implemented for the fixed time period of observation or for identified periods of time representing different features of the power quality condition of the monitored area of the power system. The identification of such periods can be achieved using cluster analysis.


3.8.3. Effect of pH on Foaming Capacity and Stability

Foam capacity (FC) and stability (FS) were measured according to the method of Jezowski et al. [ ˙ 71]. Briefly, one gram of the preparation was weighed into the tube and 200 mL of distilled water was added to it. The resulting mixture was adjusted to the appropriate pH (2, 4, 6, 8, 10 or 12) using 0.5 M NaOH or 0.5 HCl. The sample was then homogenized for 2 min at 16,000 rpm (T25 basic ULTRA-TURRAX®; IKA Werke, Staufen, Germany). The beaten sample was immediately transferred to a measuring cylinder, where the total foam volume was determined after 0, 5, 10, 30 and 60 min. FC and FS were calculated according to the following equations (Equations (2) and (3)):

$$\text{FC} = \frac{\text{VA}}{\text{VB}} \times 100 \, (\%) \tag{2}$$

where VA denotes the volume after whipping (mL), and VB is the volume before whipping (mL).

$$\text{FS} = \frac{\text{VB}}{\text{VT}} \times 100 \,\text{(\%)}\tag{3}$$

where VB denotes the volume before whipping (cm3 ), and VT is the volume after a certain time (mL).


**6. Conclusion**

52 Heat Treatment – Conventional and Novel Applications

• possibility to set initial stretch more reliably

• running smooth even in the first hours of operation

**Figure 9.** Measuring ovality using the Talyrond 73 measuring device

Table 8. The material corresponds to the prescribed values.

**Table 8.** Chemical composition of 100Cr6 bearing material in % by weight

• lower noise of the equipment when these bearings are used

• lower operating temperature even when running the equipment in

• slight increase in dynamic load (due to optimised shape of ring and tapered roll

Extract from a chemical composition protocol - chemical analysis of 100Cr6 used is shown in

**Tested element Prescribed values Measured values** C 0,9 – 1,1 1,02 Mn 0,3 – 0,5 0,35 Si 0,15 – 0,35 0,28 Cr 1,3 – 1,65 1,51 P max. 0,027 0,01 S max. 0,03 0,014 Ni max. 0,30 0,06 Cu max. 0,25 0,09 Ni+Cu max. 0,5 0,15

Extract from a metallographic analysis protocol under DIN 17230, DIN 50602, SEP 1520, and corporate standard is shown in Table 9. The material corresponds to the prescribed values.

• reduced friction and tear and wear

• minimum run-in time

raceways)

The herein described method of achieving lower internal tensions with effect on reduced deformations and ring ovality made it possible to attain ovality of finished rings of 0.003 mm compared to the standard requirements on ovality of 0.006 mm. This result was achieved with a satisfactory assessment of chemical, metrological and metallographic analysis with a further effect on improved endurance of bearings. This manufacturing method has been tested several times since then and the desired effect was confirmed. Subsequently, this procedure has been applied also to other types of the so-called thin-walled bearings for others customers, in particular from the automotive industry, who demanded stricter ovality values. The possibility to use this technology has been confirmed in all cases.

Note: Compliance with and check of prescribed processing condition are essential for heat treatment. An appropriate way how to improve checks during the heat treatment is to use a computer-controlled hardening line. Obviously, this incurs higher input costs. According to information from the company where this optimised method of heat treatment was implemented, the system started to be used for a typical hardening line and the benefit in terms of quality exceeded their expectations.


**6. Research questions and programmatic issues**

There remain a number of unanswered questions and challenges regarding the implementation and integration of effective cervical cancer screening programs into HIV care and treatment. Data regarding antiretroviral treatment and CD4 counts correlated with VIA results are important to further refine screening and treatment protocols and inform guidelines on appropriate screening strategies and intervals. Integration of cervical cancer screening for HIV+ women requires testing of different models for training, implementation and data collection. Given the information currently available of the interaction of HPV and HIV infections and the epidemiology of HIV:

244 Cancer Prevention – From Mechanisms to Translational Benefits

canal and is less effective with large lesions. This raises potential concerns in the management of HIV+ women, who may have lesions occupying a larger volume of the

One of the treatment effects with either cryotherapy or LEEP may be stimulation of the immune response, promoting clearance of HPV after treatment, even if the entire lesion or the entire transformation zone is not excised or ablated, although one small study failed to show an effect of cryotherapy on HPV clearance one year after treatment (Taylor 2010;

HIV-positive women have an increased incidence of persistence or recurrence after treatment, with some studies documenting >50% recurrence rate (Tebeu et al. 2006).

positive surgical margins with LEEP or cervical conization (present in >40% of HIV+

Most recurrences in HIV+ women appear to be low-grade disease, which may be associated with new HPV infections (Massad et al. 2007) but re-excision may be necessary in some cases (Holcomb et al. 1999; Gingelmaier et al. 2007). Follow-up with cervical cytology alone or cytology and colposcopy together at 6-month intervals over the first year after treatment

There remain limited data on the use of LEEP and cryotherapy in the setting of HIV, especially related to efficacy. A study of HIV-infected and –uninfected women in Zimbabwe, cryotherapy had a 40.5% failure rate among HIV+ women at one year of followup, compared to 15.8% failure rate among HIV- women; in the same study, LEEP had 14% and 0% failure rates, respectively, among HIV+ and HIV- women (CHirenje 2003). However, over 50% of failures were low-grade lesions. LEEP was associated with higher complication rates, including excessive bleeding,and discharge, than cryotherapy. A study from Zambia of cryotherapy-ineligible women (many of whom were HIV+), referred for further management, LEEP (performed by physicians) was feasible and safe, with low levels

Abstinence should be emphasized until complete healing has occurred after treatment for cervical dysplasia, since the treatment has been shown to dramatically increase genital tract HIV shedding (Wright 2001) and may increase risk of sexual transmission of HIV. However, a recent study from Kenya found no increase in detectable cervical HIV-1 RNA among HIV-

There remain a number of unanswered questions and challenges regarding the implementation and integration of effective cervical cancer screening programs into HIV care and treatment. Data regarding antiretroviral treatment and CD4 counts correlated with

women) (Boardman et al. 1999; Gilles et al. 2005; Lima et al. 2009).

greater immunosuppression (Holcomb et al. 1999; Shah et al. 2008)

of complications that can be managed locally (Pfaendler et al. 2008).

positive women (most on ART) after cryotherapy. (Chung et al. 2011).

**6. Research questions and programmatic issues**

cervix.

Chumworathayi et al. 2010).

Recurrence rates are increased in the following situations:

glandular involvement (Lima et al. 2009).

lack of suppressive ART (Robinson et al. 2001).

is recommended (CDC 2009; Wright et al. 2007).


**8. Hepatitis C treatments**

The ultimate goal of treatment in patients with chronic HCV is to eradicate HCV RNA, which is associated with decreases in all-cause mortality, liver-related death, need for liver trans‐ plantation, hepatocellular carcinoma rates, and liver-related complications.

Since interferon-alpha (IFN-α) was first introduced for treatment of non-A, non-B hepatitis 1990, therapy for patients with chronic HCV has improved dramatically. Sustained virological response rates (SVRs) have increased from 5% to 10% with standard interferon therapy, to over 40% when standard interferon is combined with ribavirin. The modification of interferon (pegylation) to improve its pharmacokinetics has further increased rates of SVR. Two types of pegylated interferon, pegylated interferon α2a and pegylated interferon α2b,which differ in their pharmacokinetics and chemical properties, were approved by the FDA in 2001. Treatment with combined pegylated interferon and ribavirin may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype 2 or 3 infected patients, and 54-68% of genotype 4 infected patients [46,47].

The landscape of treatment for HCV infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies, namely, boceprevir and telaprevir, in 2011. Both drugs were approved as directly acting antiviral treatments for use in HCV genotype 1 infection, in combination with pegylated interferon and ribavirin. These NS3/4A protease inhibitors have been shown to substantially increase rates of SVR to 59-75% in both treatment-naive and previously treated patients, compared with dual therapy [48-52]. Although their development was a major advance, both agents are associated with significant toxicity, numerous drug-drug interactions, and low response rates in those patients with cirrhosis and nonresponders to previous treatment. In addition, boceprevir and telaprevir required the addition of pegylated interferon and ribavirin for 24 to 48 weeks, which markedly increased the overall cost of therapy, and are associated with the emergence of resistanceassociated variants in the majority of patients who fail treatment [53].

In 2013 and 2014, the FDA approved new direct acting antiviral treatments, including second generation protease inhibitors, NS5A inhibitors, and NS5B RNA-dependent RNA polymerase inhibitors with HCV eradication rates of >95%.

The eradication of HCV RNA is predicted by the achievement of SVR and defined by the absence of HCV RNA by polymerase chain reaction three to 6 months after stopping treatment. An SVR is associated with a 99% chance of being HCV RNA negative during long-term followup and can therefore be considered an indication of a cure of the HCV infection. With the growing availability of highly effective interferon-free regimens for HCV infection, a curative all-oral treatment is becoming a possibility for the vast majority of patients. The secondgeneration protease inhibitors that have been approved for treatment of HCV and are available in the market are simeprevir, sofosbuvir, ledipasvir/sofosbuvir, daclatasvir, and the combi‐ nation of ombitasvir-paritaprevir-ritonavir and dasabuvir. Trials are still ongoing on other new products, many of which are expected to appear in the near future.

### **8.1. Simeprevir (Olysio®, Janssen Therapeutics)**

**8. Hepatitis C treatments**

86 Recent Advances in Liver Diseases and Surgery

infected patients [46,47].

The ultimate goal of treatment in patients with chronic HCV is to eradicate HCV RNA, which is associated with decreases in all-cause mortality, liver-related death, need for liver trans‐

Since interferon-alpha (IFN-α) was first introduced for treatment of non-A, non-B hepatitis 1990, therapy for patients with chronic HCV has improved dramatically. Sustained virological response rates (SVRs) have increased from 5% to 10% with standard interferon therapy, to over 40% when standard interferon is combined with ribavirin. The modification of interferon (pegylation) to improve its pharmacokinetics has further increased rates of SVR. Two types of pegylated interferon, pegylated interferon α2a and pegylated interferon α2b,which differ in their pharmacokinetics and chemical properties, were approved by the FDA in 2001. Treatment with combined pegylated interferon and ribavirin may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype 2 or 3 infected patients, and 54-68% of genotype 4

The landscape of treatment for HCV infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies, namely, boceprevir and telaprevir, in 2011. Both drugs were approved as directly acting antiviral treatments for use in HCV genotype 1 infection, in combination with pegylated interferon and ribavirin. These NS3/4A protease inhibitors have been shown to substantially increase rates of SVR to 59-75% in both treatment-naive and previously treated patients, compared with dual therapy [48-52]. Although their development was a major advance, both agents are associated with significant toxicity, numerous drug-drug interactions, and low response rates in those patients with cirrhosis and nonresponders to previous treatment. In addition, boceprevir and telaprevir required the addition of pegylated interferon and ribavirin for 24 to 48 weeks, which markedly increased the overall cost of therapy, and are associated with the emergence of resistance-

In 2013 and 2014, the FDA approved new direct acting antiviral treatments, including second generation protease inhibitors, NS5A inhibitors, and NS5B RNA-dependent RNA polymerase

The eradication of HCV RNA is predicted by the achievement of SVR and defined by the absence of HCV RNA by polymerase chain reaction three to 6 months after stopping treatment. An SVR is associated with a 99% chance of being HCV RNA negative during long-term followup and can therefore be considered an indication of a cure of the HCV infection. With the growing availability of highly effective interferon-free regimens for HCV infection, a curative all-oral treatment is becoming a possibility for the vast majority of patients. The secondgeneration protease inhibitors that have been approved for treatment of HCV and are available in the market are simeprevir, sofosbuvir, ledipasvir/sofosbuvir, daclatasvir, and the combi‐ nation of ombitasvir-paritaprevir-ritonavir and dasabuvir. Trials are still ongoing on other

plantation, hepatocellular carcinoma rates, and liver-related complications.

associated variants in the majority of patients who fail treatment [53].

new products, many of which are expected to appear in the near future.

inhibitors with HCV eradication rates of >95%.

This is the first available second-generation protease inhibitor (NS3/4A protease inhibitor) indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen [54]. Simeprevir is available in 150 mg capsules to be taken orally once daily with food. The elimination of simeprevir is by the liver, and no dose adjustment is required in the setting of renal impairment [55]. Simeprevir is not recommended in patients with hepatic impairment Child-Pugh Class B and C because of two- to five-fold increases in exposure. In general, simeprevir is well tolerated. Its most common adverse effects are rash (including a potentially serious photosensitivity reaction), pruritus, and nausea. The photo‐ sensitivity reaction that related to simeprevir usually occurs during the first 4 weeks of therapy but can develop at any time on treatment. Patients taking simeprevir may experience transient increases in serum bilirubin levels that peak at week 2 of treatment, but these are typically mild in severity and not associated with elevated hepatic aminotransferase levels [56,57]. The coadministration of simeprevir with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended, as this may lead to signifi‐ cantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions. A number of compounds are contraindicated in patients receiving simeprevir, including the following:

Simeprevir is safe in patients using immunosuppressants, such as cyclosporine and tacrolimus, with no dose adjustment, and safe in those using lamivudine, emtricitabine, tenofovir, abacavir, raltegravir, maraviroc, and rilpivirine. The dose of simeprevir needs adjustment with some antiarrhythmics, warfarin, HMG Co-A reductase inhibitors, sedative/anxiolytics, and calcium channel blockers [58-64].

#### **8.2. Sofosbuvir (Sovaldi®, Gilead Sciences)**

This is an HCV nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. Sofosbuvir is available as a 400-mg tablet. The recommended dose of sofosbuvir is 400 mg taken orally once daily, with or without food, regardless of the patient's genotype or prior hepatitis C treatment experience. No dose adjustment is needed for mild-to-moderate renal impairment or with mild, moderate, or severe hepatic impairment. Currently, no dose recommendation can be given for patients with severe renal impairment (estimated glomer‐ ular filtration rate <30 ml/min) or with end-stage renal disease due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite. Sofosbuvir has pan-genotypic HCV activity and is effective in treatment-naive, treatment-experienced, and HIV-coinfected patients with compensated cirrhosis, and in patients with hepatocellular carcinoma meeting Milan criteria awaiting liver transplantation. Sofosbuvir has been very well tolerated in clinical trials. The most common adverse effects (≥20%) observed with sofosbuvir, when used in combination with ribavirin, have been fatigue and headaches. The most common adverse events (≥20%) observed in combination with pegylated IFN-α and ribavirin were fatigue, headaches, nausea, insomnia, and anemia. Drugs that are potent P-glycoprotein (P-gp) inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with other known inducers of P-gp, such as rifampin, carbamazepine, phenytoin or St. John's wort [62,65-77].

#### **8.3. Ledipasvir-sofosbuvir (Harvoni®, Gilead Sciences)**

The nucleotide polymerase inhibitor sofosbuvir (400 mg) has been combined with the NS5A inhibitor ledipasvir (90 mg) in a single tablet regimen (SOF/LDV) administered once daily. The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir/sofosbuvir is recommended. Severe renal impairment (estimated glomerular filtration rate <30 mL/min) does not substantially affect the pharmacokinetics of ledipasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data. Thus, no dosage recommendation has been given for patients with severe renal impair‐ ment or end-stage renal disease requiring dialysis. Available data from clinical trials have shown that the combination of ledipasvir and sofosbuvir has been very well tolerated. The most commonly reported adverse effects are fatigue and headaches. Ledipasvir, like sofosbu‐ vir, is a substrate of the P-gp drug transporter, so drugs that are potent intestinal P-gp inducers may decrease ledipasvir levels. Thus, the coadministration of ledipasvir-sofosbuvir is not recommended with rifampin, St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. In addition, ledipasvir is an inhibitor of P-gp and may increase absorption of P-gp substrates. The coadministration of ledipasvir with tenofovir results in increased levels of tenofovir, particularly in the presence of other boosting agents. Until further data are available, ledipasvir-sofosbuvir should not be used with the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and should only be used cautiously with regimens that contain tenofovir and a ritonavir-boosted protease inhibitor [73,78-83].

#### **8.4. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®, AbbVie Inc)**

The Viekira Pak is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. This regimen can be used with or without ribavirin. In the Viekira Pak, ombitasvir, paritaprevir, and ritonavir (Viekirax®) are combined as a fixed-dose tablet and the dasabuvir (Exviera®) is a separate tablet. Ombitasvir, paritaprevir, and dasabuvir are direct-acting antivirals (DAAs) that directly interfere with HCV replication. Ombitasvir is an NS5A inhibitor with potent pan-genotypic picomolar antiviral activity, paritaprevir is an inhibitor of the NS3/4A serine protease, and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Ritonavir is a CYP3A inhibitor, and it boosts the blood levels of paritaprevir. Paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) are coformulated in a single tablet taken as two tablets once daily. This tablet is combined with dasabuvir (250 mg) taken as one tablet twice daily. The regimen ombitasvir-paritaprevir-ritonavir plus dasabuvir is FDA approved for the treatment of chronic hepatitis C genotype 1, including those with compen‐ sated cirrhosis. The regimen ombitasvir-paritaprevir-ritonavir plus dasabuvir, with or without ribavirin, has primarily been studied as an all-oral (interferon-free) regimen in treatment-naive and treatment-experienced patients with genotype 1a or 1b chronic HCV infection, including those with compensated cirrhosis, HIV coinfection, and after receipt of liver transplantation. For patients with mild hepatic impairment (Child-Pugh A), no dosage adjustment is required for ombitasvir-paritaprevir-ritonavir and dasabuvir; however, this regimen is not recom‐ mended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated with severe hepatic impairment (Child-Pugh C). For patients with mild, moderate, or severe renal insufficiency, no dosing adjustment is required for the regimen ombitasvir-paritaprevirritonavir and dasabuvir; this regimen, however, has not been adequately studied in patients with end-stage renal disease on dialysis. Available data from clinical trials have demonstrated excellent tolerance with the ombitasvir-paritaprevir-ritonavir and dasabuvir regimen. The most common (greater than 10%) adverse effects observed in clinical trials when used without ribavirin have been fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. The concomitant use of ombitasvir-paritaprevir-ritonavir and dasabuvir with ethinyl estradiolcontaining medications (e.g., oral contraceptives) can result in significant elevations in hepatic aminotransferase levels; accordingly, patients should discontinue any ethinyl estradiolcontaining medications prior to starting ombitasvir-paritaprevir-ritonavir and dasabuvir. The use of ombitasvir-paritaprevir-ritonavir plus dasabuvir can potentially cause significant drugdrug interactions, primarily because of the potent ritonavir inhibition of CYP3A4 enzyme. There are a number of medications contraindicated to use concomitantly with ombitasvirparitaprevir-ritonavir and dasabuvir, like carbamazepine, phenytoin, phenobarbital, gemfi‐ brozil, rifampin, ergotamine, oral contraceptives containing ethinyl estradiol, lovastatin, simvastatin, sildenafil, orally administered midazolam, and St. John's wort. The efficacy of ombitasvir-paritaprevir-ritonavir plus dasabuvir is not known for patients with prior virologic failure and resistance with treatment that included another NS3/4A inhibitor, NS5A inhibitor, or NS5B inhibitor [84-90].

#### **8.5. Daclatasvir (Daklinza®, Bristol-Myers Squibb)**

impairment or with mild, moderate, or severe hepatic impairment. Currently, no dose recommendation can be given for patients with severe renal impairment (estimated glomer‐ ular filtration rate <30 ml/min) or with end-stage renal disease due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite. Sofosbuvir has pan-genotypic HCV activity and is effective in treatment-naive, treatment-experienced, and HIV-coinfected patients with compensated cirrhosis, and in patients with hepatocellular carcinoma meeting Milan criteria awaiting liver transplantation. Sofosbuvir has been very well tolerated in clinical trials. The most common adverse effects (≥20%) observed with sofosbuvir, when used in combination with ribavirin, have been fatigue and headaches. The most common adverse events (≥20%) observed in combination with pegylated IFN-α and ribavirin were fatigue, headaches, nausea, insomnia, and anemia. Drugs that are potent P-glycoprotein (P-gp) inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with other known inducers of P-gp, such as rifampin,

The nucleotide polymerase inhibitor sofosbuvir (400 mg) has been combined with the NS5A inhibitor ledipasvir (90 mg) in a single tablet regimen (SOF/LDV) administered once daily. The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir/sofosbuvir is recommended. Severe renal impairment (estimated glomerular filtration rate <30 mL/min) does not substantially affect the pharmacokinetics of ledipasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data. Thus, no dosage recommendation has been given for patients with severe renal impair‐ ment or end-stage renal disease requiring dialysis. Available data from clinical trials have shown that the combination of ledipasvir and sofosbuvir has been very well tolerated. The most commonly reported adverse effects are fatigue and headaches. Ledipasvir, like sofosbu‐ vir, is a substrate of the P-gp drug transporter, so drugs that are potent intestinal P-gp inducers may decrease ledipasvir levels. Thus, the coadministration of ledipasvir-sofosbuvir is not recommended with rifampin, St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. In addition, ledipasvir is an inhibitor of P-gp and may increase absorption of P-gp substrates. The coadministration of ledipasvir with tenofovir results in increased levels of tenofovir, particularly in the presence of other boosting agents. Until further data are available, ledipasvir-sofosbuvir should not be used with the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and should only be used cautiously with regimens that contain tenofovir and a ritonavir-boosted protease inhibitor [73,78-83].

**8.4. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®, AbbVie Inc)**

The Viekira Pak is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. This regimen can be used with or without ribavirin. In the Viekira

carbamazepine, phenytoin or St. John's wort [62,65-77].

88 Recent Advances in Liver Diseases and Surgery

**8.3. Ledipasvir-sofosbuvir (Harvoni®, Gilead Sciences)**

The European Commission approved daclatasvir, a potent pan-genotypic NS5A replication complex inhibitor (in vitro), at the end of August 2014. Daclatasvir should be administered at the dose of 60 mg (one tablet) once per day. It is well tolerated overall. Dose adjustments are not needed in patients with Child B or C disease. Daclatasvir can be used in combination with other drugs for the treatment of chronic HCV infection genotypes 1, 2, 3, and 4 in adults. Daclatasvir*,* when used in combination with sofosbuvir, is an all-oral, interferon-free regimen that provided cure rates of more than 95% in clinical trials, including in patients with advanced liver disease, genotype 3, and those who have previously failed treatment with protease inhibitors. Across clinical studies, daclatasvir-based regimens have been generally well tolerated, with low discontinuation rates. The most common adverse effects with daclatasvir when used in combination with other drugs are fatigue, headaches, and nausea. Little information has been released on daclatasvir drug-drug interactions. Daclatasvir is a substrate of CYP34A and a substrate and inhibitor of P-gp. The daclatasvir dose should be adjusted to 30 mg daily in HIV-infected patients receiving atazanavir/ritonavir and to 90 mg daily in those receiving efavirenz. No dose adjustment is needed with tenofovir. No information on other antiretroviral drugs is available yet. No dose adjustments are required with cyclosporine or tacrolimus. Total daclatasvir AUC is decreased by 40% and 43% in patients with mild or moderate liver impairment, respectively. However, the unbound pharmacologically active fraction is unchanged; thus, dose adjustment is not needed in patients with liver impairment [77,91,92].

The direct acting antiviral treatment is usually used in combination for HCV treatment according to genotypes and stage of liver disease, and the patient is either naive or has previous experience of treatment.

The following recommendations can be used for treatment of HCV according to genotypes with a high response rate (>90%):

	- **a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1a infection.
	- **c.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks for treatment-naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1b infection. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis.
	- **d.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.

other drugs for the treatment of chronic HCV infection genotypes 1, 2, 3, and 4 in adults. Daclatasvir*,* when used in combination with sofosbuvir, is an all-oral, interferon-free regimen that provided cure rates of more than 95% in clinical trials, including in patients with advanced liver disease, genotype 3, and those who have previously failed treatment with protease inhibitors. Across clinical studies, daclatasvir-based regimens have been generally well tolerated, with low discontinuation rates. The most common adverse effects with daclatasvir when used in combination with other drugs are fatigue, headaches, and nausea. Little information has been released on daclatasvir drug-drug interactions. Daclatasvir is a substrate of CYP34A and a substrate and inhibitor of P-gp. The daclatasvir dose should be adjusted to 30 mg daily in HIV-infected patients receiving atazanavir/ritonavir and to 90 mg daily in those receiving efavirenz. No dose adjustment is needed with tenofovir. No information on other antiretroviral drugs is available yet. No dose adjustments are required with cyclosporine or tacrolimus. Total daclatasvir AUC is decreased by 40% and 43% in patients with mild or moderate liver impairment, respectively. However, the unbound pharmacologically active fraction is unchanged; thus, dose adjustment is not needed in patients with liver impairment

The direct acting antiviral treatment is usually used in combination for HCV treatment according to genotypes and stage of liver disease, and the patient is either naive or has previous

The following recommendations can be used for treatment of HCV according to genotypes

**a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24

**b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for treatment of both naive and prior pegylated interferon and ribavirin

**c.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks for treatment-naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1b infection. The addition of daily weight-based ribavirin (1000 mg [<75 kg]

**d.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment

weeks in patients with contraindications to ribavirin.

treatment failure, in patients with HCV genotype 1a infection.

to 1200 mg [>75 kg]) is recommended in patients with cirrhosis.

extended to 24 weeks in patients with contraindications to ribavirin.

[77,91,92].

experience of treatment.

with a high response rate (>90%):

90 Recent Advances in Liver Diseases and Surgery

**1.** HCV genotype 1 [91,93]

When pegylated interferon and ribavirin was the treatment for HCV, the same regimen was administered to all subjects, and patients were defined as easy or difficult to treat according to viral genotype. HCV genotypes 1 and 4 were considered to be difficult to treat, and HCV genotypes 2 and 3 were considered to be easy to treat. The SVR rates in the latter group were above 80% with shorter treatment [94,95]. The availability of interferon-free regimens has confirmed that HCV genotype 2 patients are easy to treat, while the paradigm for HCV genotype 3 patients has been reversed compared to "older, difficult-to-treat" HCV genotype 1 patients. In fact, today, with available direct acting antiviral drugs, patients with HCV genotype 3 are the most difficult to treat patients. In large studies on HCV genotype 3 to assess the effectiveness of 12-16 weeks treatment with sofosbuvir and ribavirin, it has been shown that 12 weeks of therapy in treatment-naive patients resulted in an SVR in 61% and 34% of noncirrhotic and cirrhotic patients, respectively. Moreover, the SVR rates in experienced noncirrhotic patients were 37% at 12 weeks and were increased to 63% in patients with 16 weeks' course [70,67,95]. Extended treatments to 24 weeks of sofosbuvir and ribavirin were evaluated in the valence trial, resulting in an overall SVR rate of 83%. In particular, this was the result of higher SVR rates in treatment-naive (93% and 92% in patients without and with cirrhosis, respectively) and experienced patients without cirrhosis (87%), while rates were lower in experienced (61%) patients with cirrhosis [80,95,96]. The Lonestar-2 study tested treatment with pegylated interferon/sofosbuvir/ribavirin for 12 weeks in treatment-experi‐ enced HCV-2 and HCV-3 patients. The SVR in HCV genotype 3 patients was 83% with no difference in relation to baseline cirrhosis (SVR 83% vs. 83%, respectively) [69]. The second study tested a combination of daclatasvir/sofosbuvir, resulting in an SVR of 89% of 18 treatment-naive patients with HCV genotype 3 [97].

The following treatment options with similar efficacy can be used in genotype 3 naive patients and patients in whom prior pegylated interferon and ribavirin treatment has failed [91-93,97]:

	- **a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, and treatment can be extended to 24 weeks in patients with cirrhosis.
	- **c.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **d.** Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **e.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks.

A few data are available to help guide decision making for patients infected with HCV genotype 5 or 6, but currently the following are the recommendations until more data are available:

**a.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks

The following treatment options with similar efficacy can be used in genotype 3 naive patients and patients in whom prior pegylated interferon and ribavirin treatment has failed [91-93,97]: **a.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis. Daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is added to regimen to treat naive and treatment-experienced patients with cirrhosis

**b.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75

**c.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks is an acceptable regimen for interferon-

**a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24

**b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, and treatment can be extended to 24 weeks in patients with

**c.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment

**d.** Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients

**e.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg

A few data are available to help guide decision making for patients infected with HCV genotype 5 or 6, but currently the following are the recommendations until more data are

**a.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg

extended to 24 weeks in patients with contraindications to ribavirin.

[>75 kg]) plus weekly pegylated interferon for 12 weeks.

[>75 kg]) plus weekly pegylated interferon for 12 weeks

eligible, treatment-naive patients with HCV genotype 3 infection.

weeks in patients with contraindications to ribavirin.

with contraindications to ribavirin.

for 24 weeks.

kg]) for 24 weeks.

92 Recent Advances in Liver Diseases and Surgery

cirrhosis.

**5.** HCV genotype 5 [91,93]

available:

**4.** HCV genotype 4 [70,91,93,98-101]

Due to the very high efficacy and the excellent tolerability of IFN-free regimens, responseguided shortening or prolongation of therapy have not been studied and, indeed, may not be needed to achieve high cure chances in the individual patient. However, given the high costs of direct antiviral drugs, HCV RNA testing during treatment may be helpful for surveillance of compliance and motivation of patients. HCV RNA should be measured at baseline, week 2 (assessment of adherence), week 4, week 12 or 24 (end of treatment), and 12 or 24 weeks after the end of therapy [102].


**Preface to "Neonatal Health Care"**

This issue of Children concerns healthcare delivery and research in neonatology. Several articles concern the work of the California Perinatal Quality Care Collaborative, including a history by founder Dr. Jeffrey Gould, and recent quality improvement work. Other articles concern methodological issues in neonatal research and findings of recent clinical studies.

> **Henry C. Lee** *Editor*