**9. Treatment of special populations with direct acting antiviral regimens**

### **9.1. HIV/HCV-coinfected individuals**

Hepatitis C virus (HCV)-related liver disease is a major source of mortality in HIV-infected patients. Approximately one third of all patients with HIV are coinfected with HCV. Patients coinfected with HIV/HCV have shown lower rates of SVR with pegylated-interferon and weight-based ribavirin as well as more rapid progression of fibrosis than those with HCV monoinfection [103]. HIV/HCV-coinfected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antire‐ troviral medications. Based on AASLD/IDSA/IAS-USA [93], the following precautions should be considered:


The management of HIV/HCV patients should take place in collaboration with an HIV practitioner. Special precautions should be taken when prescribing DAAs in patient on AIDS treatment to avoid under- or overdose in such patients as a result of drug-drug interactions. For example, ledipasvir increases tenofovir levels, concomitant use needs to be avoided in patients with CrCl below 60 mL/min. Because potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors, ledipas‐ vir should be avoided with this combination. Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which it does not have substan‐ tial interactions like atazanavir, enfuvirtide, lamivudine, emtricitabine, tenofovir, and raltegravir (and probably dolutegravir) [93].

The dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir, and then restored when HCV treatment is completed. The HIV protease inhibitor should be adminis‐ tered at the same time as the fixed-dose HCV combination. Simeprevir should only be used with antiretroviral drugs, with which it does not have clinically significant interactions like raltegravir (and probably dolutegravir), rilpivirine, maraviroc, enfuvirtide, tenofovir, emtri‐ citabine, lamivudine, and abacavir [93].

#### **9.2. Patients with decompensated cirrhosis**

In patients with Child-Pugh B or C cirrhosis awaiting transplantation, antiviral therapy may be offered on an individual basis in experienced centers, pending the presentation of more data in this population. It is possible that patients with decompensated cirrhosis who are not on a transplant list could benefit from an interferon-free treatment regimen. However, the safety and efficacy of an interferon-free regimen in patients with decompensated cirrhosis not on a transplant waiting list is unknown, and the impact on mortality in this group is not yet established. According to AASLD/IDSA/IAS-USA [93] and EASL recommendations on treatment of hepatitis C 2015 [91], the following medications can be used with high virological response >90%:

	- **•** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) and ribavirin (initial dose of 600 mg, increased as tolerated) for 12 weeks is recommended for patients with decompensated cirrhosis.

**d.** Fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) should not be used with efavirenz, rilpivirine,

**e.** Paritaprevir/ritonavir/ombitasvir with or without dasabuvir should not be used in HIV/

**f.** Simeprevir should not be used with efavirenz, etravirine, nevirapine, cobicistat, or any

The management of HIV/HCV patients should take place in collaboration with an HIV practitioner. Special precautions should be taken when prescribing DAAs in patient on AIDS treatment to avoid under- or overdose in such patients as a result of drug-drug interactions. For example, ledipasvir increases tenofovir levels, concomitant use needs to be avoided in patients with CrCl below 60 mL/min. Because potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors, ledipas‐ vir should be avoided with this combination. Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which it does not have substan‐ tial interactions like atazanavir, enfuvirtide, lamivudine, emtricitabine, tenofovir, and

The dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir, and then restored when HCV treatment is completed. The HIV protease inhibitor should be adminis‐ tered at the same time as the fixed-dose HCV combination. Simeprevir should only be used with antiretroviral drugs, with which it does not have clinically significant interactions like raltegravir (and probably dolutegravir), rilpivirine, maraviroc, enfuvirtide, tenofovir, emtri‐

In patients with Child-Pugh B or C cirrhosis awaiting transplantation, antiviral therapy may be offered on an individual basis in experienced centers, pending the presentation of more data in this population. It is possible that patients with decompensated cirrhosis who are not on a transplant list could benefit from an interferon-free treatment regimen. However, the safety and efficacy of an interferon-free regimen in patients with decompensated cirrhosis not on a transplant waiting list is unknown, and the impact on mortality in this group is not yet established. According to AASLD/IDSA/IAS-USA [93] and EASL recommendations on treatment of hepatitis C 2015 [91], the following medications can be used with high virological

**•** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) and ribavirin (initial dose of 600 mg, increased as tolerated) for 12 weeks is recommended for patients

HCV-coinfected individuals who are not taking antiretroviral therapy.

**g.** Ribavirin should not be used with didanosine, stavudine, or zidovudine.

darunavir, or ritonavir-boosted lopinavir.

raltegravir (and probably dolutegravir) [93].

citabine, lamivudine, and abacavir [93].

response >90%:

**9.2. Patients with decompensated cirrhosis**

**a.** Decompensated cirrhosis: genotypes 1 and 4

with decompensated cirrhosis.

HIV protease inhibitors.

94 Recent Advances in Liver Diseases and Surgery

**•** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) (doses need to be adjusted according to the patient's creatinine clearance rate and hemoglobin level) for up to 48 weeks is recommended for patients with HCV genotype 2 or 3 who have decompensated cirrhosis.

#### **9.3. Patients with HCV recurrence post liver transplantation**

Patients with posttransplant recurrence of HCV infection should be considered for therapy. Significant fibrosis or portal hypertension 1 year after transplantation could predict rapid disease progression and graft loss and could indicate the need for more urgent antiviral treatment. Interferon-free DAA can cure most liver transplant recipients with recurrent hepatitis C, including a majority of those with severe post-transplant liver disease. In addition to viral suppression, treatment also improves liver function. DAA treatment is generally safe and well tolerated, certainly more so than interferon-based therapy, although anemia remains a concern for people taking ribavirin. Drug-drug interactions may be important in the posttransplant setting. No clinically significant drug-drug interactions have been found between sofosbuvir, simeprevir, or daclatasvir on the one hand, and cyclosporine and tacrolimus on the other hand.

The following options proved to be useful in post-liver transplantation patients according to genotypes, with high virological response, waiting more data in near future [91,93,104,105]:


### **9.4. Patients with renal impairments**

For patients with creatinine clearance of >30 mL/min, no dosage adjustment is required when using simeprevir, sofosbuvir, daclatasvir, fixed-dose combination of ledipasvir (90 mg)/ sofosbuvir (400 mg), or fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) to treat patients with HCV infection. Simeprevir, daclatasvir, and the combination of paritaprevir, ritonavir, ombitasvir and dasabuvir are cleared by hepatic metabolism and can be used in patients with severe renal impairment [91].

EASL Recommendations on Treatment of Hepatitis C 2015 and AASLD/IDSA/IAS-USA 2014 guidelines on HCV treatment do not recommend sofosbuvir in patients with creatinine clearance of <30 mL/min or with ESRD until more data are available [91,93].

#### **9.5. Patients with acute HCV infection**

When the efficacy of the treatment of acute HCV infection was superior to the treatment of chronic infection, there was a strong impetus to identify and treat acute HCV infection with interferon [106]. The current availability of interferon-sparing HCV treatments that have high safety and efficacy reduces the advantage of early treatment of HCV infection. Until data documenting the efficacy and safety of treatment of acute hepatitis C with direct acting antiviral drugs are available, monitoring for spontaneous clearance for minimum of 6 months before initiating treatment is required. When a decision is made to treat patients after 6 months of acute infection, then the patient can be treated as described for chronic HCV [93].
