HCV is transmitted via percutaneous contact with HCV-infected blood, most commonly via shared injection drug use (IDU) equipment or contaminated blood products (before the implementation of effective screening of blood banks) or hospital equipment. Rates of mother-to-child HCV transmission generally are low but increase with maternal HIV coinfection.(5) Heterosexual transmission of HCV also is uncommon, but infectivity is increased when partners are coinfected with HIV. HCV transmission via sexual contact among men who have sex with men (MSM) in the absence of IDU increasingly has been recognized in outbreaks in the United States and Europe.(6) The risk of HCV infection via sexual contact among MSM appears to increase with HIV coinfection, concurrent sexually transmitted disease such as syphilis, drug use, and sex practices that may injure rectal epithelia, such as fisting.(6, 7, 8) Transmission via the use of shared nasal drug consumption equipment, body piercing, or tattoos has been reported, but these are thought to be uncommon modes of infection.(9)
Although many individuals have no symptoms at the time of HCV infection, a subset will develop acute HCV symptoms, which include fatigue, myalgia, jaundice, diarrhea, abdominal pain, and laboratory findings of elevated transaminase and bilirubin levels. HIV-coinfected individuals are less likely to clear HCV without treatment, with an estimated 85% developing chronic HCV after acute infection.(10) However, in some studies of acute HCV infections in HIV-infected MSM, spontaneous clearance rates as high as 40% have been reported.(11) These higher clearance rates may be attributable in part to increased surveillance for acute HCV leading to more frequent recognition of spontaneous clearance.
All HIV-infected individuals with HCV coinfection should be screened for other viral hepatitides and vaccinated against hepatitis A and hepatitis B if they are not immune. HCV-infected patients should be cautioned to limit exposure to hepatotoxins, including alcohol, excessive acetaminophen (>2 grams/day), and marijuana, which may contribute to steatosis and fibrosis.(20) Patients should be counseled about reducing the risk of transmitting HCV to others, which may occur by sharing IDU equipment and having unprotected sex. Individuals with advanced fibrosis or cirrhosis should be screened for hepatocellular carcinoma every 6-12 months with ultrasound and alpha-fetoprotein (AFP) testing.
| HCV Therapy|
Successful treatment of HCV in HIV/HCV-coinfected patients is associated with decreased liver-related mortality,(21) as well as non-liver-related mortality, and AIDS progression.(22) HCV infection is increasingly recognized to be associated with elevations in markers of endothelial dysfunction (23) and nonhepatic complications including stroke, complications that may be more common in HIV/HCV coinfection compared with HCV infection alone (24); however, it is not known whether HCV treatment reduces risk of these nonhepatic events.
HIV/HCV-coinfected individuals are less likely to clear HCV infection with current interferon/ribavirin-based HCV treatment. HIV-infected patients with HCV genotype 1 treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) achieve sustained virologic response (SVR) rates of 15-35%, compared with approximately 50% in HCV-monoinfected patients.(9) Similarly, 43-73% of HIV-coinfected patients with genotype 2 or 3 attain an SVR, compared with rates of 65-98% for HCV-monoinfected patients (see Table
| Treatment of Acute HCV|
As in HCV-monoinfected patients, treatment of HIV/HCV-coinfected patients during the first year of infection is associated with a better response to therapy than is treatment of chronic infection, with 50-91% of these patients achieving an SVR after treatment with up to 48 weeks of PEG-IFN and RBV.(25) Although HIV-uninfected patients respond well to PEG-IFN monotherapy for 24 weeks,(26) the optimal acute HCV treatment and duration in HIV coinfection is unclear. Cotreatment with RBV is recommended by most experts, owing to the generally poorer response of HIV-coinfected patients to therapy. PEG-IFN should be given (with RBV) for at least 24 weeks.(1) Ultimately, data may support tailoring treatment duration to individual virologic response, as in treatment of chronic HCV. Waiting 12 weeks from the estimated date of infection is recommended before initiating HCV treatment, to ensure that spontaneous clearance has not occurred.(25, 27)
| Treatment of Chronic HCV|
Despite the lower rates of response to therapy in HIV/HCV-coinfected patients, HCV treatment should be a consideration for all such patients with adequately controlled HIV infection (eg, CD4 count of >150 cells/µL) in whom HCV treatment is not contraindicated. Contraindications to IFN-based HCV treatment include decompensated liver disease, poorly controlled psychiatric disease, solid organ transplant, autoimmune disease, untreated thyroid disease, inability to comply with contraception (both women and men, because of teratogenicity of RBV), and limited life expectancy owing to other severe concurrent morbidities.(9) Patients with decompensated cirrhosis who are potential transplant candidates should be referred promptly for transplant evaluation at a center with an experienced staff, if feasible.
| Staging of Liver Disease in Chronic HCV Infection|
Staging of liver disease via biopsy may help in targeting the optimal timing for initiation of HCV treatment, but it is not essential before initiating treatment. Liver biopsy is unnecessary in individuals being treated for acute infection and in patients who are committed to treating their HCV infection regardless of the fibrosis score, and it may be unnecessary in individuals with HCV genotypes 2 and 3, for which outcomes generally are favorable. Noninvasive alternatives to liver biopsy are increasingly available, including serum biomarker tests such as APRI and Fib-4, and transient elastography, which measures liver stiffness. Both methodologies are able to distinguish lack of fibrosis from cirrhosis but are limited in their ability to discriminate moderate amounts of liver disease.
| Timing of Therapy in Chronic HCV Infection|
For individuals with advanced liver disease staged by biopsy or a noninvasive evaluation, initiation of HCV treatment should not be delayed, if there are no contraindications to initiating therapy. Even moderate liver fibrosis of stage 2 (on a scale of 0-4) is associated with twice the risk of adverse events (end-stage liver disease, hepatocellular carcinoma, or death) as fibrosis stage of 0-1.(28) Patients with no or minimal fibrosis may consider delaying treatment and opt for close monitoring. Given that fibrosis can progress quickly in HIV/HCV coinfection, those patents who defer therapy on the basis of limited fibrosis should consider serial evaluations of fibrosis progression every 2-3 years with repeat biopsies (29) or noninvasive evaluations. A normal alanine aminotransferase (ALT) test result is not a reliable indicator of lack of liver fibrosis, particularly in HIV infection.(30)
| Optimization before Starting HCV Treatment|
Given the intensity of IFN-based treatment and its significant side effects, extensive pretreatment education and optimization are recommended to ensure the best possible outcomes. Although many factors associated with a poor response to HCV therapy cannot be modified (eg, male sex, African American ethnicity, HCV genotype 1 or 4, high HCV RNA), several patient-related variables can be optimized before the initiation of treatment. Weight loss for obese patients should be advised; this also may decrease insulin resistance, which is a negative predictor for HCV treatment response. Reduction or avoidance of hepatotoxins such as alcohol should be recommended.
RBV induces hemolytic anemia; thus, preexisting anemia should be corrected before treatment initiation, and hemoglobin and hematocrit should be monitored during therapy. IFN occasionally causes retinopathy, so a baseline eye examination is recommended, with repeated funduscopic examination if any visual complaints develop. IFN also is associated with the development and exacerbation of autoimmune disease. Before starting HCV treatment, patients should be questioned about a history of autoimmune disease, and thyroid function should be tested. Patients who are found to have abnormal thyroid function should undergo further evaluation. Autoimmune thyroiditis is a relative contraindication to the use of IFN-based treatment.(9) IFN has numerous psychiatric side effects and may induce or exacerbate anxiety, depression, psychosis, and suicidality.(31) Pretreatment psychiatric assessment is strongly recommended, as is treatment and stabilization of any preexisting psychiatric disease. Most providers consider prior suicidal ideation or attempt to be a contraindication to HCV treatment. A peer support and education group for individuals contemplating and undergoing HCV treatment is a key component of many successful hepatitis treatment programs.
Some antiretroviral (ARV) medications should not be used for patients receiving treatment for HCV. Didanosine (ddI) is contraindicated for use by patients who are receiving RBV, as RBV raises intracellular ddI levels, thus increasing the risk of ddI-associated toxicities such as lactic acidosis and pancreatitis.(32) Zidovudine (ZDV) may exacerbate RBV-induced anemia and should not be used if alternative ARV medications are available. There has been controversy as to whether abacavir (ABC) is associated with poorer HCV clearance rates. However, when used in conjunction with weight-based RBV dosing, ABC use has not been convincingly associated with worse HCV treatment response.(33)
| Length of Therapy and Monitoring on Therapy|
The U.S. Centers for Disease Control and Prevention (CDC) guidelines recommend 48 weeks of PEG-IFN plus RBV for all HIV/HCV-coinfected patients, regardless of genotype (Table
2).(34) Patients for whom a 2 log10 reduction in HCV RNA at 12 weeks (early virologic response [EVR]) is not achieved and those who have any detectable HCV RNA at 24 weeks should discontinue HCV treatment because the likelihood of attaining an SVR is very low. Alternatively, the HIV-HCV International Panel and the European AIDS Clinical Society have recommended treatment guidelines for PEG-IFN and RBV with more flexible durations than those in the U.S. guidelines, based on genotype and virologic response to therapy at week 4 (rapid virologic response [RVR], defined as undetectable HCV RNA at week 4 of HCV treatment) and 12-week EVR (Figure
1). Twenty-four weeks of therapy can be considered for patients with genotype 2 or 3 who achieve RVR (35) if other favorable factors are present, including lack of advanced fibrosis and good adherence. However, European guidelines advise that 48 weeks of therapy may be recommended with genotypes 2 and 3 if any poor prognostic factors are present, until further data to support a shorter duration of therapy are available. Conversely, extension of treatment to week 72 can be considered for patients with genotype 1 or 4 who do not attain RVR but do attain EVR as well as subsequent undetectable RNA at 24 weeks. However, patient tolerance of IFN/RBV for longer than 48 weeks is poor, and those with only a partial EVR (>2 log10 drop of HCV RNA without complete HCV RNA suppression) will likely continue to have low rates of SVR, as low as 17% in a recent AIDS Clinical Trials Group study,(36) despite 72 weeks of treatment.
Weight-based RBV (1,000-1,200 mg daily) for patients with genotype 1 generally has been recommended to maximize RBV exposure and therapeutic response.(1) However, a randomized trial comparing 800 mg RBV daily with weight-based RBV in HIV/HCV-coinfected patients found a similar SVR rate with the 2 dosing regimens, although there was a nonsignificant trend toward improved SVR in African Americans on higher doses of RBV.(37) Genotype 2 and 3 infections typically are treated with RBV 800 mg daily in both HCV-monoinfected and HIV/HCV-coinfected patients. Higher dosages of IFN have not been shown to improve SVR in several small studies of coinfected patients, although some data suggest a benefit to elevated IFN dosages for monoinfected patients.(1)
HIV-coinfected patients experience more anemia and neutropenia on HCV therapy than do monoinfected patients, and they should be monitored closely for hematologic toxicity and treated with growth factors as needed. IFN-induced neutropenia will cause depression of the absolute CD4 cell count without affecting the CD4 percentage. Although there are only limited data regarding the risk of opportunistic infections in patients with high CD4 percentages but low absolute CD4 cell counts in the setting of IFN treatment, many providers will reinstitute Pneumocystis jiroveci pneumonia prophylaxis if the CD4 count drops to <200 cells/µL, even for patients who are on suppressive ART. Owing to the risk of IFN-induced autoimmune disease, antinuclear antibody (ANA) and thyroid-stimulating hormone (TSH) should be monitored every 3 months.(38) Ongoing monitoring for psychiatric well-being of patients on IFN is strongly recommended.
| ARV Use in HIV/HCV-Coinfection|
Hepatoxicity following ART initiation is more common in HIV/HCV-coinfected patients, with the highest risk in those with more advanced liver disease.(39) Although nevirapine, stavudine, ddI, and tipranavir in particular have been associated with development of hepatoxicity, all ARV classes are associated with some risk of hepatotoxicity. Therefore, liver function must be monitored closely in all HIV/HCV-coinfected patients who are receiving ART. Elevations of transaminases >5 times the upper limit of normal should trigger evaluation for alternative causes of liver injury, including viral hepatitis and toxicity associated with use of alcohol or other drugs.(29) The risk of ART-related hepatoxicity is higher in patients with abnormal transaminase levels before ART initiation and in those with concomitant hepatitis B virus coinfection. Successful treatment of HCV infection is associated with reduced risk of ART-induced hepatotoxicity.(40)
HCV-related immune reconstitution inflammatory syndrome (IRIS) can occur after ART initiation, but it is a diagnosis of exclusion.(41) ART interruption should be avoided unless symptoms of hypersensitivity are present (eg, fever, lymphadenopathy, rash), hepatitis is symptomatic (eg, nausea, vomiting, abdominal pain, jaundice), or transaminases are elevated to >10 times the upper limit of normal.(29)
| Timing of ART in Relation to HCV Treatment|
Individuals with CD4 counts of <500 cells/µL should start ART before initiating HCV therapy, given the improved response to HCV treatment seen in patients with higher CD4 counts as well as the risk of complications owing to untreated HIV at CD4 counts of <500 cells/µL. The optimal timing of HIV treatment in relationship to HCV therapy for patients with higher CD4 cell counts is a matter of controversy. The rationale for starting ART before starting HCV treatment includes the following points:
Treating HIV may slow progression of HCV-induced fibrosis.(34)
Treating HIV may improve the immune modulatory effects of IFN-based HCV treatment and thus could improve response to HCV treatment.
IFN-based treatment can decrease overall white blood cell count, leading to CD4 cell count declines that are difficult to interpret in patients with untreated HIV.
The arguments for deferring ART treatment until after completion of HCV therapy in individuals with high CD4 cell counts include the following points:
ART initiation in the setting of untreated HCV is associated with more hepatoxicity,(31) whereas successful treatment of HCV reduces ART-associated hepatotoxicity.(40)
Overlapping drug toxicities from HIV and HCV regimens can be avoided.
There are no randomized, controlled trials evaluating the optimal timing of HCV treatment in relationship to initiation of ART. As ART is being initiated earlier in the course of HIV disease, many providers are initiating ART before starting HCV therapy, regardless of the CD4 count.
| Future Directions for HCV Treatment in HIV Infection|
Several classes of potent new HCV treatments are in development, including protease and polymerase inhibitors. As these agents directly target HCV activity, they are known as directly acting agents (DAAs) (Figure
| HCV Protease Inhibitors|
In spring 2011, the HCV protease inhibitors telaprevir (TVR) and boceprevir (BOC) were approved by the U.S. Food and Drug Administration. Most of the data currently available are from use in HIV-uninfected HCV patients; these show that in treatment-naive patients, use of TVR or BOC leads to SVR rates that are nearly double those seen with PEG-IFN/RBV alone . Twelve weeks of TVR with 48 weeks of PEG-IFN/RBV resulted in SVR of 61-75% vs 41-44% in the control arms given 48 weeks of PEG-IFN/RBV alone (Figure
4).(42, 43) Forty-four weeks of BOC with PEG-IFN/RBV given after 4 weeks of initial PEG-IFN/RBV led to SVR of 68-75%, compared with 38-44% with PEG-IFN/RBV alone (Figure
2).(44, 45) In some of these studies, patients whose HCV became undetectable after 4 weeks of treatment were given a shortened therapy duration of 24 weeks (response-guided therapy).
In HCV-monoinfected patients who experienced treatment failure on previous IFN-based regimens, the response to HCV protease inhibitors in conjunction with PEG-IFN/RBV is encouraging. In the PROVE 3 study of patients with prior nonresponse, breakthrough, or relapse, 12 weeks of TVR with 48 weeks of PEG-IFN/RBV led to SVR in 38%, 62%, and 76% of patients respectively, compared with 9%, 40%, and 20% in the control arm (48 weeks of PEG-IFN/RBV).(46) (Nonresponse means that HCV RNA was never undetectable during prior treatment; breakthrough means that HCV RNA was undetectable during treatment but later was detectable during treatment; relapse means HCV RNA was undetectable during prior treatment for at least 42 weeks but became detectable after treatment, and no SVR was attained). Similarly, in the REALIZE study, 12 weeks of TVR with 48 weeks of PEG/RBV was associated with SVR in 29%, 59%, and 83% of those with nonresponse, partial response, and relapse, respectively, compared to 5%, 15%, and 24% in the 48-week PEG/RBV control group (Figure
5).(47) (In this study, partial response was defined as a reduction of 2 log10 or more after 12 weeks but with detectable HCV RNA subsequently). In the HCV RESPOND-2 study, SVR was attained in 21% of subjects who received 44 weeks of PEG-IFN/RBV (control arm), compared with 59% of subjects who received response-guided therapy (32 weeks BOC/PEG-IFN/RBV followed by an additional 12 weeks of PEG-IFN/RBV if the HCV RNA was detectable at week 8) and 66% of those who received 44 weeks of BOC/PEG-IFN/RBV, after an initial lead-in of 4 weeks of PEG-IFN/RBV in all groups (Figure
With these HCV protease inhibitors (unlike with standard PEG-IFN/RBV treatment), the HCV genotype subtype appears to influence treatment response; response rates are higher in patients with genotype 1b than in those with genotype 1a.(47, 49)
HCV protease inhibitors have a low genetic barrier to resistance, so currently they must be given as components of combination therapy with PEG-IFN and RBV. However, there is active investigation of DAA combinations that may effectively treat HCV without PEG-IFN.
| HCV Protease Inhibitors in HIV Coinfection|
Data for use of HCV protease inhibitors in persons with HIV/HCV coinfection are very limited, as are data on drug-drug interactions between these agents and HIV ARVs.
Available clinical data on TVR in coinfected patients comes from a Phase II study of HCV treatment-naive patients with genotype 1 HCV.(50) Participants could be receiving or not receiving ART; if receiving ART, they were permitted to take only efavirenz- or atazanavir/ritonavir-based regimens. (For efavirenz recipients, the dosage of TVR was increased to 1,125 mg every 8 hours.) After 12 weeks of PEG-IFN/RBV plus TVR, 71%, 75%, and 57% of participants on no ART, efavirenz-based ART, and atazanavir/ritonavir-based ART had undetectable HCV RNA (complete EVR), respectively, compared with 17%, 12%, and 12% of patients on PEG-IFN/RBV only. SVR data are forthcoming. No data for clinical outcomes with HIV/HCV-coinfected patients treated with BOC are available.
A Phase II study of BOC in HIV/HCV coinfected patients randomized 98 patients to BOC + PEG/RBV, or standard PEG/RBV. At week 4, HCV suppression rates in the triple-therapy group were 37.5% compared with 14.7% in the standard therapy group, and at week 12, EVR rates were 59.3% and 25.8%, respectively, indicating a promising response in HIV-infected patients treated with BOC + PEG/RBV (51).
TVR is an inhibitor and substrate of CYP3A4, so drug interactions with some HIV protease inhibitors and NNRTIs are anticipated. Pharmacokinetic (PK) studies to date have indicated that efavirenz decreases TVR levels significantly, requiring a dosage increase of TVR to 1,250 mg every 8 hours; and TVR conversely lowers efavirenz levels slightly.(49) The effect on HIV protease inhibitors has been more heterogeneous, with TVR raising atazanavir and lopinavir/ritonavir levels but decreasing fosamprenavir and darunavir levels.All HIV protease inhibitors lowered TVR AUC and Cmin; however, atazanavir decreased TVR levels the least. Currently, ritonavir-boosted atazanavir is the only HIV protease inhibitor that can be coadministered with TVR; TVR dosage adjustment is not required.(52) Raltegravir coadministration has minimal effect on TVR levels; TVR increases raltegravir AUC by 30% and Cmin by 78%.(53) Given this data, raltegravir is an option for coadministration with TVR, although data from clinical studies are lacking.
BOC is a significant inhibitor and modest substrate of CYP3A4; thus, interactions with protease inhibitors and NNRTIs also are expected. The available PK data on BOC interactions with ARVs are limited, and mostly come from studies with healthy volunteers. EFV decreases BOC AUC by 19% and Cmin by 44%; the clinical significance of that is unclear.(49) Conversely, BOC slightly increased EFV AUC0-24 (20%) and Cmax (11%). Until further data are available, coadministration of NNRTIs and BOC is not recommended. BOC substantially reduced the trough levels of ritonavir-boosted protease inhibitors (atazanavir by 49%, darunavir by 59%, and lopinavir by 43%), and also reduced the AUC and Cmax concentrations of those drugs.(54) Ritonavir-boosted atazanavir did not reduce BOC exposure, but darunavir/ritonavir and lopinavir/ritonavir lowered BOC exposure by 32% and 45%, respectively. Given these data, coadministration of BOC with any HIV protease inhibitor also is not recommended. Raltegravir coadministration is not anticipated to result in significant drug interactions with BOC, although PK and clinical data are limited.(54)
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