Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection is a multi-faceted, chronic condition that significantly impacts public health. According to the World Health Organization (WHO), 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to accelerated liver disease. The burden of co-infection is especially high in certain high-risk groups, such as intravenous drug users and men who have sex with men. [1] These individuals who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission including, but not limited to, exposure to HIV-positive blood, sexual intercourse, and passage of the Hepatitis C virus from mother to infant during childbirth. [2]
Infection with HCV can be asymptomatic, resolve itself without treatment, or can lead to cirrhosis or cancer.
Although symptoms of HIV and HCV mono-infection have been well-studied over the years, the symptoms associated with HIV and HCV co-infection remain a developing field of research. Many co-infected individuals report a difficulty in attributing their symptoms to a particular viral infection, indicating an overlap in symptoms of both diseases. This suggests that interventions aiming to reduce the disease burden associated with HIV and HCV co-infection must consist of strategies to manage symptoms of each individual infection.[ citation needed ]
In contrast to HIV and HCV co-infection, there has been significant research delineating the signs and symptoms of each of these individual illnesses. Common symptoms experienced by HIV-infected individuals include fever, night sweats, diarrhea, nausea, headache, and fatigue. [3] On the other hand, symptoms associated with HCV infection include fatigue, depression, urticaria, peripheral neuropathy, joint pain, and irritability. Co-infected individuals can experience a range of these symptoms, with some studies showing fatigue to be the most prevalent symptom. [4]
Due to the similar routes of transmission of HIV and HCV, HIV-positive individuals are at great risk of HIV and HCV co-infection. [5] These routes of transmission include percutaneous blood exposure, sexual intercourse, and mother-to-child transmission. [2] In the United States, injection drug use is known to be the most common mode of transmission of HCV. [6] Some studies have shown that co-infection is significantly associated with older age as well as illicit intravenous and non-intravenous drug use, and HIV-infected individuals have a higher overall risk of HCV infection irrespective of intravenous drug use or other risk factors. [7]
HIV is contracted by coming in contact with the bodily fluids of someone HIV positive. These fluids include blood, semen, pre-seminal fluid, rectal fluids, vaginal fluids, and breast milk. An individual can become infected with HIV if these fluids enter the bloodstream by way of a mucous membrane, damaged tissue or injection. Common HIV routes of transmission include sharing needles, having unprotected sex with someone who is HIV positive, mother to fetus during pregnancy, being stuck with an HIV-contaminated sharp object, etc. [8] Once the virus has entered the blood stream, it attaches to and enters T helper cells (CD4 cells) in order to replicate. After reverse transcription, the new viral DNA integrates itself into the host cell's DNA and instructs the cell to produce viral proteins. These viral proteins bud off of the host CD4 cell and move on to infect other CD4 cells which is how the virus spreads in the body and destroys the immune system. [9]
HCV is transmitted by coming in contact with the blood of someone infected with HCV. The virus is commonly spread by sharing needles, mother to infant during birth, improperly sterilized medical equipment, intercourse with an infected individual, and unregulated tattoos. [10] Once inside the body, the virus enters the liver's hepatocyte cells via receptor-mediated endocytosis. Inside the cell, the viral RNA undergoes translation and at the end of the whole process, viral proteins are created. These proteins fuse with lipid droplets in the cytosol of the hepatocyte to form a cell known as a high-density HCV precursor. In the golgi apparatus, the HCV precursor cell fuses with two more cells before becoming the HCV lipoviral particle. HCV in this particle form is protected from antibody neutralization which would normally stop the virus from spreading. These lipoviral particles are released out of the hepatocyte to find other hepatocytes to infect. [11]
Since the two viruses can be spread in similar ways, it is possible for cotransmission to occur where an individual gets infected with both viruses at the same time. People who are coinfected with HIV and HCV by way of blood contact are more likely to be infected with HCV before HIV. Studies have shown that in comparison to HIV, there is up to a 10 fold greater risk of transmitting HCV after contact with an infected needle. [12]
To diagnose an individual with HIV, a test must be taken to determine if the virus is present in their system. There are several test options including ELISA, at-home, saliva, viral load, and western blot. [13] To establish the presence of the HIV virus, some tests measure the level of HIV antibodies in the blood and/or saliva or the level of both HIV antigens and antibodies in the blood. Other tests can detect the presence of the HIV virus by calculating the amount of actual virus present in the blood. None of the tests available can determine if a person is positive immediately after they believe they have been exposed to the virus. Each test has a window of time after the initial exposure occurred until the test can accurately tell if an individual has been infected or not. One reason for this is because the focus of some of the tests are antibodies. After the initial exposure to the virus, it usually takes 3–4 weeks but it can take up to six months for antibodies to be produced by the body. For nucleic acid tests, like the viral load blood test, it can take anywhere from 10–33 days for the test to provide an accurate result. If an individual's first HIV test is positive, it is recommended for them to take a second test to confirm the results. If this follow-up test is also positive, an HIV positive diagnosis can likely be made. [14]
For an individual to be diagnosed with HCV, they must first take the hepatitis C antibody (HCV Ab) screening test. This test is used to determine the presence of HCV antibodies in the blood. It can take anywhere from 3–12 weeks after the time of initial exposure for antibodies to appear in the blood. Therefore, even if a person is infected with HCV, an HCV Ab test may not show a positive result until after that amount of time has passed. If the HCV Ab test result is positive for HCV antibodies, then the individual either has an active HCV infection or previously had an infection which has since cleared. The individual must follow-up with a quantitative and/or qualitative HCV RNA blood test which provides a count of the HCV viral load and indicates if the infection is chronic or not. The virus RNA can be detected in the blood 1–2 weeks after exposure. For a quantitative test, a low viral load is any value below <800,000 IU/L and anything above 800,000 IU/L is considered a high viral load. Lower viral loads at the start of treatment have been associated with greater likelihood to clear the infection. [15] A positive result for a qualitative HCV RNA blood test confirms that the active virus is present in the individual's bloodstream and that the infection is chronic. A negative result can indicate that the person's immune system was able to spontaneously clear their body of the infection without treatment. Lastly, there is an HCV genotype test which is done to identify the particular genotype (or strain) of the HCV virus the individual is infected with. There are a total of six different HCV genotypes. Knowing the specific genotype of the virus is important when deciding on treatment options because some antiviral medications are more effective against certain genotypes. [16]
Persons living with an HCV-HIV co-infection are at higher risk for certain adverse medical outcomes, such as accelerated hepatic fibrosis, [17] hepatic decompensation, [18] and immune dysregulation. [6] Due to higher mortality rates in co-infected individuals as a result of accelerated liver disease – in comparison to individuals with HIV mono-infection [19] [20] – pursuing HCV treatment and cure is a priority in these individuals with optimal suppression of HIV replication and avoidance of drug-drug interactions. [21]
In individuals living with HIV, anti-retroviral therapy (ART) has been shown to preserve immune function, reduce the effects of HIV-related inflammation, and delay hepatic disease. Therefore, treatment plans for individuals with HIV/HCV co-infection include: an initial ART regimen (as recommended for HIV mono-infected individuals); simultaneous HCV treatment involving oral direct-acting antivirals (DAA); and special consideration given to potential for severe drug-drug interactions between the selected medication regimens. [22] When initiating DAA therapy, the individual is typically assessed for ART-naivety. It is recommended that the individual, if not previously already on ART for HIV maintenance, initiate ART 4–6 weeks prior to DAA administration in order to adequately adjust to regimen and provide a greater foundation for efficacious response to HCV treatment. [23]
The overall goal of HCV DAA therapy is to create a Sustained Virological Response for 12 consecutive weeks (SVR12) to ensure the Hepatitis C virus is not detected in the blood. [24] In clinical trials, the use of the following DAA combinations have shown similar efficacy rates (by achieving SVR12) in individuals with HIV/HCV co-infection as those with HCV mono-infection: [21]
Due to limited clinical safety data, the following DAA combinations, while available, are not considered as first-line therapies: [21]
Barriers to care exist when discussing therapeutic options for HCV/HIV co-infected individuals. For example, other co-morbidities such as severe hepatic decompensation, cardiac disease, and renal disorders contribute to treatment barriers since these individuals would not be eligible for anti-retroviral therapy. [28] [29] Individuals with continued alcohol/drug/substance abuse and those that exhibit depressive symptoms along with suicidal ideations are also subject to ineligible status for HCV treatment in HCV/HIV co-infected persons. [30]
At the lowest estimate, there are 35 million individuals infected with HIV and 80 million infected with Hepatitis C worldwide. [31] With the significant global effect of each of these viruses, it is also important to note that there is a considerable overlap of HIV-positive individuals co-infected with HCV. In fact, 20% of HIV-positive individuals also have Hepatitis C. This overlap is related to the common ways these viruses are spread, including contaminated blood and bodily fluids such as semen and vaginal fluids. [32]
There are marked differences between groups affected by this co-infection. However, it is consistent that HIV-positive individuals have a higher prevalence of Hepatitis C infection. Of those co-infected with HIV and HCV, almost 60% are intravenous drug users, a high risk group for mono-infection with HIV or HCV. Additionally, prevalence varies by geographical location with the highest prevalence of co-infection located in North Africa and the Middle East versus the lowest prevalence located in East Africa. [33]
Over time, liver disease and its complications have arisen as both a morbidity and mortality concern for people with HIV. Studies have determined that co-infection with HIV and HCV is associated with both faster and more severe liver damage than HCV infection alone. [31] In fact, mortality due to liver disease is now one of the top three causes of death in HIV-infected individuals, with 66% of these liver disease-related deaths due to concurrent HCV infection. [34] Additionally, due to the development of novel therapies to treat HIV, antiretroviral therapies, HIV-positive individuals are taking chronic medications to prevent the progression of HIV to AIDS. However, these medications can have negative side effects on the liver, and can therefore worsen liver disease. [35]
The effects of HIV infection on HCV have been widely studied. However, the data on the effects of HCV infection on HIV are conflicting. Some studies show that HCV infection does not affect HIV progression, while others have shown a faster progression of HIV in those co-infected with HCV. When considering this conflicting information, it is important to note that many of these studies were completed before the introduction of antiretroviral therapies for HIV, which are now the standard-of-care for HIV-positive individuals. [6]
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.
Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV). HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).
HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA.
Hepatitis A is an infectious disease of the liver caused by Hepatovirus A (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is two–six weeks. When symptoms occur, they typically last eight weeks and may include nausea, vomiting, diarrhea, jaundice, fever, and abdominal pain. Around 10–15% of people experience a recurrence of symptoms during the 6 months after the initial infection. Acute liver failure may rarely occur, with this being more common in the elderly.
In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins to produce antibodies in response. Before seroconversion, the antigen itself may or may not be detectable, but the antibody is absent. During seroconversion, the antibody is present but not yet detectable. After seroconversion, the antibody is detectable by standard techniques and remains detectable unless the individual seroreverts, in a phenomenon called seroreversion, or loss of antibody detectability, which can occur due to weakening of the immune system or decreasing antibody concentrations over time. Seroconversion refers the production of specific antibodies against specific antigens, meaning that a single infection could cause multiple waves of seroconversion against different antigens. Similarly, a single antigen could cause multiple waves of seroconversion with different classes of antibodies. For example, most antigens prompt seroconversion for the IgM class of antibodies first, and subsequently the IgG class.
Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).
Coinfection is the simultaneous infection of a host by multiple pathogen species. In virology, coinfection includes simultaneous infection of a single cell by two or more virus particles. An example is the coinfection of liver cells with hepatitis B virus and hepatitis D virus, which can arise incrementally by initial infection followed by superinfection.
The hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus of the family Flaviviridae. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer and lymphomas in humans.
GB virus C (GBV-C), formerly known as hepatitis G virus (HGV) and also known as human pegivirus – HPgV is a virus in the family Flaviviridae and a member of the Pegivirus, is known to infect humans, but is not known to cause human disease. Reportedly, HIV patients coinfected with GBV-C can survive longer than those without GBV-C, but the patients may be different in other ways. Research is active into the virus' effects on the immune system in patients coinfected with GBV-C and HIV.
Hepatitis B is an infectious disease caused by the Hepatitis B virus (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Hepatitis B virus (HBV) is a partially double-stranded DNA virus, a species of the genus Orthohepadnavirus and a member of the Hepadnaviridae family of viruses. This virus causes the disease hepatitis B.
Stuart C. Ray is an American physician. He is Vice Chair of Medicine for Data Integrity and Analytics, Associate Director of the Infectious Diseases Fellowship Training Program at the Johns Hopkins School of Medicine, and a Professor in the Department of Medicine, Division of Infectious Diseases. Ray also holds appointments in Viral Oncology and the Division of Health Sciences Informatics. He is affiliated with the Institute for Computational Medicine at Johns Hopkins and is licensed to practice medicine in Maryland.
Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.
Infections of the hepatitis C virus (HCV) in children and pregnant women are less understood than those in other adults. Worldwide, the prevalence of HCV infection in pregnant women and children has been estimated to 1-8% and 0.05-5% respectively. The vertical transmission rate has been estimated to be 3-5% and there is a high rate of spontaneous clearance (25-50%) in the children. Higher rates have been reported for both vertical transmission. and prevalence in children (15%).
Beclabuvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection that has been studied in clinical trials. In February 2017, Bristol-Myers Squibb began sponsoring a post-marketing trial of beclabuvir, in combination with asunaprevir and daclatasvir, to study the combination's safety profile with regard to liver function. From February 2014 to November 2016, a phase II clinical trial was conducted on the combination of asunaprevir/daclatasvir/beclabuvir on patients infected with both HIV and HCV. Furthermore, a recent meta-analysis of six published six clinical trials showed high response rates in HCV genotype 1-infected patients treated with daclatasvir, asunaprevir, and beclabuvir irrespective of ribavirin use, prior interferon-based therapy, or restriction on noncirrhotic patients, IL28B genotype, or baseline resistance-associated variants
Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.
Hepatitis C virus (HCV) genotypes refer to the genetic variations that occurs in the hepatitis C virus. Hepatitis C is a contagious disease that primarily affects the liver, causing severe damage as the disease progresses. It is caused by the Hepatitis C virus, a small, enveloped RNA virus. The transmission of hepatitis C is through the contact with the blood of the infected person, for example by sharing the needles or by using non-sterile medical equipment. HCV is transmitted globally because of the high infection rate and is also associated with a high mortality rate. The World Health Organization indicates the 3.3% of the world population is infected by the HCV virus. Statistical records show that there are about 13 million HCV affected persons in Сhina, 3.5 million affected persons in the United States, and about 10 million people are affected by HCV in Pakistan. In all cases, the viral genotype of the HCV stays the same, occasionally mutations do occur making the treatment more complex by targeting the changes in the genotype. Hepatitis C virus genotype is considered more common than the Hepatitis B virus infection contributing to more than a million cases annually and is considered one of the major reason for liver transplantation in United States. Some of the HCV genotypes may develop in people without symptoms leading to dangerous conditions like liver cirrhosis causing a permanent damage to liver and the unnoticed HCV conditions will affect brain, joints, blood vessels, bones, and kidneys.
HPgV-2 is the second human pegivirus discovered. It was first identified in 2005 in blood of transfusion recipients and initially named hepegivirus 1 because it shared some genetic features with both pegiviruses and hepaciviruses. HPgV-2 was later independently discovered by another group in the blood of a HCV-infected patient who had undergone multiple blood transfusions and died from sepsis of unclear etiology. It was then named human pegivirus 2. HPgV-2 is now classified in the pegivirus genus as part of Pegivirus H species.
Interferon lambda 4 is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.