Hepatitis C and HIV coinfection


Human Immunodeficiency Virus and Hepatitis C Virus co-infection is an important global health challenge. According to the World Health Organization, 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to 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. This is because patients 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 from a mother to her infant during childbirth.
Infection with HCV can be asymptomatic, resolve itself without treatment, or can cause cirrhosis or cancer.

Diagnosis

HIV:

To diagnose an individual with HIV, they must take a test 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. To establish the presence of the HIV virus, some tests can 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 a count of 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.

HCV:

For an individual to be diagnosed with HCV, they must first take the screening test HCV Ab. This test is used to determine the presence of HCV antibodies in the blood.

Mechanism

Characteristics

The morbidity and mortality caused by HCV have increased since the inception of highly active antiretroviral therapy. This is because HIV patients are living longer from powerful antiretroviral therapies and prevention of traditional opportunistic infections. The effect of HCV on the natural history of HIV remains inconclusive – some contradictory studies document no effect, while others show an increase to an AIDS-defining illness or death. In the United States, approximately 150,000 to 300,000 people are co-infected with HIV and HCV. They represents 15% to 30% of all HIV infected patients and 5% to 10% of all HCV patients. Reduced HCV antibody production, drug interactions, other causes of liver disease, differing epidemiologic characteristics and natural history complicate the management of HCV/HIV patients. Until recently, there was little data published regarding the treatment of HIV–HCV co-infected patients; fortunately, recent trials have been published about the safety and efficacy of current treatment options.

Signs and Symptoms

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 patients 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.
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 patients include fever, night sweats, diarrhea, nausea, headache, and fatigue. On the other hand, symptoms associated with HCV infection include fatigue, depression, urticaria, peripheral neuropathy, joint pain, and irritability. Co-infected patients can experience a range of these symptoms, with some studies showing fatigue to be the most prevalent symptom.

Risk Factors

Due to the similar routes of transmission of HIV and HCV, HIV-positive individuals are at great risk of HIV and HCV co-infection. These routes of transmission include percutaneous blood exposure, sexual intercourse, and mother-to-child transmission. Some studies have shown that co-infection is significantly associated with older age as well as illicit intravenous and non-intravenous drug use.

Epidemiology

At the lowest estimate, there are 35 million individuals infected with HIV and 80 million infected with Hepatitis C worldwide. 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 having 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.
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.

History

Over time, liver disease and its complications have arisen as both a morbidity and mortality concern for HIV patients. Studies have determined that co-infection with HIV and HCV is associated with both faster and more severe liver damage than HCV infection alone. In fact, mortality due to liver disease is now one of the top three causes of death in HIV patients, with 66% of these liver disease-related deaths due to concurrent HCV infection. 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. This is especially important when considering those co-infected with HCV.
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. Further research in this area would be beneficial, and is necessary, to determine the effects of HCV infection on HIV disease progression.

Treatment

The primary objective of HCV therapy is permanent eradication of the virus. The secondary potential benefit of eradication is a reduction in the risk of liver failure and liver cancer. Currently, peginterferon alfa-2a plus ribavirin is the only FDA approved treatment for HIV–HCV co-infected patients. Interferons bind to specific cell surface receptors of virus-infected cells, which induces a complex cascade of protein-protein interactions and a rapid activation of gene transcription. The antiviral effects of interferons are mediated through inhibition of viral penetration or uncoating, inhibiting viral replication or translation of viral proteins, and/or viral assembly and release. The difference between peginterferon and interferon is the addition of a polyethylene glycol polymer. The addition of PEG decreases plasma clearance considerably, protects the molecule from proteolytic degradation and reduces its immunogenicity. Peak concentrations are approximately 1.5–2 fold higher than trough concentrations and the half-life is 80 hours. Ribavirin is a synthetic nucleoside analogue, but its mechanism of action is not clearly established. Ribavirin inhibits the replication of a wide range of RNA and DNA viruses. Pharmacokinetics are similar in patients with HIV co-infection compared with HCV mono-infection.

Pegylated Interferon Alfa-2B (Peg Intron) plus Ribavirin versus Standard Interferon Alfa-2B (Intron A) plus Ribavirin

This was a randomized, phase 3, open-label, parallel group study. Four hundred sixteen treatment naïve patients were assigned to 1.5 µg/kg peginterferon alfa-2b once weekly plus ribavirin 800 mg daily or 3 million units of standard interferon alfa-2a plus ribavirin 800 mg daily for 48 weeks. 6 Patients were evaluated at weeks 2 and 4, then every 4 weeks after treatment and then at weeks 4, 12, and 24 post-treatment until week 72 was reached. The primary end-point was a sustained viral response, defined as undetectable serum HCV-RNA at week 72. The secondary endpoint was histological improvement. In the standard interferon group, 20% of the 207 patients obtained an SVR, and in the peginterferon group 27% of the 205 patients obtained an SVR. At week 24, undectable HCV RNA levels were achieved in 28% and 40% of patients, respectively, respectively. At 48 weeks, the end of treatment virologic responses were 21% and 35% of their respective groups. In patients who had genotype 1 or 4, peginterferon achieved a higher rate of SVR than interferon p=0.006. However, in genotypes 2, 3 or 5, the rates of SVR were similar. The withdrawal and adverse event rates were similar.

Pegylated Interferon Alfa-2A (Pegasys) plus Ribavirin versus Interferon Alfa-2A plus Ribavirin

In the study by Chung, et al. 66 treatment-naïve patients received 180 µg weekly of peginterferon or 6 million units thrice weekly of interferon for 12 weeks and then switched to 3 million units thrice weekly for 48 weeks. Both groups received ribavirin. The
main endpoint was to detect the differences in virologic response rates between the two groups. At week 24, subjects who did not have a virologic response underwent a liver biopsy and treatment was continued in patients who showed a histological improvement.

Tolerability

In the first trial, approximately the same number of patients from each group withdrew due to laboratory abnormalities or adverse events. The doses were modified more frequently in the peginterferon group due to lab abnormalities or adverse events . Neutropenia and weight loss were significantly higher in the peginterferon group; whereas, insomnia was higher in the interferon group. In the second study, 12% in each group withdrew due to lab abnormalities or adverse
events. Both groups experienced similar number of episodes of neutropenia, but two subjects in the peginterferon group dropped out due to grade 4 neutropenia.
The other patients were managed by dose reduction. One case of
clinically significant pancreatitis occurred in a patient who was receiving didanosine. In the last study, about the same number of patients dropped out of the study due to lab abnormalities, but the patients who dropped out from adverse reactions varied. Overall, most patients withdrew from the interferon plus ribavirin arm and the least from the peginterferon plus ribavirin arm.
The major difference was that there was a higher incidence of neutropenia in the peginterferon groups.

Predictors of an SVR

In the trials described above, the only common predictor of SVR among all three was the treatment of HCV other than type 1.6–8 In the trial by Chung et al., patient characteristics that predicted an SVR were treatment with peginterferon and ribavirin, absence of prior drug abuse, a detectable level of HIV-1 RNA, and a Karnofsky score of 100. The Karnofsky score is a subjective measure of how well the patient is doing. A score of 100 indicates that the patient has no complaints or evidence of disease, a score of 50 indicates that the patient requires considerable assistance and frequent medical care, and a score of 0 indicates that the patient is dead. In the study by Carrat et al., no protease inhibitor therapy, an age of 40 years or younger, or a baseline alanine aminotransferase greater than three times the upper limit of normal predicted a sustained virological response. In the study by Torrani et al., SVR was predicted by HCV genotype other than 1 and a baseline HCV RNA level of 800,000 IU or less per milliliter.
In a study involving 21 HIV co-infected patients, pre-treatment baseline plasma levels of IP-10 predicted the reduction of HCV RNA during the first days of interferon/ribavirin therapy for HCV genotypes 1–3, as is also the case in HCV mono-infected patients. Pre-treatment IP-10 levels below 150 pg/mL are predictive of a favorable response, and may thus be useful in encouraging these otherwise difficult-to-treat patients to initiate therapy.