Effects of HIV on the Natural History of Chronic Hepatitis C

Immune Response to HCV and Spontaneous Viral Clearance

HCV viral loads are significantly higher in the blood and livers of coinfected people compared to people with HCV alone.^26-28 Data suggest the higher HCV viral loads may result from the fact that HCV replicates in not only in the liver but also in immune cells ( lymphocytes) and lymph nodes of people with HIV.^29,30 While high HCV viral loads have been correlated with decreased response rates to interferon-based therapy, the effect (if any) of viral load on the progression of HCV-related liver disease among coinfected persons is unclear at this time.³¹

Evidence from multiple studies indicates HIV accelerates the progression of HCV-related liver disease.^32-36 A study of 547 people found the time from infection to cirrhosis was substantially shorter (7 years) in people coinfected with HIV compared to people with HCV alone (23 years).³¹ Another 3-year study of 489 people found 8.4% of coinfected persons had liver failure (decompensation) compared to no cases among those with HCV only.³⁷ These findings are supported by a separate study that found the rate of fibrosis progression (liver scarring) was much faster in HIV/HCV coinfected people than in those with HCV only.³⁸ Data from several studies indicate the rate of fibrosis progression in coinfected persons is related to immune function. Low levels of CD4 cells have been linked to higher rates of fibrosis progression in coinfected people.^32,33 A research group analyzed eight studies that examined the effects of HIV on HCV-related disease progression. The studies analyzed were conducted between 1996 and June 1999. Compared to people infected with HCV only, coinfected persons were found to have two times the risk for cirrhosis and approximately six times the risk for liver failure (decompensation).³⁵ As in people infected with HCV alone, several studies have shown that alcohol consumption further accelerates the already rapid liver disease progression in those with HIV/HCV coinfection. People with HIV/HCV coinfection should avoid any alcohol consumption.

Coinfection also appears to increase the risk liver cancer. A study from the Veterans Affairs Medical Center in Houston, Texas found a 1.2% incidence of liver cancer (hepatocellular carcinoma) among coinfected people compared to no cases in people with HCV alone over a 3-year study period.³⁶ A small study conducted in Spain suggests liver cancer occurs at a younger age and after a shorter duration of HCV infection among coinfected persons compared to those with HCV only.³⁹

Effects of HAART on HCV Disease Progression

It is important to note that the studies demonstrating accelerated disease progression associated with HIV coinfection were performed or involved data collected before the widespread use of highly active antiretroviral therapy (HAART) for HIV. HAART was introduced in 1996 and was a substantial breakthrough in the treatment of HIV infection. For many people, HAART has transformed HIV infection from an imminent life-threatening illness to a condition more akin to a chronic disease. With HAART, HIV viral loads are often reduced to undetectable levels and T cell counts generally rebound substantially. With the introduction of HAART, HIV-related death rates have dropped substantially and survival time has increased dramatically. While serious infections and related deaths have declined steadily in the HIV-infected population since the introduction of HAART, death rates from HCV-related disease have been consistently increasing (see Figure 3).^33,40-45

Figure 3: Mortality Rates Due to End-Stage Liver Disease
Among HIV/HCV Coinfected Persons³¹

In short, the introduction of HAART has enabled HIV/HCV coinfected people to live long enough to experience the effects of chronic hepatitis C. However, since HAART has only been used for a relatively short period of time, it is unclear whether the use of HAART may slow the accelerated HCV disease progression seen in coinfected persons. One preliminary study of 182 HIV/HCV coinfected people found the fibrosis stage on liver biopsy was lower in people who had been on combination therapy with a protease inhibitor (one of the drugs used in HAART) compared to people who had never taken a protease inhibitor. The estimated cirrhosis rates at 5, 15, and 25 years post-HVC infection are shown in Figure 4.

Figure 4: Estimated Cirrhosis Rates in HIV/HCV Coinfected People⁴⁶

Benhamou Y, Di Martino V, Bochet M, Colombet G, Thibault V, Liou A, Katlama C, Poynard T; MultivirC Group. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology. 2001;34(2):283-7.

A more recent study of HIV/HCV coinfected persons published in 2004 found protease inhibitor-base HAART therapy seemed to have a protective effect against liver fibrosis. However, HAART therapy that included the drug nevirapine (Viramune^®) seemed to increase the rate of fibrosis progression.⁴⁷ Large-scale research studies are needed to determine conclusively the specific effects of HAART therapy on HCV disease progression in coinfected persons.

Effects of HAART on HCV Viral Load and Liver Enzymes

Liver enzyme levels increase in approximately 5-10% of HIV-infected people after beginning HAART therapy.⁴⁸ Such increases have been observed in up to 30% of persons coinfected with HCV.^49-61 Some anti-HIV drugs such as nevirapine, ^51,59,60 ritonavir, ⁶⁰ and stavudine ^62,63 are more likely to cause elevations in liver enzymes than others are.⁶⁴ A group of anti-HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs; for example, ddI, ddC and AZT) have also been reported to cause liver enzyme elevations.^53,65 It appears the increased susceptibility to anti-HIV drug-related liver injury among people coinfected with HIV/HCV is caused by the interplay of many factors. Some of the drugs appear to be directly hepatotoxic, meaning they chemically injure liver cells. People with chronic hepatitis may be more susceptible to this type of injury because an inflamed and/or scarred liver may be less capable of processing medications.

Both HCV⁶⁶and some anti-HIV medications have the ability to damage structures called mitochondria inside liver cells. Mitochondria are the "powerhouses" of cells. They provide the energy needed for cells to function properly. When mitochondria are damaged, liver cells do not have the energy to function normally and liver damage occurs. Mitochondrial damage is thought to be one of the mechanisms of liver injury and liver enzyme elevations seen in some HIV/HCV coinfected people on HAART.^67-70 HAART-associated mitochondrial damage appears to be heightened in the presence of underlying hepatitis C.

Another possible mechanism of HAART-associated liver injury is called immune reconstitution. HIV attacks the immune system and reduces its normal ability to attack disease-causing bacteria and viruses. When HAART is successful, the HIV viral load drops and the immune system recovers some of its normal functions, a process known as immune reconstitution. One effect of immune reconstitution in those with HIV/HCV coinfection may be an abrupt immune system attack on HCV-infected liver cells. This attack could cause the sudden death of large numbers of HCV-infected liver cells leading to extremely elevated liver enzyme levels.^71-73 It seems this mechanism for sudden spikes in liver enzymes after HAART initiation in coinfected patients is more likely in people with markedly low CD4 counts. However, immune reconstitution is thought to be a rare cause of HAART-induced liver toxicity among coinfected persons. ⁷⁴

An alternative mechanism for a sudden spike in liver enzymes after initiating HAART therapy in HIV/HCV coinfected persons is the emergence of aggressive HCV quasispecies. Quasispecies are viruses that have undergone small genetic changes (mutations). Although quasispecies are very closely related to their parent viruses, the small genetic changes may allow them to be more damaging than the parent virus. Several HCV quasispecies can exist in the same person. Researchers theorize that immune reconstitution may lead to mass destruction of liver cells containing parent viruses but open the door for rapid replication of HCV quasispecies. These quasispecies may then mount a new and more severe attack on the liver leading to elevated liver enzymes.^75,76

In 2004, the HCV-HIV International Panel published treatment guidelines entitled, "Care of patients with hepatitis C and HIV coinfection."⁷⁷ With regard to the hepatotoxicity of antiretroviral drugs, the panel made this recommendation:

Liver enzyme elevations after beginning antiretroviral therapy are more frequent in patients with underlying chronic hepatitis B and C. Therefore, drugs with more hepatotoxic profiles (i.e., nevirapine, ritonavir) should be used cautiously in coinfected patients. Treatment should be discontinued in patients with symptoms or grade 4 increases in aminotransferase levels… The close monitoring of these patients during the first weeks may enable them to remain on therapy, because they experience a progressive resolution of liver abnormalities without discontinuing treatment.

Effects of HCV on the Natural History of HIV/Aids

Research has shown clearly that coinfection with HIV accelerates the natural course of HCV infection. However, the impact of HCV on the natural history of HIV infection remains controversial. Clinical studies to investigate this question have been conflicting. A study of 416 people in Italy found patients coinfected with HIV/HCV and those infected with HIV alone progressed to AIDS at a similar rate.⁷⁸ A larger study of 1,955 people conducted in Baltimore, Maryland also found no difference in the progression to AIDS or death among coinfected persons compared to people with HIV only.⁷⁹ However, a study of 3,111 HIV-infected persons in Switzerland reported that those coinfected with HCV had a modestly increased risk for progression to AIDS or death.⁸⁰ Investigators in this study also noted that the rebound in CD4 cells after the initiation of HAART was less pronounced in people coinfected with HCV compared to people with HIV alone. The authors concluded this might indicate coinfection with HCV limits the immune reconstitution that typically occurs after beginning HAART. Investigators studying a population of 1,320 patients in Italy found a similar blunting of immune reconstitution among coinfected persons.⁸¹ However, two studies by other investigators did not show the this effect.^75,79

Conflicting results from studies examining the effects of HCV on the natural history of HIV are not surprising. The population of people coinfected with HIV/HCV is diverse in many ways, and also differs from the populations of people infected with either HIV or HCV alone.³¹ Trying to sort out factors other than coinfection that may well influence disease progression is complex and challenging. This remains an area of active research. Hopefully, we will have some conclusive data in the near future.

Coinfection and Lipodystrophy

Lipodystrophy is a group of fat metabolism disorders commonly seen in people with HIV.^82-84 These disorders can cause several changes in the body including:

Loss of fat in the arms, legs, buttocks, and/or face is called lipoatrophy. Such fat loss can cause the veins of the arms and legs to protrude and give the face a sunken appearance.

Lipohypertrophy is a build up of fat stores in the gut, breasts, shoulders, and/or back of the neck. The abdomen often appears bloated and feels hard. The fat around the gut reflects an accumulation of fatty tissue in the abdominal cavity leading to a swollen look.

Some changes in fat metabolism are not visible but are nonetheless abnormal. Levels of fats such as cholesterol and triglycerides in the blood can become abnormally high with lipodystrophy. High levels of fat may increase the risk for heart disease, stroke, and other disorders.

The exact mechanisms that lead to lipodystrophy in people with HIV are being actively researched. However, it seems clear that several factors are involved including some associated with the virus itself and others associated with anti-HIV therapy. Researchers have found evidence that coinfection with HCV may contribute to the development of lipodystrophy in coinfected persons.⁸⁵HCV damages the powerhouses of liver cells (the mitochondria), thus interrupting normal fat breakdown and storage.^86,87 One study suggests the incidence of lipoatrophy is higher in people coinfected with HIV and HCV than it is in those infected with HIV only.⁸⁸ The redistribution of fat from the arms and legs into the abdomen also causes increased fat in the liver, a situation that can further damage an HCV-infected liver.

HAART-related lipodystrophy has been associated with another condition known as insulin resistance (IR).⁸⁹ People with insulin resistance have abnormally high blood sugar (glucose) levels. Some researchers have reported the incidence of IR is higher in HIV/HCV coinfected persons on HAART compared to persons with HIV only.⁹⁰Investigators speculate HAART-related IR may result from anti-HIV medication directly impairing glucose uptake by muscle, effects of HIV per se, or indirect effects such as fat redistribution.⁹¹ Clinical scientists hope to soon find effective ways to treat the metabolic abnormalities associated with HAART, HIV, and HIV/HCV coinfection.

Harm Reduction

People with HIV/HCV coinfection are at increased risk for other infectious diseases. It is important to take steps to protect yourself from exposure to other infectious diseases.

The simplest and most effective way to protect yourself from food-borne illnesses is hand washing. Although it sounds trivial, hand washing goes a long way toward protecting yourself from many illnesses. A few simple rules to keep in mind include:

Always wash your hands before eating or preparing food. Be sure everyone in your household does the same.

Always wash your hands after using the restroom.

Wash all fresh fruits and vegetables before eating.

Commercial fruit and vegetable washes are not necessary. Simply rub the fruit or vegetable with your washed hands under running water. Fruits or vegetables with a hard exterior should be scrubbed with a clean vegetable brush. You can clean your vegetable brush in the dishwasher.

Hand washing not only protects you from food-borne illnesses but also helps prevent the spread of cold and flu viruses.

Safe sex practices are also essential for coinfected persons. These practices will prevent the spread of HIV and/or HCV to others, and will protect you from being exposed to sexually transmitted infections such as hepatitis B, gonorrhea, syphilis, herpes, chlamydia, and others.

Injection drug use poses many threats to wellness. It is best for coinfected person to avoid all injection drug use and other recreational drug use. However, if you are injecting drugs, be sure to use scrupulously clean injection habits. Avoid reusing needles, and never share needles with others.

People who are coinfected and drink alcohol are at greatly increased risk of developing severe liver disease, cirrhosis, and/or liver cancer. All people infected with HCV should avoid alcohol, but it is even more important for coinfected persons. People coinfected with HIV/HCV should not drink any alcohol. If you have difficulty abstaining from alcohol, you might be addicted to alcohol. Talk with your health care providers about the problem. Many resources are available to help you eliminate alcohol from your life. For additional information about the effects of alcohol in HCV and treatment options, see Chapter 2, Alcohol and Hepatitis C and Appendix II, How to Cut Down on Your Drinking.

Hepatitis A and B

Due to shared routes of transmission, people coinfected with HIV and HCV are at increased risk for also contracting hepatitis B. A recent study conducted in Spain found that among people with HIV, 79% of injection drug users were also infected with both HCV and HBV. Triple infection rates among those with other risk factors ranged from 10-20%.⁹²

Unlike HIV, HCV, and HBV, hepatitis A is a food-borne illness. Hepatitis A causes an acute form of viral hepatitis; there is no chronic form of hepatitis A. Although HAV infection alone is usually a relatively mild disease, it is often a more serious illness in people with HIV, HCV, and/or HBV. Fulminant hepatitis is a rapidly progressive condition characterized by a massive loss of liver cells and liver failure. Fulminant hepatitis is a rare complication of HAV infection (0.3 - 1.8% of cases).⁹³Although there have been some conflicting reports,⁹⁴ most investigators agree that acute hepatitis A in people with chronic hepatitis C is associated with an increased risk for fulminant hepatitis ranging from 0-40%.^94-101

Infections with HBV and HAV among HIV/HCV coinfected persons can be life threatening. All persons with HIV should be tested for HCV and HBV. Most health care providers recommend that coinfected persons not already infected or immune to HAV and HBV should be vaccinated against these viruses. The vaccines contain no live viruses, so there is no risk of infection from the vaccines. The two vaccines can be given simultaneous. Hepatitis A and B vaccines are available for little to no cost at public health clinics in the United States and many other countries.

If you have not been previously vaccinated or infected with HAV and are exposed to the virus, treatment with immune globulin is recommended.⁹³ Immune globulin should be given as soon as possible after exposure, but must be given within two weeks of exposure to be effective. Similarly, people who have been exposed to HBV should be treated with hepatitis B immune globulin (HBIG) as soon as possible after exposure, preferably within 24 hours.¹⁰²  The effectiveness of HBIG when administered more than seven days after exposure is unknown. The first shot in the hepatitis B vaccine series can be given at the same time as HBIG. If the HBV vaccine is indicated, it too should be given as soon as possible and preferably within 24 hours.

Depending upon risk factors, from 14-90% of people with HIV are also chronically infected with HCV. Coinfection with HIV adversely affects hepatitis C disease progression increasing the risk of cirrhosis, liver failure, and liver cancer. The effects of HCV on HIV disease progression are less clear.

Harm reduction is especially important for people with HIV/HCV coinfection. Vaccination against HAV and HBV is particularly important. Lifestyle choices such as safe sexual practices, avoiding recreational drug use or using clean needles, and abstaining from alcohol can enhance overall wellness and improve quality of life.