Co-infection with HIV and hepatitis C: an overview.

This report provides an overview of hepatitis C infection and special issues regarding co-infection with HIV. However, it was not possible to cover all aspects of this topic in depth. For a thorough review, RITA! recommends referring to the recent Treatment Action Group report by Tracy Swan and Daniel Raymond, "Hepatitis C Virus (HCV) and HIV/HCV Coinfection: A Critical Review of Research and Treatment" available online at aidsinfonyc.org/tag/coinf/hcv2004.

EPIDEMIOLOGY OF HCV AND HIV/HCV CO-INFECTION

For many people infected with HIV, co-infection with hepatitis C virus (HCV) is a very real problem. These 2 viruses share many features, as both are blood-borne pathogens, share certain routes of transmission, are refractory to complete eradication by currently available treatments, and have extremely high replication rates. HCV is the most common blood-borne infection and is the leading cause of chronic liver disease in the US. (1) There are an estimated 170 million people worldwide infected with HCV, about 3% of the world's population. (2) (See Figure 1.) The NHANES III study (the third National Health and Nutrition Examination Survey conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention), studied samples from 21,241 subjects for antibody to HCV (anti-HCV) and reported an overall prevalence of 1.8%, corresponding to an estimated 3.9 million US residents who have been infected with HCV (including some who clear the infection spontaneously). (1) In addition, 74% of this study population was positive for HCV RNA, suggesting that about 2.7 million people in the US are chronically infected with HCV (ie, those who do not spontaneously clear infection). In this large sampling, 65% of those positive for anti-HCV were between 30 to 49 years of age. HCV infection was more prevalent in male subjects and African-Americans. However, the estimate of 1.8% deduced in the NHANES III may be somewhat conservative as incarcerated and homeless people, 2 populations with high HCV prevalence rates, were not included. In prisons worldwide, HCV prevalence is reported to be anywhere from 31% to 50%. In the US, 30% to 40% of the 1.8 million inmates are infected with HCV. (3)

[FIGURE 1 OMITTED]

HCV is a small, enveloped RNA virus that is part of the Flaviviridae family. Humans are the only known hosts of HCV, but the virus can be transmitted experimentally in chimpanzees. (2) HCV is structurally unrelated to hepatitis A or hepatitis B and was initially referred to as "non-A, non-B hepatitis." Like HIV, HCV has significant genetic diversity. (4) There are 6 genotypes (genotypes 1 through 6) and about 100 subtypes (a, b, c, etc.). Genotypes 1 through 3 are found worldwide, genotypes 4 and 5 are tbund predominantly in Africa, and genotype 6 is found primarily in Asia. (2) Genotype 1 is the most prevalent genotype in the US. (1,4-6) Unfortunately, genotypes 1, 4, and 5 are not as sensitive to currently available HCV treatments and result in poorer response rates depending on genotype.

Of the approximately 800,000 people living with HIV/AIDS in the US, (7) an estimated 200,000 persons are co-infected with HCV. (8) Though different research cohorts report somewhat disparate rates of co-infection, the consensus is that approximately 25% to 30% of the HIV-positive population in the US is co-infected with HCV. (7,9,10) Nonetheless, the risk of acquiring HCV varies widely according to a patient's risk factors and thus depends on the makeup of the particular patient population. A 2002 study from the US Adult AIDS Clinical Trials Group estimated an overall co-infection rate of 16.1%, but this rate varied greatly according a patient's risk factors. For example, 72.7% of the "high-risk" subjects were HCV positive, while only 3.5% of the "low-risk" patients were positive. (6) Moreover, some believe that injection drug users, a group seriously at risk for contracting HCV, were underrepresented in this study and therefore the co-intection rate is much higher. (8) Indeed, the co-infection rate in Europe also appears to be closer to 30%, according to unpublished data from the EuroSIDA study. (8)

ROUTES OF HCV TRANSMISSION

HCV is transmitted through direct contact with blood from an infected person (see Figure 2). The sharing of injection equipment during injection drug use (IDU) is by far the most common way to contract HCV. Receipt of previously unscreened blood, blood products, or organs was a risk factor, but extensive screening and viral inactivation procedures in developed countries have minimized this risk in the past 2 decades. Other potential routes of transmission include sexual contact with an HCV positive partner, mother-to-infant transmission, exposure to contaminated needles or sharps (usually in healthcare settings), or use of inadequately sterilized instruments during medical or dental procedures. (2,11,12) In 9% of cases, the source of infection cannot be identified. (11) Many of these risk factors are escalated in developing countries (particularly exposure to infected blood or blood products, or contaminated needles or sharps) as screening procedures may not be in place or enforced. Other sources of transmission include scarification, tattooing, and ear and body piercing when equipment is not properly sterilized. (2) HCV is not transmitted through casual contact or through kissing, hugging, sneezing, coughing, or sharing food utensils or drinking glasses. (11)

Injection drug use

There is little doubt that IDU bears with it a significant risk of transmitting HCV. IDU is responsible for the largest proportion of HCV infections; (2, 11) 20% to 40% of injection drug users will be infected within the first year of having used needles, increasing to over 50% for those with 1 to 5 years of use, and reaching up to 92% tot those with greater than 5 years of use. (2) A recent study of 428 injection drug users in London reported an HCV incidence of 41.8%. (13) In US and European cities, 50% to 90% of persons who contracted HIV infection from IDU were already infected with HCV. (8) A history of intranasal cocaine use may also be a risk factor, but this has not been proven. (11)

Contaminated blood products

In the US, HCV transmission attributable to blood transfusion is very low, with a risk of 0.004% to 0.0004% per unit transferred. The risk can be significantly higher in developing countries where inconsistent screening policies may be in place or absent altogether. (2) Prior to 1990, the risk of transmission through blood transfusions was about 10%. (11) Unfortunately, before the introduction of virus-inactivating procedures in 1984, many hemophiliacs received contaminated clotting factor and were infected with HCV, in addition to HIV and hepatitis B. (14-16)

Mother-to-infant transmission

Mother-to-infant transmission (MTIT) of HCV does occur, but the risk is probably less than 5%. (2) Indeed, an extensive review of studies examining MTIT estimated that the rate of MTIT was between 1% and 5% in women who were positive for anti-HCV. (12) Factors that increase the rate of MTIT are maternal co-infection with HIV, maternal use of injection drugs, and higher maternal HCV RNA levels. (2,12) Regardless of these low percentages, MTIT transmission can still be a significant worldwide predicament. Yeung and colleagues (12) note that if 35% of the 170 million people infected worldwide are women of child-bearing age and have an annual fertility rate of 2%, 10,000 to 60,000 infants will be infected with HCV each year. Unlike with MTIT of HIV, specific procedures to reduce HCV transmission from mother to child have not been discovered. Rates of HCV transmission are similar regardless of mode of infant delivery (vaginal versus cesarean) and whether the infant is breast-fed. (2,12) Although no cases of HCV transmission via breast-feeding have been reported, HCV RNA has been detected in breast milk. (12) Obviously, bleeding nipples as a result of breastfeeding could increase the risk of HCV transmission to an infant.

Other potential risk factors

Transmission of HCV in healthcare settings via exposure to contaminated needles or sharps can occur; but is relatively rare with a rate of approximately 4% in healthcare workers frequently exposed to blood. (11) Documented cases show that HCV has been transmitted through medical procedures using contaminated equipment and unsafe injection practices (ie, re-use of disposable needles/syringes and contamination of multiple-dose medication vials). In developed countries, the risk of contracting HCV during surgery or dental procedures, (1) tattooing, acupuncture, or ear piercing is very low. (2,11) HCV can be transmitted percutaneously through shared use of razors or other objects that might be exposed to blood, but this risk is most likely limited. (2) In one study of HCV-positive hemophiliacs and their families, only one case out of 228 household contacts was detected. (14)

Sexual transmission of HCV

HCV transmission via sexual contact is not as efficient as HIV and hepatitis B. (14,16,17) Nevertheless, the actual risk of HCV transmission through sexual contact is a subject under great debate. (18) The high prevalence of HCV transmission among sex workers, men who have sex with men (MSM), persons with multiple sex partners, partners of HCV-infected persons, and patients who visit sexually transmitted disease clinics cannot be ignored and suggests that sexual transmission may occur. (18-20) Moreover, according to the US Centers for Disease Control and Prevention (CDC), approximately 18% of cases occur in persons with no other risk factors other than exposure to an infected sexual partner or exposure to multiple sex partners. (11) However, studies investigating female sexual partners of male hemophiliacs report HCV transmission rates of 2.6% (17) and 2.7%, (21) rates similar to the worldwide rate of 3%. (2) Other studies report no evidence of sexual transmission, (16) and the majority of HCV serodiscordant couples have unprotected sex without ever transmitting HCV. (22)

The consensus seems to be that there is a real risk of HCV transmission through sexual contact, but that this risk is low. (17,18,20,23-26) Further, HCV RNA has been detected in normal cervical smears front HCV-positive women (19) as well as in semen samples from HCV-positive men (24) and HIV/HCV co-infected men. (22) These HCV viral loads were detected in only some of the patients (19,22,24) and were low in semen samples, (24) thus possibly explaining wily the risk of HCV transmission through sexual contact is low, but still present. Factors that might affect HCV transmission are the stage of a person's HCV disease, duration of infection, HCV viral load, HIV status, and period of exposure. (18)

EFFECT OF HIV ON HCV TRANSMISSION

Though the connection between sexual activity and HCV transmission is debatable, there is some evidence that co-infection with HIV may increase the likelihood of HCV transmission by acting as a "cofactor." (17,25,26) A correlation between HIV seropositivity and HCV transmission has been reported, whereby there was a significantly greater likelihood of HCV seropositivity in MSM who were HIV-positive, compared with men who were HIV-negative. (27) In addition, a study of female sexual partners of male hemophiliacs reported that the frequency of HCV transmission was 5 times higher when HIV was also transmitted. (17) However, other studies have failed to detect this relationship and have dismissed the idea that HIV could act as a cofactor in facilitating HCV transmission. (16,21) Nevertheless, pre-existing infection with other agents, such as hepatitis B, gonorrhea, anogenital herpes, and syphilis is associated with an increased risk of HCV transmission. (1,26,27) But these studies do not specify whether certain sexual behaviors or practices could have contributed to this increased risk of transmission.

Increased HIV RNA levels have also been linked to the presence of HCV RNA. In fact, for each unit increase in log HIV RNA level, the chances of having a positive HCV RNA test increased 86%. (6) Some researchers speculate that changes to the immune system, rather than the sexual transmission route, is responsible for this association sometimes detected between HIV and HCV transmission. (8,27) One hypothesis is that the immune suppression caused by HIV aids the transmission of HCV. For example, among subjects considered to be at high risk for transmitting HCV, 100% of those with CD4 T cell counts less than or equal to 100 cells/[mm.sup.3] were HCV positive, while only 68.6% of those with CD4 T cell counts greater than 100 cells/[mm.sup.3] were positive for HCV. (6) Other reports of unusually high HCV transmission rates in patients with hematologic malignancies and severe aplastic anemia (conditions associated with compromised immune systems), despite strict blood-screening procedures, provide further evidence that HCV transmission may be enhanced among immunosuppressed patients. (28) In support of an association, there is some preliminary evidence that HCV can replicate extrahepatically under conditions of immunodeficiency. (29)

CLINICAL ASPECTS OF HCV INFECTION

Diagnosis of HCV infection

According to the CDC website (cdc.gov), testing should be routinely offered to persons most likely to be infected with HCV. Abnormalities in levels of liver enzymes, specifically alanine transaminase (ALT), may suggest a diagnosis of HCV. Patients infected with HCV typically develop antibodies to HCV within 6 weeks to 6 months; however, some individuals will not generate antibodies until much later. (30) The third-generation enzyme immunoassay (EIA-3) is currently recommended as a first-line method for detecting HCV antibodies, but false-positive results can occur. (2,31) Therefore, all positive EIA results should be confirmed with an HCV RNA test, as chronic HCV is diagnosed by the presence of HCV RNA in serum. In addition, patients who test negative for HCV antibody, but who are at high risk for HCV infection, should also undergo testing to detect HCV RNA. (31) Persons at risk who test negative for HCV antibody and who have undetectable HCV RNA should be re-tested 6 months after initial testing, as this is the only way to confirm or rule out chronic HCV infection.

Diagnosis of HCV infection is similar in HIV-positive patients. However, immunosuppressed individuals (including organ transplant recipients and HIV-positive patients, especially those with CD4 T cell counts below 200 cells/[mm.sup.3]) should also undergo HCV RNA testing as many fail to generate antibodies to HCV, and HIV infection itself can impair antibody responses to HCV. (8,30) In fact, some studies have reported that up to 6% of co-infected patients are actually anti-HCV negative. (8) Testing for HCV in HIV-positive patients is not routinely performed, (6) though current guidelines from the CDC suggest that HIV-positive individuals would benefit from testing. Also, the National Institutes of Health (NIH) Consensus Statement on Management of Hepatitis C: 2002 (consensus.nih.gov/cons/116/116cdc_intro.htm) recommends that all persons with HIV be tested for HCV. The advantages are clear in HIV-positive patients with additional risk factors (ie, injection drug users and hemophiliacs); however, it is not clear if universal screening of low-risk, HIV-positive patients would be beneficial. (6)

Clinical course of HCV infection

Acute HCV infection is relatively mild and asymptomatic with only about 20% to 30% of individuals experiencing symptoms. Spontaneous recovery from HCV infection occurs in approximately 15% to 30% of HIV-negative people. (2,8) (In co-infected patients, the spontaneous clearance rate drops to only 5% to 10%, dropping even further in patients with lower CD4 T cell counts. (8,32)) Widespread hepatocyte involvement is a characteristic of chronic HCV infection, (33) and the major site of viral replication is the liver; (8) though HCV replication has also been reported in monocytes and lymphocytes. (8,19) Thus far, it is unknown if HCV replicates in organs other than the liver or in the central nervous system. (34) HCV RNA has been detected in semen from HCV-infected men (24) and HIV/HCV co-infected men, (22) as well as in normal cervical smears from HCV-infected women. (19) Moreover; preliminary evidence indicates that under conditions of immunodeficiency, HCV can replicate extrahepatically. Specifically, HCV was detected in peripheral blood mononuclear cells, and in the lymph nodes, pancreas, and adrenal glands of HIV/HCV co-infected patients. (29)

In individuals infected with HCV alone, infection can fallow an indolent course for decades before causing liver cirrhosis, which can lead to hepatocellular carcinoma (HCC) and liver failure, but outcomes vary widely. (2) Conditions affecting systems outside the liver include cutaneous manifestations (sporadic porphyria cutanea tarda and lichen planus), ocular lesions (Mooren's ulcers), sialadenitis, and B-cell lymphoma. (2) Factors that influence the rate of progression to these more serious hepatic conditions are heavy alcohol use, (2,32,35,36) age, (2,35,37) duration of infection, (2) severity of liver histology at initial biopsy, (9) and possibly other factors such as HCV viral load and co-infection with hepatitis B or HIV (see page 13). (2) Studies assessing the pathogenesis of one HCV genotype versus another are conflicting. (5,37,38) One report demonstrated that HCV genotype lb was associated with more advanced histologic deterioration in the liver compared with genotype (2,38) while other studies have failed to detect a relationship between genotype and stage or severity of liver disease. (5,37) In fact, infections caused by all of the HCV genotypes can progress to HCC. (37) In addition, fatigue and depression are the most common symptoms of HCV infection.

Treatment of HCV Infection

According to the NIH Consensus Statement on Management of Hepatitis C: 2002, HCV treatment is recommended for patients with an increased risk of developing cirrhosis, specifically those patients with detectable HCV RNA levels higher than 50 IU/mL, a liver biopsy showing portal or bridging fibrosis, and at least moderate liver inflammation and necrosis. Other factors include HCV genotype, patient motivation, patient age, HCV symptoms, and the presence of comorbid illnesses. A liver biopsy is the most reliable way to assess liver damage and to determine the need for HCV treatment. Liver enzymes are regularly monitored, as many chronically infected patients have elevated ALT levels. However, these tests cannot be used to accurately assess disease stage or progression. For instance, 30% of HCV-infected patients have normal ALT levels and another 40% have ALT levels less than 2 times the upper limit of normal.

In the HCV-infected patient, treatment typically lasts for 24 or 48 weeks, depending on the HCV genotype. Patients infected with genotypes 2 or 3 usually require 24 weeks of treatment, while those infected with genotypes 1 or 4 require longer treatment (which may still not be effective). (2) At one time, the standard treatment for HCV-infected patients was interferon plus ribavirin. The development of a pegylated version of interferon (peginterferon) has made this formulation, combined with ribavirin, the new standard treatment for HCV infection. (39) The pegylated version has a longer half-life and allows for weekly dosing by injection, compared to standard interferon, which requires injections 3 times a week. The combination of peginterferon [alpha]-2b plus ribavirin produces a sustained viral response (SVR) rate in many patients, but is not as effective in patients with genotype 1 virus (see Table). In contrast, patients with genotype 2 or 3 respond well to this treatment. (39) While results tend to be disappointing in patients infected with genotype 1, the pegylated formulation has improved the SVR rate (42% versus 33% with standard interferon (39)).

Side effects from HCV treatment are frequent and sometimes severe. The most common side effect of ribavirin is anemia. Side effects common to peginterferon and standard interferon are injection site reactions, a flu-like syndrome (asthenia, fatigue, pyrexia, rigors, myalgia, and headache), arthralgia, chest pain, nausea, vomiting, diarrhea, anorexia, neutropenia, lymphopenia, thrombocytopenia, infection, alopecia, thyroid dysfunction, dizziness, and insomniaa. (39,45) In addition to the above side effects, standard interferon and peginterferon treatment can cause psychiatric side effects including irritability, relapse of drug use, drug overdose, depression, suicidal ideation, and suicide. Considering the severity of these side effects, a psychiatric evaluation may be warranted before commencing treatment. The adverse event profile is similar for standard interferon and peginterferon, though comparison studies have reported that patients receiving peginterferon experienced injection site reactions, flu-like syndrome, neutropenia, and thrombocytopenia more frequently than standard interferon. (39,42,46) Despite the side effect profiles of these medications, many patients have been able to successfully complete therapy and achieve improved clinical status.

In most instances, the benefits of HCV treatment counterbalance the risks. However, patients and their physicians must weigh the likelihood and severity of adverse events from HCV medications with the likelihood of a response to these medications and the risk of progression of liver disease. Several studies suggest that patients (both mono-and co-infected) who do not experience a significant decrease in HCV RNA (early viral response or EVR) within 12 or 24 weeks of starting treatment will probably not achieve viral clearance after the course of treatment and may want to discontinue treatment if they have minimal or no fibrosis. (39,42,47) The absence of an EVR at week 12 strongly predicts that treatment will not be successful and may be stopped. However, patients, especially those with more serious liver fibrosis, may still benefit from HCV treatment even if they do not achieve an SVR. In tact, responses have been detected histologically in patients who do not achieve a viral response, indicating that HCV maintenance strategies may be beneficial as a way to slow the progression of fibrosis, particularly in co-infected patients with moderate to advanced fibrosis. (47)

Obviously, more effective treatments are necessary for both HCV-infection and HIV/HCV co-infection. Peginterferon plus ribavirin produces sustained HCV responses in a number of HIV/HCV co-infected patients, but many are still not responding to this therapy, particularly those infected with HCV genotypes other than 2 and 3 (see Table). Potential new treatments are being developed and are discussed in detail in this issue of RITA! (see page 21).

SPECIAL CONSIDERATIONS FOR TREATING HIV/HCV CO-INFECTION

In both mono- and co-infected patients, the major treatment objective has been the prevention of cirrhosis, end-stage liver disease, and HCC. For HIV/HCV co-infected patients, HCV treatment is generally considered in patients with stable HIV viral load and CD4 T cell counts over 500 cells/[mm.sup.3] because the efficacy of HCV treatment is questionable in immunosuppressed patients with higher HIV viral loads. (48) However, successful treatment has been achieved in patients with lower CD4 T cell counts, (49) though clinicians must take into consideration the increased risk of end-stage liver disease in patients with decreasing CD4 T cell counts. The medical management of patients co-infected with HIV and HCV is extremely challenging for various reasons, most notably the complexity of both infections, the potential for drug interactions, and a lack of published information regarding how best to treat this patient population. Currently, there are no FDA-approved medications for this specific indication, although Roche Pharmaceuticals is currently seeking approval of their product for an indication in co-infected patients.

Unfortunately, studies to determine the tolerability and efficacy of HCV treatments in HIV-positive people have lagged behind those conducted in people with HCV alone. The strategy thus far has been to take treatments that work in HCV-infected patients and apply these to HIV/HCV co-infected patients. Regardless of treatment options, co-infected patients must be advised on ways to prevent or to minimize liver damage and HCV transmission, and to abstain from drinking alcohol. In addition, these patients should be evaluated for chronic liver disease, as well as tested for and vaccinated against hepatitis A (to avoid fulminant liver failure and death) and hepatitis B (which can increase the severity of HCV). (8,11) However, these vaccines can be less immunogenic in persons infected with HIV (especially in patients with CD4 T cell counts less than 200 cells/[mm.sup.3]) and therefore may not protect the patient against these viruses. Measuring response to these vaccines may be necessary.

Several randomized studies have recently investigated the activity of peginterferon [alpha]--2a (42,47) and peginterferon [alpha]-2b (46) combined with ribavirin in co-inflected patients, the majority of whom were taking antiretroviral medications (also see Table). HCV treatment with these drug combinations was associated with higher rates of SVR compared with standard interferon, but rates were still lower than those observed in HCV-infected patients and ranged from 27% to 44%. SVR rates varied depending on the specific study but were generally worse for patients infected with HCV genotype 1, with rates ranging from 14% to 38% (although the 38% rate was for a group that also included patients with genotype 4 (46)), compared to 53% to 73% for patients co-infected with other genotypes. Of note, HCV treatment did not have a negative effect on H1V disease progression, as shown by unchanged (46,47) or even reduced HIV RNA levels in patients who had detectable HIV viral loads at baseline. (42) However, interferon can produce transient decreases in CD4 T cell counts, which usually return to baseline values after completion of treatment. Possible reasons for variability in SVR rates include differences in study design, patient population, and ribavirin dose, as well as administration of 2 different types of peginterferon (peginterferon [alpha]-2a versus peginterferon [alpha]-2b). Differences in patient population in terms of severity of liver damage could further explain the variability in results. For example, the level of fibrosis did affect SVR, as patients with more advanced fibrosis did not experience SVR as frequently. (46)

Co-infected patients typically experience similar side effects to HCV treatment as do patients infected with HCV alone. (42,46,47) In addition, a recent report suggests that peginterferon [alpha]-2b can also cause ophthalmic problems in HIV/HCV co-infected patients and recommends increased monitoring of patients being treated with this drug. (50) Thirty-five percent of the study patients developed ophthalmic adverse events that included cotton wool spots, cataracts, and decreased color vision. Also, HCV and HIV medications share several common side effects (eg, diarrhea, nausea, vomiting, various cytopenias, etc.). Clinicians need to be aware of the potential for additive side effects and toxicities and that patients may require supportive care agents, such as growth factors, anti-emetics, anti-diarrheal agents, etc.

Of note, drug interactions can occur between HCV medications and antiretrovirals used to treat HIV. In particular, ribavirin may interact with nucleoside reverse transcriptase inhibitors as it is a guanosine nucleoside analog. When ribavirin is combined with antiretrovirals (specifically nucleoside reverse transcriptase inhibitors) to treat HIV, mitochondrial toxicity can be a complication. In fact, one case report documents 2 HIV/HCV co-infected patients receiving concurrent HCV treatment and antiretroviral treatment who experienced mitochondrial toxicity, multi-organ dysfunction, and lactic academia. (51) In addition, ribavirin can be antagonistic to the antiretroviral activity of stavudine (Zerit, d4T) and zidovudine (Retrovir, AZT). The combination of didanosine (Videx, ddI) and ribavirin can also lead to pancreatitis and lactic acidosis and is therefore not recommended. Additionally, because zidovudine can also cause anemia, this agent should not be taken concomitantly with ribavirin. Finally, because all antiretrovitals are potentially hepatotoxic, liver enzymes must be carefully monitored regularly when patients are also taking ribavirin.

CHALLENGES TO TREATING CO-INFECTED PATIENTS

Poor responses to HCV treatment in co-infected patients

Why do HCV treatments work less effectively in co-infected patients as compared with patients infected with HCV alone? Researchers speculate that the higher levels of HCV RNA detected in co-infected patients (6,31,52,53) may be responsible, as could an altered immune system that may prevent co-infected patients from clearing HCV. In general, an HCV viral load less than 2 million copies is considered a favorable prognostic factor. Soriano and colleagues (54) hypothesize that HIV infection may alter HCV viral kinetics, particularly under drug pressure. Furthermore, post-treatment relapses (where HCV again becomes detectable) occur almost twice as often in co-infected patients as they do in HCV mono-infected patients within 6 months of discontinuing treatment. (54) As Far as which patients relapse, there seems to be no significant difference in terms of HCV treatment (standard interferon versus peginterferon), HCV genotype, CD4 T cell count, use of antiretroviral therapy, HIV viral load, or any other baseline characteristic.

Several reports examining HCV treatment in co-infected patients have speculated on ways to improve the response rate. One idea is to alter the doses of HCV medications, particularly ribavirin, by either increasing the dose in a step-wise manner or administering "dose-optimized" (weight-based) ribavirin. (47) Anemia is a common side effect of ribavirin and can be treatment limiting. This can be managed by concomitant use of epoetin (Epogen), a ribavirin dose reduction, or both. Extending the treatment period beyond 48 weeks is another strategy that may improve response to therapy. (54) Some patients have experienced success with this approach (see page 28 in this issue of RITA!). Though patients with HCV genotype 2 or 3 are typically treated for only 24 weeks, researchers recommend the lull 48 weeks of treatment for HIV/HCV co-infected patients, even those infected with these HCV genotypes. (42) Liver transplantation is a potential treatment for co-infected patients with advanced cirrhosis, but this is still considered investigational (see page 17 in this issue of RITA!).

Other issues

An important question is whether HIV and HCV affect each other's disease progression. Despite a great deal of study in this area, no concrete answers to this question have been found. Evidence suggests that HIV alters tim natural history of HCV and negatively affects HCV disease progression, though it is not clear if liver damage is a result of HIV co-infection or drug-related toxicity. As discussed above, standard HCV treatments are not as effective in the HIV/HCV co-infected population. (42,46,47) Moreover, the presence of HIV results in increased HCV persistence and HCV RNA levels. (6,31,52,53) In addition, by comparing HCV-positive patients who were seropositive for HIV with those who were seronegative, investigations have demonstrated that co-infected patients experience accelerated progression to cirrhosis, (36,55) and liver failure. (15) Others have specifically reported that HIV co-infection accelerates HCV-related liver fibrosis progression. (35) Though HCV disease progression is accelerated in co-infected patients, cirrhosis still takes many years to develop. In fact, one study reported that the median duration from HCV infection to cirrhosis was 26 years in co-infected patients, compared with 38 years in HCV mono-infected patients. (35) Regardless of this prolonged time frame, co-infected individuals have a higher rate of mortality from liver-related disease. (56) In fact, liver failure is the leading cause of death in the HIV-infected population in the US.

Evidence supporting a negative effect of HCV on HIV disease progression is not as strong as that for the inverse relationship. However, several studies have reported evidence that HCV negatively affects the course of HIV infection. Accelerated clinical progression has been observed in HIV/HCV co-infected patients compared with HIV-positive, HCV-negative patients, implicating HCV as a prognostic factor for disease progression in these patients. (57) Moreover, one study reported that HCV appeared to accelerate HIV infection, as co-infected patients were 3 times as likely to experience a new AIDS-defining event or death. (58) These findings are in agreement with another study by Anderson and colleagues, which demonstrated that HIV/HCV co-infected patients have a decreased survival time from the point of HIV or AIDS diagnosis. (9) Although, other life factors associated with poorer outcomes (homelessness, disparities in health care, drug inadherence, etc.) must also be considered in populations with a high prevalence of HCV. In addition, a recent investigation found that HIV/HCV co-infected patients tend to perform worse cognitively and are more likely to be diagnosed with HIV-associated dementia, findings that could not be explained by the presence of liver disease. (34) Nonetheless, other studies report no effect of HCV on HIV disease progression. (59-62) Specifically, these studies found that HCV did not influence progression to AIDS (59,61,62) or survival time. (60-62)

One possible explanation for these disparate results focuses on the time in which these studies were conducted, specifically before or after the introduction of highly active antiretroviral therapy (HAART). The widespread availability of HAART has changed the landscape of HIV disease, and while it has obviously benefited HIV-positive patients, the increased survival afforded by HAART has also allowed certain conditions to progress, such as liver disease, in those patients co-infected with HCV. For example, an earlier pre-HAART study performed by the same group as Anderson and colleagues (9) failed to detect any effect of HCV on HIV disease progression. (61) Moreover, many of the studies that reported no evidence of HCV's effect on HIV were conducted in the early to mid 1990s, most likely before HAART was available, (59,60) though some patients did receive HAART in another study. (69) Indeed, a recent study comparing the effect of HCV infection on HIV disease progression before and after the introduction of HAART reported no association between co-infection and disease progression before HAART. But this study did find that co-infected patients progressed faster than HIV-positive, HCV-negative patients in the HAART era. (63) One point that must be emphasized is that the makeup of pre- and post-HAART populations is not identical, and thus there may be other factors influencing these observations. For example, the shifting demographics of the HIV epidemic may have led to differing study populations, making comparisons more difficult.

At this time, no direct interactions between HIV and HCV have been identified that would explain the potential effect of each virus on the other. In terms of HIV's effect on HCV, some authors speculate that an impaired or altered immune response could help explain the negative effect HIV has on HCV disease progression. (4) Several studies have reported that the level of immunosuppression may influence HCV viral load (52,55) and liver fibrosis rate. (35) Of note, the effect of HIV on HCV is consistent with another scenario describing HCV-positive patients who were immunocompromised because of a condition called hypogammaglobulinemia. In these patients, HCV-related liver disease was severe and progressed rapidly. (64)

Though the influence of HCV on HIV disease progression is still somewhat murky, several studies have provided evidence that co-infection with HCV could at least complicate the management HIV disease. One hypothesis is that HCV blunts the immune system's T-cell response to antiretroviral medications, (58) but others have shown no evidence of this phenomenon. (9,62) Notably, because of altered liver function caused by HCV infection, successful use of antiretroviral medications may be limited because hepatotoxicity is such an obvious concern. (6,35) However, it is unclear whether chronic HCV infection affects the tolerability of and response to antiretroviral medications. Clinicians who are reluctant to prescribe HIV medications should reconsider because patients can be successfully managed with careful selection of antiretrovirals and regular monitoring of liver enzyme levels. In one study, hepatotoxicity was more prevalent in co-infected patients compared with patients positive for HIV only, though the majority of these co-infected patients tolerated the medications and no irreversible outcomes were observed among those patients experiencing severe toxicity. (65) These findings led the authors to conclude that antiretroviral therapy should not be withheld in co-infected patients because of concerns of hepatotoxicity, even in the presence of mild-to-moderate hepatic ALT elevations--as long as the patients are carefully monitored.

CONCLUSION

The greatest challenge to treating HIV/HCV co-infected patients is that there are few published studies on how best to treat such patients. Specifically, in the US there are no formal treatment guidelines available for treating co-infected patients. This lack of guidance is further complicated because co-infected individuals are frequently excluded from clinical trials that examine potential treatments. In addition, those populations with the highest prevalence of co-infection are also often excluded (eg, drug/alcohol users and incarcerated individuals). Part of the challenge exists because of the current patient care infrastructure, as many patients do not have access to healthcare (see page 17 for a complete discussion on policy issues affecting individuals with HIV and HCV). Liver disease is obviously a leading cause of morbidity and mortality in co-infected individuals--and the leading cause of death among HIV-infected individuals in the US--but physicians that specialize in infectious disease, including many HIV specialists, are not always familiar with hepatic disease. Moreover, hepatologists and gastroenterologists may not be familiar with treating HIV. This situation leaves the patient without a consistent healthcare provider who can simultaneously monitor, assess, and treat both illnesses. Programs that focus on HCV screening and prevention are impeded by a lack of funding, and injection drug users (a group most at risk for contracting HCV) are confronted with enormous hurdles when and if they attempt to receive care. Obviously, both diseases are responsible for significant mortality and morbidity in the US and worldwide. Though great strides have been made in treatment of HIV and HCV as separate diseases, much is still required to effectively treat those patients facing co-infection with both diseases.

Table. Sustained virologic response (SVR) rates from HCV treatment
trials by HIV status and HCV genotype

Author                    Population    Sample Size   % SVR,
                                                     Overall

Manns et al. (39)           HCV         N = 511         54%
Fried et al. (40)           HCV         N = 453         58%
Hadziyannis et al. (14)     HCV         N = 424         61%
Torriani et al. (42)      HIV/HCV       N = 289         40%
Chung et al. (43)         HIV/HCV       N = 66           27%
Perrone et al. (44)       HIV/HCV       N = 205         27%

Author                      % SVR,         % SVR,
                          Genotype 1   Genotype 2 or 3

Manns et al. (39)             42%           82%
Fried et al. (40)             44%           70% *
Hadziyannis et al. (41)       51%           80%
Torriani et al. (42)          29%           62%
Chung et al. (43)             15%           44%
Perrone et al. (44)           15%           44%

Special thanks to Tracy Swan for assembling this table.

* This includes genotypes 4, 5, & 6.

Figure 2. Sources of hepatitis C
infection in the US

HIV/HCV co-infection is
common (50%-90%)
among HIV-infected IDUs

Injecting drug use         60%

Unknown                    10%

Other *                     5%

Transfusion
(before screening)         10%

Sexual                     15%

* Nosocomial;
Healthcare work;
Perinatal

Note: Table made from pie-chart.

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