Identification of Coinfection

The Decision to Treat HIV, HCV, or Both

As discussed in Chapter 20 Section 1, Overview of HIV/HCV Coinfection, it is clear that HIV infection accelerates HCV disease progression.^12-18 Further, coinfection appears to increase the risk of liver cancer (hepatocellular carcinoma).^16,19 Thus, the health risks of untreated HCV infection are higher among coinfected persons than in those with HCV alone.

The effects of HCV on HIV disease progression are unclear. Several clinical studies evaluating this topic have shown conflicting results.^{2,6, 8,20,21} Therefore, while the possibility exists that HCV may negatively impact the natural history of HIV, further study is needed before this can be determined conclusively.

Both HIV and HCV are potentially life threatening infections. The stakes involved in treatment decisions are very high and the issues are complex. Therefore, we urge all coinfected persons to consult with health care providers who have experience managing coinfection.

The decision to treat HIV, HCV, or both infections simultaneous depends on many factors including:

the timing of diagnosis

Were the infections diagnosed at the same time or was one of the infections acquired after the other had been present for some time?

immune status

What is the CD4 count? What is the HIV viral load? Is the client HIV-positive only or has there been disease progression to AIDS? Is the client already on anti-HIV medications? What medications have been prescribed?

HCV-related factors

Is there evidence of fibrosis and/or cirrhosis? Is there evidence of liver failure (decompensation)? What are the liver enzyme levels? What is the HCV viral load? What is the genotype? Has the client received previous treatment for HCV?

mental health issues

Does the client currently have or have a history of depression or other major mental illness? Is there active substance abuse (drugs or alcohol)?

overall health status

Are there other active illnesses? Are they well-controlled?

Depending on the specific circumstances, one of the following choices may be made:

Treat the HIV infection first until it can be controlled, then consider treatment for HCV.

An HIV treatment break may be taken during HCV therapy, or HIV treatment may be continued during HCV therapy. The rationale behind this approach is that the partial restoration of immune function that often occurs after beginning highly active antiretroviral therapy (HAART)²² for HIV may increase the likelihood of response to interferon-based therapy for HCV. Further, there is one preliminary study that suggests HAART may actually slow the accelerated HCV disease progression usually observed with coinfection.²³ However, as discussed in Section 1 of this chapter, liver enzyme levels and HCV viral loads often increase when HAART is initiated.^24-36 The long-term effects of these spike in liver enzymes and HCV viral loads are unclear.

Treat HCV first, then begin HIV treatment.

This approach has two potential advantages. It may eliminate the immediate threat of HCV-related liver disease by halting disease progression and allowing for at least partial restoration of liver health. A liver that has been partially or completely restored to normal function is better able to process antiviral drugs when HIV treatment is initiated. This approach is usually reserved for people who have not received previous therapy for either infection and whose CD4 counts are greater than 350 cells/µL.¹¹

Treat both infections simultaneously.

This approach addresses both infections at the same time. Caution is required due to potential interactions between anti-HCV and anti-HIV medications.

Interferon-Based Therapy for HCV in People with HIV/HCV Coinfection

There are currently no therapies approved by the Food and Drug Administration (FDA) for the treatment of HCV in people coinfected with HIV. Nonetheless, coinfected patients are routinely treated with the same therapies used in people with HCV alone.

Combination therapy with pegylated interferon plus ribavirin has emerged as the treatment of choice for chronic hepatitis C (See Chapter 9, Sections 1 and 2 for additional information about pegylated interferon plus ribavirin therapy.) While overall sustained response rates with this treatment have been reported to be approximately 50-60% in people with HCV only, response rates are lower in coinfected persons. Overall sustained response rates in coinfected persons has been reported to be 20-35%, approximately half that seen in those with HCV only.^37-45 Further, relapses are more frequent in the coinfected population compared to people infected with HCV only. ^38,43 Researchers speculate the decreased response rate and increased relapse rate may be partially due to the reduced immune function seen in HIV-infected persons. Other possible factors that may contribute include: ¹¹

higher rates of advanced liver fibrosis and/or cirrhosis

higher rates of fat in the liver (steatosis)

higher HCV viral loads

lower initial rates of HCV clearance

higher rates of serious side effects leading to treatment discontinuation

lower compliance with therapy

Recent studies have shown that the early clearance of HCV after beginning pegylated interferon plus ribavirin therapy is slower in coinfected patients than in those with HCV alone.⁴⁶ Because of the slower initial viral clearance, some doctors are concerned that the usual practice of discontinuing therapy if an early viral response (at least a 2 log reduction in viral load) is not seen by week 12 may not be appropriate for coinfected persons. However, preliminary data suggests that despite the slower viral clearance, the 12-week early response is nonetheless predictive of sustained response in coinfection.⁴⁷

Although the early response rate rule of thumb appears to hold true for the coinfected population, there is concern that the optimal duration of therapy may be longer among coinfected persons, regardless of genotype. Some experts are calling for clinical trials to study this important question.¹¹

Candidates for Interferon-Based Therapy

An international panel of experts who recently published coinfection treatment guidelines recommend that all HIV/HCV persons should be evaluated for anti-HCV treatment. As noted in Section 1 of this chapter, response to therapy is partially dependent on the CD4 cell count. ^48,49 Therefore, many doctors prefer treating only coinfected patients with CD4 cell counts greater than 350 cells/µL.¹¹ Others use a higher threshold of 500 CD4 cells/µL.¹² The decision to treat people who have been on long-term therapy with HAART and have CD4 cell counts between 200 and 350 (or 500) cells/µL is made on a case-by-case basis. All factors that may affect response to therapy should be considered such as the HCV genotype, the presence of fibrosis and/or cirrhosis, current alcohol consumption or drug use, and mental health status. Anti-HCV therapy is rarely prescribed for people with CD4 counts less than 200 cell/µL because of the response rate is very low.^{48, 49} If the CD4 count comes up at a later date, the decision to treat can be reconsidered.

As with people who are infected with HCV only, coinfected persons with liver decompensation are not candidates for interferon-based therapy. Anyone with liver decompensation should be referred for a liver transplant evaluation.

Other relative contraindications to interferon-based therapy are the same in the coinfected population as they are in those with HCV only. They include:

active substance abuse (alcohol or illicit drugs)

active mental illness

history of severe mental illness

There is disagreement about the role of liver biopsy in the decision to treat HCV in coinfected persons. Many experts believe the high risk for end-stage liver disease and the increased risk for liver cancer among coinfected persons are sufficient indicators to treat any coinfected person who is otherwise eligible for treatment regardless of whether a liver biopsy has been performed. Other experts believe anti-HCV therapy should be attempted only in coinfected persons who have evidence of significant fibrosis on liver biopsy. Those who take this approach believe the risks of serious side-effects associated with treatment and the relatively low response rate to interferon-based therapy in the coinfected population justifies the requirement for liver biopsy.

Side Effects of HCV Therapy in Coinfected Persons

People with coinfection are subject to the same side effects from combined pegylated interferon plus ribavirin therapy as those with HCV alone (see Chapter 9, Section 2 for additional information about the side effects of interferon and ribavirin). However, since coinfected people may already have HIV-related symptoms or HAART-related side effects, additional side effects may prove more difficult to tolerate. The high rate of discontinuation of therapy ^40-43 in coinfected people may be related to this phenomenon.

White blood cellcounts may drop as a side effect of pegylated interferon. In coinfected persons with already reduced CD4 counts, further decreases can be particularly troublesome. ^{48, 50,51}

Depression is a common side effect of interferon-based therapy. It is important to report any symptoms of depression to your health care provider to prevent this side effect from interfering with completion of therapy. Common symptoms of depression include:

sleep disturbances - either poor sleep or sleeping too much
appetite disturbances - eating more or less than usual
loss of interest in things that used to give you pleasure
withdrawal from loved ones
feelings of hopelessness or helplessness
loss of interest in sex
suicidal thoughts

Toxic Interactions Between Anti-HIV and Anti-HCV Therapies

Anemia

Anemia is a frequent side effect of ribavirin.⁵² Interferon adds to this problem by decreasing the production of both red and white blood cells. Overall, significant anemia occurs in approximately 7-9% of HCV-infected people treated with combination therapy.⁵³ A recent study suggests this side effect of pegylated interferon plus ribavirin is more frequent in coinfected persons than in those infected with HCV alone.⁵⁴ The anti-HIV drug zidovudine (AZT, Retrovir^®) is also known to cause anemia. Therefore, most doctors discontinue zidovudine before prescribing ribavirin; it is usually replaced by another drug in the same class.

Mitochondrial Toxicity

As noted in Section 1 of this chapter, HCV can damage the "powerhouses" of liver cells, the mitochondria.⁵⁵ A significant problem in the simultaneous treatment of coinfection is the fact that certain HIV medications also damage the mitchondria. Anti-HIV drugs that have been associated with mitochondrial damage include zidovudine (AZT, Retrovir^®), lamivudine (3TC, Epivir^®), stavudine (D4T, Zerit^®), didanosine (ddI, Videx^®), nelfinavir (Viracept^®), nevirapine (Viramune^®), and zalcitabine (ddC, HIVID^®).⁵⁶

Lactic acidosis is a potentially life-threatening condition that may develop with severe mitochondrial toxicity. Lactic acid is a normal byproduct of the energy production process that occurs inside the mitochondria. When the mitochondria are damaged, lactic acid can build up and upset the delicate chemical balances necessary for normal body functions. Symptoms of lactic acidosis include:

muscular weakness - most noticeable in the arms and legs; the weakness is often severe

nausea and/or vomiting

abdominal pain

breathing difficulty or shortness of breath

numbness or tingling in the extremities

A blood test is used to confirm the diagnosis of lactic acidosis. If you develop any of the symptoms above, see your doctor immediately. This rare but very serious complication has been specifically linked to didanosine (ddI, Videx^®), but has also been linked less frequently with lamivudine (3TC, Epivir^®), zidovudine (AZT, Retrovir^®), stavudine (D4T, Zerit^®), and abacavir (Ziagen^®). There have been reports of fatal reactions when didanosine and ribavirin were taken together. ^57,58 These two drugs should not be taken at the same time.

Chronic HCV infection can eventually lead to end-stage liver disease. In end-stage disease, the liver is no longer capable of performing its many vital body functions. Anti-HCV treatment is not useful in such circumstances because the liver has been damaged beyond repair. The only treatment option available once liver disease has progressed to this point is liver transplantation.

Prior to the introduction of HAART , coinfected persons were not eligible for liver transplantation because the likelihood of survival was extremely low.⁵⁹ The introduction of HAART, with its ability to suppress HIV replication and the related rebound in immune function, has improved HIV prognosis to the point that coinfection is no longer a contraindication to liver transplantation.

Candidates for liver transplantation typically meet the following criteria:

no history of opportunistic infections

CD4 count greater than 100 cells/µL

undetectable HIV-RNA

no alcohol or illicit drug consumption for at least six months

A recent study reported a 92% post-transplant survival among people with HIV, a rate equivalent to that seen in all liver transplant patients (87.9%). ^60,61

HCV recurrence in transplanted livers occurs in 100% of people with detectable HCV-RNA prior to transplant. Up to 20% of transplanted livers that become reinfected with HCV develop cirrhosis within 5 years. People with genotype 1 HCV appear to be at greater risk for rapid fibrosis progression in transplanted livers compared to other genotypes.⁶² The accelerated HCV-related disease progression seen in coinfected persons makes the long-term viability of transplanted liver an issue of great concern. Most experts recommend anti-HCV therapy within one to three months post-transplant. A small study of 32 patients found an 18% response rate to pegylated interferon plus ribavirin in liver transplant patients who had been previous non-responders to standard interferon plus ribavirin.⁶³ Although the response rate is low, it offers some hope to liver transplant recipients. Other strategies to prevent reinfection of transplanted livers are being researched in clinical trials.

Coinfection Treatment Guidelines

The management of HIV/HCV coinfection is an area of active clinical research. Recent developments in the treatment of HCV and emerging research data makes defining ideal treatment much like chasing a moving target. Nonetheless, a group of nine international experts published a series of recommendations for the care of people with hepatitis C and HIV coinfection.¹¹ A synopsis of the panel's findings and recommendations are shown in Table 1.

Table 1: Issues and Consensus Findings/Recommendations from an
International Panel on
CARE OF PATIENTS WITH HEPATITIS C AND HIV COINFECTION ⁷

Adapted from: Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV coinfection. AIDS. 2004;18:1-12.

The Hepatitis C Consensus Development Conference National Institutes Of Health, 2002

In 2002, the National Institutes of Health (NIH) held a Consensus Development Conference on the Management of Hepatitis C. The primary sponsors of the meeting were the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Medical Applications of Research (OMAR) of the NIH. Cosponsors were the National Institute of Child Health and Human Development (NICHD); the National Cancer Institute (NCI); the National Center for Complementary and Alternative Medicine (NCCAM); the National Institute on Alcohol Abuse and Alcoholism (NIAAA); the National Institute on Drug Abuse (NIDA); the National Institute of Allergy and Infectious Diseases (NIAID); the National Heart, Lung, and Blood Institute (NHLBI); the Centers for Medicare & Medicaid Services (CMS); the Centers for Disease Control and Prevention (CDC); the U.S. Food and Drug Administration (FDA); and the U.S. Department of Veterans Affairs (VA).

The conference examined the current state of knowledge regarding the management of hepatitis C and identified directions for future research. Experts presented the latest hepatitis C research findings to an independent, non-federal, consensus development panel. After weighing the scientific evidence, a consensus statement was drafted. The statement was finalized in September 2002.

Following is the section of the consensus statement pertaining to HIV/HCV coinfection.

All HIV-infected persons should be screened for HCV. Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of HCV disease. Therefore, although there are no HCV therapies specifically approved for patients co-infected with HIV, these patients should be considered for treatment. Thus far, studies have enrolled only patients with stable HIV infection and well-compensated liver disease. In co-infected persons, an SVR* can be achieved with HCV treatment. Preliminary data suggest better responses to pegylated interferon with ribavirin than to standard interferon with ribavirin. Thus treatment of HCV infection in patients with HIV is recommended on a case-by-case basis. Although treatment of HCV does not appear to compromise treatment of the HIV infection, additional data are needed. Monitoring for potential adverse effects from these treatments, including lactic acidosis, is strongly recommended.

*SVR = Sustained Viral Response

To view the complete Consensus Statement on Hepatitis C, go to: consensus.nih.gov/cons/116/091202116cdc_statement.htm

Summary

Due to common routes of transmission and shared risk factors, a large number of people are coinfected with HIV and HCV. Coinfection with HIV is associated with accelerated HCV disease progression and increased risk for liver cancer. Since the introduction of HAART, significant numbers of coinfected persons are experiencing the effects of HCV-related liver disease.

The increased risks associated with coinfection raise the stakes involved in treatment decisions. The management and effective treatment of HIV/HCV coinfection are complex and should be conducted by health care providers experienced in this subgroup of clients. All persons being treated for both HIV and HCV must be closely monitored for potentially serious complications.

Many aspects of coinfection are currently being investigated. As these studies are completed, we hope to use the information to develop safer, more effective therapies. The ultimate goal is to reduce the disease burdens currently borne by coinfected persons.