by Daniel Raymond

TAG reviewed the NIH’s draft consensus statement and submitted comments on June 19, 2002.

Summary of comments:

• The recommendation of needle exchange as a prevention strategy should prioritize subgroups of injection drug users at risk of hepatitis C infection, including young and newer injectors, casual or infrequent users, women, people exchanging sex for money or drugs, and cocaine injectors.
• There is a strong need for a more detailed and comprehensive review of HIV/HCV coinfection treatment with a fuller discussion of treatment strategies and management of hepatotoxicity associated with HIV antiretroviral medication. Clinicians and patients would benefit from the establishment of coinfection treatment and monitoring guidelines.
• Research on HIV/HCV coinfection should undertake to clarify questions about pathogenesis and natural history, optimal treatment, and the effects of HCV infection on immune response to HIV treatment and complications of antiretroviral therapy, including diabetes, lactic acidosis, and elevated cholesterol levels.
• A Hepatitis Clinical Research Network, conducting long-term natural history and treatment studies in a broad range of populations that includes HIV/HCV coinfected patients and drug users, should be established with involvement and input from hepatitis and HIV/HCV advocates and people living with HCV.

The release on June 12th of a new NIH draft consensus statement, “Management of Hepatitis C: 2002” represents an important milestone in treatment, care, and research in hepatitis C (HCV) infection. The consensus statement was drafted by an expert panel chaired by Dr. James Boyer following two days of presentations by researchers with a question and answer period open to the public. The NIH characterizes the consensus statement as an independent report, rather than a policy paper. When the previous consensus statement was released in 1997, alpha interferon monotherapy was the standard of care, as ribavirin had not yet been approved for use in combination therapy. The new statement endorses combination therapy in all patients with biopsy results indicating portal or bridging fibrosis and inflammation and necrosis. The panel recommends first line therapy using ribavirin in combination with pegylated interferon, a newer formulation requiring only once-weekly dosing and providing an improved sustained virological response (undetectable HCV viral load six months after treatment) approaching 50% in mono-infected patients with genotype 1 and about 80% in patients with genotypes 2 and 3. These response rates are roughly equivalent in studies using ribavirin in combination with Peg-Intron (pegylated interferon alfa-2b, approved by the FDA) and Pegasys (pegylated interferon alfa-2a, submitted for FDA approval), though a comparison study of the two versions has not been conducted.

The 2002 statement also supports treating injection drug users (IDUs), reversing the 1997 stance of withholding treatment until at least six months of abstinence from drugs. The original statement was guided here more by assumption than evidence, which was scant. A letter signed by a broad group of activists, service providers, doctors and researchers supported this revision in the new statement. Drug users have not always fared so well in the efforts of hepatitis advocates; certain established groups have attempted to downplay the prevalence of HCV among IDUs – as high as to 70-90%, according to some studies – out of concern for associating the stigma of drug use with people suffering from hepatitis C. However, an explosion of interest and concern regarding this population in recent years among service providers has led to widespread initiatives promoting education and testing, particularly in HIV outreach and needle exchange programs.

The endorsement of needle exchange programs as a strategy to prevent transmission should be the point of departure for a concerted effort to reduce HCV incidence among IDUs. Local and state resistance and the continued ban on federal funding of these programs have hindered the expansion of needle exchange programs. Increased access to needle exchange remains a critical public health priority, and a comprehensive approach requires expanding access to drug treatment, decriminalizing syringe possession, and legalizing pharmacy sale of syringes. Targeted outreach and education efforts should focus on subgroups of IDUs who may be at particular risk of infection due to patterns of drug use and access to sterile syringes. These groups include young and newer injectors, casual or infrequent (vs. daily) users, women, people exchanging sex for money or drugs, and cocaine injectors; consideration should also be given to the potential risk of HCV infection among hormone and steroid injectors.

The current state of HCV knowledge – and its limitations – is reflected in the guidance on HIV/HCV coinfection. The consensus statement notes that based on available data, HCV treatment appears safe and reasonably effective in people with HIV; the panel calls for more research into natural history and pathogenesis, treatment safety and outcomes, and optimal dosing and duration of therapy. However, the recommendations fail to address – or, in the current version, acknowledge – the most urgent and vexing question among coinfected people and their doctors in recent years: which should be treated first, HIV or HCV – or both, simultaneously? And when is the optimal time to initiate HCV treatment in coinfected patients? Research indicates that people with a CD4 count below 200 have a significantly increased risk of progression to cirrhosis, while response rates to HCV treatment improve with higher CD4 levels. A liver disease specialist looking to this document for guidance on treating a coinfected patients would not find adequate reference to the influence of CD4 counts on disease progression and treatment response rates.

Hepatotoxicity and the Uses and Limits of the Consensus Statement 

Estimates of HCV prevalence among people with HIV in the United States range from 30% – 50%, with even higher rates among people infected through injection drug use. In the USA, end stage liver disease has become a leading cause of death in people with HIV. Major concerns for coinfected persons and their doctors include balancing decisions about whether and when to start HCV treatment with the risks of hepatotoxicity from antiretroviral (ARV) medications used to treat HIV. The clinical relevance of ARV hepatotoxicity to risk of HCV disease progression has not been established; however, the incidence of HAART-related hepatotoxicity is significantly higher in people coinfected with HCV (and/or with hepatitis B). Certain medications, including nevirapine and ritonavir, have been linked to a higher rate of hepatotoxicity, but it’s not clear how that should inform decisions about treatment regimens, though frequent monitoring of ALT levels and for symptoms is clearly necessary.

Severe (grade 3 or 4) hepatotoxicity warrants discontinuing or switching antiretroviral medication, but how should mild or moderate hepatotoxicity, as indicated by elevated ALTs, be regarded in people with chronic hepatitis C infection? Could an extended length of time on antiretroviral therapy with some associated hepatotoxicity, even at mild levels, correlate with an increased risk of developing cirrhosis? And would that risk vary according to baseline fibrosis score? The question becomes significant when considering that most people with HIV on treatment can expect to be taking medications for an extended, even indefinite, length of time. However, the consensus statement does not take up questions concerning the hepatotoxicity of antiretroviral medications.

The newly issued 2002 Guidelines for Preventing Opportunistic Infections from the Public Health Service and the Infectious Disease Society of America simply state that the risk of elevations in liver enzymes should not disqualify coinfected people from HAART treatment, and that such elevations “might not require treatment modifications.” The current preference, shared by many (but not all) clinicians, for treating HCV before HIV – assuming relatively stable HIV disease with CD4 counts high enough to allow for deferring antiretroviral therapy – gains some support from the prospect of reducing the incidence of hepatotoxicity from ARVs. However, as of yet no research has confirmed the assumption that coinfected individuals with a sustained virologic response to hepatitis C treatment will have a lower incidence of hepatotoxicity on subsequent HAART.

Perhaps it is unreasonable to expect a substantial discussion of ARV hepatotoxicity in the consensus statement, which uses broad strokes to depict the current state of knowledge in management of hepatitis C. The omission of any recommendation for hepatitis A and B vaccinations among people with hepatitis C might imply that the NIH panel does not intend for this manual to be a comprehensive guide for clinical management, though the 1997 statement did recommend vaccination. However, given the safety and high level of efficacy of the vaccines, the risk of fulminant hepatitis when people with chronic hepatitis C become infected with hepatitis A, and the overlapping transmission risks and as yet unknown impact on disease progression of HBV and HCV infection, the omission is puzzling and should be remedied.

Furthermore, both statements endorse serial ALT and HCV viral load monitoring while pointing to their limitations as prognostic markers and calling for further research on their utility, yet neither statement offers clear suggestions for frequency of monitoring for individuals not on HCV treatment. Clinicians facing these decisions certainly have a variety of sources and channels beyond the consensus statement for staying abreast of emerging trends in clinical practice; combination therapy became the de facto standard of care well before the appearance of the current draft. Yet the consensus statement clearly can influence treatment practices; the 1997 version played a major role in the legitimation of withholding treatment from active drug users. In the absence of a formal federal guidelines process similar to that used for the Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, many clinicians will turn to the hepatitis C consensus statement as a main point of reference.

For that reason, the consensus statement can play an important part in foregrounding issues where broad variations in current treatment practices persist. Some clinicians recommend starting on antidepressant medication prior to initiating HCV treatment in order to manage the potential psychiatric side effects of interferon. Depression related to interferon treatment is a major factor in premature discontinuation of therapy and drop-out rates in clinical trials. While data from controlled comparison studies on this strategy have not been presented, the approach bears noting as an option. Similarly, while linkages between HCV treatment and substance abuse programs are recommended in the draft in the context of treating IDUs, some clinicians have raised concerns about the risk of substance use relapse to former IDUs treated with a drug that can have potent effects on mood and requires injection. This important consideration for a substantial patient population merits direct reference in the statement.

Of course, even formal disease management guidelines do not always or automatically steer practice in clinical settings. A CDC review of coinfected patient data from 10 cities to examine adherence to USPHS guidelines for preventing opportunistic infections indicates that only a very small percentage of coinfected individuals in care were vaccinated for HAV, which was recommended by the US PHS in its OI prevention guidelines as well as in its 1997 hepatitis guidelines. Some key issues in managing hepatitis C reflect on the potential complexity of coordinating care between a range of practitioners which may include hepatologists, infectious disease specialists, and potentially psychiatrists, substance abuse providers, and others. For coinfected individuals, proper management would also involve their HIV primary care doctor. This returns to the question of whether more detailed guidance on clinical care is warranted. The Guidelines for the Use of Antiretroviral Therapy, for example, are more limited in scope but provide a much more thorough review of information on their subject. Such a comprehensive approach is necessary in HIV treatment in a way that arguably does not apply to hepatitis C monoinfection because of the significantly greater complexity of antiretroviral treatment, but the treatment of coinfection would benefit from synthesizing the array of knowledge currently fragmented between the OI guidelines, HCV Consensus Statement, and the Guidelines on ART (which discuss hepatotoxicity, but not treatment strategies for coinfection).

The current state of coinfection research:

Does HCV affect immune reconstitution?

A great deal of uncertainty and guesswork still governs the thinking among both patients and clinicians in the treatment of HIV/HCV coinfection. A rapidly increasing number of studies explore a range of questions related to treatment strategies, but they often yield conflicting results, use small sample sizes, have limited follow-up, or lack randomized controls. Comparisons between studies are made difficult due to inconsistent analysis and reporting of variables that may influence results. For instance, as Michael Marco reported in the May 2001 TAGline (volume 8, issue 4), while HIV infection’s tendency to accelerate HCV disease progression has been well documented, it’s less clear whether HCV infection worsens HIV disease.

More recently, a number of studies have examined the effect of HCV on immune reconstitution following the initiation of HAART. The touchstone for this debate is the Swiss HIV Cohort Study, which reported that coinfected patients showed a blunted immunological recovery on treatment which could not be attributed to poorer virologic response (Greub 2000). A subset analysis of 56 coinfected subjects matched for baseline HIV viral load and CD4 count as well as age and sex found no correlation between HCV viral load and immunologic response, though genotype 3a was significantly associated with CD4 increases below 50 in the first year on potent antiretroviral therapy. The interpretation of the subset analysis is complicated by the fact that 25% of the coinfected subjects had no detectable HCV viremia, implying a resolved infection. Some subsequent studies have found that despite comparable virologic responses, coinfected patients exhibit a diminished immunologic response to treatment as measured by gains in CD4 cells; others, however, report no immunologic differences.

This question has potential implications for treatment decisions, but a conclusive answer does not seem forthcoming. Some of the confusion relates to differences in study design. Three studies presented this year at the 9th Conference on Retroviruses and Opportunistic Infections illustrate this theme. The ACTG 383 study (which added a retrospective component to a prospective study when the original trial failed to meet its target enrollment of 60 patients) found no differences in immunological response to HAART, following subjects out to 48 weeks (Chung 2002); however, a Spanish prospective cohort study following clinic patients for 24 months found that impaired immunological recovery among coinfected patients becomes evident after the first year of HAART (Moreno 2002). A Thai analysis from the HIV-NAT trial (Law 2002) also reported diminished immune reconstitution among HIV/HCV coinfected patients, though at 48 weeks there were no significant differences in risk of HIV disease progression. A report from an observational study of the Frankfurt HIV Clinic Cohort (Sabin 2002) also found that coinfected patients experienced CD4 cell increases of lesser magnitude, but qualified by noting that in their sample HCV infection was closely linked to a history of injection drug use, which could be associated with another variable – the authors suggested adherence – that accounted for impaired immunologic response.

How should these divergent results be interpreted? Coinfection studies – particularly those involving HAART – pose a potentially overwhelming array of confounding variables. In HCV research, age, sex, degree of fibrosis, HCV viral load, race, genotype, and alcohol use can influence disease progression and/or response to treatment; various biochemical markers as well as quasispecies diversity may also play a role. HIV studies can incorporate variables including baseline CD4 count and viral load, nadir CD4 count, history of ARV treatment, specific drug classes and regimens, adherence, and other more esoteric virological and host immunological factors such as phenotype and immune activation. None of the studies listed above consider all of these factors, nor could they; the resolution of such debates lies in identifying factors most likely to influence outcomes. For instance, an accumulating body of evidence implicates chronic immune activation as a key factor in HIV pathogenesis. HCV viremia could conceivably drive immune activation and offset some of the gains in CD4 count achievable on HAART. A trial design stratified by initial HCV viral load could test the hypothesis that coinfected patients with an HCV viral load exceeding 2 million IUs would gain fewer CD4 cells on HAART than those with under 2 million IUs (or another threshold could be used). Of the four Retrovirus presentations, only the ACTG reported HCV viral load, noting that those starting with baseline CD4 counts below 350 experienced an increase in HCV viremia during the 48 weeks of observation.

These lines of inquiry may ultimately lead us towards a less monolithic view of coinfection, as understanding of the interaction between the two viruses (and potentially HBV and HGV) and host responses continues to improve. It would be helpful to explore the possibility of identifying of varying patterns of coinfection based on rate of progression. Accelerated disease progression of one virus, or both might for instance, characterize a particular coinfection pattern, or neither until CD4 counts fall below a certain threshold. Such a classification system would have significant relevance to treatment decisions, but would ultimately require long-range cohort studies to better characterize the natural history of coinfection and the long-term clinical impact of various interventions.

Prospects and Priorities for Future Research

The new statement makes a number of recommendations for further research which, compared to the 1997 statement, reflect the rapid growth of both new data and new questions over the last five years. The most far-reaching proposal calls for the establishment of a Hepatitis Clinical Research Network examining natural history, prevention, and treatment. Such a network would fill a void in current research efforts, most notably in the need for more data regarding pathogenesis and natural history in various sub-populations and the current knowledge about long-term clinical outcomes and determinants of variations in response rates to current treatment.

Much of the current available knowledge in these areas has been generated by clinic-based cohort studies with relatively homogenous patient populations and treatment follow-up rates currently limited to five years at most. Existing multi-center networks that have studied HCV generally have a narrow focus or limited capacity for large scale, long-term research. For instance, the Adult AIDS Clinical Trials Group and the American Foundation for AIDS Research have sponsored studies on HIV/HCV coinfection, while the industry-sponsored Hepatitis Research Network’s Clinical Trials Group has focused on treatment strategies. NIAID’s Division of Microbiology and Infectious Diseases (DMID) has begun to develop research networks, including the Hepatitis C Research Recovery Network and the Hepatitis C Cooperative Research Centers. This work should be supported and expanded, with a pressing need for increased resources and for strong leadership and strategic direction developed in collaboration among researchers, clinicians, people infected with HCV, and their advocates.

The consensus statement points to the urgent need for “developing less toxic therapies and molecular-based agents that specifically inhibit viral replication and/or translation of viral RNA.” Current research on candidates including inhibitors of protease, helicase, and IMPDH, as well as antisense oligonucleotides and antifibrotic agents, should take high priority and be expanded, when safety has been established, to sub-populations including patients with cirrhosis and coinfected people as early as is feasible and appropriate. Recent advances in basic research on HCV, including progress towards reliable cell culture systems, a mouse model for HCV infection with transplanted human hepatocytes, and further characterization of the immune response to HCV infection, will certainly aid in the understanding of pathogenesis and the development of new drugs and vaccines. However, much work remains in each of these areas, which require increased funding and collaboration.

Finally, research into clinical care and treatment outcomes must address the following questions, many of which are enumerated in the consensus statement:

• What is the long-term clinical benefit of the histologic improvement noted in some virologic nonresponders to HCV therapy, and what factors predict a histologic response?
• What is the appropriate role of biopsy in monitoring HCV infection? How often should patients not on treatment receive biopsies, and can noninvasive techniques for measuring fibrosis using biochemical markers play a role in monitoring?
• What are the determinants of the degree of immunologic response to HAART in coinfected patients who respondvirologically to HAART?
• What is the value (particularly with regard to hepatotoxicity risk) of treating HCV before HIV in coinfected patients with persistently normal ALTs or moderately elevated ALT levels without significant fibrosis?
• What are the effects on HCV progression of long-term ARV-related hepatotoxicity?
• What are the effects of HCV on HAART-associated complications (diabetes mellitus, lactic acidosis, elevated cholesterol levels)?
• How does HIV-related immune dysregulation affect host response to HCV infection at various stages of HIV disease?

The authors of the new consensus statement should be commended for their attention to increasing the availability of treatment and the need for research in populations including IDUs and people with HIV/HCV coinfection. The call for a Hepatitis Clinical Research Network would help to elaborate on the current state of knowledge over the years to come. Should such a network be established, it is to be hoped that hepatitis and HIV/HCV advocates and people living with HCV will be closely involved in its activities.

Notes

Chung et al., Successful Immune Recovery Is Associated with Persistent Increases in HCV RNA, Infrequent LFT Flares, and Appears Unimpaired by HCV in Co- infected Subjects. 9th Conference on Retroviruses and Opportunistic Infections (CROI), poster session 84, abstract 637-M, 2001.

Greub et al., Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356: 1800-05.

Law et al., Impact of Viral Hepatitis Co-Infection on Response to Antiretroviral Therapy among a Cohort of Thai HIV-Infected Patients Enrolled in HIV-NAT Trials. 9th CROI, poster session 87, abstract 661-M, 2001.

Moreno et al., Immune Recovery during Antiretroviral Therapy in Patients Infected with HIV-1 and Hepatitis C Virus Co-Infection: A Cohort Study. 9th CROI, poster session 84, abstract 638-M, 2001.

Sabin et al., Poorer Immunological Response to HAART in HIV+ Individuals Co-Infected with Hepatitis C Virus. 9th CROI, poster session 84, abstract 639-M, 2001.