Management Guidelines for the HCV/HIV Co- Infected Adult
Recommendations of a Multidisciplinary Expert Panel

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IV) HIV Plan

Treatment of HIV infection should follow recommended guidelines as per HIV infected patients without HCV. Initiation of therapy should be guided by immune status (CD4 cell counts), viral replication (HIV RNA levels) and patients willingness and ability to adhere to combination antiretroviral therapy [19-22]. Combinations based on triple reverse transcriptase inhibitors, non-nucleoside inhibitors and protease inhibitors are all recommended as acceptable therapies [19,20]. For patients with addiction issues, simple combinations with directly observed therapy at street clinics, needle exchanges or methadone treatment centers should be considered.

Should Treatment of HIV infection precede, follow or be concurrent with therapy for HCV?

There is no available peer reviewed literature upon which to make firm recommendations. Until such data can be gathered, all co-infected patients should be encouraged to initiate HCV therapy within the context of a cohort or randomized controlled clinical trial where available.

The theoretical basis for initial management of HCV is based on the concern of the hepatotoxicity of many of the antiretroviral agents in current use, which could be more marked in the presence of HCV [56,57]. However, it remains unclear whether prior therapy for HCV can decrease subsequent toxicity to HIV medications. In addition, the immune restoration associated with HAART therapy could lead to an increase in the immunologic response against HCV and potential worsening of the liver disease [58,59]. In contrast, the beneficial effects of management of HIV have been demonstrated in controlled clinical trials, and should not be deferred to treat HCV first, if HIV treatment is indicated.

Recommendations:

In general, HIV should be addressed first and managed according to guidelines (I A). Once the patient has stabilized on combination antiretroviral therapy, consideration could be given to starting therapy for HCV. (III C)

For patients with stable HIV infection, not requiring immediate therapy (i.e. CD4> 350-500/mm ³ , HIV RNA< 5000-30,000 copies/ml) consideration could be given to treatment of HCV first. (III C)


A treatment holiday from HIV therapy prior to the initiation of HCV therapy in order to decrease drug toxicity cannot be recommended at this time. (III C)

Because of the complexities and overlapping toxicities associated with therapies for HIV and HCV, the initiation of both treatments at the same time should be avoided. (III C). The patient should be stabilized on one treatment before the second is introduced.

What are the preferred antiretroviral agents for the co-infected patient?

All antiretroviral agents have the potential to cause hepatotoxicity. Certain drugs have been associated with an increased risk in the co-infected patient and should be used with caution, especially when there is evidence of baseline liver dysfunction.

Recommendation:

Full dose ritonavir and nevirapine should be avoided or used with caution in the co-infected patient (II-3 B).

Should patients with co-infection be monitored more frequently?

Initiation of HAART has been associated with hepatic decompensation and/or increases in serum aminotransferases in HCV coinfection [58,59]. The mechanism of the toxicity and the natural history of abnormalities of liver biochemical tests in the presence or absence of HCV is unknown. The role of immune restoration is speculative. The relationship to lipodystrophy, mitochondrial toxicity, and hepatic steatosis is unknown, but potentially important.

Recommendation:

No recommendations are currently available to adjust doses of antiretroviral agents in the setting of liver abnormalities. (III C)

Co-infected patients should be monitored closely for signs and symptoms of hepatic dysfunction. No recommendation can be made as to what level of ALT should lead to discontinuation of antiretroviral agents. (III C)

No data are available to make a recommendation as to whether or not the patient can be rechallenged with the same (or class) antiretroviral agent after toxicity resolves.(III C)

Should Nucleoside Reverse Transcriptase Inhibitors be Discontinued when Ribavirin is used?

The nucleoside reverse transcriptase inhibitors are taken up into host cells and are then triphosphorylated into active agents by cellular kinases. AZT (zidovudine) and d4T (stavudine) are analogues of thymidine and ddC (dideoxycytidine) and 3TC (lamivudine) are analogues of cytidine. Ribavirin is a guanosine analogue that also requires phosphorylation to an active form by cellular kinases. It has been shown in vitro that ribavirin can competitively inhibit the thymidine kinase required for the phosphorylation of AZT and possibly other agents in this class.[96,97] Ribavirin in vitro can also inhibit the metabolism of DDI resulting in increased concentrations of this agent and theoretical potentiation of the antiviral activity. The clinical relevance of these in vitro observations remains uncertain, but no significant variation in HIV replication was observed in a recent study of "combination therapy" in a co-infected population [98].

Recommendation:

There are insufficient clinical data to avoid or select specific agents of the nucleoside reverse transcriptase inhibitors class during concurrent therapy with ribavirin because of concerns of competition for phosphorylation (III C)

Until more data are available, monitoring for continued control of HIV viral replication one month following initiation of treatment for HCV is warranted. Note that non-specific increases in HIV RNA may be observed at this point. If HIV RNA increases at one month , the viral load should be repeated 2 months after the initiation of therapy for HCV. If it remains increased, consideration should be given to modification of antiretroviral therapy ( or of hepatitis C therapy). (III C)

Should certain antiretroviral agents be avoided during concurrent therapy of HCV?

Recommendation:

As ribavirin and interferon can cause toxicities that overlap with those of certain antiretroviral agents, their concurrent use should be with caution and careful monitoring (III C). For example:
Myelosuppression - AZT, hydroxyurea and interferon
Depression - efavirenz and Interferon

Antiretroviral combinations or prophylactic agents may require modification prior to the initiation of treatment of HCV

The Setting for Management of the Co-infected Patient

Initial assessment can take place in the primary care setting. It is important to ensure that all virologic tests, medical imaging and pathology are performed in centers with the expertise to ensure reliability and reproducibility of test results. Once a co-infected patient is identified, the patients should ideally be referred to a center(s) where patients have access to experts in the management of addictions (where appropriate), HIV and HCV [99,100]. In isolated or rural areas, some of this communication may be via satellite clinics or telephone consultation. Although specialist physician input into the management strategy is felt mandatory, specially trained nurse practitioners or trained primary care physicians (salaried where possible) could be responsible for ongoing care. The physician expert (s) need to be readily available to help with the decision- making and management of complications.

For patients with addiction related issues, to improve acceptance, minimize clinic visits and to improve adherence, the provision of care and education should be moved where possible toward the client population and linked to existing facilities, such as street clinics, methadone clinics or needle exchange sites. In these settings, combined addiction, HIV and HCV management on one site is preferable. Simplifying the HIV regimen, combined with methadone management and directly observed therapy, may be required in certain circumstances. Ongoing education towards risk reduction strategies needs to be structured so as to overcome language and cultural barriers. For first nations individuals, the cultural differences and beliefs in native remedies needs to be recognized and integrated into the treatment plan.

Resource/Funding Issues

The management of co-infected patients is extremely complex. Management teams with the appropriate expertise, and their availability is crucial to optimize outcomes. The process of evaluation (see algorithm) is essential and to ensure that the appropriate patients receive therapy (and vice versa), to minimize drug adverse events, interactions and toxicities, to ensure that the social, psychological and physical needs of patients are met, not only before, but also during and after therapy. Management requires not only the availability and appropriate use of drugs but also the laboratory facilities for monitoring treatment effects and toxicities, personnel to maintain close and regular contact with patients, emergency access to psychiatry and addiction counselors. These programs need to have global or envelope funding so that resources can be allocated as needed and can adapt to changing priorities. In the prison setting, there is a need for increased health care funding and supervision to establish realistic harm reduction strategies, treatment of addictions, and co-infections. Financing of the drugs used in treatment is a provincial matter, but needs to be continually re-evaluated as new data emerge so that patients expected to benefit have access and financial coverage to needed therapies.

Research Priorities

Natural History

1. What is the natural history of HCV in HIV patients treated with HAART? Does HAART change the rate of progression of fibrosis compared with those not on HAART? Does a normal ALT exclude progression of HCV? Is the predictive value of a normal or near normal liver biopsy in the co-infected patient similar to that of the HCV positive but HIV negative patient?

2. What is the incidence of hepatitis C related mortality in persons with HIV?

3. What is the contribution of alcohol use in the progression of liver disease in co-infected patients? What impact does addiction counseling and/or treatment have on this progression?

Treatment Issues

1. Should we treat HIV or HCV first or both simultaneously?

2. What is the natural history and mechanism of liver abnormalities in the co-infected patient on HAART?

3. What impact does addiction counseling and/or treatment have on adherence, tolerance and efficacy of treatment of the viral infections?

4. What are the in vivo correlates of inhibition of phosphorylation of ribavirin and NRTI?

5. What is the best marker to evaluate the response to therapy in the co-infected patients? Is there an early marker of non-response to spare toxicity and cost of longer term therapy?

6. Are there any significant drug interactions between antiviral agents used to treat HIV, HCV and the pharmaceuticals used to treat substance related disorders such as methadone, buphenorphine, antabuse, naltrexone, bupropion and acamprosate?

7. Can substance users with controlled addictions be managed for HCV without the risk of re-infection?

8. Is DOT an effective means of administering therapy for HIV and HCV?

9. Should HIV therapy for the co-infected patient include or spare a protease inhibitor?

10. What is the proper dose of ribavirin for use in the co-infected patient?

11. Is the rate of long term sustained response to HCV in the co-infected patient similar to that of the HIV negative?

12. What is the optimal duration of anti-HCV treatment in the co-infected patient to obtain maximal responses without excessive toxicity? What are the predictors of response to treatment: virologic, immunologic, clinical/behavioural?

13. Is liver transplantation an appropriate treatment for decompensated liver disease from HCV in a patient with stable HIV infection?

14. What are the immunological and virologic changes in either HIV or HCV associated with co-infection? How are these affected by treatment?

15. Can these guidelines improve management of the co-infected patient?

Figure 1

Categories for Quality of Evidence

Level of Evidence

Level	Description
I	Evidence from at least one well-designed, randomized controlled trial
II-1	Evidence from well-designed, controlled trials without randomization
II-2	Evidence from well-designed cohort (prospective or retrospective) or case control studies, preferable from more than one investigational center
II-3	Evidence from observational cross-sectional studies or from dramatic results in uncontrolled experiments
III	Opinions of respected clinical experts or evidence from descriptive studies and case reports

Table 2: Categories of strength of recommendations

Category	Description
A	Good evidence to support a recommendation for use of diagnostic test, treatment or intervention
B	Moderate evidence to support a recommendation for use
C	Poor evidence to support a recommendation for or against use
D	Moderate evidence to support a recommendation against use
E	Good evidence to support a recommendation against use.

Algorithm For The Management Of HIV/HIC Coinfected Patients

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