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HIV/Hepatitis Coinfections: Special Treatment Issues in Patients With Liver Disease: An Expert Interview With Paula Greiger, MD


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Editor's Note:
Diseases such as end-stage liver disease are replacing opportunistic infections as leading causes of mortality in patients with HIV disease. In some patient populations, almost all individuals will carry both HIV and hepatitis C virus (HCV), many will have hepatitis B virus (HBV) coinfection, and some will be infected with all 3 viruses. At the 3rd IAS Conference on HIV Pathogenesis and Treatment, July 24-27, 2005, in Rio de Janeiro, Brazil, Mary E. Anderson, PhD, Clinical Editor, Medscape HIV/AIDS, interviewed Paula Greiger, MD, Director of the AIDS Clinic at Mount Vernon Hospital and NY Medical College in Mount Vernon, New York, to discuss the additional challenges posed by these coinfections.

Medscape: Dr. Greiger, at the International AIDS Conferences we are always reminded of the great differences around the world in HIV clinical care settings. How would you describe the clinical setting in which you practice?

Dr. Greiger: The clinical setting in which I practice is an inner-city population. In terms of demographics, my patients are predominantly African American -- around 85% -- and 15% are Hispanic. We have a very high incidence of coinfection, especially with hepatitis C, and some patients are infected with both hepatitis B and C viruses.

Medscape: How does your own patient population profile in this regard compare against the average coinfection rates in North America and Europe?

Dr. Greiger: Although the coinfection rate is high, my patient population has a very high percentage of patients who acquired their HIV infection from intravenous-drug use. So, the high incidence of coinfection is not unusual in the IV drug-abuser population. Overall, the prevalence of HBV coinfection is about 10% in the United States, and about 25% are dually infected with HIV and HCV. In patients who acquire HIV infection sexually, HCV coinfection is rare, but in the case of transmission through shared needles, most patients in the United States have HCV coinfection. In that sense, my patient population resembles that in other areas of the United States where intravenous-drug use is the predominant transmission route.

Medscape: In clinical settings where potent antiretroviral therapy is available, deaths due to certain conditions, such as some malignancies and end-stage liver disease, have surpassed traditional HIV-related opportunistic infections as significant contributors to the overall mortality in HIV-infected patients. How does your own experience compare?

Dr. Greiger: I have been taking care of patients with HIV disease since 1981, '82, so I started when opportunistic infections were the primary manifestation of HIV disease and the most common cause of mortality and morbidity. Obviously since 1996 things have changed; we don't see as much except in patients who are newly diagnosed. If HIV infection is not diagnosed early, patients may receive their diagnosis when they present with opportunistic infections. Other than that it is very rare to see opportunistic infections. Now that HIV/AIDS has become a chronic disease and patients do live a normal life , the coinfection with HCV represents a big challenge. When not treated and in the presence of HIV, HCV leads to a increased progression of liver failure and/or hepatoma and eventually death.

Medscape: You have been involved in several studies that have looked at incidence and management of antiretroviral toxicities. Some of the antiretrovirals that are used to treat HIV, such as the protease inhibitor (PI) ritonavir and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, are known to be hepatotoxic even among HIV-monoinfected patients. How do the specific concerns with PIs vs NNRTIs differ in regard to hepatotoxicity in coinfected patients?

Dr. Greiger: Actually, I have done quite a few studies on hepatitis C and PI treatment; I started with nelfinavir years ago and I have a recent one on Kaletra [lopinavir/ritonavir]. In the HCV-coinfected patients [at my clinic], we really don't see that much higher incidence of liver toxicity. In that respect, we have to think that ritonavir in the past years was used at a high dose; now we're talking about ritonavir used as a booster for the other PI. So the incidence of hepatotoxicity is much, much lower. Obviously when you have a patient who has underlying liver disease, you follow up closely, and if you see any abnormality you jump on it, but it doesn't prevent one from using PIs.

With respect to the NNRTIs, we have seen a lot of hepatotoxicity with nevirapine, especially in women with an elevated CD4+ cell count. In fact, it is now recommended that nevirapine should be avoided in women with CD4+ cell counts > 250 cells/microliter (mcL) and in men with CD4+ cell counts > 400 cells/mcL.[1] As I have said before, everything has to be done judiciously and followed closely.

Medscape: What about the NRTI (nucleoside reverse transcriptase inhibitor) class? Almost all medications in that class carry a black-box warning that includes lactic acidosis with hepatic steatosis as one of the major, albeit rare, toxicities of concern. What are particular management issues relating to specific NRTIs that clinicians should be aware of when treating their coinfected patients?

Dr. Greiger: Well, the major NRTI that was causing lactic acidosis was d4T [stavudine]; nevertheless we have seen it with AZT [zidovudine] too -- the thymidine analogs in the NRTI class. Now stavudine is not used as frequently because of these side effects. Although it's a potent drug you have to be very careful using it. And now, in the day of the once-a-day regimen, we all try not to use twice-a-day medication, there are fewer opportunities to use this drug.

When you are treating both the HIV and the HCV, you have to educate the patient very well, because the treatment has many side effects, some intolerable to the patients. Also you should be aware of all pharmacologic interactions and adjust accordingly. For example, zidovudine and ribavirin both cause bone marrow suppression, and the patient becomes quickly anemic when both are used together,[2] so you have to be careful. On the other hand, we are learning more about how to manage the adverse effects of ribavirin by using erythropoietin.[3,4]

Medscape: There were some new data presented at this year's IAS meeting with respect to hepatotoxicity or lack thereof with some antiretrovirals. Can you give us a summary of some of that new data?

Dr. Greiger: Yes. There was a study by Dr. Edwin DeJesus[5] on Lexiva (fosamprenavir/ritonavir), and his data are the same as mine with lopinavir/ritonavir -- meaning that you have to be careful, but that hepatotoxicity is not very elevated in patients treated with a ritonavir-boosted PI. This report was a substudy of the SOLO study, and it compared liver enzyme changes in patients without hepatitis with those with either hepatitis B or hepatitis C virus infection. Not surprisingly, baseline ALT [alanine aminotransferase] and AST [aspartate aminotransferase] were higher for patients with HIV-hepatitis virus coinfection. However, after 120 weeks of follow-up, there was a mean decrease in ALT and AST in all groups. In another study from Italy, Torti and colleagues[6] also found that single or ritonavir-boosted PIs were not associated with a higher risk for toxicity. In this study, treatment-experienced patients prescribed NNRTIs (either nevirapine or efavirenz) had a higher risk for relevant hepatotoxicity than those prescribed either single or multiple protease inhibitor-based regimens. However, it should also be noted that there is, in general, a higher risk for hepatotoxicity with nevirapine compared with efavirenz among patients with CD4+ cell counts > 250 cells/mcL.

Medscape: Were there any data on NRTIs?

Dr. Greiger: We go back to the SOLO study,[7] in which they also didn't see a lot of hepatotoxicity in patients who were treated either with Lexiva or nelfinavir with the backbone abacavir and lamivudine (3TC). At this meeting, Zhao and coworkers[8] looked more specifically at adverse effects in HBV- or HCV-coinfected patients from 4 large clinical trials. They found that lamivudine/abacavir was equally well tolerated in patients with or without hepatitis coinfection.

Medscape: For antiretroviral-treated coinfected patients who experience liver toxicity, what is your basic treatment algorithm? Do you replace the offending agent and modify dosage?

Dr. Greiger: When it's possible I modify the agent, but it's not always possible -- especially in the heavily treatment-experienced patient.

Medscape: Outside of this meeting, what are the most important issues related to toxicity management in coinfected patients that have been reported in the last few months?

Dr. Greiger: There have been many studies that have looked at toxicity in coinfected patients, but the conclusion is basically the same: You have to be careful, follow the patient closely, and act quickly [upon detection of significant toxicities].

Medscape: Are there any special issues that you've observed in terms of the danger of hepatotoxicity in the context of alcohol abuse or stage of fibrosis?

Dr. Greiger: Anything that can damage the liver further is going to aggravate the HCV, and we know that HIV increases the progression of HCV. Ideally, we should try to treat the hepatitis C first, when possible, and later treat the patient with antiretrovirals.

Medscape: Turning again to this meeting, treatment of HCV has been characterized by multiple challenges, including the difficulty in treating certain genotypes and the challenge of HIV/HCV coinfection. Were there any new data at this meeting that better informed clinicians about the treatment of hepatitis C?

Dr. Greiger: Yes; there were quite a few special results with the APRICOT [AIDS Pegasys Ribavirin International Coinfection Trial] study in which I was one of the coinvestigators. The APRICOT trial, which was originally published last year, in 2004, showed that sustained virologic responses (SVRs) could be achieved in 40% of HIV/HCV-coinfected patients who were treated with pegylated interferon plus ribavirin for 48 weeks.[9] As you know, in the United States we have mainly a genotype, HCV genotype 1, which is not too susceptible to therapy. But the results of the APRICOT study were fairly good, I think. SVR rates for genotype 1 were 29% compared with 62% for genotypes 2 and 3. At this meeting, Soriano[10] presented data from the APRICOT study that showed a 38% response rate (SVR) in patients with genotype 4 HCV infection, and Sulkowski[11] presented data that documented that adverse events compromised the treatment of HCV, resulting in lower SVRs.

And in patients who remain in the study, interferon also might have had a small impact on the sustained viral replication capacity and overall health. We've used interferon in the past, too, and we know that it had a little impact on the virus, but not a lot -- not enough to use as an antiretroviral, however.

Medscape: As a person with extensive experience in treating patients coinfected with HIV and hepatitis virus(es), what final piece of advice would you like to share with people who are less experienced? What might they find confusing in terms of clinical decisions?

Dr. Greiger: I think there is a question that physicians ask themselves: Should I treat the hepatitis C first or treat the HIV first? Ideally you should treat the hepatitis C first but "ideally" is not in the everyday world. So if you can, yes -- you treat the HCV first and then you treat the HIV, but in most cases I do treat both at the same time. If the patient is at a stage where treatment is needed, HAART should not be postponed.

Finally, you have to be careful and be aware of the immune reconstitution syndrome. So if you have a patient who has coinfection (and in general I'm talking about HCV more than HBV, because HBV is less common), you might see a transient aggravation of the hepatitis because the patient is doing better on the drugs, his immune system is stronger, and that's the immune reconstitution syndrome. There is no treatment; it's transient and it goes away, but you have to be aware of it.

Erratum: Dr. Greiger's original interview transcript incorrectly reported results of the Torti study on hepatotoxicity of NNRTIs. The original text stated: "Torti and colleagues also found that single or ritonavir-boosted PIs were not associated with a higher risk for toxicity, but that the risk for hepatotoxicity was higher with nevirapine than with efavirenz. "In fact, the study did not show a difference between efavirenz and nevirapine, but did show a difference between NNRTIs and PIs (either single or ritonavir-boosted). The corrected text, which appears in the report above, states: "In this study, treatment-experienced patients prescribed NNRTIs (either nevirapine or efavirenz) had a higher risk for relevant hepatotoxicity than those prescribed either single or multiple protease inhibitor-based regimens. However, it should also be noted that there is, in general, a higher risk for hepatotoxicity with nevirapine compared with efavirenz among patients with CD4+ cell counts > 250 cells/mcL."