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TheBody.com/The Body PRO Covers The 48th Annual ICAAC/IDSA 46th Annual Meeting

New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology

Highlights From ICAAC/IDSA 2008

February 25, 2009

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Note: This CME/CE activity expired on Feb. 25, 2010. For a list of currently available activities, click here.


Introduction

Daniel Fierer, M.D.
Daniel Fierer, M.D.

Hepatitis C (HCV) coinfection has become an increasingly important topic as morbidity and mortality from liver disease appear to be increasing among HIV-infected patients despite their living longer and doing better from an HIV standpoint. There has been much investigation of late into the factors causing liver disease, new treatments, treatment approaches with the old drugs and the changing epidemiology of new infections, and most scientific meetings topical for HIV infection contain interesting developments in hepatitis C coinfection.

ICAAC/IDSA 2008 (the 48th Annual ICAAC/IDSA 46th Annual Meeting) was an enormous combined meeting, but as it was mostly about microbiology, there weren't many posters or talks devoted to hepatitis C in HIV-infected people. That said, there were a number of interesting posters and presentations focusing on HIV/HCV coinfection that are worth discussing.


Early Nonresponse and Cessation of Anti-HCV Therapy

HCV in the HIV-Infected Patient: Case Study, 56-Year-Old Caucasian Male With HIV and Hepatitis C
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The meeting started with an interactive symposium. David Thomas, M.D., M.P.H., from Johns Hopkins University began his overview with a case presentation.1 He presented the case of an HIV long-term nonprogressor who also had been infected with HCV for a number of years. Dr. Thomas pointed out that about six years prior to his current presentation, the patient had a biopsy that showed essentially no fibrosis or inflammation. However, the patient returned six or seven years later for a serologic test, the result of which suggested an F3 or F4 stage of fibrosis. (Dr. Thomas has pointed out in a few of his recent discussions that fibrosis progression in HIV-infected patients may be variable and can be quite rapid.)

The patient then was initiated on traditional HCV treatment with pegylated interferon (Pegasys, Peginterferon, PEG-Intron) and ribavirin (Copegus, Rebetol) treatment.1 He experienced what is considered an early virologic response: more than a 2-log10 drop in HCV viremia by 12 weeks. However, he was never able to achieve an undetectable HCV viral load; at 24 weeks, his reduction in HCV viral load had slowed, and was now at 3.42 log IU. This raised the inevitable question: Should HCV treatment be continued?

To answer this question, Dr. Thomas referred his audience to an important study: ACTG 5178, also called the SLAM-C study.2 In SLAM-C, patients who did not have an early virological response to HCV therapy were randomized to either continue or discontinue their interferon and ribavirin treatment.

HCV in the HIV-Infected Patient: ACTG 5178 No Benefit of Maintenance
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At 72 weeks, there was no difference in outcome between the patients who continued or the patients who had discontinued. This was quite a sobering finding; many of us had hoped there would be benefits from continuing the interferon, both from a histological standpoint and in terms of clinical outcome.

Thus, the upshot of SLAM-C is that HCV treatment continuation would likely be unwise in the case of Dr. Thomas's patient. Given that the patient had a creatinine level of 1.0 (normal), an ALT (alanine transaminase) level of 74 units/L (slightly above normal) and an international normalized ratio of 1.0 (normal) at HCV treatment discontinuation, Dr. Thomas suggested that the best course of action at this stage would be to hold off on further therapeutic interventions and refer the patient for counseling to prevent secondary transmission of HCV.


Balancing Antiretroviral Therapy and HCV Therapy: Drug Interactions

During his presentation, Dr. Thomas also discussed important antiretroviral management strategies to employ during hepatitis C treatment. He reminded us that didanosine (ddI, Videx) should not be used concurrently with ribavirin treatment due to significant toxicity.3 Zidovudine (AZT, Retrovir) should probably be avoided as well, due to the anemia that can emerge when the drug is taken concurrently with ribavirin.4

In addition, Dr. Thomas mentioned two observational studies (which have, to my knowledge, not yet been published) suggesting that concurrent abacavir (ABC, Ziagen) treatment was associated with a worse prognosis for hepatitis C treatment.5,6

However, at ICAAC/IDSA 2008, Rohit Talwani et al presented a study that did not see an indication that abacavir use adversely impacted hepatitis C treatment.7

Ritonavir-Boosted PI Not Abacavir Adversely Impacts HCV Treatment: Treatment Response by Regimen Type (n = 27)
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In this trial, 27 HIV/HCV-coinfected patients who were receiving antiretroviral therapy that included abacavir were examined. Specifically, no significant differences between the patients who received or did not receive abacavir as part of their ARV (antiretroviral) backbone were found.

Dr. Talwani did find, however, that there was a significantly worse outcome in terms of sustained virological response among patients who were taking ritonavir (RTV, Norvir)-boosted regimens compared to those who were on antiretroviral regimens that did not contain ritonavir.

At the same time, no difference was seen based on whether patients received a PI (protease inhibitor)-based regimen; therefore, the researchers felt the results potentially implicated ritonavir-boosted regimens in particular.

This study is small and observational, so it needs to be repeated with a larger patient sample before we can truly take its findings to heart. But these observations drive home the need for a large, randomized study to establish which antiretrovirals are the best choices for HIV/HCV-coinfected patients who are being concurrently treated for their chronic hepatitis C coinfection.

Resolving this issue becomes especially important if abacavir, didanosine and zidovudine cannot be used. Although currently a highly popular choice are regimens based on tenofovir/emtricitabine (TDF/FTC, Truvada), that's still a restrictive formulary for use in our patients.


Balancing Antiretroviral Therapy and HCV Therapy: Complications of Treatment

One of the recurring issues debated when attempting to decide whether to begin HCV treatment in HIV/HCV-coinfected patients is whether the toxicity of interferon and ribavirin treatment outweighs the benefits of therapy. If we had effective medication that was non-toxic, everyone would be treated for HCV sooner. It's a similar situation to what had long been the case with antiretrovirals, except that HCV treatment is even more significantly toxic than what we saw in the early days of antiretrovirals.

In particular, neutropenia and anemia are often cited as treatment-limiting toxicities in patients who may otherwise be prime candidates for HCV treatment.

Interferon is clearly associated with significant neutropenia, as well as a decline in CD4+ cell count (sometimes to below 200 copies/mL), which dramatically increases a patient's risk for developing comorbidities. When this occurs in one of our patients, the question inevitably comes up as to whether treatment should be discontinued entirely or simply modified.

Infectious Complications During Peg-IFN Plus Ribavirin in HIV-Infected Patients With Chronic Hepatitis C: Patients and Methods
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In hopes of addressing this question, Ana Moreno and colleagues from Hospital Ramón y Cajal in Madrid, Spain, conducted a prospective, nonrandomized study of 174 HIV/HCV-coinfected patients who initiated therapy for chronic HCV between January 2001 and March 2006.8 All patients received a weight-adjusted dose of ribavirin along with either peginterferon alfa-2a or peginterferon alfa-2b. The primary goal of the study was to assess the incidence of infectious complications among this patient population.

Infectious Complications During Peg-IFN Plus Ribavirin in HIV-Infected Patients With Chronic Hepatitis C: Results
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Moreno et al found that during the course of their HCV treatment, infectious complications were common: 84 patients, or 48% of the population, experienced a total of 117 infections. In most cases (54 out of 174 patients, or 31%), these infections occurred in the respiratory tract. On the plus side, however, the researchers saw no significant opportunistic infections and no irreversible infections.

Fifty-one of the patients, or 29%, experienced grade 3 to 4 neutropenia, a complication that, if I saw it in one of my own patients, would cause me to become significantly concerned. However, Dr. Moreno noted no difference in the rate of infectious complications between patients who became significantly neutropenic and those who did not.

Perhaps even more importantly, there was no significant difference in the infection rate between patients whose CD4+ cell counts dropped below 200 cells/mm3 and those whose CD4+ cell counts remained higher. (Interestingly, the researchers used granulocyte-colony stimulating factor [G-CSF] to treat 30 of their 51 severely neutropenic patients, but they did not discontinue interferon in any of them.)

All things considered, I think that this study is reassuring. Although it's not clear that we really need to use G-CSF in patients who have significant neutropenia, it is comforting to see evidence that we are not likely to induce opportunistic infections with HCV therapy.


Balancing Antiretroviral Therapy and HCV Therapy: Treatment at Higher CD4+ Cell Counts

As the HIV treatment pendulum swings toward earlier ART (antiretroviral therapy) initiation,9 we increasingly face the question regarding how to manage HIV treatment in our HIV/HCV-coinfected patients.

If a patient has a high enough CD4+ cell count that HIV treatment can wait, should we begin ART anyway before commencing HCV therapy? After all, an important observation about HCV disease progression in HIV/HCV-coinfected patients is that patients with AIDS or a very low CD4+ cell count appear to progress more quickly in their HCV disease than patients with much better-controlled HIV infection who are taking antiretroviral therapy. Do the protective effects of ART on HCV progression extend to people with higher CD4+ cell counts as well?

There was an interesting Spanish study presented at ICAAC/IDSA 2008 that addressed this issue by focusing on the incidence of hepatic necroinflammatory activity in patients with a high CD4+ cell count.10

HAART Is Associated With a Lower Level of Hepatic Necroinflammatory Activity: Characteristics of Study Population
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J. F. Pascual Pareja and colleagues from Hospital La Paz in Madrid, Spain, performed liver biopsies on 119 HIV/HCV-coinfected patients who had a CD4+ cell count greater than 350 cells/mm3 at the time of their biopsy.

Of this group, 93 of the patients (78%) were receiving antiretrovirals; 60% of study participants had an HIV viral load below 400 copies/mL at the time of their biopsy, and 48% had a prior AIDS diagnosis. Of the 26 patients who were not receiving antiretrovirals, 19 were antiretroviral naive; the remaining seven patients had interrupted their therapy for a median of 106 weeks before their biopsy.

HAART Is Associated With a Lower Level of Hepatic Necroinflammatory Activity: Factors Associated With Necroinflammatory Activity ≥ 3
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The researchers found that necroinflammation in patients who were not receiving antiretrovirals was much higher than in patients who were receiving antiretrovirals. Thirty patients (25%) had a necroinflammatory score of greater than or equal to 3 (out of 4). These patients were significantly less likely to be receiving antiretrovirals than patients with a necroinflammatory score of less than 3 (67% versus 82%, P = .024). In addition, the patients with higher inflammation scores had much more scarring, or fibrosis, than patients with lower scores (77% versus 5%, P < .001).

The association between inflammation and fibrosis progression is known. But what I do not believe has been described before was the possibility that having a high CD4+ cell count and being off antiretrovirals may lead to more rapid HCV progression.10 This needs to be investigated further, but if it holds up to further study, it might add yet another weight to the scales in favor of starting ARVs at a somewhat higher CD4+ cell count in HIV/HCV-coinfected patients.


Why Are So Many HIV/HCV-Coinfected Patients Deferring HCV Therapy?

Because the drug toxicities associated with interferon treatment may be severe, many chronically infected patients (or their physicians) are reluctant to begin HCV treatment.

In addition, there is a broad category known as "contraindications" to HCV treatment listed in official treatment guidelines.11 Some of the diseases make treatment very risky, for instance decompensated liver cirrhosis and perhaps severe lung disease. This list of contraindications, however, may have become something of a wastebasket over time, since it also includes such things as anemia and substance abuse, which unless incapacitating, most experienced HCV-treaters do not consider significant barriers to treatment.

Thus, before deciding on HCV treatment, patients and their providers weigh the relative risks of toxicities and contraindications, so that they can come to an educated decision about whether the benefits of initiating therapy outweigh the potential dangers.

A large proportion of patients with HIV/HCV coinfection end up deciding against HCV treatment.

To find out why most HIV/HCV-coinfected patients defer HCV treatment, and just how common an occurrence is this deferral, Adeel Butt, M.D., et al conducted a systematic examination of HCV-infected individuals in U.S. Veterans Affairs National Patient Care Database.12

The researchers identified 1,225 HIV/HCV-coinfected patients on whom there was enough clinical information to make a determination as to why those patients may not have gotten treated and compared them to 27,452 patients who were HCV monoinfected.

HCV Treatment Eligibility in ERCHIVES: Characteristics of HCV and HCV/HIV-Coinfected Subjects With and Without HCV RNA Availability
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This was an almost entirely male cohort; the mean age of the coinfected patients was 48.6 years, while the mean age of the monoinfected patients was 50.5. Many of the coinfected patients had significant comorbidities, including anemia, decompensated liver disease and serious lung disease.

HCV Treatment Eligibility in ERCHIVES:.Flowchart of Treatment Eligibility and Contraindications in the HCV/HIV-.Coinfected Subjects
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Only 28.4% of HIV/HCV-coinfected patients in the cohort had no contraindications to HCV treatment as per current treatment guidelines. (By comparison, 43.8% of HCV-monoinfected patients had no contraindications to HCV treatment.)

Anemia was by far the most common contraindication among coinfected patients, at 43.2%, followed by decompensated liver disease (29%), renal failure (19.8%) and recent drug use (14.1%), which was defined as having one inpatient admission for which drug use was the primary reason, or as having visited a drug rehabilitation clinic two or more times since 12 months prior to entering the cohort.

As if the 28.4% treatment eligibility figure wasn't bad enough, Butt et al found that, in the end, only 15% of the HIV/HCV-coinfected patients received any treatment for HCV. That was compared to 23% of those who only had HCV.

Low HCV Treatment Rates After a Liver Biopsy: Liver Biopsy Findings Batts-Ludwig Scale F0-F4 (n = 163)
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Another interesting way to look at rates of HCV treatment in patients who are eligible for it was a retrospective study presented by Oluwatoyin Adeyemi, M.D., and colleagues in Chicago, Ill.13 They performed liver biopsies on 163 patients at Chicago's CORE Center who were infected with HCV genotype 1, 83 of whom also had HIV infection. This was a predominantly male (75%), majority African-American (63%) cohort. Although 58% of patients' liver biopsies revealed significant fibrosis (F2 or greater), only 37% of patients who received liver biopsies ultimately received HCV therapy.

Adeyemi et al did not break down all of their figures to compare HIV-infected patients to those without HIV infection, but the findings are still fairly bleak: All of these patients had HCV disease that had progressed far enough to warrant a liver biopsy, and yet only approximately one third of them received HCV treatment.

Low HCV Treatment Rates After a Liver Biopsy: Predictors of HCV Treatment Post-Liver Biopsy
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The likelihood of treatment by degree of fibrosis was then examined. Reasonably, study patients with less fibrosis (F0 or F1) were less likely to be treated for HCV; 22% of these patients received HCV therapy. However, the treatment rate among patients with F2 or greater fibrosis, though significantly higher, was still just 49%.

Race and sex appeared to play a significant role: Men were less likely than women to receive HCV treatment (32% versus 50%, P = .05), and African Americans were less likely to receive HCV treatment than the rest of the study population (27% versus 50%, P = .01).

Low HCV Treatment Rates After a Liver Biopsy: Reasons for Non-Treatment Post-Liver Biopsy
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Other common reasons for not receiving HCV therapy included simply refusing treatment and being lost to follow-up.

Interestingly, among patients with F2 or greater fibrosis, HIV-infected patients were much more likely to refuse treatment than their HIV-uninfected counterparts (57% versus 27%), but much less likely to be lost to follow-up (23% versus 59%).

In other words, we're keeping HIV-infected patients in care, but are apparently having difficulty convincing them that treatment for their HCV is a good idea, thus adding another layer to the difficulties that we have in curing our patients of hepatitis C infection. Then we have the other barriers to treatment thrown in: significant medical illness and specifically, very advanced liver disease due to the HCV infection itself. This problem, combined with the significant toxicity of the treatment and the poor success (sustained virological response or SVR) rate in HIV/HCV-coinfected patients would certainly explain why few patients are being treated.

Yet morbidity and mortality from HCV-related liver disease are a big problem. How do we solve this problem? Well, we have no hope of interferon-less therapy in the next decade so the toxicity problem is fixed for the foreseeable future, instead we might have to rethink when to treat. The one fixable problem in this bunch would be to treat before people get so sick. In taking a "watchful waiting" approach in those who are perceived or proved to have little liver disease, we face the problem that Dr. Thomas discussed in his talk that the rate of progression can be variable but very fast, going from no apparent fibrosis to cirrhosis in just a few years.1 And the success rate of treatment decreases with increasing fibrosis so waiting decreases treatment success. We seem therefore to be caught between Scylla and Charybdis, deferring therapy when there is little fibrosis due to the toxicity of treatment only to have the treatment success diminished or contraindicated altogether in patients who really need it. Perhaps we should consider reviving the ARV mantra of the mid-90s, "hit early, hit hard" for HCV infection.


Chronic HCV Treatment With High-Dose Ribavirin, Erythropoietin

For the relatively small percentage of HIV/HCV-coinfected patients who do get treated for HCV, there were some interesting posters presented at ICAAC/IDSA 2008 regarding optimal strategies for HCV treatment.

In one study, Vicente Soriano from Hospital Carlos III in Madrid, Spain, along with colleagues from the multicenter PERICO study, examined whether the administration of high-dose ribavirin to HIV/HCV-coinfected patients during the first month of HCV treatment could enhance the rate of rapid virological response, defined as an undetectable hepatitis C viral load by four weeks of treatment.14 This kind of response has been highly associated with a sustained virological response.

Low ribavirin levels in the blood have been associated with a worse treatment outcome. Previous studies have attempted to increase the ribavirin dose in hopes of improving treatment outcomes, but this has resulted in an increase in toxicity (especially anemia).

In the study by Soriano et al, 149 patients were randomized to receive either 2,000 mg per day of ribavirin or a standard, weight-based dose of ribavirin (which generally ranges from 1,000 mg to 1,200 mg).14 Both arms also received 180 µg per week of peginterferon alfa-2a and, in hopes of curbing the incidence of anemia, a pre-emptive dose of erythropoietin at 30,000 IU per week during the first four weeks of HCV therapy.

PERICO: Main Results at Week 4 of Hepatitis C Therapy According to Treatment Arm
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The results were somewhat disappointing. Rapid virologic response rates in the high-dose ribavirin group were not noted to be superior to the standard-dose ribavirin group; 22% of patients in each arm achieved rapid virologic response. This was in contrast to a previously published study (in which erythropoietin was not used) that suggested rapid virological response was better among patients who received high-dose ribavirin.

Anemia incidence did not differ significantly between the two study arms either; two of 74 patients in the high-dose ribavirin arm compared to four of 75 patients in the standard-dose arm developed severe anemia by week four (P = .4).14 There was, however, a statistically significant difference in mean hemoglobin levels at week 4 -- in favor of the high-dose ribavirin arm. Four-week hemoglobin averaged 13.4 g/dL in the high-dose arm versus 12.7 g/dL in the standard-dose arm (P = .04).

Nonetheless, the rapid virologic response findings were underwhelming. Soriano et al hypothesized that the reason for the lack of rapid response in the high-dose ribavirin arm may actually have been due to the erythropoietin: They posited that the patients' resulting regeneration of red blood cells may have led to absorption of the higher ribavirin dose, therefore neutralizing the effect. However, there is currently no evidence to support that explanation.

Where we should leave this idea for now is that while it seems attractive to administer higher doses of ribavirin in the early weeks of hepatitis C treatment to improve rapid virologic response rates, the practice should still be considered experimental.


The (Dim) Future of Anti-HCV Therapy

New HCV Drugs in the Pipeline:.Sustained Virological Response in Subgroups of Interest
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There are two currently available pegylated interferon products: peginterferon alfa-2a and peginterferon alfa-2b. Head-to-head comparisons between the two have been relatively few and far between; however, during a symposium presentation at ICAAC/IDSA 2008, Mark Sulkowski, M.D.,15 described a large trial (with more than 1,000 patients) in which patients were randomized to one of the two agents. Reassuringly, no difference was seen in any clinical outcome between these two agents.

Does the Choice of peg-IFN Formulation Affect Safety or Efficacy in HIV/HCV-Coinfected Patients Receiving Weight-Adjusted Ribavirin?: Overall Outcomes According to peg-IFN Formulation
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Similar findings, although on a much smaller scale, were also described in a poster presented by Ana Moreno and colleagues.16 (Dr. Moreno had also presented a poster on neutropenia, which I summarized earlier in this article.8) In their retrospective study, Dr. Moreno et al administered the alfa-2a preparation to 93 patients and the alfa-2b preparation to 81 patients.16 No differences in early or sustained virological response were seen between the two arms, nor did they note any difference in terms of toxicity.

The fact remains, however, as mentioned previously, that existing HCV therapy is far from optimal. In his symposium at ICAAC/IDSA 2008, Dr. Sulkowski emphasized that our 2008 goal for HCV treatment is viral eradication.15 (This goal is clearly not as realistic as our 2008 goal for HIV therapy, which is to help everyone on HIV treatment attain an undetectable viral load and which we need to aspire to with HCV as well.)

However, from a simple review of the two studies comparing existing peginterferon products,15,16 we can see that the overall rate of virological eradication using currently approved HCV treatments is quite low. Although there have been some improvements over the years with pegylated interferon and ribavirin, sustained virological response rates in HIV-infected patients are still, at best, in the 40% range, which is inadequate.

Although the goal in HCV medicine is the development of new agents that would enable us to achieve 100% eradication,15 or at least get close, unfortunately, the reality of what's in the current HCV pipeline only drives home the point that this target is clearly a long way off.

New HCV Drugs in the Pipeline: Multiple Direct Antiviral Agents Have Entered Clinical Development
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Drugs in the HCV treatment pipeline include protease inhibitors and polymerase inhibitors, both of which follow basic mechanisms that we're very familiar with in the context of HIV treatment. There are, however, only two protease inhibitors in advanced clinical trials for HCV therapy: telaprevir and boceprevir. Neither is an ideal candidate: They both require dosing multiple times a day (there are a few protease inhibitors coming along that have perhaps once-a-day dosing, but they are, at best, in the very early stages of development). Moreover, these agents also have significant side effects. In addition, they have thus far only been tested to a significant extent in HIV-uninfected people, so we really do not know what the response will be in HIV/HCV-coinfected people. However, we know that even in people who do not have HIV infection, the rate of response we see with these investigational HCV therapies tends to be only incremental; we have seen no "home runs" providing complete eradication.

As for the polymerase drugs, they too have been plagued by toxicities; many have been pulled from development in very early stages for this reason.

Beyond these two classes of HCV medications, there are a few drugs with novel mechanisms that are in even earlier development, but they are not yet worth summarizing in an overview such as this.

In summary, then, it appears that we will not see approval of any of these products until perhaps 2011, when telaprevir may get its run through the U.S. Food and Drug Administration gauntlet.

However, even when these new agents finally reach the market, their improvement over current therapy will not likely be dramatic. They will likely be tested individually and administered in addition to peginterferon and ribavirin and will not serve as a replacement for them. We may not see a combination of virus-specific (i.e., against specific viral functions) drugs for many years. So, although we should take heart as HCV-treating clinicians that a new generation of HCV therapy is on its way, we are not going to see it anytime soon.


Comorbidities Associated With HCV Infection

Although I've just detailed some of the shortfalls of currently available HCV therapy, we cannot deny that the dangers of HCV itself can be far worse.

SMART*: Primary and Major Secondary End Points
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In fact, there are parallels with HIV. Before "SMART" it was thought that the toxicities of HIV therapy were driving many of the cardiovascular side effects in patients infected only with HIV. Despite the findings that specific antiretrovirals may be associated with cardiovascular disease in some high-risk patients, "SMART" results showed that ART on the whole appears to reduce the risk of cardiovascular complications that HIV itself appears to cause.17

The relationship between HIV and cardiovascular risk may have special ramifications for HIV/HCV-coinfected patients. Although the reasons for HIV's cardiovascular effects have not yet been well delineated, given the high prevalence of HCV coinfection among HIV-infected patients, some wonder whether the possible increase in cardiovascular complications may be due at least in part to HCV coinfection.

Hepatitis C Virus Infection and the Risk of Coronary Disease: Results
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To resolve this question, we first need to determine whether HCV infection can be linked to cardiovascular risk. A very large study was presented by Adeel Butt, M.D.18 (who also presented a study mentioned earlier detailing reasons for HCV therapy deferral12). Dr. Butt's study,18 which was funded by the U.S. National Institutes of Health, was an examination of the records of 82,083 HCV-infected U.S. military veterans compared to 89,582 HCV-uninfected patients. HIV-infected patients were specifically excluded from this study.

Hepatitis C Virus Infection and the Risk of Coronary Disease: Results: Factors Associated With CAD (Multivariable Cox)
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After adjusting for traditional risk factors for coronary artery disease (CAD), Dr. Butt et al found that patients with HCV infection had a 27% increased risk of CAD diagnosis compared to patients without HCV infection during the retrospective study period, which spanned 2001 to 2006. This was despite the finding that hyperlipidemia was marginally less common among HCV-infected patients than HCV-uninfected patients.

So while this study specifically excluded patients with HIV infection, it may be something we really need to watch for. I encourage the authors to go back and analyze their data to look at HIV-infected patients with HCV as well; this is a very powerful cohort that they can use to examine this subject.

HIV Infection and the Risk of Diabetes Mellitus: Baseline Characteristics of HIV-Infected and Uninfected Persons in the Veterans Aging Cohort Study
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HIV Infection and the Risk of Diabetes Mellitus: Baseline Characteristics of HIV-Infected and Uninfected Persons in the Veterans Aging Cohort Study (Continued)
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In yet another study presented by Dr. Butt,19 data from the prospective Veterans Aging Cohort Study was examined to discover other health risk factors associated with HIV status, particularly diabetes mellitus. The records of 3,327 HIV-infected patients were compared to those of 3,240 HIV-uninfected patients. As with most veterans' studies, the population was almost entirely male. The mean age was approximately 50 years old, and about two thirds of the study population was black. HCV infection was far more common among HIV-infected patients than HIV-uninfected patients (31% versus 15%, P < .001).

HIV Infection and the Risk of Diabetes Mellitus: Discussion
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The most important finding of this study was that among HIV-infected patients with HCV coinfection, in a multivariate analysis, the risk of diabetes was increased by 36%; by comparison, among HIV-uninfected patients with HCV, the increased risk was 28%. Interestingly, however, HIV itself was associated with a significantly lower risk of diabetes (14.9% versus 21.4%, P < .001).

Based on these findings, the authors suggested that we as practitioners should be more vigilant for cardiovascular risk factors in patients with HCV infection. Although they offered few specific treatment remedies, we can see that for our HIV/HCV-coinfected patients enhanced surveillance might be the most effective tool, since they already appear to have lower lipid levels than HCV-monoinfected patients.

Of course, it also would be prudent to encourage our patients to stop smoking and try to minimize other risk factors, such as obesity, high blood pressure and lack of exercise.


The Impact of Hepatitis B Vaccination

While we're on the topic of standard-of-care practices for patients with hepatitis C coinfection, there was one study at ICAAC/IDSA 2008 that addressed the importance of vaccination against hepatitis B (HBV) in patients who have chronic hepatitis C infection.

Evangelista Sagnelli, of the Second University of Naples, Italy, and her collaborators performed a small study on HBV superinfection in HCV-infected patients who did not have HIV.20 Twenty-nine patients with chronic HCV who then acquired HBV were compared to 29 patients who did not have chronic HCV and had acute HBV infection.

Strikingly, among the patients who had underlying HCV at the time of their acute HBV infection, one of the patients died due to hepatitis disease progression, and one quickly required liver transplantation. This is a surprisingly severe outcome. In fact, the proportion of people who had severe HBV was much greater in the group who had underlying HCV (34.5% vs. 6.9%, P < .05).

However, something very interesting was observed on the other side of the equation: During the acute phase of HBV infection, all of the HCV-infected patients became HCV aviremic. In fact, six of the 28 HBV/HCV-coinfected patients who survived continued to have an undetectable HCV viral load as far out as six years of follow-up.

While an apparent cure for HCV infection is tantalizing, this "treatment," HBV to cure hepatitis C, would be extreme -- particularly given the coinfected patient who died and the patient who required liver transplantation. Despite the high proportion of cases of hepatitis C that were cured, this demonstration of the high morbidity and mortality from acute hepatitis B infection reinforces the recommendation to vaccinate hepatitis B-naive patients who have chronic hepatitis C: bottom line, preventing acute HBV is the prudent course.


New Findings in HCV Epidemiology

Finally, let's turn our attention away from the clinical management of HCV to focus briefly on the changing epidemiology of HCV infection.

At ICAAC/IDSA 2008, Santiago Moreno, of the Hospital Ramón y Cajal in Madrid, Spain, and colleagues looked at two Spanish cohorts to establish the prevalence of HCV over time.21 In total, 5,170 HIV-infected patients joined their cohort from 1997 through 2006. The researchers observed that HCV prevalence in their cohort was almost 71% among those who entered the cohort in 1997, but was only 16% among those who entered in 2006.

Sharp Decline in the Seroprevalence of Hepatitis C Virus Among HIV-Infected Patients in Spain: Baseline Characteristics
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Moreno et al attribute this large decrease in HCV prevalence to the changing routes of HIV acquisition: Earlier entrants into the cohort had likely become HIV infected predominantly through injection drug use (IDU). The more recent entrants, however, had become HIV infected predominantly through sexual transmission (IDU prevalence was 67% in 1997 versus 15% in 2006).

The authors didn't specifically present the proportion of heterosexual versus homosexual HIV transmissions in this study, but they make the case that the decline in HCV prevalence was because the risk of becoming infected with HCV sexually is so much lower than becoming infected via needle sharing.

While this is a strongly optimistic note that there are fewer HCV transmissions occurring now thanks to less injection drug use, I have to add a strong cautionary note.

Outbreaks of sexually transmitted HCV have been reported among men who have sex with men (MSM) across other Western European cities over the last few years.22 Some of those reports suggest an incidence rate that actually approached that seen in earlier years during which time injection drug use was the primary mode of HCV transmission.

There has been relatively little information about this phenomenon in the United States. However, my group at Mt. Sinai has been investigating an outbreak of HCV among MSM in Manhattan.23 Some of that work I presented at the ICAAC/IDSA 2008 meeting.24

Acute Hepatitis C: Management and New Epidemiology: Risk Factors for Acute HCV: Case-Control Study
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We performed a case-controlled study of 21 HIV-infected patients with acute HCV and 21 age-matched, HIV-infected MSM who did not have HCV. We found that unprotected, receptive anal and oral sex were associated with acute HCV infection (P = .04 and P = .03, respectively), while those same acts using a condom or insertive anal and oral sex were not. In addition, MSM who reported having "sex while high" were significantly more likely to have acute HCV (P = .01), although the only specific drug that was found to be associated with HCV infection was marijuana (this finding I cannot explain physiologically).

Acute Hepatitis C: Management and New Epidemiology: Fibrosis During Acute HCV Infection in HIV-Positive Men
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The truly alarming finding in our study, however, was that out of 20 HIV-infected patients with acute hepatitis C who underwent liver biopsy a median of four months after detection of the HCV, 17 had stage 2 (out of 4) fibrosis. This was observed as early as three weeks after the first elevation in ALT. In some patients this was observed a year or two years after their initial diagnosis, suggesting that this was not a transient phenomenon: This fibrosis does persist. These finds suggest a much more accelerated course than what has traditionally been thought to occur.

The good news was that in 10 of our patients who were treated during the acute phase, eight had a sustained virological response. This rate compares favorably to the overall 64% that were reported from the general European cohort at the 2008 Conference on Retroviruses and Opportunistic Infections.25

Although this is a great success rate compared to the treatment success rate we typically see in chronic HCV (30% or 40%), it is still a long way off from the 100% that I think we need to achieve.15 That's particularly important in this cohort, given that they almost uniformly have moderately advanced liver disease early in their infection;24 we have to be very concerned about an even more accelerated disease course in patients who are not cured of their HCV infection.

Acute Hepatitis C: Management and New Epidemiology: Acute HCV Infection of HIV-Positive Men Who Have Sex With Men (MSM): Conclusions
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Finally, from our findings,23 as well as those across Europe,22 we have to consider that HIV-infected men are, in fact, a new risk group for acquiring HCV. Very close surveillance should be done to make sure we don't miss this typically asymptomatic disease. I also believe that HIV treatment guidelines should be changed to include HCV antibody testing for HIV-infected MSM at least once every year.

In addition, once we recognize that HIV-infected MSM are at significant risk for becoming HCV infected, we have to be vigilant for new increases in their liver function tests. In our experience, those increases have been frequently attributed to their antiretroviral therapy, when in fact the patients turned out to have HCV infection. So a greater degree of suspicion is very important to ensure that we make an early diagnosis and get these patients into HCV treatment -- without necessarily stopping antiretrovirals. (As far as we have seen, and as the study I reviewed earlier suggests,11 interrupting treatment has been associated with worse HCV outcomes.) Be vigilant for hepatitis C in this new risk group; it will increase your ability to prevent significant liver disease and make the correct management decisions.


Conclusion

In summary, ICAAC/IDSA 2008 continues the theme set at previous conferences, which is that there is still no home-run treatment for HCV in our HIV/HCV-coinfected patients that will be available in the near future. For the foreseeable future, we will remain stuck with the same interferon- and ribavirin-based treatment, and the same suboptimal response rate.1,2

New drugs dangle tantalizingly on the horizon, but they have not yet been investigated in HIV-infected patients.15 The complications of interferon-based therapy are well known and increasingly well documented,3-8,18,19 leading us to look forward to treatments that are less toxic -- but, again, not in the near future. We also heard a little bit more about the changing epidemiology of HCV infection,21-25 which provides a reminder that we must remain vigilant so we may detect this coinfection early in HIV-infected MSM.


References

  1. Thomas D. Management of patients with HIV-hepatitis C co-infection. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract 849.
  2. Sherman K, Andersen J, Butt A, et al, and ACTG A5178 Study Team. Sustained long-term antiviral maintenance with pegylated interferon in HCV/HIV-co-infected patients: early viral response and effect on fibrosis in treated and control subjects. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 59.
  3. Bani-Sadr F, Lapidus N, Bedossa P, et al, and the French National Agency for Research on AIDS and Viral Hepatitis-HC02-Ribavic Study Team. Progression of fibrosis in HIV and hepatitis C virus-coinfected patients treated with interferon plus ribavirin-based therapy: analysis of risk factors. Clin Infect Dis. March 1, 2008;46(5):768-774.
  4. Bani-Sadr F, Goderel I, Penalba C, et al, and the ANRS HC02 - Ribavic Study Team. Risk factors for anaemia in human immunodeficiency virus/hepatitis C virus-coinfected patients treated with interferon plus ribavirin. J Viral Hepat. September 2007;14(9):639-644.
  5. Bani-Sadr F, Denoeud L, Morand P, et al, and the ANRS HC02 - Ribavic Study Team. Factors associated with virological non-response to peg-interferon + ribavirin therapy in HIV/HCV-co-infected patients: the role of abacavir. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 897.
  6. Mira J, Lopez-Cortes L, Barreiro P, et al. Efficacy of pegylated interferon + ribavirin treatment in HIV/HCV-co-infected patients receiving abacavir + lamivudine or tenofovir + either lamivudine or emtricitabine as nucleoside analogue backbone. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 1074.
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  7. Talwani R, Reisler R, Polk C, Gilliam B, Redfield R. Ritonavir-boosted PI and not abacavir adversely impacts HCV treatment. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1632.
  8. Quereda C, Moreno A, Perez-Elias MJ, et al. Infectious complications during peg-IFN plus ribavirin in HIV-infected patients with chronic hepatitis C (CHC). In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1633.
  9. Kitahata MM, Gange SJ, Moore RD, and the North American AIDS Cohort Collaboration on ReSearch and Design. Initiating rather than deferring HAART at a CD4+ count between 351-500 cells/mm3 is associated with improved survival. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-896b.
  10. Pascual Pareja J, Caminoa A, Larrauri J, et al. HAART is associated with a lower level of hepatic necroinflammatory activity in HIV-HCV coinfected patients with CD4 > 350 at the time of liver biopsy. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-2319.
  11. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis management and treatment of hepatitis C: AASLD practice guidelines [NATAP Web site]. March 22, 2004. Available at: www.natap.org/2004/pdf/AASLD_Prac._Guide_Hep_C.pdf. Accessed January 23, 2009.
  12. Butt AA, McGinnis K, Skanderson M, Justice A. HCV treatment eligibility in ERCHIVES (Electronically Retrieved Cohort of HCV-Infected Veterans). In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1634.
  13. Adeyemi OM, Attar B, Huhn G, Wolen D, Gallagher M, Goldberg R. Low HCV treatment rates after a liver biopsy. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1637.
  14. Soriano V, Vispo E, Portu J, Guardiola JM, and the Perico Study Team. Failure of high ribavirin doses plus pre-emptive erythropoietin along with pegIFN to increase ribavirin plasma exposure and improve rapid virological response in HCV/HIV positive patients. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-2321.
  15. Sulkowski M. New HCV drugs in the pipeline. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract 850.
  16. Moreno A, Quereda C, Perez-Elias MJ, et al. Does the choice of peg-IFN formulation affect safety or efficacy in HIV/HCV-coinfected patients receiving weight-adjusted ribavirin? In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1631.
  17. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. April 15, 2008;197(8):1133-1144.
  18. Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-4219.
  19. Butt AA, McGinnis K, Rodriguez-Barradas M, et al. HIV infection and the risk of diabetes mellitus. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract H-2306.
  20. Sagnelli E, Coppola N, Pisaturo M, et al. HBV superinfection in chronic HCV carriers: clinical and virological long-term follow-up study. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1628.
  21. Perez Cachafeiro S, Garcia L, Berenguer J, et al. Sharp decline in the seroprevalence of hepatitis C virus among HIV-infected patients in Spain. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract V-1629.
  22. Giraudon I, Ruf M, Maguire H, et al. Increase in diagnosed newly acquired hepatitis C in HIV-positive men who have sex with men across London and Brighton, 2002-2006: is this an outbreak? Sex Transm Infect. April 1, 2008;84(2):111-115.
  23. Fierer DS, Uriel AJ, Carriero DC, et al. Liver fibrosis during an outbreak of acute hepatitis C virus infection in HIV-infected men: a prospective cohort study. J Infect Dis. September 1, 2008;198(5):683-686.
  24. Fierer D. Acute hepatitis C: management and new epidemiology. In: Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting; October 25-28, 2008; Washington, D.C. Abstract 851.
  25. Dominguez S, Bhagani S, Vogel M, et al. High rate of sustained virological response to an early course of anti-HCV treatment for acute HCV hepatitis in HIV-positive patients. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 1072.

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