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Editor-in-Chief, HCV Advocate
Session Eight: Management of Treatment for HIV
Dr. Michael Saag, University of Alabama at Birmingham
Dr. Saag opened his session with what he felt were the goals of HIV therapy and how the standard of treatment has evolved over the last couple of decades. He stated that the goals were to prevent clinical disease progression and to prevent/delay development of resistance. The long-term goal of treatment is to get the HIV virus to undetectable levels. When HIV was first identified the treatment strategy that was adopted was to treat early and hit hard as it was thought that this treatment strategy would prevent resistance from developing, preserve immune system integrity and create viral heterogenesis. The problem with this strategy was that is was hard to sustain adherence because it was difficult for patients to tolerate the medications due to toxicity and many wanted to discontinue use prior to meeting treatment goals. At that time the HIV medications that were available did not have an acceptable long-term tolerability profile to warrant such an approach. In addition, the drugs available did not have consistent pharmacokinetic and pharmacodynamic profiles so it was difficult to tailor regimens to be effective as well as tolerable. This approach left patients in a position when they stopped therapy that their immune system had not reconstituted and there was only near suppression of the virus. At the onset of HIV treatment, clinicians would use the HIV viral load as a marker to determine when to start therapy. It was only later determined that in fact the CD4 T-cell count is a better marker for the timing to initiate therapy. Dr. Saag believes that treatment must be initiated prior to the CD4 count being <200 as if the count is lower the probability of a positive result is diminished.
Dr. Saag then went on to discuss how the treatment strategies have also changed considerably. When protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) became available for the treatment of HIV it was believed that every patient should have a certain regimen and there was little individualization of treatment. Now the school of thought in the treatment of HIV according to Dr. Saag is to concentrate on adherence and what the patient is able to tolerate especially as it relates to pill count. Dr. Saag quoted a study that showed that pill count was the largest contributor to lack of adherence. The initial regimen that all patients were treated lasted 1 ½ to 2 years.
Dr. Saag closed by posing a question. As we move forward in the treatment of HIV, what is considered failure in HIV treatment and how can one predict failure?
Session Nine: Management of Treatment for HCV
Dr. Jay Hoofnagle, DDDN, NIDDK, NIH
Dr. Hoofnagle opened his session by discussing the NHANES epidemiological data. He felt that it was a poor representation of HCV statistics in the United States because the prevalence survey was non-institutionalized. What that means is that for the most part it did not capture prevalence data among the poor, IDU’s and prisoners that is thought to represent a large portion of the HCV population.
Usually in Chronic HCV infection HCV-RNA titers range from 104 to 108 copies/ml. Viral load however neither predicts disease severity nor the likelihood of progression to cirrhosis. Dr. Hoofnagle stated that during ESLD HCV-RNA levels actually drop because the liver is no longer able to replicate virus. HCV-RNA titers however, will impact the likelihood of treatment success and therefore should be done along with genotyping and a liver biopsy prior to treatment.
The last NIH HCV consensus conference was held in 1997. Many of the recommendations made are now antiquated and will be updated at a 2002 NIH HCV Conference that will be held June 10th – June 12th 2002.
Dr. Hoofnagle listed special populations that really need to be addressed at the HIH HCV Consensus Conference. These special populations included:
- Patients with renal failure or those on dialysis
- Transplant recipients
- Patients with HIV/HCV coinfection
- Patients with HBV/HCV coinfection
- Patients on public assistance
Dr. Hoofnagle discussed the progression of HCV treatment over the next decade with the most recent Rebetron data that changed treatment duration for Genotype 2 and 3 to 6 months instead of the recommended one-year of therapy for the Genotype 1 patient. He also discussed the controversy of treating low viral load genotype 1 for 6 months even though he agreed that the jury is not out on that recommendation. Genotype 1 high viral load definitely needs to be treated for 1 year or longer. Dr. Hoofnagle briefly discussed utilizing low dose interferon or pegylated interferon for maintenance in those patients that were not able to clear virus during treatment due to histological improvement.
Dr. Hoofnagle introduced the Mann data recently published in the Lancet article on Peg Intron and ribavirin. After presenting the data, Mr. Brian Klein from Hepatitis C Action and Advocacy (HAAC), a patient advocate, pointed out a misinterpretation of the results of the study and cross referenced the Mann data with the Peg Intron /RBV package insert (The FDA’s package insert approved after the agency reviewed all the Mann data). The confusion was over genotype 1 patients who based upon the limited data presented in the Mann article would appear to benefit taking Peg Intron 1.5mg/kg plus RBV versus Rebetron, the current standard of care. After Mr. Klein pointed out that this overall genotype 1 result was swayed by statistical significance over Rebetron only being achieved in the genotype 1 low viral load patient group and there was no statistical significance in the genotype 1 high viral load. The presentation then moved away from pegylated interferon.
[A frustrating part of this presentation and others in general is that the two pegylated interferons are not differentiated. It is not appropriate to present clinical data obtained from one pegylated interferon and translate it into being an outcome expected of both pegylated interferons. The two pegylated interferons are very different and presenting data in this way is confusing to both providers and patients. – editor].
Session Ten: Management of Care and Treatment for HIV/HCV Coinfection
Dr. Lorna Dove, Center for Liver Diseases and Transplantation-Columbia University
Dr. Dove opened her session discussing treatment strategies in the HIV/HCV coinfected patient. To date there is very little data on the treatment of HIV/HCV coinfection and this has led to many physicians unwilling to treat, but instead are referring their patients to clinical trials. Dr. Dove stated that in a HIV/HCV coinfected patient, the development of fibrosis is likely to be accelerated. She prefers the Metavir Fibrosis Index and feels that if a physician waits until a patient has a CD4 count less than 220, then that patient will have a higher risk of progressing to cirrhosis.
Dr. Dove discussed an article published in Hepatology 2000 on a small study that was conducted on HIV/HCV patients that were taking antiretroviral agents including protease inhibitors. This study even though she said was a poor design did yield some interesting results. The reason that Dr. Dove thought that it was a poorly designed study is because there was selection bias, the study was retrospective and if a group of physicians had a strong bias the data could be easily swayed. Protease inhibitors were found not to be dangerous if there was underlying liver disease. She did say however that she cautiously believes that HAART has a positive impact on fibrosis.
Dr. Dove then discussed the goals of therapy. She said that it was too early to tell with the available data if in fact treating HCV improves mortality but the primary goal still should be to eradicate HCV infection. Secondary goals include slowing HCV disease progression, improving histology, reducing the risk of hepatocellular carcinoma (HCC) and improving health related quality of life (QOL).
Dr. Dove felt that the issues of treating an HIV/HCV coinfected patient include medication toxicities, the potential for drug interactions and possible liver biopsy concerns. She followed that by saying that she feels that a liver biopsy should be done in an HIV/HCV coinfected patient just like it would in a patient monoinfected with HCV. In addition Dr. Dove commented that there are issues surrounding a HIV/HCV coinfected patient being able to adhere to therapy due to toxicities including anemia which is not only a risk with having HIV but also can be further exacerbated by ribavirin. Another issue to consider in treating the HIV/HCV coinfected patient is potentially compounding existing depression. Dr. Dove felt that in some cases in the HIV/HCV coinfected patient, monotherapy with interferon would be warranted and in the limited data available SVR achieved is similar to that seen in patients with HCV monoinfection.
Dr. Dove then discussed the limited data that is available treating HIV/HCV coinfected patients with combination therapy (Rebetron). In a small study of 60 patients End of Treatment Results (ETR) at 24 weeks was 30% and 55% at 48 weeks, which is very similar to the results seen in the non-coinfected patients. During combination therapy there seems to be a drop in CD4 count but it returns to pretreatment levels about 6 months after therapy in the majority of the patients. In another small combination trial with HIV/HCV coinfected patients that was presented by Dr. Doug Dieterich from New York the results were as follows:
||Naïve and non-responders
Dr. Dove referred to another small ongoing study with HIV/HCV coinfected patients that were treated with either daily interferon/RBV or three times a week (TIW) Rebetron. In this study there were180 patients and they were randomized to one of the two arms and treated for 48 weeks. In a 12-week interim analysis there were undetectable levels in 35.3% of the daily regimen and 8.1% in the Rebetron regimen. This study still needs to be completed and properly accessed.
The next area that was covered is the complications that can be expected when treating HCV in a HIV/HCV coinfected patient. Such complications include ribavirin-induced anemia that maybe helped by erythropoietin (Procrit). In addition, interferon may decrease CD4 counts that rebound after treatment in most cases but not always therefore during treatment it is important to monitor HIV viral load. There have been no cases though of infections due to the decrease in CD4 count, as the percentage of cells is not changing. Another concern with ribavirin is that it has the potential of raising levels of DDI (Didansoine), which puts the patient at higher risk for lactic acidosis.
Dr. Dove ended her talk by discussing research needs in the HIV/HCV coinfected patient. She feels that we need to have better documented studies to show SVR by genotype as well as appropriate length of treatment so that patients can make informed decisions about appropriateness of treatment for them. Dr. Dove commented on how important it is to do more research to identify the potential complications for treatment of HCV in this coinfected population. The last area that she mentioned is the need to do studies that will help the clinician predict successful outcome of HCV therapy based upon HIV markers like CD4 count and HIV-RNA.
Session Eleven: After Diagnosis: Addressing Barriers to Treatment
Dr. Sharon Stancliff, AIDS Institute, New York
Dr. Stancliff opened her session by listing what she perceives as the main barriers to treatment. The first barrier is economics. Medical insurance companies, public health agencies and patients have to deal with the financial issues around:
- Concerns that therapy is going to break the bank
- The cost of the necessary lab work to determine if treatment is appropriate
- The cost of a liver biopsy
- The cost of clinic visits
- The cost of psychiatric visits
- The additional costs associated with adjunctive therapy to deal with the adverse effects
- ADAP (AIDS Drug Assistance Program) – perceived barrier
What was very interesting is some data that Dr. Stancliff shared on claim costs for HCV treatment in four major states and what percentage these claims were of the overall ADAP prescription spends. The results were as follows:
||0.0023% of total spends
||0.2 – 0.3% (this is equivalent to 30 approvals/month)
Dr. Stancliff believes that ADAP enrollment is driven by desire for HAART therapy not treatment for HCV in the HIV/HCV coinfected patient.
The next area that was discussed was prisons. It is estimated that a third of the patients with chronic HCV may be in prison in a given year. Very few prisoners receive treatment even though guidelines are under development in some states. In the state of Rhode Island a group of prisoners with HCV were screened to determine eligibility for HCV treatment. 60% were excluded because they had 15 months or less until discharge, 30% refused to be treated, 9% had contraindications – drugs/alcohol so only 1% of the patients screened were eligible for HCV treatment.
The state of New York does have published guidelines for management of the HIV/HCV coinfected patient. These guidelines were written in March 2000 and can be reviewed at www.hivguidelines.org
What needs to be done across the country to break down some of these barriers to treatment? Firstly, both patients and physicians need to be educated on the options for treatment of the HIV/HCV coinfected patient and weigh the side effects versus the efficacy versus the likelihood of progression versus quality of life (QOL). Do patients have the needed access to liver biopsies?
Depression is a common condition of HIV/HCV coinfection and that was confirmed by a large trial that was conducted in HIV patient care clinics in 1996. Of the 2864 patients screened 36% had depression, 26.5% had dysthymia (chronic depression > 2years), 15.8% had anxiety and 10.5% had panic attacks. With a psychiatric profile like this maybe that is an additional reason why the HIV/HCV coinfected patient is not being treated.
Part Four of conference will report on the remaining sessions:
- Session Twelve: Panel Management of Treatment for HIV/HCV Coinfection
Moderator: Dr. Douglas Dietrich
Members; Jules Levin, Michael Marco, Dr. Margaret Ragni and Dr. Teresa Wright
- Session Thirteen: Antiretroviral-associated Hepatotoxicity: The Role of Chronic Viral Hepatitis
Dr. Mark Sulkowski
- Session Fourteen: Liver Transplantation in the HIV Positive Candidate
Dr. John Fung
- Session Fifteen: Management and Treatment of HBV/HIV Coinfection in 2001.
Dr. Marion Peters
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