Contents I CO-INFECTIONS. A. Coming up: updates on hepatitis C. Available on the World Wide Web at

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1 TreatmentUpdate 168 Vol. 20, No. 4 June/July 2008 ISSN Available on the World Wide Web at Contents I CO-INFECTIONS A. Coming up: updates on hepatitis C 1 B. The growing problem of insulin resistance 2 C. Risk factors for insulin resistance in hep C 3 D. French study finds recovery from hep C blocked by insulin resistance 4 E. Dangerous liaisons: risky sex, drugs and hep C 5 F. Rapid liver damage after recent HCV co-infection 7 G. Some good news about HAART and liver health 8 H. Unexpected liver damage is ddi to blame? 8 I. The disturbing issue of HCV re-infection 9 J. Predicting recovery from hep C 10 I CO-INFECTIONS A. Coming up: updates on hepatitis C Hepatitis C virus (HCV) and HIV are spread through similar means, such as sharing contaminated equipment for substance use and tattooing and having unprotected sex. As a result, co-infections with HCV and HIV are relatively common. In high-income countries, the widespread availability of highly active antiretroviral therapy (HAART) has greatly diminished the risk of death from AIDS-related infections. But HCV is not an AIDS-related infection. While there is treatment for HCV infection (a combination of interferon and ribavirin), recovery rates in coinfected people are disappointing. The challenge in the years to come will be to find ways to prevent the spread of HCV infection and also extend the lives of people living with HIV and HCV. Perhaps this will include some new drugs under development for HCV mono-infection or the availability of liver transplants. In parts of the European Union and the United States, liver transplants for co-infected people who need them can be done, often as part of research. However, for the present time in Canada, liver transplants for co-infected people are not routinely done. As researchers continue to study these infections, more information about how each virus influences the other becomes available. In many cases, researchers are uncovering complications caused by HCV. This then stimulates further research to find ways of relieving these complications. In this issue of TreatmentUpdate, we present new developments in HCV research. Most of our produced by 555 Richmond Street West, Suite 505 Box 1104 Toronto, Ontario M5V 3B1 Canada phone: toll-free: fax: charitable registration number: RR

2 Page 2 TreatmentUpdate 168 Vol. 20 No. 4 focus is on co-infection. However, we also report on progress that has been made in HCV monoinfection (HCV infection only) that may be relevant to co-infection. In addition, we continue to explore troubling reports of apparently sexually transmitted HCV infection in HIV positive men. B. The growing problem of insulin resistance Insulin is an important hormone that is made by the pancreas gland. This hormone helps cells absorb sugar (glucose) from the blood. Inside a cell, glucose is burned to release energy that the cell needs to operate efficiently. Researchers are finding that insulin-related problems are occurring in HCV positive people regardless of HIV co-infection. These problems, if left untreated, can reduce the chances of recovering from HCV infection and can also lead to diabetes. Before delving into these issues, we first need to explain some background information about insulin. The rise and fall of a hormone Under normal conditions, insulin levels in the blood rise after a meal. In such cases, insulin helps cells absorb glucose. High insulin levels can also have other effects, such as suppressing the breakdown of fat. Between meals, insulin levels fall. This shift triggers changes to other hormones and together they cause the body to make and release glucose into the blood. Under conditions of low insulin levels, fat can be more easily broken down and converted into energy. Resisting insulin In some cases, the body resists the effect of insulin; this is called insulin resistance (IR). As a result, cells do not remove insulin from the blood and blood sugar levels continue to rise. As blood sugar levels rise and remain high for elevated periods, the pancreas gland is stimulated to produce greater amounts of insulin to help lower blood sugar. For a time, this strategy seems to work. However, over the long term, prolonged, high levels of insulin suppress the breakdown of fat so fatty molecules build up in the body. Eventually, the pancreas gland becomes exhausted and diabetes develops. Assessing insulin resistance Routine analysis of insulin resistance is not done outside of a study or research centre. Still, to estimate the degree of IR, fasting blood samples are checked for glucose and insulin concentrations. Then, by inputting these into an equation, a reasonable estimate of IR can be had. This type of assessment is called HOMA-IR (homeostatic model of assessment). Different studies define normal HOMA-IR somewhat differently. In general however, HOMA scores are interpreted as follows: the greater the number, the greater the degree of IR. Causes of insulin resistance Traditionally, risk factors for IR can include the following: a family history of diabetes obesity not getting enough exercise being a person of colour In HCV infection, the risk of developing IR seems greater than in HCV negative people. Researchers are not certain why, but they suspect that proteins produced by HCV may interfere with the body s ability to detect and respond to insulin. In cases of IR, the body can convert the excess sugar in the blood into fat that is stored. And since higher-than-normal levels of insulin inhibit the breakdown of fat, IR can lead to increased weight. In addition to causing excess weight and diabetes, IR poses another challenge it reduces the chances of recovery from HCV infection. Clearly, more research is needed to find out exactly how HCV infection increases the risk of IR. But researchers are also thinking of ways to reduce IR in this population. For now, the simplest ways to reduce IR in people who are HCV positive (regardless of HIV co-infection) are natural, as follows: getting advice from a registered dietician or nutritionist about losing weight and implementing this advice gradually building up activity levels so that exercise becomes easier and routine

3 TreatmentUpdate 168 Vol. 20 No. 4 Page 3 REFERENCES: 1. Powers AC. Diabetes Mellitus. In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison s Principles of Internal Medicine. 17th ed. McGraw-Hill Companies, Inc.; p Neuschwander-Tetri BA. Hepatitis C virus-induced insulin resistance: not all genotypes are the same. Gastroenterology Feb;134(2): C. Risk factors for insulin resistance in hep C Researchers are increasingly finding that HCV infection causes many problems, some of them unexpected. Initially, HCV was thought of as a liver infection that damaged that organ. But researchers now know that HCV can cause additional problems, including the following: changes to cholesterol levels in the blood damage to the mitochondria (a cell s powerplant) damaged mitochondria don t produce enough energy, and, as a result, cells can malfunction and die. With less available energy, HCV positive people may feel tired more easily. increased levels of oxidation, which leads to an increase in compounds that can damage cells Several reports have linked HCV infection to diabetes or pre-diabetic conditions such as insulin resistance (IR). In these early studies, diabetes seemed to be linked to having a fatty liver, an extremely damaged liver or being infected with HCV genotype 3. To better explore the issue of viral hepatitis and insulin resistance, a research team in France conducted a large study of people infected with either HCV or hepatitis B virus (HBV). They found that about 33% of participants with HCV had IR and that this problem was always linked to some degree of liver damage. Study details For their study, researchers enrolled 600 consecutive volunteers who had HCV or HBV mono-infection. The average profile of 500 HCV positive participants was as follows: 43% females, 57% males age 48 years 42% of participants were obese or overweight levels of the liver enzyme ALT were nearly 3 times higher than the upper limit of normal The distribution of HCV genotypes was as follows: genotype 1: 57% genotype 2: 6% genotype 3: 16% genotype 4: 19% The average profile of 100 HBV positive volunteers was as follows: 25% females, 75% males age 40 years ALT levels were at least double the upper limit of normal All 600 participants underwent a liver biopsy and had blood drawn for analysis. Insulin resistance was calculated using HOMA-IR and confirmed with another methodology, QUICKI. The threshold for having IR in this study was set relatively high at 3.0 or greater. Results Insulin resistance in HCV Insulin resistance was diagnosed in 32% of participants with HCV. People with IR were more likely to have the following profile: over 40 years of age overweight having HCV genotypes 1 and 4 having a high HCV viral load The researchers also found this trend: the greater the level of IR, the more likely that participants had greater degrees of liver damage (inflammation and scar tissue). Results Insulin resistance by HCV genotype The study team found that 17% of people with HCV genotype 2 or 3 had IR. The only factor closely associated with IR in these people was being overweight. Results Hepatitis B virus Researchers found that only 5% of HBV positive people had IR and so they do not consider IR to be a complication of HBV mono-infection. Key points Insulin resistance, if left untreated, can lead to diabetes. Diabetes can lead to weight gain and an increased risk for heart attacks and strokes as well as kidney dysfunction, nerve damage and blindness.

4 Page 4 TreatmentUpdate 168 Vol. 20 No. 4 Exactly how HCV might cause IR is not yet clear. IR is connected to liver damage, with high levels of IR linked to high levels of liver damage. The study found that about 32% of HCV monoinfected people had IR. Bear in mind that the researchers used relatively strict criteria to define IR. Therefore, it is likely that the true extent of IR in this population was greater, perhaps approaching 40%. Researchers need to find ways to reverse IR. Such methods could include clinical trials of diet, exercise programs and insulin-sensitizing drugs or supplements such as chromium. Although this study focused on HIV negative people, another study of more than 200 HIV/HCV co-infected people found that a similar proportion had IR. Details appear in the next story. REFERENCES: 1. Powers AC. Diabetes Mellitus. In: Fauci AS, Braunwald E, Kasper DL, editors. Harrison s Principles of Internal Medicine. 17th ed. McGraw-Hill Companies, Inc.; p Neuschwander-Tetri BA. Hepatitis C virus-induced insulin resistance: not all genotypes are the same. Gastroenterology Feb;134(2): Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology Feb;134(2): Bernsmeier C, Duong FH, Christen V, et al. Virus induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C. Journal of Hepatology. 2008; in press. 5. Delgado-Borrego A, Liu YS, Jordan SH, et al. Prospective study of liver transplant recipients with HCV infection: evidence for a causal relationship between HCV and insulin resistance. Liver transplantation Feb;14(2): Squillace N, Lapadula G, Torti C, et al. Hepatitis C virus antibody-positive patients with HIV infection have a high risk of insulin resistance: a cross-sectional study. HIV Medicine Mar;9(3): D. French study finds recovery from hep C blocked by insulin resistance Researchers in Paris, France, conducted a study to assess the impact of insulin resistance (IR) on recovery from HCV infection in people coinfected with HIV. In this study of more than 200 participants, 32% had insulin resistance. Troublingly, rates of recovery from HCV infection were reduced in cases of IR. Study details Researchers recruited a total of 238 co-infected participants who had the following average profile: 26% females, 74% males age 40 years most common genotypes were 2 and 3 Participants underwent liver biopsies before they started treatment, which consisted of pegylated interferon and ribavirin, taken for 48 weeks. After this, participants were monitored for an additional 24 weeks. Results Before hepatitis therapy, 32% of participants had IR; scarring of the liver was found in 74% of participants. Of the 238 volunteers who entered the study, 96 people (40% of the group) were able to recover from HCV infection, demonstrating a sustained virologic response (SVR). Factors linked to recovery Taking many factors into account, the study team found that the following factors were linked to recovery from HCV: having a low level of IR being infected with genotypes 2 or 3 (these two generally respond better to therapy than do genotypes 1 and 4) Even among participants who had genotypes 2 and 3, the greater their degree of IR, the lower their chances of recovering from HCV infection. Key points IR appears to be relatively common in HIV/HCV co-infected people. IR reduces the chances of recovery from HCV.

5 TreatmentUpdate 168 Vol. 20 No. 4 Page 5 Clinical trials are needed to find out if reducing IR before or during hepatitis therapy improves recovery from HCV infection. REFERENCE: Halfon C. Insulin resistance impairs sustained response rate to Peginterferon Plus Ribavirin in HIV/HCV co-infected patients: HOMAVIC-ANRS HC-02 Study. 4th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 2. E. Dangerous liaisons: risky sex, drugs and hep C Over the past several years, reports from Australia, Western Europe and the United States suggest that outbreaks of HCV infection are occurring among HIV positive bisexual and gay men who do not inject drugs. These findings raise the possibility of HCV being a sexually transmitted infection. To find out exactly why some men who have sex with men (MSM) are susceptible to HCV, researchers in the UK conducted a study with extensive interviews and molecular analysis of HCV. Here are their findings in context. Historically speaking Based on research in HIV negative heterosexual couples in monogamous relationships where one partner was HCV positive, sexual transmission of HCV was considered uncommon. The American National Institutes of Health (NIH) has not recommended the use of condoms to prevent HCV transmission in such monogamous couples. Indeed, sexual transmission of HCV in these couples is considered a low risk. Then things began to change In the past 10 years, reports of HCV infections in some MSM have emerged. What was unusual about these reports is that the men apparently were not injection drug users. So some researchers concluded that sexual transmission of HCV among these men was a possibility. The big question Faced with this, some researchers began to ask themselves and their colleagues this question: Why are these outbreaks of HCV occurring among MSM who are HIV positive but apparently not among HIV negative men who engage in the same sexual practices? So far, outbreaks of HCV in HIV negative men who do not inject street drugs have not been detected. One possibility is that these HIV negative men engage in less frequent risky behaviours or have fewer encounters with the health care system. But another possibility is that having HIV infection makes some people more susceptible to HCV infection. Support for this idea has arisen because studies have found the following: The immune system in the intestinal tract of HIV positive people is particularly weak. This could result in weakened local immunity in the anus and rectum. It may also explain why HIV positive people are susceptible to HCV infection regardless of their CD4+ count. Another factor could be that high levels of HCV have been found in the semen of HIV/HCV co-infected men. If these men then have unprotected intercourse, their risk for transmitting HCV would be relatively high. Sexually transmitted infections (STIs) are common in some MSM. Indeed, for the past several years, outbreaks of syphilis and gonorrhea have been reported among HIV positive MSM in several high-income countries, including Canada. Many STIs can cause sores or lesions and could weaken local immunity in the genitals. These factors increase the risk that STIs can help facilitate the transmission of HCV. Sex and risk As part of a study tracing the origins of a recent outbreak of HCV in HIV positive men, researchers in the UK asked the men to complete detailed questionnaires. The researchers asked extensive questions about the men s sex lives and substance-using behaviour. A total of 60 men (54% of the group) returned completed questionnaires. For comparison, researchers collected and analysed health-related information from 130 HIV positive men who did not have HCV infection. In assessing the behaviours of the two groups, researchers found that men who became infected with HCV were more likely to have engaged in the following behaviours: unprotected anal sex (active or passive) with or without ejaculation unprotected group sex

6 Page 6 TreatmentUpdate 168 Vol. 20 No. 4 fisting rimming use of sex toys substance use More about street drugs Men with HCV were more likely to have sex while under the influence of street drugs, particularly the following: crystal meth ketamine (special K) GHB (gamma hydroxybutyrate) poppers ecstasy LSD Context is everything It is likely that when using street drugs the men s judgment, critical thinking and sense of safety were distorted. This would then place them at risk for HCV infection. It is also possible that the men may have thought they had little to fear from other STIs because they already had HIV, and so they felt free to engage in unprotected sex with other HIV positive men. They may not have known that HCV may be sexually transmitted. Some of the street drugs previously listed can weaken the immune system and dry mucous membranes in the anus, increasing the risk for getting STIs and developing cuts or abrasions. Having unprotected sex with multiple partners increases the chance of exposure to more germs, including HCV. The need for education Educational programs for HIV positive people now need to note the following: HIV makes the body susceptible to many infections. One of those infections is HCV. Unprotected intercourse also places HIV positive people at risk for many STIs. The greater the number of unprotected sexual encounters, the greater the risk of exposure to STIs. These germs can create sores or lesions that increase the risk of getting and passing on HCV, HIV and other STIs. In people who are already HIV positive, subsequent infection with HCV can result in accelerated liver damage, leading to painful complications and, in some cases, liver cancer and death. Indeed, doctors have reported that some people with HIV have died in as little as three years after subsequently becoming infected with HCV. While there are treatments for HCV infection, they are, at best, unpleasant. Moreover, HCV genotype 1, the most common genotype found in North America, responds poorly to therapy in co-infected people. Indeed, it appears that only about 30% of HIV/HCV co-infected people with genotype 1 recover from HCV infection. Overall, these should be very compelling reasons to engage in safer sex, regardless of HIV or HCV status. While our report has focused on research in HIV positive men, it is likely that unprotected intercourse also poses a risk of HCV transmission to HIV positive women. REFERENCES: 1. Gambotti L, Batisse D, Colin-de-Verdiere N, et al. Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, Euro Surveillance 2005; 10: Browne R, Asboe D, Gilleece Y, et al. Increased numbers of acute hepatitis C infections in HIV positive homosexual men; is sexual transmission feeding the increase? Sexually Transmitted Infections. 2004; 80: Rauch A, Rickenbach M, Weber R, et al. Unsafe sex and increased incidence of hepatitis C virus infection among HIV-infected men who have sex with men: the Swiss HIV Cohort Study. Clinical Infectious Diseases Aug 1;41(3): van de Laar TJW, van der Bij AK, Prins M, et al. Increase in HCV incidence among men who have sex with men in Amsterdam most likely caused by sexual transmission. Journal of Infectious Diseases. 2007; 196: Danta M, Brown D, Bhagani S, et al. Recent epidemic of acute hepatitis C virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours. HIV and Acute HCV (HAAC) Group. AIDS. 2007; 21: Cohen DE, Russell CJ, Golub SA, Mayer KH. Prevalence of hepatitis C virus infection among men who have sex with men at a Boston community health center and its association with markers of high-risk behavior. AIDS Patient Care & STDs. 2006; 20: 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, : is this an outbreak? Sexually Transmitted Infections Apr;84(2): Jones R, Low E, Rodgers A, et al. Hepatitis C (HC) viraemia following sustained virological response (SVR) to Pegylated Interferon (Peg-IFN) and Ribavarin (RBV) in HIV positive men who have sex with men (MSM) Reinfection or Late Relapse? 4th International HIV and

7 TreatmentUpdate 168 Vol. 20 No. 4 Page 7 Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract Gallotta G, Gali L, De Bona A, et al. Acute hepatitis C virus in HIV co-infected men who have sex with men: Milan th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 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. Journal of Infectious Diseases. 2008; in press. F. Rapid liver damage after recent HCV co-infection HCV infection of the liver triggers a process of gradually increasing damage to that organ. With HCV, healthy liver tissue is replaced by inflamed and scarred tissue (fibrosis). In people with HCV mono-infection, it can take up to several decades before severe liver damage, liver cancer and death occur. HCV-related liver damage can result in many complications, including kidney dysfunction and damage. When HCV positive people are given a kidney transplant, they also receive drugs that suppress their immune system so that it does not attack or reject the transplanted organ. But this immune suppression allows HCV-related liver damage to speed up. A similar effect is also noted in HCV positive drug users who later become HIV positive, as HIV also causes immune dysfunction. A different picture appears in people whose immune systems are already suppressed when they become HCV positive. In these cases, the consequences can be dire. In reviewing cases of HCV infection that occurred later in people with immune dysfunction, researchers have found that very rapid liver damage and death can occur in as little as three years after HCV infection. Such cases have included the following: recipients of organ transplants people with bone marrow problems people with antibody deficits and other inherited immune deficiencies people who got HIV via transfusion or needlestick injuries Now reports have appeared of sexually transmitted HCV in high-income countries. In New York City, researchers interviewed and studied blood and liver samples from 11 HIV positive men recently infected with HCV. Their findings are disturbing. Study details The average profile of the men was as follows: age mid-40s CD4+ counts ranged between 170 and 842 cells most had HIV viral loads below the 100-copy mark none were alcoholics none of the men had symptoms of HIV or AIDS These men came to the attention of the research team because when they sought routine care, their liver enzyme levels were very high. Results Risk factors for HCV Based on interviews with the men, here s what the research team found: Ten of the men revealed that they had recently engaged in receptive, unprotected anal intercourse; in some cases, with many men. In the past year, none of the men had any STIs known to cause ulcers or sores. Three of the men reported that they recently injected crystal meth and one of these three men said that he remembered sharing injection equipment. Two other men remembered sharing equipment for snorting street drugs, on several occasions with several men. In total, five of the men denied injecting or snorting street drugs. None of the men were obese or had diabetes. Results In the liver Analysis of liver samples revealed, on average, a moderate degree of liver damage or fibrosis. This was graded on a scale from zero to four, and 9 of the 11 men had fibrosis that was graded at stage 2 or F2. When looking at the liver samples under a microscope, technicians found dead regions and inflamed cells, and nearly all the samples looked similar. Such a degree of liver damage should not occur after recent HCV infection.

8 Page 8 TreatmentUpdate 168 Vol. 20 No. 4 The study team calculates that liver damage occurred at a rate five times faster than in people who have HCV infection alone. As a result of their findings, the New York researchers recommend that physicians should perform more intensive screening for HCV infection in HIV positive men. REFERENCE: 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. Journal of Infectious Diseases. 2008; in press. G. Some good news about HAART and liver health The weakened immunity associated with HIV infection can accelerate HCV-related liver damage. Because HAART can help to partially restore the immune system, researchers have wondered if it can indirectly help decrease HCVrelated damage. Results from a German study suggest that this is indeed the case. Study details Researchers in Bonn, Germany, enrolled 84 HCV mono-infected people and 57 HIV/HCV co-infected people, whose average profile at the start of the study was as follows: 8 females, 49 males age 42 years 82% had HCV genotype 1 83% were taking HAART CD4+ count 430 cells The team used a special ultrasound scan called FibroScan to assess the degree of liver damage. Although FibroScan is often routinely used in France and other parts of Western Europe, it remains a research tool in Canada and the United States. FibroScan has limitations it does not always accurately assess liver health. Liver specialists in North America prefer to have liver biopsies done to determine their patients liver health. Results There was no difference in the degree of liver damage in HIV/HCV co-infected people compared to people who were HCV monoinfected. This led the Bonn team to conclude that when HAART is successful it may decrease the rate of liver damage in co-infected people to nearnormal levels; that is, to what would be seen had these people been HCV mono-infected. These results are promising and hopefully other research centres will conduct similar studies to confirm the German results. REFERENCE: Grünhage F, Wasmuth J-C, Vidovic N, et al. No difference in liver fibrosis in a cohort of HIV/HCV-coinfected patients on HAART as compared to HIV-negative HCV-patients assessed by transient elastography. 4th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 8. H. Unexpected liver damage is ddi to blame? Liver damage is not common in the average HIV positive person living in high-income regions who is not co-infected with hepatitis-causing viruses. Yet cases of unexplained liver disease have been reported in this population. To explore this issue, research teams in Spain and Italy collaborated in reviewing the health of their coinfected patients. Their findings suggest that exposure to the anti-hiv drug ddi (didanosine, Videx or Videx EC) may be the culprit. Study details Researchers analysed health information, collected from three clinics, of HIV positive patients with unexplained and unexpected liver disease. All patients underwent extensive medical tests to try to find the cause of their problem(s). In total, the teams found 13 patients (2 females and 11 males) who had the following features in common: all had higher-than-normal levels of liver enzymes there were no obvious causes of liver problems no hepatitis-causing viruses were detected none of the participants were alcoholics swollen blood vessels in the throat and abdomen bleeding in the throat or abdomen water retention in the abdomen unintentional weight loss black stools exposure to ddi for at least two years

9 TreatmentUpdate 168 Vol. 20 No. 4 Page 9 Researchers decided that all 13 patients should discontinue ddi and replace it with another suitable anti-hiv drug. Once this was done, liver enzyme levels fell and symptoms began to resolve. Why did this happen? Researchers speculate that ddi may have decreased levels of a protective compound called GSH (glutathione) in cells. GSH is used to make enzymes that help detoxify harmful chemicals. Low levels of GSH may result in liver cells being susceptible to ddi-related toxicity. Studies in the 1980s and 1990s found less-thannormal levels of GSH in the blood of some HIV positive people not on treatment. It appears that HIV infection may eventually trigger a GSH deficiency, possibly by increasing the body s need for an amino acid called cysteine that is used to make GSH. It is possible that ddi exposure may intensify the GSH deficit in HIV infection. Experiments with HIV positive people suggest that supplements of the amino acid cysteine (which is converted into GSH inside cells) can raise GSH levels in the blood. A formulation of cysteine called NAC (N-acetyl-cysteine) is used to help detoxify the liver in cases of overdose with the pain medication acetaminophen (Tylenol). To our knowledge, no clinical trials of NAC have been done in ddi users to assess its impact on GSH and liver health. The study team did not recommend that ddi be avoided. However, their work does highlight the possible liver-damaging effect of ddi. REFERENCES: 1. Atkuri KR, Mantovani JJ, Herzenberg LA, et al. N-Acetylcysteine a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology Aug;7(4): Choi J, Liu RM, Kundu RK, et al. Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. Journal of Biological Chemistry Feb 4;275(5): van der Ven AJ, Blom HJ, Peters W, et al. Glutathione homeostasis is disturbed in CD4-positive lymphocytes of HIV-seropositive individuals. European Journal of Clinical Investigation Mar;28(3): Micke P, Beeh KM, Buhl R. Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients. European Journal of Nutrition Feb;41(1): Moling O, Cairon E, Rimenti G, et al. Severe hepatotoxicity after therapeutic doses of acetaminophen. Clinical Therapeutics May;28(5): De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. European Journal of Clinical Investigation Oct;30(10): Breitkreutz R, Holm S, Pittack N, et al. Massive loss of sulfur in HIV infection. AIDS Research and Human Retroviruses Feb 10;16(3): Vispo E. Upper gastrointestinal bleeding may unmask didanosine-associated portal hepatopathy in HIV/HCV coinfected patients. 4th International HIV and Hepatitis Coinfection Workshop June 2008, Madrid, Spain. Abstract Maida I. Severe portal hypertension in HIV patients with no primary liver disease: prevalence, histology and potential etiology. 4th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 10. I. The disturbing issue of HCV re-infection Researchers in London, England, reviewed their database of HIV positive people to find out if there were any cases of renewed HCV activity after this virus had previously been cured. They found 227 cases of HCV infection in HIV positive men. Of those that had been successfully treated, 22 cases of another episode of HCV infection were noted. Twenty-one of these men denied injecting street drugs. The study team found that nearly all of the 21 men had been diagnosed with a sexually transmitted infection during the period when they were first recovering from HCV infection. These STIs included the following: syphilis gonorrhea herpes chlamydia Many of these infections weaken the local immune system in the genitals and can cause sores, lesions and inflammation that can help facilitate HIV infection or, in this case, HCV infection. In analysing HCV samples from the first and second episodes of HCV in these men, the team found the following: In many cases, HCV genotype 1 was the cause of the second bout of HCV infection. This strain of HCV responds poorly to treatment, particularly in co-infected people.

10 Page 10 TreatmentUpdate 168 Vol. 20 No. 4 In at least 10 cases, molecular analysis suggested that the second bout of HCV was due to a different sub-type of virus than the first round of infection. In two cases, the type of HCV found in both outbreaks was very similar. This raises the possibility that perhaps these men had a relapse. However, this is extremely unusual and the second bout of HCV occurred 2.5 and 5 years, respectively, after the first round of HCV infection had been treated. This makes relapse highly unlikely. What is probably the case is that these two men had unprotected sex with the same person. The researchers concluded that ongoing high-risk sex was responsible for the re-infection of the men. In a stunning expression of frustration, they asked this question: If the re-emergence of HCV equals re-infection rather than relapse, should patients be offered retreatment? Unfortunately, unless educational programs can change high-risk behaviour, this question may become more common. REFERENCE: Jones R, Low E, Rodgers A, et al. Hepatitis C (HC) viraemia following sustained virological response (SVR) to Pegylated Interferon (Peg-IFN) and Ribavarin (RBV) in HIV positive men who have sex with men (MSM) Re-infection or Late Relapse? 4th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 12. virologic responses to HCV therapy to see if they can predict who will recover in the long term. In this way, patients may be spared unnecessary exposure to interferon and ribavirin and their side effects. Study details Researchers reviewed their clinic databases and selected certain patients for data-analysis, as follows: All patients had received standard doses of pegylated interferon once weekly. Their dose of ribavirin was adjusted for their weight (this is roughly equivalent to about 1,200 mg/day). Patients with the easier-to-treat genotypes 2 and 3 were given between 24 and 48 weeks of therapy. Patients with the more difficult genotypes 1 and 4 were given 48 weeks of therapy. After therapy, all patients were monitored for 24 more weeks. At the end of this time, blood tests were done to detect HCV. There were a total of 227 co-infected patients available for analysis with the following average profile: 27% females, 73% males 60% were taking HAART age 41 years CD4+ count 531 cells HIV viral load 12,000 copies The distribution of HCV genotypes was as follows: J. Predicting recovery from hep C The standard of care for HCV infection is a combination of the following drugs: a long-lasting form of interferon called pegylated interferon (Pegasys or Pegetron) the nucleoside analogue ribavirin These therapies have side effects and usually have to be taken for one year. After that time, an additional six months of observation is necessary before doctors can be sure that HCV is cured. The rate of recovery from HCV in co-infected people is poor compared to HCV mono-infected people. Researchers in Bonn and Köln, Germany, have been trying to find ways to assess the early genotype 1: 56% genotype 2: 6% genotype 3: 31% genotype 4: 7% Results The overall virologic results of participants were as follows: recovery: 41% no response: 40% relapse: 11% no detectable HCV but liver enzymes were strangely elevated, suggesting that HCV was still present deep within the liver: 8%

11 Predicting recovery Factors that suggested patients were likely to recover were as follows: TreatmentUpdate 168 Vol. 20 No. 4 Page 11 infection with genotype 2 or 3 having a rapid HCV virologic response (RVR) this means having HCV that becomes undetectable after four weeks of treatment having an early HCV virologic response (EVR) having viral load decrease by at least 2 logs after 12 weeks of treatment The following factors were useful in predicting an EVR: having HCV genotype 2 or 3 having an RVR not using HAART while receiving treatment for hepatitis C The study team offered two reasons why, in this preliminary analysis, not using HAART appeared to be associated with an EVR: People not taking HAART would be more likely to have a strong immune system (high CD4 counts and/or stabilized HIV infection) and this may be a factor associated with an EVR. Drug interactions between HAART and hep C treatment may be a factor associated with an EVR. People not taking HAART would not experience such interactions. More research is needed to understand the potential relationship between HAART and an EVR. Because retrospective studies such as this are based on looking back, the researchers may have missed collecting and analyzing important data. Therefore, biased interpretation of their results cannot be ruled out. In such cases, prospective studies are needed to confirm the conclusions reached by the German team. REFERENCE: Janke M, Luchters G, Vogel M, et al. Which factors predict early and sustained virological response under combination hepatitic C therapy in HIV/HCV co-infected patients? 4th International HIV and Hepatitis Co-infection Workshop June 2008, Madrid, Spain. Abstract 14.

12 Page 12 TreatmentUpdate 168 Vol. 20 No. 4 Disclaimer Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about HIV-related illness and the treatments in question. The Canadian AIDS Treatment Information Exchange (CATIE) in good faith provides information resources to help people living with HIV/AIDS who wish to manage their own health care in partnership with their care providers. Information accessed through or published or provided by CATIE, however, is not to be considered medical advice. We do not recommend or advocate particular treatments and we urge users to consult as broad a range of sources as possible. We strongly urge users to consult with a qualified medical practitioner prior to undertaking any decision, use or action of a medical nature. We do not guarantee the accuracy or completeness of any information accessed through or published or provided by CATIE. Users relying on this information do so entirely at their own risk. Neither CATIE nor the Public Health Agency of Canada nor any of their employees, directors, officers or volunteers may be held liable for damages of any kind that may result from the use or misuse of any such information. The views expressed herein or in any article or publication accessed or published or provided by CATIE are solely those of the authors and do not reflect the policies or opinions of CATIE or the views of the Public Health Agency of Canada. Permission to Reproduce This document is copyrighted. It may be reprinted and distributed in its entirety for non-commercial purposes without prior permission, but permission must be obtained to edit its content. The following credit must appear on any reprint: This information was provided by the Canadian AIDS Treatment Information Exchange (CATIE). For more information, contact CATIE at Writer Editor Credits Sean Hosein RonniLyn Pustil CATIE, Vol. 20, No. 4 June/July 2008 Production of this newsletter has been made possible through a financial contribution from the Public Health Agency of Canada. What CATIE Does The Canadian AIDS Treatment Information Exchange (CATIE) is committed to improving the health and quality of life of all people living with HIV/AIDS in Canada. CATIE serves people living with HIV/AIDS, and the people and organizations that support them, by providing accessible, accurate, unbiased and timely treatment information. CATIE provides such information through a comprehensive Web site, a bilingual toll-free phone service, electronic and print publications, a national reference library and workshops and exhibits at conferences across Canada. CATIE Publications TreatmentUpdate CATIE s flagship treatment digest on cutting-edge developments in HIV/AIDS research and treatment. Subscribe to TreatmentUpdate and automatically receive an notifying you the moment a new issue is available on-line or contact us at to receive a print subscription. A Practical Guide to HAART The latest on what is known about the various aspects of treatment, including a description of the virus and the immune system, the stages of HIV disease, the tests used to assess health status, and anti-hiv medications. A Practical Guide to HIV Drug Side Effects The latest on what is known about various side effects related to treatment, from appetite loss to sexual difficulties, and tips for countering or preventing them. The Practical Guide series also includes: A Practical Guide to Nutrition A Practical Guide to Complementary Therapies A Practical Guide to Herbal Therapies The Positive Side magazine Holistic health information and views for PHAs. Fact Sheets & Supplement Sheets Concise overviews of conditions, symptoms, medications, side effects, complementary therapies, vitamins, herbs and other treatment issues. pre*fix A harm reduction booklet for HIV+ drug users. Contact CATIE by info@catie.ca on the Web: by telephone: (toll-free) by fax: by post: Richmond Street W Box 1104 Toronto, Ontario M5V 3B1 Canada