CROI 2009: Cancer Incidence in Clinical Trials of Raltegravir (Isentress)

The first-in-class HIV integrase inhibitor, raltegravir (Isentress), was approved by the U.S. Food and Drug Administration in October 2007. During the drug's development, some clinical trials suggested that participants taking raltegravir had a higher rate of malignancies, though this was not confirmed in later studies.

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CROI 2009: Studies from Europe and the U.S. Provide Further Information on Sexual Transmission of Hepatitis C Virus among HIV Positive Men

Starting in 2000, clinicians in several large European cities began reporting clusters of apparently sexually transmitted acute hepatitis C virus (HCV) infection, primarily among HIV positive men who have sex with men (MSM). More recently, similar outbreaks have also been reported in the U.S. In several posters presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, researchers provided further data on the maturing HIV/HCV epidemics in Europe and the newer outbreaks in the U.S.

Ongoing Epidemic in France

Jade Ghosn and colleagues presented evidence of ongoing sexual transmission of HCV among MSM in France, based on a national survey of acute hepatitis C cases conducted by the French National Institute for Public Health Surveillance in 2006-2007.

The survey included a sample of patients from 115 medical wards across the country, based on the number of HIV and AIDS cases in MSM reported to the National HIV surveillance system. Acute HCV was defined as a positive HCV antibody or HCV RNA within 1 year of a documented negative test.

Complete clinical, biological, and HCV-NS5b genetic sequencing data were available for 32 of the 94 cases meeting the acute HCV definition. The median age at HCV diagnosis was about 40 years and the median time between HIV and HCV diagnosis was 10 years.

Within this group, a majority were receiving combination antiretroviral therapy (ART), 22 had undetectable HIV viral load, and most had a CD4 count above 350 cells/mm3. Most patients were diagnosed with acute HCV due to elevated transaminase (ALT and/or AST) levels during routine HIV-related monitoring.

About two-thirds of these patients (20) had other sexually transmitted diseases (STDs) present at the time of acute HCV diagnosis, including 14 cases of syphilis and 2 cases of lymphogranuloma venereum. A majority reported unprotected anal sex, though just 5 reported "highly at-risk" sexual activities, i.e., fisting. Having undergone surgery or endoscopy was also a significant risk, suggesting "nosocomial" (within a healthcare setting) transmission might possibly play a role.

Half the extensively analyzed patients (16) had HCV genotype 4d, which is generally uncommon in France, and 14 had genotype 1a. Among the 16 genotype 4d viruses, 15 segregated into a single cluster, while among the 14 genotype 1a viruses, 10 segregated into 3 clusters. Furthermore, the 15 clustered genotype 4d viruses isolated in 2006-2007 were closely related to 4d viruses isolated in Paris in 2001-2003, indicating an ongoing epidemic of sexual transmission.

"We show evidence for ongoing sexual transmission of HCV in HIV-infected MSM in France, with an ongoing epidemic transmission of genotype 4d virus in the Parisian area," the investigators concluded. "Our results support the need for regular screening for HCV infection in HIV-infected MSM."

Rapid Rise in Amsterdam

Guido Van Den Berk and colleagues reported a rapid rise in acute hepatitis C cases at OLVG Hospital in Amsterdam, which currently cares for more than 1800 HIV positive patients, about three-quarters of them MSM.

The researchers retrospectively reviewed data on HIV positive MSM identified with HCV coinfection between January 2000 and August 2008. Stored blood samples here tested for HCV antibodies and HCV RNA in an attempt to narrow the potential seroconversion interval.

A total of 49 cases of acute HCV were identified. No cases occurred between 2000 and 2002, 2 cases occurred in 2003, 1 occurred in 2004, 9 occurred in 2005, and 11 occurred in 2006. The number fell to 7 in 2007, but then more than doubled to 20 between January and August 2008 -- accounting for more than 1.5% of all HIV positive MSM seen annually at the hospital.

All but 2 of these patients experienced a marked increase in transaminase levels. About one-third had an HCV seroconversion interval less than 6 months, and approximately another third between 6 months and 1 year, but nearly 15% had an interval between 1 and 2 years, and almost 20% had an interval greater than 2 years.

None of the coinfected patients had any "classical" risk factors for HCV infection such as injection drug use or direct blood exposure in endemic countries, but most did engage in unprotected sex.

Among 46 cases in which HCV genotype was determined, 35 patients (76%) had genotype 1, 1 each (2.2%) had genotypes 2 and 3, and 9 (20%) had genotype 4.

"Our study confirmed a marked increase in the occurrence of acute HCV starting from 2003 and escalating in 2008, and mostly involving HCV genotypes with a poor response to therapy," the investigators concluded. "In the absence of classical risk factors, HCV has become a sexually transmitted disease in HIV-infected MSM. Efforts to contain this epidemic should be started rapidly."

Risk Factors in New York vs the U.K.

Researchers at Mt. Sinai Hospital and School of Medicine in New York City were among the first to report an outbreak of apparently sexually transmitted HCV among MSM in the U.S.

Sarah Fishman and colleagues undertook an analysis comparing characteristics and risk behaviors among HIV positive men with acute hepatitis C in New York and in the United Kingdom, where the first European cases were reported.

The researchers used the Danta risk factor questionnaire, developed by Mark Danta of St. Vincent's Hospital in Sydney and Royal Free and University College Medical School in London, who authored some of the earliest reports on the current acute hepatitis C epidemic. The questionnaire was administered to 21 HIV positive MSM with acute HCV infection in New York, and their responses were compared to previously published responses from 60 U.K. men.

The men involved in both the New York and U.K. were relatively older (median 40 and 36 years, respectively) than the average age of clients typically seen at STD clinics. The youngest affected men were 29 in New York and 24 in the U.K., while the oldest were 49 and 58, respectively. In both groups, the median CD4 count was above 500 cells/mm3 and similar proportions were on HAART.

The median duration of HIV infection among the New York men was 8 years, compared with 4 years in the U.K. In both outbreaks, however, some men had been infected with HIV for less than 1 year when they became coinfected with HCV.

In the 12 months prior to study enrollment, the New York men reported less fisting than the U.K. men (33% vs 73% for active; 24% vs 57% for receptive); even more striking, U.K. men were nearly 6 times more likely to report active fisting in a group sex setting (12% vs 67%), though the difference was not so great for getting fisted in a group setting (29% vs 56%). A majority of men in both New York and the U.K. had had both active (65% vs 85%) and receptive (77% vs 94%) unprotected anal intercourse in a group setting.

New York men were significantly more likely to use condoms while performing and receiving oral sex (which has not previously been reported as a major risk factor for HCV transmission). Approximately half as many New Yorkers as U.K. men reported a lifetime history of STDs (38% vs 85%), in particular non-specific urethritis.

In both groups, direct blood-to-blood (parenteral) exposure could not account for most cases of acute HCV. Although significantly more men in New York had a history of injection drug use, this only reached 24%, compared with just 3% in the U.K. Use of non-injection recreational drugs was significantly more common among the U.K. men -- including ketamine ("Special K"; 24% vs 80%), non-crack cocaine (38% vs 77%), LSD (0% vs 33%), and ecstasy (38% vs 80%). The New York men, however, reported more sharing of implements for drug smoking (48% vs 20%) and drug injection (15% vs 2%).

"HCV transmission among HIV-infected [MSM] is not the result of adolescent risk taking, rather transmission is occurring primarily in men over the age of 35 years," the investigators concluded. "This demographic feature raises the possibility that older age may be a risk factor for sexual transmission of HCV, as previously reported. The greater use of non-injection recreational drugs in the U.K. cases was a notable finding."

Liver Disease Progression

The Mt. Sinai team also presented the latest data on liver disease progression and treatment response in HIV positive individuals with acute HCV infection.

Daniel Fierer first reported at the 2007 CROI that HIV positive MSM with acute hepatitis C showed evidence of unusually rapid and severe liver fibrosis, which typically develops much later in the course of HCV infection. He followed up with similar findings at the 2008 CROI and published further data in the September 1, 2008 issue of the Journal of Infectious Diseases,

As of this report, the investigators had enrolled 45 HIV positive MSM with acute hepatitis C, defined as newly identified HCV antibody seropositivity with either ALT elevation, >1 log HCV viral load fluctuation, or high clinical suspicion. The median age was 40 years, the median CD4 count was 525 cells/mm3, and 94% had HIV viral load < 400 copies/mL; 89% had HCv genotype 1 (this cohort overlaps with the New York group described above).

Just 4 patients (9%) spontaneously cleared HCV infection -- lower than the 25% or so typically seen in studies of HIV negative people with acute hepatitis C. Of the remainder, 15 started hepatitis C therapy, all with pegylated interferon plus ribavirin, while 20 refused or deferred treatment and 6 were still being evaluated.

Of the 10 patients who completed a 24-week post-treatment follow-up period, 8 achieved sustained virological response (SVR) while 2 were non-responders (others are still undergoing treatment).

For 24 participants, liver biopsies were performed a median of 4 months after the first identified ALT elevation. Within this group, 1 patient (4%) had stage 3 fibrosis (using the 0-4 Scheuer scale), 18 (75%) had stage 2, 3 (13%) had stage 1, and 2 (8%) had stage 0.

In a case-control study of 21 matched HCV infected/HCV-uninfected pairs, significant risk factors for HCV infection were unprotected receptive anal intercourse with or without ejaculation (P = 0.03-0.04), unprotected receptive oral sex with ejaculation (P = 0.03), use of sex toys (P = 0.03), sex while high on drugs (P = 0.01), and use of marijuana (P = 0.04). Interestingly, in this analysis getting fisted was not a risk factor, while active fisting was associated with a slightly higher risk that did not reach statistical significance.

"Acquisition of HCV infection in the outbreak of acute HCV infection in HIV-infected MSM in New York City is associated with receptive, unprotected sex and results in early and rapid progression of liver fibrosis," the researchers concluded, confirming their earlier findings.

"Treatment is highly successful when initiated in the acute phase but many do not receive prompt treatment, missing the opportunity to prevent further progression of the already significant liver fibrosis," they continued.

"We therefore recommend at least quarterly ALT and yearly HCV testing for all HIV-infected MSM and rapid referral to an HCV treatment expert upon suspicion of HCV" they added. "Promotion of safe sex and decreased drug use is also warranted."

Screening in 6 U.S. Cities

Finally, Karen Hoover with the Centers for Disease Control and Prevention (CDC) and colleagues estimated the proportion of HIV positive MSM receiving care at 8 HIV clinics who were ever screened for hepatitis A virus (HAV), hepatitis B virus (HBV), or HCV.

HIV management guidelines have consistently recommended that HIV positive individuals should be screened for HBV, which can be prevented with a vaccine if a person is unexposed; there is also a vaccine for HAV, but not for HCV. Despite the mounting evidence that HCV is sexually transmitted among HIV positive MSM, screening is not yet routine.

The present analysis looked at medical record of 1607 patients who made approximately 12,000 visits to 8 clinics in 6 cities (Atlanta, Chicago, Los Angeles, Miami, New York, and San Francisco) since 1998.

The investigators found that while just 45% of the men had been tested for HAV and 48% for HCV, the rate for HBV was much higher, at 89%.

"Screening for HBV and HAV infection and vaccination of susceptible persons are important preventive services in the management of HIV-infected persons," the researchers concluded. "Screening for HBV and HCV infection and evaluation of those persons with chronic infection is important to identify those who require treatment and may be at risk for progressive liver disease."



J Ghosn, C Larsen,L Piroth, and others. Evidence for Ongoing Epidemic Sexual Transmission of HCV (2006 to 2007) among HIV-1-infected Men who Have Sex with Men: France. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 800.

G Van Den Berk, W Blok, H Barends, and others. Rapid Rise of Acute HCV Cases among HIV-1-infected Men Who Have Sex with Men, Amsterdam. CROI 2009. Abstract 804.

S Fishman, K Childs, D Dieterich, and others. Age and Risky Behaviors of HIV-infected Men with Acute HCV Infection in New York City Are Similar, but not Identical, to those in a European Outbreak. CROI 2009. Abstract 801.

D Fierer, S Fishman, A Uriel, and others. Characterization of an Outbreak of Acute HCV Infection in HIV-infected Men in New York City. CROI 2009. Abstract 802.

K Hoover, K Workowski, S Follansbee, and others. Hepatitis Screening of HIV-infected Men Who Have Sex with Men: 8 US Clinics. CROI 2009. Abstract 803.

CROI 2009: Treatment Intensification with Raltegravir (Isentress) Does Not Eradicate Residual HIV

Effective combination antiretroviral therapy can reduce HIV viral load to an undetectable level in the blood using standard tests, but it does not completely eradicate the virus from the body. As Robert Siliciano of Johns Hopkins School of Medicine discussed in a plenary address at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal, experts have long debated whether residual HIV is the result of continuing low-level viral replication or release of virus from stable reservoir sites.


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CROI 2009: Nicotine Replacement Aids Smoking Cessation in Program for HIV Positive Participants

It is well known that tobacco smoking is a risk factor for lung cancer, cardiovascular disease, and other illnesses, and several surveys have indicated that people with HIV are more likely to smoke (50%-70% in some studies) relative to the general population (20%) -- a major concern since HIV positive people taking antiretroviral therapy (ART) are already at increased risk for these conditions.


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CROI 2009: High HCV Viral Load Is Associated with an Increased Risk of Death in HIV-HCV Coinfected Individuals

In contrast with HIV, most studies to date indicate that hepatitis C virus (HCV) viral load is not associated with disease progression. But this may not be the case for HIV-HCV coinfected individuals, according to a study presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) last month in Montreal.


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