Predictors of response to hepatitis A vaccine in HIV-positive patients
US Public Health Service/Infectious Diseases Society of America guidelines for the prevention of opportunistic infections in HIV-infected individuals recommend that hepatitis A virus (HAV) vaccination be given to all HIV+ patients, particularly those with other chronic conditions such as hepatitis C virus infection. To determine the predictors of immune response to the HAV vaccine, researchers in New Haven, CT retrospectively examined the medical records of outpatients attending area HIV clinics. At these clinics baseline and post-vaccination HAV antibodies are measured routinely. Those who are found to be HAV susceptible are administered two doses of the HAV vaccine (1440 ELISA units given IM 6-12 months part). Of the 503 patients who had HAV serologic testing performed, 138 were HAV seronegative at baseline and completed both injections of the series. Less than half (48.5%) of these patients had evidence of a serologic response to the HAV vaccine series. In a multivariate analysis examining response to the HAV vaccine, being female and having a CD4 count >200 cell/mm3 at the time of initial vaccination were independent predictors of adequate response. Hepatitis C virus (HCV) exposure, antiretroviral therapy use, age and race were not different between responders and non-responders. These data suggest that delay of HAV vaccination until CD4 cell counts increase following HAART initiation may improve immune responses to HAV vaccine, especially among men.

Weissman S, Feucht C, Moore BA. Journal of Viral Hepatitis. 2006;13(2):81-86.

A comparison of entecavir and lamivudine for chronic hepatitis B virus infection.
Two large clinical trials pitted entecavir and lamivudine for the treatment of chronic HBV infection in HIV-uninfected patients. Chang and colleagues in Taiwan randomized 715 HBeAg-positive patients naïve to nucleoside analogues to lamivudine or entecavir for at least 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level. At 48 weeks, histologic improvement was seen in 72% of the entecavir assigned patients compared to 62% of those receiving lamivudine (p = 0.009). Further, entecavir treated patients had deeper declines in HBV viral load (6.9 vs. 5.4 log10 copies/mL, P<0.001). There was no difference in HBeAg seroconversion between the study arms (~20% in each group). Entecavir resistance was not detected durin g the first year of treatment and tolerability to the two agents was similar.

Lai and colleagues across the South China Sea in Hong Kong conducted a similar head-to-head of entecavir and lamivudine but enrolled HBeAg-negative patients. A total of 648 patients were randomized and as was seen in the trial of HBeAg-positive patients, entecavir yielded significantly greater rates of histologic improvement. Again, 70% of those assigned entecavir versus 60% of those receiving lamivudine had histologic improvement on liver biopsy (p = 0.01). HBV DNA levels were undetectable in 90% of the entecavir group compared to 72% of the lamivudine group (p < 0.001). Normalization of ALT levels was seen in 78% and 71% of the entecavir and lamivudine patients, respectively (p = 0.045). As in the Taiwanese study, resistance to entecavir was not observed and there were no differences between arms in safety parameters.

In an editorial accompanying these papers, Jay Hoofnagle, MD of the National Institutes of Health, adds some temperance to any irrational exuberance concerning these results pointing out that current HBV therapies suppress but do not eradicate HBV infection - unlike successful HCV therapy. Therefore, there remains debate regarding which patients should be treated, with which agent(s) and for how long (see Main Article). These studies do demonstrate that entecavir is potent, relatively less prone to cultivate drug resistance and seemingly safe (high does of the drug in mice have been found to cause cancer). These qualities, Dr. Hoofnagle writes, make entecavir along with adefovir a reasonable first line therapy choice for HIV-negative chronic HBV-infected patients.

Chang TT, Gish R, de Man, R et al. A Comparison of Entecavir and Lamivudine for HbeAg-Positive Chronic Hepatitis B. N Engl J Med. 2006;354(10):1001-10.

Lai CL, Shouval D, Lok AS. Entecavir verus lamivudine for patients with HbeAg-negative chronic hepatits B. N Engl J Med. 2006;354(10):1011-20

Hoofnagle J. Hepatitis B--preventable and now treatable. N Engl J Med. 2006 Mar 9;354(10):1074-76.

FDA updates black box warning on
Aptivus (tipranavir)
On June 30th, 2006 the FDA updated the black box warning on tipranavir protease inhibitor that is used in combination therapy with ritonavir (Norvir) for HIV-infected patients resistant to other drugs. The new warning is a result of 14 documented cases of intracranial hemorrhage in 13 of 6,840 people who took tipranavir during clinical trials. Eight of the 13 people died as a result of the hemorrhaging. According to the company, during an in-vitro experiment, tipranavir was observed to inhibit human platelet aggregation. Further, studies in rodents found an increase in coagulation parameters - increased prothrombin time (PT) and activated partial thromboplastin time (PTT). Such changes were not observed in experiments of dogs. A 'Dear Doctor' letter sent to providers recommends that tipranavir/ritonavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents or anticoagulants. The warning label has previously sited liver failure as a possible effect of the drug.

http://www.fda.gov/medwatch/safety/2006/Aptivus-tipranavir_DHCP.pdf

http://www.fda.gov/medwatch/safety/2006/Aptivus_PI.pdf

FDA Approves New HIV Medications:

Fixed dose tenofovir, emtricitabine and efavirenz (Atripla)
The US Food and Drug Administration on July 12th approved a fixed dose once daily tablet combining efavirenz, emtricitabine and tenofovir - efavirenz - for the initial treatment of adults with HIV-1 infection. In the Department of Health and Human Services Guidelines for the Use of Antiretroviral agents in HIV-1-Infected Adults and Adolescents, the components of Atripla are recommended as one of the first-line regimens for treatment naïve patients. The side effects of the medication should be no different than its individual components. In patients with chronic hepatitis B virus (HBV) infection, the disruption of this new treament may cause greater severity of HBV infection as tenofovir and emtricitabine are potent anti-HBV agents. The efficacy and safety of this new treament was demonstrated in a 48 week long clinical study and pharmacokinetic studies indicate comparable bioavailability of the components to that observed when administered individually.

The U.S. Food and Drug Administration. FDA News. Available at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01408.html

Darunavir (Prezista)
Tibotec's darunavir, also known as TMC-114, a new protease inhibitor for HIV-infected patients who have developed resistance to other ARV therapy received accelerated FDA approval in June. The drug, co-administered with ritonavir, was approved based on the findings of two randomized controlled studies examining the safety and efficacy of the darunavir/ritonavir in heavily treatment experienced patients. As a condition of the accelerated approval of the drug, Tibotec will conduct studies to evaluate the clinical benefits of darunavir. It will also perform studies on the effects of the drug in children and patients with liver dysfunction.

The U.S. Food and Drug Administration. FDA News. Available
http://www.fda.gov/bbs/topics/NEWS/2006/NEW01395.html

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