Tenofovir (Viread) Suppresses HBV Viral Load Long-term in HIV/HBV Coinfected Patients, but Kidney Function May Decline

		SUMMARY: HIV/HBV coinfected individuals treated with agents that are dually active against both virus experience rapid suppression of hepatitis B virus (HBV), and about 15% of those taking tenofovir plus emtricitabine (the drugs in the Truvada coformulation) achieve hepatitis B "e" antigen (HBeAg) seroconversion, according to a study presented this past weekend at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston. With long-term use, however, some coinfected patients may develop persistent kidney impairment.

By Liz Highleyman

Some nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) -- including tenofovir (Viread), lamivudine (3TC; Epivir), and emtricitabine (Emtriva) -- are dually active against both HIV and HBV. Current antiretroviral therapy (ART) guidelines recommend that HIV/HBV coinfected patients should include these drugs in their antiretroviral regimen.

A team of Austrian researchers performed a retrospective analysis of clinical and laboratory data from all HIV/HBV coinfected patients treated at the HIV outpatient clinic at the Medical University of Vienna between 1998 and 2009.

A total of 107 patients were included in the analysis. A majority (78%) were men and the average age was about 40 years. Most patients (81%) were on highly active combination ART; 62% used tenofovir, 42% used lamivudine, and 30% used emtricitabine.

The mean HBV DNA viral load was 4.35 x10(9) IU/mL before ART initiation. About two-thirds (65%) of participants were initially HBeAg positive, and HBeAg positive patients had significantly higher HBV DNA levels than HBeAg negative patients (6.45 vs 2.12 x 10(9) IU/mL, respectively). The most common HBV genotypes were A (56%) and D (38%). The mean FibroScan liver stiffness measurement was 4.7 kPa at an average of 7 years after HBV diagnosis, indicating absent to mild liver fibrosis.

Results

	Over a median observation period of 61 month, 90% of patients achieved full HBV viral load suppression (< 350 IU/mL).
	57% of patients experience HBeAg seroconversion, with a cumulative annual probability of 12.0%.
	The cumulative annual rate of hepatitis B surface antigen (HBsAg) loss was 6.6% in HBeAg positive patients and 7.9% in HBeAg negative patients.
	Patients receiving tenofovir plus emtricitabine had a slightly higher annual HBeAg seroconversion rate (14.5%) than those receiving lamivudine (9.2%) or tenofovir (11.4%) as the sole dually active agent, but the difference was not statistically significant.
	Patients receiving tenofovir plus emtricitabine also had a higher annual rate of HBsAg loss (10.3%) compared with those taking only lamivudine (6.0%) or tenofovir (7.9%), but again this was not a significant difference.
	Annual HBeAg seroconversion rates were similar regardless of pre-treatment CD4 cell count (11.3% if > 500 cells/mm3; 13.3% if 200-500 cells/mm3; 12.1% if < 200 cells/mm3).
	Annual HBsAg loss rates likewise did not differ significantly according to pre-treatment CD4 count (10.3%, 8.3%, and 9.1%, respectively).
	12% of patients had transient aminotransferase (ALT or AST) elevations after ART initiation.
	None, however, experienced serious (grade 3 or 4) liver toxicity.

Based on these findings, the researchers concluded that HIV/HBV coinfected patients treated with dually active combination ART "show rapid suppression of HBV replication despite high baseline viremia and low levels of liver stiffness without significant hepatoxicity."

They added that ART containing tenofovir plus emtricitabine "leads to high rates of HBeAg seroconversion (14.5%/year) and HBsAg loss (10.3%/year) irrespective of CD4 cell counts."

Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria; Division of Immunodermatology & Infectious Diseases, Medical University of Vienna, Vienna, Austria.

Tenofovir Kidney Toxicity

While data are mixed, some research indicates that tenofovir can cause kidney function impairment in a small proportion of HIV patients, especially those with co-existing risk factors. However, this association has not been extensively studied in HIV/HBV coinfected individuals.

In another study presented at the AASLD meeting, Dutch researchers assessed the long-term efficacy and safety of tenofovir as a part of ART in a cohort of 102 HIV/HBV coinfected patients who took the drug for at least 6 months.

About three-quarters (77%) of participants had detectable HBV DNA at baseline. Nearly two-thirds (61%) had previously used lamivudine, and 42% had lamivudine resistance mutations at baseline.

Patients were monitored every 6 months, for a median follow-up period of 56 months. A standard measure of kidney function, estimated glomerular filtration rate (eGFR), was calculated using the Modification of Diet in Renal Disease (MDRD) equation, based on patient sex, age, race, and serum creatinine level. Kidney impairment was defined as eGFR less than 60 mL/min/1.73 m2.

Results

	Among 66 HBeAg positive patients, the cumulative probability of achieving virological response over time was:
	1 year: 41%; 2 years: 74%; 3 years: 82%; 4 years: 86%; 5 years: 89%.
	There was no significant difference in response rates between patients with or without lamivudine resistance at baseline.
	After 5 years on tenofovir, the rate of HBeAg loss reached 40% and the rate of HBsAg loss reached 9%.
	Among 13 initially HBeAg negative patients, the cumulative probability of virological response was:
	1 year: 54%; 2 years: 72%; 4 years: 100%.
	8% of these patients experienced HBsAg loss.
	23 patients (all HBeAg negative) had undetectable HBV DNA at baseline.
	Within this subgroup, over a median 53 months of follow-up, all but 1 (96%) maintained virological suppression, but none experienced HBsAg loss.
	Overall, 4 of 102 patients (4%) experienced viral breakthrough, although none showed evidence of tenofovir resistance mutations.
	The mean eGFR at baseline was 105 mL/min, decreasing significantly to 94 mL/min by the end of follow-up (P < 0.001).
	During follow-up, 9 patients (9%) developed kidney impairment.
	In 3 patients, impairment persisted for more than 3 months.
	3 participants stopped taking tenofovir due to kidney problems.

"[Tenofovir] is an effective anti-HBV agent through 5 years of therapy," the investigators concluded. "Nevertheless, patients should be carefully monitored for development of renal impairment, as [tenofovir] therapy is associated with a significant decline in eGFR."

Department of Gastroenterology & Hepatology, Department of Internal Medicine-Infectious Diseases, and Department of Virology, Erasmus MC, University Medical Center, Rotterdam, Netherlands; Department of Medical Microbiology (CINIMA) and Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, Amsterdam, Netherlands.

11/3/09

Reference

LM Kosi, T Reiberger, K Rutter, and others. High rates of HBeAg seroconversion and HBsAg loss with Tenofovir + Emtricitabine in patients with HBV-HIV co-infection irrespective of CD4+ cell count. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 391

JG Reijnders, T de Vries-Sluijs, BE Hansen, and others. Five year tenofovir therapy is associated with maintained virologic response, but significant decline in renal function in HIV/HBV coinfected patients. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 425.