Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues
Long-Term Therapy With Tenofovir Is Effective for Patients Co-Infected With Human Immunodeficiency Virus and Hepatitis B Virus
Long-Term Therapy With Tenofovir Is Effective for Patients Co ...Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), ... Long-term therapy is indicated for all HIV/HBV co-infected and most HBV mono-infected patients treated with oral nucleos(t)ide analogues because a sustained response after ... Virologic Response in Patients With Detectable HBV DNA at Baseline ... www.natap.org/2010/HBV/102710_03.htm
Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues
Martin-Carbonero, Luz; Teixeira, Tiago; Poveda, Eva; Plaza, Zulema; Vispo, Eugenia; González-Lahoz, Juan; Soriano, Vincent
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
2 January 2011
Background: Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals and increases liver-related mortality. Nucleos(t)ide analogues with activity against both HBV and HIV are widely used in coinfected patients, but its long-term effect on liver disease is unknown.
Methods: Clinical outcomes, HBsAg and/or HBeAg clearance, and changes in liver stiffness were longitudinally evaluated retrospectively in all HIV-HBV-coinfected individuals followed at our institution.
Results: A total of 92 patients with HIV-HBV coinfection were identified, 19 of them superinfected with hepatitis delta virus. Their median time of follow-up was 35 months. Overall, 94% received lamivudine/emtricitabine and 82% tenofovir. Serum HBV-DNA was undetectable in 89%. Seven patients cleared serum HBsAg (2.6/100 patient-years), in four of them accompanied with anti-HBs seroconversion. Of note, two of them had hepatitis delta. Another 11 out of 42 HBeAg-positive patients cleared HBeAg (9/100 patient-years) and five of them experienced anti-HBe seroconversion. Liver decompensation and death occurred in eight (2.9/100 patient-years) and six (2.2/100 patient-years), respectively.
At baseline, liver fibrosis was defined as null-mild (48%), moderate-advanced (28%) or cirrhosis (24%). At last visit, after a median of 40 months in 71 patients, 75% showed no changes, whereas improvement was recognized in 17% and worsening in 8%.
Conclusion: Most HIV-HBV-coinfected patients treated with anti-HBV active nucleos(t)ide analogues experience an amelioration of liver fibrosis progression, with low rates of hepatic decompensation and death. Serum HBeAg or HBsAg seroconversion occurs at yearly rates of 9 and 2.6%, respectively, even in patients with delta hepatitis.
HIV infection worsens the course of chronic hepatitis B virus (HBV) infection, increasing hepatic decompensation events and liver-related deaths [1-3]. The use of nucleos(t)ide analogues as part of antiretroviral combinations with dual activity against HIV and HBV has favored that many HIV-HBV-coinfected individuals have controlled HBV replication for long periods [4,5]. This is particularly true since the advent of tenofovir, which depicts a more robust anti-HBV activity than lamivudine, whose long-term benefit is hampered by the selection of drug resistance [6,7]. Different lines of evidence suggest that the course of chronic hepatitis B has improved over the last few years in HIV-infected individuals as a result of a wide use of potent anti-HBV agents as part of HAART . However, the long-term effect on liver disease and on HBV markers of a prolonged use of anti-HBV active nucleos(t)ide analogues as part of antiretroviral regimens is unknown.
Transient elastography has been extensively validated as a noninvasive tool to assess liver fibrosis mainly in patients with chronic hepatitis C virus (HCV) infection, including patients coinfected with HIV [9-12]. More recently, several studies have examined the accuracy of this method in patients with chronic hepatitis B, in whom lower thresholds in liver stiffness may discriminate better distinct fibrosis stages [13-17]. The simplicity of elastography allows a longitudinal evaluation of hepatic damage in large populations, which would be almost impossible using repeated liver biopsies.
The objective of our study was the evaluation of the long-term impact of prolonged anti-HBV active nucleos(t)ide analogue therapy in a relatively large group of HIV-HBV-coinfected individuals, considering as end-point variables both clinical and virological data. An additional analysis was conducted exploring which are the current predictors of liver fibrosis in this population.
Patients and methods
All patients with confirmed HIV-1 infection and positive serum HBsAg for longer than 6 months on regular follow-up at our institution were retrospectively identified. Those who at least had an evaluation of liver stiffness using FibroScan (Echosens, Paris, France) were chosen. This noninvasive tool for assessing liver fibrosis was introduced in our clinic in September 2004 and its main characteristics and performance have been reported elsewhere [9,10]. Briefly, all examinations were performed by trained personnel on the right liver lobe through intercostal spaces in patients lying on his back, with their right arm in maximal abduction. The procedure was considered valid if at least 10 validated measurements were performed, with a success rate above 60%. Liver stiffness values were recorded as the median value of all tests expressed as kilopascals (kPa). Following recent reports [14,16,17], liver fibrosis estimates were categorized as null-mild (for <7.5 kPa), moderate-advanced (7.5-12 kPa) and cirrhosis (if >12 kPa).
Main demographics (age, sex, HIV risk factor), coinfection with other viruses (HCV, delta), laboratory parameters [HIV-RNA, CD4 cell count, alanine amino transferase (ALT), HBV-DNA, HBeAg, HBsAg, HBV genotype), length of HIV infection and antiretroviral therapy were all recorded at baseline, at the time of the first assessment of liver stiffness. High alcohol intake was defined for estimates of prolonged (>1 year) alcohol consumption above 50 g daily.
Several studies have highlighted the deleterious impact of chronic hepatitis B on the survival of HIV-infected individuals. Both progression of hepatic disease as well as HIV-associated immunodeficiency and overall and liver-related survival are worst in coinfected individuals [1-3,18-20]. These studies, however, did not control for HBV replication, which currently is known to be the main determinant of the natural history of chronic hepatitis B, including the rate of progression to cirrhosis  and development of hepatocellular carcinoma . Since lamivudine and particularly tenofovir were firstly approved as antiretroviral agents, and only thereafter as therapy for HBV, exposure to these drugs may have been longer in HIV-HBV-coinfected individuals, offering a unique opportunity to evaluate the long-term impact of complete HBV suppression on HBV-related liver disease. In our retrospective analysis of 92 coinfected individuals followed for a median of 35 months, 89% of whom had undetectable serum HBV-DNA under tenofovir and/or lamivudine/emtricitabine, serum HBeAg and HBsAg clearance occurred at the rates of 9 and 2.6 per 100 patient-years of follow-up, respectively. Accompanying this good serological outcome, estimates of liver fibrosis stage using elastometry improved in 17% of patients. Finally, deaths and hepatic decompensation events were rare (2.2 and 2.9 per 100 patient-years of follow-up, respectively), with a mortality similar to that recently reported for the general HIV population with access to HAART .
Although our data strongly suggest that long-term control of HBV replication with potent anti-HBV active antiretroviral regimens may slow down liver fibrosis progression in HIV-HBV-coinfected patients, patients with low CD4 cell counts and those with positive serum HCV antibody seem to remain at increased risk for developing cirrhosis. Moreover, hepatic decompensation events and deaths continued to occur in the presence of delta superinfection or as a result of developing hepatocellular carcinoma. Of note, liver cancer may develop in this setting even in the absence of cirrhosis, as in one of our patients, and, therefore, periodic screening for this tumor with periodic assessment of alphafetoprotein and abdominal ultrasound is warranted.
The deleterious impact of coinfection with multiple hepatitis viruses on prognosis has already been noticed in several studies in HIV-negative individuals [24-27]. Moreover, the recognition of delta superinfection in up to one-fifth of our HBsAg-positive patients, and that accounted for half of hepatic decompensation events is in agreement with the severity of HDV infection [28,29]. Altogether, our data supports the current recommendation to discharge HCV and HDV coinfections in all HIV-infected patients with chronic hepatitis B .
The recognition of low CD4 cell counts as independent predictor of progression to cirrhosis in our HIV-HBV-coinfected population is not surprising. Similar findings have already been reported by others  and reinforce the current recommendation to initiate HAART regardless of CD4 cell counts in all HIV-infected individuals with chronic hepatitis B [30-33].
Clearance of serum HBsAg is the most ambitious objective of antiviral therapy in chronic hepatitis B . It clearly improves the prognosis of liver disease; however, it is rarely achieved with oral antiviral therapy and, hence, it is often considered a nonrealistic goal. Rates of spontaneous HBsAg seroconversion in HBV-monoinfected carriers are below 2% [35,36]. It may increase to 12% following interferon therapy [34,37], whereas it remains below 5% when using oral nucleos(t)ide analogues. In our study conducted in HIV-HBV-coinfected individuals, the annual incidence of serum HBsAg clearance was 2.6% with nucleos(t)ide analogues, in agreement with data from other coinfected patient populations receiving lamivudine and/or tenofovir [5,38,39]. It is noteworthy that HBsAg clearance occurred recently (year 2009) in two patients with chronic hepatitis delta, who since then became aviremic for serum HDV-RNA. In our knowledge, this is the first report of such observation. Interestingly, however, none of these two patients showed anti-HBs seroconversion, which hypothetically may lead to a reappearance of HBsAg along with HDV replication if anti-HBV drugs discontinued. For the safety of patients, we decided to continue the same anti-HBV active antiretroviral regimen in these two patients. Thus, the proof-of-concept of hepatitis delta cure with nucleos(t)ide analogues remains unanswered. In the mean time, our findings and the report of a decline in serum HDV-RNA in at least a subset of patients with chronic hepatitis delta exposed to nucleos(t)ide analogues  encourage to give potent anti-HBV therapy to these patients, which otherwise envision the worst prognosis of all viral hepatitis carriers [28,29].
Studies conducted in HBV-monoinfected individuals have shown that clearance of serum HBeAg reduces the risk of hepatic decompensation and improves survival [34,37]. In the subset of HBsAg-positive/HBeAg-positive adults with elevated ALT, the yearly rate of spontaneous HBeAg clearance ranges from 8 to 12% . It is much lower in patients who are in the immune-tolerant phase and in those with immunosuppression [41,42]. Treatment with nucleos(t)ide analogues increases serum HBeAg clearance to 12-21% per year in HIV-negatives. In our HIV-HBV-coinfected population, we saw a yearly rate of 9%, which is in agreement with findings from others [5,38]. Thus, HBeAg clearance driven by nucleos(t)ide analogues in the HIV setting might be lower, although we cannot exclude that differences with HIV-negatives could be due to different study designs.
Our study has the limitation of being retrospective. Moreover, hepatic fibrosis was assessed using elastometry instead of liver biopsies. Following the advice of recent studies conducted in chronic hepatitis B patients, lower thresholds in elastometric values than those recommended for chronic hepatitis C were used [13-17]. The fact that all but one of the patients who experienced hepatic decompensation had baseline elastometric values above 20 kPa indirectly supports that our diagnostic approach was not wrong and hence the value of our longitudinal assessment.
In summary, the use of potent nucleos(t)ide analogues as part of antiretroviral therapy in HIV-HBV-coinfected patients seems to be associated with increased rates of serum HBeAg and HBsAg clearance and amelioration of liver fibrosis progression, which ultimately leads to an improvement of survival. In less extent, this benefit may also apply to the subset of patients superinfected with delta virus. However, oral nucleos(t)ide analogue therapy do not entirely annul the risk of hepatic decompensation events or death in this population, including the development of hepatocellular carcinoma.
A total of 92 HIV-infected patients with chronic hepatitis B with at least one liver stiffness measurement were identified. Table 1 records the main baseline characteristics of this population. Most patients were male (88%) and had a median age of 41 years. The median time since first HIV and HBV diagnosis was 4.1 (0.5-8.2) years. A total of 42 patients (45.7%) were serum HBeAg-positive. The most prevalent HBV genotypes were A (48.8%) and D (37.7%). Overall, 75% received antiretroviral treatment at baseline, including in all cases at least one drug with dual activity against both HIV and HBV: 12 patients were only on lamivudine and 63 received tenofovir always co-formulated with emtricitabine (Truvada). In 23 patients (25%), FibroScan was performed before introducing HAART. Hepatitis delta was present in 19 (21.1%) patients, and in 14 of them serum hepatitis delta virus (HDV)-RNA could be assessed being positive in all of them (median: 5.4 log IU/ml; IQR: 5.38/5.69). Of the 28 (30.4%) patients who were positive for serum anti-HCV, only 13 were positive for serum HCV-RNA. Of note, five had never been treated and eight had not responded to HCV treatment. Of the 15 patients negative for serum HCV-RNA, 11 had spontaneous clearance and five had achieved sustained virological response with HCV therapy.
The median baseline liver stiffness was 7.7 kPa, with a range between 3.1 and 73.9. Overall, 47.8% of patients had null-mild fibrosis, 28.3% moderate-advanced fibrosis and 23.9% had cirrhosis. The median follow-up was 35 (13-49) months. Overall, 13 patients were lost to follow-up. Of the remaining 79 patients, all but two received anti-HBV active antiretroviral therapy during the study period. It should be highlighted that tenofovir plus either lamivudine or emtricitabine was prescribed in 65 (82.3%) of them. In two patients, tenofovir had to be discontinued following development of kidney tubular dysfunction. At the end of follow-up, serum HBV-DNA was undetectable in 89% of patients (65 of 73). In the remaining eight patients, serum HBV-DNA was detectable. In more detail, two persisted without treatment by voluntary decision, one patient had poor drug adherence, one developed hepatocellular carcinoma and died soon thereafter, one was treated with entecavir after developing Fancony syndrome with tenofovir and had multiple polymerase resistance mutations in HBV due to older prolonged lamivudine monotherapy, and three patients depicted low serum HBV-DNA despite being on tenofovir for a while. Although HBV viremia was detectable, these three patients had experienced a dramatic decline in viremia from baseline. Table 2 records the main differences between baseline and last visit in this population followed longitudinally.
Overall, seven patients cleared serum HBsAg (2.6/100 patient-years), five of them accompanied with anti-HBs seroconversion. All the seven patients had undetectable serum HBV-DNA during the previous 12 months under anti-HBV oral nucleos(t)ide analogues, which had been in all cases lamivudine or emtricitabine for a median (range) of 45 (13-107) months, along with tenofovir in six of them for a median of 23.5 (12-128) months. It should be highlighted that all these patients were serum HBeAg-negative at baseline and two of them were also coinfected with HDV and had detectable serum HDV-RNA at baseline. Serum HDV-RNA became undetectable following HBsAg clearance in them. Moreover, these two patients with delta hepatitis were also positive for anti-HCV antibodies, although they did not show detectable serum HCV-RNA. Interestingly, these two patients were the only ones who did not experience anti-HBs seroconversion following HBsAg clearance. Information on HBV genotype could be obtained testing old stored specimens in four of the seven individuals who cleared HBsAg: two were infected with HBV-A, one HBV-D and one HBV-F. Table 3 summarizes the main characteristics of this population who cleared HBsAg.
Eleven out of 42 serum HBeAg-positive patients cleared HBeAg (9/100 patient-years), although only five of them showed anti-HBe seroconversion. No significant differences were noticed when comparing these patients with those who did not clear serum HBeAg, in terms of ALT levels, liver fibrosis estimates and/or use of anti-HBV active antiretroviral agents. Of note, all had undetectable serum HBV-DNA and all but one received tenofovir at the time of HBeAg clearance. One patient voluntarily discontinued antiviral therapy 6 months after HBeAg clearance and before anti-HBe seroconversion; she experienced serum HBV-DNA rebound along with the reappearance of HBeAg.
Six patients died during follow-up, leading to a death incidence of 2.2/100 patient-years, four of these deaths being liver-related. Another patient died because of chronic lung disease and the remaining individual died for unclear reasons without any prior liver decompensation event.
Eight patients experienced at least one episode of liver decompensation during the study period, leading to an incidence rate of 2.9/100 patient-years. All but one had baseline liver stiffness values above 20 kPa. The remaining patient had 7 kPa at baseline, was not coinfected with either HDV or HCV, but developed hepatocellular carcinoma at the age of 62 years. Only one other patient developed hepatocellular carcinoma in our series. The other patient was a cirrhotic with delta hepatitis. It should be highlighted that half (four of eight) of the patients who experienced liver decompensation during the study period were coinfected with HDV. Figure 1 displays the survival and incidence of liver decompensation in the study population.
Liver fibrosis progression
A second liver stiffness measurement could be obtained in 71 of the original 92 HIV-HBV-coinfected patients. The median (IQR) time between both measurements was 40.1 (21.9-54.1) months. Of note, median liver stiffness slightly declined although it did not differ significantly comparing both examinations (7.7 vs. 6.5; P = 0.9). However, the proportion of patients with null-mild liver fibrosis estimates was significantly greater at the last examination compared with baseline (64.7 vs. 47.8%; P = 0.03).
Overall, most patients (74.7%) stayed on their original liver fibrosis stage (Table 4). However, six patients (8.4%) showed a worsening, with progression from null-mild to moderate-advanced fibrosis (four cases) or from moderate-advanced to cirrhosis (two cases). Conversely, 12 (16.9%) patients experienced an improvement in liver fibrosis staging, with nine switching from moderate-advanced to null-mild fibrosis, two from cirrhosis to moderate-advanced, and one from cirrhosis to null-mild fibrosis.
Predictors of liver cirrhosis
Baseline variables associated with cirrhosis in the univariate analysis were elevated ALT, HDV superinfection, HCV seropositivity and low CD4 cell counts (Table 5). In the multivariate analysis, only positive anti-HCV antibody and low CD4 cell counts remained as independently associated with cirrhosis.
A worsening or improvement of liver fibrosis could not be associated with any single variable, although only one-quarter of patients experienced a change in liver fibrosis stage during the study period. Thus, the limited size of the study population precluded any robust analysis.