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Hepatitis B in the HIV-Coinfected Patient

Benhamou, Yves MD

Author Information

From the Service d'Hépato-Gastro-Entérologie, Hospitalier Pitié-Salpêtrière, Paris, France.

Reprints: Yves Benhamou, MD, Service d'Hépato-Gastro-Entérologie, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l’Hopital-Cedex 13, Paris, France 75651 (e-mail: [email protected]).

JAIDS Journal of Acquired Immune Deficiency Syndromes: July 1, 2007 - Volume 45 - Issue - p S57-S65
doi: 10.1097/QAI.0b013e318068d1dd
  • Free

Abstract

EPIDEMIOLOGY

Highlight

  • Hepatitis B virus (HBV) prevalence is higher among HIV-infected persons than among the general population.

Approximately 5% to 10% of the estimated 40 million persons infected with HIV worldwide are chronically infected with HBV. HBV is spread by percutaneous and mucous membrane contact with infectious blood and with body fluids that contain blood.1 Perinatal, parenteral, and sexual exposures to HBV are highly efficient modes of transmission, and person-to-person spread of HBV can occur among household contacts of a chronically infected person.

The prevalence of HBV infection varies by risk factor and geographic region. Within geographic regions, prevalence is influenced primarily by the age at which most infections occur (Table 1).1 Endemicity of infection is high in those parts of the world where almost all infections occur during the perinatal period or early in childhood (Southeast Asia and sub-Saharan Africa). It is intermediate in areas with mixed patterns of infant, early childhood, and adult acquisition (Eastern Europe, Middle East, and Russia) and low in other parts of the world (Western Europe, Australia, and the United States).

T1-5
TABLE 1:
Prevalence of HBV by Typical Age of Infection and Geographic Region

The highest incidence of acute infection in developed nations occurs among young adults in high-risk groups (eg, injection drug users, persons with multiple heterosexual partners, and men who have sex with men [MSM]).1 Specific transmission patterns vary with geographic region. In Western and Southern Europe, high-risk sexual activity (heterosexual and MSM) accounts for most cases of newly acquired hepatitis B; in Northern Europe, most cases are attributed to injection drug use.1 In the United States, persons reporting high-risk sexual activity comprise nearly half (47%) of acute hepatitis B cases. Acknowledged injection drug use accounted for 15% of cases.2

Sexual contact and injection drug use also account for most HIV infections in developed countries. Persons in high-risk groups who are coinfected with HIV represent pockets of elevated HBV prevalence; HBV prevalence among HIV-coinfected persons may be ≥10-fold higher than that of the background population. Chronic HBV infection occurs in 6% to 14% of HIV-infected persons in Western Europe and the United States overall. Within risk groups, infection rates are 4% to 6% of heterosexuals, 9% to 17% of MSM, and 7% to 10% of injection drug users.1

INFLUENCE OF HEPATITIS B VIRUS ON HIV

Highlight

  • HBV coinfection does not substantially affect the course of HIV disease.

Studies of how HBV affects progression of HIV disease have produced conflicting results. In the final analysis, extended follow-up of patients treated with highly active antiretroviral therapy (HAART) suggests that HBV coinfection does not substantially alter HIV-related mortality.

A persistent state of immune activation has been described in patients with chronic hepatitis B, with chronic HBV replication possibly upregulating HIV replication. It has been suggested that the HBV protein (HBx) superinduces ongoing HIV-1 replication and HIV-1 long-term repeated transcription by synergizing with tat-protein and T-cell activation signals. These findings indicate that HBx could promote faster progression to AIDS in HBV/HIV-coinfected individuals.

Studies from the pre-HAART era did not demonstrate a significant impact of HBV carriage on HIV disease progression, however. Recent data from the EuroSIDA cohort found that hepatitis B surface antigen (HBsAg) positivity did not affect the incidence of a new AIDS-defining event, even after adjustment for confounding factors (use of HAART, baseline viral loads, CD4 cell counts, age, race, and risk factors for transmission of HIV).3 HBsAg status also did not affect the time required for patients to reach undetectable HIV viral loads (<400 copies/mL) or a 25% increase in CD4 cell counts after 6 to 12 months of HAART.3

These findings were reinforced recently by a study examining the impact of viral hepatitis coinfection on HIV disease outcomes after commencement of combination antiretroviral therapy (ART) in a developing country setting.4 HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of Thai HIV-infected patients enrolled in 8 randomized controlled trials of ART (n = 692). The prevalence of HBV coinfection was 8.7%. Interestingly, median HIV RNA reductions (log10 copies/mL) were similar for those with and without HBV coinfection (ie, approximately 1.5 log10 copies/mL from weeks 4-48). Mean increases in CD4 cell count were significantly lower among HIV/HBV subgroups at week 4 (HIV, 62 cells/μL; HIV/HBV, 29 cells/μL) but were similar by week 48 (HIV, 115 cells/μL; HIV/HBV, 113 cells/μL). Estimated progression to an AIDS-related event or death at week 48 was 3.3% (95% confidence interval [CI]: 2.0 to 5.1) for HIV and 6.7% (95% CI: 2.5 to 14.6) for HIV/HBV (P = not significant [NS]). The authors concluded that the early delay in CD4 cell count recovery among HIV/HBV-coinfected patients was not associated with increased HIV disease progression.4

INFLUENCE OF HIV AND HAART ON HEPATITIS B VIRUS

Highlights

  • HIV infection increases the risk of acute HBV infection becoming chronic.
  • HIV infection is associated with a higher level of HBV replication.
  • Risk of liver-related death is higher among HIV/HBV-coinfected persons than among those infected with either virus alone.
  • Immune reconstitution associated with HAART can improve control of HBV replication but also can lead to hepatitis reactivation.
  • In general, early use of HAART may be beneficial.

Coinfection with HIV and treatment with HAART each modify the natural history of HBV infection. Most of the liver damage associated with HBV infection stems from the immune system response to HBV. HIV infection can dampen this immunologic response.5 HAART leads to immune system reconstitution, which can be advantageous or deleterious in HBV-infected patients. These phenomena may explain some of the effects of HIV coinfection and HAART on HBV.

Acute HBV infection is eliminated in 90% to 95% of otherwise healthy adults.6 Clearance rates are reduced in persons with HIV infection, by approximately 60% in the case of hepatitis B virus e antigen (HBeAg).5 Most HIV-infected patients do not mount a significant immune response against HBV and do not seroconvert to anti-HBe. HIV coinfection therefore is associated with a higher risk of chronicity after acute HBV infection compared with HIV-negative persons.7,8

Anti-HBV drug therapy does not seem to prevent acute HBV infection. Treatment with lamivudine, a drug with dual activity against HBV and HIV, prevented acute HBV infection in 1 persistently exposed HIV-positive woman.9 A large cohort study of HIV-infected subjects did not confirm this finding, however. Use of lamivudine as an antiretroviral was not associated with a decreased incidence of acute hepatitis B infection compared with use of HAART or ART regimens not containing lamivudine.10

In addition, in some but not all studies, HIV infection has been associated with a higher level of HBV replication7,8,11,12 and a higher rate of reactivation compared with persons without HIV coinfection.12 HBV reactivation has been linked to CD4+ cell depletion.12

Some cohort studies from the pre-HAART era show significantly less necroinflammatory activity in HIV/HBV-coinfected patients compared with HBV-monoinfected patients.8 Liver fibrosis progression to cirrhosis was not studied, however. Mild liver inflammation was attributed to an immune tolerance state related to impairment of the immune system.

The immunologic reconstitution associated with ART can improve control of HBV replication. Anecdotal reports indicate that it can even lead to HBsAg and HBeAg seroconversion.13-15 Conversely, ART-associated immune reconstitution can lead to increased liver injury (so-called “immune restoration hepatitis”) and liver disease progression.13,16-19

Evidence generally points to an increased risk of hepatic death in HIV/HBV-coinfected patients compared with HBV-monoinfected patients, although data are mixed. A recent case-control study of 5293 MSM concluded that the risk of liver-related death was higher in HIV/HBV-coinfected individuals than in those infected by either virus alone.20 Risk of liver death in individuals with HIV was associated with HBsAg seropositivity independent of age, history of drug use, and number of male sexual partners. Another cohort study has confirmed the elevated risk of death in HIV/HBV-coinfected patients compared with those with HIV alone.21

Both of the aforementioned studies were conducted during the HAART era, which may help to explain their findings. Higher risk of liver-related death in HBV/HIV-coinfected patients compared with monoinfected patients may stem from greater liver injury as a result of the immune reconstitution associated with HAART. The hepatotoxicity of certain anti-HIV therapies also may play a role. Additionally, HAART therapy may prolong survival, such that patients live long enough to develop life-threatening liver disease.6

Immune restoration hepatitis seems to occur most commonly in severely immunosuppressed patients (<200 cells/mm3).22 Both of the aforementioned investigations as well as others found that HBsAg-positive patients with a low CD4+ cell count nadir faced an increased risk of liver-related death.20,21 Data derived from HIV-negative persons suggest that higher levels of HBV DNA (>4 log10 copies/mL) may be associated with an increased risk of cirrhosis and hepatocellular carcinoma; however, the relation between HBV DNA level and clinical outcomes has not been adequately studied in coinfected persons.23,24 Hepatitis flares have been reported to occur despite the inclusion of anti-HBV active agents in the initial ART regimen.19

The significance of alanine aminotransferase (ALT) elevation after HAART initiation in HIV/HBV-coinfected patients is complex. Briefly, it can be related to 5 different situations: (1) HAART-related hepatotoxicity; (2) HBV resistance to antiretrovirals with dual activity included in the HAART regimen; (3) discontinuation of a HAART regimen, including anti-HBV drugs, in a noncompliant patient; (4) super delta virus or HCV infection or other causes; and (5) more frequently, ALT flares in association with the control of HBV replication.5,25 In this latter situation, ALT returns to normal levels in 4 to 12 weeks if anti-HBV drug therapy is maintained and liver lesions improve.26

Recent findings from the Italian Cohort of Naive for Antiretrovirals (ICONA) reported that a lamivudine-containing HAART regimen was independently associated with a decreased risk of liver decompensation.27 This may point to a role for earlier use of HAART with dual activity to slow HBV liver disease progression before severe immunocompromise occurs.28 Current thinking therefore holds that early use of HAART containing dual-activity agents is generally positive for preventing severe immune dysfunction, controlling HBV replication, slowing liver disease progression, and preventing immune-reconstitution hepatitis.

INITIAL ASSESSMENT

Highlight

  • Patients with newly diagnosed HBV infection should be questioned about risk factors and evaluated for signs of liver disease.

Evaluation of a patient with HBV infection should incorporate questions about injection drug use, sexual activity, transfusions, jaundice, alcohol use, family history of HBV infection, liver disease, and prior testing for hepatitis. Physical examination should include surveillance for signs of chronic liver disease (see the article by Bonacini in this issue28a). Patients should be advised to abstain from alcohol, injection drug use, and high-risk sexual behavior.5Table 2 lists areas that should be covered by laboratory testing. Patients should be vaccinated against hepatitis A virus if they are seronegative for this virus.5

T2-5
TABLE 2:
Initial Laboratory Testing of HBsAg-Positive Patients

HBV-related liver disease is generally confined to patients with evidence of ongoing viral replication, usually with HBeAg positivity and high HBV DNA levels detected by polymerase chain reaction (PCR) or another nucleic acid amplification test.5 Age, alcohol consumption (>40 g/d), and serum HBV DNA have been independently associated with fibrosis score in a cohort study of patients with chronic HBV infection.12 Age and low CD4 count (<200 cells/mm3 during follow-up) have been independently associated with increased risk of progression to cirrhosis in the same population.12 Another cohort study identified low CD4 cell count as a significant predictor of mortality due to liver disease in persons infected with HIV and HBV and/or HCV.21 Predictors of HBV-related liver disease severity include age, alcohol consumption, necroinflammation, fibrosis stage, ongoing HBV replication, HBeAg seropositivity, and low CD4 cell count.12,20,29

TREATMENT OF HEPATITIS B VIRUS IN HIV-COINFECTED PATIENTS

Highlights

  • Goals of therapy include HBeAg seroconversion or, failing that, prolonged HBV suppression.
  • Patients generally need long-term maintenance therapy and combination therapy.
  • Stopping anti-HBV therapy has been associated with HBV reactivation.
  • Development of resistance is a drawback of long-term therapy.
  • HBV DNA thresholds for anti-HBV treatment are the same in HIV-coinfected and HBV-monoinfected patients.
  • Choice and timing of treatment initiation depend on clinical and serologic status of HBV and HIV.

The absence of controlled trials and the dual activity of some agents complicate management of chronic hepatitis B infection in HIV-coinfected patients. Treatment should be pragmatic, based on studies of HBV-monoinfected and HIV/HBV-coinfected patients and on clinical experience and judgment. Treatment regimens depend on the clinical status of HIV and HBV and whether both infections are treated concurrently.

Goals of Therapy

The principal goals of anti-HBV treatment are to stop or decrease liver disease progression and to prevent cirrhosis and hepatocellular carcinoma.30 As mentioned previously, HIV-coinfected patients only infrequently seroconvert to anti-HBe. Seroconversion remains an objective, but a more realistic virologic goal is prolonged suppression of HBV replication. Attaining this milestone leads to histologic improvement, a significant decrease or normalization of aminotransferases, and prevention of progression to cirrhosis and end-stage liver disease.22,31

Sustained viral control requires long-term maintenance therapy. Short-term courses are usually impractical even in HBV-monoinfected patients. This is because viral covalently closed circular DNA persists in the liver despite a reduced viral load in the serum.32 Treatment discontinuation, especially of lamivudine, has been associated with HBV reactivation and ALT flares.16,33 In rare cases, ALT flares related to treatment withdrawal have been associated with hepatic decompensation.33-35 The drawback of long-term therapy is the possibility of resistance.

That said, only individuals who maintain HBe seroconversion associated with controlled viral replication may be candidates for a short course of therapy.25

Most coinfected patients require combination therapy for anti-HBV treatment. Single agents have been recommended for HBV monoinfection. The high rate of resistance to lamivudine monotherapy in coinfected patients (20% per year in one study)36 and the need for an indefinite duration of anti-HBV therapy argue for combination therapy in this population, however.

When to Treat Hepatitis B Virus

Indications for anti-HBV therapy have been recently recommended by the first European Consensus Conference on the Treatment of HBV and HCV in HIV-Coinfected Patients (Fig. 1).22 The optimal time to initiate anti-HBV treatment in HIV-coinfected patients is not established. Based on available evidence, the consensus conference advised using the HBV DNA criteria applied to HBV-monoinfected patients. These depend on HBeAg serostatus (see Fig. 1). In HBeAg-positive patients, a serum HBV DNA level >20,000 IU/mL justifies consideration of anti-HBV therapy. In HBeAg-negative patients, the cutoff is a serum HBV DNA level >2000 IU/mL.22 ALT levels also should be considered. If the results of liver function tests are out of proportion to HBV DNA levels, it is prudent to investigate other causes of liver disease.5

F1-5
FIGURE 1:
Treatment algorithm of chronic hepatitis B in HIV-coinfected patients. ADV indicates adefovir dipivoxil; ARV, antiretroviral; ETV, entecavir; NRTI, nucleoside reverse transcriptase inhibitor; PEG IFN, pegylated interferon. *High HBV DNA: >20,000 IU/mL in HBeAg-positive patients, >2000 IU/mL in HBeAg-negative patients. Adapted from J Hepatol. 2005;42:615-624 .

If the patient meets the HBV DNA thresholds for considering anti-HBV therapy, the next step depends on whether he or she requires anti-HIV therapy.

Patients who do not meet criteria for anti-HIV treatment should undergo evaluation of hepatic inflammation and fibrosis stage. This can be accomplished by a biopsy or validated noninvasive markers (see the article by Bonacini in this issue28a).22 Those with a METAVIR ≥A2 and/or ≥F2 should receive anti-HBV therapy.22

These patients should not receive anti-HBV agents with dual (anti-HIV) activity (lamivudine, tenofovir disoproxil fumarate, and emtricitabine). Using anti-HIV therapy at this juncture raises the risk of early HIV resistance, with consequent limitations of HIV therapeutic options. In HBeAg-positive patients, consider pegylated interferon α-2a, adefovir dipivoxil, or entecavir.30 Typically, pegylated interferon is not preferred for the treatment of HBeAg-negative patients, because the chance to achieve HBsAg seroconversion and to maintain HBV DNA suppression off therapy is low.

Although not demonstrated, many experts would recommend combination therapy of a nucleoside and a nucleotide for such patients rather than monotherapy or peginterferon. Furthermore, to date, peginterferon alone or in combination with oral anti-HBV drugs has not been studied in HIV/HBV-coinfected persons.

Recently approved and investigational anti-HBV drugs with no anti-HIV activity may hold promise for coinfected patients who do not need anti-HIV therapy. Two examples are the nucleoside analogues telbivudine and clevudine.30 In a phase 3 clinical trial, telbivudine demonstrated significantly greater anti-HBV activity and proportionately fewer treatment failures compared with lamivudine at 1 year (n = 921 HBeAg-positive subjects, n = 446 HBeAg-negative subjects).37 Investigators also have documented significantly greater HBV DNA reduction with telbivudine than with adefovir in HBeAg-positive patients with chronic hepatitis B at 24 weeks (N = 133).38 Telbivudine is approved in the United States and Switzerland for treatment of chronic HBV infection. Early findings indicate that clevudine therapy leads to significant viral suppression in treatment-naive patients after 48 weeks of therapy (n = 31).39

Some HIV/HBV-coinfected patients who do not require anti-HIV therapy may have a high serum HBV DNA level (>4-5 log10 copies/mL) and no or mild liver disease. These patients should be managed as if they meet the criteria for treatment of both viruses so as to prevent hepatitis of immune reconstitution.30

Patients who meet criteria for anti-HIV and anti-HBV treatment need not undergo measurement of liver necroinflammatory activity and fibrosis stage before moving to treatment. A baseline liver biopsy is valuable for follow-up of the disease course but is not required to determine the need for therapy.22 HAART that includes 2 dual-acting drugs (tenofovir, emtricitabine, or lamivudine) constitutes the preferred option for these patients.22 The best choice is to combine a nucleoside and a nucleotide analogue to prevent long-term resistance (ie, tenofovir plus lamivudine or emtricitabine). Adefovir can be substituted for tenofovir if the latter is contraindicated or otherwise not a desirable option. Similarly, entecavir offers an alternative to emtricitabine or lamivudine.30

When patients change anti-HIV treatments because of intolerance or lack of efficacy, the anti-HBV component should be continued even if it is not part of the subsequent anti-HIV regimen.5 This is because stopping anti-HBV therapy has been associated with reactivation of HBV infection and ALT flares.16

Patients who need anti-HIV therapy but not anti-HBV therapy. Individuals with persistent controlled HBV replication (serum HBV DNA level <4 log10 copies/mL) may not need agents with dual activity. Monitor ALT and serum HBV DNA every 3 or 4 months.30 If anti-HBV therapy does not begin at the same time as ART, delay its introduction until HIV replication is controlled or there is evidence of liver disease. Specifically, monitor HBV DNA for the anti-HBV treatment thresholds as mentioned previously (see Fig. 1).

Patients with HBV resistance to lamivudine. These patients require a HAART regimen with maximum activity against both viruses.22 Tenofovir should be included, and lamivudine should be maintained.

Patients with cirrhosis. Sustained control of HBV replication in patients with cirrhosis is critical to prevent liver decompensation, hepatocellular carcinoma, and death. Preventing resistance and ensuring compliance are paramount considerations. Therefore, cirrhotic patients should receive combination anti-HBV therapy (ie, tenofovir plus emtricitabine or lamivudine included in the HAART regimen or adefovir plus entecavir or telbivudine if there is no indication for anti-HIV therapy). Patients with cirrhosis should be monitored closely during the first 12 to 24 weeks of therapy because of the risk of ALT flare and immune reconstitution hepatitis. Serum HBV DNA should be assessed every 12 weeks. This is especially true for those with CD4 counts <200 cells/mm3.22 Patients with liver decompensation should be treated with combination anti-HBV therapy and considered for liver transplantation.

Endpoints in Hepatitis B Virus Therapy

All patients should have a full biochemical profile, including bilirubin, albumin, liver enzymes, and a complete blood cell count, at least every 6 months.5 Prothrombin time should be measured if there is clinical or biochemical evidence of disease progression.

Assessment of treatment efficacy has been poorly studied in HIV/HBV-coinfected patients. The following summarizes recommendations based on available evidence. It also is important to assess drug compliance, because any interruption may lead to a rebound of viral replication and ALT flares.

Hepatitis B Virus DNA Levels

Monitoring of serum HBV DNA levels is mandatory to assess the initial and ongoing antiviral response, HBe seroconversion, and development of drug resistance. The initial response to anti-HBV therapy with nucleotide and nucleoside analogues is defined as a ≥1-log10 drop in HBV DNA levels within 1 to 3 months.22 After the first 1 to 3 months on treatment, HBV DNA should be assessed every 3 to 6 months.25

No HBV DNA goal has been established in HIV/HBV-coinfected patients. The European consensus conference recommends <2000 IU/mL as a threshold in initially HBeAg-negative patients. A much better goal is undetectable HBV DNA by PCR.

HBV drug resistance is defined by a viral load increase of ≥1 log10 compared with the nadir value during therapy.40 Emergence of resistance exposes patients to progression of liver disease, liver decompensation, and death. The prevalence of drug resistance in coinfected patients has been reported for lamivudine (discussed elsewhere in this article) but not for adefovir, tenofovir, or emtricitabine.

Detection of polymerase mutations by sequencing, line probe assay, and other means should help clinicians to adapt new treatments to the mutation profile in the DNA polymerase gene.41-44

Loss of Hepatitis B Virus e Antigen and Seroconversion

The rate of HBe seroconversion remains low with currently available anti-HBV agents. Still, improved anti-HBV strategies and restoration of the anti-HBV immune responses with HAART make seroconversion an achievable goal.

Alanine Aminotransferase Levels

ALT levels usually follow changes in HBV DNA. Generally, there is a clear correlation between the decrease of viral load and ALT improvement. That said, ALT flares in the first 12 weeks or so of anti-HBV therapy have been reported in HIV-coinfected patients. These flares are associated with a decline of serum HBV DNA25 but not with liver decompensation in noncirrhotic patients; increases in serum bilirubin or prothrombin time are uncommon. In cases of immune activation followed by seroconversion, ALT typically declines.

ALT levels may also reflect the occurrence of drug-induced liver injury in HIV-infected patients receiving HAART or many other drugs used to treat or prevent opportunistic infections. Interpretation of ALT elevations is therefore challenging. Monitoring HBV viral load can help to determine whether a flare is related to control of HBV replication, viral drug resistance, or drug-related hepatotoxicity. Figure 2 summarizes assessment of the most frequent causes of ALT increases in HIV/HBV-coinfected patients.

F2-5
FIGURE 2:
Significance of ALT elevation in HIV/HBV-coinfected patients. HDV indicates hepatitis D virus.

Liver Histology

In HIV-coinfected patients, declining viral loads and improving ALT levels are expected to be associated with improvement in the histologic activity index and liver fibrosis score. Data on the histologic benefit of anti-HBV treatment in this population are limited, however. No large-scale study has examined whether such associations occur in HIV-coinfected patients.

Noninvasive serum markers of liver damage may be useful in the future to confirm these correlations in coinfected patients. (For more information about noninvasive markers, see the article by Bonacini in this issue.28a)

Anti-Hepatitis B Virus Therapy

Six therapeutic agents are currently approved for treatment of chronic HBV in the United States and the European Union: interferon-α and pegylated interferon α-2a, lamivudine (100 mg/d), adefovir, entecavir, and telbivudine. Three agents with anti-HBV activity are licensed for the treatment of HIV: lamivudine (300 mg/d), tenofovir, and emtricitabine. With the exception of telbivudine, all these drugs have been tested in HIV/HBV-coinfected patients (Table 3).30

T3-5
TABLE 3:
Responses to Anti-HBV Agents Tested in HIV/HBV-Coinfected Patients

Interferon-α

Historically, standard interferon-α (5 MU daily or 9-10 MU 3 times weekly) has been the first-line therapy for HBV monoinfection.45 Data conflict about the value of interferon-α in HIV-positive patients with chronic hepatitis B.46 Some evidence suggests a similar response regardless of HIV coinfection;47 other findings document a lower response rate in HIV-coinfected patients.12 One small, randomized, dose-ranging study reported that interferon α-2a therapy was no better than the absence of anti-HBV therapy in HIV-coinfected patients.48 In another randomized trial, HIV-coinfected subjects were one fifth as likely to respond to interferon-α as HIV-negative patients.49 Most of these studies were conducted in a small number of deeply immunosuppressed patients before the HAART era.

Pegylated interferon is becoming the standard therapy for HBV.22 The optimal dose and duration of pegylated interferon remain unknown. The objective should be HBeAg seroconversion, however. Pegylated interferon α-2a at a dosage of 180 μg/wk for 1 year demonstrated its efficacy in HBeAg-positive monoinfected patients, resulting in 27% HBsAg seroconversion at 48 weeks.50 Pegylated interferon has never been tested in coinfected patients. The same dose and duration may be used in coinfected HbeAg-positive patients who do not need anti-HIV therapy, however. Pegylated interferon may not result in sustained HBV DNA suppression off therapy in patients who do not seroconvert to anti-HBeAb and in patients with precore mutant HBV (HBeAg-negative).22,51

Lamivudine

This nucleoside analogue offers anti-HIV and anti-HBV activity. It inhibits HBV replication in up to 87% of HIV/HBV-coinfected patients.52 Rates of anti-HBe seroconversion are highly variable, ranging up to 11% of patients in some studies.52,53 Lamivudine is generally well tolerated.

As noted, HBV resistance is a major problem with lamivudine. Emergence of lamivudine resistance has been associated with HBV reactivation and ALT flares.54 Such resistance was characterized by detection of specific mutations in the YMDD motif of the viral DNA polymerase. None of the following variables were associated with an increased risk of lamivudine resistance: age, associated protease inhibitor therapy, Centers for Disease Control and Prevention (CDC) stage C, known HIV infection duration, serum HBV DNA level at baseline, CD4 cell count, or serum ALT levels at baseline and at HBV replication suppression (2 months of lamivudine).36 Our group has observed that lamivudine resistance develops in 47% of patients at 2 years and in 90% at 4 years of treatment.36

Adefovir Dipivoxil

This once-daily nucleotide analogue reverse transcriptase inhibitor is active against wild-type and lamivudine-resistant HBV. In 35 HIV/HBV-coinfected lamivudine-resistant patients, adding once-daily adefovir at a dose of 10 mg reduced serum HBV DNA (Amplicor HBV Monitor, Hoffmann-La Roche Inc., Nutley, NJ [OBAS]) by a median of 4.7, 5.5, and 5.9 log10 copies/mL at weeks 48, 96, and 144, respectively.55 No adefovir-associated HBV and HIV mutations surfaced during 144 weeks of follow-up.55 Coinfected patients generally tolerate adefovir well during short- and long-term therapy. No renal toxicity has been reported other than 2 cases of mild serum creatinine elevations during the first 48 weeks of therapy.55

Entecavir

This agent is a purine-derived nucleoside analogue with anti-HBV activity and no anti-HIV activity. Entecavir reduced HBV DNA by nearly 7 log10 copies/mL with no observed resistance over 48 weeks in HBV-monoinfected lamivudine-naive patients.56

In HIV-coinfected lamivudine-resistant patients, adding entecavir rather than placebo reduced HBV DNA by a mean reduction of 3.66 log10 copies/mL compared with baseline over 24 weeks.57

Current guidelines list entecavir as a reasonable alternative in patients not requiring HAART.58 This is based on the reported absence of clinically relevant anti-HIV activity.58 Evidence of potent HIV inhibition and resistance has recently been reported, however, and may lead to a revision of these recommendations.59 Cases of 3 HIV/HBV-coinfected patients who experienced a 1-log decline in their HIV RNA level during entecavir monotherapy led researchers to study in vitro dose-response curves for entecavir inhibition of HIV. HIV RNA was extracted from 1 HIV/HBV-coinfected patient at several time points during entecavir monotherapy and then was amplified, cloned, and sequenced. Entecavir inhibited HIV replication, with a median inhibitory concentration (IC50) lower than the plasma concentrations achieved in vivo at doses given for anti-HBV therapy and 100- to 1000-fold lower than that of zidovudine in the same system. After 4 months of entecavir therapy, 61% of isolates from the coinfected patient contained the M184V mutation, and at 6 months, 96% showed the mutation. This variant confers high-level resistance to entecavir. It should be noted that these findings have only been reported in 1 patient in an unpublished oral abstract presented at the 2007 Conference on Retroviruses and Opportunistic Infections (CROI) and that more studies have to be conducted and reviewed before considering a change in the guidelines or practice; however, entecavir should be used with caution in HIV-positive patients not taking HAART.

HIV Agents With Hepatitis B Virus Activity

Emtricitabine

This newer nucleoside reverse transcriptase inhibitor is a 5-fluorinated derivative of lamivudine.60 Analysis of data from randomized controlled trials of HIV infection revealed that emtricitabine (200 mg/d) reduced serum HBV DNA by up to 3.13 log10 copies/mL (HBV Hybrid Capture Assay; Digene Corp., Gaithersburg, MD) in HIV/HBV-coinfected patients.61 Serum HBV DNA was undetectable (<4700 copies/mL) in 49% of coinfected patients at week 48.61 In 39 treatment-naive HIV/HBV-coinfected patients, the incidence of mutations in the viral polymerase after 1 year of therapy with emtricitabine was 12%.62 Emtricitabine was generally well tolerated in these few studies.

Tenofovir Disoproxil Fumarate

This agent, an acyclic nucleotide reverse transcriptase inhibitor, is effective against HIV and against wild-type and lamivudine-resistant HBV.63

An exploratory analysis in HIV-coinfected patients revealed that the mean log10 decline in HBV DNA after 48 weeks of tenofovir therapy was −4.7 with tenofovir plus lamivudine (n = 5) compared with −3.0 with lamivudine alone (n = 6).64 Tenofovir anti-HBV activity was similar for patients with wild-type (−5.3 log10) and lamivudine-resistant (−4.6 log10) HBV.64

A larger (n = 118) retrospective multicenter trial of tenofovir in HIV/HBV-coinfected patients reported a median reduction in HBV DNA of −3.95 log10 copies/mL after a median follow-up of 9 months.65 Among 54 HBeAg-positive patients, serum HBV DNA became undetectable in 29.6%, 7.4% lost HBeAg, and 3.7% seroconverted to anti-HBe (median follow-up of 12 months).66

In a randomized controlled trial to assess the noninferiority of tenofovir compared with adefovir, the mean log10 time-weighted average change from baseline to week 48 was −4.44 log10 copies/mL with tenofovir and −3.21 log10 copies/mL with adefovir.67

It is interesting to note that no HBV resistance to tenofovir has been reported yet in HIV/HBV-coinfected patients. Almost all the HIV/HBV-coinfected patients in published tenofovir studies were receiving concomitant lamivudine therapy as a part of HAART, however. This add-on strategy may reduce the risk of HBV resistance to tenofovir.

Tenofovir use may be limited by renal toxicity (tubulopathy) that can occur even years after initiation. Creatinine and potassium levels should be monitored every 3 or 4 months.

CONCLUSIONS

The interactions of HIV, HBV, and HAART complicate disease course and management of patients coinfected with HIV and HBV. HBV coinfection does not substantially affect the course of HIV disease, but HIV coinfection does significantly alter the course of HBV disease. On the whole, early use of HAART is beneficial in coinfected patients who meet the criteria for ART. Patients with low CD4 cell counts and high HBV viral loads at initiation of HAART are at increased risk for immune reconstitution hepatitis and should be monitored closely.

Availability of agents with dual activity against HIV and HBV facilitates management of coinfected patients. It also mandates careful monitoring of treatment effects on both infections to detect and avoid triggering resistance or relapse.

The lack of conclusive data about management of HIV/HBV coinfection complicates treatment decisions. Nevertheless, the introduction of new agents in recent years and the studies of investigational agents should increase our understanding.

REFERENCES

1. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(Suppl):S6-S9.
2. Centers for Disease Control. Incidence of acute hepatitis B-United States, 1990-2002. Morb Mort Wkly Rep. 2004;52:1252-1254.
3. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19:593-601.
4. Law WP, Duncombe CJ, Mahanontharit A, et al. Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort. AIDS. 2004;18:1169-1177.
5. Brook MG, Gilson R, Wilkins E, and the BHIVA Hepatitis Coinfection Guideline Committee on behalf of the British HIV Association. BHIVA guidelines: HIV and chronic hepatitis: co-infection with HIV and hepatitis B virus infection. 2005. Available at: http://www.bhiva.org/guidelines/2005/BHIVA-guidelines/index.html. Accessed March 6, 2007.
6. Thimme R, Spangenberg HC, Blum HE. Hepatitis B or hepatitis C and human immunodeficiency virus infection. J Hepatol. 2005;42(Suppl):S37-S44.
7. Krogsgaard K, Lindhart BO, Nielsen JO, et al. The influence of HTLV III infection on the natural history of hepatitis B virus infection in male homosexual HBsAg carriers. Hepatology. 1987;7:37-41.
8. Bodsworth N, Donovan B, Nightingale BN. The effects of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J Infect Dis. 1989;160:577-582.
9. Liuzzi G, Zaccarelli M, Sette P, et al. Acute hepatitis B by sexual transmission after interruption of lamivudine-containing antiretroviral regimen. AIDS. 2001;15:2062-2063.
10. Kellerman SE, Hanson DL, McNaghten AD, et al. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human immunodeficiency virus-infected subjects. J Infect Dis. 2003;188:571-577.
11. Koblin BA, Taylor PE, Rubinstein P, et al. Effect of duration of hepatitis B virus infection on the association between human immunodeficiency virus type-1 and hepatitis B viral replication. Hepatology. 1992;15:590-592.
12. Di Martino V, Thevenot T, Colin J, et al. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812-1822.
13. Carr A, Cooper DA. Restoration of immunity to chronic hepatitis B infection in HIV-infected patients on protease inhibitors. Lancet. 1997;349:995-996.
14. Velasco M, Morán A, Téllez MJ. Resolution of chronic hepatitis after ritonavir treatment in an HIV infected patient. N Engl J Med. 1999;340:1765-1766.
15. Piroth L, Grappin M, Buisson M, et al. Hepatitis B virus seroconversion in HIV-HBV coinfected patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2000;23:356-357.
16. Bessesen M, Ives D, Condreay L, et al. Chronic active hepatitis B exacerbation in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis. 1999;28:1032-1035.
17. Proia LA, Ngui SL, Kaur S, et al. Reactivation of hepatitis B in patients with human immunodeficiency virus infection treated with combination antiretroviral therapy. Am J Med. 2000;108:249-251.
18. Manegold C, Hannoun C, Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis. 2001;32:144-148.
19. Drake A, Mijch A, Sasadeusz J. Immune reconstitution hepatitis in HIV and hepatitis B coinfection, despite lamivudine therapy as a part of HAART. Clin Infect Dis. 2004;39:129-132.
20. Thio C, Seaberg E, Skolasky R, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the MACS. Lancet. 2002;360:1921-1926.
21. Bonacini M, Louie S, Bzowej N, et al. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS. 2004;18:2039-2046.
22. Alberti A, Clumeck N, Collins S, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol. 2005;42:615-624.
23. Iloeje UH, Yang HI, Su J, et al, for the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686.
24. Chen C-J, Yang H-I, Su J, et al, for the REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73.
25. Zoulim F. Assessment of treatment efficacy in HBV infection and disease. J Hepatol. 2006;44(Suppl):S95-S99.
26. Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus. Lancet. 2001;358:718-723.
27. Puoti M, Cozzi-Lepri A, Ancarani F, et al. The management of hepatitis B virus/HIV-1 co-infected patients starting their first HAART regimen. Treating two infections at the price of one drug? Antivir Ther. 2004;9:811-817.
28. Puoti M, Torti C, Bruno R, et al. Natural history of chronic hepatitis B in co-infected patients. J Hepatol. 2006;44(Suppl):S65-S70.
28a. Bonacini M. Diagnosis and management of cirrhosis in coinfected patients. J Aquir Immune Defic Syndr. 2007;45(Suppl 2):S38-S46.
29. Housset C, Pol S, Carnot F, et al. Interactions between human immunodeficiency virus-1, hepatitis delta and hepatitis B virus infection in 260 chronic carriers of hepatitis B virus. Hepatology. 1992;15:578-583.
30. Benhamou Y. Treatment algorithm for chronic hepatitis B in HIV-infected patients. J Hepatol. 2006;44(Suppl):S90-S94.
31. Keeffe EB, Dieterich DT, Han SHB, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004;2:87-106.
32. Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology. 2004;126:1750-1758.
33. Neau D, Schvoerer E, Robert D, et al. Hepatitis B exacerbation with a precore mutant virus following withdrawal of lamivudine in a human immunodeficiency virus-infected patient. J Infect. 2000;41:192-194.
34. Bonacini M, Kurz A, Locarnini S, et al. Fulminant hepatitis B due to a lamivudine-resistant mutant of HBV in a patient coinfected with HIV. Gastroenterology. 2002;122:244-245.
35. Bruno R, Sacchi P, Malfitano A, et al. YMDD-mutant HBV strain as a cause of liver failure in an HIV-infected patient. Gastroenterology. 2001;121:1027-1028.
36. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999;30:1302-1306.
37. Gane E, Lai CL, Liaw YF, et al. Phase III comparison of telbivudine vs. lamivudine in HBeAg-positive patients with chronic hepatitis B: efficacy, safety, and predictors of response at 1 year [abstract 493]. Presented at: 41st Annual Meeting of the European Association for the Study of the Liver (EASL); 2006; Vienna.
38. Chan HLY, Lai CL, Cho M, et al. A randomized trial of telbivudine (LDT) vs. adefovir for HBeAg-positive chronic hepatitis B: results of the primary week 24 analysis [abstract 52]. Presented at: 41st Annual Meeting of the European Association for the Study of the Liver (EASL); 2006; Vienna.
39. Chung YH, Lee KS, Kim JH, et al. Six month maintenance therapy with 10 mg clevudine maintains the viral suppression and biochemical improvement achieved with six months therapy with 30 mg [abstract LB19]. Hepatology. 2006;44(Suppl 1):698A.
40. Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance in patients with chronic hepatitis B. Antivir Ther. 2004;9:679-693.
41. Lok AS, Zoulim F, Locarnini S, et al. Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO-LiPA HBV DR assay. J Clin Microbiol. 2002;40:3729-3734.
42. Nafa S, Ahmed S, Tavan D, et al. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B. Hepatology. 2000;32:1078-1088.
43. Durantel D, Carrouee-Durantel S, Werle-Lapostolle B, et al. A new strategy for studying in vitro the drug susceptibility of clinical isolates of human hepatitis B virus. Hepatology. 2004;40:855-864.
44. Yang H, Westland C, Xiong S, et al. In vitro antiviral susceptibility of full-length clinical hepatitis B virus isolates cloned with a novel expression vector. Antiviral Res. 2004;61:27-36.
45. EASL Jury. Consensus statement. EASL International Consensus Conference on Hepatitis B, 13-14 September 2002, Geneva, Switzerland. J Hepatol. 2003;38:533-540.
46. Thio CL, Sulkowski MS, Thomas DL. Treatment of chronic hepatitis B in HIV-infected persons: thinking outside the black box. Clin Infect Dis. 2005;41:1371.
47. Zylberberg H, Jiang J, Pialoux G, et al. Alpha-interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients. Gastroenterol Clin Biol. 1996;20:968-971.
48. McDonald JA, Caruso L, Karayannis P, et al. Diminished responsiveness of male homosexual chronic hepatitis B virus carriers with HTLV III antibodies to recombinant alpha interferon. Hepatology. 1987;7:719-723.
49. Wong DK, Yim C, Naylor CD, et al. Interferon alfa treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology. 1995;108:165-171.
50. Lau GKK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-2695.
51. Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and adolescents. MMWR Recomm Rep. 2004;53(RR15):1-112. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5315a1.htm. Accessed February 16, 2006.
52. Benhamou Y, Katlama C, Lunel F, et al. Effects of lamivudine on replication of hepatitis B virus in HIV-infected men. Ann Intern Med. 1996;125:705-712.
53. Dore GJ, Cooper DA, Barrett C, et al, for the CAESAR Coordinating Committee. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis. 1999;180:607-613.
54. GlaxoSmithKline. Epivir-HBV® prescribing information. Precautions. Research Triangle Park, NC; GlaxoSmithKline; 2004.
55. Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol. 2006;44:62-67.
56. Chang TT, Gish R, de Mann R, et al. Entecavir is superior to lamivudine for the treatment of HBeAg (+) chronic hepatitis B: results of phase III study ETV-022 in nucleoside-naïve patients [abstract 70]. Hepatology. 2004;40(Suppl 1):193A.
57. Pessoa W, Gazzard B, Huang A, et al. Entecavir in HIV/HBV-co-infected patients: safety and efficacy in a phase II study (ETV-038) [abstract 123]. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2005; Boston.
58. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents-A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October 10, 2006. Available at: http://AIDSinfo.nih.gov. Accessed February 16, 2006.
59. McMahon M, Jilek B, Breenen T, et al. The anti-hepatitis B drug entecavir inhibits HIV-1 replication and selects HIV-1 variants resistant to antiretroviral drugs [abstract 136LB]. Presented at: 14th Conference on Retroviruses and Opportunistic Infections (CROI); 2007; Los Angeles.
60. Papatheodoridis G, Dimou E, Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B: antiviral efficacy and viral resistance. Am J Gastroenterol. 2002;97:1618-1628.
61. Raffi F, Snow A, Borroto-Esoda K, et al. Anti-HBV activity of emtricitabine in patients co-infected with HIV and hepatitis B virus [abstract]. In: Abstracts of the Second International AIDS Society Conference on HIV Pathogenesis and Treatment. Paris; 2003:215.
62. Harris J, Snow A, Borroto-Esoda K, et al. Emtricitabine therapy for hepatitis infection in HIV+ patients co-infected with hepatitis B: efficacy and genotypic findings in antiretroviral treatment naïve patients [abstract 836]. Presented at: 11th Conference on Retroviruses and Opportunistic Infection (CROI); 2004; San Francisco.
63. Ying C, De Clercq E, Nicholson W, et al. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral Hepat. 2000;7:161-165.
64. Dore GJ, Cooper DA, Pozniak AL, et al, for the 903 and 907 Study Teams. Efficacy of tenofovir DF in antiretroviral therapy-naive and -experienced patients. J Infect Dis. 2004;189:1185-1192.
65. Benhamou Y, Katlama C, Rozembaum W, et al. Anti-hepatitis B virus (HBV) activity of tenofovir DF in human immunodeficiency virus (HIV) co-infected patients [abstract]. Hepatology. 2003;38(Suppl 1):712A.
66. Benhamou Y, Fleury H, Trimoulet P, et al, for the TECOVIR Study Group. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006;43:548-555.
67. Peters MG, Andersen J, Lynch P, et al, for the Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44:1110-1116.
Keywords:

hepatitis B; hepatitis C virus treatment; HIV; HIV/hepatitis B virus coinfection

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