HBV-HIV Coinfection Key Clinical Management Issues by vos69278



HBV-HIV Coinfection:
Key Clinical Management Issues
Frank Trinh, MD and Vivian Levy, MD

Hepatitis B virus (HBV) coinfection is a considerable problem                                                The prevalence of past infection
in HIV-infected persons, leading to significant liver-related                                             (anti–hepatitis B core antigen
morbidity and mortality. Optimizing HBV treatment requires                                                [HBcAg]-positive) ranges from 10%
balancing the need for antiretroviral therapy and the severity                                            to 40% among sexually transmitted
                                                                                                          disease clinic patients and from 10%
of liver disease with the risk of drug-resistant HBV and HIV
                                                                                                          to 25% among men who have sex
variants. Combination therapy with tenofovir plus either                                                  with men and are younger than 30
lamivudine or emtricitabine is recommended for patients                                                   years.2 In US and European cohorts
who require treatment for HBV infection and combination                                                   of HIV-infected persons, 7% to 10%
antiretroviral therapy for HIV infection. Pegylated interferon                                            have chronic HBV infection, which is
alfa and adefovir dipivoxil are HBV treatment options for                                                 defined as the persistence of surface
coinfected patients who do not require antiretroviral therapy                                             antigen in the serum for at least 6
for HIV infection. For patients who have received therapy for                                             months.1,3
HBV infection, the types of HBV mutations should help guide                                                  HIV infection increases the risk of
treatment selection. [Infect Med. 2007;24:196-206]                                                        chronic HBV infection. Chronic HBV
                                                                                                          infection develops in 23% of coin-
                                                                                                          fected adults but in only 4% of those
Key words: Hepatitis B virus ■ HIV/AIDS ■ HBV-HIV coinfection
                                                                                                          without HIV infection.4
                                                                                                             In addition, spontaneous hepatitis

        iven the shared risk factors                  HIV drug-resistance.                                B surface antigen (HBsAg) and hep-
        for transmission, coinfection                    In this article, we briefly review               atitis B e antigen (HBeAg) serocon-
        with hepatitis B virus (HBV)                  the epidemiology and natural histo-                 version (the loss of HBsAg with de-
and HIV is common. HIV infection                      ry of HBV-HIV coinfection, and then                 velopment of anti-HBsAg and the
increases the risk of chronic HBV in-                 we describe the current treatment                   loss of HBeAg with development of
fection and hastens the progression                   options.                                            anti-HBeAg, respectively) is less
of liver disease in patients with                                                                         likely with coinfection. Elevated and
chronic HBV infection.                                EPIDEMIOLOGY AND                                    sustained serum HBV DNA levels
   The treatment of chronic HBV in-                   NATURAL HISTORY                                     are often seen in HBV-HIV coinfect-
fection needs to be carefully coordi-                 An estimated 60,000 persons in the                  ed patients, while liver enzyme ele-
nated with HIV management in                          United States have chronic coinfec-                 vations are usually milder in these
HBV-HIV coinfected patients. The                      tion with HBV and HIV.1 The highest                 patients than in those with HBV
main goals of treatment for HBV in-                   incidence of acute HBV infection is                 monoinfection.5
fection are to suppress HBV replica-                  in adults who are aged 25 to 45 years.                 Clinical studies have demonstrat-
tion, improve liver function, and                     Most of these infections are sexually               ed that the risk of end-stage liver dis-
minimize the emergence of HBV and                     acquired.                                           ease is increased in HBV-HIV coin-
                                                                                                          fected patients. A recent population-
                                                                                                          based prospective study of 3653
Dr Trinh is a postdoctoral fellow and Dr Levy is clinical instructor in the division of infectious dis-
eases at Stanford University School of Medicine, Stanford, Calif. Dr Trinh is also affiliated with the    HBsAg-positive, HIV-negative pa-
Peninsula AIDS Research Center and the San Mateo County Foundation.                                       tients found that the incidence of he-


patocellular carcinoma increased             Precore and core promoter mu-          serum HBV DNA levels (more than
with serum HBV DNA level at study         tant viruses occur mainly in persons      104 copies/mL) and elevated ALT
entry, independent of HBeAg sero-         who have HBV genotypes other than         levels.
status, serum alanine aminotrans-         A. Therefore, these viruses are un-          Patients who are starting HIV an-
ferase (ALT) level, and the presence      common in the United States where         tiretroviral therapy and who have
of liver cirrhosis.6 Another study that   genotype A predominates, but they         HBV DNA levels of less than 104
included 3582 HBV-monoinfected            are very common in Asian and              copies/mL and normal ALT levels
patients found a similar relationship     southern European countries where         may not need anti-HBV therapy.
between serum HBV DNA level and           other genotypes are prevalent.11 In       However, their serum HBV DNA
cirrhosis.7                               addition to the association between       and ALT levels should be monitored
    Among 5293 men in the Multicen-       HBV genotype and precore and core         every 3 to 6 months. Close surveil-
ter AIDS Cohort Study, coinfected         promoter mutations, evidence is           lance of serum HBV DNA and ALT
men were almost 19 times more like-       mounting that HBV genotype corre-         levels is important given their fluc-
ly to die of liver disease than those     lates with disease progression and        tuating nature in chronic HBV infec-
infected with HBV alone and more          clinical outcomes.12,13                   tion.20,21 If antiretroviral therapy for
than 8 times more likely to die of           Occult HBV (HBV DNA in the ab-         HIV is not indicated, HBV treatment
liver disease than those infected with    sence of HBsAg) is often marked by        should be considered for patients
HIV-1 alone.8 Among coinfected            the anti-HBc–alone pattern. The re-       who have serum HBV DNA levels of
men, higher liver-related mortality       ported prevalence of occult HBV in-       greater than 104 copies/mL and ele-
was observed for each risk factor         fection in HIV-1–infected persons         vated ALT levels. The use of anti-
evaluated, but none was statistically     varies widely.14,15 Conflicting results   HBV drugs without HIV activity is
significant. In an observational study    have been found concerning wheth-         preferred in this case.19
of more than 23,000 HIV-infected          er occult HBV infection in HIV-              Histological staging of liver dis-
persons followed in Europe, the           infected persons increases hepatic        ease is useful in the decision to start
United States, and Australia, active      flares (elevations of liver enzyme        HBV therapy. Liver biopsy is recom-
HBV infection (defined as HBsAg-          levels) after the start of combination    mended but not required in all coin-
positive, HBeAg-positive, or HBV          antiretroviral therapy.16,17              fected patients before starting anti-
DNA–positive) was an independent             Persons who continue to have cir-      HBV therapy.20 Patients with HIV-
predictor of liver-related death (ad-     culating HBsAg with low or unde-          HBV coinfection have been found to
justed relative risk, 3.73).9             tectable levels of HBV DNA are in-        have cirrhosis with lower ALT levels
    During the initial stage of chronic   active carriers. Inactive carriers usu-   than patients with HBV monoinfec-
HBV infection, serum HBV DNA              ally have a benign clinical course,       tion.22 Therefore, liver biopsy can
levels are high and HBeAg is pres-        although up to 30% may have reac-         sometimes be helpful in the setting
ent. In most persons with chronic         tivation of HBV infection with asso-      of persistently normal transaminase
HBV infection, seroconversion from        ciated flares and progression of liver    levels.
HBeAg to anti-HBeAg eventually            disease.18                                   Recent guidelines for HBV-
occurs,10 HBV DNA levels decrease,                                                  monoinfected patients recommend
ALT levels normalize, and hepatic         CANDIDATES FOR                            liver biopsy for those with HBV
inflammation decreases.                   HBV TREATMENT                             DNA levels of 104 copies/mL or
    During seroconversion of HBeAg        The ideal time to initiate HBV-specif-    higher and normal ALT levels, espe-
to anti-HBeAg, precore and core pro-      ic treatment in coinfected persons is     cially for patients older than 35 to 40
moter mutant viruses that are inef-       based on the need for combination         years. Treatment for HBV infection
fectively controlled by the immune        antiretroviral therapy; the level of      should be considered for patients
response may develop in a subset of       HBV viremia; HBeAg serostatus; de-        with moderate to severe fibrosis
patients. Patients with these mutant      gree of liver disease; and considera-     (stage 2 or greater) and/or signifi-
viruses tend to have more severe he-      tion of potential adverse events, in-     cant inflammation on liver biopsy.23
patic inflammation and a higher like-     cluding drug resistance (Figure).19 If       The primary goals of HBV treat-
lihood of cirrhosis. The likelihood of    antiretroviral therapy for HIV infec-     ment are the reduction of HBV DNA
these mutant viruses developing is        tion is indicated, a regimen with         levels, normalization of ALT levels,
related to the duration of infection,     both anti-HIV and anti-HBV activity       and improvement in liver histology.
as suggested by an older age at clin-     should be strongly considered, espe-      Durable HBV suppression will lead
ical presentation.                        cially in patients who have high          to histological improvement and

                                                                                    May 2007 INFECTIONS in MEDICINE 197
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ALT normalization. Furthermore,           patients who had low CD4+ T-cell          IFN alfa for chronic hepatitis C in
treatment may reduce the risk of he-      counts.26                                 HIV-infected persons reported ad-
patic decompensation and hepato-              The duration of treatment is 4 to 6   verse-event rates similar to those
cellular carcinoma in the setting of      months for HBeAg-positive patients        for patients with hepatitis C virus
advanced fibrosis or cirrhosis.24         and up to 12 months or more for           monoinfection.31,32
Meeting these goals requires long-        HBeAg-negative patients, since IFN
term therapy because of intrahepatic      alfa is more effective in HBeAg-pos-      Lamivudine
persistence of HBV DNA in the form        itive patients with chronic HBV in-       This cytosine analogue reverse tran-
of covalently closed circular DNA         fection.20 High ALT levels (more          scriptase inhibitor has activity
(cccDNA).25                               than 2 times the upper limit of nor-      against both HBV and HIV. The ap-
   HBV cccDNA functions as the in-        mal) and low serum HBV DNA lev-           proved dosages for lamivudine are
tracellular template for continued        els are the best predictors of re-        100 mg once daily for chronic HBV
viral replication and is unlikely to be   sponse.27 Treatment duration is lim-      infection and 300 mg daily for HIV
eradicated by current HBV therapy.        ited by adverse effects, including        infection. In HBV-HIV coinfected pa-
As a result, indefinite treatment may     bone marrow suppression, flu-like         tients, lamivudine should be given
be necessary to maintain viral sup-       symptoms, depression, and thyroid         only at the 300-mg daily dose (either
pression. HBeAg seroconversion is         dysfunction.                              300 mg once daily or 150 mg twice
another treatment goal in HBeAg-              IFN alfa should be used with cau-     daily) and in the setting of combina-
positive patients. HBsAg serocon-         tion in patients who have compen-         tion antiretroviral therapy to prevent
version is an ideal but unlikely goal     sated cirrhosis, because hepatic          the appearance of lamivudine-resis-
in HBV therapy.                           necroinflammatory flares with ther-       tant HIV.
                                          apy may lead to decompensation.              Lamivudine is associated with
HBV TREATMENT OPTIONS                     Treatment is contraindicated in pa-       significant viral suppression and im-
Six drugs have been approved by the       tients with decompensated cirrhosis.      provement in ALT levels in both
FDA for the treatment of chronic              Peg-IFN alfa has now supplanted       HBV-HIV coinfected and HBV-
HBV infection: interferon (IFN) alfa      standard IFN alfa. To date, no data       monoinfected patients. Undetectable
2b in 1992, pegylated IFN (Peg-IFN)       have been published regarding the         HBV DNA was documented in 40%
alfa 2a in 2005, lamivudine (at 100       effectiveness of Peg-IFN in coinfect-     to 87% of coinfected patients treated
mg daily) in 1998, adefovir dipivoxil     ed patients. In HBeAg-positive HBV-       with lamivudine 300 mg/d for 13 to
in 2002, entecavir in 2005, and tel-      monoinfected patients, a 24-week          24 months.33,34 HBeAg seroconver-
bivudine in 2006. In addition, 3          course of Peg-IFN was found to be         sion rates with lamivudine treatment
drugs active against HBV have been        more effective than 24 weeks of stan-     in coinfected patients have ranged
approved for HIV treatment: la-           dard IFN, with a comparable ad-           from 22% to 29%.33,34
mivudine (at 300 mg daily), tenofo-       verse-event profile.28 Peg-IFN alfa          Lamivudine-resistant HBV with
vir, and emtricitabine.                   was also found to be more effective       mutations in the YMDD motif of the
                                          than lamivudine over 48 weeks of          polymerase gene emerges at a high
IFN alfa                                  therapy in both HBeAg-positive and        rate with lamivudine monotherapy
HBV-HIV–coinfected patients have a        HBeAg-negative patients without           in both coinfected and HBV-mono-
poorer response to IFN alfa than          HIV infection. The combination of         infected patients. The cumulative
HBV-monoinfected patients. Pub-           Peg-IFN alfa plus lamivudine was          risk of lamivudine resistance in coin-
lished data evaluating the response       not more effective than Peg-IFN alfa      fected patients is linear, with a 20%
to IFN alfa in patients with HIV coin-    alone.29,30                               annual incidence and an estimated 4-
fection are from the pre-HAART era            Peg-IFN alfa is a potential option    year resistance rate of 90%.35 Selec-
involving significantly immunosup-        for initial HBV treatment in coinfect-    tion of YMDD mutants may lead to
pressed patients. One retrospective       ed patients who have high CD4+ T-         acute exacerbation of HBV infection
study showed that coinfected pa-          cell counts, high ALT levels, and low     with flares in ALT levels and pro-
tients treated with IFN had lower         HBV DNA levels. In addition, the          gression of liver disease.20
rates of HBV DNA loss and HBeAg           lack of anti-HIV activity makes IFN          Because of the high potential for
seroconversion and a higher rate of       alfa a good treatment choice in suit-     resistance, recent treatment guide-
HBV reactivation than HBV-mono-           able coinfected patients who do not       lines for HBV monoinfection no
infected patients had.26 A poorer re-     yet require antiretroviral therapy for    longer recommend lamivudine
sponse was observed in coinfected         HIV infection. Clinical trials of Peg-    monotherapy as first-line therapy.23


                          Figure – Treatment algorithm for hepatitis B virus infection
                                                                                    Patient is HBsAg-positive

                                                                                          ALT level is                    ALT level is elevated
                                   ALT level is normal                                   mildly elevated                  more than 2 upper
                                                                                                                             limit of normal

                       HBV DNA level is           HBV DNA level is              Patient is               Patient is
                       > 104 copies/mL            < 104 copies/mL             HBeAg-negative           HBeAg-positive

           Histology is              Histology           HBV DNA level is           HBV DNA level is
                                      shows                                                                                      Treat
              normal                                     < 104 copies/mL            > 104 copies/mL

                                                                    Monitor*            Treat

             Monitor*                  Treat

                HBsAg, hepatitis B surface antigen; ALT, alanine aminotransferase; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen.
                *Monitor HBV DNA and ALT levels every 6 - 12 months. On initial diagnosis, monitor every 3 months for 1 year to ensure stability.
                    Fibrosis stage 2 or higher or significant inflammation.

Lamivudine withdrawal may result                          monoinfected patients, the incidence                    sulted in a 4.20 log10 copies/mL drop
in a spectrum of subclinical and clin-                    of resistance mutations at 1 year                       in HBV DNA levels, and HBV DNA
ical hepatic responses, ranging from                      seems to be lower with emtricitabine                    levels of less than 300 copies/mL
asymptomatic elevation of ALT lev-                        (about 9%).36 Available efficacy data                   were achieved in 9% of patients at 48
els to fulminant hepatic failure.                         in HIV-HBV coinfection are limited.                     weeks.38 Resistance to entecavir re-
                                                                                                                  quires the preexistence of lamivu-
Emtricitabine                                             Entecavir                                               dine resistance mutations plus an
This cytosine analogue is similar to                      This is a purine nucleoside analogue                    additional mutation in the HBV re-
lamivudine in molecular structure,                        with potent anti-HBV activity that                      verse transcriptase (rtT184, rtS202, or
antiviral activity, and resistance pat-                   was recently found to have anti-HIV                     rtM250). In the above-mentioned
tern. The effective dosage of emtri-                      activity and to select for M184V                        study, 2 of the 43 coinfected patients
citabine for HBV is the same as for                       drug-resistant variant virus.37 The                     had entecavir resistance mutations
HIV—200 mg once daily.36 Emtri-                           recommended dosage of entecavir in                      (rtT184S and rtS202C) present at
citabine can be used in place of la-                      HBV-HIV–coinfected patients is 1                        study entry, but no new mutations
mivudine unless lamivudine-resis-                         mg once daily in lamivudine-experi-                     associated with phenotypic entec-
tant HBV has been selected.                               enced patients.                                         avir resistance appeared during
   Both drugs share the same mech-                           In a group of 43 coinfected pa-                      treatment.38
anism of resistance through YMDD                          tients with lamivudine-resistant                           Entecavir should not be used in
motif mutations, but in HBV-                              HBV, the addition of entecavir re-                      HIV-HBV–coinfected persons who

                                                                                                                  May 2007 INFECTIONS in MEDICINE 199
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are not on a fully suppressive HIV                       been described in a small proportion     HBeAg-negative patients, respec-
regimen.                                                 of patients. Adefovir treatment fail-    tively. Serum HBV DNA became un-
                                                         ure was reported in 3 coinfected pa-     detectable in 29.6% of HBeAg-posi-
Adefovir dipivoxil                                       tients who had lamivudine resis-         tive patients and 81.6% of HBeAg-
This nucleotide analogue reverse                         tance in the absence of any known        negative patients.42 Among 4 pa-
transcriptase inhibitor has activity                     adefovir resistance mutations.40         tients who did not have a decrease in
against both wild-type and lamivu-                       These coinfected patients subse-         serum HBV DNA level from base-
dine-resistant HBV in HBeAg-posi-                        quently responded to tenofovir. In       line, genotyping analysis did not re-
tive and HBeAg-negative patients.                        HBV-monoinfected patients, a novel       veal tenofovir- or adefovir-related
The approved dosage of adefovir                          rtI233V mutation in the reverse tran-    HBV resistance mutations.42
dipivoxil for chronic HBV infection                      scriptase domain is associated with         The AIDS Clinical Trials Group
is 10 mg once daily.                                     primary adefovir resistance.41           A5127 was a prospective, random-
    In a group of 35 HBV-HIV–coin-                                                                ized, controlled study that com-
fected patients with lamivudine-                         Tenofovir disoproxil fumarate            pared tenofovir disoproxil fumarate
resistant HBV, adefovir added to                         Tenofovir is another nucleotide ana-     with adefovir in 52 coinfected pa-
lamivudine produced median re-                           logue reverse transcriptase inhibitor    tients who were receiving stable an-
ductions in serum HBV DNA levels                         active against wild-type, lamivu-        tiretroviral therapy. The mean de-
of 4.7 log10 copies/mL and 5.9 log10                     dine-resistant, and adefovir-resistant   cline in serum HBV DNA level at 48
copies/mL at weeks 48 and 144,                           HBV.19,40 The drug is not yet licensed   weeks of treatment was 4.44 log10
respectively.39 Undetectable HBV                         in the United States for treatment of    copies/mL with tenofovir and 3.21
DNA (limit of detection less than 2.3                    chronic HBV infection, but it has        log10 copies/mL with adefovir. No
log10 copies/mL) was found in 25%                        been approved for HIV therapy at a       difference in toxicity was seen be-
of patients, with 45% of patients                        dosage of 300 mg once daily.             tween the 2 groups.43
achieving HBV DNA levels of less                            A retrospective study evaluated
than 3 log10 copies/mL.39 No HBV                         the HBV virological response of 65       Telbivudine
polymerase mutations associated                          coinfected patients receiving teno-      This L-nucleoside analogue of thymi-
with adefovir resistance (N236T or                       fovir disoproxil fumarate for more       dine without anti-HIV activity was
A181V) or HIV reverse transcriptase                      than 6 months.42 The median decline      recently approved for chronic HBV
codon mutations (K65R or K70E)                           in serum HBV DNA level was 4.56          infection. The effective dosage of tel-
were found at 144 weeks.39                               log10 copies/mL and 2.53 log10           bivudine in HBV monoinfection is
    Primary resistance to adefovir has                   copies/mL in HBeAg-positive and          600 mg once daily.
                                                                                                     No efficacy data in HBV-HIV–
                                                                                                  coinfected patients have been pub-
              Table – Possible causes of hepatic flares in                                        lished. In HBV-monoinfected pa-
            HBV-HIV–infected persons receiving combination                                        tients, telbivudine achieves signifi-
                         antiretroviral therapy                                                   cantly greater reduction in serum
                                                                                                  HBV DNA levels and higher rates of
   • Immune reconstitution syndrome                                                               undetectable HBV DNA by poly-
                                                                                                  merase chain reaction, compared
   • Hepatotoxicity from antiretrovirals
                                                                                                  with both lamivudine and adefovir.44
   • Hepatoxicity from other drugs                                                                However, telbivudine shares cross-
     (including isoniazid, rifampin, and pyrazinamide) or alcohol
                                                                                                  resistance with lamivudine via M204
   • Hypersensitivity                                                                             variants in the YMDD motif.20,44
   • Emergence of lamivudine-resistant HBV strains
                                                                                                  Combination therapy
   • Reactivation or exacerbations of HBV (reported after stopping lamivudine)
                                                                                                  The use of combination therapy for
   • HBeAg or HBsAg seroconversion                                                                HBV in HBV-HIV–coinfected pa-
   • Superinfection with another hepatitis virus (hepatitis A or D virus)                         tients is being evaluated in clinical
                                                                                                  trials. An ideal HBV treatment regi-
   HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.      men would maximize HBV suppres-
                                                                                                  sion, prevent the emergence of HBV
                                                                                                  and HIV reverse transcriptase muta-

 HIV/AIDS continued

tions that lead to drug resistance,       Antiretroviral toxicity                   seroconversion and superinfection
and minimize toxicity. While combi-       Flares in the elevation of liver en-      with another hepatitis virus (such as
nation therapy is theoretically attrac-   zyme levels in HBV-HIV–coinfected         hepatitis A or D virus).
tive as a strategy to achieve viral       persons who are receiving combina-
suppression and prevent the emer-         tion antiretroviral therapy have a va-    HBV VACCINATION
gence of drug resistance, trials have     riety of possible causes that are im-     All HIV-infected persons should be
not consistently shown improved           portant to consider before changing       screened for HBV markers soon after
antiviral activity with drug combi-       any antiretroviral agent (Table).19       HIV diagnosis. HBV vaccination is
nations. Data are not available to        Chronic HBV infection is associated       indicated for all HIV-infected per-
evaluate long-term drug resistance        with increased hepatic flares in pa-      sons who lack evidence of previous
rates in combined regimens.               tients who have begun antiretroviral      infection or immunity. A national
   Emerging data support the use of       therapy.47                                survey of HIV outpatient study sites
tenofovir/lamivudine combination             Early flares, usually occurring        in 7 US cities found that only 32% of
therapy for coinfected patients.          within the first 3 months of starting     patients eligible for the hepatitis B
Among HBV-HIV–coinfected pa-              combination antiretroviral therapy,       vaccine had received at least 1
tients who were lamivudine-naive,         may be the result of an immune re-        dose.51
tenofovir/lamivudine combination          constitution syndrome and not nec-            Household, sex, and needle-shar-
therapy was superior to tenofovir or      essarily direct antiretroviral hepato-    ing contacts of HBsAg-positive per-
lamivudine alone. For lamivudine-         toxicity.48 Immune reconstitution         sons should be identified, tested for
experienced patients, adding teno-        flares may be followed by normal-         susceptibility to HBV infection, and
fovir to lamivudine or switching to       ization of ALT levels and clearance       given the first dose of HBV vaccine
tenofovir was superior to continuing      of HBV DNA. Close monitoring of           after collection of blood for serolog-
lamivudine.45 In coinfected persons,      patients with suspected immune re-        ical testing. The sex partners of
combination therapy with tenofovir        constitution flares may allow the         HBsAg-positive persons should be
and lamivudine appeared to more           continuation of therapy, since abnor-     counseled to use condoms unless
effectively suppress both HBV repli-      malities in liver enzyme levels pro-      they are immune or were previously
cation and the development of la-         gressively improve while the patient      infected.2
mivudine resistance compared with         continues combination antiretroviral          HIV-infected persons, especially
lamivudine alone.46                       therapy.                                  those with advanced immunosup-
   The decision to use combination           Coinfected persons who are re-         pression, have weaker antibody re-
therapy for coinfected persons            ceiving antiretrovirals that have         sponses to HBV vaccination and lose
should be based on the need for anti-     more significant hepatotoxic profiles     protective antibodies after vaccina-
retroviral therapy. For those who         (nevirapine, efavirenz, or full-dose      tion more quickly. After completing
need HBV treatment but not anti-          ritonavir) necessitate more frequent      the 3-dose HBV vaccine series, the
retroviral therapy, Peg-IFN and adef-     monitoring. Steatohepatitis mediat-       response rate (defined as greater
ovir are potential treatment options.     ed by inhibition of mitochondrial         than 10 IU/mL) is 87% in HIV-in-
IFN treatment should be limited to        DNA polymerase gamma may occur            fected persons with CD4+ cell counts
coinfected patients who are HBeAg-        in patients receiving nucleoside ana-     greater than 500/µL, compared with
positive and have high CD4+ T-cell        logues, especially stavudine, didan-      only 33% in persons with CD4+ cell
counts, high ALT levels, and low          osine, and zidovudine. Hypersensi-        counts between 200 and 500/µL.20 In
serum HBV DNA levels.                     tivity reactions to abacavir, nevira-     a retrospective cohort study of fac-
   For coinfected patients who need       pine, or amprenavir are not reported      tors that predicted HBV vaccination
both HBV and HIV treatment, the           more frequently in persons with           success in HIV-infected persons,
antiretroviral regimen should in-         chronic HBV infection.20                  only undetectable plasma HIV RNA
clude agents with dual activity              In patients with chronic HBV in-       at the time of vaccination was associ-
(tenofovir, lamivudine, emtricita-        fection, flares have been reported        ated with a protective antibody re-
bine). These patients should receive      with discontinuation of nucleoside        sponse.52 Therefore, immune recon-
a nucleotide analogue (tenofovir)         or nucleotide analogues49,50 and with     stitution with combination antiretro-
combined with a nucleoside ana-           the emergence of lamivudine- or           viral therapy should be attempted
logue (either lamivudine or em-           emtricitabine-resistant strains.20 Less   before HBV vaccination.
tricitabine) to prevent long-term         likely causes of flares in dual-infect-       Postvaccination antibody levels (1
resistance.20,21                          ed persons are HBeAg or HBsAg             to 3 months after completing the se-

  HIV/AIDS continued

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                                                            fluence of human immunodeficiency virus                       men. Hepatology. 1999;29:1306-1310.
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                                                            1138-1140.                                                    ic hepatitis B virus infection in the United
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                                                            homosexual men: effects on the natural history          24.   Liaw YF, Sung JJ, Chow WC, et al. Lamivudine
dose should be attempted in patients                        of infection. AIDS. 1997;11:597-606.                          for patients with chronic hepatitis B and ad-
in whom adequate antibody levels                         6. Chen CJ, Yang HI, Su J, et al. Risk of hepatocel-             vanced liver disease. N Engl J Med. 2004;351:
do not develop. ❖                                           lular carcinoma across a biological gradient of
                                                            serum hepatitis B virus DNA level. JAMA.                25.
                                                                                                                          Werle-Lapostolle B, Bowden S, Locarnini S, et
                                                            2006;295:65-73.                                               al. Persistence of cccDNA during the natural
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                                                            1, hepatitis B virus, and risk of liver related
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