The selection of HBV variants with lamivudine resistance (YMDD mutants) may be associated with acute exacerbation (severe flare of serum ALT and HBV DNA), that can lead to fulminant liver failure [84–86]. In addition, a reversion of histological improvement and progression of liver disease occurs in most patients after selecting lamivudine-resistant strains [87–91]. When lamivudine resistance is suspected, the addition of a second anti-HBV agent rather than its replacement is preferred by many experts, although the Gilead 461 trial did not show any benefit of keeping lamivudine with adefovir. However, as approximately 10% of patients seem to show a lack of susceptibility to adefovir, for reasons that are still unclear, a period of 3 months under both drugs seems to be worthwhile before discontinuing lamivudine, and with clear evidence of HBV suppression by adefovir.
Emtricitabine has recently been approved for the treatment of HIV, and is being evaluated as an anti-HBV agent . The effective dose for HBV seems to be 200 mg once a day , which is the same dose approved for HIV therapy. Like lamivudine, emtricitabine is a cytosine analogue with both anti-HIV and anti-HBV activity. Its similarity to lamivudine makes it appropriate in terms of tolerance and dosing as long as no lamivudine resistance has been selected by either HIV or HBV, given that these compounds share cross-resistance .
At different doses (25–300 mg a day), emtricitabine has been shown in HBV-monoinfected patients to produce an intense and rapid HBV-DNA reduction (mean of −3.4 log in 56 days) . The low level of HBV DNA is still maintained after 48 weeks of treatment in more than half the patients. The drug is well tolerated with no dose-limiting adverse events [92,93]. Preliminary clinical results suggest that resistance to emtricitabine may occur less frequently than with lamivudine .
Lamivudine and emtricitabine are pyrimidine analogues with excellent safety profiles, and both anti-HIV and anti-HBV activities. They should be considered interchangeable and not additive. Given their low genetic barrier for resistance, they should not be used as monotherapy in HIV/HBV-co-infected patients. They are particularly recommended in patients on antiretroviral therapy and in those taking other concomitant antiretroviral drugs, particularly in HBeAg-negative chronic hepatitis B patients, who will often need prolonged periods of therapy. SCORE: A1.
In contrast to nucleoside analogues, nucleotide analogues are phosphorylated pro-drugs, and are active against lamivudine-resistant HBV strains [96–98]. Two are currently available as anti-HBV agents: adefovir and tenofovir.
Adefovir was the first approved nucleotide analogue for the treatment of chronic hepatitis B. The dose recommended is 10 mg a day, which does not show activity against HIV. In one study conducted in 35 HIV/HBV-co-infected patients with lamivudine-resistant HBV, the addition of adefovir to lamivudine provided a significant reduction in serum HBV-DNA levels, which was maintained for 192 weeks, along with the normalization of transaminases in most cases (Fig. 6) . In up to 144 weeks of therapy, adefovir resistance mutations had not been selected in HBV or in HIV. These results are similar to those obtained in HBV-monoinfected patients [61,100], although a mutation at codon rt236 has been shown to be selected in nearly 2% of HBV-monoinfected patients on adefovir after 2 years of follow-up [101,102]. In-vitro studies have confirmed that this change is associated with a significant reduction in HBV susceptibility to adefovir . Another mutation, A181V, has also recently been associated with adefovir resistance . Importantly, adefovir-resistant HBV remains sensitive to lamivudine, emtricitabine and entecavir . Recent reports, however, have suggested that some HIV/HBV-co-infected patients may show a lack of susceptibility to adefovir in the absence of resistance mutations. Interestingly, all these patients responded to subsequent tenofovir treatment .
Lamivudine along with adefovir and IFN-α are the only drugs so far approved for the treatment of hepatitis B. As already highlighted, the rapid development of resistance represents a major drawback for lamivudine monotherapy. This is particularly worrisome in HIV-positive patients, in whom lamivudine is a frequently prescribed antiretroviral drug, and in whom HBV-resistant strains seem to be selected more rapidly . For these reasons, there is much interest in the use of other oral anti-HBV compounds, to be used either alone or in combination with lamivudine. In-vitro data have shown additive to synergistic antiviral effects of adefovir when combined with other anti-HBV nucleoside analogues . However, given that tenofovir, but not adefovir, has been approved and is already widely used as an antiretroviral agent, its potent anti-HBV activity  has attracted much attention. During the past year, several in-vitro  and in-vivo [107–113] studies have demonstrated that tenofovir is active against lamivudine-resistant HBV strains (Table 7). In an extended follow-up, additional results in support of those findings have been reported, with 70% of patients showing undetectable serum HBV-DNA levels after 2 years on tenofovir and 15% of patients showing HBeAg seroconversion .
In addition to being used as a rescue intervention in individuals with lamivudine-resistant HBV strains, tenofovir is being investigated alone as part of a combination therapy with lamivudine and emtricitabine in drug-naive individuals. These combinations may increase anti-HBV activity and may lead to a reduced risk of selecting YMDD mutant viruses. In the Gilead 903 trial, which compared tenofovir versus stavudine in HIV-positive drug-naive individuals who initiated HAART with a backbone of efavirenz and lamivudine, a retrospective study in 11 HBsAg-positive patients has recently been conducted . After 144 weeks of therapy, the mean reduction in serum HBV-DNA levels among the six subjects receiving tenofovir plus lamivudine was of 4.5 log copies/ml. while it was of 1.9 log copies/ml in the five patients in the lamivudine monotherapy arm. All five patients on lamivudine monotherapy for HBV developed lamivudine-resistant strains, whereas resistance only developed in one out of six subjects receiving tenofovir plus lamivudine. Despite the retrospective nature of the study and the relatively small number of patients examined, the data argue in favour of the use of combination therapy over monotherapy for the treatment of hepatitis B, at least in HIV-co-infected patients. A recent report in six French HBV/HIV-co-infected patients has also confirmed the great efficacy of the dual combination of tenofovir and lamivudine in drug-naive patients . Clearly, these data suggest that combination therapy for HBV could be beneficial to enhance antiviral activity as well as for delaying the selection of HBV-resistant strains. Whereas this benefit may be seen combining some of the new potent drugs, no encouraging data in favour of combination therapy have been obtained so far when using IFN-α, lamivudine or adefovir together, which are the only currently approved anti-HBV agents. Table 8 summarizes the therapeutic armamentarium against HBV, including approved antiretroviral agents with anti-HBV activity and drugs such as entecavir, which is soon expected to be available.
The use of combination therapy for HBV infection is currently under investigation. Whereas some combinations have proved to provide greater antiviral activity, others have not. For example, in one study conducted in HIV-negative patients , adefovir alone was compared with adefovir and lamivudine given together, and the combination was not found to be more potent than adefovir alone in the first year of treatment. At this time, combination therapy should be explored further clinically, especially for patients who are unable to achieve complete HBV-DNA suppression during monotherapy.
Adefovir at a dose of 10 mg a day is active against HBV but not against HIV. In contrast, tenofovir at a dose of 300 mg a day is active against both viruses. These drugs show a more robust genetic barrier to resistance than lamivudine and emtricitabine. Moreover, adefovir resistance mutations in HBV are selected at different positions than for lamivudine or emtricitabine. When possible, combination therapy with one nucleoside and one nucleotide analogue should be preferred to monotherapy with any of these drugs in HIV/HBV-co-infected patients. SCORE: B2.
The new compounds being tested for the treatment of HBV infection may be grouped into two categories. The first includes drugs active against both HBV and HIV. Another group includes medications with activity against HBV alone. Compounds from the latter group might be preferentially indicated in individuals who have not yet met the criteria for beginning HIV therapy. More than 15 molecules with potential activity against HBV are under investigation. Several of them are already in the final steps of clinical development, such as entecavir, clevudine and telbivudine. Overall, they show much greater antiviral potency, and may produce a decline of cccDNA in hepatocytes, which so far has only been seen for adefovir but not for lamivudine.
Entecavir is probably the next drug to be approved for the treatment of HBV infection. It is a deoxyguanosine analogue specific for HBV and lacks any anti-HIV activity. It is one of the most potent anti-HBV agents examined so far [118,119] and shows a relatively good safety profile . Phase 3 trials are ongoing worldwide, including a few in HIV/HBV-co-infected patients. Virological responses are seen in patients with lamivudine-resistant HBV, although they tend to be slightly lower than in lamivudine-naive patients. Resistance to entecavir seems to result from the accumulation of multiple changes in the HBV polymerase, including those causing lamivudine resistance (Table 9) . For this reason, entecavir doses of 0.5 mg a day are recommended in drug-naive patients, but doses of 1.0 mg a day are preferred for patients with previous exposure to lamivudine [121,122]. Moreover, a dose of 1.0 mg a day will probably be recommended for HBV/HIV-co-infected individuals. Given the good safety profile of entecavir, including the absence of mitochondrial toxicity, and its lack of anti-HIV activity, it is likely that this drug will be the first oral product to manage HBV infection independently in HIV/HBV-co-infected patients.
Clevudine is a pyrimidine nucleoside analogue. Different doses were tested in 31 HBV-monoinfected patients . A 3 log viral load reduction was observed at week 4 of therapy, with normalization in ALT values in approximately 70% of patients .
Telbivudine is an L-nucleoside analogue of thymidine. At different doses (400 and 600 mg a day) it produces a more profound HBV-DNA reduction than lamivudine at 52 weeks in HBV-monoinfected patients [122,124]. However, the combination of lamivudine and telbivudine does not produce higher virological suppression than telbivudine alone. Moreover, those drugs share cross-resistance (Table 9). The rate of anti-HBeAg seroconversion appeared to be higher with telbivudine than with lamivudine (33 versus 28%), and lower when telbivudine and lamivudine are combined (17%). Finally, the proportion of patients who normalize transaminase levels is higher with telbivudine than with lamivudine (86 versus 63%) .
New nucleoside analogues show strong anti-HBV activity and do not inhibit HIV. They may be used as monotherapy in HBV/HIV-co-infected patients not taking antiretroviral drugs. Entecavir, clevudine and telbivudine are the most promising agents, with a good safety profile. The activity of clevudine and telbivudine is halted in the presence of YMDD mutants, whereas the activity of entecavir is only slightly reduced in the face of lamivudine resistance. None of these compounds show cross-resistance with adefovir or tenofovir. Particularly in combination, they may further improve efficacy and avoid viral breakthroughs. SCORE: C2.
Significant liver enzyme elevations occur on average in 5–10% of HIV-positive patients who start triple antiretroviral therapy . The rate is higher in patients with underlying chronic hepatitis B [126–132]. Moreover, some drugs (i.e. nevirapine, efavirenz or ritonavir at full doses) cause hepatotoxicity more frequently than the rest [125,133]. Liver function tests should thus be closely monitored in patients who initiate antiretroviral treatment, particularly when some of the drugs mentioned above are administered to individuals with chronic hepatitis B.
Cumulative toxicity may explain the steady liver enzyme elevations when using some compounds. If not apparent shortly after beginning therapy, it may be manifested much later, often after 4–6 months on therapy. This has been seen with drugs such as nevirapine [134–136].
Liver enzyme elevations as a result of antiretroviral treatment may occur by other mechanisms than the direct injury of the drug(s) prescribed. Immune reconstitution phenomena and hypersensitivity reactions may account for some additional cases . In patients with low CD4 cell counts or high HIV-RNA titers, successful anti-HIV therapy may enhance the immune responses to such a degree that hepatic cells harbouring HBV antigens may be recognized and destroyed massively. As long as the patient remains asymptomatic and transaminase levels do not rise above 10 times the limit of normal values (grade 4 toxicity), treatment could be continued with close monitoring of laboratory values, as the return of liver enzymes to baseline values or even complete HBV clearance may occur [137,138]. On the other hand, allergic phenomena that may develop shortly after exposure to nevirapine, abacavir or amprenavir may be accompanied by liver enzyme elevations in the context of a more generalized reaction. The presence of underlying chronic hepatitis B does not seem to play a role in the occurrence of this phenomenon .
Liver toxicity may also occur as a consequence of mitochondrial damage in patients receiving nucleoside analogues, particularly zidovudine, stavudine or didanosine. Histological features of hepatic steatosis are more common in women, obese individuals, and when two of these drugs are taken together or for long periods [139,140].
Liver enzyme elevations after beginning antiretroviral therapy are more frequent in patients with underlying chronic hepatitis B. Therefore, drugs with more hepatotoxic profiles (i.e. nevirapine, efavirenz, full-dose ritonavir) should be used cautiously in co-infected patients. Treatment should be discontinued in patients with symptoms or grade 4 increases in aminotransferase levels. In certain cases, immune reconstitution phenomena may lead to liver enzyme elevations after starting HAART. Close monitoring of these patients during the first weeks may allow them to be kept on therapy, because they tend to experience a progressive resolution of liver abnormalities without discontinuing treatment. Mitochondrial toxicity of some nucleoside analogues (mainly zidovudine, stavudine or didanosine) may result in steatohepatitis. SCORE: A2.
Liver function can further deteriorate in HIV/HBV co-infected patients as a result of other hepatotropic viruses (hepatitis A, C, D, E), the administration of drugs other than antiretroviral agents, or substance abuse, including alcohol.
There is an increased rate of severe/fulminant hepatitis after acute hepatitis A virus (HAV) infection in HBV carriers . HAV vaccination should thus be provided to all individuals with chronic hepatitis B without serum anti-HAV IgG. The vaccine response is lower in patients with low CD4 cell counts. HAV immunization should be performed as early as possible, and in patients who have low CD4 cell counts, re-vaccination should be considered after the CD4 cell levels have risen with HAART .
Fulminant hepatitis, more aggressive liver disease and hepatocellular carcinoma are more frequent in the presence of chronic hepatitis B and concomitant infection with HCV or hepatitis D virus (HDV) [143–146]. The effect is generally additive rather than multiplicative. Although the transmission of HCV and HDV is usually parenteral, sexual transmission may also occur . Therefore, as there are no vaccines to protect from infection with HCV or HDV, preventative measures are important, such as avoiding risky injecting practices and unprotected sex.
There is an additive effect of alcohol and HBV in terms of the evolution to fulminant hepatitis, aggressive chronic liver disease and hepatocellular carcinoma . This relationship is linear and proportional to the extent of alcohol intake and duration. There is no ‘safe’ threshold above which alcohol begins to be deleterious, although more than 60 g a day is often considered risky. The encouragement of alcohol withdrawal with psychological support and professional detoxification programmes driven by specialists, and including the use of drugs when appropriate (i.e. acamprosate, naltrexone) is of benefit and should be advised .
Chronic HBV carriers are more prone to develop hepatotoxicity after exposure to some drugs. In HBV/HIV-co-infected patients, particular attention should be paid to anti-tuberculous agents . Isoniazid, rifampin and pyrazinamide, particularly when taken together, often result in liver enzyme elevations, and force treatment withdrawal. The use of alternative agents is often required to treat these patients.
All non-immunized HBV carriers should be vaccinated for HAV. HAV serostatus should be checked in pre-vaccinated individuals and if low or absent titers are found, re-vaccination should be offered, particularly to patients with rising CD4 cell counts in response to HAART. Proper hygiene counseling should be offered to avoid exposure to HAV and hepatitis E virus. With respect to HCV and HDV, for which there are no prophylactic vaccines, counseling should be focused on avoiding risky injection practices and unprotected sex. When necessary, pharmacological and psychological support should be instituted to reduce alcohol consumption. Hepatotoxic drugs, such as anti-tuberculous agents, should be given with caution. SCORE: B2.
The screening of serum HBV markers should be requested after the first HIV diagnosis. Individuals lacking HBV markers should be vaccinated. In the case of negative HAV markers, combination vaccination is advisable. In patients with more advanced immunodeficiency, the response to the HBV vaccine is much poorer and extra doses are often needed to obtain protective anti-hepatitis B surface antibody (HBsAb) titers (>100 IU/ml) [151,152]. Moreover, periodic monitoring of these antibodies is warranted because they may decline progressively over time, and may put the patient at risk of acute infection in the case of exposure .
HIV-positive patients develop weaker humoral responses to HBV vaccine, especially if the CD4 cell count is below 500 cells/μl, and lose protective antibodies faster. After three vaccine doses, the response rate is 87% in HIV-positive patients with CD4 cell counts greater than 500 cells/μl, but is only 33% in patients with CD4 cell counts between 200 and 500 cells/μl . Ongoing viral replication and concomitant immune system activation in HIV-infected patients decreases the ability of B lymphocytes to respond to HBV vaccination .
HBV vaccination should start with the conventional dose (20 μg at months 0, 1, and 6–12) for patients with CD4 cell counts greater than 500 cells/μl. In individuals with CD4 cell counts between 200 and 500 cells/μl, an intensive schedule is recommended (20 μg at months 0, 1, 2 and 12). Patients who do not respond to the first cycle should receive booster doses or a new vaccination cycle with 40 μg at months 0, 1, 2 and 6–12, until they show detectable serum anti-HBsAb, ideally greater than 100 IU/l. Patients with CD4 cell counts of less than 200 cells/μl who are not on antiretroviral therapy should receive HAART first and thereafter HBV immunization, preferentially after the CD4 cell count has increased above 200 cells/μl. After successful immunization, anti-HBsAb levels should be checked yearly and booster doses should be given to those with anti-HBsAb levels of less than 100 IU/l .
HBV vaccination should be provided to all HIV-positive individuals with no serum HBV markers. In the case of negative HAV markers, combination vaccination is advisable. The response to HBV vaccine is lower in HIV-positive individuals, particularly among those with lower CD4 cell counts. Anti-HBsAb titers should be checked 12 weeks after ending the vaccination cycle and booster doses or extra cycles are advisable when no appropriate humoral responses have been obtained. In patients with CD4 cell counts of less than 500 cells/μl, intensive schedules are initially warranted. SCORE: A2.
The occurrence of liver enzyme flare-ups in HIV-positive individuals with chronic hepatitis B is not a rare phenomenon. They may occur in two different settings. First, in HBsAg-positive patients with complete serum HBV suppression while taking antiretroviral therapy including drugs with anti-HBV activity. The interpretation of HBV reactivations in these individuals may be difficult because many reasons may account for it (see Table 10). For example, the discontinuation of lamivudine (emtricitabine) or tenofovir for any reason [156–158] or the development of lamivudine (emtricitabine) resistance by HBV (which occurs in 30–50% of HIV-infected patients after 12 months of therapy)  may be accompanied by abrupt transaminase flares , which may be wrongly interpreted as hepatotoxicity of current antiretroviral drugs. A rapid improvement in the immune function as a result of potent antiretroviral therapy may also be involved in flares of clinical hepatitis in these patients .
On the other hand, hepatitis B reactivation has been reported in HIV-infected individuals who had fully recovered from HBV infection, developing anti-HBsAb . It has also been seen in patients with isolated anti-hepatitis B core positivity . HBV reactivations are accompanied by an increase in serum transaminase levels, and the reappearance of serum HBsAg and an increase in HBV DNA. Although HBV reinfection may be the cause of these episodes, reactivation of the previous infecting HBV variant is the most frequent cause. Accordingly, reactivation in these patients is often seen in those who have received immunosuppressive agents for treating neoplasias, such as lymphomas or Kaposi's sarcoma [163,164]. More rarely, HBV reactivations are seen in patients presenting with very low CD4 cell counts. These reactivations indirectly support the notion that HBV establishes a longstanding infection that is never truly eradicated. Therefore, in HIV-infected patients with serum markers of past HBV infection, pre-emptive therapy should be considered for minimizing the risk of HBV reactivation in the case of cancer chemotherapy. The use of nucleos(t)ide analogues rather than IFN-α seems to be most appropriate in this setting.
HIV-infected patients with serum markers of previous hepatitis B (anti-HBsAb or anti-hepatitis B core antibody) or HBsAg-positive carriers with complete suppression of HBV replication under antiviral agents may experience abrupt flare-ups in transaminase levels, which may occasionally be fatal. In most instances, HBV reactivations rather than reinfections are the cause. The withdrawal of anti-HBV agents, the development of resistance, or the use of immunosuppressive agents often account for most of these episodes. SCORE: B3.
Multiple chronic hepatitis virus infections are not rare in HIV-infected patients, because most of these agents share their transmission routes. This is particularly true among IDU, in whom more than 75% of chronic hepatitis B patients show anti-HCV antibodies. Moreover, HDV often accompanies HCV in the Mediterranean basin and other prevalent regions for the virus.
Although chronic hepatitis caused by multiple viruses tends to be more aggressive than hepatitis caused by single agents, the interaction between these agents is complex . In patients without immunosuppression, HDV is almost always driving liver damage in the case of multiple hepatitis virus infections. In uncontrolled HIV infection, multiple virus escape often exists, with no evidence of inhibitory competition or interference between hepatotropic viruses. High serum HDV-RNA titers and delta antigen are often seen in the bloodstream of HIV-positive patients, along with markers of HBV or HCV replication [166,167]. As a result of this complex interaction, conflicting data have been reported for liver histology in HIV-positive patients with hepatitis B accompanied by HDV or HCV infections [166–170], although evolution towards liver cirrhosis tends to be faster and the outcome is generally much worse in these multiply co-infected patients than in individuals with monoinfections [146,170,171]. Therefore, the treatment of patients with multiple hepatitis viruses is warranted. However, responses tend to be poor and the most convenient therapeutic schemes are unclear at this time. The treatment of HDV with high doses of IFN-α plus or minus lamivudine and for long periods is rarely followed by sustained HDV-RNA clearance [172–174]. The use of anti-HBV nucleoside analogues alone generally does not confer any benefit to patients with hepatitis delta . Finally, co-infection with HCV rarely responds to combination therapy with IFN-α plus ribavirin when delta virus is present.
Chronic hepatitis B is not rarely accompanied by serological evidence of hepatitis C and D virus infections, particularly among IDU. In patients with uncontrolled HIV infection, the escape (replication) of multiple viruses rather than competition between them is often seen. More severe liver damage in patients with multiple hepatitis leads to a greater urgency to treat them; however, convenient drugs, doses and schedules have not yet been defined, and overall response rates tend to be much worse than for single hepatitis virus infections. SCORE: C3.
HIV-infected patients with end-stage liver disease caused by HBV develop classic complications of decompensated liver cirrhosis, including ascites, jaundice, gastrointestinal bleeding, spontaneous peritonitis and encephalopathy. Moreover, these patients are at risk of developing hepatocellular carcinoma. Occasionally, this tumour may develop without cirrhosis, although advanced fibrosis is found in most instances. In the setting of HIV infection, hepatocellular carcinoma may appear at a younger age and may be more aggressive . Screening for this neoplasia with ultrasonography and alphafetoprotein should be performed in all HBV/HIV cirrhotic patients every 6 months.
In patients with end-stage HBV-related liver disease, the only treatment available is orthotopic liver transplantation (OLT). Initial attempts before the introduction of HAART regimens provided very poor results [177,178]. Those reports showed that only a small percentage of transplanted HIV-positive recipients maintained good organ function, whereas most experienced an accelerated course to AIDS [177,178]. Since the introduction of HAART, HIV-infected liver transplant recipients have improved their short and mid-term survival [177,180]. Now, the outcome of transplantation is no longer compromised as long as HIV infection is controlled with HAART in the post-transplant period.
The criteria currently used for liver transplantation in HIV-positive patients includes the following: no previous history of opportunistic infections, CD4 cell counts greater than 100–200 cells/μl and undetectable plasma HIV-RNA levels on HAART (or available drugs for successful treatment in the post-OLT period). In the literature there have been at least 10 HIV-positive patients with end-stage liver disease caused by chronic hepatitis B who underwent OLT and all remained alive, in some cases up to 3 years [179,180]. A poorer prognosis has been reported for HCV [179,180], although this difference has only been reported in comparing patients without HIV co-infection, and is mainly a result of the almost universal HCV recurrence in the allograft followed by rapid progression to liver cirrhosis in nearly 20% of cases within 5 years . In contrast, prophylactic administration of oral anti-HBV agents plus hepatitis B immunoglobulin preceding the liver transplant aborts HBV recurrence in the allograft in most instances . Recurrent HBV is currently limited to cases of the emergence of lamivudine-resistant strains. The treatment of established recurrent HBV remains controversial, although new hopes have emerged with the availability of adefovir and tenofovir .
The main experiences derived from OLT in patients with end-stage chronic hepatitis B are the following: (i) The risk of opportunistic infections in the post-transplant period is very low when HIV replication is well controlled with HAART, keeping most cases with an undetectable viral load. Furthermore, CD4 cell counts remain stable or even increase with HAART. Therefore, the use of standard immunosuppressive therapy in patients with well-controlled HIV-infection does not increase their susceptibility to opportunistic infections or malignant conditions. (ii) Cyclosporin and tacrolimus can inhibit HIV replication and mycophenolate mofetil may potentiate abacavir. The benefit of these interactions is currently being explored. (iii) There are important pharmacokinetic interactions between some antiretroviral agents, protease inhibitors and non-nucleoside reverse transcriptase inhibitors, and immunosuppressive agents, mainly cyclosporin and tacrolimus. Protease inhibitors may increase the levels of cyclosporin and tacrolimus, whereas non-nucleoside reverse transcriptase inhibitors may reduce their levels, as a result of their opposite effects over cytochrome p450. These interactions have caused some episodes of acute rejection in patients who stopped protease inhibitors while taking calcineurin inhibitors. The therapeutic drug monitoring of immunosuppressive agents is mandatory, especially when taking antiretroviral drugs . (iv) Hepatotoxicity associated with HAART regimens can also be observed in liver allografts, and liver function should be closely monitored. (v) HBV recurrence may occur after OLT, but this risk has been dramatically reduced using hepatitis B immunoglobulin and lamivudine, adefovir or tenofovir. (vi) As survival in the waiting list seems to be much shorter in HIV-co-infected patients, strategies to make liver transplantation available sooner after a patient's assignment to this procedure should be underlined.
All HIV-infected patients with end-stage HBV-related liver disease should be considered as candidates for liver transplantation as long as they do not have advanced HIV disease. In those with severe immunodeficiency (<100 CD4 cells/μl) the control of HIV replication and immune restoration should be prioritized. The evaluation and the pre and postoperative medical management of HIV-positive candidates for OLT must include an interdisciplinary team composed of hepatologists, infectious diseases specialists, surgeons, psychologists, and social workers. HIV-positive candidates should have no previous history of opportunistic infections (except tuberculosis and perhaps oesophageal candidosis), and current CD4 cell counts greater than 100 cells/μl and plasma HIV-RNA levels below 200 copies/ml or with optional drugs for successful treatment in the future. Moreover, they should have abstained from the consumption of alcohol or illegal drugs for at least 6 months. The administration of oral anti-HBV agents before transplantation followed by these compounds plus hepatitis B immunoglobulin after transplantation is critical to avoid HBV recurrence in the allograft. SCORE: B2.
The authors would like to thank Stephen Locarnini (Australia), Maria Buti (Spain), Carlo Ferrari (Italy), Geoffrey Dusheiko (UK), and Javier Garcia-Samaniego (Spain), for their review and comments.
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