Treatment of chronic hepatitis B in patients with HIV

INTRODUCTION — The use of potent antiretroviral therapy (ART) to treat HIV infection has led to declining rates of opportunistic infections and the need to manage other causes of morbidity in individuals with HIV, such as end-stage liver disease secondary to chronic hepatitis B virus (HBV) infection. The treatment and prevention of HBV infection has taken on great significance in light of the negative impact HIV has on the natural history of chronic HBV infection. In coinfected patients, HBV infection is best treated with oral antiviral agents that can also be used to treat HIV. Once initiated, they are continued indefinitely in most individuals to maintain suppression of both viruses.

This topic will review the treatment of chronic HBV infection in patients with HIV. Other relevant topics include:

●(See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

●(See "Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV".)

●(See "Monitoring the patient with HIV and chronic hepatitis B virus infection".)

●(See "Prevention of hepatitis B virus infection in adults with HIV".)

RATIONALE FOR TREATMENT — Patients with HIV and chronic HBV infection should receive treatment to suppress both viruses regardless of HBV DNA level or degree of liver damage [1-5]. Chronic HBV infection is defined as a positive (ie, reactive) hepatitis B surface antigen (HBsAg) on two occasions at least six months apart.

This approach to treatment differs from that used in patients who have HBV monoinfection, in which the decision to initiate therapy is based upon the blood HBV DNA level, as well as the degree of liver damage and inflammation. (See "Hepatitis B virus: Overview of management".)

The rationale for the difference in treatment of chronic HBV infection in persons with HIV is as follows:

●Prevent HIV and HBV drug resistance – Guidelines for the treatment of adults with HIV recommend antiretroviral therapy (ART) for all patients, regardless of CD4 cell count [1,5]. Certain antiretroviral agents used to treat HIV are also used to treat HBV. As a result, coinfected patients may be initiated on medications for their HIV that have activity against HBV. To prevent the development of HIV and/or HBV drug resistance, it is important that both infections be optimally treated at the same time.

●Slow progression of chronic HBV infection, which has an accelerated course in coinfected patients – The course of chronic HBV infection is accelerated in patients with HIV and treatment may reduce the risk of disease progression [6-8]. HIV/HBV-coinfected patients have faster progression of fibrosis and an increased risk of cirrhosis, end-stage liver disease, and hepatocellular carcinoma compared with HBV-monoinfected patients [9-13]. This may be due, in part, to less immunologic control of HBV infection, which is reflected by the higher levels of HBV DNA in coinfected compared with monoinfected patients [13].

Liver-related mortality is also greater in coinfected individuals compared with patients with HIV or chronic HBV infection alone [14-16]. As an example, in a cohort study of men with HIV, individuals with HIV/HBV coinfection were approximately 17 times more likely to die of liver-related causes compared with those with HBV monoinfection [14,17]. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

●Reduce the incidence of immune reconstitution inflammatory syndrome (IRIS) – By treating both HIV and HBV concurrently, it may be possible to reduce the incidence of an IRIS. In patients with advanced immunosuppression (ie, CD4 cell count <200 cells/microL), initiating ART in a patient not treated for HBV infection may result in acute hepatitis due to immune reconstitution (see "Immune reconstitution inflammatory syndrome", section on 'IRIS associated with hepatitis B and C'). Although no studies have evaluated whether or not the incidence of IRIS is reduced by treating both infections simultaneously, there is a theoretical benefit since the risk of IRIS related to HBV infection is increased in patients with high levels of HBV viremia [18].

Patients with occult hepatitis B should also receive treatment to suppress both viruses. Such patients have a detectable HBV DNA and a positive hepatitis B core antibody (anti-HBc), but have negative serologies for HBsAg on two occasions at least six months apart (ie, they do not have resolving or chronic HBV). The clinical significance of occult hepatitis B in individuals with HIV is not clear [19]. However, in a patient with occult hepatitis B, it is important that an HIV regimen be fully active against HBV to prevent the development of drug-resistant HBV. (See 'Approach to treatment' below.)

EVALUATION PRIOR TO HBV TREATMENT — The pretreatment evaluation of patients with chronic HBV and HIV coinfection includes a detailed history and physical examination to assess for hepatotoxic medications and evidence of advanced liver disease; laboratory testing to evaluate markers of HBV activity, kidney function, liver function, and coexisting causes of liver disease; testing to determine the stage and activity of liver disease; and ultrasound imaging to screen for evidence of hepatocellular carcinoma. In addition, a baseline HBV resistance panel is sometimes obtained in patients with prior exposure to lamivudine or emtricitabine since HBV resistance has been reported in patients using these agents (especially if they were used as monotherapy). A detailed discussion of the pretreatment evaluation of patients with HIV/HBV coinfection is found elsewhere. (See "Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV".)

ANTIVIRAL MEDICATIONS FOR HBV — Tenofovir, entecavir, lamivudine (and the closely related agent, emtricitabine), telbivudine, and adefovir are nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that can suppress hepatitis B virus (HBV) DNA, prevent or slow the development of hepatic complications, and decrease liver-related death [20-23]. All are renally metabolized. The doses of these agents should be reduced for patients with reduced kidney function and are described in the individual drug monographs within UpToDate.

Tenofovir — Tenofovir is a nucleotide reverse transcriptase inhibitor with activity against HIV and HBV. (See "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir' and "Tenofovir and adefovir for the treatment of chronic HBV infection".)

Tenofovir is considered a first-line agent for patients with chronic HBV infection because the virologic efficacy is high and the risk of HBV resistance is low; it is also active against lamivudine-resistant HBV [24-29]. In a meta-analysis of HIV/HBV-coinfected patients, tenofovir disoproxil fumarate (TDF) suppressed HBV DNA to undetectable levels in approximately 90 percent of coinfected patients, with the proportion increasing rapidly over the first two years, and then slowly rising after that [20]. HBV resistance to TDF is uncommon, but a quadruple mutation has been described in two patients that increased the IC50 to tenofovir 1.3-fold [30].

Tenofovir is available in two preparations, TDF and tenofovir alafenamide (TAF). Both agents are available as part of several different coformulated tablets (table 1).

On occasion, TDF can lead to renal impairment (characterized by increases in serum creatinine, proteinuria, glycosuria, increased urinary phosphorous excretion, hypophosphatemia, and acute tubular necrosis), as well as bone loss. The TAF formulation is associated with less renal toxicity and has less effect on bone density [31,32], but may been associated with increased metabolic complications such as weight gain and higher cholesterol [33]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Commonly used agents' and "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

Both TDF and TAF have been found to be effective in suppressing HIV and HBV [34-37]. In a study of 72 HIV/HBV-coinfected patients who switched from a fully suppressive HIV regimen to EVG/c/FTC/TAF, 92 percent either maintained or achieved suppression of HIV and HBV over 48 weeks [37]. In addition, two large randomized trials of HBV monoinfected patients found that TAF was noninferior to TDF for the treatment of HBV in both treatment-naïve and treatment-experienced patients [38,39].

Entecavir — Entecavir is a potent inhibitor of hepatitis B polymerase that results in greater HBV suppression compared with lamivudine. Although HBV resistance to entecavir rarely develops in patients who are HBV treatment-naïve, the risk increases in patients with lamivudine-resistant HBV (approximately 50 percent after five years of treatment) [40]. Thus, this agent is generally not used for patients with evidence of (or concerns for) lamivudine-resistant HBV. (See 'Approach to treatment' below.)

Entecavir monotherapy for HBV is not recommended in patients with HIV unless it is used in combination with a fully active antiretroviral (ART) regimen to treat HIV. Entecavir has anti-HIV activity that results in an approximate one-log drop in HIV RNA, and when entecavir monotherapy is administered to HIV/HBV-coinfected patients, the M184V HIV resistance mutation can develop [29,31].

We typically administer entecavir as 1.0 mg/day to all patients, since there is a low risk of toxicity. However, other providers only administer this dose to patients with lamivudine-resistant virus and/or cirrhosis, and use a lower dose (0.5 mg/day) of entecavir for HBV treatment-naïve patients without cirrhosis. (See "Entecavir in the treatment of chronic hepatitis B virus infection".)

Lamivudine/emtricitabine — Lamivudine and emtricitabine are closely related agents that are used to treat HIV and have demonstrated efficacy against HBV infection in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients [41-44]. However, in people with HIV, they should not be used without TDF or TAF since they have a low genetic barrier to HBV resistance. Management of patients who cannot take tenofovir is discussed below. (See 'If tenofovir should not be used' below.)

The development of lamivudine resistant HBV in HIV/HBV-coinfected patients has been associated with duration of treatment; no relationship between baseline HBV DNA level, aminotransferases, or CD4 cell count has been seen [41,45,46]. As an example, in a retrospective analysis of 81 chronically infected HIV/HBV-coinfected patients receiving lamivudine monotherapy for HBV, lamivudine-resistant HBV developed in approximately 50 percent after two years and more than 90 percent after four years of treatment [45]. The onset of lamivudine resistance has been associated with exacerbations of hepatitis and hepatic failure [47].

The primary lamivudine resistance mutations are located at rtM204, with the methionine replaced by either an isoleucine or a valine (rtM204V/I) [48]. Secondary compensatory mutations may also occur in association with rtM204V/I, and certain ones (ie, rtI169T, rtS202I, and rtT184S/G) can contribute to entecavir resistance. The rtA181T mutation can occur in the absence of rtM204V/I and can confer resistance to adefovir as well [49].

Less commonly used agents — Pegylated interferon alfa can also be used to treat HBV but is not commonly used in patients with HIV. (See "Hepatitis B virus: Overview of management", section on 'Overview of antiviral agents'.)

APPROACH TO TREATMENT

General principles — Patients with HIV and chronic HBV infection should receive treatment to suppress both viruses regardless of HBV DNA level or degree of liver damage [1-5]. Such patients should be treated with a regimen that is effective against both HBV and HIV. (See 'Rationale for treatment' above.)

●For most patients, we administer a regimen that includes tenofovir. Tenofovir is effective for the treatment of HBV in both treatment-naïve and treatment-experienced patients (eg, those who have received lamivudine, emtricitabine, or entecavir), including those with lamivudine-resistant HBV. It is also a first-line agent for the treatment of HIV. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Tenofovir is available in two preparations, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Both agents are effective for the treatment of HBV and HIV. Although there is more experience with TDF, there is less toxicity associated with the TAF formulation. (See 'Tenofovir' above and 'Preferred regimens' below.)

●Entecavir may be a suitable alternative in select settings when tenofovir should not be used. (See 'If tenofovir should not be used' below.)

However, if entecavir is used, it must be administered in conjunction with a fully active HIV antiretroviral (ART) regimen, since entecavir, although partially active against HIV, lacks significant virologic potency and can lead to the development of the HIV drug-resistant mutation M184V. If entecavir is used, we prefer a nucleoside-sparing ART regimen. (See 'Entecavir' above and 'When entecavir is used' below.)

●We avoid an HIV ART regimen that uses lamivudine or emtricitabine monotherapy for the treatment of HBV (eg, one that uses abacavir-lamivudine as the nucleoside combination or the use of a two-drug regimen such as dolutegravir-lamivudine) because of the rapid emergence of lamivudine-resistant HBV due to a mutation within the YMDD motif (rtM204V) of HBV reverse transcriptase [41,46]. (See 'Lamivudine/emtricitabine' above.)

On rare occasion, concurrent treatment of HIV and HBV may not be possible (eg, patient refuses HIV therapy). Although this scenario should be discouraged, pegylated interferon alfa (PegIFN) can be used for the treatment of HBV since PegIFN does not induce HIV drug resistance. A more detailed discussion of interferon therapy for HBV is found elsewhere. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

Preferred regimens — We recommend a tenofovir-containing regimen for the treatment of HIV and HBV in almost all patients with HIV/HBV coinfection. There are only rare instances in which an alternative regimen should be considered (eg, patients with a history of a severe adverse reaction to TDF, those with an estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m² who are not receiving dialysis, and those with severe osteoporosis). (See 'If tenofovir should not be used' below.)

In general, we administer one of the following tenofovir-containing ART regimens:

●Dolutegravir plus tenofovir alafenamide-emtricitabine (TAF/FTC)

●Bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF)

Detailed discussions of how to select an ART regimen are found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)

In some cases, TAF may not be available or should be avoided because of drug interactions (eg, certain anticonvulsants). In these settings, TDF can be used instead of TAF (eg, dolutegravir plus TDF/FTC) if the patient has normal kidney function (eGFR ≥60 mL/min/1.73 m²). There is extensive experience with TDF for the treatment of HBV and HIV. However, the risk of kidney disease (eg, proximal tubular injury and worsening chronic kidney disease) and bone loss is greater with TDF compared with TAF. (See 'Tenofovir' above and "Overview of antiretroviral agents used to treat HIV", section on 'Tenofovir'.)

Special considerations

Tenofovir in patients with reduced kidney function — For patients with reduced kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²), we make all efforts to administer a tenofovir-containing ART regimen. Tenofovir (particularly TDF) has been associated with renal dysfunction; however, this is less likely to occur with TAF. Our general approach is as follows:

●For patients with an eGFR ≥30 mL/min/1.73 m², an ART regimen that includes TAF should be used. (See 'Preferred regimens' above.)

●For patients with more severely reduced kidney function, our approach depends upon the degree of renal insufficiency:

•For patients with an eGFR ≥15 mL/min/1.73 m² and those on hemodialysis, we administer an ART regimen that includes TAF/FTC. (See 'Preferred regimens' above.)

Although some guidelines suggest that the combination of TAF/FTC be avoided in patients with an eGFR <30 mL/min/1.73 m² who are not on hemodialysis [5], we feel comfortable using this regimen for patients with HIV/HBV coinfection and an eGFR ≥15 mL/min/1.73 m², since TAF monotherapy is approved for patients with an eGFR in this range and there are data supporting the safety of regimens containing TAF/FTC in patients on hemodialysis [50].

•For patients with HIV and an eGFR <15 mL/min/1.73 m² who are not on hemodialysis, there are insufficient safety data to recommend TAF in combination with FTC. Since TAF achieves high intracellular concentrations, there could be a potential increased risk of toxicity (eg, lactic acidosis/severe hepatomegaly with steatosis), particularly when the two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are coadministered. Thus, for this group, optimal treatment sometimes involves complex tradeoffs, such as the risk of toxicity with TAF or worsening kidney function with dose-reduced TDF versus the risk of treatment failure with an alternative agent. (See 'If tenofovir should not be used' below.)

If TAF is not available or should not be used, patients should be managed in conjunction with a provider experienced in the treatment of HIV and HBV.

If tenofovir should not be used — On rare occasion, a tenofovir-containing ART regimen cannot be used (eg, adverse reaction to tenofovir) or may not be ideal (eg, severe osteoporosis, certain drug interactions, eGFR <15 mL/min/1.73 m² and not on hemodialysis). (See 'Tenofovir in patients with reduced kidney function' above.)

Choice of agent — When tenofovir should be avoided, the choice of agent used to treat HBV depends primarily upon the individual's prior treatment history.

●HBV treatment-naïve – If tenofovir should be avoided in HBV treatment-naïve patients (ie, those who have never been treated with emtricitabine, lamivudine, or entecavir), entecavir can be used for the treatment of HBV in combination with a fully active HIV ART regimen. Additional considerations when using entecavir are described below. (See 'When entecavir is used' below.)

●Treatment-experienced – Entecavir monotherapy is associated with a high rate of resistance in lamivudine-refractory patients. Thus, for treatment-experienced patients who cannot take tenofovir, the treatment regimen depends in large part upon the number of HBV drug-resistant mutations detected.

•For patients who have a suppressed HBV DNA or who have a detectable HBV DNA level with ≤1 lamivudine resistance mutation (ie, rtM204V/I), we administer entecavir (1 mg/day) with a fully active HIV ART regimen. (See 'When entecavir is used' below.)

•For those with multiple drug-resistant mutations (ie, the rtM204V/I mutation plus one or more entecavir mutation), tenofovir remains the preferred choice for treatment of HBV, and the reasons for not using tenofovir must be reassessed. These patients should be managed in conjunction with a provider experienced in the treatment of HBV.

When entecavir is used — If entecavir is used for the treatment of HBV, the dose of entecavir should be adjusted in those with reduced kidney function. Dose adjustments are described in the Lexicomp drug information topic within UpToDate.

In addition, entecavir must be administered with a fully active HIV ART regimen. We generally prefer a nucleoside-sparing HIV ART regimen (ie, one that does not contain lamivudine or emtricitabine) for patients who are taking entecavir for the treatment of their HBV. The rationale for this approach is based upon a theoretical risk that patients who take lamivudine and entecavir together are at greater risk for the development of HBV resistance compared with those who take entecavir alone since lamivudine and entecavir share resistance mutations [51,52]. However, since this risk is theoretical, we only use a nucleoside-sparing regimen if it is thought to be noninferior to an ART regimen that contains a nucleoside backbone. Such patients should be managed in consultation with an expert in HIV.

Avoiding regimens with lamivudine monotherapy — Some patients with HIV/HBV-coinfection may be receiving an HIV regimen that only provides lamivudine monotherapy for HBV (eg, dolutegravir-abacavir-lamivudine or dolutegravir-lamivudine). For such patients, we modify the ART regimen to include tenofovir (TAF or TDF), unless tenofovir is contraindicated. (See 'If tenofovir should not be used' above.)

When modifying a regimen, the approach depends upon the patient's viral load. As examples:

●If a patient has an undetectable HIV RNA and is receiving an ART regimen that uses abacavir-lamivudine as the nucleoside combination, a combination pill that contains tenofovir-emtricitabine can be substituted if the HIV RNA is suppressed and there is no known HIV resistance. (See 'Preferred regimens' above and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

●If the patient has a detectable HIV RNA and there are concerns for HIV resistance, the HIV regimen should be optimized and tenofovir should be included if possible. These patients should be managed in conjunction with a provider experienced in the treatment of HBV and HIV. Additional considerations for patients changing their HIV regimen are described below. (See 'Patients changing their HIV regimen' below.)

Patients changing their HIV regimen — Certain patients will require a change in their HIV regimen. Reasons include adverse reactions to the ART regimen as well as the development of a detectable HIV RNA with HIV resistance mutations. (See "Evaluation of the treatment-experienced patient failing HIV therapy".)

Tenofovir should be continued for the treatment of HBV when changing an HIV regimen. For patients with drug-resistant HIV, other suitable agents should be added to achieve HIV suppression. If tenofovir cannot be used (eg, adverse drug reaction), another fully active HBV agent, such as entecavir, must be used in conjunction with a fully active HIV ART regimen. (See 'If tenofovir should not be used' above and 'When entecavir is used' above.)

It is important to maintain optimal HBV therapy to prevent a flare of HBV as well as an immune reconstitution syndrome. This approach is particularly important for those who have cirrhosis or are hepatitis B e antigen (HBeAg)-positive and have not achieved seroconversion to hepatitis B e antibody (anti-HBe) [9].

Duration of therapy — Most patients with HIV and hepatitis B virus (HBV) coinfection will receive indefinite treatment for HIV and HBV, typically with a regimen containing tenofovir. This is based upon the chronic nature of HBV infection and the fact that patients with HIV require life-long ART. If the HIV or HBV regimen must be modified because of adverse effects, the new regimen should follow the principles outlined above. (See 'General principles' above and 'Patients changing their HIV regimen' above.)

Patients should be advised against self-discontinuation of HIV or HBV treatment as withdrawal of therapy has been associated with exacerbations of hepatitis and hepatic failure in up to 30 percent of patients [47,53-56]. This is particularly important in patients with cirrhosis to avoid developing the complications associated with untreated HBV.

A limited number of patients will become hepatitis B surface antigen (HBsAg)-negative and hepatitis B surface antibody (anti-HBs)-positive following prolonged suppressive therapy, and these individuals are functionally cured. We continue such patients on anti-HBV therapy for an additional 12 months to increase the likelihood of a durable response, after which anti-HBV therapy can be discontinued (provided they do not have cirrhosis). This approach is supported by the Asian-Pacific consensus statement on the management of chronic hepatitis B [57]. However, patients who discontinue treatment for HBV must be maintained on a fully suppressive HIV regimen. In addition, they must be monitored closely for a relapse of their HBV infection. (See 'Monitoring therapy for HBV' below.)

MONITORING THERAPY FOR HBV

What to monitor — Clinical evaluation and laboratory monitoring are important to evaluate the efficacy of hepatitis B virus (HBV) treatment as well as potential toxicity. A detailed discussion regarding patient monitoring for HBV is found elsewhere and summarized below. (See "Monitoring the patient with HIV and chronic hepatitis B virus infection".)

Briefly, we monitor:

●Clinical signs and symptoms of hepatitis (right upper quadrant pain, nausea, vomiting, fatigue, jaundice, loss of appetite).

●HBV DNA every three months until undetectable for at least two consecutive visits. We then decrease the frequency to every six months.

●Aminotransferases every three months as a marker of drug-induced hepatotoxicity, immune reconstitution, or disease activity. The frequency can be decreased to every six months in patients with an undetectable HBV DNA.

●Hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) every six months in patients who are HBeAg-positive to determine if seroconversion has occurred. If HBeAg seroconversion has occurred, we repeat the HBeAg to confirm the result. We do not monitor the HBeAg after that unless there is an increase in the aminotransferase levels or antiretroviral therapy (ART) is stopped with a subsequent increase in the HIV RNA.

●Screening for hepatocellular carcinoma.

We also check other laboratory studies (eg, serum creatinine, urinalysis) according to the guidelines for the monitoring of HIV-infected patients receiving ART [5]. A detailed discussion of laboratory monitoring for patients receiving ART is found elsewhere. (See "Patient monitoring during HIV antiretroviral therapy".)

Response to therapy — The goal of treatment is complete suppression of HBV DNA by a sensitive polymerase chain reaction (PCR)-based assay. For patients on tenofovir or entecavir, we expect a 1 log₁₀ decline in HBV DNA after 12 weeks of treatment and, for most patients, a suppressed HBV DNA by one year. Compared with HIV, viral suppression of HBV can take longer to achieve. (See 'Tenofovir' above.)

If a patient is on tenofovir or entecavir and does not achieve a 1 log₁₀ decline in HBV DNA by 12 weeks:

●We assess for factors that could lead to subtherapeutic drug levels, such as suboptimal adherence, poor absorption, and/or drug interactions.

●In addition, we perform resistance testing in patients who are receiving entecavir monotherapy if they had been previously treated with lamivudine; this group is at high risk for treatment failure. (See 'If tenofovir should not be used' above.)

If a patient is on tenofovir or entecavir and the HBV DNA is >2000 international units/mL after receiving therapy for approximately two years [58], we use the following approach:

●We assess for factors that could lead to subtherapeutic drug levels, such as suboptimal adherence, poor absorption, and/or drug interactions.

●We check a resistance profile in patients receiving entecavir to confirm that there are no entecavir mutations present. Resistance testing is not usually helpful in such patients receiving tenofovir, since tenofovir resistance mutations for HBV are very rare [59].

•For patients with cirrhosis, and no evidence of resistance, we add a second agent (eg, entecavir to a tenofovir-containing regimen [60,61]) in order to obtain more rapid viral suppression.

•For patients without cirrhosis, and no evidence of resistance, we continue to monitor the HBV DNA and alanine transaminase (ALT). Most patients will suppress their HBV DNA within five years [20,62]. However, for those with continued ALT elevations without another cause, we add entecavir since ongoing ALT elevations suggest ongoing injury.

●If there is evidence of viral resistance to entecavir, the use of tenofovir should be reassessed. The approach to patients who cannot take tenofovir is described above. (See 'If tenofovir should not be used' above.)

Renal insufficiency on tenofovir — Tenofovir is associated with worsening kidney function in some patients. When this occurs, tenofovir usually causes chronic renal insufficiency secondary to a proximal tubulopathy [63]. Renal insufficiency is more likely to occur in patients receiving tenofovir disoproxil fumarate (TDF) compared with tenofovir alafenamide (TAF). (See 'Tenofovir' above and "Overview of kidney disease in patients with HIV", section on 'Medication nephrotoxicity'.)

For patients who were initially receiving TDF, we switch TDF to TAF as soon as the estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m² (calculator 1). However, if the patient is unable to take a TAF-containing regimen (eg, drug interactions, concerns that even TAF would continue to produce renal toxicity), the approach to treatment depends upon the presence of HBV drug resistance mutations as described above. (See 'Tenofovir in patients with reduced kidney function' above and 'If tenofovir should not be used' above.)

We discontinue tenofovir and start entecavir with fully suppressive HIV ART regimen in all patients who develop acute kidney injury or a Fanconi-like syndrome, regardless of the eGFR and baseline HBV status. The rationale for this is based upon the serious complications, including end-stage kidney disease and death, that may occur in individuals with HIV who developed these complications [63,64].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV" and "Society guideline links: Management of hepatitis B".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Hepatitis B (The Basics)")

●Beyond the Basics topic (see "Patient education: Hepatitis B (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – Patients with HIV and chronic hepatitis B virus (HBV) infection should receive treatment to suppress both viruses regardless of HBV DNA level or degree of liver damage. Such patients should be treated with a regimen that is effective against both HBV and HIV. (See 'General principles' above and 'Rationale for treatment' above.)

●Preferred regimens – For patients with HIV/HBV coinfection and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², we recommend a tenofovir-containing antiretroviral therapy (ART) regimen (Grade 1B). Tenofovir is considered a first-line agent for treatment of HIV and HBV because the virologic efficacy is high and the risk of resistance is low; it is also effective for the treatment of HBV in patients who have lamivudine-resistant virus. (See 'Antiviral Medications for HBV' above.)

•For most patients with HIV/HBV coinfection, our preferred ART regimen is dolutegravir plus tenofovir alafenamide-emtricitabine or bictegravir-emtricitabine-tenofovir alafenamide. Selecting an ART regimen is discussed in detail in a separate topic review. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions".)

TDF can be used instead of TAF for most patients with normal renal function (eGFR ≥60 mL/min/1.73 m²) if TAF is not available or should be avoided (eg, because of drug interactions); however, the risk of kidney disease and bone loss is greater with TDF compared with TAF. (See 'Preferred regimens' above and 'Tenofovir in patients with reduced kidney function' above.)

•For patients with severely reduced kidney function (eGFR <30 mL/min/1.73 m²), regimen selection depends upon the degree of renal insufficiency and the patient's prior treatment history. (See 'Tenofovir in patients with reduced kidney function' above.)

●Alternative regimens – On rare occasion, when tenofovir should not be used, entecavir may be reasonable for treatment of HBV in those who are at low risk of drug-resistant HBV. However, entecavir is associated with a high rate of HBV resistance in patients with lamivudine-resistant virus.

If a patient is treated with entecavir for HBV, it must be administered in conjunction with a fully active HIV ART regimen. For such patients, we generally prefer a nucleoside-sparing regimen for the treatment of their HIV (ie, one that does not contain lamivudine or emtricitabine). There is a theoretic risk that patients who take lamivudine and entecavir together are at greater risk for the development of HBV resistance compared with those who take entecavir alone. (See 'If tenofovir should not be used' above and 'When entecavir is used' above.)

●Avoiding regimens with lamivudine monotherapy – We avoid an HIV ART regimen that uses lamivudine monotherapy for the treatment of HBV (eg, dolutegravir-abacavir-lamivudine, dolutegravir-lamivudine) because of the rapid emergence of lamivudine-resistant HBV. If a patient is receiving an HIV regimen that only provides lamivudine monotherapy for HBV, we modify the ART regimen to include tenofovir. (See 'Avoiding regimens with lamivudine monotherapy' above.)

●Considerations when changing HIV regimens – For patients who require a change in their HIV regimen, tenofovir should be continued, if possible. If tenofovir cannot be used (eg, adverse drug reaction), another fully active HBV agent (eg, entecavir) must be used in conjunction with a fully active HIV ART regimen. (See 'Patients changing their HIV regimen' above and 'When entecavir is used' above.)

●Duration of treatment – Most patients with HIV/HBV coinfection will receive life-long treatment for HIV and HBV with an ART regimen containing tenofovir. This is based upon the chronic nature of HBV infection and the fact that patients with HIV require life-long ART. Patients should be advised against self-discontinuation of treatment as withdrawal of therapy has been associated with exacerbations of hepatitis and hepatic failure. (See 'Duration of therapy' above.)

●Monitoring on treatment – Clinical evaluation and laboratory monitoring are important to evaluate the efficacy of HBV treatment as well as potential toxicity. This is discussed in detail in a separate topic review. (See "Monitoring the patient with HIV and chronic hepatitis B virus infection".)