Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Considerations for Antiretroviral Use in People With Coinfections

Hepatitis B Virus/HIV Coinfection

Approximately 5% to 15% of people with HIV in the United States also have chronic hepatitis B virus (HBV) infection, defined as positive HBV surface antigen (HBsAg).^1-3 The progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma is more rapid in people with HBV/HIV coinfection than in people with chronic HBV mono-infection.⁴ Conversely, chronic HBV does not substantially alter the progression of HIV infection and does not influence HIV suppression or CD4 T lymphocyte cell responses following the initiation of antiretroviral therapy (ART).^5,6 Liver-associated complications may occur due to immune reconstitution after initiation,^7,8 or HBV reactivation after discontinuation of antiretroviral (ARV) drugs that are active against both HIV and HBV.^9-14

Recommendations for People With HBV/HIV

• All people with HIV should be tested for viral hepatitis, including hepatitis A virus (HAV), HBV, and hepatitis C virus (HCV). People without immunity to HAV or HBV should receive a full vaccination series (AIII).
• A survey of people with HIV/HBV coinfection in the United States revealed that 4.0% had a positive hepatitis D virus (HDV) serologic test, of which 41.7% had detectable HDV RNA.¹⁵Because HBV/HDV coinfection has been associated with serious liver complications, many experts recommend that people with HIV and chronic HBV be tested for HDV infection.^16,17 The recommended initial serologic test is an HDV antibody test, which, if positive, should be followed by HDV RNA testing. People with HIV and HBV/HDV coinfection should be referred to an expert in the management of viral hepatitis.
• All people with chronic HBV should be evaluated to assess the severity of HBV infection (see Hepatitis B Virus in the Adult and Adolescent Opportunistic Infections Guidelines). In addition, people with chronic HBV should be advised to abstain from alcohol, be screened for alcohol use disorder,¹⁸ and be counseled on prevention methods that protect against both HBV and HIV transmission.¹⁹
• Before ART is initiated, all persons who test positive for HBsAg should be tested for HBV DNA by using a quantitative assay to determine the level of HBV DNA (AIII), and the test should be repeated every 3 to 6 months to ensure effective HBV suppression. The goal of HBV therapy with nucleos(t)ide reverse transcriptase inhibitors (NRTIs) is to prevent liver disease complications by sustaining the suppression of HBV replication. A large cohort study found that persistent HBV viremia while taking ART and high HBV DNA levels were associated with a higher risk of hepatocellular carcinoma (HCC), even if HIV was suppressed; whereas sustained HBV DNA suppression for ≥1 year was associated with a 58% reduction in HCC risk.²⁰ The most common reason for persistent HBV viremia in people with HBV/HIV coinfection on tenofovir alafenamide (TAF)– or tenofovir disoproxil fumarate (TDF)–containing ART is suboptimal adherence; thus, the primary focus in this setting should be on improving adherence.²¹
• Because HBV reactivation has been observed in people with HBV infection during interferon‑free HCV treatment,^22,23 people with HCV/HIV coinfection and chronic HBV infection should receive ART that includes two agents with anti-HBV activity (such as TAF or TDF plus emtricitabine [FTC] or lamivudine [3TC]) prior to initiating HCV therapy (AIII). The diagnosis of HBV reactivation should be considered in people with current HBV infection who experience elevated liver transaminases during or immediately after HCV therapy.

Antiretroviral Drugs With Dual Activities Against HBV and HIV

The NRTIs TAF, TDF, FTC, and 3TC are active against HBV. Entecavir is an HBV nucleoside analog that has weak HIV activity. TAF is a tenofovir prodrug with HBV activity and potentially less renal and bone toxicity than TDF,^24,25 although weight gain has been observed more frequently with TAF than TDF.^26,27

The efficacy of TAF versus TDF in hepatitis B e antigen (HBeAg)–negative patients with HBV mono-infection was evaluated through a randomized controlled trial, involving both treatment-naive and treatment-experienced participants. In this study, TAF was non-inferior to TDF, based on the percentage of participants with HBV DNA levels <29 IU/mL at 48 weeks of therapy (94% for TAF vs. 93% for TDF; P = 0.47).²⁸ In another study, TAF was also non-inferior to TDF in HBeAg‑positive people with chronic HBV mono-infection, with a similar percentage of participants achieving HBV DNA levels <29 IU/mL at 48 weeks of therapy (64% for TAF vs. 67% for TDF; P = 0.25).²⁹ In both studies, people on TAF experienced significantly smaller mean percentage decreases from baseline in hip and spine bone mineral density at 48 weeks than participants receiving TDF. The median change in estimated glomerular filtration rate (eGFR) from baseline to 48 weeks also favored TAF.^28,29

In people with HBV/HIV coinfection, (TAF or TDF) plus (3TC or FTC) can be considered part of the ARV regimen; entecavir has weak anti-HIV activity and must not be considered part of an ARV regimen. In addition, TDF is fully active for the treatment of people with known or suspected 3TC-resistant HBV infection, whereas 3TC resistance compromises the activity of entecavir against HBV.

Recommended Therapy

The combination of (TAF or TDF) plus (3TC or FTC) should be used as the NRTI backbone of an ARV regimen and for the treatment of both HIV and HBV infection (AI).^30-32 The decision whether to use a TAF- or TDF-containing regimen should be based on an assessment of risk for nephrotoxicity and the acceleration of bone loss. In a switch study in people with HBV/HIV coinfection, study participants who switched from a primarily TDF-based ARV regimen to the fixed‑dose combination elvitegravir/cobicistat (EVG/c)/TAF/FTC maintained or achieved HBV suppression with improved eGFR and bone turnover markers.³³ See Appendix B, Table 12 for guidance on renal dosing of NRTIs. Although data on switching from a TDF-based to a TAF-based ARV regimen are limited, the data from the EVG/c/TAF/FTC switch study suggest that people with HBV/HIV coinfection can switch to TAF/FTC-containing regimens with a potential reduction in renal and bone toxicity while maintaining HBV suppression.

Alternative Therapy

If TDF or TAF cannot be safely used or if there is a desire to use a TAF- or TDF-sparing ART regimen, entecavir can be used as an alternative HBV therapy in addition to a fully suppressive ARV regimen (BI). Entecavir has weak activity against HIV; its use for HBV treatment without ART may result in the selection of the M184V mutation that confers HIV resistance to 3TC and FTC.^34,35 Therefore, entecavir must be used in addition to a fully suppressive ARV regimen when given to people with HBV/HIV coinfection (AII). Because entecavir and 3TC share a partially overlapping pathway to HBV resistance, it is unknown whether the combination of entecavir plus 3TC or FTC will provide greater virologic or clinical benefit than entecavir alone. In people with known or suspected 3TC-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day.³⁶ However, entecavir resistance may emerge rapidly in people with 3TC-resistant HBV infection. Therefore, entecavir should be used with caution in such people, with frequent monitoring (approximately every 3 months) of the HBV DNA level to detect viral breakthroughs.³⁵

Important Considerations

• Discontinuation of HBV-active NRTI drugs may potentially cause serious hepatocellular injury resulting from the reactivation of HBV.³⁷
• Entecavir has activity against HIV. However, when entecavir is used to treat HBV in people with HBV/HIV coinfection who are not on ART, the drug may select for the M184V mutation that confers HIV resistance to 3TC and FTC. Therefore, when used in people with HBV/HIV coinfection, entecavir must be used in addition to a fully suppressive ARV regimen (AII).³⁸
• When 3TC is the only active drug used to treat chronic HBV in people with HBV/HIV coinfection, 3TC-resistant HBV emerges in approximately 40% and 90% of people after 2 years and 4 years on 3TC, respectively. Given the similarities between FTC and 3TC, these drugs should only be used in combination with other anti-HBV drugs (AII).³⁹
• In people with HBV/HIV coinfection, immune reconstitution following the initiation of treatment for HIV and HBV can be associated with elevated liver transaminase levels, possibly because HBV-induced liver injury is primarily an immune-mediated disease.⁴⁰
• Some ARV agents (especially older drugs, such as nevirapine, tipranavir, and high-dose ritonavir) can increase liver transaminase levels. The incidence and magnitude of these increases were higher with HBV/HIV coinfection than with HIV mono-infection.^41-43 The etiology and consequences of these changes in transaminases are unclear because the changes may resolve with continued ART. Nevertheless, some experts suspend the suspected agent(s) when the serum alanine transferase (ALT) level increases to 5 to 10 times the upper limit of normal, or at a lower threshold if the person has symptoms of hepatitis and/or new elevations in bilirubin. However, increased transaminase levels in people with HBV/HIV coinfection may indicate HBeAg seroconversion due to immune reconstitution; thus, the cause of the elevations should be investigated before medications are discontinued. In people with increases in transaminase, HBeAg seroconversion should be evaluated by testing for HBeAg and anti-HBe, as well as HBV DNA levels, which should decrease in the setting of immune reconstitution. Other causes of ALT elevation—such as HCV or HDV infection, alcohol use, metabolic dysfunction-associated steatotic liver disease, and hepatotoxicity from non-ARV agents—should also be considered.

HBV Drugs Not Recommended

Adefovir in combination with 3TC or FTC with a fully suppressive ARV regimen was studied in people with HIV/HBV coinfection.^30,44,45 Adefovir was associated with high rates of HBV treatment failure and a high incidence of renal toxicity. Therefore, the Panel does not recommend adefovir for people with HBV/HIV coinfection (AI). Pegylated interferon alfa monotherapy is a potential therapy for the treatment of HBV mono-infection; however, data on its use in people with HBV/HIV coinfection are limited, and tolerance of the therapy in people with HIV is a significant limitation to its use. As a result, the Panel does not recommend pegylated interferon alfa for people with HBV/HIV coinfection (AIII). Pegylated interferon alfa can remain a treatment option in rare cases and with the consultation of an expert.

Changing Antiretroviral Therapy

• When switching or modifying an ARV regimen in a person with HBV/HIV coinfection: ARV drugs that are active against HBV (TDF or TAF in combination with 3TC or FTC) should be continued (AII) or a specific anti-HBV drug such as entecavir should be initiated (AII).
• When ARV medications that are active against HBV in people with HBV/HIV coinfection must be discontinued: Withdrawal of HBV-active treatment in a person with chronic HBV infection is not recommended (AII). If TAF or TDF cannot be continued due to concern for safety or if there is a desire to use a TAF- or TDF-sparing regimen and entecavir cannot be used or if there is concern for entecavir resistance, the person’s clinical course should be monitored with monthly testing of liver transaminases. The risk of HBV flare in this setting is highest in people with positive HBeAg and those with active HBV. If no anti-HBV ARV drug can be used, entecavir should be added to a fully suppressive ARV regimen to prevent HBV flare (AII), especially in people with marginal hepatic reserve, such as those with compensated or decompensated cirrhosis.³⁷

Screening for HBV Before Initiating NRTI-Sparing or NRTI-Limited Antiretroviral Regimens

HBV status should be evaluated in all people with HIV who are not known to have chronic HBV before the initiation of an NRTI-sparing or NRTI-limited ARV regimen (such as long-acting cabotegravir plus rilpivirine [LA CAB/RPV], dolutegravir [DTG]/rilpivirine [RPV], or DTG/3TC). Considerations for screening include the following:

• People with HIV should be screened for HBV infection, and if not already immune or infected (including those with isolated hepatitis B core antibody [HBcAb]), vaccination should be initiated while considering these new ARV regimens (see Hepatitis B Virus Infection in the Adult and Adolescent Opportunistic Infections Guidelines).
• People with HBV/HIV coinfection were not included in clinical trials that evaluated NRTI‑sparing or NRTI-limited regimens. If LA CAB/RPV, DTG/RPV, or DTG/3TC are used in people with HBV coinfection, TAF, TDF, or entecavir should also be prescribed (AII). In people with prior exposure to 3TC monotherapy, TAF or TDF is preferred due to the risk of HBV resistance to 3TC; thus, there is a lower barrier of resistance for entecavir.
• People with HIV and prior exposure to HBV infection (negative HBsAg, positive HBcAb, and either positive or negative hepatitis B surface antibody [HBsAb]) are likely at low risk (<1%) of HBV reactivation and even lower risk of HBV reactivation hepatitis,¹⁴ although there are insufficient studies to confidently estimate the risk in this population. Of people with HIV and prior exposure to HBV infection, those with positive HBsAb are at the lowest risk for HBV reactivation, although HBV reactivation has been described when HBV-active therapy is withdrawn as part of an ART regimen.¹⁴
• For individuals with prior HBV exposure, it is reasonable and feasible to incorporate ALT monitoring into the frequent laboratory testing already recommended after switching from ART with HBV NRTI therapy (TDF, TAF, or entecavir) to LA CAB/RPV, DTG/RPV, or DTG/3TC. An increase in ALT would warrant HBV DNA testing to assess for HBV reactivation hepatitis and immediate initiation of HBV therapy once reactivation is confirmed. A monitoring strategy is considered a safe and effective way to assess for HBV reactivation in low-risk people (BIII).^46,47 The timeline for reactivation is not clear in this population. Monitoring every 1 to 3 months for 6 months after switching from HBV-active ART is consistent with current recommendations for low-risk people without HIV.

References

1. Spradling PR, Richardson JT, Buchacz K, Moorman AC, Brooks JT. Prevalence of chronic hepatitis B virus infection among patients in the HIV Outpatient Study, 1996–2007. J Viral Hepat. 2010. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20158604.
2. Kim J, Newcomb CW, Carbonari DM, et al. Hepatitis B care cascade among people with HIV/HBV coinfection in the North American AIDS Cohort Collaboration on Research and Design, 2012–2016. PLoS One. 2023;18(9):e0290889. Available at: https://pubmed.ncbi.nlm.nih.gov/37656704.
3. Platt L, French CE, McGowan CR, et al. Prevalence and burden of HBV co-infection among people living with HIV: a global systematic review and meta-analysis. 2019. Available at: https://onlinelibrary.wiley.com/doi/10.1111/jvh.13217.
4. Thio CL, Seaberg EC, Skolasky RJ, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). 2002;360(9349):1921-1926. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12493258.
5. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. 2005;19(6):593-601. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15802978.
6. Hoffmann CJ, Seaberg EC, Young S, et al. Hepatitis B and long-term HIV outcomes in coinfected HAART recipients. 2009;23(14):1881-1889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19550291.
7. Yoshikawa S, Yoshio S, Yoshida Y, et al. Impact of immune reconstitution-induced hepatic flare on hepatitis B surface antigen loss in hepatitis B Virus/human immunodeficiency virus-1 coinfected patients. J Infect Dis. 2021;223(12):2080-2089. Available at: https://pubmed.ncbi.nlm.nih.gov/33073291.
8. Iannetta M, Crea AMA, Di Lorenzo A, et al. Hepatitis B-related hepatic flare during immune reconstitution syndrome after antiretroviral treatment initiation in an HBV surface antigen-positive patient with HIV: viroimmunological and histological characterization. Open Forum Infect Dis. 2022;9(9):ofac451. Available at: https://pubmed.ncbi.nlm.nih.gov/36092833.
9. Bellini C, Keiser O, Chave JP, et al. Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort Study. HIV Med. 2009;10(1):12-18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18795964.
10. Hall SAL, Burns GS, Mooney BJ, et al. Hepatitis B virus flares after nucleot(s)ide analogue cessation are associated with activation of toll-like receptor signaling pathways. J Infect Dis. 2022;227(1):123-132. Available at: https://pubmed.ncbi.nlm.nih.gov/36108079.
11. Mican R, Busca Arenzana C, Vasquez J, Daroca G, Perez-Valero I, Martin-Carbonero L. Hepatitis B reactivation after tenofovir withdrawal in an HIV-infected patient with history of cured hepatitis B virus infection and poor immunological status. 2021;35(10):1707-1708. Available at: https://pubmed.ncbi.nlm.nih.gov/34270493.
12. Adachi E, Sedohara A, Arizono K, et al. Hepatitis B virus reactivation after switch to cabotegravir/rilpivirine in patient with low hepatitis B surface antibody. Emerg Infect Dis. 2024;30(8):1668-1671. Available at: https://pubmed.ncbi.nlm.nih.gov/39043430.
13. Pintado C, Delaugerre C, Molina JM. Acute hepatitis B infection after a switch to long-acting cabotegravir and rilpivirine. Open Forum Infect Dis. 2020;7(9):ofaa367. Available at: https://pubmed.ncbi.nlm.nih.gov/33005698.
14. Abdullahi A, Fopoussi OM, Torimiro J, Atkins M, Kouanfack C, Geretti AM. Hepatitis B virus (HBV) infection and re-activation during nucleos(t)ide reverse transcriptase inhibitor-sparing antiretroviral therapy in a high-HBV endemicity setting. Open Forum Infect Dis. 2018;5(10):ofy251. Available at: https://pubmed.ncbi.nlm.nih.gov/30377627.
15. Ferrante ND, Kallan MJ, Sukkestad S, et al. Prevalence and determinants of hepatitis delta virus infection among HIV/hepatitis B-coinfected adults in care in the United States. J Viral Hepat. 2023;30(11):879-888. Available at: https://pubmed.ncbi.nlm.nih.gov/37488783.
16. Pan C, Gish R, Jacobson IM, Hu K-Q, Wedemeyer H, Martin P. Diagnosis and management of hepatitis delta virus infection. Dig Dis and Sci. 2023;68(8):3237-3248. Available at: https://doi.org/10.1007/s10620-023-07960-y.
17. Hepatitis B Foundation. Testing and diagnosis. 2024. Available at: https://www.hepb.org/research-and-programs/hepdeltaconnect/testing-and-diagnosis/#:~:text=Who%20should%20be%20tested%3F,with%20hepatitis%20B%20get%20tested.
18. Jophlin LL, Singal AK, Bataller R, et al. ACG clinical guideline: alcohol-associated liver disease. 2024;119(1). Available at: https://journals.lww.com/ajg/fulltext/2024/01000/acg_clinical_guideline__alcohol_associated_liver.13.aspx.
19. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection.
20. Kim HN, Newcomb CW, Carbonari DM, et al. Risk of HCC with hepatitis B viremia among HIV/HBV-coinfected persons in North America. 2021;74(3):1190-1202. Available at: https://pubmed.ncbi.nlm.nih.gov/33780007.
21. Zhang HL, Mock M, Bushman L, Anderson PL, Kiser JJ, Naggie S. Cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatitis B coinfection with differential viral suppression. Clin Infect Dis. Available at: https://doi.org/10.1093/cid/ciae241.
22. Bersoff-Matcha SJ, Cao K, Jason M, et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration adverse event reporting system. Ann Intern Med. 2017;166(11):792-798. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28437794.
23. Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15(1):132-136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27392759.
24. Chan HLY, Buti M, Lim YS, et al. Long-term treatment with tenofovir alafenamide for chronic hepatitis B results in high rates of viral suppression and favorable renal and bone safety. Am J Gastroenterol. 2024;119(3):486-496. Available at: https://pubmed.ncbi.nlm.nih.gov/37561058.
25. Agarwal K, Brunetto M, Seto WK, et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68(4):672-681. Available at: https://pubmed.ncbi.nlm.nih.gov/29756595.
26. Wood BR, Huhn GD. Excess weight gain with integrase inhibitors and tenofovir alafenamide: what is the mechanism and does it matter? Open Forum Infect Dis. 2021;8(12):ofab542. Available at: https://pubmed.ncbi.nlm.nih.gov/34877366.
27. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis. 2020;71(6):1379-1389. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606734.
28. Buti M, Gane E, Seto WK, et al. GS06 - A phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg-negative, chronic hepatitis B: week 48 efficacy and safety results. J Hepatol. 2016;64(2, Supplement):S135-S136. Available at: https://www.sciencedirect.com/science/article/pii/S0168827816016378.
29. Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):185-195. Available at: https://pubmed.ncbi.nlm.nih.gov/28404091.
30. Peters MG, Andersen J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. 2006;44(5):1110-1116. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17058225.
31. Matthews GV, Seaberg E, Dore GJ, et al. Combination HBV therapy is linked to greater HBV DNA suppression in a cohort of lamivudine-experienced HIV/HBV coinfected individuals. 2009;23(13):1707-1715. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19584701.
32. de Vries-Sluijs TE, Reijnders JG, Hansen BE, et al. Long-term therapy with tenofovir is effective for patients co-infected with HIV and HBV. 2010. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20801123.
33. Gallant J, Brunetta J, Crofoot G, et al. Efficacy and safety of switching to a single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B coinfected adults. J Acquir Immune Defic Syndr. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27171740.
34. Soriano V, Vispo E, Labarga P, Barreiro P. A low antiretroviral activity of the antihepatitis B drug entecavir may be enough to select for M184V in HIV-1. 2008;22(7):911-912. Available at: https://pubmed.ncbi.nlm.nih.gov/18427216.
35. McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir – effects on HIV-1 replication and resistance. N Engl J Med. 2007;356(25):2614-2621. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17582071.
36. Pessoa MG, Gazzard B, Huang AK, et al. Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as part of antiretroviral therapy. 2008;22(14):1779-1787. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18753861.
37. Dore GJ, Soriano V, Rockstroh J, et al. Frequent hepatitis B virus rebound among HIV-hepatitis B virus-coinfected patients following antiretroviral therapy interruption. 2010;24(6):857-865. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20216301.
38. McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir - effects on HIV-1 replication and resistance. N Engl J Med. 2007;356(25):2614-2621. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17582071.
39. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. 1999;30(5):1302-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10534354.
40. Manegold C, Hannoun C, Wywiol A, et al. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis. 2001;32(1):144-148. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11118394.
41. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. 2000;283(1):74-80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10632283.
42. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. 2000;14(18):2895-2902. Available at: https://pubmed.ncbi.nlm.nih.gov/11153671/.
43. Neukam K, Mira JA, Collado A, et al. Liver toxicity of current antiretroviral regimens in HIV-infected patients with chronic viral hepatitis in a real-life setting: the HEPAVIR SEG-HEP cohort. PLoS One. 2016;11(2):e0148104. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26848975.
44. Benhamou Y, Bochet M, Thibault V, et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. 2001;358(9283):718-723. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11551579.
45. Ingiliz P, Valantin MA, Thibault V, et al. Efficacy and safety of adefovir dipivoxil plus pegylated interferon-alpha2a for the treatment of lamivudine-resistant hepatitis B virus infection in HIV-infected patients. Antivir Ther. 2008;13(7):895-900. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19043923.
46. Papatheodoridis GV, Lekakis V, Voulgaris T, et al. Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: a systematic review, meta-analysis, and expert opinion. J Hepatol. 2022;77(6):1670-1689. Available at: https://www.sciencedirect.com/science/article/pii/S016882782202935X.
47. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. 2018;67(4):1560-1599. Available at: https://pubmed.ncbi.nlm.nih.gov/29405329.