Tenofovir in HIV/HBV-Coinfected Patients 

Abstracts & Commentary 

Synopsis: Tenofovir effectively reduces HBV replication over 24 weeks of therapy in HIV-coinfected patients.

Sources:Ristig MB, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-a and lamivudine therapy have failed.J Infect Dis. 2002;186:1844-1847; Nelson M, et al. An open-label study of tenofovir in HIV-1 and hepatitis B virus co-infected individuals.AIDS. 2003;17:F7-F10; Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus.N Engl J Med. 2003;348:177-178; Núñez M, et al. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine.AIDS. 2002;16:2352-2354.

A series of small, noncomparative studies have examined the effect of tenofovir on hepatitis B virus (HBV) infection in individuals with HBV/HIV coinfection. Benhamou and colleagues administered tenofovir disoproxil fumarate (TDF) 300 mg daily to 12 coinfected men, all of whom had detectable HBV DNA in plasma despite ongoing treatment with lamivudine (150 mg b.i.d.). Ten patients had documented HBV polymerase mutations associated with resistance to lamivudine. After 24 weeks of therapy, plasma HBV DNA decreased by a mean of 3.83 ± 0.38 log10. None had loss of HBeAg or development of anti-HBe. TDF was discontinued in 1 patient with polycystic kidney disease whose creatinine increased from 2.8 mg/dL to 4.5 mg/dL. No new mutations were detected at 24 weeks.

Núñez and colleagues in Madrid administered TDF (300 mg q.d.) to 11 men and 1 woman with HIV/HBV coinfection receiving lamivudine as part of an antiretroviral regimen; three were also anti-HCV-positive. Nine were HBeAg-positive and 7 of 11 examined had HBV mutations associated with lamivudine resistance. The median decrease in plasma HBV DNA at 24 weeks was 3.78 log10. One subject cleared both HBsAg and HBeAg, as well as HBV DNA.

Ristig and colleagues in St. Louis enrolled 6 HIV/HBV-coinfected patients with evidence of persistent HBV replication despite ongoing receipt of lamivudine or emtricitabine and prior IFN-a treatment. All were HBeAg positive. Four of 5 who underwent biopsy had evidence of cirrhosis. Treatment with TDF 300 mg q.d. was associated with a decrease in plasma HBV DNA at 24 weeks of 3.6 ± 0.4 log10. Two had HBV DNA levels below the level of detection (< 1.5 × 103), but none developed anti-HBe.

Nelson and colleagues treated 20 HIV/HBV-coinfected patients with tenofovir 245 mg q.d. together with their other antiretroviral therapy. Eleven of the 15 lamivudine-experienced patients had YMDD or YIDD mutations in HBV DNA. The median decrease in plasma HBV DNA was 4.0 log10 at 24 weeks.

The HBV DNA viral load initially declined more rapidly in those who harbored 3TC-resistant mutations compared with those who did not (P = 0.046). Seven of 20 had undetectable plasma HBV DNA at 24 weeks, and 13 had undetectable levels (< 104 copies/mL) at 52 weeks. Two converted to anti-HBe-positive at 24 weeks, while a total of 5 seroconverted at 52 weeks. Approximately one-half normalized their ALT.

In addition to these noncomparative studies, some information is available from a randomized trial of treatment of HIV infection in which either tenofovir or stavudine was added to efavirenz and lamivudine. Although conclusions are necessarily limited by the small sample number of HBV/HIV coinfected patients (11), those who received both tenofovir and lamivudine had greater decreases in HBV DNA, as well as in ALT, and were less likely to develop 3TC resistance than those receiving lamivudine without tenofovir.1

Comment by Stan Deresinski, MD, FACP

Tenofovir is a nucleotide analog reverse transcriptase inhibitor that is used in the treatment of HIV infection.2 Like its progenitor, adefovir,3-5 tenofovir is also active against HBV.

The World Health Organization estimates that 350 million people worldwide are chronically infected with HBV and that three-fourths of the world’s population live in areas with high levels (> 8%) of infection.4 Many of the areas of high HBV prevalence, such as parts of Africa and Asia, also have a high prevalence of HIV infection and, thus, many individuals with HIV/HBV coinfection. In the United States, coinfection is most common among injection drug users.

Lamivudine is also active against both viruses and is frequently used in coinfected patients. Its activity against HBV appears to be comparable to that of tenofovir, resulting in an approximately 4 log10 decrease in circulating HBV DNA concentration after 24 weeks of therapy.6 Unfortunately, HBV, like HIV, commonly becomes resistant to this nucleoside analog during treatment as a result of mutations in the YMDD motifs of their reverse transcriptase genes.

The studies reviewed here demonstrate that tenofovir is effective in reducing HBV replication in coinfected patients, with a mean or median decrease in HBV load of approximately 4 log10 after 24 weeks of therapy (see Table, below). Although the data set is small, these virological responses appeared to be independent of the degree of immunodeficiency, as well as the presence of YMDD mutations. HBeAg clearance at 24 weeks is infrequent, a finding not different from that seen with lamivudine. HBV virological rebound indicative of the emergence of resistance to tenofovir was not described in these relatively short-term studies. This is consistent with the adefovir experience.

Table.

Results of Tenofovir Therapy on HBV in HIV Coinfected Patients

Reference # Patients HBV log10 decrease HBe Clearance
Núñez 12 3.78 (median) 1
Ristig 6 3.6 (mean) 0
Benhamou 12  3.83 (mean) 0
Nelson 20  4.0 (mean) 2*
Cooper**  5 4.7 (mean) 1
*5 at 52 weeks

**tenofovir and lamivudine


There is, however, a potential downside to the dual activity of these drugs. Abrupt discontinuation of anti-HBV therapy may lead to viral resurgence and flares of liver disease that clinically resemble acute HBV infection. These flares may also occur with continued lamivudine therapy in association with the increased HBV replication seen with the emergence of resistance. Such flares of hepatitis result in worsening of liver histology and, occasionally, liver failure.7

All HIV-infected patients should be screened for HBV infection; the converse is also true. In dually infected patients, some clinicians may deliberately elect to use lamivudine or tenofovir as part of their anti-HIV regimen in order to reduce HBV replication as well. Whether HBV resistance to tenofovir will commonly emerge with administration of this nucleotide analog remains to be seen. At any rate, such patients must be carefully observed if tenofovir therapy is discontinued.

References

1. Cooper D, et al. Tenofovir DF and lamivudine combination therapy compared to lamivudine alone for HBV in therapy-naïve HIV/HBV co-infected patients: 48-week interim results [Abstract 825]. 10th Conference on Retroviruses and Opportunistic Infections; Seattle, WA;Boston, 2003.

2. Deresinski S. Special Feature: Tenofovir-A new antiretroviral agent. Infectious Disease Alert. 2001; 21:36-39.

3. Elliott WT, Chan J. Pharmacology Update: Adefovir (Hepsera) for the treatment of chronic hepatitis B infection. Infectious Disease Alert. 2002;22: 46-47.

4. Marcellin P, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816.

5. Hadziyannis SJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-807.

6. Honkoop P, et al. Quantitative hepatitis B virus DNA assessment by the limiting-dilution polymerase chain reaction in chronic hepatitis B patients: Evidence of continuing viral suppression with longer duration and higher dose of lamivudine therapy. J Viral Hepat. 1998;5:307-312.

7. Leung N. Treatment of chronic hepatitis B: Case selection and duration of therapy. J Gastroenterol Hepatol. 2002;17:409-414.