Is There a Simple Way to Treat a Patient Who Is Coinfected With Hepatitis B Virus and HIV?
Richard K.
Sterling,
MD, MSc, FACP, FACG
The simple answer to this question is yes and no. The majority of those infected with human immunodeficiency virus (HIV) have been exposed to hepatitis B virus (HBV). Before you think about initiating anti-HBV therapy, you need to understand the epidemiology and natural history of HBV in those with HIV. Only then can you consider the treatment options.
Epidemiology
Similar to coinfection of HIV and HCV, with shared modes of transmission, there is also concern over the liver-related health risks of HBV-HIV, which were previously overshadowed by the morbidity and mortality of HIV until the introduction of highly active antiretroviral therapy (HAART). It is known that 70% to 90% of patients with HIV show evidence of prior exposure to HBV. In a cohort of 232 HIV-infected patients, 9% suffered from chronic HBV infection (HBsAg positive), 82% of whom had detectable HBeAg and 86% of whom had detectable HBV DNA.1 This study also showed that coinfection was associated with reduced survival compared to controls.
Natural History
Impact of HIV on HBV
It is now known that the natural history of HBV is altered by the presence of concurrent HIV infection. HIV infection impairs cell-mediated immunity and is likely to modify the course of HBV via uncontrolled viral replication and decreased hepatocellular necrosis. Colin et al2 investigated the influence of HIV on chronic HBV utilizing biochemical tests and histologic severity indices in a cohort of homosexual non-drug-addicted men, all with HBV with and without HIV. The HIV-HBV–positive patients had lower serum alanine aminotransferase (ALT) levels, lower serum albumin, and higher serum HBV DNA levels compared to those with only HBV. Multivariate analysis also demonstrated that HIV positivity was associated with an increased risk of cirrhosis (relative risk of 4.20) without increased necroinflammatory process. This contrasts somewhat with the findings of an earlier study by Housset et al,3 who found no difference in mean ALT values, histologic activity index, or prevalence of cirrhosis in HIV-positive versus HIV-negative patients with chronic HBV; however, follow-up analysis in this series found a lower clearance rate of HBV DNA in HIV-positive patients, indicating the impact of coinfection.
The Multicenter Cohort Study (MACS) results demonstrated that coinfected individuals had a higher liver-related mortality rate than those with either HIV or HBV infection alone.4 Coinfected men were 8 times more likely to die from liver disease than those with HIV alone and were 19 times more likely to die than those with HBV alone. The rate of liver-related death also increased when nadir CD4 count dropped to less than 100, with HBsAg positivity carrying a relative risk of 11.6 with a CD4 count less than 100 compared to a relative risk of 6.8 when cell count was greater than 250. This suggests that identification and comprehensive management of coinfection is paramount to treatment success, especially in the HAART era.
Impact of HBV on HIV
Little is known about the effect of HBV on HIV, and the idea that HBV could accelerate HIV progression is controversial. HBV is considered predominately hepatotropic but is also lymphotropic. Proteins encoded by the HBV genome may have an effect on HIV replication through the fourth major coding region of the HBV genome, denoted X. The HBV X protein presumably interacts with NF-kB transcription factors to allow the factors to bind to specific HIV long terminal repeat sequences and increases the rate of transcription, thereby enhancing HIV replication in cells coinfected with HIV and HBV. The duration of latency of HIV may also be shortened by the presence of HBV in HIV-infected mononuclear cells that would diminish the antiviral effects of interferons on the replication of HIV.
Evaluation and Treatment of HBV in the Setting of HIV
Chronic HBV effectively behaves as an opportunistic infection in the setting of concurrent HIV infection. All patients found to have HBV should also be tested for HDV and have periodic surveillance for hepatocellular carcinoma (HCC). The determination also needs to be made as to which virus needs treatment—HBV, HIV, or both. All patients with evidence of active HBV infection (HBsAg positive) with HBeAg positive or HBV DNA 104 copies/mL or 2000 IU/L, evidence of necroinflammation as demonstrated by liver biopsy or elevated ALT, or evidence of cirrhosis with HBV DNA 103 copies/mL (or greater than 200 IU/L) should be considered candidates for treatment. As with the treatment of HBV in patients without coinfection, the necessity of treatment compliance is also a pertinent issue.
Overall goals in the treatment of chronic HBV are to reduce liver-related mortality, to improve necroinflammation, and to suppress active HBV replication by either significant reduction or clearance of HBV DNA. Treatment should also focus on conversion from active to nonreplicative virus, as reflected by conversion of HBeAg positive to HBeAb positive, and to pursue the disappearance of chronic carrier status. There are also goals unique to those patients with HIV, including the reduction of antiretroviral drug hepatotoxicity and avoidance of any HBV therapy that would negatively impact the patients HIV therapy. The choice of therapy needs to take into account the overall effectiveness, the risk of resistant mutations, and the potential interactions HBV medication will have on HIV therapy. The options for treating HBV and their impact on HIV are outlined in Table 16-1.
Interferon (IFN)
There are little data on the effectiveness of interferon-alpha for the treatment of chronic HBV in the coinfected patient. DiMartino and colleagues5 performed a retrospective analysis of the influence of coinfection on response to IFN-alpha therapy, virologic status, and progression to cirrhosis in 141 HBeAg positive patients, 69 of whom were also HIV positive. There was no significant short-term response difference to interferon therapy between HIV-positive and HIV-negative patients, but response was poorer in patients with low CD4 count (<200/mm3). However, long-term seroconversion was only 15.4% in coinfected patients compared to 52% in HIV-negative patients. HIV coinfection was also associated with increased frequency of HBV reactivations, 35.7% in HIV-positive versus 9% in HIV-negative patients. The risk of cirrhosis was also increased in coinfected patients with a CD4 count <200 (relative risk 4.57), but IFN-alpha therapy decreased the incidence of HBV cirrhosis regardless of serologic response or HIV status. Although there is little information regarding the use of peginterferon in the HAART era, it may be a viable option is those without cirrhosis.
Lamivudine (LMV)
LMV is a nucleoside analogue that is effective against both HIV and HBV. Fang and colleagues6 studied the use of HAART containing LMV with comparison of HBV dynamics between HBeAg-positive and HBeAg-negative coinfected patients. Their findings were that the regimen containing LMV effectively suppressed HBV DNA levels by 10−3 to 10−5-fold over baseline in coinfected patients, but there was a residual HBV viremia in most HBeAg-positive patients. This suggests that more potent antiviral regimens are needed in HBeAg-positive patients to effectively suppress HBV replication. Also, since the regimen containing LMV did not effectively suppress HBV replication in these patients, regimens containing LMV as a monotherapy for chronic HBV should not be prescribed in coinfected patients with HBeAg positivity without evidence of active hepatitis, due to the high risk of development of HBV resistance to LMV. Benhamou and colleagues7 detailed this development of LMV resistance in coinfected patients in a study that demonstrated that LMV therapy led to HBV replication inhibition in 86.4% of coinfected patients. However, they also found that there is development of HBV resistance in the YMDD motif of the DNA polymerase to LMV in up to 50% of patients within the first 2 years of treatment, with a roughly linear annual incidence rate of 20% and an expected actuarial survival curve that showed a potential for 91% HBV resistance at 4 years. This pattern of resistance was only observed in HBeAg carriers, but it was also noted that 1 in 9 patients who had seroconverted also developed LMV resistance.
Adefovir (ADV)
ADV is a nucleotide analogue approved for the treatment of chronic hepatitis B. In one large randomized controlled trial of HBeAg-positive patients where 10 mg of ADV was compared to placebo, there was a significant reduction in HBV DNA levels, 3.52 log10 copies/mL with ADV.8 There was also found to be a biochemical improvement in 55% of patients as well as a 48% rate of histological improvement. However, HBeAg seroconversion was relatively low and occurred in only 14% of patients.
ADV is also effective in those with HBV DNA–positive, HBeAg-negative HBV and in those with LMV resistance. It is important to note that there can be transient elevation of ALT with the initiation of ADV therapy in the coinfected patient, and that ADV at 10 mg/d is not effective against HIV.
Tenofovir (TNF)
TNF is a nucleotide analogue that has activity against both HBV and HIV. Dore and colleagues9 concluded that TNF had efficacy against HBV in both HAART-experienced and HAART-naïve coinfected patients. There was a mean
reduction in HBV DNA by 4 to 5 log10 copies/mL in HAART-experienced patients after 48 weeks of treatment with TNF and a similar reduction in HBV DNA in HAART-naïve patients who received combination therapy with LMV and TNF as a component of initial HAART 3-drug regimen. There was a trend toward reduced YMDD resistance and greater HBV DNA suppression in coinfected patients receiving LMV and TNF as opposed to LMV alone. Nelson and colleagues10 also studied TNF in a cohort of 20 coinfected patients, 15 of whom had LMV experience. Patients were given TNF in addition to or as part of antiretroviral therapy. They found a significant decrease in HBV DNA and ALT levels and 25% of patients underwent HBeAg seroconversion. It was also concluded that TNF appears to overcome LMV resistance with a 4 log10 reduction in HBV viral load in the study population. Benhamou and colleagues11 demonstrated the efficacy of TNF against wild-type, presumed precore mutants and LAM-resistant HBV when used as part of HAART in coinfected patients. They used TNF in combination with LMV in both HBeAg-positive and HBeAg-negative patients and found a significant reduction of HBV DNA in both groups, and HBV DNA became undetectable in 29.6% and 81.6% of HBeAg positive and negative patients, respectively. Finally, a recent study by Peters and colleagues12 on the ACTG A5127 reported similar response of TNF and ADV in a cohort of 52 HIV-HBV coinfected patients.
Emtricitabine (FTC)
FTC is a nucleoside analogue that is similar to LMV and is approved for HIV treatment. It has been shown to produce up to a 3.3 log10 copies/mL serum HBV DNA reduction in coinfected patients but also has been found to have an incidence of 12% of YMDD mutations in patients following 1 year of FTC therapy.13 However, FTC will have little impact when used alone or in combination with TNF in LMV-experienced patients.
TNF/FTC Combination
Combination of TNF and FTC (Truvada, Gilead Sciences) has become a first-line agent in treating HIV. Because of the potent antiviral effect on HBV, it has become the ideal choice in those needing both HIV and HBV therapy.14-16 However, its long-term efficacy on HBV DNA suppression is not known and, therefore, those on therapy will require monitoring for emergence of HBV mutations.
Entecavir (ENT)
ENT is a purine-derived nucleoside analogue that is effective against HBV. It has been shown to be very potent against HBV in monoinfected patients, with a 7 log10 copies/mL reduction in HBV DNA and no resistance at 48 weeks in LMV naïve patients, and has shown a mean reduction of HBV DNA by 3.66 log10 copies/mL versus placebo in LMV-resistant coinfected patients. Although effective against LMV-resistant HBV, efficacy is reduced and higher doses are required. However, the recent observation of increases in HIV RNA when used alone in HIV-HBV coinfected patients may limit its use as monotherapy.
Telbivudine
I am not aware of any data on the use of telbivudine in those coinfected with HIV and therefore cannot recommend it as a treatment option at this time.
Summary of Management of HIV-HBV Coinfection
As with hepatitis C virus (HCV), the recognition that HBV is a significant cause of morbidity and mortality in the HIV-infected population has led to significant advances in our understanding of the impact of HIV on HBV disease progression. All patients with evidence of active HBV replication or evidence of necroinflammation should be considered as candidates for treatment, but the optimal time for the initiation of HBV therapy or the ideal medication regimen is not yet clearly elucidated. Goals of HBV therapy are the loss of active replication, the improvement of necroinflammation, the reduction of liver-related mortality, as well as the reduction of antiretroviral hepatotoxicity. Initial evaluation of the HBsAg-positive patient involves testing HBV DNA viral load, ALT, HBeAg, and HBeAb and excluding coexisting HCV or hepatitis D virus (HDV), as well as screening for HCC. Liver biopsy is also indicated in tandem with immunologic testing to evaluate the degree of necroinflammation and histologic severity of disease. We have outlined a proposed algorithm for the evaluation and management of HBV-HIV coinfection (Figure 16-1). The key is to determine which viruses need treatment. The algorithm starts with determining HBV surface antigen (SAg) status and, if positive, evaluating for HDV coinfection. For those with positive SAg, the next step involves determining HBV DNA level and e-antigen/antibody (eAg/eAb) status. For those with negative eAg, low (<104 IU/mL) HBV DNA, and normal (Nl) ALT, no additional HBV therapy is indicated and patients should be monitored every 3 months for reactivation. If HIV requires therapy, then I would avoid LMV and FTC unless TNF is part of HAART. If ALT is elevated (elev), then other causes of hepatitis need to be excluded, such as HCV, HDV, steatohepatitis, alcohol, and medication. If HBV DNA is high (>104 IU/mL), then a precore/core mutation is suspected and patients similarly follow those with wild-type eAg-positive HBV and should undergo liver biopsy to assess disease severity. If mild disease is found on biopsy and HIV does not require therapy, these individuals should be monitored for disease flares. For those with moderate to severe disease noted on biopsy, treatment will depend on past or current HIV therapy. If the patient is treatment naïve and does not require HIV therapy, then options include ADV or pegylated interferon (PEG-IFN). If HIV treatment naïve and HIV also requires treatment, then HAART should include TNF with either FTC or LMV. If LMV experienced, then consider HIV resistance testing and adding TNF with or without LVM or FTC or adding ENT to existing HAART. As with HCV-HIV coinfection, there have been significant advances in the care of HIV patients coinfected with HCV and HBV, giving optimism for this challenging patient population.
Figure 16-1. Algorithm HBV-HIV infection.
References
1. Ockenga J, Tillman HL, Trautwein C, et al. Hepatitis B and C in HIV-infected patients. J Hepatol. 1997;27:18-24.
2. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306-1310.
3. Housset C, Pol S, Carnot F, et al. Interactions between human immunodeficiency virus-1, hepatitis delta virus and hepatitis B virus infections in 260 chronic carriers of hepatitis B virus. Hepatology. 1992;15:578-583.
4. Thio CL, Seaberg EC, Skolasky R, et al. HIV-1, hepatitis B virus, and the risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921-1926.
5. DiMartino, V, Thevenot T, Colin, JF et al: Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812-1822.
6. Fang CT, Chen PJ, Chen MY, et al. Dynamics of plasma hepatitis B virus levels after highly active antiretroviral therapy in patients with HIV infection. J Hepatol. 2003;39(6):1028-1035.
7. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999;30:1302-1306.
8. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816.
9. Dore GJ, Cooper DA, Pozniak AL, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189(7):1185-1192.
10. Nelson M, Portsmouth S, Stebbing J, et al. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. AIDS. 2003;17(1):F7-10.
11. Benhamou Y, Fleury H, Trimoulet P, et al: Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006;43:548-555.
12. Peters MG, Anderson J, Lynch P, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44:1110-1116.
13. Snow A, Harris J, Borroto-Esoda K, et al: Emtricitabine therapy for hepatitis infection in HIV + patients co-infected with hepatitis B: efficacy and genotypic findings in antiretroviral treatment naïve patients. 11th conference on retroviruses and opportunistic infection. San Francisco, CA;2004. p. 836 [abstract].
14. Thio CL. Hepatitis B virus infection in HIV-infected persons. Current Hepatitis Reports. 2004;3:91-97.
15. Nunez M, Puoti M, Camino N, Soriano V. Treatment of chronic hepatitis B in the human immunodeficiency virus-infected patient: present and future. Clin Infect Dis. 2003;37:1678-1685.
16. Benhamou Y. Antiretroviral therapy and HIV/hepatitis B coinfection. Clin Infect Dis. 2004;38(Suppl2)98-103.
17. Pessoa W, Gazzard B, Huang A, et al. Entecavir in HIV/HBV co-infected patients: safety and efficacy in a phase II study (ETV-038). Conference on retroviruses and opportunistic infections, Boston, MA; 2005. p. 123 [abstract].