Lamivudine vs Tenofovir in HIV/HBV Coinfection
Lamivudine vs Tenofovir in HIV/HBV Coinfection
We report the first study in sub-Saharan Africa that prospectively compared HBV-related outcomes between lamivudine- and tenofovir-containing cART for HIV infection. Among HIV-HBV–coinfected antiretroviral-naive individuals in Zambia and South Africa, tenofovir-containing first-line cART provided potent HBV-active therapy with a superior resistance profile to lamivudine monotherapy. Despite the fact that our study did not demonstrate differential HBV suppression or HBsAg loss between tenofovir and lamivudine treatment during the first year of cART, our findings together with previous reports provide support for use of tenofovir over lamivudine monotherapy in HIV-HBV–coinfected persons in resource-limited countries to prevent the development of HBV drug resistance and improve control of viral replication, as advocated in the latest WHO guidelines. We found an overall baseline prevalence of HBsAg seropositivity in 7.4% of patients, which is within the range of previous reports (4.8%–22.9%) from South Africa.
Lamivudine is known to have a low genetic barrier to resistance and is associated with the emergence of mutations in the YMDD (tyrosine, methionine, aspartate, aspartate) motif of HBV pol domain C and with upstream compensatory mutations in polymerase domains A and B that, collectively, reduce treatment effectiveness. Previous studies from industrialized countries in chronic HBV-monoinfected patients have reported lamivudine-resistant mutations in 23% of patients receiving lamivudine monotherapy after 1 year, increasing to 65% after 5 years, and YMDD mutations in 49% after a median of 32.4 months of lamivudine monotherapy. One report observed significantly more hepatocellular carcinomas shortly after development of lamivudine resistance, which is largely explained by the recurrence of viral replication. Moreover, lamivudine resistance induces cross-resistance to emtricitabine, telbivudine, and entecavir, thus reducing the options for subsequent treatment. By contrast, tenofovir has a good resistance profile, and in phase 3 trials in HBV-monoinfected patients, no evidence of tenofovir resistance was shown up to 144 weeks of treatment. To date, potential tenofovir resistance, ie, the A194T mutation, has been described in only 2 HIV-HBV–coinfected patients. However, the association between this mutation and tenofovir resistance was not confirmed in another study.
The proportion of tenofovir-treated patients who achieved HBV suppression accords with findings in European cohorts. A small randomized study in Thailand (n = 16) found that cART with tenofovir–emtricitabine in antiretroviral-naive HIV-HBV–coinfected persons resulted in a greater proportion of patients with HBV suppression at week 48 than emtricitabine monotherapy. Another small randomized study in antiretroviral-naive HIV-HBV–coinfected persons in Thailand (n = 36) demonstrated higher virological failure rates and early resistance development for lamivudine monotherapy, compared with tenofovir monotherapy, but did not demonstrate any short-term advantage of HBV dual therapy. The Phidisa II trial in South Africa found little additional benefit of lamivudine monotherapy in HIV-HBV–coinfected persons, compared with cART without any HBV activity. HBsAg loss rates in this study concur with findings in the Phidisa II trial but are higher than reported in studies from Europe and Taiwan.
Chronic HBV coinfection in our cohort was not associated with a reduced CD4 lymphocyte recovery during cART. Several observational studies did not find a sustained negative effect of HBV on CD4 cell count recovery, although in a report from Nigeria CD4 recovery was delayed in the Hepatitis B e antigen (HBeAg)-positive subgroup. The Phidisa II trial in South Africa found no difference in CD4 recovery over 2 years of follow-up between HIV-monoinfected and HIV-HBV–coinfected persons receiving an HBV-active regimen with lamivudine. Based on available data, there is no justification to adjust the expected goals for recovery of CD4 cell counts during cART.
The study population had markers of highly active hepatitis B disease with a baseline median HBV-DNA above 6 log10 IU/mL, with only 34% having low-level HBV viremia. High values of HBV-DNA have been suggested to be attributable to HIV infection delaying transition to the inactive carrier phase (identified by anti-HBe, absence of HBeAg, and low levels of HBV-DNA) or reactivation with reversion to the immune-active phase during AIDS-related immune suppression. Serological evidence of a history of HBV exposure (chronic hepatitis B indicated by HBsAg or any exposure indicated by anti-HBc) was present in 53% of participants, which is in agreement with previous studies from Africa.
Compared with HIV-uninfected individuals, HIV-infected individuals appear to have increased prevalence of occult HBV infection in studies from South Africa and Cote d'Ivoire, ranging from 10% to 23%. In our cohort, HBV-active cART, containing either lamivudine or tenofovir, resulted in HBV viral suppression in a high (≥90%) proportion of patients with occult infection. Although this finding suggests that occult HBV infection may be more a diagnostic than a clinical problem, extended follow-up studies are needed to determine whether it is associated with long-term liver-related complications in regions of high HBV endemicity.
The role of HBV genotypes in the natural history of the infection and in the response to therapy in patients with HIV coinfection is unclear. For example, in southern Africa, an increased risk of hepatocellular carcinoma has been linked to genotype A1. Therefore, studies that more clearly define the role of genotype on the natural history are warranted.
The study has some limitations. First, participant attrition in our cohort because of mortality and loss to follow-up in the first year of cART was considerable (26%), yet consistent with other reports from the region. Also, a number of specimens were unobtainable for retrospective HBV laboratory testing. Second, confounding by treatment indication is likely to be limited because cART regimens were typically prescribed in concordance with national guidelines rather than on an individual basis. Third, participants were assessed neither for hepatitis C virus or hepatitis delta coinfection, which may be associated with lower HBV replication and worse outcomes, nor for HBeAg, which precluded a more detailed assessment of HBV immune control during cART. Fourth, population-based sequencing is not able to detect minority resistant viral strains, thus potentially underestimating resistance.
In conclusion, tenofovir-containing cART provides potent anti-HBV therapy with a good resistance profile, relative to lamivudine, for HIV-HBV–coinfected persons in southern Africa. In countries with high HBV endemicity, all HIV-infected individuals should be screened for HBsAg before starting cART. As per WHO recommendations, coinfected patients with an indication for treatment of either HBV or HIV should receive a triple combination of antiretroviral agents, including tenofovir. Nonetheless, despite progress, by 2010, only 20% of first-line cART regimens contained tenofovir, potentially exposing millions of HIV-HBV–coinfected Africans to suboptimal HBV therapy. Improved access to tenofovir in Africa is an urgent priority. To reduce global HBV-related morbidity and mortality, improved understanding of the epidemiology of chronic HBV in regions with high HBV endemicity and the long-term effectiveness of cART regimens in patients with HIV–HBV coinfection is required.
Discussion
We report the first study in sub-Saharan Africa that prospectively compared HBV-related outcomes between lamivudine- and tenofovir-containing cART for HIV infection. Among HIV-HBV–coinfected antiretroviral-naive individuals in Zambia and South Africa, tenofovir-containing first-line cART provided potent HBV-active therapy with a superior resistance profile to lamivudine monotherapy. Despite the fact that our study did not demonstrate differential HBV suppression or HBsAg loss between tenofovir and lamivudine treatment during the first year of cART, our findings together with previous reports provide support for use of tenofovir over lamivudine monotherapy in HIV-HBV–coinfected persons in resource-limited countries to prevent the development of HBV drug resistance and improve control of viral replication, as advocated in the latest WHO guidelines. We found an overall baseline prevalence of HBsAg seropositivity in 7.4% of patients, which is within the range of previous reports (4.8%–22.9%) from South Africa.
Lamivudine is known to have a low genetic barrier to resistance and is associated with the emergence of mutations in the YMDD (tyrosine, methionine, aspartate, aspartate) motif of HBV pol domain C and with upstream compensatory mutations in polymerase domains A and B that, collectively, reduce treatment effectiveness. Previous studies from industrialized countries in chronic HBV-monoinfected patients have reported lamivudine-resistant mutations in 23% of patients receiving lamivudine monotherapy after 1 year, increasing to 65% after 5 years, and YMDD mutations in 49% after a median of 32.4 months of lamivudine monotherapy. One report observed significantly more hepatocellular carcinomas shortly after development of lamivudine resistance, which is largely explained by the recurrence of viral replication. Moreover, lamivudine resistance induces cross-resistance to emtricitabine, telbivudine, and entecavir, thus reducing the options for subsequent treatment. By contrast, tenofovir has a good resistance profile, and in phase 3 trials in HBV-monoinfected patients, no evidence of tenofovir resistance was shown up to 144 weeks of treatment. To date, potential tenofovir resistance, ie, the A194T mutation, has been described in only 2 HIV-HBV–coinfected patients. However, the association between this mutation and tenofovir resistance was not confirmed in another study.
The proportion of tenofovir-treated patients who achieved HBV suppression accords with findings in European cohorts. A small randomized study in Thailand (n = 16) found that cART with tenofovir–emtricitabine in antiretroviral-naive HIV-HBV–coinfected persons resulted in a greater proportion of patients with HBV suppression at week 48 than emtricitabine monotherapy. Another small randomized study in antiretroviral-naive HIV-HBV–coinfected persons in Thailand (n = 36) demonstrated higher virological failure rates and early resistance development for lamivudine monotherapy, compared with tenofovir monotherapy, but did not demonstrate any short-term advantage of HBV dual therapy. The Phidisa II trial in South Africa found little additional benefit of lamivudine monotherapy in HIV-HBV–coinfected persons, compared with cART without any HBV activity. HBsAg loss rates in this study concur with findings in the Phidisa II trial but are higher than reported in studies from Europe and Taiwan.
Chronic HBV coinfection in our cohort was not associated with a reduced CD4 lymphocyte recovery during cART. Several observational studies did not find a sustained negative effect of HBV on CD4 cell count recovery, although in a report from Nigeria CD4 recovery was delayed in the Hepatitis B e antigen (HBeAg)-positive subgroup. The Phidisa II trial in South Africa found no difference in CD4 recovery over 2 years of follow-up between HIV-monoinfected and HIV-HBV–coinfected persons receiving an HBV-active regimen with lamivudine. Based on available data, there is no justification to adjust the expected goals for recovery of CD4 cell counts during cART.
The study population had markers of highly active hepatitis B disease with a baseline median HBV-DNA above 6 log10 IU/mL, with only 34% having low-level HBV viremia. High values of HBV-DNA have been suggested to be attributable to HIV infection delaying transition to the inactive carrier phase (identified by anti-HBe, absence of HBeAg, and low levels of HBV-DNA) or reactivation with reversion to the immune-active phase during AIDS-related immune suppression. Serological evidence of a history of HBV exposure (chronic hepatitis B indicated by HBsAg or any exposure indicated by anti-HBc) was present in 53% of participants, which is in agreement with previous studies from Africa.
Compared with HIV-uninfected individuals, HIV-infected individuals appear to have increased prevalence of occult HBV infection in studies from South Africa and Cote d'Ivoire, ranging from 10% to 23%. In our cohort, HBV-active cART, containing either lamivudine or tenofovir, resulted in HBV viral suppression in a high (≥90%) proportion of patients with occult infection. Although this finding suggests that occult HBV infection may be more a diagnostic than a clinical problem, extended follow-up studies are needed to determine whether it is associated with long-term liver-related complications in regions of high HBV endemicity.
The role of HBV genotypes in the natural history of the infection and in the response to therapy in patients with HIV coinfection is unclear. For example, in southern Africa, an increased risk of hepatocellular carcinoma has been linked to genotype A1. Therefore, studies that more clearly define the role of genotype on the natural history are warranted.
The study has some limitations. First, participant attrition in our cohort because of mortality and loss to follow-up in the first year of cART was considerable (26%), yet consistent with other reports from the region. Also, a number of specimens were unobtainable for retrospective HBV laboratory testing. Second, confounding by treatment indication is likely to be limited because cART regimens were typically prescribed in concordance with national guidelines rather than on an individual basis. Third, participants were assessed neither for hepatitis C virus or hepatitis delta coinfection, which may be associated with lower HBV replication and worse outcomes, nor for HBeAg, which precluded a more detailed assessment of HBV immune control during cART. Fourth, population-based sequencing is not able to detect minority resistant viral strains, thus potentially underestimating resistance.
In conclusion, tenofovir-containing cART provides potent anti-HBV therapy with a good resistance profile, relative to lamivudine, for HIV-HBV–coinfected persons in southern Africa. In countries with high HBV endemicity, all HIV-infected individuals should be screened for HBsAg before starting cART. As per WHO recommendations, coinfected patients with an indication for treatment of either HBV or HIV should receive a triple combination of antiretroviral agents, including tenofovir. Nonetheless, despite progress, by 2010, only 20% of first-line cART regimens contained tenofovir, potentially exposing millions of HIV-HBV–coinfected Africans to suboptimal HBV therapy. Improved access to tenofovir in Africa is an urgent priority. To reduce global HBV-related morbidity and mortality, improved understanding of the epidemiology of chronic HBV in regions with high HBV endemicity and the long-term effectiveness of cART regimens in patients with HIV–HBV coinfection is required.
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