HBV infection characteristics at first visit significantly differed between the two groups. Six HIV-positive patients (2.3%) were HBs Ag negative at first visit, three of them with positive HBs Ab. Although HBe status was not systematically assessed for all patients (especially in HIV-co-infected patients), positive HBe antigenemia at first visit was significantly more frequently encountered in HIV-positive than in HIV-negative patients (103 of 178, 57.9% versus 54 of 189, 28.6%; P < 10−4).
When considering not only the first visit but the first period of follow-up (i.e. without and before any HBV treatment), this difference persisted: positive HBe Ag 140 of 196, 71.4% of HBV–HIV co-infected patients versus 82 of 202, 40.6% HBV mono-infected ones, P < 10−4. In contrast, anti-HBe positive infections were less often observed in HIV-positive than in HIV-negative patients.
HBV DNA levels did not significantly differ between the two groups of patients, 50 to 60% of them with a first HBV DNA above 20 000 IU/ml. Liver histological evaluation was initially less frequently performed in HIV-positive patients. Nevertheless, the proportion of cirrhosis was higher in HBV–HIV co-infected than in HBV mono-infected patients, even when considering only the results from liver biopsies (eight of 39, 17% versus eight of 95, 7.6%; P = 0.05).
Evolution in hepatitis B virus serology and virology over time in the study population: comparison of HIV-positive versus HIV-negative patients
Anti-HBV treatments are summarized in Table 3. HIV-positive patients received HBV treatment more frequently and for a longer period of time, whatever the reason. Among the patients treated for HBV, an HBV combination therapy was used more frequently in HBV–HIV co-infected than in HBV mono-infected patients (145 of /227, 63.9% versus 45 of 94, 47.9%; P < 0.01). This difference persisted when considering the current HBV treatment in October 2005, with only 32 of 74 (43.2%) HBV mono-infected patients on combined HBV treatment versus 124 of 213 (58.2%) HBV–HIV co-infected patients (P < 0.03).
Although drugs with dual activity (mainly lamivudine and tenofovir) were more often used in HBV–HIV co-infected patients, adefovir and interferon (standard or pegylated-interferon) treatments alone or in combination were used in 11.9 and 16.3% of HBV–HIV-co-infected patients, respectively. No significant difference was observed between groups regarding clinical presentation. However, the use of specific anti-HBV drugs significantly decreased over time in HBV–HIV co-infected patients, with 21 of 213 (9.9%) and four of 213 (1.9%) of these on adefovir and interferon, respectively, in October 2005.
HBs Ag loss was observed in nine HIV positive and six HIV negative patients (P = 0.86). HBs seroconversion was present in eight HIV-positive and one HIV-negative patients (P = 0.10, incidence rates of HBs seroconversion 0.7/100 and 0.2/100 patient-years, respectively). In patients with positive HBe Ag during the first period and with subsequent serological reevaluation, HBe Ag loss was observed in 24 of 105 (22.9%) HIV-positive and 17 of 41 (41.5%) HIV-negative patients (P = 0.04). HBe seroconversion was noted in 18 of 105 (17.1%) HIV-positive and 17 of 41 (41.5%) HIV-negative patients (P = 0.0008, the incidence rate of HBe seroconversion 2.6/100 patient-years and 10.0.100 patient-years, respectively).
Liver histology (either via liver biopsy or non-invasive biological surrogate markers) was assessed at least once in only 87 (33%) HIV-positive versus121 (56%) HIV-negative patients (P < 10−4). Liver biopsy was the most frequently used method, more frequently in HIV-positive than HIV-negative patients (86 versus 77%; P = 0.04). In contrast, non-invasive biological surrogate markers were less frequently measured at least once in HIV-positive than HIV-negative patients (16.1 versus 30.6% of those who underwent liver histological assessment, P = 0.02). HBe antigen loss was associated with histological improvement in patients who underwent at least two liver biopsy assessments. Indeed, mean differences in METAVIR scores in HIV-positive patients who had lost HBe antigen in comparison with those who had not were −0.9 ± 1.3 versus −0.1 ± 0.5 for activity (P = 0.02), and −0.5 ± 0.9 versus +0.2 ± 0.6 for fibrosis (P = 0.01, the annual progression rate for fibrosis was −0.1 ± 0.14 versus +0.12 ± 0.26).
Evolution according to hepatitis B virus treatment in Hepatitis V virus–HIV co-infected patients
In HBV–HIV co-infected patients, apart from lamivudine monotherapy, which was very often used as first-line HBV treatment, the most frequent HBV treatments used during the entire medical history were tenofovir in combination (with either lamivudine or emtricitabine, 117 patients, 32 of whom had never been treated for HBV), and tenofovir alone (36 patients, all but two lamivudine-experienced). Adefovir was used in 27 cases (mainly alone or in combination with lamivudine). Standard or pegylated interferon was used alone in 21 cases (in 81% of these as a first-line treatment) or in combination in 26 cases (91% following previous HBV therapy). Interferon monotherapy was used earlier (median year 1996, mainly before any antiretroviral treatment) than combinations with interferon (2001) and tenofovir treatment (2003).
The description of and comparisons between patients on tenofovir, adefovir (both either used as HBV monotherapy or in combination with another analogue, but not with interferon) and interferon (standard or pegylated) combined with analogues are shown in Table 4. Patients in this latter group were on standard (12 cases) or pegylated (14 cases) interferon, associated with analogue bitherapy (mainly lamivudine and tenofovir) in 10 cases or analogue monotherapy (mainly lamivudine) in 16 cases. The baseline characteristics of patients were not significantly different between groups, since most of the patients were antiretroviral (and anti-HBV) treatment experienced. However, the mean ALT level was higher in the adefovir monotherapy group, since two of the 12 patients experienced hepatic flares at the time of adefovir introduction (ALT values > 2000 IU/l). Despite similar baseline HBV DNA levels for the two groups, HBV DNA levels below 2000 IU/ml (although assessed in only 52% of the patients) were reached or maintained in more than 60% on tenofovir or combined interferon, more than that observed with adefovir. Among patients who were HBe Ag positive at the beginning of the period, HBe Ag loss and HBe seroconversion were never observed in patients on monotherapy but only in those on combined HBV therapy. Moreover, two patients seroconverted against HBe on combined pegylated-interferon despite prior standard interferon monotherapy (a few years before). This suggests the potential interest of combinations (since no HBe seroconversions were observed in 11 other patients on interferon monotherapy) of pegylated interferon, as well as the potential impact of immune reconstitution.
When focusing on patients treated with tenofovir bitherapy, those never previously treated against HBV had a lower CD4 cell count (239 ± 162 versus 359 ± 249 cells/μl; P = 0.03), a higher HIV viral load (3.6 ± 2.3 versus 1.6 ± 2.0 log10 copies/ml; P < 10−4), and a higher HBV DNA baseline level (5.1 ± 2.7 versus 3.7 ± 2.7 log10 IU/ml; P < 10−4) than experienced patients. As a result, HBV DNA decrease was greater in naive patients (−5.4 ± 2.6 versus −2.0 ± 2.8 log10 IU/ml, P < 10−4). However, the proportion of patients reaching an HBV DNA level < 2000 IU/ml was similar (66%) in pre-treated patients (supposedly infected with a lamivudine-resistant HBV) and in naive patients (supposedly on true combination therapy), whereas the proportions of patients losing HBe Ag or seroconverting against HBe were not significantly different between groups (two of seven versus four of 30 and two of seven versus one of 30; P = 0.32 and P = 0.15, respectively).
The first main result of our study is the still insufficient assessment of HBV infection in HIV-positive patients. Initially, patients with chronic HBV infection should have HBe antigen, anti-HBe antibodies, HBV DNA levels and HDV status assessed [7,8]. However, initial determination of HBe status is less often performed in HBV–HIV co-infected than in HBV mono-infected patients (67 versus 89%, Table 2), as was the case for determination of HDV status during the follow up (Table 1). Although it could be said that, for 30% of patients, the follow up started before 1995, at a time when hepatitis B was not a major concern in HIV-positive patients and interferon was the only effective treatment against HBV, the difference has decreased but persists in the more recently followed patients. Histological evaluation is also rarely performed, while the use of non-invasive liver fibrosis tests is slowly increasing, despite insufficient validation in HBV-HIV co-infected patients. Recent guidelines may not require histological assessment, but they do recommend on-treatment biochemical, serological and virological re-evaluations, which are too rarely performed at the moment.
Secondly, our study shows that positive HBe antigenemia is more often encountered in HBV-HIV co-infected patients (in almost two-thirds of these patients) associated with a lower frequency of pre-core mutants. The geographical origin of the patients is unlikely to explain this difference. Unfortunately, HBV genotypes were rarely available in this study. A few patients acquired HBV infection while they were already being followed for HIV infection, as already reported . This underlines the need for a wider use of HBV vaccination in HIV-infected patients in addition to other preventive measures. Some patients reactivated HBV infections despite pre-existing HBs Ab, which reinforces the arguments for repetitive serological assessments . The low rate of HBV–HIV co-infected patients with positive HBe Ab and no HBV DNA replication suggests that there is probably a lower rate of spontaneous HBe seroconversion than in mono-infected patients .
Thirdly, in 2005, the clinical status of HIV-positive and HIV-negative patients did not appear to be significantly different. However, the baseline HBV DNA and HIV RNA levels observed in treatment-naive HBV-HIV co-infected patients were lower than generally reported, suggesting that patients with higher HBV DNA and HIV RNA values were under-represented in our study population because of a worse clinical evolution. The proportion of patients with histologically proven cirrhosis was higher in our HBV–HIV-positive patients in comparison with HBV mono-infected patients [1,11]. The 10% per year rate of HBe Ag loss and HBe seroconversion observed in our HBV mono-infected patients remains within the range of those spontaneously observed (5 to 12% per year [12,13]), but it is surprisingly low as nearly half of the patients had been treated or were on treatment. Nevertheless, this rate was nearly four times higher than that observed in HIV-positive patients, despite the higher frequency and duration of HBV treatment in the latter population. Considering the lower rate of HBe seroconversion, but also the trend toward a higher rate of HBs seroconversion in HBV–HIV co-infected patients, it could be speculated that, although the immune control of HBV infection is less frequent due to HIV-related immune impairment, not only anti-HBV but also anti-HIV efficient treatments may lead to such a control. It would be thus more often complete, that is, that HBe seroconversion would more often be followed by HBs seroconversion (albeit rare ), than as naturally occurs in HBV mono-infected patients. This hypothesis needs to be further confirmed.
Fourthly, in HBV mono-infected patients, HBe Ag loss/seroconversion is associated with improved histological findings in the liver . In the present study, for the first time, such benefits were observed in HBV–HIV co-infected patients experiencing HBe Ag loss. Therapeutic approaches should aim to suppress HBV DNA replication and promote HBe Ag loss/seroconversion in positive HBe Ag-HIV co-infected patients .
Finally, the best therapeutic strategy in HIV-infected patients is still to be established, since there is a lack of therapeutic trials in the field of HIV–HBV co-infection. Regarding the use of HBV drugs without antiretroviral activity, adefovir was often used in HIV-infected patients (10% at any time), but surprisingly mainly associated with antiretroviral treatment. Adefovir may be the drug of choice as a first-line treatment in HIV-positive patients who do not need HAART, as it leads to HBV DNA suppression in 25% and HBe seroconversion in 6.9% of cases, and, according to reports published so far, without causing HBV resistance . This contrasts with the results in lamivudine pre-treated HBV mono-infected patients [17–19]. The theoretical risk of triggering HIV K65R mutation  has not been confirmed [16,21]. Entecavir may be of interest, although there is a lack of studies in HBV–HIV co-infected patients. Interferon alpha (now pegylated interferon alpha) may be another choice, even though its efficacy (10% of HBe seroconversion) tended to be lower in HIV-positive than in HIV-negative patients [22–24]. Nevertheless, interferon therapy was also shown to decrease the risk of cirrhosis regardless of the serological response .
Drugs with dual activity against HIV and HBV are very often used in HIV-positive patients. Lamivudine is no longer used alone considering the high risk of HBV resistance . Tenofovir is frequently used and with greater efficacy than adefovir . The mean HBV DNA decrease we observed in naive patients is close to that reported by others, from −3.5 to −4.5 log, as well as the HBe seroconversion rate ranging from 3.7 to 5.3% [27,28].
Combination therapies may be of interest, although their benefits on resistance and efficacy are still to be proved . On the one hand, it seems likely that nucleoside/tide combination therapy reduces the risk of resistance , whereas on the other hand, we failed to observe a superior short/medium term efficacy of nucleoside/tide combinations, as we experienced a lower rate of HBe seroconversion than reported in two previous smaller studies in 20 and six patients [27,31]. There is a risk of relapse following the interruption of nucleoside/tide combination therapy, not described with interferon alpha, which reinforces arguments for long-duration nucleoside/tide treatments [15,32]. In HIV-infected patients, the potential need for HAART modifications linked to the development of HIV resistance, the possibility of HAART interruptions and the development of new strategies without nucleoside/tide backbones underline the potential interest of time-limited HBV treatment strategies. Pegylated interferon therapy seemed to increase the rate of HBe seroconversion in our few pre-treated patients without previous HBe Ag loss, suggesting that additional or sequential pegylated interferon therapy may be of interest, as proposed in HBV mono-infected patients [32,33].
Our study has several strengths. Our results are supported by the large number of HBV–HIV co-infected patients from numerous centers in a real-life setting. All patients seen in the participating centers at the time of the study were included, thus limiting selection biases. A direct comparison of HBV–HIV co-infected with HBV mono-infected patients was performed. The design also allowed a longitudinal study of the biochemical, serological, virological and histological evolution of HBV infection in HIV infected patients, in particular according to therapeutic options. However, several limitations, mostly linked to the retrospective data collection, have to be acknowledged. It is likely that some patients followed in the participating centers a long time ago were not included in this study because of a poor clinical evolution. Comparisons between HBV–HIV co-infected and HBV mono-infected patients according to HBV treatments are limited since tenofovir was very rarely used in HBV mono-infected patients, thus restricting comparisons to the few patients who received adefovir or interferon. Analyses were often limited to subsets of patients, because of missing values, even though these missing values are informative regarding routine practice.
In conclusion, this study shows that in HBV–HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. The use of specific HBV treatment in HIV-positive patients still has to be considered, as pegylated interferon therapy following nucleoside/tide therapy may be of interest. However, no strategy was found to be clearly superior to another, apart from lamivudine monotherapy. Current guidelines have to be more closely applied and their relevance has to be assessed in a prospective way in HBV–HIV co-infected patients.
The authors thank Virginie Danaire and all the study technicians who collected the data, Philip Bastable for his help in reviewing this manuscript and Christine Angenard for her help in the GERMIVIC study group. They are also grateful to the medical teams of Angoulême (Dr A. Riche); Archet – Nice (Dr E. Rosenthal); Avicenne - Bobigny (Dr M. Bentata); Clermont de l'Oise, Paul Brousse-Villejuif, Reims (Dr C. Rouger); and Saint André - Bordeaux, Villeneuve Saint Georges (Dr O. Patey) hospitals who participated in this study. This study was supported in part by unrestricted grants from Gilead and Roche laboratories.
The authors do not have a commercial or other type of association that might pose a conflict of interest.
Members of the GERMIVIC study group
Amiens: B. Pautard-Huchemblé, J.L. Schmit; Angouleme: M. Bonnefoy; Annecy: J.P. Bru, J. Gaillat; Antibes: L. Lerousseau; Arras: D. Dubois; Avignon: A. Azzedine, A. De La Blanchardière, G. Lepeu; Belfort: J.P. Faller; Besancon: P. Balvay, F. Barale, J.M. Estavoyer, D. Vuitton; Bobigny: M. Bentata, P. Cohen, L. Guillevin, B. Jarrousse, B. Padrazzi; Bordeaux: J. Beylot, N. Bernard, J. Constans, I. Loury, F. Moreau, P. Morlat, J.M. Ragnaud, J.F. Viaud, D. Lacoste; Boulogne Billancourt: A. Baglin, M. Dorra, C. Dupont, T. Hanslik, E. Rouveix; Bourg en Bresse: P. Granier; Brest: A. Cénac; Caen: C. Bazin, P. Hazera, R. Verdon; Cebazat: J. Schmidt; Chambery: O. Rogeaux; Charleville: C. Menalba; Clamart: F. Boué, R. Fior, P. Galanaud; Clermont de l'Oise: J.J. Pik; Clermont-Ferrand: J. Beytout, H. Laurichesse, M. Ruivard; Colmar: G. Laplatte, B. Audoy, N. Plaisance, C. Bouterra, G. Laylotte; Colombes: E. Delarocque, P. Vinceneux; Creteil: M. Chousterman, P. Lesprit, A. Schaeffer; Dijon: M. Grappin, L. Piroth, H. Portier; Dolle: J. Guillaumie; Eaubonne: P. Dournovo; Garches: P. De Truchis, C. Perronne; Grenoble: O. Bouchard, M. Micoud, P. Morand; Hyeres: J. Boucher, P. Chambourlier, C. Renou; La Reunion: C. Arvin-Berod, P. Poubeau; La Roche sur Yon: P. Perre; Lille: E. Hachulla, B. Devulder, P.Y. Hatron; Limoges: V. Loustaud-Ratti; Lons le Saunier: J.D. Berthou, D. Baborier; Luneville: E. Constant, E. Dufay; Lyon: D. Peyramond; Mantes la Jolie: F. Trémolières; Marseille: A. Bourgeade, J.M. Durand, J.A. Gastaut, H. Gallais, J. Moreau, J.L. Perret, I. Poizot-Martin, J. Soubeyrand; Mende: P. Meissonnier; Menton: R. Hayek; Metz: C. Constant, J.J. Raabe, A. Wang; Montpellier: J. Astruc, F. Blanc, P. Perney, A. Vandôme; Nantes: D. Bautoille, C. Guerbois, C. Loyau, F. Raffi, D. Villers; Nancy: C. Burty, P. Canton, J.D. de Korwin, G. Thibaut, D. Wahl; Nice: P. Dellamonica, J.P. Cassuto, C. Ceppi, J.G. Fuzibet, M. Poirée, C. Pradier, E. Rosenthal; Nimes: C. Raffanel; Orleans: P. Arsac, G. Calamy, C. Mille; Paris: Z. Amoura, H. Aumaitre, F. Bani-Sadr, J.F. Bergmann, F. Bissuel, A. Boissonnas, E. Bouvet, F. Bricaire, J. Cabane, A. Cabié, P. Cacoub, R. Caquet, C. Carbon, C. Caulin, K. Chemlal, J.P. Coulaud, T. de Beaumont, F. Devars du Mayne, C. Dupont, B. Durand, D. Farge, P. Galanaud, C. Gaudebout, J. Gilquin, C. Goujard, P. Hausfater, C. Katlama, M. Karmochkine, F. Krainik, P. Le Bras, V. Le Moing, C. Leport, J. Modaï, J.M. Molina, J. Moussali, G. Pialoux, J.C. Piette, Y. Poinsignon, S. Pol, Y. Quertainmont, G. Raguin, W. Rozenbaum, D. Sène, D. Sereni, D. Sicard, J. Simon, F. Vachon, A.J. Valleron, J.L. Vildé; Pessac: P. Mercie, J.L. Pellegrin; Poitiers: B. Becq-Giraudon, J.P. Breux, G. Le Moal; Rennes: O. Boucher, C. Michelet, F. Cartier; Reims: I. Beguinot, G. Rémy; Rouen: I. Gueit, F. Borsa-Lebas, G. Humbert; Roubaix: J. Wemeau; St Brieux: C. Hascouet, B. Le Cam; St Denis: M.A. Khuong, D. Mechali, X. Roblin; St. Etienne: C. Defontaine, F. Lucht; St Germain en Laye: S. Fégueux, C. Veyssier-Belot; St Laurent du Var: D. Ouzan; Sete: B. Kitschke; Sens: C. Clément-Bertoldo, G. Gonzales; St Pierre (La Reunion): P. Poubeau; Strasbourg: P. Fischer, J.M. Lang, D. Rey, A. Ruellan, J.L. Schlienger; Suresnes: D. Zucman, O. Blétry; Thonon les Bains: P. Romand; Toulouse: L. Alric, L. Cuzin, M. Duffaut; Tourcoing: F. Ajana, Y. Mouton, Y. Yazdanpanah; Tours: J.C. Borderon, P. Choutet, Y. Guimard; Villeneuve St Georges: O. Patey.
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
hepatitis B virus; HIV; co-infection; treatment; evolution