Background
Elimination of viral hepatitis as a major public health threat by 2030 is part of the Sustainable Development Goals. The World Health Organization (WHO) adopted a global strategy in 2016, which aims to reduce the number of new cases of chronic hepatitis B and C by 90% and the number of deaths associated with these diseases by 65% by 2030 [
1]. Testing, treatment, and virologic suppression are crucial elements of this strategy.
Hepatitis B is a major concern in Africa, especially in HIV-infected patients who have a greater risk of liver failure, cirrhosis, hepatocellular carcinoma, and death [
2]. Of the 36.7 million people living with HIV worldwide in 2015, approximately 2.7 million (7.4%) were coinfected with hepatitis B virus (HBV) [
3]. Nearly three quarters of the latter resided in Africa. In a recent meta-analysis, the prevalence of HBV infection in people living with HIV was estimated at 8.4% worldwide and up to 12.4% in West and Central Africa [
4].
Since 2010, the WHO has recommended that if feasible, all patients be tested for hepatitis B surface antigen (HBsAg) at the time of HIV diagnosis [
5,
6]. It also recommends the concomitant use of two drugs which are active against both HIV and HBV - tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC) or emtricitabine (FTC) - as part of antiretroviral therapy (ART) in coinfected patients. Since 2013, TDF + 3TC (or FTC) has been the nucleos(t)ide reverse transcriptase inhibitor backbone of the preferred first-line regimen for all HIV-infected adolescent and adult patients [
7].
Unfortunately, access to HBV testing and adequate treatment for HIV-infected patients remains a challenge in Africa, and data on the therapeutic response in the routine healthcare setting are lacking because HBV DNA level is not monitored. Only a small proportion of HIV-infected patients are tested for HBV because of laboratory limitations (especially in rural settings) and patients’ financial constraints [
8]. Until recently, most HIV/HBV coinfected patients received 3TC-based ART without TDF and were likely to develop HBV resistance [
9,
10]. TDF + 3TC (or FTC)-based ART is now increasingly used but the WHO has underlined the need for data on the real coverage of this treatment in HIV/HBV coinfected patients [
3]. We therefore aimed to describe HBV testing uptake, treatment, and virologic suppression in HIV-infected adult patients followed up in Cameroon’s national antiretroviral programme.
Discussion
This large multicentre study in Cameroon showed that key elements of the cascade of HBV care – namely testing, treatment, and virologic suppression - were poorly managed in HIV-infected patients, although these latter were followed up in the national antiretroviral programme. As a consequence, a substantial proportion of HIV/HBV coinfected patients had a high risk of liver disease progression. This situation was especially worrying given that this study also confirmed that HIV/HBV coinfection is frequent in the country (9.3%).
One of the main results was indeed that the response to anti-HBV treatment was rather poor, with 27.4% of coinfected patients having an unsuppressed HBV viral load after a median time on ART of approximately 4 years [
17]. It is worth noting that elevated HBV viral load is a risk factor for liver cirrhosis and hepatocellular carcinoma [
18,
19]. The poor therapeutic response could be related to ART adherence issues. Although this hypothesis was not supported by the analysis of the association between self-reported adherence in the previous 4 weeks and HBV suppression, it was suggested by the concomitant relatively low proportion of coinfected patients with undetectable HIV viral load (76.4%) and the strong positive relationship between HIV viremia and HBV viremia.
In addition, patients with unsuppressed HBV viral load were more likely to have an increased ALT level, suggesting uncontrolled liver inflammation and fibrosis. Increased ALT level is also a risk factor for hepatocellular carcinoma [
20]. In a context where HBV DNA level is generally not monitored, HIV viral load and ALT level could provide useful indications for the management of HBV infection.
Although the nationally and internationally recommended treatment of TDF + 3TC (or FTC) was more commonly used as part of ART in the few patients who had known HBV coinfection prior to the study, than in those who had been found HBsAg negative or who had not been tested, 15% of the former did not receive this treatment [
6,
21]. Moreover, approximately 40% of all HIV/HBV coinfected patients diagnosed in this study did not receive the recommended treatment because HBV testing in the routine healthcare setting was scarce and because TDF + 3TC (or FTC) in HIV-infected patients was not systematically provided. This association became the preferred choice in Cameroon after the study in 2015.
A history of HBV testing was indeed very uncommon overall (17.7%) but also very heterogeneous across the 19 study hospitals (ranging from 0.8 to 72.5%). These data are in accordance with published data in Africa. In The Gambia, 21.5% of patients followed up in the largest HIV treatment centre had been tested [
22]. A multi-country study also reported a proportion of 21.5% overall, with large differences between the countries - between 0.7% (in Kenya) and 96.0% (in South Africa) [
8]. Moreover, similarly to our finding, a study in Zambia showed a great heterogeneity between 15 treatment centres [
23]. The reasons for such a heterogeneity in our study are unclear and merit further investigations, especially as a history of HBV testing was not associated with available characteristics of study hospitals (but it was probably associated with unmeasured characteristics).
Patients who started ART in 2010 or later were slightly more likely to have been tested for HBV than those who started ART earlier (19.9% versus 14.5%). The increase in testing from 2010 onwards reflects data in other African countries [
8,
23] and could be related to the addition of HBsAg testing in the 2010 WHO recommendations [
5]. However, our findings suggest that HIV-infected patients not tested for HBV before starting ART were rarely tested subsequently. This sub-population should be tested as soon as possible so that patients diagnosed with HBV can be started on TDF + 3TC (or FTC), maintained on anti-HBV drugs as part of ART (even in case of drug-related side effects or HIV resistance) to avoid HBV flare, monitored for liver disease progression, and educated on prevention of disease progression and HBV transmission [
24,
25].
Our figures suggest that women are much more disadvantaged in terms of the possibility to have HBV testing as compared to men (15.7% versus 23.2%). A similar finding has been reported in Zambia [
23]. This female vulnerability has two main detrimental effects: poorer management of HBV infection in women, and increased risk of mother-to-child or sexual transmission of HBV [
26].
The main strength of this study is that HBV testing, treatment and virologic suppression in HIV-infected patients were investigated in several very different hospital settings (e.g. urban versus rural, primary versus secondary, public versus private).
However, this study has several limitations. First, our study population may not be representative of the whole population followed up in Cameroon’s national antiretroviral programme. Indeed, the study was performed only in the two regions that include the two major cities (Yaoundé and Douala, the political and economic capitals, respectively) and that are the most experienced in HIV care (out of all 10 regions in Cameroon). In addition, although we sought to select a representative sample of hospitals in these two regions and then a representative sample of patients in these hospitals, urban hospitals were over-represented. Lastly, patients who died or were lost to follow-up prior to the study – and were therefore not included in this cross-sectional survey - are less likely to be tested and/or appropriately treated than included patients. As a result, the management of HBV coinfection in people living with HIV in Cameroon could be even poorer than what was observed in this study.
Second, this study was performed in 2014 and TDF + 3TC (or FTC) is now more commonly used in first-line antiretroviral regimens. However, this study showed that it is not enough to provide TDF-based ART to ensure good HBV care (28.7% of coinfected patients on TDF + XTC had unsuppressed HBV viral load). HBV testing remains crucial for the management of HBV infection (e.g. monitoring of HBV-related complications and choice of second- or third-line ART). The decision of some AIDS programmes (including Cameroon’s since 2016) not to test for HBV because TDF + 3TC (or FTC) is included in standard antiretroviral regimens should be reviewed. In addition, HBV DNA level is not monitored in the routine healthcare setting and data are useful to inform programmes and minimise the risk of liver disease progression. Finally, this study provides baseline data to assess progress towards the 2030 elimination targets.
Third, HBV coinfections could have been missed as HBsAg-negative samples were not further tested. On the one hand, occult hepatitis B can arise especially in HIV-infected patients [
27,
28]. On the other hand, HBsAg may have been lost in a substantial proportion of patients as most of them had received ART for several years prior to the study [
29,
30]. For instance, 26.5% of the patients who had been found HBsAg positive prior to the study were HBsAg negative at the time of the study (although false results may not be excluded). HBsAg loss on ART may have led to an under-estimation of HBV suppression as patients who lose their HBsAg are always HBV suppressed.
Acknowledgements
We thank all the patients and staff of the participating hospitals, as well as the staff of the CREMER laboratory (Centre de Recherche sur les Maladies Emergentes et Ré-émergentes) who participated in the study. We also thank Jude Sweeney (Milan, Italy) for the English revision and editing of the manuscript.
The EVOLCAM study group
C. Kuaban, L. Vidal (principal investigators); G. Maradan, A. Ambani, O. Ndalle, P. Momo, C. Tong (field coordination team); S. Boyer, V. Boyer, P.J. Coulaud, L. March, M. Mora, L. Sagaon Teyssier, M. de Sèze, B. Spire, M. Suzan Monti (UMR912 – SESTIM); C. Laurent, F. Liégeois, E. Delaporte, S. Eymard-Duvernay, A. Riondel (TransVIHMI); F. Chabrol, E. Kouakam, O. Ossanga, H. Essama Owona, C. Biloa, M.T. Mengue (UCAC); E. Mpoudi-Ngolé (CREMER); P.J. Fouda, C. Kouanfack, H. Abessolo, N. Noumssi, M. Defo, H. Meli (Hôpital Central, Yaoundé); Z. Nanga, Y. Perfura, M.Ngo Tonye, O. Kouambo, U. Olinga, E Soh (Hôpital Jamot, Yaoundé); C. Ejangue, E. Njom Nlend, A. Simo Ndongo (Hôpital de la Caisse, Yaoundé); E Abeng Mbozo’o, M. Mpoudi Ngole, N. Manga, C. Danwe, L. Ayangma, B. Taman (Hôpital Militaire, Yaoundé); E.C. Njitoyap Ndam, B. Fangam Molu, J. Meli, H. Hadja, J. Lindou (Hôpital Général, Yaoundé); J.M. Bob Oyono, S. Beke, (Hôpital Djoungolo, Yaoundé); D. Eloundou, G. Touko, (District Hospital, Sa’a); J.J. Ze, M. Fokoua, L.Ngum, C.Ewolo, C.Bondze (District Hospital, Obala); J.D. Ngan Bilong, D. S.Maninzou, A. Nono Toche (Hôpital St Luc, Mbalmayo); M.Tsoungi Akoa, P. Ateba, S. Abia (District Hospital, Mbalmayo); A. Guterrez, R. Garcia, P. Thumerel (Catholic Health Centre, Bikop); E. Belley Priso, Y Mapoure, A. Malongue, A.P. Meledie Ndjong, B. Mbatchou, J. Hachu, S. Ngwane (Hôpital Général, Douala); J. Dissongo, M. Mbangue, Ida Penda, H. Mossi, G. Tchatchoua, Yoyo Ngongang, C.Nouboue, I. Wandji, L. Ndalle, J. Djene (Hôpital Laquintinie, Douala); M.J. Gomez, A. Mafuta, M. Mgantcha (Catholic Hospital St Albert Legrand, Douala); E.H. Moby, M.C. Kuitcheu, A.L. Mawe, Ngam Engonwei (District Hospital, Bonassama); L.J. Bitang, M. Ndam, R.B.Pallawo, Issiakou Adamou, G.Temgoua (District Hospital,Deido); C.Ndjie Essaga, C. Tchimou, A. Yeffou, I. Ngo, H. Fokam, H. Nyemb (District Hospital, Nylon); L.R. Njock, S. Omgnesseck, E. Kamto, B. Takou (District Hospital, Edea); L.JG Buffeteau, F. Ndoumbe, JD Noah, I. Seyep (Hôpital St Jean de Malte, Njombe).
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