In this large cohort of HIV infected sub-Sahara African patients, we found that whereas chronic HBV and HCV were frequent diagnoses, liver disease was not common; although investigated only when there were overt clinical symptoms. Overall, one out of every five patients had HBV and more than a tenth had HCV. Almost every patient that was recruited at the beginning of study was screened for HBV and HCV. This is rather remarkable for a resource limited setting and much higher than obtainable in some cohorts in Thailand[5,6
]. The fact that our study site benefited from grants for research and involved the services of specialists may explain the high hepatitis screening rate. However, this initial enthusiasm was not sustained, as there has been a significant decline in the rates of screening for hepatitis during the study period. Interestingly, diagnoses of HBV and HCV showed significant rising trends. We note that there may be a selection bias in this regard as people tend to go to tertiary care centres to seek treatment.
Our findings corroborate the reports of other researchers who had observed higher prevalence of HBV and HCV infection among HIV-infected patients than in the general population[12
]. Studies of prevalence of HBV in the general population of people living within the study area during the period between 2002 and 2007 had found rates of between 10.3% and 15.1%[13-16
]. These confirm that the rates of hepatitides are higher in the HIV patients than in the general population of Nigeria. The fact that HIV and hepatitis viruses share the same routes of transmission supports this explanation. However, it remains unknown whether hepatitis occurs at the same time as HIV infection or predates it.
The precise modes of transmission of HBV and HCV in our cohort are not known. However, it has been reported that transmission of HBV most commonly occurs in early childhood among African populations[17
], compared to high transmission rates among adults in industrialised countries[18
]. Whereas intravenous drug use is the major route of transmission of HIV and indeed hepatitis viruses in western industrialised countries, heterosexual and horizontal routes, as well as indiscriminate injections (unsterile needles) are thought to be the prevalent modes of transmission of these viral infections in African communities[19
]. Many patients may have iatrogenic transmission from poor sterilisation during routine medical, obstetric, dental and surgical procedures. Most HIV/hepatitis co-infected patients in Nigeria are postulated to have become infected by hepatitis viruses before HIV[17
]. Longitudinal studies will be required to appropriately determine patients that may have acquired hepatitis before, at the same time or after HIV infection. Such a study has the advantage of providing additional information for reinforcing prevention methods, for example HBV vaccination not only for the present cohort but for HIV infected patients in HBV endemic regions.
The incidence of liver disease in the present study was not assiduously documented, although observed to be common. Only 11 patients were documented to have had primary liver cancer in the present study. Eight of these patients were screened for hepatitis. While four were HBsAg positive, 4 were negative to both HBV and HCV. As population-based cancer registries are not routinely available and/or reliable in Nigeria owing to poor registration of diseases and deaths, we did not compare the incidence of primary liver cancer in the present cohort with those from the general population. However, studies in United States have confirmed that primary liver cancer occurs about 6 times more commonly in HIV infected individuals than in the general population[20,21
]. With such a high rate of HBV and HCV infection in this African cohort, there is a chance that a large number of primary liver cancer cases were missed or will yet manifest. It should be noted that prior to free provision of ART to HIV patients in Nigeria from 2004, the cost of these medications was prohibitive and the incidence of HIV mirrored its mortality[22
]. It is thus likely that most patients would have died earlier than they could present with HCC. Furthermore, with prolonged ART, many of these patients will survive longer and HCC could become more frequently diagnosed.
Unfortunately, the study design did not allow for prospective evaluation of hepatitis status. In addition, the patients were treated with ARVs (e.g.,Truvada) that in some cases may have been both active on hepatitis and HIV infection. The baseline evaluation and hepatitis status seems to indicate that other non-infectious causes of hepatic disease may need to be considered. It will be anticipated that HIV hepatitis co-infected patients would have higher incidence of liver disease. This would have been the case if we restricted the definition of liver disease to end stage liver disease (fibrosis, cirrhosis and liver cancer). However, we included hepatotoxicity of ARVs in the definition. This would explain, in part the higher incidence of liver disease in HIV mono-infected patients. Chronic liver disease was small in the cohort, perhaps due to under reporting, or perhaps a high threshold for recording cases in the database. Reasons for the apparent rarity of liver disease in HIV/hepatitis co-infected patients and higher cases of liver disease in HIV mono-infected than hepatitis co-infected patients require further studies.
At baseline, patients with hepatitis co-infection had higher HIV RNA than patients with HIV mono-infection. Correspondingly, a higher proportion of patients co-infected with HBV had CD4+ cell counts below 200/mL compared to HIV mono-infected individuals. The finding of higher HIV RNA at baseline corroborates earlier findings in a study of a small number of patients (1564) from the same study site[23
], as well as another study from China[24
]. Following HAART, the gain in CD4+ cell count was significantly diminished in those patients who had HBV co-infection compared to those with HIV mono-infection. In contrast to our findings, two studies that assessed the impact of HBV on response to HAART found no difference in CD4+ cell gain[25,26
]. Reasons for the differential outcomes are not obvious. Differences in environment are unlikely, as our findings contrast the observation of a study of South African patients[27
]. We note however, that whereas the South Africa study had a shorter duration of follow up (1.5 years), the present cohort was followed for a longer duration on ART (4.4 years). Nevertheless, results of HBV and long-term HIV outcomes (7 years) in the US found no difference in the HIV load suppression and CD4+ cell gain. Be that as it may, as the natural history of HBV is likely to differ between US and African populations, owing to differential age at acquisition of hepatitis infections, studies comparing African patients on long-term ART would provide a better assessment.
Our findings suggest that CD4+ cell loss by HIV is accentuated by HBV, despite on-going HIV treatment. A few studies have highlighted that active HBV infection is associated with T-lymphocyte exhaustion[28,29
]. This has been further strengthened by the fact that inhibition of HBV DNA replication using anti-HBV drugs resulted in immune restoration[30,31
]. One would expect such an effect to be universal. However, variable outcomes of HAART in regards to HIV load suppression and/or increases in CD4+ cell count in HBV co-infected versus HIV mono-infected patients have been reported. While some studies found no differences between HBV and HIV mono-infected groups[27,32
], others found non-sustained differences in CD4+ cell increases[25,33
]. Studies of HIV treatment outcomes of HBV co-infected and HIV mono-infected African patients comparing HBV suppressive agents versus regimens that are non HBV suppressing will be required to adequately characterise the importance of HBV in the era of HAART.
Our study was not without limitations. First, the use of HBsAg positivity as the sole indicator of chronic HBV infection may be misleading. Definition of chronic HBV would require a positive HBsAg assay consecutively carried out at least 6 mo apart. As single HBsAg was utilised to define cases of HBV in this current study, cases of misclassification might have occurred. Also, delineating HBV cases by their HBV DNA loads and HBeAg status would have provided more meaningful analyses. However, as it is generally known that HBV infection in Africans occur more commonly in childhood, the chance of falsely misclassifying HBV is low. For want of resources, we could not perform HBeAg and HBV DNA. Another issue that could have led to misclassification to hepatitis status is reliance on HCV Ab result to define active HCV infection. Earlier data (unpublished) from a sub group of the current cohort had found HCV viraemia of 33% in those that were HCV Ab positive. It is thus possible that of the patients that were classified “HCV”; only a third may actually be HCV viraemic. More studies with better characterisation of HCV status in this cohort would be required. Missing data was another issue we encountered. In some of the patients, HBsAg and HCV Ab and baseline CD4+ data results were unavailable. Also, we relied on diagnosis of liver diseases (hepatotoxicity, cirrhosis and primary liver cancer) on clinical notes of the patients, where available. As a result of these, we only analysed the rates of hepatitis among those that had hepatitis results. Also, CD4 cell gain was analysed for 3012 patients for whom there were baseline and follow up results and who were on HAART.
In conclusion, high and increasing rates of HBV, HCV and HBV/HCV co-infections were found in this large HIV infected cohort of Africans. The prevalence of liver disease, particularly liver cancer was low; mostly reported among HBV/HIV and HIV-only individuals. HBV co-infection was associated with high HIV RNA load and decreased CD4+ cell counts at baseline and attenuated immunological recovery after a median follow up duration on HAART of 4.4 years. Our findings underscore the urgent need to maintain a strict hepatitis screening policy among HIV infected patients undergoing HAART as well as inclusion of ART regimens with potent anti-HBV activities in HBV endemic regions of the world. Longitudinal studies in African patients to ascertain super-infection of HIV by hepatitis, assessments of impact of HBV-suppressive versus HBV non-suppressive HAART regimens and predictive value of hepatitis on the mortality of the present cohort will form a significant contribution to future research.