As far back as 1990, a call was made for more research to be conducted on the horizontal transmission of HBV in sub-Saharan Africa, as it was felt that both the impending HIV epidemic and the introduction of HBV vaccination would change the epidemiology of HBV to such an extent that this information would be lost forever (58). Since then, several reports have raised further questions about the long-term success of HBV vaccination, and the control of HBV, in the face of the rising prevalence of HIV in the region. The following sections will discuss possible implications for HBV and HIV co-infection in sub-Saharan Africa, against a backdrop of what is currently known about the interactions between these two viruses, using data from around the globe.
Which is acquired first in sub-Saharan Africa – HBV or HIV?
The vast majority of the inhabitants of sub-Saharan Africa have been exposed to HBV as children, with chronic carrier rates almost equal to that of adults being established by the age of 5 years. There are small increases in HBV prevalence rates when children first attend school, and again when they become sexually active (2, 4). Apart from transmission of HIV from pregnant mothers to their babies, it is at the time when sexual activity commences that they first become exposed to HIV. Thus, it is clear that most sub-Saharan Africans have already been exposed to HBV by the time they become sexually active, with the minority being exposed to both viruses more or less simultaneously. However, there are increasing numbers of babies born to HIV-positive mothers, who, without intervention with anti-retroviral drugs, acquire HIV vertically, either at the same time or before being exposed to HBV. Some of these babies are born in countries that have already introduced the HBV vaccine into their EPI, and are theoretically protected from horizontal transmission of HBV in early childhood.
Increase in carriers with active HBV
As discussed earlier, many studies have indicated a higher prevalence of HBV infection among HIV-positive individuals. This has been found to be true in non-African countries (6–11), as well as in some areas of sub-Saharan Africa (28, 46–51, 55, 57). In sub-Saharan Africa (and other areas of high HBV endemicity), where most sexually active adolescents and adults have been exposed to HBV before being exposed to HIV, the association between HIV and HBV infection is not expected to be as strong as in countries of low HBV endemicity. For example, in the United States of America, up to almost seven-fold increases in HBV infections have been reported in HIV-positive patients (8), whereas most of the sub-Saharan studies that have found an association have reported increases less than two-fold (46, 48–51, 55), with only one reporting as much as a four-fold increase (28).
Thus, the above studies have found no massive increase in HBV prevalence in HIV-positive adults in sub-Saharan Africa, and it appears that only the minority of those exposed to HBV (as the majority are immune to HBV) are harbouring active HBV infections. In a large 3-year study involving 864 pregnant women in South Africa, no increase in prevalence of active HBV infection was observed in HIV-infected antenatal women (46). Where there is an increase in prevalence of active HBV infection in HIV co-infected adults, this can be accounted for in a number of ways. Firstly, the immunosuppression brought about by HIV could cause reactivation of infection in ‘silent’ chronic carriers (11, 40–41). Secondly, there may be an increase of newly acquired HBV infections in HIV-positive people (40), who have lost their protective HBV antibodies due to HIV immunosuppression (11). Thirdly, the minority that are already HIV-infected by the time they are exposed to HBV for the first time are at a higher risk of becoming HBV carriers (6, 7, 9, 11, 21–23). Also, there is evidence that HIV-infected individuals who are subsequently infected with HBV are more likely to have a high HBV replication rate (7, 9, 11, 59), increasing the risk of HBV transmission, and are more likely to be HBeAg-positive for a much longer time (7, 9). This situation would increase the risk of HIV-positive pregnant women passing HBV on to their babies, especially if these women are HBeAg positive. This risk is considerable, as HIV-negative women who have acute HBV infections are already seven times more likely (regardless of their HBeAg status) to pass HBV onto their offspring than chronically infected women (60).
Changes in disease progression
There are a number of studies in this area of research from non-African countries. Some of these suggest that HIV immunosuppression may reduce liver damage as a result of a less aggressive HBV-specific immune response (7, 9), and this is supported by reports of a reduction in icteric illness in acute HBV infections, in HIV-positive patients (6, 11, 21). However, HIV infection has been found to exacerbate liver disease, with an early study finding death from liver failure in four of five HIV-positive HBV carriers, compared with two of six HIV-negative HBV carriers (59). More recently, it was found that HIV and HBV co-infected patients have a significantly increased risk of dying from liver disease. This risk was found to increase after starting treatment for HIV using highly active antiretroviral therapy (HAART) (61). In addition, there have been reports of hepatotoxicity (62) and reactivation (63) of HBV in co-infected individuals, when using HAART.
Conversely, there is no convincing evidence that HBV hastens progression to AIDS (6, 10, 11, 23), in HIV and HBV co-infected patients, although there were early speculations that HBV infection may be a co-factor (64). Most of these speculations were based on very small studies, while larger studies have shown no association between HBV infection and progression to AIDS (11).
In sub-Saharan Africa, the majority of chronic HBV patients who later acquire HIV co-infection are more likely to die from HIV than from HBV infection. Morbidity and mortality as a result of HBV chronic infection (attributable to chronic hepatitis, cirrhosis, and HCC) occur many years after primary exposure to the virus.
Implications for laboratory diagnosis
Occult or ‘sero-silent’ HBV infection (the presence of HBV DNA in the absence of HBsAg) is a well-defined clinical entity, which has been well researched in regions of low endemicity (particularly Europe and the United States of America) (65, 66), while few studies have been conducted in areas of high endemicity (67, 68). In regions of low endemicity, it has been estimated that about 10–20% of all individuals who are positive for HBV markers have an ‘anti-HBc alone’ serological pattern. Of these, about 10% are positive for HBV DNA (65). The mechanisms resulting in occult HBV infection and the burden of these infections in sub-Saharan Africa are largely undefined.
Of interest is the fact that occult HBV infection has increasingly been detected in HIV-positive individuals throughout the world (65, 69–71), including the sub-Sahara (72), with some studies finding as many as 85% of ‘anti-HBc alone’ HIV-positive patients being positive for HBV DNA (65). Laboratory detection of HBV forms an important aspect of the global prevention and control of hepatitis B disease. In sub-Saharan Africa and other regions severely affected by the HIV pandemic, the increased prevalence of occult HBV infections caused by HIV may have a negative impact on the prevention and control of HBV, and will add greatly to the problem of unravelling how the epidemiology of HBV is being affected. This is a challenge not only to effective laboratory diagnosis and management of hepatitis B in HIV co-infected patients, but also to the total control of the burden of HBV infections in HIV endemic regions of the world, such as sub-Saharan Africa, where PCR-based HBV detection methods are not widely available.
In addition, occult HBV infections can have a negative impact on unprotected HCWs who have been occupationally exposed to HBV, but who are not given PEP because of the source serum testing HBsAg negative. PEP for HCWs generally follows internationally accepted guidelines, and thus will not be given in this case (39). The only solution in this case would be to perform HBV DNA testing on all ‘anti-HBc alone’ sera, and ideally also on sera positive for anti-HBs alone, as HBV DNA has previously been detected in healthy African sera positive for only anti-HBs (68).
Implications for current HBV therapies
Of the two antiviral drugs currently approved for HBV infection (IFN-α and lamivudine), the latter is the drug of choice in HIV and HBV co-infections (9), as HIV-positive patients do not respond well to IFN-α (7, 9). Lamivudine is a nucleoside analogue that has been shown to clear both HBV and HIV, and should be considered for inclusion in any HAART regimen for HBV and HIV co-infection (9). The drawback is that HBV resistance occurs frequently with long-term application of lamivudine (9, 73), and this has serious implications in HIV-endemic areas such as sub-Saharan Africa, where the majority of HBV chronic carriers are likely to be HIV positive. However, treatment of chronic HBV infection with antivirals including lamivudine does not seem to be a common occurrence in the region as these drugs are unaffordable in most centres.
Conversely, anti-retroviral therapy for HIV is becoming more widely available, as most manufacturers are now reducing their prices. The implication is that many countries in the region will soon use anti-retroviral drugs, including lamivudine, which is active against both HBV and HIV. Once again, the possibility exists that long-term usage of lamivudine could cause resistance in both HBV and HIV, when co-infection exists. It has been recommended that HBeAg-positive co-infected patients without clinical hepatitis should not be prescribed lamivudine as part of the HAART regimen (74). Instead, this should be reserved until clinical hepatitis does arise, so that lamivudine resistance will not have developed in these patients when they need it most. This recommendation was based on the finding that the risk for long-term lamivudine resistance is greater in HBeAg-positive patients (74). There is also the possibility of HBV reactivation and severe hepatitis in HBV and HIV co-infected patients receiving HAART (specifically regimens including the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and efavirenz, as well as protease inhibitors (62)). Liver damage is thought to result indirectly from an increased number of circulating cytotoxic T cells after the immune response has been restored by HAART (61), or directly from liver toxicity or raised ALT levels caused by protease inhibitors and NNRTIs (62). Another possibility is that HAART causes reactivation of HBV, either directly, or indirectly because of mutations resulting from immune pressure (63). This hypothesis would explain reactivation that occurs independent of lamivudine resistance or withdrawal of lamivudine (63). Thus, when administering HAART, it will be important to monitor HIV and HBV co-infected patients closely. Data from sub-Saharan Africa on this important health problem are lacking.
Implications for immunisation programmes
In Africa, the only logical approach to prevent early childhood transmission of HBV is by mass immunisation of newborns and infants. HBV vaccines can be administered some weeks after birth while babies are still protected by maternal antibodies (1), and before they are overly exposed to siblings or other toddlers who are HBV positive (2–4). For example, the hepatitis B vaccine is given at birth, 2, and 9 months in Botswana; at birth, 2, and 4 months in The Gambia; at 6, 10, and 14 weeks in South Africa; and at 3, 4, and 9 months in Zimbabwe (75)), so that horizontal transmission of the virus in childhood does not occur. Thus, new chronic carriers are not being added to the population, and in a few decades it is hoped that HBV infection will be contained in those countries that have included the HBV vaccine in their EPI. However, the burgeoning prevalence of HIV, especially in pregnant women, may present major challenges to the HBV vaccine programmes of sub-Saharan countries.
Firstly, there is a risk that a certain percentage of HIV-positive pregnant women could be harbouring actively replicating HBV, which they are likely to pass on to their babies, especially if these women are HBeAg positive. It is well established that in situations where babies acquire HBV infection perinatally from HBeAg- and/or HBsAg-positive mothers, such babies have up to a 90% risk of becoming chronic HBV carriers (25, 60, 76). Many studies conducted before the HIV/AIDS pandemic reached current levels have clearly indicated that perinatal transmission of HBV in sub-Saharan Africa is not as common as it is in Asia, as a result of the generally low (0–18.6%) HBeAg carriage in pregnant women (2). But recent data are lacking, and it is not known whether previous findings hold true in the face of the growing HIV/AIDS pandemic in the region. Clearly, this does raise concern since (a) it is not standard practice to screen pregnant women for HBV infection; (b) there is no birth dose of HBIg or hepatitis B vaccine to those born to HBeAg and/or HBsAg carrier mothers; and (c) in most sub-Saharan countries where routine immunisations are available, the first dose of hepatitis B vaccine is delayed by several weeks (except in countries where all babies receive a birth dose of hepatitis B vaccine, such as Botswana and The Gambia).
Secondly, it has been shown in many parts of the world that some of the babies born to HBeAg- and/or HBsAg-positive mothers, who are infected with HBV at birth and are given the HBV vaccine, experience vaccine failures, with some giving rise to HBV vaccine-escape mutants (77). Most African countries do not have long-standing experience of HBV vaccination, but an example of HBV vaccine failure can be drawn from The Gambia, which was the first country in the region to introduce the HBV vaccine into the national childhood immunisation programme. Fortuin et al. (35) investigated HBV infection markers in 720 four-year-old children who received the birth dose of HBV vaccine, and subsequent doses at 2, 4, and 9 months of age in a longitudinal study. Of these 720, 39 (5.4%) experienced vaccine failures, with four (0.6%) progressing to chronic carriage. Of the four carriers, three were born to HBsAg-positive carrier mothers, two of whom had detectable HBeAg. The two children born to HBeAg-positive mothers never responded to the full HBV immunisation regimen, and both were infected during the first year of life. However, one of the four babies was born to an HBsAg-negative mother and was infected at the age of 3 years because the baby was not fully immunised (only one dose of the vaccine was received) and never mounted sufficient protective anti-HBs (i.e. the baby had <10 mIU/ml) (35).
A lesson to be learnt from the above study is that it is important to comply with the vaccination regimen. High dropout rates in the administration of the second and third doses (78) will be disastrous, as this will lead to vaccine failures and leave a large proportion of susceptible babies at risk. Another lesson is that it is likely that many countries in the region will experience cases of vaccine failure originating from ‘rare’ perinatal transmission of HBV. What impact HIV/AIDS will have on the prevalence of active HBV infection in women of childbearing age, and subsequent possible vaccine failures, is unknown. If some of the HIV-positive pregnant women are harbouring actively replicating HBV infections for whatever reason, then they are likely to pass these on to their babies, adding to the problem of vaccine failures in the region. Studies are therefore urgently needed to evaluate the efficacy of HBV vaccination in the face of the growing HIV/AIDS pandemic.
The importance of HBV mutants is a controversial issue, and has raised questions about current HBV vaccines eventually losing their efficacy (76, 77, 79–81). It was also suggested that the HBV mutant strain G145R may replace the wild-type strain as the major source of infection within the next 60–100 years, and the wild-type HBV may disappear in 200 years (79). It has already been shown that the G145R mutant is able to infect unvaccinated chimpanzees, but is not able to infect vaccinated chimpanzees (80); however, the situation in humans is unknown. Nevertheless, there is no reason to suspect that HBV mutants pose a serious threat to HBV immunisation programmes in the short term, based on available data. Clearly, more studies are needed to evaluate the global prevalence of these mutants, especially in HBV-endemic countries. It is also imperative that continual monitoring of the efficacy of current HBV vaccines is given a high priority in all sub-Saharan countries that have included this vaccine within their EPI. Unfortunately, this may become a very difficult and expensive task, as it is highly likely that some vaccine-escape mutants will not be detected by current standard serological tests. Detection and confirmation of the occurrence of HBV vaccine-escape mutants and other variants will require PCR testing and sequence analysis.
Lastly, it is well established in non-African countries that immunocompromised individuals, such as HIV positives, haemophiliacs, renal transplant patients, cancer patients receiving chemotherapy, etc., do not respond optimally to the HBV vaccine (7, 22, 82–86). A recent review has reported that serological responses to hepatitis B vaccines are generally lower for HIV-infected children and adults than for uninfected individuals, and that HIV-infected individuals who respond well to the initial three-dose regimen experience a more rapid decline in antibody titre than uninfected persons (85). Attempts to overcome the decreased immune response by increasing the vaccine dosages or number of doses from three to six in HIV-positive patients, greatly improved the response rate; however, it was found that persistence of anti-HBs was short-lived (86). The situation in sub-Saharan Africa, where there is a high background of HIV infection, and many babies are exposed to HIV through vertical transmission, is not known. However, one South African study suggested that the response to the HBV vaccine in HIV-positive babies may be sub-optimal (87). In addition, another recent South African study reported vaccine failure in a baby possibly due to HIV immunosuppression (36). In this study, three of 756 vaccinated children were found to be HBsAg positive. Of the mothers of the three, one was known to be HIV positive, while the HIV status of the other two mothers was unknown. The baby of the HIV-positive mother had a history of failure to thrive. Although the HIV status of the baby was not known, this case may suggest that HIV-positive babies are most at risk for becoming infected with HBV, even if they have been vaccinated.
Thus, continual surveillance of the performance of the HBV vaccine in HIV-infected babies is necessary. Future studies should resolve whether HIV-positive babies may be at an increased risk of being infected with HBV, despite being vaccinated, due to sub-optimal response to the vaccine.