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HBV and HIV co-infection in sub-Saharan Africa: a call for further investigation
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Some 387 million people worldwide are estimated to be chronic carriers of HBV, representing over 5% of the global population.....About 45% of the global population reside in areas of high endemicity (>=8% HBV carriage), which includes Asia (with 75% of the world's HBV carriers), sub-Saharan Africa (with the second largest population of carriers, estimated to be at about 50 million), and the Western Pacific.....12% of the global population live in areas of low endemicity (<2% HBV carriage), which includes Western Europe, North America, and Australia. Lifetime risk of infection in these areas is less than 20%, and mostly adults belonging to specific risk groups are at risk......
Liver International
April 2005
R. J. Burnett1, G. François2, M. C. Kew3, G. Leroux-Roels4, A. Meheus2, A. A. Hoosen5 and M. J. Mphahlele1
1Department of Virology, University of Limpopo - MEDUNSA campus, South Africa, 2WHO Collaborating Centre for Prevention and Control of Viral Hepatitis, Department of Epidemiology and Social Medicine, University of Antwerpen, Belgium, 3MRC/CANSA/WITS University Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, South Africa, 4Centre for Vaccinology, Department of Clinical Biology, Microbiology and Immunology, Ghent University, Belgium, 5Department of Medical Microbiology, Medical University of Southern Africa, South Africa
Abstract:
A growing body of evidence indicates that human immunodeficiency virus (HIV)-positive individuals are more likely to be infected with hepatitis B virus (HBV) than HIV-negative individuals, possibly as a result of shared risk factors. There is also evidence that HIV-positive individuals who are subsequently infected with HBV are more likely to become HBV chronic carriers, have a high HBV replication rate, and remain hepatitis Be antigen positive for a much longer period. In addition, it is evident that immunosuppression brought about by HIV infection may cause reactivation or reinfection in those previously exposed to HBV. Furthermore, HIV infection exacerbates liver disease in HBV co-infected individuals, and there is an even greater risk of liver disease when HIV and HBV co-infected patients are treated with highly active anti-retroviral therapy (HAART). Complicating matters further, there have been several reports linking HIV infection to 'sero-silent' HBV infections, which presents serious problems for diagnosis, prevention, and control. In sub-Saharan Africa, where both HIV and HBV are endemic, little is known about the burden of co-infection and the interaction between these two viruses. This paper reviews studies that have investigated HIV and HBV co-infection in sub-Saharan Africa, against a backdrop of what is currently known about the interactions between these two viruses.
The global burden of HBV and HIV infections
UNAIDS has described AIDS as 'the most devastating disease humankind has ever faced', with HIV having infected more than 60 million people in the past 20 years (12). Out of the 42 million people currently living with HIV/AIDS, 29.4 million reside in sub-Saharan Africa (13). The only other region in the world where prevalence rates are above 1% is the Caribbean, with a prevalence of 2.4%. The global adult prevalence rate has been estimated at 1.2% (13).
It is clear that the southern African countries are currently experiencing the worst of the pandemic, with the highest adult prevalence rates being reported in Botswana (38.8%), Lesotho (31%), Swaziland (33.4%), and Zimbabwe (33.7%). On the other hand, central and west African countries are still in the early stages of the HIV epidemic, with prevalence rates ranging from less than 1% (Senegal) to 12.9% (Central African Republic). In East Africa, Uganda has already experienced the peak of its HIV epidemic (29.5% prevalence in 1992), and has managed to bring prevalence rates down to 11.2% in 2000. The average adult prevalence rate for the entire sub-continent has been estimated at 8.8%, whereas that for North Africa and the Middle East is only 0.3% (13).
Some 387 million people worldwide are estimated to be chronic carriers of HBV, representing over 5% of the global population (15). About 45% of the global population reside in areas of high endemicity (>=8% HBV carriage), which includes Asia (with 75% of the world's HBV carriers), sub-Saharan Africa (with the second largest population of carriers, estimated to be at about 50 million), and the Western Pacific. In these areas, the lifetime risk of HBV infection is estimated at greater than 60%, with early childhood infections being most common. Areas of intermediate endemicity (2-7% HBV carriage) where 43% of the global population lives, include, among other regions, North Africa, and Southern and Eastern Europe. Here, lifetime risk of infection ranges from 20% to 60%, with all age groups being at risk. Lastly, 12% of the global population live in areas of low endemicity (<2% HBV carriage), which includes Western Europe, North America, and Australia. Lifetime risk of infection in these areas is less than 20%, and mostly adults belonging to specific risk groups are at risk (14, 16).
HBV infection in sub-Saharan Africa
Routes of transmission
HBV epidemiological studies undertaken before the HIV/AIDS pandemic reached current levels found the major route of transmission in this region to be horizontal in childhood, with most carriers being infected by the age of 5 years. Thereafter, in adolescence and early adulthood, sexual transmission becomes the dominant route (1-4). These studies, conducted in the 1980s and early 1990s, found that vertical (in utero) and perinatal HBV transmission did not play a major role in the region, because of the relatively low carriage (between 0% and 18.6%) of hepatitis Be antigen (HBeAg) in pregnant sub-Saharan HBV carriers (1-4). Most African babies were protected by maternal antibodies, which are passively transferred by 50-80% of anti-HBs-positive mothers, and persist for 6 months to a year (1). Thus, exposure before the age of 6 months was thought to be rare. However, a more recent South African study has found that 8.1% of 0-6-month-old babies, and 8.9% of 7-12-month-old babies, are hepatitis B surface antigen (HBsAg) positive (17), which suggests that transmission in early infancy may be on the increase, and that maternal HBV antibodies are not being passively transferred to the same extent as in the past.
Outcome of HBV infection
The outcomes of primary HBV infection can range from asymptomatic to symptomatic infection, and include rare cases of death from fulminant hepatitis, and chronic hepatitis that can eventually lead to cirrhosis and hepatocellular carcinoma (HCC) (1-4, 15, 18, 19). Generally, infection in adults often results in jaundice, which is usually self-limiting. Contrary to this, infants and very young children rarely develop jaundice, but 80-90% become chronic carriers of the virus, which can ultimately lead to death from cirrhosis and/or HCC (1-4, 15).
It is estimated that 60-80% of all patients with cirrhosis will develop HCC (18), while 25% of chronic HBV carriers develop HCC (15). Whether oncogenesis results from transcriptional errors caused by the continual regeneration of new hepatocytes (indirect oncogenesis), or from viral integration into host DNA (direct oncogenesis), is not yet understood (15, 19). The basic immunologic defect in neonates born to HBeAg-positive carrier mothers resides in a T-helper tolerance, specific for HBc/HBe antigens, which is generated via exposure to HBeAg during gestation. This tolerance is responsible for the poor or non-responsiveness of these neonates to HBV, and the ensuing chronic course of the infection (20). Since there is little or no immune response, hepatocytes are not destroyed and no symptoms are produced. However, over time the tolerance wanes and around puberty an increasing immune response towards HBV is observed. This leads to increasing inflammation, hepatocellular damage and repair processes that may ultimately lead to cirrhosis or HCC. Tolerance caused by an inadequate immune response is also seen in individuals who are immuno-compromised, either because of various diseases such as HIV infection (6, 7, 9-11, 21-23), some forms of leukaemia, and end-stage renal disease, or because of immunosuppressive therapies (24).
In sub-Saharan Africa, most HBV infections are asymptomatic following predominant horizontal transmission of HBV in early childhood, resulting in a large proportion of those infected at this early age progressing to chronicity (1-4, 25). It has been shown that 56-98% of the population had been exposed to HBV, with 9-20% becoming chronic carriers. Of these, 25% are expected to die from liver disease (3), with 20% of cirrhosis cases and 70% of all HCC cases in the region thought to be due to HBV infection (2). Thus, it has been estimated that 50 million inhabitants are chronic carriers (1, 3), which will result in the death from liver disease, of 12.5 million (3). This translates to 230 000 deaths from HBV infection per year. In addition, 50-70% of the annual three million acute viral hepatitis cases in the region are caused by HBV (2).
Prevalence patterns
Past reviews of HBV epidemiological studies conducted in sub-Saharan countries in the last three decades have shown that HBV infection is highly endemic in sub-Saharan Africa (1-4). It has been estimated that HBsAg carrier rates in the region range from 9.6% in South Africa to 20.6% in the Democratic Republic of the Congo (DRC), while HBV exposure rates range from 56.2% in Kenya to 91% in Senegal (3).
The black ethnic groups of sub-Saharan Africa have a much higher HBV prevalence rate than other racial groups living in Africa, and as they form the vast majority of the population, the prevalence figures quoted in this review thus far reflect the situation within the black populations of the sub-continent. In stark contrast, studies from South Africa show that whites and Indians have a carrier rate of just 0.2% and a total exposure rate of 5%, while those of mixed descent (European-Africans) have a carrier rate of 0.4-3%, and a total exposure rate of 18-25%, and South African Chinese have a carrier rate of 5.3% and a total exposure rate of 50% (2). In some countries in sub-Saharan Africa, there is a marked difference in prevalence rates between rural and urban populations. South Africa is one such country, with a prevalence of HBV chronic carriers in the rural former Transkei (Eastern Cape) of 15.5%, while that in urban areas is much lower: Durban, 7.4%, and Soweto, 1.3% (2).
Although both sexes are equally exposed to HBV, HBsAg carriage is higher in sub-Saharan males. However, this is not unique to the region, as it is seen in most other countries as well. Male:female ratios in the region range from 1.5:1 to 4:1 (1, 2).
Prevention and control
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Screening of blood donations
Many centres in the region continue not to screen for HBV or HIV or both, mainly as a result of financial constraints (26-28). This is apparent from a number of studies that have detected either or both these viruses in blood donors (26-29).
Injection safety
It has been estimated that 60-96% of visits to outpatient clinics in sub-Saharan Africa involve the administration of an injection, with most being unnecessary, and with between 20% and >90% of these injections being unsafe in many countries in the region (30). Some reports have linked the history of injecting in Africa to the emergence and spread of HIV (31), while it is well established that both HBV and HIV are spread in this manner (30). It is estimated that globally, 8-16 million HBV infections result annually from unsafe injections (32). Unsafe injections include those in which the needle or the syringe, or both, have been re-used but have not been sterilised. This occurs in a number of impoverished countries in the region, because of the cost of the syringes and needles, as well as the cost of their safe disposal. In recognition of this problem, the World Health Organization (WHO) now hosts the secretariat of the Safe Injection Global Network (SIGN), an organisation committed to helping the developing world eradicate this practice. Strategies include providing auto-disable syringes at prices comparable with standard disposable syringes, encouraging behavioural change in health-care workers (HCWs) and patients to decrease the demand for unnecessary injections, and training HCWs in methods of safe sharps disposal, using small, locally built incinerators (32).
National immunisation programmes
Several governments (Botswana, The Gambia, Mauritius, Reunion, Seychelles, South Africa, Swaziland, and Zimbabwe) in the region had introduced the HBV vaccine into their respective Expanded Programmes on Immunisation (EPI) between 1990 and the end of 2001, while Côte d'Ivoire, Ghana, Kenya, Madagascar, Malawi, Mozambique, Rwanda, Tanzania, and Uganda had introduced the vaccine by June 2002, and Benin, Burkina Faso, Burundi, Comoros, Gabon, Lesotho, Mali, Senegal, São Tomé, and Zambia are in the planning stages (4, 33, 34). The Global Alliance for Vaccines and Immunization (GAVI) has, since 1999, assisted a number of these countries with this endeavour, providing both information and financial assistance (33). Since the introduction of the HBV vaccine into the EPI of these countries, various studies have shown the vaccine to be both immunogenic and efficacious (35-37).
HCWs
All countries in the region recommend HBV vaccination for HCWs, before exposure to potentially infectious patients or specimens. However, not all health centres are able to offer this free of charge, and because it is often not compulsory, most HCWs remain unprotected, despite recognising HBV infection as an important occupational risk. The risk is most often linked to needle stick injuries.
Postexposure prophylaxis (PEP)
Healthy pregnant women in the region are generally not tested for HBsAg, as this is considered impractical and not cost-effective (38), as a result of the relatively low incidence of perinatal transmission, and the rarity of vertical (in utero) transmission. Thus, PEP for babies, in the form of hepatitis B immunoglobulin (HBIg) and HBV vaccination, is confined to babies of known HBV carriers (i.e. mothers who have been previously diagnosed as chronic carriers) who can afford this treatment, as it is not standard practice. PEP for HCWs who have been exposed to HBsAg-positive blood generally follows internationally accepted guidelines (39). These include the administration of HBIg, as well as the initiation of the HBV vaccine series, for unvaccinated HCWs. For vaccinated known non-responders, the same PEP is followed, although twice the HBIg dose can be administered. For vaccinated HCWs who do not know their antibody response, it is recommended that anti-HBs levels be determined first. If this is adequate (>=10 mIU/ml), no treatment is recommended, but if it is not, HBIg and a booster dose of HBV vaccine are recommended (39).
The global burden of HBV and HIV co-infection
Data from non-African countries
Most of the research on HIV and HBV co-infection has been conducted in areas of low HBV endemicity, where a number of studies have found a significantly higher prevalence of HBV infections in HIV-positive individuals (6-11). The majority of people in these areas are unprotected by antibodies to natural HBV infection at the time they reach sexual maturity; thus, the shared transmission routes of HBV and HIV result in specific adolescent or adult risk groups being exposed to both viruses at more or less the same time. Individuals who 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). In individuals previously exposed to HBV before being exposed to HIV, it has been shown that immunosuppression brought about by HIV may cause reactivation of recovered (previously anti-HBs positive) as well as 'silent' chronic infections (11, 40-41); also, there may be an increase of newly acquired HBV infections in HIV-positive people with prior resolved HBV infections (11, 40).
Data from sub-Saharan Africa
Although there have been a number of studies that have examined the epidemiology of both HIV and HBV in various countries in the region, there are relatively few that have studied HIV and HBV co-infection, and the effect that the increased prevalence of HIV may be having on the epidemiology of HBV. Generally, most of the studies that do not support an increased prevalence of HBV in HIV-positive individuals have either been conducted in populations at a time when HIV was at a relatively low level (26, 42) or have been conducted on small samples (26, 43-45), or both (26) (Table 2). Conversely, most of the studies that have shown an increased prevalence of HBV in HIV-infected subjects have been conducted in populations or countries where the HIV epidemic had either reached high levels, or have included larger numbers of HIV-positive individuals (46-51) (table 3). To contradict the above generalisations, two studies in Côte d'Ivoire and Malawi (52, 53) included a large number of HIV-positive individuals, and yet found no association (Table 2).
Two studies have found no increased prevalence of exposure to HBV in HIV-positive individuals, but have nevertheless raised concern about the impact that HIV may be having on the epidemiology of HBV. The first is a study in the DRC (29), which found that despite a similar prevalence of HBV exposure in HIV-positive and -negative pregnant women (n=500, 18 being HIV positive), there was a significant increase (11.1% in HIV positive, 2.7% in HIV negative) in specimens that were positive for all three markers (HBsAg, anti-HBs, and anti-HBc), suggesting reinfection or reactivation. Similarly, the same study found an increase in specimens positive for all three markers in 94 HIV-positive patients (15.9%) compared with 51 HIV-negative blood donors (5.9%) (29).
The other study was conducted on pregnant women (n=1861, 340 being HIV positive) in Zambia (54). A slight non-significant increase in HBsAg prevalence was found in the HIV-positive group (7.1% as opposed to 5.4% in the HIV-negative group), but of interest was the high prevalence of HBeAg positivity in the HBsAg-positive/HIV-positive women (25% as opposed to 8.5% in the HIV-negative women), suggesting a much higher rate of infectivity.
In summary, it can be said that most of the studies that have included relatively large numbers of HIV-positive individuals have shown that there is an increased prevalence of HBV exposure in these individuals (Table 3). However, this increased prevalence is not as dramatic as that found in non-African countries. Most studies in sub-Saharan Africa reported less than a two-fold increase (46, 48-51, 55), and only one study reported a four-fold increase (28). As no figures for the numbers of HIV-negative and -positive individuals found to be HBsAg positive were reported in the above study (28), it has not been included in Table 3.
Possible impact of HBV and HIV co-infection in sub-Saharan Africa
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-alpha 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-alpha (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.
Unresolved issues and recommendations
It is unclear at the moment whether or not the high prevalence of HIV in sub-Saharan Africa will (a) increase the pool of highly viraemic HBV carriers, (b) result in poor response to the HBV vaccine in HIV-positive babies, (c) result in vaccine failures in babies born to HIV and HBV co-infected mothers, perhaps leading to the emergence of vaccine-escape mutants because of sub-optimal response to the HBV vaccine or perinatal transmission, (d) modify HBV disease presentation or progression, (e) complicate laboratory diagnosis of HBV infection, or (f) complicate PEP and treatment for chronic HBV. This information can only be obtained through continuous surveillance of the effectiveness of immunisation programmes, as well as studies to monitor other prevention and control measures of HBV infection throughout the region. It is also important to monitor whether HIV immunosuppression may compromise the efficacy of the other vaccines within the EPI as well. This would provide added support for treatment of all AIDS cases with anti-retrovirals, and would increase the urgency of developing a vaccine for HIV.
Conclusion
Although there have been a number of studies that have examined the epidemiology of both HIV and HBV in various countries in the region, relatively few of them have studied the burden of HIV and HBV co-infection, and the effect that the increased prevalence of HIV/AIDS in the region may be having on the epidemiology of HBV infection. Data generated from these few studies have so far yielded divergent results. While there is sufficient evidence that both HIV and HBV infections are major public health problems in the region, there is no real solution in sight for the control and prevention of new HIV infections. In contrast to this, various sub-Saharan countries are currently incorporating the HBV vaccine into their EPI, and this has been a major success for those countries that have done so, and must remain a major goal for those still striving to do so.
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