The clinical impact of HBV and HCV coinfection for PLWH may be greater than for the general population.1,7
Although HBV and HCV seem to have little or no effect on HIV progression, HIV may profoundly affect the course of HBV and HCV.1
Coinfection is associated with greater risk of chronic hepatitis B and C after acute infection, lower rates of hepatitis virus clearance, higher risk of cirrhosis, increased incidence of hepatocellular carcinoma (HCC), and increased liver-related morbidity and mortality.1
Progression to liver failure also seems to occur sooner than when HIV is not present.1
Although screenings for HBV and HCV are routine elements of HIV primary care in industrialized settings,26–28
such screening is not part of the national HIV management guidelines in most resource-limited settings, including Botswana.29
Because options for first-line ART backbones in Botswana and many other resource-limited settings now include tenofovir-emtricitabine (TDF-FTC)—an antiretroviral combination also active against HBV—a diagnosis of concomitant HBV infection may affect the optimization of ART regimens for coinfected persons.29
Additionally, there are other implications to unappreciated HBV coinfection in HIV-infected patients, as discussed below. Given the non-availability of effective treatment of HCV in most resource-limited settings, the implications of diagnosis by screening are less clear but would include intensive lifestyle counseling, such as avoidance of factors that may exacerbate HCV progression, including alcohol abuse, and education on reducing the risk of transmission.
At 5.3%, the prevalence of positive HBsAg results in our clinic population is substantial. This may be an underestimate given our study's limitations, including defining hepatitis B coinfection based on a single positive HBsAg result as opposed to a more rigorous definition using sequential HBsAg results, HBV DNA testing, hepatitis B core antibodies, or a combination of these tests. Also, our population consisted of patients with a range of ARV exposure and degree of viral control; the even higher HBsAg prevalence in the other contemporary Gaborone-based study17
performed in ARV-naïve patients with a median CD4 count of 104 cells/mm3
is likely reflecting higher risk of active HBV in untreated severely immunosuppressed PLWH.
As well, given the principally urban nature of our population, if the higher rural HBV prevalence noted elsewhere in southern Africa is true of Botswana, we may expect HBV coinfection among PLWH in rural Botswana to be higher than 5.3%.7
The subgroup prevalence of 4.6% among childbearing-aged females (ages 18–44) suggests that a substantial number of infants born to HIV-infected mothers in Botswana are at risk of perinatally transmitted HBV as well as, of course, HIV.
As noted elsewhere in southern Africa, hepatitis C screening results in the FMC population at the BCOE showed very low prevalence of coinfection in PLWH: less than 1%.
In Botswana, broader seroprevalence assessments may be feasible to inform policy recommendations; systematic laboratory screening of newly diagnosed HIV patients for other coinfections and comorbidities is already standard, and the addition of HBsAg screening in some ART sites may be possible. The availability of data from a wider variety of locales and populations in Botswana would make it possible to determine whether the addition of HBV screening to the national testing protocol for newly diagnosed PLWH would be appropriate.
There is considerable interest globally in the formulation of packages of services for HIV-infected persons in resource-limited settings, including the screening and management of coinfections.30,31
Botswana's national adult HIV management guidelines address some of these issues, although routine hepatitis B and C screenings are not included, and also, immunization against HBV is not included.29
(Although universal childhood immunization against HBV was introduced in 2000, most adults remain at risk for HBV acquisition and disease progression.) Current HBV-specific advice in Botswana's national adult HIV management guidelines recommends assessing HBV by HBsAg only if a hepatitis flare is suspected in patients who discontinue treatment with TDF or lamivudine (3TC/FTC)-containing regimens.29
Other approaches where routine baseline HBV assessment is not part of management for all HIV-infected adults include South Africa's current HIV Treatment Guidelines, wherein HBsAg is assessed only if initial ALT is elevated in patients eligible for ART.32
Given that only 21.4% of our patients with HBV coinfection had elevated transaminases, even this broader approach would have missed a substantial proportion of HBV coinfected patients.
In settings where routine HBV testing is not performed and tenofovir is not available, patients will be initiated on first-line regimens containing only one drug with antihepatitis B activity—lamivudine or emtricitabine. Hepatitis B has a well-known propensity to develop lamivudine resistance when lamivudine is used without a second drug with antihepatitis B activity.33
However, in settings where other antiretrovirals with antihepatitis B activity—such as tenofovir—are available as first-line regimens, opportunity exists to ensure that hepatitis B-coinfected PLWH who require ART are initiated on regimens using backbones of tenofovir plus lamivudine or emtricitabine, with which the risk of developing lamivudine-resistant hepatitis B is less.33
The availability of tenofovir is expanding in resource-limited settings, making this approach more relevant. Indeed, recently updated World Health Organization recommendations for ART in adolescents and adults support this approach as do national ART guidelines in most industrialized nations.26–28,30,34
Another clinical concern for PLWH on ART with undiagnosed HBV coinfection is the risk of precipitating a flare of underlying quiescent hepatitis, including in some cases, fulminant hepatic failure and death when ART containing lamivudine, emtricitabine, or tenofovir (i.e., antiretrovirals with antihepatitis B activity) is withdrawn suddenly.35
Studies show the prevalence of severe withdrawal hepatitis in coinfected patients to be as high as 50%.35
Almost all patients requiring ART in resource-limited settings are initiated on lamivudine-containing regimens.34
Suspensions and discontinuations of therapy—intentional and otherwise—occur during ART for a variety of reasons. In settings where hepatitis B is reasonably common but patients' hepatitis B status is not generally known, those patients at risk for hepatic complications if ART is suddenly withdrawn remain unrecognized.36
Another consideration highlighting the importance of HBV coinfection involves the perinatal transmission of hepatitis B. Much attention has been paid to the prevention of mother to child transmission (PMTCT) of HIV globally, and great success has been seen in this realm; Botswana, for example, is the first higher-prevalence country in sub-Saharan Africa to achieve a national MTCT rate of < 5%.37
However, PMTCT of hepatitis B occupies a much less clear position in the hierarchy of interventions offered through maternal–child health services in Botswana and many other resource-limited settings.
Because most individuals infected with hepatitis B in resource-limited settings acquire their infection perinatally or in early childhood, preventing MTCT of HBV is a key public health intervention in settings of higher HBV prevalence.38
Because maternal HIV coinfection correlates with higher HBV viral load, which is also a major determinant of HBV MTCT risk, interventions to prevent MTCT of HBV may be of even greater impact in regions of higher HIV prevalence.39–41
Where such interventions are available, realization of HBV status through screening has substantial value.
A birth dose of HBV vaccine alone is 70–75% effective for prevention of MTCT of HBV, and the addition of a birth dose of hepatitis B immunoglobulin (HBIg) brings efficacy to 95%.38
The Botswana national healthcare system currently provides an at-birth HBV vaccine dose to all children born in healthcare facilities; although it does stock HBIg, it is rarely delivered at birth, because pregnant women are not routinely screened for HBV. Screening for HBV status would allow for the rational use of a birth dose of HBIg to decrease perinatal HBV transmission.
Although knowledge of PLWH's HCV coinfection status is helpful in terms of recommending avoidance of alcohol, hepatotoxic medications, and supplements, educating on preventing the risk of transmission, and encouraging appropriate screening for HCC and liver cirrhosis, hepatitis C management is both complex and expensive in the developing world. Standard treatment protocols present challenges in Botswana and other resource-limited settings, where HCV RNA assays are generally not available and the high costs of pegylated interferon and ribavirin and the necessary associated monitoring required during treatment prohibit standard HCV management. Given the very low HCV IgG rates found in this and other regional studies and the lack of available treatment in these contexts, there seems to be little justification for recommending the addition of routine hepatitis C screening to Botswana's HIV management guidelines or other regional guidelines.
Because the prevalence of occult hepatitis B infection with a negative HBsAg but detectable HBV DNA is higher in HIV-infected individuals, HBsAg testing alone can miss occult HBV infections.7
Accordingly, the additional prevalence and clinical significance of occult hepatitis B coinfection merits additional study. Other aspects of HBV and HCV coinfection with HIV in resource-limited settings that merit additional study include the effect of TDF-FTC–containing ART regimens in pregnancy on perinatal HBV transmission, the morbidity associated with reactivation hepatitis in the setting of intermittent poor adherence to TDF- and/or 3TC/FTC-containing ART, and the changes in HBV coinfection prevalence created by the recent adoption of universal infant HBV vaccination in some countries in many resource-limited settings.