Hepatitis B in Uganda: Transmission and prevention strategies among infants and HIV-infected adults

Abstract

This thesis is focused on hepatitis B virus (HBV) transmission and prevention in the setting of human immune deficiency syndrome (HIV) infection. HBV is common among HIV-infected persons in part due to shared modes of transmission, where HBV may accelerate HIV disease progression. Also, HIV may accelerate the HBV disease progression to cirrhosis and its complications. Coinfection with HBV and HIV is therefore associated with an increased risk for liver disease-related morbidity and mortality. Because of the high population prevalence of HBV and HIV in Uganda, we set out first to examine HBV disease transmission in two populations (infants and HIV-infected adults) that are at high risk for grave consequences chronic disease including cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC). Specifically, we determined whether HBV transmission occurs in infants prior to receipt of the first dose of the HBV vaccine -whether born to mothers infected or uninfected with HIV in northern Uganda. Early childhood transmission is a main determinant for chronic HBV infection. We also studied the transmission of HBV in a subpopulation of HIV-infected adults, whose ability to spontaneously recover from HBV infection is diminished, which may lead to HBV chronicity and life-threatening risks of cirrhosis, hepatocellular carcinoma and liver failure – complications which may also occur at faster rates than in HBV mono-infected patients. Lastly, we assessed the humoral response of HIV-infected adults to the HBV vaccine, given as a strategy for preventing this disease and its transmission. Three manuscripts have been written: 1) paper one examines the incidence of HBV among infants born to HIV positive and HIV-negative mothers in Gulu district of Northern Uganda; 2) the second paper examines the incidence of HBV and the impact of anti-retroviral therapy on HBV transmission in Rakai district of Southwestern Uganda; and 3) the third reports on how HIV-infected adults at Mulago hospital in Kampala, Uganda respond to the vaccine against HBV through examining the role of ART, CD4 T-cell count and HIV viral load on the humoral response to the vaccine. 1) In the first study, pregnant women and later their infants (at least 6-week old) presenting for their postnatal care and first HBV vaccine dose respectively were recruited. Pregnant women were tested postnatally for hepatitis B core antibody (anti-HBc-IgG) and hepatitis B surface antigen (HBsAg). HBsAg-positive sera were tested for hepatitis B e antigen (HBeAg) and HBV viral load (HBVDNA). Infants were tested for HBsAg at presentation for the first vaccine dose (6 weeks of age) and then at the last immunization visit, usually at 9 months of age. Serum of HBsAg-negative infants were tested for HBVDNA at 9 months. Incident HBV infection was defined by either a positive HBsAg or HBVDNA test. Results: A total of 612 pregnant women were recruited, with a median age of 23 years (IQR 20-28). Of these, 53 (8.7%) women were HBsAg-positive and 339 (61.5 %) anti-HBc-IgG-positive. Ten (18.9%) of the HBsAg positive women were also HBeAg-positive. Fifty one (96.2%) had detectable HBV DNA including 15(28.3%) who had levels below the lower limit of quantification. Median HBV-DNA levels of HBV-infected mothers was 5.0 (IQR 4.0-10) X105IU/mL with 9 (17.6%) having levels ≥ 105IU/mL. Eighty (13.3%) mothers were HIV-infected, of whom 9 (11.5%) were co-infected with HBV. No infant tested HBsAg or HBVDNA positive. Conclusions: From this study, we showed that vertical transmission does not seem or appear to contribute substantially to the high HBV endemicity in northern Uganda. These results indicate that the current practice of administering the first HBV vaccine to babies in Uganda at six weeks of age may be adequate in control of early infant HBV transmission. 2) For the second study, we screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study for evidence of HBV exposure. Serum from participants who tested anti-HBc negative (497) at baseline were tested over 3-7 consecutive survey rounds (with each at about 18 months) for incident HBV. Results: Thirty-nine infections occurred over 3,342 person-years (p-y), with an incidence 1.17/100 p-y. HBV incidence was significantly lower with ART use: (0.49 /100 p-y) with ART and (2.3/100 p-y) without ART [aHR=0.25 (95% CI, 0.1-0.5) p<0.001], specifically with lamivudine (3TC) use: (0.58/100 p-y) with 3TC and (2.25/100 p-y) without 3TC [aHR= 0.32(0.1-0.7), p=<0.007)]. No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 py with ≤400 copies/mL and 4.0/100 py with >400 copies/mL [aHR= 6.4(2.2-19.0), p<0.001] and with age: 15-29 years vs 40-50 years [aHR=3.2 (1.2-9.0)]; 30-39 years vs 40-50 years [aHR=2.1(0.9-5.3)]. Conclusions: From this study we concluded that HBV transmission continues in adulthood among HIV-positive Ugandans, and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa. 3) In the third study, we recruited HIV-positive adults with no evidence of prior exposure or immunity to HBV on screening. Three (20µg) HBV vaccine doses were administered at intervals of 0, 1 and 6 months. Anti-HBs titre levels were measured at 4 weeks after the third vaccine dose. Response and high response to the vaccine were defined as anti-HBs levels ≥ 10 and 100 IU/L respectively. Results: Of 251 HIV-positive adults screened, 132 (53%) had no prior evidence of HBV infection or vaccination, and were eligible for enrollment. Most participants were women 89 (67%); median (IQR) age was 32 years (27-41), and 68 (52%) had received antiretroviral therapy (ART) for more than 3 months. Median (IQR) CD4 cell count was 426 (261-583), and 64 (94%) of the 68 receiving ART had undetectable plasma HIV RNA. Overall, 117 (92%) participants seroconverted to the vaccine (anti-HBs titers ≥10 IU/L), with 109 (86%) participants having high-level response (anti-HBs ≥100IU/L). Eight (6.3%) were low-level responders (anti-HBs 10-99 IU/L), and 10 (7.9%) were non-responders (anti-HBs <10 IU/L). In multivariate analysis, only baseline CD4 >200 cells/mm3 was associated with both response [OR=6.97 (1.34-34.71), p=0.02] and high-level response [OR=4.25 (1.15-15.69)], p=0.03]. Conclusions: From this study we concluded that HBV vaccination was effective in eliciting a protective humoral immunologic response, particularly among those with higher CD4 counts. Half of the screened patients did not have immunity to HBV infection, suggesting a large at-risk population for HBV infection among HIV-positive adults in Uganda. Our findings support including HBV vaccination as part of routine care among HIV-positive adults.