World Gastroenterology Organisation

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HIV/HBV and HIV/HCV Co-infection in Sub-Saharan Africa: Transmission, Disease Outcomes, and Treatment Options

Mark W. Sonderup, MD

Mark W. Sonderup, MD
Senior Consultant Hepatologist, Division of Hepatology
Department of Medicine, Faculty of Health Sciences
University of Cape Town
Cape Town, South Africa

   
C. Wendy Spearman, MD

C. Wendy Spearman, MD
Head: Division of Hepatology
Department of Medicine, Faculty of Health Sciences
University of Cape Town
Cape Town, South Africa

Introduction

Liver disease, particularly in the post antiretroviral era of HIV/AIDS, has emerged as a major cause of morbidity and mortality in Hepatitis B (HBV) or Hepatitis C (HCV) co-infected patients 1-4.

Sub-Saharan Africa, an epicenter of HIV infection, comprises 11% of the global population, but 70% of those infected with HIV. This translates to 24 million HIV infected individuals in a region that is simultaneously highly endemic for hepatitis B with an estimated >8% population  prevalence or some 65 million people. The population prevalence data for hepatitis C is limited for most sub-Saharan African regions, however it is estimated that almost 30 million are infected. In contrast to developed countries, HBV co-infection outnumbers HCV co-infection in sub-Saharan Africa and probably reflects the low prevalence of injecting drug use (IDU). Rates of co-infection with hepatitis B of up to 36% are reported with the highest rates recorded in West and Southern sub-Saharan Africa 5.

Transmission and acquisition of HIV, Hepatitis B and Hepatitis C in sub-Saharan Africa

In sub-Saharan Africa, HIV and HBV transmission occurs mostly independent of each other with HBV infections usually occurring via horizontal transmission before the age of 5 and HIV heterosexually acquired during adulthood. However, HIV and hepatitis B may share routes of acquisition in neonates as a result of perinatal mother-to-child transmission. Maternal HIV infection increases mother-to-child transmission up to 2.5 fold as HIV promotes Hepatitis B replication and HIV/HBV co-infected mothers are more likely to be HBeAg positive and are thus potentially more infectious leading to increased perinatal transmission risk 6.

As opposed to IDU, the predominant mode of HCV transmission in sub-Saharan Africa is thought to be iatrogenic via inadequate screening of blood products or the reuse of syringes in health care facilities. Although HIV is thought to increase the risk of vertical HCV transmission 2.8 fold, studies suggest low rates of <5% vertical HCV transmission in sub-Saharan Africa 7, 8.

Hepatitis B and Hepatitis C genotype distribution

Genotypes A, D and E are the predominant hepatitis B genotypes in Africa. Genotype A accounts for up to 90% of HBV infections in southern, eastern and central Africa with genotype E occurring in West Africa. Genotype D occurs mainly in North Africa 9. Genotype A predisposes to chronicity with an elevated risk of hepatocellular carcinoma, but is also more responsive to alpha-interferon treatment. Genotype D is  associated with reduced response rates to alpha-interferon and with acute infection, is associated with an increased risk of fulminant hepatitis.

Hepatitis C Genotypes 1, 2, 4 and 5 have endemic origins in Africa. Hepatitis C Genotypes 1 and 2 occur throughout Africa with Genotype 4 occurring in Egypt and parts of Central Africa. Genotype 5 occurs in Southern Africa and less commonly, in some parts of Central Africa.

Outcomes of HIV/HBV and HIV/ HCV co-infection

HIV promotes chronicity of infection, liver fibrosis and increases the risk of hepatocellular carcinoma in both chronic hepatitis B and C, particularly in the clinical setting of low CD4 counts 1-4.

HIV co-infection augments the risk of reactivation or sero-reversion of hepatitis B. In adult-acquired hepatitis B infection, concurrently acquired or existing HIV infection increases the risk of fulminant hepatitis. Occult hepatitis B is also more prevalent in HIV infected people  and HCC occurs at a younger age and is more aggressive 10, 11.

HIV/HBV co-infected individuals have higher HBV DNA levels and liver-related mortality from chronic hepatitis B was increased in the pre- HAART era (RR of liver death 17.7 in co-infected compared to mono-infected individuals) 12.

Liver-related mortality is twice as high for chronic hepatitis B co-infected as for chronic hepatitis C co-infected individuals. A CD4 count of <200 cells/mm3 is associated with a 16.2 fold increase in risk of liver-related death compared to a CD4 count of >350 cells/mm3 13. Additionally, a potential association with adverse HIV outcomes in HBV co-infected individuals was demonstrated in the SMART study where HIV associated immune deficiency was enhanced by active HBV replication 14. Also, an HBeAg positive status has demonstrated an  association with a slower virological response to HAART, compared to an HBeAg negative status 15. However, no long-term effect on clinical HIV outcome has been demonstrated in co-infection.

Management of HIV/Hepatitis B and HIV/Hepatitis C co-infection

Ideally, all HIV positive patients must be screened for HBsAg and hepatitis C antibody using existing HIV diagnostic infrastructures. However, there is limited infrastructure for molecular virology in sub-Saharan Africa and screening tests are costly. In order to correctly diagnose and manage HIV co-infections, there is a need for affordable, sensitive and specific point-of-care testing for HIV, HBV and HCV. Here, the need for WHO pre-qualified diagnostic tests to be approved and available is crucial.

Advocacy for the screening of mothers for HIV, hepatitis B and hepatitis C with initiation of appropriate anti-retroviral therapy, mother-to-child prevention therapy together with a birth dose of HBV vaccination, would significantly assist in decreasing the neonatal and infant transmission of HIV and HBV.

A meta-analysis of 550 HIV/HBV co-infected patients confirmed that Tenofovir suppresses HBV to undetectable levels in the majority of HBV/HIV co-infected patients with the proportion fully suppressed continuing to increase with time on treatment. Prior treatment with Lamivudine or Emtricitabine does not alter the efficacy of Tenofovir treatment 16. The fixed dose combination once daily therapy of  Lamivudine or Emtricitabine, Tenofovir and Efavirenz is easy to administer and benefits adherence, an essential factor for viral suppression.  The immune reconstitution syndrome, following the initiation of HAART, can lead to potentially life-threatening flares of hepatitis B,  especially in individuals with low CD4 counts. Cirrhosis risk in HBV co-infected individuals virally suppressed on Tenofovir-based HAART is low 17.

Peg-Interferon and Ribavirin treatment can be considered in HIV/HCV patients with CD4 counts of >500 cells/mm3, however, given the need for intensive monitoring, risk of adverse effects, cost and lack of availability, it is not appropriate for many regions in sub-Saharan Africa. The new era of all oral Direct-Acting Antiviral (DAA) therapy for hepatitis C is the ideal for sub-Saharan Africa. Pan-genotypic combination  AA therapy with high efficacy requiring a minimum of diagnostics and monitoring, would allow for simpler management of co-infected  patients without the requisite need for complex diagnostics. The PHOTON-1 study has demonstrated efficacy for Sofosbuvir, a pan-genotypic  NS5B polymerase inhibitor plus Ribavirin given for 12-24 weeks to HCV genotype 1-3 co-infected patients, all of whom were on stable HAART therapy. Sustained virological response (SVR) rates ranged from 76-94% 18. Improved efficacy approaching 100% SVR rates has  been demonstrated with other pan-genotypic DAAs such as the NS5A inhibitor, Daclatasvir in combination with Sofosbuvir. The challenge will be the accessibility and affordability of these therapies.

The phenomenal success in upscaling HAART in sub-Saharan Africa has provided the model as to how this can be achieved and access to  therapies for hepatitis C should follow similar principles.

Conclusion

Liver disease due to chronic hepatitis B and C is a significant cause of morbidity and mortality in HIV infected individuals. Early diagnosis of co-infections, initiation of HAART at CD4 counts ≥350 cells/mm3 and the effective treatment of hepatitis C are essential to prevent liver disease.

References

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