Study in Malawi shows importance of screening HIV-positive patients for HBV co-infection and using tenofovir-containing regimens

Hepatitis B virus (HBV) genotype A1 infection is associated with poor virological control and the rapid emergence of drug resistance among people living with HIV who are starting antiretroviral therapy in Malawi in the absence of tenofovir, investigators report in the online edition of Clinical Infectious Diseases.

The study looked at people starting HIV therapy between 2007 and 2009. Antiretroviral therapy (ART) consisted of fixed-dose lamivudine, stavudine and nevirapine. This meant that lamivudine was the only drug in their combination which was active against hepatitis B.

“A substantial proportion of HIV-1 infected patients … were at risk of progressive liver fibrosis and excess mortality due to poorly controlled HBV co-infection,” comment the investigators. “Suboptimal HBV suppression and emergence of resistance was most evidence in subjects that tested HBeAg-positive and had HBV viral load at treatment initiation.”

A substantial proportion of people living with HIV have hepatitis B virus co-infection. HIV increases hepatitis B virus replication and the risk of liver-related disease, especially in the context of low CD4 counts and high hepatitis B viral load.

Guidelines recommend that everyone living with HIV should be intensively screened for hepatitis B and that people with hepatitis B co-infection should receive antiretroviral therapy that includes two drugs with activity against both HIV and hepatitis B, typically tenofovir with emtricitabine or lamivudine.

Hepatitis B is highly prevalent in sub-Saharan Africa. However, few people living with HIV in the region are screened for hepatitis B and ART is usually initiated without knowledge of co-infection status. This is especially concerning as, until recently, the only drug with hepatitis B activity used in HIV treatment combinations in the region was lamivudine; hepatitis B monotherapy with this drug is associated with the rapid emergence of drug resistance.

Hepatitis B virus genotype A1 is unique to Africa and some investigators have proposed that it is associated with a relatively benign disease course.

To see if this was the case, investigators monitored hepatitis B levels among people living with HIV in Malawi who had hepatitis B genotype A1 co-infection and who received ART that included lamivudine as the only hepatitis B-active drug. Follow-up lasted for up to twelve months. A variety of sequencing techniques were used to detect hepatitis B resistance-associated mutations.

A total of 1117 people started therapy during the study period and 12% tested HBsAg-positive. Half of these patients were HBeAg-positive. HBeAg-positive status was associated with higher HBV DNA detection rates (p = 0.0014), an increased likelihood of having HBV DNA levels above 2000 iu/ml (p = 0.0006) and higher HBV DNA levels (p < 0.001).

Approximately three-quarters of patients (72%) were retained in care six months after starting HIV treatment and 41% were still in care after twelve months.

At the last follow-up, 96% of patients had achieved an undetectable HIV viral load (below 40 copies/ml). Half the people with hepatitis B co-infection achieved HBV DNA suppression below 14 iu/ml; half the patients with persistent HBV DNA levels achieved HBV RNA suppression.

"HBV outcomes were poor among HBeAg-positive patients,” note the authors. “HBV DNA levels initially declined by 4.5 log₁₀ iu/ml, then rebounded, coinciding with the rapid emergence of resistance.”

Use of the Sanger sequencing technique showed that none of the people with HIV and hepatitis B co-infection had HBV resistance associated mutations at baseline. However, prevalence was 8% after six months of follow-up, increasing to 33% at the twelve-month follow-up interval. The incidence of resistance was 34 per 100 person-years.

Deep sequencing revealed a higher prevalence of HBV resistance-associated mutations. Prevalence was zero at baseline, 19% six months after starting ART and 35% after twelve months of follow-up.

The combined Sanger and deep sequencing results showed that HBV resistance rates were significantly higher in HBeAg-positive patients compared to HBeAg-negative patients (49% vs 4%, p < 0.0001). Higher baseline HBV DNA was also associated with the emergence of resistance (p < 0.0001).

“Our data provide clear evidence in support of the motion that HBsAg testing should be introduced as part of routine HIV care in sub-Saharan Africa in order to guide ART selection and early adoption of tenofovir, and to identify patients that require follow-up for liver disease,” conclude the authors.