Review question
Can antenatal (administered during pregnancy) antiviral combination drugs prevent transfer of hepatitis B virus from mother to baby in pregnant women suffering from both human immunodeficiency virus (HIV) and hepatitis B virus (HBV)?
Key messages
The evidence from five small randomised clinical trials showed neither beneficial nor harmful effects of tenofovir-containing antiviral combination drugs compared with zidovudine alone or non-tenofovir-containing antiviral drugs, in pregnant women suffering from both HIV and HBV, measured by infant death from any cause, or serious adverse events in infants and mothers.
Only one trial reported on infant death from any cause or serious adverse events in infants while only two trials reported on serious adverse events in mothers.
Whilst this trial indicated that a tenofovir-based antiviral combination regimen could increase the number of infants with serious adverse events, this result is very uncertain due to the lack of studies (i.e. only one was found) and the low number of participants.
What is HBV-HIV co-infection in pregnancy?
The HBV-HIV co-infection in pregnancy is the occurrence of the two infections in one pregnant individual. When the two infections co-exist in an individual, HIV actively encourages the worsening of hepatitis B disease progression. When a pregnant woman is living with both HBV and HIV, treatment of HBV alone, without treating the HIV she also suffers from, may lead to the emergence of HIV types that are resistant to anti-HIV drugs.
How is HBV-HIV co-infection in pregnancy treated?
HBV-HIV co-infection in pregnancy can be treated with tenofovir-based antiviral combination regimens (drugs). They could be in the form of tenofovir alone or in combination with lamivudine, or emtricitabine, or zidovudine, or any other antiviral drugs.
What did we want to find out?
We wanted to find out whether antenatal use of tenofovir-containing antiviral combination drugs (drugs administered during pregnancy) was better than placebo, or tenofovir alone, or any non-tenofovir-containing antiviral drugs (either alone or in combination with at least two), for improving all causes of death for both baby and mother, transfer of HBV infection from mother to baby, mothers with detectable HBV DNA (hepatitis B hereditary material) before delivery, or maternal hepatitis B seroconversion (recovery from hepatitis B) before delivery in pregnant women living with both HIV and HBV.
We also wanted to find out if antenatal use of tenofovir-containing antiviral combination drugs (drugs administered during pregnancy) compared with placebo, or tenofovir alone, or any non-tenofovir-containing antiviral drugs (either alone or in combination with at least two), was associated with any unwanted effects in the baby and mother.
What did we do?
We searched for randomised clinical trials (studies in which participants are allocated to groups by a play of chance) that assessed the benefits and harms of antenatal use of tenofovir-containing antiviral combination drugs (drugs administered during pregnancy), compared with placebo, or tenofovir alone, or any non-tenofovir-containing antiviral drugs (either alone or in combination), for pregnant women living with both HIV and HBV infection. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found five randomised trials that included 533 pregnant women suffering from both HIV and HBV who were followed up throughout pregnancy and delivery with their infants being followed up to two years after birth. All the results were inconclusive between groups. The evidence from five small randomised clinical trial showed neither beneficial nor harmful effects of tenofovir-containing antiviral combination drugs compared with zidovudine alone, or non-tenofovir-containing antiviral drugs, in pregnant women suffering from both HIV and HBV, measured by infant death from any cause, or serious adverse events in infants and mothers. Only one trial reported on infant death from any cause or serious adverse events in infants, while only two trials reported on serious adverse events in mothers. Whilst this trial indicated that a tenofovir-based antiviral combination regimen could increase the number of infants with serious adverse events, this result is very uncertain due to the lack of studies (i.e. only one was found) and the low number of participants. We did not find data on the other outcomes of interest. None of the studies used placebo or tenofovir alone. All the trials received support from industry.
What are the limitations of the evidence?
We are not confident in the evidence because not all the studies provided data about everything that we were interested in. It was not clear whether people in the studies were aware of which treatment they were receiving. Also, there were not enough studies to be certain about the results of our outcomes.
How up-to-date is this evidence?
The evidence is up-to-date to 30 January 2023.
We do not know what the effects of tenofovir-based antiviral combination regimens are on all-cause infant mortality, proportion of infants with serious adverse events and proportion of mothers with serious adverse events, proportion of infants with adverse events not considered serious, and proportion of mothers with detectable HBV DNA before delivery because the certainty of evidence was very low. Only one or two trials, with insufficient power, contributed data for analyses. We lack randomised clinical trials at low risk of systematic and random errors, and fully reporting all-cause infant mortality, serious adverse events and reporting on clinical and laboratory outcomes, such as infants with HBV mother-to-child transmission, all-cause maternal mortality, maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion before delivery and maternal adverse events not considered serious.
Hepatitis B virus (HBV)-human Immunodeficiency virus (HIV) co-infection promotes an aggressive disease course of HBV infection. In the only available non-Cochrane systematic review on antiviral therapy during pregnancy for prevention of mother-to-child transmission of HBV, none of the women studied had HBV-HIV co-infection but were either HBV- or HIV-seropositive. Treatment of HBV alone may develop HIV-strains that are resistant to non-nucleoside reverse transcriptase inhibitors. Accordingly, co-treatment of the HIV infection is recommended.
To evaluate the benefits and harms of tenofovir-based antiviral combination regimens versus placebo, tenofovir alone, or non-tenofovir-based antiviral regimen either alone or in combination with HBV for the prevention of mother-to-child transmission of HBV in HIV-positive pregnant women co-infected with HBV.
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, LILACS (Bireme), Science Citation Index Expanded (Web of Science), and Conference Proceedings Citation Index-Science (Web of Science) on 30 January 2023. We manually searched the reference lists of included trials, searched on-line trial registries, and contacted experts in the field and pharmaceutical companies for any further potential trials.
We aimed to include randomised clinical trials comparing tenofovir-based antiviral combination regimens (anti-HIV regimen with lopinavir-ritonavir therapy, or any other antiviral therapy, and two drugs with activity against HBV, specifically, tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), plus lamivudine or emtricitabine) with placebo alone, or tenofovir alone, or non-tenofovir-based antiviral regimen (zidovudine, lamivudine, telbivudine, emtricitabine, entecavir, lopinavir-ritonavir, or any other antiviral therapy) either alone or in combination with at least two other antivirals.
We used standard methodological procedures expected by Cochrane. Primary outcomes included all-cause infant mortality, proportion of infants with serious adverse events, proportion of infants with HBV mother-to-child transmission, all-cause maternal mortality, and proportion of mothers with serious adverse events. Secondary outcomes included proportion of infants with adverse events not considered serious, proportion of mothers with detectable HBV DNA (deoxyribonucleic acid) (before delivery), maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. We used RevMan Web to carry out analyses and presented results, where feasible, using a random-effects model and risk ratios (RR) with 95% confidence intervals (CIs). We performed sensitivity analysis. We assessed risk of bias using predefined domains, assessed the certainty of the evidence using GRADE, controlled risk of random errors with Trial Sequential Analysis, and presented outcome results in a summary of findings table.
Five completed trials were included, of which four trials contributed data to one or more of the outcomes. They included a total of 533 participants randomised to tenofovir-based antiviral combination regimens (196 participants) versus control (337 participants). The control groups received non-tenofovir-based antiviral regimens either as zidovudine alone (three trials) or as a combination of zidovudine, lamivudine and lopinavir-ritonavir (five trials). None of the trials used placebo or tenofovir alone. All trials were at unclear risk of bias. Four trials used intention-to-treat analyses. In the remaining trial, two participants in the intervention group and two in the control group were lost to follow-up. However, the outcomes of these four participants were not described.
Tenofovir-based antiviral combination regimen versus control
We are very uncertain about the effect of a tenofovir-based antiviral combination regimen versus control on all-cause infant mortality (RR 2.24, 95% CI 0.72 to 6.96; participants = 132; trials = 1; very low-certainty evidence); proportion of infants with serious adverse events (RR 1.76, 95% CI 1.27 to 2.43; participants = 132; trials = 1; very low-certainty evidence), and proportion of mothers with serious adverse events (RR 0.90, 95% CI 0.62 to 1.32; participants = 262; trials = 2; very low-certainty evidence). No trial reported data on the proportion of infants with HBV mother-to-child transmission and all-cause maternal mortality.
We are also very uncertain about the effect of tenofovir-based antiviral combination regimens versus control on the proportion of infants with adverse events not considered serious (RR 0.94, 95% CI 0.06 to 13.68; participants = 31; trials = 1; very low-certainty evidence), and proportion of mothers with detectable HBV DNA (before delivery) (RR 0.66, 95% CI 0.42 to 1.02; participants = 169; trials = 2; very low-certainty evidence). No trial reported data on maternal hepatitis B e antigen (HBeAg) to HBe-antibody seroconversion (before delivery) and maternal adverse events not considered serious. All trials received support from industry.