The Lancet HIV: An expert review of the benefits and risks of using HIV PrEP in people with HBV

For medical professionals only

There are more than 250 million chronic HBV infections in the world [¹], due to the common transmission route, HBV infected people are also high-risk groups of HIV infection, globally, nearly 10% of HIV-infected people have HBV infection [^2], the latest systematic reviews and meta-analyses show that the proportion of co-infection in China is as high as 11.
3% ^[3].

。

In the absence of effective treatment for HBV infection, HBV/HIV co-infected patients have accelerated liver disease progression and increased incidence of liver cancer and risk of all-cause mortality compared with HIV-infected patients alone ^[4,5].

However, even though tenofovir (TFV)-based dual nucleoside reverse transcriptase inhibitor (NRTI) regimens reduce mortality in co-infected individuals to levels similar to those in HIV-infected individuals alone, the results have been inconsistent, with some studies suggesting that co-infected individuals may have higher mortality even after immediate initiation of antiretroviral therapy (ART) and correction for HIV-related factors ^[6-8].

Therefore, prevention of HIV infection is particularly important
in people with chronic HBV infection.

Tenofovir disoproxil fumarate / emtricitabine (TDF/FTC) is an effective regimen for HIV pre-exposure prophylaxis (PrEP) with anti-HBV activity and effective inhibition of HBV DNA replication
.
However, not all patients with HBV infection require antiviral therapy, and abrupt discontinuation of TDF can lead to HBV DNA reactivation, which is associated with hepatitis activity and acute liver failure ^[9,10].

These uncertainties create some barriers to medical decision-making for people with HBV to initiate PrEP, and current clinical guidelines are missing guidance
.

To fill this gap, The Lancet HIV journal recently published a review article ^[11] exploring the benefits and risks
of receiving HIV PrEP in people with chronic HBV infection.
In this issue, we specially invited Professor Sun Yongtao from Tangdu Hospital of the Fourth Military Medical University to interpret and comment
on this review.

Benefits and risks of using PrEP in patients with chronic HBV infection

The effectiveness of TDF/FTC in HIV PrEP has been demonstrated in randomized controlled trials and can significantly reduce the incidence of HIV infection cost-effectively
, even if adherence is not optimal.

Although not approved for combination antiviral therapy for HBV, TDF/FTC is effective in inhibiting HBV DNA replication, and most HBV-infected patients treated with TDF or TDF/FTC achieve HBV DNA below the lower detection limit
.
TDF monotherapy has been shown to significantly reduce HBV DNA in both HBeAg-positive and negative infected patients [^12,13], as demonstrated in real-world studies ^[14-16].

According to current international guidelines, not all patients with chronic HBV infection meet the indications for initiation of antiviral therapy, and guidelines generally recommend treatment for HBV-infected patients with active HBV replication and active hepatitis, although there are studies to support the expansion of antiviral therapy and benefit in patients with HBV infection who do not fully meet the indicated requirements ^[17,18].

However, abrupt withdrawal of treatment for chronic HBV infection is associated with HBV DNA reactivation and hepatitis activity, and some even progress to acute liver failure
.
Thus, following initiation of PrEP for TDF/FTC, poor adherence or on-demand PrEP regimens may be at risk of HBV-related comorbidities ^[19].

This makes PrEP clinical trials generally exclude people with HBV infection, and there is limited
evidence to assess the risk of HBV reactivation in chronically infected people with HBV using PrEP.

In a phase 2 clinical trial of TDF-based PrEP, 23 HBsAg-positive participants reported no hepatitis activity during the nearly one-year follow-up period ^[20], while in the FEM-PrEP study, one HBsAg-negative, anti-HBV surface antibody positive and no vaccination history developed HBV-associated hepatitis after taking TDF/FTC for a period of discontinuation but due to lack of HBV sequencing.
The researchers are uncertain whether this participant had HBV reactivation or reinfection ^[10].

The large PrEP clinical trial iPrEx did not explicitly exclude HBV-infected patients, including a total of 12 HBV-infected patients, of which 6 were assigned to the TDF/FTC group, 3 had HBV reactivation during TDF/FTC discontinuation, and 2 of which had ALT transiently elevated to 2- to 3 times the upper limit of normal (ULN), but these participants did not achieve study-defined hepatitis activity and did not develop resistance to TDF or FTC ^[9].

。

This suggests that TDF/FTC is safe for PrEP in HBV-infected patients and also reduces concerns
about another theoretical potential risk that intermittent exposure to TDF may increase the risk of drug resistance ^[11].

New implications for HBV treatment interruption research

Long-term oral TDF/FTC prevention of HIV infection has a clear double benefit for HBV-infected patients, but the potential risk of discontinuing TDF/FTC is a major barrier
to expanding the use of PrEP in HBV-infected patients.
In the absence of high-quality PrEP clinical trials and observational studies, we may be able to gain some new supporting evidence
from hepatology studies.

The lack of clear consensus in HBV clinical guidelines on whether and when antiviral therapy can be discontinued has facilitated treatment discontinuation studies
.

A study of 691 participants in Taiwan ^[21] found that 80% of participants experienced HBV DNA reactivation after discontinuation of the drug, of which 61% had a >2-fold ULN increase in ALT, and 41% required restarting antiviral therapy, but it is worth noting that 13% of discontinued participants experienced HBsAg clearance within 6 years, with a higher annual incidence than the historical control group with continuous treatment (1.
78% vs.
0.
15%).
Indicates potential long-term benefit
from discontinuation.

A systematic review of observational studies shows similar estimates of HBV DNA reactivation and hepatitis activity after discontinuation ^[22,23].

The largest multicenter observational study to date ^[24] included 1552 participants with a follow-up of up to 4 years, of which 83% had HBV DNA reactivation, 61% hepatitis activity, ALT > 2 times ULN, 31% ALT > 5 times ULN, 19 (1%) infected patients developed liver decompensation, 14 (1%) developed liver cancer, and HBsAg clearance was about 3% per year
。

Three other small clinical trials in HBeAg-negative patients ^[25-27] have yielded similar results
in HBV DNA reactivation, hepatitis activity, and HBsAg clearance.

Figure The benefits and risks of using TFV-based PrEP in HBV-infected patients

People infected with HBV receive PrEP advice

This limits the generalization
of the study data due to differences between treatment interruption and discontinuous or short-term use of PrEP.

Participants in treatment discontinuation studies were rigorously screened and tested for comorbidities, and had HBV DNA below the lower limit of detection for a long time before discontinuation of the drug, whereas many people with HBV infection using PrEP may stop the drug without reaching the lower limit of detection, which may lead to more severe HBV reactivation and hepatitis activity
.
In addition, the use of TDF/FTC may also lead to HBV DNA reactivation or hepatitis activity
in HBeAg-negative patients who are not eligible for treatment.

Treatment interruption studies provide an important reference
for the safety and selection of PrEP in HBV-infected patients.

Data provided by the Study of Treatment Interruption in People with HBV

Based on the data provided by the study, the review authors recommend that all HBV infected people who initiate tenofovir-based PrEP need close follow-up and monitoring of HBV DNA, aminotransferases and HBV serological results, recommend choosing a daily regimen for long-term use of PrEP, consider discontinuation if HBsAg clearance or low levels when they are no longer at high risk of HIV exposure, and have HBV DNA and aminotransferase testing at least every 3 months for at least one year after discontinuation
。

Expert reviews

The use of tenofovir-based PrEP in HBV-infected patients can both prevent HIV infection and inhibit HBV replication, helping to significantly reduce HIV/HBV co-infection
.

However, there are still some obstacles, mainly the risk of
HBV DNA reactivation and hepatitis activity after discontinuation of the drug.
Although the benefits of using PrEP in infected patients with detectable HBV DNA levels may be higher than those below the lower limit of testing, there is also a greater risk of discontinuation, especially in infected individuals
who do not use PrEP continuously in the absence of laboratory monitoring.

In addition, hepatitis outbreaks after drug discontinuation can be divided into two types, one is the host's immune response to HBV infection, and finally the immune system clears HBsAg to achieve functional cure, and the other is liver dysfunction caused by extensive HBV replication, which not only fails to clear HBsAg, but also leads to liver disease progression, and clinicians are currently unable to predict
these two conditions.

However, HBV treatment interruption studies may help clarify these differences, providing a potential predictive tool
for screening infected patients who can achieve HBsAg clearance after HBV DNA reactivation after drug withdrawal.

Figure Research focus on the use of PrEP in patients with chronic HBV infection

In countries and regions with high HBV prevalence such as China, the promotion of PrEP is of great public health significance, and regular laboratory monitoring after discontinuation can also help better manage HBV infection in the long term
.
Therefore, in the future, like other countries, China also needs to carry out more well-designed high-quality studies, including clinical trials, observational studies and modeling studies, to better clarify the benefits and risks of PrEP in HBV infected patients at different clinical stages, and provide evidence
for clinical guidelines.