Guide to Hepatitis B for People Living With HIV

Section 4: HBV Disease Progression and the Impact of HIV Coinfection

One of the most perplexing aspects of HBV infection is its disease progression. In fact, researchers still don't fully understand why some people with HBV have no associated health problems, while others progress to serious liver disease; however, we do know that HBV disease progression is driven by the immune system's ability to control HBV replication, and that damages to the liver result from this dynamic process.

HIV worsens HBV because HIV directly attacks the immune system and gradually suppresses immune function by lowering the CD4 cell count. HIV infection also triggers persistent immune activation, which causes low-level inflammation throughout the body. These immune dysfunctions alter HBV disease progression.

Chronic HBV disease progression varies widely among individuals, but in general there are four distinct disease phases. Not everyone will go through every phase, and there can be fluctuations and reversions.

Phase 1: Immune Tolerant

During this phase, HBV is infecting liver cells and replicating at a very high rate, but the immune system either does not recognize the infection or is incapable of mounting an effective defense -- the immune system is tolerating the virus. Since there is little-to-no immune response, the risk of liver damage is very low, and treatment is not recommended.

Primarily seen in people infected at birth or in early childhood, the immune tolerant phase can last decades, so most people can remain in this phase until their twenties and thirties. People infected as adults usually will not have an obvious immune tolerant phase.

The impact of HIV infection on the immune tolerant phase is not clear. Since HIV disease progresses faster than HBV-related liver damage can develop, the immune tolerant phase will not make a difference in treatment decisions in HIV/HBV coinfection.

Phase 2: Immune Clearance

Researchers are still not sure what triggers the immune system to activate and attempt to control a previously unnoticed HBV infection, but when it does, the immune-clearance phase has begun. During this phase, the immune system and HBV battle for control. The amount of virus in the body will rise and fall in response to the intensity of the immune activation. This phase can last from years to decades, primarily in people younger than 35, during which time liver damage can develop. Because of the risk of liver damage, people in the immune clearance phase are often recommended to go on treatment.

During immune clearance, HIV-positive people have more HBV in the body than people without HIV; at the same time, their immune responses to HBV are less intense. This makes it harder for them to clear HBV infection without treatment. As a result, they are more likely to remain in the immune clearance phase for a longer period of time. As their weakened immune systems attempt to control HBV repeatedly and without success, causing low but persistent liver inflammation, HIV-positive people are more likely to develop serious liver damage during the immune clearance phase.

Phase 3: Inactive

When the immune system is able to gain the upper hand, people with HBV will pass into an inactive disease phase. There may still be some very low-level HBV replication, but it will elicit little or no immune response and will not cause liver damage. Chronic HBV is considered to be in remission. In some people, especially those who did not develop liver damage during the immune clearance phase, HBV stays in remission indefinitely; nonetheless, those people still have a low risk of developing liver cancer as they age, possibly because of previous liver damage or other unknown effects of prolonged HBV infection.

Since the inactive phase is dependent on immune control of HBV, immune suppression caused by HIV will upset this balance. As HIV disease progresses, people will likely lose the ability to control HBV. HIV-positive people are unlikely to stay in remission without treatment and may revert to the immune clearance phase or progress to the next phase: reactivation.

Phase 4: Reactivation

Chronic HBV can reactivate in some people after a period of inactivity. This generally starts to occur as men reach the age of 40 and women reach the age of 50 who have been infected at birth, and the likelihood of reactivation increases as they get older. Researchers believe this is caused by the combined effects of the loss of immune function associated with aging, and naturally occurring HBV mutations (in the pre-core or basal-core regions of the viral genome). As the weakened immune system cannot recognize and sufficiently control these HBV mutations, more viral replication follows.

During reactivation, a moderate rise in HBV levels triggers an immune response, causing liver damage. Reactivation increases the risk for serious liver damage and liver cancer.

Another type of reactivation is seen in people who have cleared HBV either spontaneously or with treatment. This can happen when the immune system is affected by chemotherapy, high-dose steroids, or other immunosuppressive therapies such as those commonly used during bone-marrow and stem-cell transplantation. Rarely, people have become infected with HBV after liver transplantation with an organ from a previously infected donor, even when the donor had cleared HBV spontaneously.

Reactivation can be more severe in HIV-positive people and rapidly cause serious liver damage. It is also possible for HBV to reactivate in HIV-positive people who have spontaneously cleared HBV in the past. As immune function often fluctuates in HIV disease, repeated episodes of reactivation are more likely in HIV/HBV coinfection; these can cause more liver scarring, speed up liver damage, and lead to a higher rate of developing cirrhosis. It is difficult to provide a more precise risk ratio of liver damage in HIV/HBV coinfection, since the availability of treatment has largely been effective in halting HBV disease progression.