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University New South Wales
Department of Infectious Diseases
St Vincent's Hospital
Prof Gail Matthews, MD, PhD, has disclosed that she has received consulting fees from AstraZeneca and Janssen and funds for research support from AbbVie, Gilead Sciences, and ViiV.
New approaches to antiretroviral therapy (ART), including 2-drug regimens and the advent of long-acting injectables, offer potentially exciting new options for patients and may change our current treatment paradigms. But are they suitable for everyone and what are their potential pitfalls?
A Patient Case
I recently saw a 40-year-old Thai-born man with HIV who has been suppressed with bictegravir/emtricitabine (FTC)/tenofovir alafenamide (TAF) for many years with a CD4+ cell count of 450 cells/mm3 and an undetectable HIV-1 RNA. He had heard about long-acting injectable therapy as an alternative to his oral regimen and wondered whether it would be a suitable option for him as he would prefer not to take daily pills.
Further examination of his notes revealed that he was diagnosed with HIV/hepatitis B virus (HBV coinfection) 15 years ago, with a normal alanine aminotransferase and consistently undetectable HBV DNA level. His FibroScan score was 6.5 kPa, consistent with absent or mild fibrosis, and he was hepatitis B e antigen negative.
Treatment and Cure of HBV: Where We Stand Today
Current European AIDS Clinical Society and International Antiviral Society–USA guidelines recommend the immediate initiation of HBV-active ART—which should include a tenofovir-based agent unless contraindicated—in all individuals with HIV/HBV coinfection. Untreated HBV infection drives higher rates of morbidity and mortality in individuals with HIV due to progressive liver disease and hepatocellular carcinoma risk.
Fortunately, most first-line regimens, excluding dolutegravir/lamivudine (3TC), contain either tenofovir disoproxil fumarate (TDF) or TAF in combination with 3TC or FTC. Both TDF and TAF are highly effective anti-HBV agents with low rates of HBV resistance, but they generally act only as suppressive therapy and rates of hepatitis B surface antigen (HBsAg) loss—which is considered a functional cure—are low, occurring in only a small percentage of patients with HBV monoinfection. Thus, recommendations are usually for lifelong therapy in the absence of HBsAg, especially in individuals with advanced fibrosis or cirrhosis.
Withdrawal of HBV active therapy in individuals without HBsAg loss can be dangerous and potentially life-threatening. Hepatic flare in the context of rebounding HBV DNA can trigger fatal hepatic decompensation and has been described in patients with and without HIV who have had therapy withdrawn, either deliberately or inadvertently.
Long-acting regimens such as cabotegravir (CAB) and rilpivirine (RPV) do not contain HBV active agents, and therefore, it is vital to assess an individual's hepatitis B status before switching to CAB and RPV. This will limit inadvertent harm due to undiagnosed HBV infection or in situations where the presence of well-controlled HBV for many years was overlooked by the healthcare provider.
Currently, the best marker of active hepatitis B infection is a positive HBsAg test. This denotes the presence of ongoing viral turnover within hepatocytes regardless of other control markers. Access to HBsAg testing through standard enzyme-linked immunoassay methodology or rapid point-of-care testing is an essential part of screening all individuals with HIV and should be prioritized globally.
As with HIV, significant developments in HBV therapeutics aimed at achieving HBsAg loss or functional cure continue. Multiple agents with different modalities including antivirals acting at different stages of the viral life cycle and immunomodulatory agents are in clinical trials. The next decade heralds exciting prospects for the development of HBV curative strategies, but there are many questions still to be answered about their role and safety in individuals with coinfection and issues of global affordability and access.
Back to the Patient
Unfortunately, the answer for my patient is that switching to long-acting CAB and RPV would not be recommended unless he has lost HBsAg or unless he is also willing to continue receiving TDF or TAF in pill format. In that case, a careful switch with monitoring could be considered. In the absence of HBsAg loss, HBV viral rebound is likely and, although this may be tolerated in younger patients with mild fibrosis, it may trigger significant hepatic flare and is not recommended. It should also be noted that a “normal” FibroScan result while on treatment should be interpreted with caution as it may mask underlying pretreatment cirrhosis.
In summary, HIV/HBV coinfection is not uncommon, particularly in certain geographical areas or higher-risk populations, and yet HBV management is often overlooked and considered secondary to HIV management. As we move to new, exciting options for HIV therapy, it is critical that HBV infection is not forgotten. To aid in the selection of ART for patients who are coinfected with HIV and HBV, the HIV-ASSIST tool can be considered.
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