• What approach for HBV prevention should be taken in this patient?
The patient’s serologies confirm no prior exposure to HBV, and he should be offered HBV vaccination. His CD4 cell count is below 350/µL and he has ongoing HIV viremia, which increases his risk for an inadequate response. However, vaccination should not be delayed, particularly given his high risk of sexual transmission. The patient should be counseled regarding all high-risk behaviors. As discussed above, 3 or 4 doses of the higher dose vaccine (40 µg/mL) should be administered depending on what type of recombinant vaccine is available. An anti-HBs level should be checked 1 month after completion. A full repeat vaccine series using the 40 µg/mL dose should be considered for nonresponders who initially received a standard vaccine series. Experts also recommend checking annual anti-HBs levels to monitor for waning immunity, with a booster dose given if the anti-HBs level drops below the protective range.
• What vaccination strategy should be used in patients with isolated positive anti-HBc?
The clinical implications of an isolated positive anti-HBc for vaccination are still uncertain. This serologic pattern may represent a false-positive test, remote HBV infection with loss of anti-HBs, or occult HBV infection with undetectable HBsAg. The latter scenario appears more commonly in HIV-infected patients, particularly with concomitant HCV infection [15].
A recent study suggested that patients with an isolated positive anti-HBc with a negative anamnestic antibody response (anti-HBs titer of < 10 IU/mL 4 weeks after a single 20 µg dose of recombinant HBV vaccine) should be further vaccinated with the double-dose for a 3-dose schedule [6]. Additionally, another study followed HIV/HCV coinfected patients for 9.5 years and found that an isolated positive anti-HBc was not associated with accelerated liver disease progression [16].
Treatment of HIV-1 Infection
Current HIV guidelines recommend initiation of ART for all HIV-infected patients regardless of their CD4 count [17]. ART for a treatment-naïve patient usually consists of 2 nucleotide/nucleoside reverse-transcriptase inhibitors (NRTIs; the “backbone”) combined with a third agent (the “anchor”), which can be a nonnucleoside reverse-transcriptase inhibitor (NNRTI), a protease inhibitor (PI) boosted with a boosting agent, or an integrase strand-transfer inhibitor (INSTI) [18,19].
There are numerous studies indicating that incident HBV risk can be reduced by placing those at risk for HBV acquisition on ART containing a combination of tenofovir disoproxil fumarate (TDF), lamivudine, or emtricitabine [20,21]. Another study in MSM found those on ART with HIV viral load < 400 copies/mL were protected from developing HBV compared to those not on ART [22]. Given this patient’s higher risk for HBV acquisition, placing him on emtricitabine/TDF backbone as part of ART could be protective against incident HBV [23].
Case Patient 2
Initial Presentation and History
A 32-year-old man diagnosed with HIV infection 8 years ago now on ART presents for follow-up. The patient is an MSM with a history of inconsistent condom use. At the time of HIV diagnosis 8 years ago, the patient had a CD4 cell count of 250 cells/µL and an HIV viral load of 648,000 copies/mL. The patient was initiated on lamivudine/zidovudine and lopinavir/ritonavir, and he achieved complete virologic suppression at 20 weeks, with a CD4 cell count of 455 cells/µL at 1 year. The patient has remained on this regimen without major side effects; however, he reports frequent missed doses over the last 2 years due to “pill fatigue.” Previous testing for HBV and HCV at the time of his initial HIV diagnosis was negative, but he failed to complete the HBV vaccine series. He denies alcohol or injection drug use.
Physical Examination and Laboratory Testing
Physical examination is normal. Laboratory studies reveal normal electrolytes and renal function, hemoglobin of 11 g/dL, and platelet count of 235,000/µL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are 34 U/L and 44 U/L, respectively, with an INR of 1.1 and albumin level of 3.4 g/dL. CD4 cell count is 320 cells/µL with an HIV viral load of 24,500 copies/mL. Viral hepatitis serologies show anti-HAV positive, anti-HCV negative, HBsAg positive, anti-HBc IgG positive, hepatitis Be antigen (HBeAg) negative, and hepatitis B e antibody (anti-HBe) positive. HBV DNA viral load is 685,000 IU/mL.
• What is the natural history of HIV/HBV coinfection?
Chronic HBV infection affects about 10% of HIV-infected patients globally. Epidemiologic studies indicate that HIV-infected patients have higher rates of reactivation and progression to chronic HBV infection and chronic liver disease than HIV-negative patients [24–26]. Coinfected patients demonstrate higher serum HBV DNA levels, which lead to more rapid progression of hepatic fibrosis and may increase the risk of cirrhosis and HCC [24,27,28]. HIV infection, however, can mediate the necroinflammatory response through blunting of the immune response that drives pathogenesis in HBV infection. Aminotransferase levels may be only slightly elevated or even normal, particularly in the severely immune suppressed. However, elevation in liver enzymes (hepatitis flare) can occur if a patient stops ART, or if HBV resistance develops. Patients being treated for HIV/HBV coinfection should be counseled that stopping HIV treatment puts them at risk of developing a hepatitis flare.
Large cohort studies of HIV/HBV coinfected patients indicate increased risk of liver-related mortality, most pronounced with lower CD4 cell counts [1,28,29]. Introduction of ART appears to increase rather than attenuate this liver-related mortality, possibly by decreasing AIDS-related mortality and allowing more time for liver disease progression. Finally, a recent meta-analysis including 12,382 patients demonstrated a significant effect of HIV/HBV coinfection on all-cause mortality, with a pooled effect estimate of 1.36 [30].
• What diagnostic testing should be done in coinfected patients?
Diagnostic Testing and Evaluation
Persistence of HBsAg for more than 6 months is diagnostic of chronic HBV infection and warrants further serologic evaluation. Patients with chronic HBV infection should be tested for HBeAg, anti-HBe, and HBV DNA levels and have AST and ALT levels measured. Elevation of AST and ALT can be seen with untreated HBV. For those on treatment, a hepatitis flare could be caused by abrupt discontinuation of HBV treatment, development of HBV resistance, or superinfection with another viral pathogen.
HBeAg is a marker of active viral replication and is associated with higher levels of HBV DNA and active liver disease. Seroconversion, or loss of HBeAg and development of anti-HBe, heralds a favorable treatment response for those who were initially HBeAg-positive. However, some HBV variants have precore or core promoter mutations that lead to higher levels of HBV DNA in the absence of HBeAg. This highlights the importance of monitoring HBV DNA levels in all patients with chronic HBV infection. Favorable response to therapy in HBeAg-negative patients is marked by normalization of aminotransferases and HBV DNA suppression.Hepatitis D virus (HDV) is a defective virus particle that can only replicate in the presence of HBV. Coinfected patients should be tested for anti-HDV if they are injection drug users or are from a high-prevalence region such as the Mediterranean and Amazon basins. Newly acquired HDV infection should also be considered in the context of hepatitis flares.
Although these routine diagnostic tests are essential for management, studies show low adherence rates to HBV testing guidelines by HIV providers [31,32].
• What is the role of HBV genotype and resistance testing?
HBV can be classified into 10 different genotypes, A through J, based on genomic sequence variations. Each genotype has a distinct ethnic and geographic distribution, with genotypes A and D predominating in North America. HBV genotyping appears to have important prognostic as well as treatment implications [19]. However, data are still preliminary and the guidelines do not recommend routine genotype testing.
Resistance testing in HBV allows for detection of mutations that decrease effectiveness of antivirals. Exposure to lamivudine can lead to mutations in the YMDD region of the HBV DNA polymerase, resulting in drug resistance. Resistance to lamivudine develops at a rate of approximately 25% after 1 year of drug exposure in HIV/HBV coinfection [33]. On the other hand, studies have shown that entecavir is active against HIV and, most importantly, selects for the M184V mutation in HIV. M184V is associated with lamivudine resistance for HIV treatment, thus limiting treatment options [34,35]. After these findings, the FDA advised against monotherapy with entecavir in patients with HIV/HBV coinfection. The case patient was on lamivudine during the time of HBV acquisition, and therefore YMDD mutation must be taken into consideration for therapy purposes. He should be switched to a regimen that suppresses both viruses. The development of drug resistance should be assessed in all patients with persistent or breakthrough HBV viremia on ART, particularly the nucleoside analogues. HIV providers treating HIV/HBV coinfection should regularly monitor both HIV and HBV viral load to assess for therapeutic efficacy.