Once a NUC is started, viremia should be tested with sensitive PCR assay every 3 months until undetectability (<10–15 IU/mL) is confirmed on two separate occasions, and every 6 months for the following years. Monitoring of HBV DNA is important also to differentiate between treatment failures. Primary non-response, defined as less than 1 log₁₀ IU/mL decrease in HBV DNA levels from baseline to month 3 of therapy, occurs in 2–3 % of the patients only; partial virological response (PVR), i.e., detectable serum HBV DNA at week 48 of treatment in a compliant patient, ranges from 5 to 50 % according to baseline levels of viremia; virological breakthrough, defined as a confirmed increase in HBV DNA level of more than 1 log₁₀ IU/mL compared to the lowest HBV DNA level, is a rare event during long-term ETV or TDF therapy. In HBeAg-positive patients, HBeAg/anti-HBe should be assessed every 6 months whereas HBsAg should be tested every 6–12 months in patients who are HBeAg-negative with persistently undetectable serum HBV DNA to detect HBsAg seroclearance.

As all NUCs are excreted through the kidneys , appropriate dosing adjustments are recommended. All patients should be tested at baseline and during treatment for serum creatinine to calculate the eGFR by MDRD formula to adjust NUC dose if eGFR falls below 50 mL/min, or <60 mL/min for some TDF treated patients [60], or had a rapid decrease during treatment. In addition, the baseline renal risk should be assessed for all patients. High renal risk includes one or more of the following factors: decompensated cirrhosis, creatinine clearance <60 mL/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs, solid organ transplantation. All CHB patients receiving TDF should be monitored every 3 months with serum creatinine, eGFR and serum phosphate whereas CHB patients on ETV should be monitored with serum creatinine levels and eGFR only if at high renal risk [3]. Closer renal monitoring is required in those patients with mild, or at risk for, renal impairment. While there is no enough evidence to recommend monitoring of bone density by DEXA scan in all patients receiving TDF-based antiviral regimens, bone mineral density should be assessed in selected patients, i.e., those who have a history of pathologic bone fractures or other risk factors for osteoporosis or bone loss , such as cirrhosis, independently of NUC therapy.

Antiviral therapy with ETV or TDF has negligible rates of resistance, though the few cases of ETV-R in NUC-naïve patients occurred in patients with PVR [61]. The optimal management of such patients is currently debatable, it seems reasonable that the HBV DNA levels at week 48 and their kinetics must be taken into account. Patients with residual viremia ≤1000 IU/mL or with continuous decline of serum HBV DNA levels could be maintained on the same drug given the progressive increase of virological responses over time and the negligible risk of resistance. For those with a flat pattern of HBV DNA or with a residual viremia >1000 IU/mL a rescue strategy with a non cross-resistant analogue, i.e., TDF for partial response to ETV and contrariwise , can be recommended [62].

CHB patients with advanced fibrosis or cirrhosis demonstrated histological improvement and reversal of fibrosis and cirrhosis after long-term treatment with both ETV and TDF. In 57 patients under long-term ETV treatment, a second liver biopsy evaluation after a median of 6 years showed a significant histological improvement (a ≥1 point improvement in the Ishak fibrosis score) in 88 % of patients, including all 10 patients with advanced fibrosis or cirrhosis at baseline [63]. A reduction in Ishak fibrosis score to 4 or less was observed for all four patients who had cirrhosis at baseline [64]. More strong evidence of beneficial effect on fibrosis and cirrhosis regression was reported during 5-year TDF treatment [65]. Of the 348 patients who completed 240 weeks treatment and had biopsy results at baseline and at week 240, 304 (87 %) had histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and 176 (51 %) had regression of fibrosis (≥1 unit decrease in the Ishak staging score). Of the 96 patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74 %) had cirrhosis histologically reversed, whereas 3 (1.2 %) of 252 patients without cirrhosis at baseline progressed to cirrhosis during treatment. Low BMI, absence of diabetes mellitus, normal ALT levels, and mild or absent necroinflammation at year 5 of treatment were associated with a higher likelihood of cirrhosis regression [65]. Clinical decompensation is fully prevented in compensated cirrhotic patients through the 3–5 years of effective ETV and TDF treatment [36, 54, 66–68], whereas among patients with decompensated liver disease survival is significantly improved by antiviral therapy as persistent HBV DNA suppression led to reversal of clinical decompensation in most patients [69]. Recently, several studies evaluated the role of NUC on HCC risk reduction. Annual incidence of HCC among NUC-naïve CHB patients without cirrhosis ranged from 0.6 % to 1.4 % and 0.8 % to 1.4 % in Asian and European patients treated with ETV, respectively [36, 68, 70–73] whereas among TDF-treated non cirrhotic patients the annual HCC risk ranged from 0.4 to 1 % [54, 73]. In ETV-treated cirrhotic patients, annual incidence of HCC ranged from 2 to 4.1 % in Asian studies [68, 71, 72, 74] and was 2.6 % in European studies [36, 73] while data from European studies in TDF-treated cirrhotics revealed that the risk ranged from 3.7 to 4 % [54, 73]. These HCC rates are very similar to what has been estimated from natural history studies in untreated patients [75].

The best stopping rule for NUC-treated patients is HBsAg loss and anti-HBs seroconversion, the latter is the sole safe stopping rule for cirrhotic patients. This endpoint is however rarely achieved (~1 %) in HBeAg-negative patients and in HBeAg-positive patients infected at birth. By converse, in NUC-treated HBeAg-positive patients with good predictors of response, such as short duration of infection, genotype A, elevated ALT levels and moderate levels of HBV DNA, this stopping rule can be achieved in up to 20 % of the patients after 5 years of treatment. In HBeAg-positive patients without cirrhosis, NUC treatment could be stopped after a confirmed and maintained (≥12 months) anti-HBe seroconversion combined with undetectable HBV DNA, an event that is observed in approximately 40–50 % of the HBeAg-positive treated patients after 5 years of therapy. However, viremia and hepatitis will relapse in up to 50 % of these patients after NUC discontinuation, thus suggesting a very strict monitoring strategy in the post-treatment follow-up to early detect virological rebound and restart therapy. For HBeAg-negative CHB patients there is no consensus between international guidelines about timing of treatment discontinuation. European (EASL) and American (AASLD) guidelines recommend HBsAg seroclearance as NUC stopping rule while Asian-Pacific (APASL) guidelines suggests that NUC cessation could be tempted after at least 2 years of treatment if HBV DNA is undetectable on three separate occasions 6 months apart [1–3]. Two Asian studies evaluated the off-treatment durability of response in HBeAg-negative CHB following ETV discontinuation according to APASL guidelines. Both studies reported high relapse rates (45 % and 91 %, respectively) in the year after treatment discontinuation, suggesting that NUC therapy should be continued indefinitely until the recognized treatment end-point of HBsAg seroclearance [76, 77]. However, this remains a major discussion point as strategies may be country specific [78, 79]. In countries where drug cost is an issue, full reimbursement for therapy and or monitoring is not in place and compliance tends to fade over time, NUC withdrawal might be worth to be carefully explored in selected HBeAg-negative patients. By converse, for patients leaving in countries where oral therapy, and HBV management in general, is fully reimbursed, and/or for those with cirrhosis or poor compliance to off-treatment monitoring, long-term administration till HBsAg clearance might still be the best strategy.

Chronic HBV infection in pregnancy is an important global health problem as mother-to-child transmission is the most common mode of acquiring chronic HBV infection in endemic areas [80]. Data on the natural history of CHB during pregnancy are conflicting : some data suggest no worsening of liver disease in the majority of HBV-infected pregnant women while case reports show hepatic exacerbations and fulminant hepatic failures during pregnancy [81–85]. Some additional studies suggest that HBV infection is associated with adverse pregnancy outcomes, including higher rates of preterm birth, gestational diabetes, and antepartum hemorrhage [81–85]. All women should be routinely tested for HBsAg during their first trimester of pregnancy and those resulting positive should be referred for additional assessment and medical management [2, 3]. Without immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and HBV vaccination within 12 h of birth, up to 90 % of infants born to HBeAg-positive mothers become HBV chronically infected [86, 87]. However, up to 28 % risk of perinatal transmission still persist in HBeAg-positive mothers with high HBV DNA levels despite immunoprophylaxis and vaccination [88–91], whereas antiviral prophylaxis in the third trimester of pregnancy has been shown to decrease the risk of HBV transmission [92–98]. Maternal viremia plays a significant role in vertical transmission, with increased risk which starts from HBV DNA levels greater than 6 log₁₀ IU/mL [87, 88, 99]. For this reason, all pregnant women with serum HBV DNA >6 log₁₀ IU/mL in the third trimester, or with HBV perinatal transmission in a prior pregnancy, need to be treated with NUC to initiate between weeks 28–32, with careful discussion of the risks and benefits. In fact, no anti-HBV agent has been approved for use in pregnancy and all NUCs are classified as Food and Drug Administration (FDA) pregnancy risk category C, except for TDF and LdT, which are category B. However, LdT has limited efficacy and moderate to high resistant rates therefore the drug of choice is TDF, due to its potency, leading to a rapid reduction of serum HBV DNA, the null risk of resistance and the excellent safety profile without significant increase in birth defects or adverse outcomes, so far [100–102]. Despite infant plasma TDF concentrations are lower than maternal plasma or breast milk, the label recommends against its use during breastfeeding [103]. However, recent study identified that the exposure to the drug is lower from breastfeeding than from in utero exposure concluding that there is no contraindication to TDF use during breastfeeding [104]. If administered only for prevention of mother-to-child transmission TDF may be discontinued within the first 3 months after delivery whereas in pregnant women who require anti-HBV treatment for their own health, therapy should be maintained. Moreover, pregnant women who need antiviral therapy due to the advanced liver disease may be safely treated with TDF starting from the first trimester while women with advanced liver disease who becomes pregnant under category C NUC need to be immediately switched to TDF, due to the risk of withdrawal flare that could result in reactivation and even decompensation of liver disease.