Globally, 5–10% of HIV-positive patients are co-infected with hepatitis B virus (HBV) infection. HBV/HIV co-infection carries a higher risk of liver-related death and increased all-cause mortality compared to HIV infection alone [1–3].
International and National guidelines are available for the treatment of HIV/HBV co-infection and recommend combination treatment with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or lamivudine (3TC) as part of the antiretroviral (ART) regimen [4,5].
The aim of HIV treatment is an undetectable HIV RNA, defined as less than 50 copies/ml by a sensitive assay, within 6 months [5,6]. The aim of HBV treatment is a virological response defined as an undetectable HBV DNA, measured using a sensitive real-time PCR assay (<10–15 IU/ml) . A partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after 6 months of treatment in compliant patients . Tenofovir and entecavir are potent nucleo(t)side analogues with a high genetic barrier to resistance [6,7]. European guidelines for the management of HBV mono-infection suggest consideration of modification of therapy in patients with a partial virological response after 12 months of either tenofovir or entecavir; however, advise that if HBV DNA is continuing to decline, clinicians can continue with same drug due to the low risk of resistance . There is no guidance as to how to proceed with HIV/HBV patients who still have detectable HBV after 48 weeks of TDF.
The aim of this study was to identify patients achieving an undetectable HIV RNA but not an undetectable HBV DNA after 48 weeks of TDF/3(F)TC treatment. We further aimed to identify demographic and virological factors associated with this response and to report the virological outcome in these individuals.
This was a retrospective case-control study. Patients were recruited from King's College Hospital Institute of Liver Studies Co-infection clinic for patients with HIV and viral hepatitis. This is a tertiary referral clinic with cases from across South-East England. The clinic was established in April 2009 and patients initiated on TDF with either FTC or 3TC [TDF/3(F)TC] either from April 2009 or prior to this date were reviewed. All patients meeting the definition of either a case or control were included.
Defined as those patients with persistently detectable HBV DNA (>20 IU/ml) with undetectable HIV RNA (<40 copies/ml) after 48 weeks TDF/3(F)TC therapy.
Defined as both undetectable HIV and HBV after 48 weeks of TDF/3(F)TC.
Demographic, HBV and HIV parameters and medication information were gathered from case notes and electronic record review.
Hepatitis B virus genotyping with an in-house direct sequencing test for the determination of HBV genotypes A–H and direct sequencing of HBV polymerase with a nested PCR for HBV reverse-transciptase mutations conferring drug resistance was performed at baseline in delayed responders and virological responders and at 48 weeks in delayed responders. HBV DNA (log10 IU/ml) testing with COBAS AmpliPrep/COBAS TaqMan HBV test (CAP-CTM; Roche Molecular Systems, Roche Diagnostics Ltd, UK) (LL<20 IU/ml) was performed at baseline and appropriate time-points at the clinician's discretion. HIV RNA testing was performed every 3–4 months.
Statistical analysis was carried out using SPSS version 19.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables were expressed as medians with interquartile ranges and compared using the Mann–Whitney test. Categorical variables were compared using the chi-squared or Fisher's exact test. P-values less than 0.05 were considered significant.
Twenty-three cases of delayed responders, who had failed to suppress HBV after 48 weeks of a TDF/3(F)TC-based regime whilst suppressing HIV, were identified and matched to 24 controls or virological responders who had suppressed both HBV and HIV within 48 weeks of commencing TDF/3(F)TC.
There were no significant differences in age or race: the delayed responders had a median age of 42.6 years (34.8, 44.0); 73.9% were black African. The virological responders had a median age of 42.8 (33.7,45.6) and 70.8% were of black African ethnicity. Ninety-one per cent of delayed responders and 71% of virological responders were men (Table 1).
The delayed responders had a longer duration of HIV infection; 4.2 (0.15, 11.5) years compared to 1.9 (0.22, 7.3) years in virological responders, this was not significant (P = 0.16). There was a trend towards lower nadir CD4 in the delayed responders: 72 cells/μl (32, 188) vs. 192 cells/μl (56, 305) in virological responders (P = 0.1).
Hepatitis B virus parameters
Baseline HBV genotypes were available in 21 delayed responders and 21 virological responders. 47.8% of delayed responders and 41.7% of virological responders were genotype A.
39.1% of delayed responders had received previous 3(F)TC without TDF as part of their ART, resulting in effective monotherapy for HBV, as had 29.2% virological responders (P = 0.5).
The majority of the delayed responders were eAg-positive: 87 vs. 46% in virological responders (P = 0.005).
Pre 3(F)TC HBV DNA levels were known in nine delayed responders and 14 virological responders, pre-TDF DNA results were available in 18 delayed responders and 23 virological responders. Both levels were higher in the delayed responders: pre-3(F)TC HBV DNA was 1.2 × 108 IU/ml (6.2 × 107,3.4 × 108) in delayed responders and 3.1 × 106 IU/ml (5680, 2.7 × 107) in virological responders (P = 0.009). Pre-TDF DNA was 1.1 × 105 IU/ml (4.0 × 105, 1.3 × 108) in delayed responders and 2.6 × 104 IU/ml (1270, 2.5 × 107) in virological responders (P = 0.012).
Hepatitis B virus resistance profiling prior to commencing TDF was available in 20/23 delayed responders and 17/24 virological responders. Six delayed responders had at least one mutation and four virological responders had at least one mutation. Neither a delayed responder nor a virological responder patient had evidence of the A194T mutation which has been associated with reduced TDF sensitivity in HIV/HBV co-infection .
Hepatitis B virus virological outcome
Sixteen of the 23 delayed responders went on to achieve undetectable HBV DNA after a median of 42.2 (27.2, 54.9) months. Six delayed responders still have detectable HBV DNA, after a median duration of 46.2 (28.2, 65.6) months (Fig. 1).
No delayed responder patient developed TDF resistance. Only one of 23 delayed responder, who had detectable HBV viraemia for 90 months, developed additional 3TC mutations. The baseline test showed rtM204V and rtL180M; the patient developed rtV173L in addition to this and was commenced on additional entecavir. HBV DNA became undetectable within 4 months.
We report a monocentric experience of HIV/HBV co-infected patients failing to achieve undetectable HBV after 48 weeks TDF/3(F)TC despite undetectable HIV viraemia. This group of patients provides the opportunity to determine factors associated with failure to suppress HBV on TDF/3(F)TC despite optimal adherence as demonstrated by undetectable HIV RNA.
Most patients with HBV mono-infection achieve undetectable virus on TDF. 76% of treatment naïve HBV eAg-positive patients and 93% of eAg-negative patients achieved undetectable HBV (<69 IU/ml) after 48 weeks of TDF .
Rates of HBV virological response to TDF-based regimens in HBV/HIV co-infected patients vary from 31 to 87% by 48 weeks, although prolonged follow-up in one cohort showed that 90% had a complete virological response to TDF after 5 years [9–11]. The rates of achieving complete suppression of HIV viraemia in these studies varied.
We found that factors associated with a failure to fully suppress HBV after 48 weeks of TDF were eAg-positivity and higher HBV DNA levels. Our data is in keeping with a published study in treatment-naive HBV mono-infected patients where high baseline HBV DNA and eAg-positivity predicted a partial response to entecavir. The majority of these patients went on to achieve virological suppression without modifying their treatment .
There is limited evidence directing clinicians how to proceed in the management of HIV/HBV co-infected patients with suppressed HIV but persistently detectable HBV. Smaller series of these patients have been reported where the approach has been divided between intensifying with entecavir or continuing with TDF/3(F)TC. In 13 HIV/HBV co-infected patients who failed to suppress HBV (<10IU/ml) after 6 months on TDF/3TC with undetectable or low HIV RNA (<400 copies), the HBV regimen was intensified with entecavir. This resulted in 40% of patients going on to achieve an undetectable HBV DNA within a further year of follow up . A randomized control study of 10 co-infected patients on TDF/FTC with detectable HBV and undetectable HIV showed that five patients receiving intensification with entecavir suppressed HBV DNA within 48 weeks. Of the five continuing TDF/FTC alone, three suppressed HBV within 12 weeks .
In another series of seven patients with ‘delayed response’, defined as a less than 1-log drop in HBV DNA within 3 months of TDF/FTC the patients were monitored and no further drugs added. All patients went on to achieve undetectable HBV DNA within a median of 20 months, without the development of TDF resistance mutations .
In our study 65% of delayed responders went on to achieve undetectable HBV DNA after a median follow-up of 42 months. The delayed responder patients experienced low-level viraemia for a prolonged period, yet this did not lead to the development of HBV drug resistance. Tenofovir is known to have a high genetic barrier to resistance so at this low level of viraemia, resistance may not develop. It is also possible, however, that HBV with reduced sensitivity to TDF was present at very low copy number and, by inference in these adherent patients, drug levels were sufficient to prevent the partially sensitive virus becoming the dominant quasi-species.
No patient developed TDF resistance or reduced sensitivity mutations and only one patient developed a further 3(F)TC resistance mutation, data which is in agreement with that shown in other, smaller studies [10,14]. The one patient in our study with new 3(F)TC mutation received entecavir and achieved undetectable HBV DNA.
Our findings indicate that intensification of HBV treatment with entecavir in the absence of viral rebound or the development of new resistance mutations is not necessary. In the published report of HIV/HBV patients with persistently detectable HBV whose TDF/FTC treatment was intensified with entecavir, only 40% achieved suppression of HBV after another year of follow-up . The majority of our delayed responder patients achieved undetectable HBV without modification of their anti-HBV therapy. The addition of entecavir carries additional pill burden, risk of side effects and increased financial cost.
Our study was a retrospective case–control study and as such, has several limitations. This is not a cohort study, therefore we cannot report the overall frequency of detectable HBV viraemia in co-infected patients receiving TDF/3(F)TC. Prior to the introduction of current guidelines on standardized HBV DNA monitoring , this test was requested at the clinician's discretion, consequently the number of HBV DNA measurements per patient was variable. Other limitations include the small number of patients and variable length of follow up.
There is increasing evidence in HBV mono-infection that HBV surface antigen (SAg) kinetics are an early marker of treatment outcome with both pegylated interferon and nucleos(t)ides and this could be a focus for future work [15,16].
In conclusion we report the largest series of HIV/HBV co-infected patients with detectable HBV after 48 weeks TDF/3(F)TC despite optimal adherence. We would not recommend intensifying with entecavir in this situation in the absence of viral rebound or development of new 3(F)TC resistance mutations as no patient developed TDF resistance and the majority went on to achieve virological suppression of HBV without further intervention.
Conflicts of interest
There are no conflicts of interest.
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