HIV/HBV and HIV/HCV coinfection,and outcomes following highly active antiretroviral therapy

Objectives

To assess the prevalence and risk factors for HBV and HCV coinfection in the Australia HIV Observational Database (AHOD), and examine outcomes of HIV disease following initiation of highly active antiretroviral therapy (HAART).

Methods

Analyses were based on 2086 participants recruited to AHOD by September 2002. Of these, 1605 (77%) had been tested for HBV surface antigen, 1704 (82%) for anti‐HCV antibody and 1453 (70%) for both. Demographic and clinical predictors of HBV and HCV coinfection were examined. The impact of HBV and HCV coinfection on HIV disease progression was assessed by Kaplan‐Meier survival curves and Cox proportional hazard model of time to AIDS events and death.

Results

Among those tested, prevalence of HBV surface antigen and HCV antibody were 6.3% and 13.1%, respectively (4.8% and 10.7%, respectively, among the entire cohort). In multivariate analyses, the only independent risk factor for HIV/HBV coinfection was coinfection with HCV. Independent risk factors for HIV/HCV coinfection were HIV exposure category (with people who reported injecting drug use [MSM & IDU, IDU only] or receipt of blood or blood products at markedly increased risk) and HBV coinfection. HIV disease outcomes following first initiation of a HAART regimen were similar for HIV/HBV and HIV/HCV coinfected patients compared with HIV‐only patients in terms of AIDS‐free survival and detectable HIV virus during the first 12 months. However, patients coinfected with HIV/HCV appeared to have a poorer response to HAART in terms of CD4 count changes, with a CD4 count increase of 32 cells/μL (95% CI 1–67) less than HIV‐only patients.

Conclusions

Coinfection with HBV or HCV is relatively common among HIV‐infected participants in AHOD. HIV disease outcomes following HAART do not appear to be adversely affected by HBV/HCV coinfection, except for slightly poorer CD4 count responses in HIV/HCV coinfected patients.

     

Current treatment of HIV/hepatitis B virus coinfection

Coinfection with HIV and hepatitis B virus (HBV) has become a significant global health problem. Liver disease is now one of the leading causes of morbidity and mortality in individuals with HIV, particularly those with viral hepatitis. There are a number of agents available with dual activity against HIV and HBV, and effective treatment depends on understanding the potential advantages and pitfalls in using these agents. There are a number of unresolved issues in the management of HIV/HBV coinfection. These include the role of liver biopsy, the significance of normal aminotransferase levels, serum HBV DNA threshold for treatment, treatment end-points, and the treatment of HBV when HIV does not yet require treatment. Treatment of HBV should be considered in individuals with HIV/HBV coinfection with evidence of significant fibrosis (>/=F2), or with elevated serum HBV DNA levels (>2000 IU/mL). Sustained suppression of serum HBV DNA to below the level of detection by the most sensitive available assay should be the goal of therapy, and, at present, treatment of HBV in HIV/HBV coinfection is lifelong. If antiretroviral therapy is required, then two agents with anti-HBV activity should be incorporated into the regimen. If antiretroviral therapy is not required, then the options are pegylated interferon, adefovir or the early introduction of antiretroviral therapy. Close monitoring is necessary to detect treatment failure or hepatic flares, such as immune reconstitution disease. Further studies of newer anti-HBV agents in individuals HIV/HBV coinfection may advance treatment of this important condition.     

Prolonged use of tenofovir in HIV/hepatitis B virus (HBV)-coinfected individuals does not lead to HBV polymerase mutations and is associated with persistence of lamivudine HBV polymerase mutations

Objectives

The aim of the study was to identify and characterize hepatitis B virus (HBV) polymerase gene mutations associated with ongoing HBV replication in HIV/HBV‐coinfected individuals receiving tenofovir (TDF).

Methods

This retrospective cross‐sectional study identified 28 HIV/HBV‐coinfected individuals who had received TDF for at least 3 months. All patients had samples available while receiving TDF (on‐TDF), and 24 also had samples available prior to treatment (pre‐TDF). Case records were reviewed to obtain clinical and virological data at the times of sampling (±3 months). The HBV DNA of all samples was amplified using polymerase chain reaction (PCR), and the polymerase region of PCR‐positive samples was sequenced and compared with reference HBV data.

Results

Of the pre‐TDF samples, 15 of 24 (63%) were HBV PCR positive. Of the on‐TDF samples, four of 28 (14%) were HBV PCR positive (mean time on TDF 13.5 months; range 3–23 months). Lamivudine (3TC)‐resistance mutations were detected in three of four (75%) of these viraemic samples. The previously identified putative TDF‐resistance mutations, rtA194T+rtL180M+rtM204V, were not detected in any individual.

Conclusions

Unique mutations in the HBV polymerase gene associated with TDF resistance are rare in HIV/HBV coinfection. 3TC‐resistance mutations persist and a significant proportion of patients are HBV PCR positive despite the addition of TDF.     

Hepatitis C/HIV co‐infection is associated with higher mortality in hospitalized patients with Hepatitis C or HIV

Summary. Up to 10% of all patients with Hepatitis C virus (HCV) infection are co‐infected with human immunodeficiency virus (HIV); 25–30% of HIV patients are co‐infected with HCV. The aim of this study was to examine the association of HCV/HIV co‐infection with outcomes of hospitalized patients compared to those with HCV or HIV monoinfection. Using the 2006 Nationwide Inpatient Sample, patients with HCV or HIV monoinfection or HCV/HIV co‐infection were identified using ICD‐9‐CM codes. We compared liver‐related and infection‐related admission between the three groups of patients. Multivariate logistic regression was performed to identify independent predictors of in‐hospital mortality. A total of 474 843 discharges with HCV monoinfection, 206 758 with HIV monoinfection and 56 304 with HCV/HIV co‐infection were included. Liver‐related admissions were more common in co‐infected patients (15.4%) compared to those with HIV monoinfection (3.3%, P < 0.001). Primary infectious hospitalizations were more common in HIV monoinfection (33.9%) compared to co‐infected patients (26%, P < 0.001). HCV/HIV co‐infection was associated with higher mortality compared to HCV monoinfection (OR 1.41, 95% CI 1.20–1.65) but not when compared to monoinfected‐HIV patients. HCV‐associated cirrhosis or complications thereof conferred four times greater mortality risk in patients with HIV (OR 3.96, 95% CI 3.29–4.79). The rate of hospitalization for HCV/HIV co‐infected patients (23.5%) was significantly higher than those with HCV (14.8%) or HIV (19.9%) (P < 0.001). HCV/HIV co‐infection is associated with significantly higher rates of hospitalization and is a risk factor for in‐hospital mortality compared to patients with isolated HCV.     

HCV对HIV/HCV共感染患者病情进展的影响

目的探讨HCV对HIV/HCV共感染病情进展的影响。方法研究对象为2012年8月到北京佑安医院随访的HIV/HCV共感染者29例及HIV单独感染者20例。两组患者年龄、性别及HIV感染时间及感染方式、感染的HIV病毒亚型均具有可比性。外周血生化指标检测并采用瞬时弹性扫描仪FibroScan评估肝脏功能及纤维化程度,运用流式细胞技术检测外周血CD4+T、CD8+T细胞绝对计数。两组计量资料比较采用t检验,计数资料比较采用χ2检验。结果 HIV/HCV共感染组ALT、AST及TBil水平分别为(76.16±81.25)U/L、(87.66±71.32)U/L、(14.21±9.56)μmol/L,明显高于HIV单独感染组[(27.74±20.63)U/L、(45.65±16.95)U/L、(10.26±3.22)μmol/L],差异具有统计学意义(P值分别为0.004、0.005及0.046)。与HIV单独感染组相比,HIV/HCV共感染组Stiffness指数有升高的趋势,但差异无统计学意义(t=1.889,P=0.080)。HIV/HCV共感染组HIV病毒载量(拷贝/ml)的对数值为3.66±0.97明显高于HIV单独感染组的3.02±0.90(t=2.251,P=0.030)。HIV/HCV共感染组、HIV单独感染组CD4+T淋巴细胞计数及CD4+T/CD8+T细胞比例分别为(374.25±185.48)/μl及(0.33±0.17)、(496.45±230.98)/μl及(0.46±0.27),HIV/HCV共感染组CD4+T淋巴细胞计数及CD4+T/CD8+T细胞比例低于HIV单独感染组,差异具有统计学意义,P值分别为0.048、0.043。共感染组艾滋病发病率(27.59%)呈现出较HIV单独感染组(5%)高的趋势(P=0.063)。结论HCV促进HIV/HCV共感染者肝脏损伤,增强HIV复制,加剧机体免疫功能损伤,HCV可能加速HIV/HCV共感染者的病情进展。     

人类免疫缺陷病毒与乙型肝炎病毒混合感染的研究进展

高效抗逆转录病毒疗法（HAART）使人类免疫缺陷病毒（HIV）感染者机会性感染发生率明显下降，因而原有的一些慢性疾病如慢性肝炎对HIV感染者的病死率起着越来越重要的作用。在美国的一些医院HIV感染者死亡原因中，慢性病毒性肝炎可占45％。在我国乙型肝炎病毒（HBV）携带者约占总人口的10％，而HIV感染者也在不断增加，HIV／HBV混合感染者必将逐渐增多。     

Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: factors associated with response

As therapy for human immunodeficiency virus (HIV) infection evolves, optimizing hepatitis B virus (HBV) treatment and identifying factors that impact its response in the HIV/HBV-coinfected population is critical. We identified retrospectively 45 HBV/HIV-coinfected patients with detectable HBV DNA by the Bayer VERSANT HBV 3.0 bDNA assay (limit of quantification 2000 copies/mL) at baseline and/or year 1 of therapy. Patients were divided into three groups based on the active HBV agent in their antiretroviral regimen: group 1 (n = 15) received lamivudine; group 2 (n = 10), lamivudine plus tenofovir and group 3 (n = 20), lamivudine followed by lamivudine plus tenofovir. HBV genotypes and resistance profiles were determined by the Bayer Trugene HBV 1.0 assay. More patients in group 2 achieved HBV DNA suppression below 2000 copies/mL (80%), loss of HBe antigen (HBeAg) (40%) and loss of HBeAg and gain of anti-HBe (20%) than did patients in group 1 or 3. More patients with HBV genotype A, achieved HBV DNA suppression <2000 copies/mL than did patients with non-A genotypes [74% (26/35) vs 20% (2/10)], respectively (P = 0.003). Risk for virological nonresponse was significant in those with non-A genotypes [odds ratio (OR) 11.1; 95% CI: 2.0-50], previous HIV therapy (OR 6.5; 95% CI: 1.2-35) and <90% compliance (OR 3.7; 95% CI: 0.99-14.3). Simultaneous therapy with lamivudine/tenofovir suppresses HBV DNA more effectively than lamivudine or tenofovir added to lamivudine. More patients infected with HBV genotype A responded than the non-A patients, regardless of therapeutic regimen, compliance or prior HIV therapy.     

Persistent Hepatitis B Viraemia with Polymerase Mutations among HIV/HBV Co-Infected Patients on HBV-Active ART in KwaZulu-Natal,South Africa

To understand the problem of persistent Hepatitis B virus (HBV) viraemia in HIV/HBV co-infected patients on HBV-active antiretroviral therapy (ART), we assessed the rate of HBV virological response in patients on HBV-active ART in KwaZulu-Natal, South Africa, and analysed factors associated with persistent HBV viraemia. One hundred and fifty eligible participants with a chronic HBV diagnosis, with or without HIV coinfection, were enrolled and followed up after 6 months. The HBV pol gene was sequenced by next-generation sequencing and mutations were determined using the Stanford HBVseq database. Logistic regression analysis was used to assess factors associated with HBV viraemia at 6-month follow-up. The mean duration of HBV-active ART was 24 months. Thirty-seven of one hundred and six (35%) participants receiving HBV-active ART for longer than 6 months had virological failure. Advanced immunosuppression with CD4+ cell counts <200 cells/μL was independently associated with persistent HBV viraemia, aOR 5.276 (95% CI 1.575–17.670) p = 0.007. A high proportion of patients on HBV-active ART are unsuppressed, which will ultimately have an impact on global elimination goals. Better monitoring should be implemented, especially in HIV-coinfected patients with low CD4+ cell counts and followed by early HBV drug-resistance testing.     

HBV重叠HIV感染患者细胞免疫功能及临床特征的研究

目的：探讨HBV（乙肝病毒）重叠HIV（人类免疫缺陷病毒）感染患者的临床特征，以及细胞免疫功能损害情况。方法：回顾性分析我院2004—2007年收治的HBV重叠HIV感染的AIDS（获得性免疫缺陷综合征）患者30例的临床资料、免疫状态和转归，分析30例HBV重叠HIV感染者、50例单纯AIDS患者以及20例正常对照者的CD3、CIM、CD8细胞百分比以及CD4／CD8比值。结果：在30例HBV重叠HIV感染者中，6例死亡，均死于肝功能衰竭或肝硬化并发症。实验检查发现其肝功能以低蛋白血症为主要表现，转氨酶、胆红素轻度升高，透明质酸（HA）升高明显，HBV复制异常高拷贝。CIM、CD3的检测值，在3组之间两两比较差异有统计学意义，CD3及CIM细胞计数表现为HBV／HIV重叠感染组〈AIDS组〈正常对照组（P〈0．01），CD8细胞计数3组间两两比较差异无统计学意义。CD4／CD8比值降低，HBV／HIV重叠感染组、AIDS感染组均〈正常对照组（P〈0．01）。B超均显示肝回声增粗，弥漫性肝损害6例、腹水5例、肝肿大10例、脾大10例。结论：HBV重叠HIV感染者临床表现肝脏炎症反应较轻，但全身情况差，并发症多，增强了与HBV感染相关的终末期肝病风险，病死率也明显升高，同时CD4淋巴细胞衰减明显，细胞免疫损害明显。     

Increased risk of hip fracture associated with dually treated HIV/hepatitis B virus coinfection

HIV and hepatitis B virus (HBV) infections are each associated with reduced bone mineral density, but it is unclear whether HIV/HBV coinfection is associated with an increased risk of fracture. We determined whether dually treated HIV/HBV patients had a higher incidence of hip fracture compared to treated HBV‐monoinfected, antiretroviral therapy (ART)‐treated HIV‐monoinfected and HIV/HBV‐uninfected patients. We conducted a cohort study among 4156 dually treated HIV/HBV‐coinfected, 2053 treated HBV‐monoinfected, 96 253 ART‐treated HIV‐monoinfected, and 746 794 randomly sampled uninfected persons within the US Medicaid populations of California, Florida, New York, Ohio and Pennsylvania (1999–2007). Coinfected patients were matched on propensity score to persons in each comparator cohort. Weighted survival models accounting for competing risks were used to estimate cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hip fracture for dually treated coinfected patients compared to (i) HBV‐monoinfected receiving nucleos(t)ide analogue or interferon alfa therapy, (ii) HIV‐monoinfected on ART and (iii) uninfected persons. Dually treated coinfected patients had a higher cumulative incidence of hip fracture compared to ART‐treated HIV‐monoinfected (at 5 years: 1.70% vs 1.24%; adjusted HR, 1.37 [95% CI, 1.03–1.83]) and uninfected (at 5 years: 1.64% vs 1.22%; adjusted HR, 1.35 [95% CI, 1.03–1.84]) persons. The cumulative incidence of hip fracture was higher among coinfected than treated HBV‐monoinfected patients (at 5 years: 0.70% vs 0.27%), but this difference was not statistically significant in competing risk analysis (adjusted HR, 2.62 [95% CI, 0.92–7.51]). Among Medicaid enrollees, the risk of hip fracture was higher among dually treated HIV/HBV‐coinfected patients than ART‐treated HIV‐monoinfected and uninfected persons.     

HIV急性期/早期感染者合并HBV感染的临床特征

目的探讨艾滋病病毒(HIV)急性期/早期感染者合并感染乙型肝炎病毒(HBV)的临床特点及实验室特征,进一步明确影响HIV/HBV重叠感染疾病进展的关键因素。方法采用回顾性分析的方法,了解单独HIV急性期/早期感染者(单独HIV感染组)和合并HBV的HIV急性期/早期感染者(HIV/HBV重叠感染组)的初始CD+4T淋巴细胞(简称CD4细胞)计数和病毒载量调定点,以及两组病人感染HIV一年内CD4细胞计数和HIV病毒载量的动态变化,和HIV急性期/早期合并HBV感染的临床特征。结果 20例HIV/HBV重叠感染组的初始CD4细胞计数平均值为(443.55±197.00)个/μL(213~985个/μL),病毒载量调定点(4.34±0.99)Log10拷贝/mL(1.82~5.47Log10拷贝/mL)。30例单独HIV感染组病人的初始CD4细胞计数平均值为(497.37±121.29)个/μL(196~792个/μL),病毒载量调定点(3.87±0.62)Log10拷贝/mL(2.77~5.19Log10拷贝/mL)。HIV/HBV重叠感染组的初始CD4细胞计数明显低于单独HIV感染组,两组比较差异有统计学意义(P0.05)。HIV/HBV重叠感染组的病毒载量调定点明显高于单独HIV感染组,两组间差异有统计学意义(P0.05)。结论在我国HIV急性期/早期感染者中,HIV/HBV重叠感染者与单独HIV感染者比较,初始CD4细胞计数明显降低,病毒载量调定点明显升高,HIV病毒复制更为活跃。     

Safety and efficacy of raltegravir in patients with HIV-1 and hepatitis B and/or C virus coinfection

Objective

The aim was to examine the long‐term safety and efficacy of raltegravir in patients with HIV‐1 and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) coinfection in three double‐blind, randomized, controlled Phase III studies.

Methods

In STARTMRK, treatment‐naïve patients received raltegravir 400 mg twice a day (bid) or efavirenz 600 mg at bedtime, both with tenofovir/emtricitabine. In BENCHMRK‐1 and ‐2, highly treatment‐experienced patients with multi‐drug resistant virus and prior treatment failure received raltegravir 400 mg bid or placebo, both with optimized background therapy. Patients with chronic HBV and/or HCV coinfection were enrolled if baseline liver function tests were ≤5 times the upper limit of normal. HBV infection was defined as HBV surface antigen positivity for all studies; HCV infection was defined as HCV RNA positivity for STARTMRK and HCV antibody positivity for BENCHMRK.

Results

Hepatitis coinfection was present in 6% (34 of 563) of treatment‐naïve patients (4% HBV only, 2% HCV only and 0.2% HBV+HCV) and 16% (114 of 699) of treatment‐experienced patients (6% HBV only, 9% HCV only and 1% HBV+HCV). The incidence of drug‐related adverse events was similar in raltegravir recipients with and without hepatitis coinfection in both STARTMRK (50 vs. 47%) and BENCHMRK (34 vs. 38.5%). Grade 2–4 liver enzyme elevations were more frequent in coinfected vs. monoinfected patients, but were not different between the raltegravir and control groups. At week 96, the proportion of raltegravir recipients with HIV RNA <50 HIV‐1 RNA copies/mL was similar between coinfected and monoinfected patients (93 vs. 90% in STARTMRK; 63 vs. 61% in BENCHMRK).

Conclusion

Raltegravir was generally well tolerated and efficacious up to 96 weeks in HIV‐infected patients with HBV/HCV coinfection.     

2000例门诊和住院患者中HIV与HBV、HCV混合感染的血清学分析

目的分析医院对艾滋病病毒(HIV)抗体筛选结果,了解HIV感染与HBV、HCV肝炎病毒混合感染的关系.方法1998年6月～1999年6月采用ELISA法、MEIA(微粒子酶免法)对HIV、HBV、HCV检测.结果(1)抗HIV感染率为1.4%,其中男性占1.8%,女性占0.9%.民族分布维吾尔族占3.09%,汉族占0.27%,回族占0.77%;维吾尔族与汉族感染率有极显著性差异(χ2=25.34;P＜0.01).(2)在HIV阳性血清中抗HIV单一感染率14.29%;HIV、HCV双重感染率60.71%,HIV、HBV、HCV三重感染率25%;HIV、HCV与HIV、HBV、HCV混合感染率有极显著性差异(χ2=23.9;P＜0.01).结论在本组血清中HIV感染率高,HCV阳性在HIV/AIDS病人血清中混合感染率高,这与青年人静注毒品有关.HIV与HCV有共同传播途径--血液传播.     

Hepatitis B and C virus coinfection in The TREAT Asia HIV Observational Database

BACKGROUND AND AIM: Most studies of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection with HIV have been conducted among Western patient populations. This study aims to assess rates of HBV and HCV coinfection, and their impact on response to antiretroviral therapy and mortality, using data from The TREAT Asia HIV Observational Database (TAHOD), a multi-center cohort of patients with HIV in the Asia-Pacific region. METHODS: Patients who had been tested either HBV surface antigen (HBsAg) or HCV antibody were included. Patients who ever tested positive for HBV or HCV were regarded as coinfected for the duration of the study. RESULTS: Results of hepatitis tests were available for 55% (HBV) and 49% (HCV) of 2979 TAHOD patients, with prevalence of HBV and HCV coinfection both at approximately 10%. Mean CD4 change at 180 days after antiretroviral treatment initiation was 118.8 cells/muL and patients with either HBV or HCV had a lower but non-significant CD4 increase compared with patients with HIV only. Median time to reach undetectable viral load (<400 copies/mL) was 148 days and was not independently associated with HBV or HCV. In univariate analysis, patients with HCV had increased mortality (unadjusted hazard ratio, HR 2.80, P = 0.007). However, neither HBV (adjusted HR 0.80, 95% confidence interval CI 0.24-2.64, P = 0.710) nor HCV (adjusted HR 1.06, 95% CI 0.40-2.79, P = 0.905) was associated with increased mortality after adjustment for other covariates. Both HBV and HCV remained independently associated with elevated alanine aminotransferase (ALT) in the multivariate model (HBV, adjusted HR 1.94, 95% CI 1.04-3.62, P = 0.037; HCV, adjusted HR 2.74, 95% CI 1.47-5.12, P = 0.002). CONCLUSION: The impact of hepatitis coinfection on immunological and virological responses to antiretroviral therapy and HIV disease progression among this Asian cohort are similar to that seen in Western countries. The longer-term impact of hepatitis coinfection on both HIV disease and liver disease morbidity and mortality needs to be monitored.     

Adherence to highly active antiretroviral therapy impact on clinical and economic outcomes for Medicaid enrollees with human immunodeficiency virus and hepatitis C coinfection

We examined the impact of antiretroviral treatment adherence among hepatitis C (HCV) coinfected human immunodeficiency virus (HIV) patients on survival and clinical outcomes. We analyzed Medicaid claims data from 14 southern states from 2005 to 2007, comparing survival and clinical outcomes and cost of treatment for HIV and HCV coinfected patients (N = 4115) at different levels of adherence to antiretroviral therapy (ART). More than one in five patients (20.5%) showed less than 50% adherence to antiretroviral treatment, but there were no racial/ethnic or gender disparities. Significant survival benefit was demonstrated at each incremental level of adherence to ART (one-year mortality ranging from 3.5% in the highest adherence group to 26.0% in the lowest). Low-adherence patients also had higher rates of hospitalization and emergency department visits. Relative to patients with high (>95%) ART adherence, those with less than 25% treatment adherence had fourfold greater risk of death (adjusted odds ratio 4.22 [95% CI: 3.03, 5.87]). Nondrug Medicaid expenditures were lower for high-adherence patients, but cost of medications drove total Medicaid expenditures higher for high-adherence patients. Cost per quality-adjusted life year (QALY) saved (relative to the <25% low-adherence group) ranged from $21,874 for increasing adherence to 25–50% to $37,229 for increasing adherence to 75–95%. Adherence to ART for patients with HIV and HCV coinfection is associated with lower adverse clinical outcomes at a Medicaid cost per QALY commensurate with other well-accepted treatment and prevention strategies. Further research is needed to identify interventions which can best achieve optimal ART adherence at a population scale.