Single tablet HIV regimens facilitate virologic suppression and retention in care among treatment naïve patients*

Newer HIV regimens are typically taken once daily but vary in the number of pills required. Whether the number of pills in a once-daily HIV regimen affects clinical outcomes is unknown. We retrospectively compared adherence, retention in care, and virologic outcomes between patients starting a once daily single-tablet regimen (STR) to patients starting a once-daily multi-tablet regimen (MTR) in a publicly funded clinic in the United States. Outcomes were measured in the year after starting ART and included retention in care, virologic suppression, and medication possession ratio of at least 80%. Data from patients initiating therapy from 1 January 2008 to 31 December 2011 were analyzed with both unadjusted and propensity-score adjusted regression. Overall, 622 patients started with an STR (100% efavirenz-based) and 406 with an MTR (65% atazanavir-based and 35% darunavir-based) regimen. Retention in care was achieved in 80.7% of STR patients vs. 72.7% of MTR patients (unadjusted OR 1.57, 95% CI 1.17–2.11; adjusted OR 1.49, 95% CI 1.10–2.02). Virologic suppression occurred among 84.4% of STR patients vs. 77.6% of MTR patients (unadjusted OR 1.56; 95% CI 1.14–2.15; adjusted OR 1.41; 95% CI 1.02–1.96). There was no difference in the proportion of patients achieving at least 80% adherence, as measured by medication possession ratio (33.0% of STR patients and 30.1% of MTR patients; unadjusted OR 1.14; 95% CI 0.87–1.50; adjusted OR 1.04, CI 0.79–1.38). While it is difficult to eliminate confounding in this observational study, retention in care and virologic outcomes were better in patients prescribed STRs.     

Tenofovir and abacavir combination therapy: lessons learned from an urban clinic population

Regimens containing abacavir (ABC), tenofovir (TDF), and lamivudine (3TC) have recently been demonstrated to have high failure rates. This poses a clinical dilemma of how to manage patients currently being treated with other regimens containing tenofovir/abacavir. We evaluated the outcomes of tenofovir/abacavir regimens in our clinical practice through a retrospective review of 2655 charts. Two hundred patients (7%) were on a tenofovir/abacavir-containing regimen. Fifty-nine patients met the criteria for analysis and were grouped into three groups: (1) antiretroviral na?ve, (2) virally suppressed patients switched to TDF/ABC, and (3) patients with failure of their first antiretroviral regimen. Rates of viral suppression in the na?ve, switch, and first-failure groups were 95%, 86%, and 46%, respectively. In the first-failure group, viral suppression was 66% without and 18% with a preexisting M184V. A composite analysis of the groups revealed a success rate of 86% when the regimen contained zidovudine (ZDV) and 62% when it did not. No K65R mutations were noted. These findings support continued caution in the use of TDF/ABC in combination. However, these data suggest that this combination may be successfully used in selected situations such as in combination with ZDV. In patients already virally suppressed on a TDF/ABC-containing regimen, considerations include continuing the regimen or adding zidovudine, in the attempt to protect against the development of a K65R mutation and/or virologic failure, versus changing a stable regimen.     

Observational Study on HIV-Infected Subjects Failing HAART Receiving Tenofovir Plus Didanosine as NRTI Backbone

Abstract We evaluated the efficacy of tenofovir (TDF) – and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log₁₀ cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log₁₀ cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54– 0.79, p < 0.001 for each additional log₁₀ copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81–0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94–1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of ≥ 100 cells/mm³ from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79–0.98, p = 0.04 for each additional log₁₀ copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85–0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00–1.23, p = 0.05 for each additional 100 cells/mm³). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test.     

Tenofovir Alafenamide Fumarate,Tenofovir Disoproxil Fumarate and Entecavir: Which is the Most Effective Drug for Chronic Hepatitis B? A Systematic Review and Meta-analysis

Background and AimsThe therapeutic effect of tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir (ETV) on chronic hepatitis B (CHB) patients remains inconsistent. The aim of this study was to explore the differences in virological responses to TAF, TDF and ETV in patients with CHB.MethodsLiterature searches were conducted of the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials and observational studies published up to July 21, 2020. Statistical comparisons of virological response between TDF, ETV, and TAF were carried out with pooled odds ratio (OR) values.ResultsThe virological response in TDF-treated CHB patients was notably superior to that of the ETV-treated CHB patients after 12-weeks [OR=1.12, 95% confidence interval (CI): 0.89–1.41], 24-weeks (OR=1.33, 95% CI: 1.11–1.61), 48-weeks (OR=1.62, 95% CI: 1.16–2.25), 72-weeks (OR=1.43, 95% CI: 0.78–2.62), and 96-weeks (OR=1.56, 95% CI: 0.87–2.81) treatment. No significant difference was observed for the virological responses in CHB patients after 48-weeks treatment with TAF or TDF. The virological response in TDF+ETV-treated CHB patients was superior to that of TDF-treated CHB patients after 24-weeks, 48-weeks (OR=1.54, 95% CI: 1.17–2.02), 96-weeks, and 144-weeks.ConclusionsThe virological response in TDF-treated CHB patients was superior to that in ETV-treated CHB patients, but there was no significant difference between TAF and TDF. In addition, the therapeutic effect of TDF+ETV was superior to TDF alone.     

替诺福韦酯对阿德福韦酯应答不佳患者的挽救治疗研究进展

阿德福韦酯(adefovir dipivoxil,ADV)作为常用抗HBV治疗药物,与拉米夫定(lamivudine,LAM)、替比夫定和恩替卡韦无交叉耐药,且价格相对低廉,长期以来用于初治患者和LAM耐药患者的挽救治疗。然而由于ADV耐药基因屏障较低且临床用药剂量较低,临床长期应用累积了较多ADV应答不佳患者。替诺福韦酯(tenofovir disoproxil fumarate,TDF)作为ADV应答不佳患者的挽救治疗方案之一,对ADV初治应答不佳患者和LAM耐药的ADV应答不佳患者的临床疗效略有差异。然而多项体外研究显示TDF对ADV耐药病毒株抑制作用减弱。ADV应答不佳的患者换用TDF是否会引起或加重肾损害值得临床关注。本文就TDF对ADV应答不佳患者挽救治疗的国内外研究进展作综述,为提高耐药HBV感染防治的管理提供帮助。     

Efficacy and cost-effectiveness of antiviral regimens for entecavir-resistant hepatitis B: A systematic review and network meta-analysis

BackgroundChronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance.Data sourcesWe searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)-based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate.ResultsA total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR) = 22.30; 95 % confidence interval (CI): 2.78-241.93], LAM-TDF (OR  = 70.67; 95 % CI: 5.16-1307.45) and TDF (OR = 16.90; 95 % CI: 2.28-186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in the LAM-TDF group (OR = 14.82; 95 % CI: 1.03-220.31) was significantly higher than that in the LAM/LdT-ADV group. The 1-year BR rate of ETV-TDF (OR = 28.68; 95 % CI: 1.70-1505.08) and TDF (OR = 21.79; 95 % CI: 1.43-1070.09) therapies were significantly higher than that of ETV double-dose therapy. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8 526, 17 649, 20 651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively.ConclusionsTDF-based combined therapies such as ETV-TDF and LAM-TDF therapies were the first-line treatment if financial condition is allowed.     

Practices to improve identification of adult antiretroviral therapy failure at the Lighthouse Trust clinic in Lilongwe, Malawi

Objectives Evaluating treatment failure is critical when deciding to modify antiretroviral therapy (ART). Virologic Assessment Forms (VAFs) were implemented in July 2008 as a prerequisite for ordering viral load. The form requires assessment of clinical and immunologic status. Methods Using the Electronic Medical Record (EMR), we retrospectively evaluated patients who met 2006 WHO guidelines for immunologic failure (≥15 years old; on ART ≥6 months; CD4 count 50% drop from peak OR CD4 persistently <100 cells) at the Lighthouse Trust clinic from December 2007 to December 2009. We compared virologic screening, VAF implementation and ART modification during the same period using Fisher’s exact tests and unpaired t‐tests as appropriate. Results Of 7000 enrolled ART patients ≥15 years old with at least two CD4 counts, 10% had immunologic failure with a median follow‐up time on ART of 1.4 years (IQR: 0.8–2.3). Forty (6%) viral loads were ordered: 14 (35%) were detectable (>400 HIV RNA copies/mL) and one (7%) patient was switched to second‐line therapy. Overall, 259 VAFs were completed: 67% for immunologic failure and 33% for WHO Stage 4 condition. Before VAF implementation, 1% of patients had viral loads drawn during routine care, whereas afterwards, 8% did (P < 0.0001; 95% CI: 0.03–0.08). Conclusions Clinicians did not identify a large proportion of immunologic failure patients for screening. Implementation of VAFs produced little improvement in virologic screening during routine care. Better training and monitoring systems are needed.     

First-line eradication of H pylori infection in Europe： A metaanalysis based on congress abstracts, 1997-2004

INTRODUCTIONNumerous treatment regimens have been tested for their efficacy in curing H pylori infection worldwide[1-3]. Meta-analysis has become a frequently used method for re-solving such uncertainties and obtaining sound data in evidence-based medicin…     

Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono‐rescue therapy (TDF group) and TDF plus entecavir (ETV) combination‐rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty‐three CHB patients with lamivudine and entecavir resistance were investigated. Ninety‐six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6‐24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono‐rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.     

Plasma HIV RNA decline and emergence of drug resistance mutations among patients with multiple virologic failures receiving resistance testing-guided HAART

Early recognition of virologic failure in patients with extensive drug resistance receiving salvage-HAART is essential to avoid exposure to subinhibitory regimens. We studied plasma viral load (PVL) decline and rates of drug-resistance mutation (DRM) accumulation in such patients. A prospective, 48 week study of 38 heavily pretreated patients receiving genotypic resistance testing (GRT)-guided HAART was conducted. The rate of PVL decline was studied by weekly PVL determinations. To assess DRM accumulation, serial GRTs were performed in all nonresponders (never reaching PVL <50 or two PVLs >50 copies/ml after suppression). Over 48 weeks, 10 patients (26%) were nonresponders. Receiving less then two fully active drugs and having an elevated number of PI and NRTI mutations at baseline were strongly associated with virologic failure. There was no evidence of a difference in the change from baseline PVL to week 1 and 2 between responders and nonresponders. By contrast, PVL reductions from week 2 to week 3 and thereafter were significantly greater for responders (p < 0.01). Among nonresponders, the incidence rates per patient-month (95% CI) of emergent DRM were 0.67 (0.13-1.20), 0.40 (0.00-0.74), and 0.37 (0.00-0.75) at weeks 4, 8, and 24, respectively. Having limited baseline resistance, receiving at least two fully active drugs, and showing constant PVL reductions from week 2 to week 3 and thereafter were predictive of virologic response. In contrast, early changes in PVL levels were not. Virologic failure was associated with detection of emergent DRMs. Virologic rebound in patients on salvage-HAART should be addressed aggressively.     

Human immunodeficiency virus-infected persons with mutations conferring resistance to zidovudine show reduced virologic responses to hydroxyurea and stavudine-lamivudine

The baseline predictors of poor virologic response (<0.5 log decrease in plasma virus load) were examined in two 1996 pilot trials of combination nucleoside-analogue therapy. One trial examined the addition of hydroxyurea to didanosine therapy; the other examined stavudine-lamivudine in combination. In both, predictors of virologic response included the presence of mutations associated with zidovudine resistance. For hydroxyurea, the odds ratio (OR) of failure to achieve a short-term (4 weeks) virologic response in a bivariate logistic regression model was 30.8 (95% confidence interval [CI], 1.75-543; P=.02) for use of lower dose hydroxyurea (500 mg/day) and 14.7 (95% CI, 1.1-200; P=.04) for the presence of a zidovudine-related mutation. For the stavudine-lamivudine study, the OR of failure to achieve a virologic response at 4 weeks in a multivariate logistic regression model was 23 (95% CI, 2.7-199; P=.004) for the presence of a mutation at codon 215.     

The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr

OBJECTIVES: In many industrialized countries HCV infection is characterized by an increasing prevalence during ageing; however, data on the efficacy of treatment among older patients are scarce. This study was set up to evaluate the effect of age on the treatment of chronic HCV hepatitis with peginterferon alpha plus ribavirin. METHODS: We retrospectively reviewed medical records of 153 adult patients with chronic HCV hepatitis treated with combination therapy; 30 of them (19.6%) were 65 years of age or older. RESULTS: In multivariable analysis, age groups >/=40 years had similar odds of achieving sustained virologic response (P= 0.71) and significantly lower odds of sustained response compared with younger patients (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.05-0.59, P= 0.006; OR 0.13, 95% CI 0.03-0.49, P= 0.002; OR 0.21, 95% CI 0.05-0.91, P= 0.037 for patients aged 40-49 years, 50-64 years, and older than 64 years, respectively). The effect of age was present in the 74 patients infected with genotype 1 or 4 (P= 0.04), while among the 79 patients with genotype 2 or 3 sustained virologic response rates were relatively uniform, with no statistically significant differences. CONCLUSIONS: The probability of good response to combination treatment with peginterferon alpha plus ribavirin is decreased for patients aged more than 40 years infected with genotype 1 or 4, but patients aged more than 65 had a similar rate of response to those aged 40-64 years. Combination treatment may be safely extended to elderly patients with no major contraindications.     

Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons

The outcome and predictors of virologic treatment failure of highly active antiretroviral therapy (HAART) were determined for 271 human immunodeficiency virus (HIV)-infected protease inhibitor-naive persons. During a follow-up of 48 weeks after the initiation of HAART, 6.3% of patients experienced at least one new AIDS-defining event, and 3.0% died. Virologic treatment failure occurred in 40% (indinavir, 27%; ritonavir, 30%; saquinavir, 59%; ritonavir plus saquinavir, 32%; chi2, P=.001). Risk factors for treatment failure were baseline plasma HIV-1 RNA (odds ratio [OR], 1.70 per log10 copies increase in plasma HIV-1 RNA), baseline CD4 cell count (OR, 1. 35 per 100 CD4 cells/mm3 decrease), and use of saquinavir versus other protease inhibitors (OR, 3.21). During the first year of treatment, 53% of all patients changed (part of) their original HAART regimen at least once. This was significantly more frequent for regimens containing saquinavir (62%; 27% for virologic failure) or ritonavir (64%; 55% for intolerance) as single protease inhibitor.     

Initiation of HAART in drug-naive HIV type 1 patients prevents viral breakthrough for a median period of 35.5 months in 60% of the patients

The introduction of potent combinations of antiviral drugs is a major breakthrough in the treatment of HIV. We investigated the long-term virologic outcome and the development of resistance after initiating highly active antiretroviral therapy (HAART) in drug-naive patients in daily clinical practice. Twenty-five treatment-naive HIV-1 patients were started on HAART. Fifteen patients responded with a drop in viral load below the limit of detection during 35.5 (interquartile range: 7) months of therapy. In 6 of 10 patients with virologic failure, virus with resistance-related mutations against the received drugs emerged. Compared with responders (R), nonresponding (NR) patients were in a later disease stage at therapy start (p = 0.0089) with lower CD4 cell counts at baseline (p = 0.040), and a lower proportion of nonresponders showed protease inhibitor (PI) levels above C(min) (p = 0.049). More NR patients showed secondary PI mutations at baseline (p = 0.079), and the CCR2-64I coreceptor polymorphism was absent among NR patients, compared with 38.5% of R patients displaying CCR2-64I (p = 0.053), although the differences were not significant. In conclusion, starting HAART in antiretroviral drug-naive HIV-infected patients followed in daily clinical practice prevented viral breakthrough for up to 44 months in 60% of the patients. Virologic failure was associated with the development of resistance-related mutations, a later stage of disease at start of therapy and lower PI drug levels.