TDF Combination Research Articles

Development and characterization of formulations based on combinatorial potential of antivirals against genital herpes.

Herpes simplex virus type 2 (HSV-2) treatment faces challenges due to antiviral resistance and systemic side effects of oral therapies. Local delivery of antiviral agents, such as tenofovir (TDF) and zinc acetate dihydrate (ZAD), may offer improved efficacy and reduced systemic toxicity. This study's objective is to develop and evaluate local unit dose formulations of TDF and ZAD combination for local treatment of HSV-2 infection and exploring their individual and combinatory effects in vitro. The study involved the development of immediate-release film and pessary formulations containing TDF and ZAD. These formulations were characterized for physicochemical properties and in vitro drug release profiles. Cytotoxicity and antiviral activity assays were conducted to evaluate the individual and combinatory effects of TDF and ZAD. Film formulations released over 90% of the drugs within 1h, and pessary formulations within 90min, ensuring effective local drug delivery. ZAD showed moderate antiviral activity while TDF exhibited significant antiviral activity at non-cytotoxic concentrations. The combination of TDF and ZAD demonstrated synergistic effects in co-infection treatments, reducing the concentration required for 50% inhibition of HSV-2. Developed film and pessary formulations offer consistent and predictable local drug delivery, enhancing antiviral efficacy while minimizing systemic side effects. The combination of TDF and ZAD showed potential synergy against HSV-2, particularly in co-infection treatments. Further preclinical studies on pharmacokinetics, safety, and efficacy are necessary to advance these formulations toward clinical application.

The effect of ARVs on the MEKKK1 gene promoter, inflammatory cytokine expression and signalling in acute treated Jurkat T cells

ARVs alter the methylation status of the MEKKK1 gene promoter in acute treated Jurkat T cells with inflammatory outcomes Inflammation is reduced in patients under going antiretroviral therapy; however the mechanism is not well understood. We investigated DNA methylation of the mitogen-activated protein kinase kinase kinase kinase 1 (MEKKK1) gene promoter in Jurkat T cells to determine whether the antiretroviral drugs, lamivudine, tenofovir disoproxil fumarate, dolutegravir, TLD (a combination of TDF, 3TC and DTG) and efavirenz modify the methylation status of the MEKKK1 gene – a known stimulus of inflammation. Acute antiretroviral treatments (24 h) were not cytotoxic to Jurkat T cells. MEKKK1 promoter hypomethylation occurred in cells treated with 5-aza-2’-deoxycytidine (Aza), TDF and 3TC, and MEKKK1 promoter hypermethylation occurred in cells treated with DTG; however, promoter DNA methylation of the MEKKK1 gene did not influence MEKKK1 gene expression; therefore, these drugs did not epigenetically regulate MEKKK1 and downstream signalling by promoter DNA methylation. Acute TLD and EFV treatments induced inflammation in Jurkat T cells by increasing MEKKK1, MAPK/ERK and NFκB expression, and activating tumour necrosis factor-α (TNF-α) expression. ARVs decreased IL-10 gene expression, showing no anti-inflammatory activity. The data shows that the inflammation caused by ARVs is not related to the methylation status of MEKKK1 gene promoter and suggests an alternative stimulus via post-transcriptional/post-translational modifications may activate the canonical MEKKK1/NFκB pathway that leads to inflammation. Finally, an increase in NFκB activity and pro-inflammatory cytokine activation seemed to occur via the MAPK/ERK pathway following ARV treatments in Jurkat T cells.

HIV Infection in Patients Aged Over 50 in the Infectious Diseases Unit at Brazzaville University Hospital: Prevalence and Associated Factors

Objective: The prevalence of HIV infection in people aged is of significant importance. We determined the prevalence of HIV infection with patients aged over 50 at the Brazzaville University Hospital and look for its associated factors. Patients and Method: Cases of HIV infection in patients over 50 years admitted to the Infectious Diseases Unit of Brazzaville University Hospital were examined under cross-sectional descriptive and analytical study. This survey concerns the period going from January 1, 2019 to June 30, 2021. Results: There were one hundred and ninety-four patients (8.2% of admissions). Their mean age was 57.40 ± 6.4 years [50-93], they were mostly female (n = 113; 58.2%). The most dominant population was the age group between 50-59 years (n = 136; 70.1%). They were single people (n = 80; 41.2%), without profession (n = 87; 44.8%), with a primary education level (n = 81; 41.8%), hypertensive (n = 27; 13.9%), diabetics (n = 15; 7.7%). HIV infection was discovered during hospitalization (n = 111; 57.2%), for deterioration of the general condition (n = 72; 37.1%), long-term fever (n = 56; 28.9%), chronic cough (n = 40; 20.6%). The patients were at WHO stage 3 (n = 133; 68.6%). The mean CD4 were 188.5 ± 11.7 / mm3 [19-433]. In 172 cases (88.7%), the patients had two sexual partners and did not use a condom (n = 189; 97.4%). The main opportunistic infections were tuberculosis (n = 74; 18.1%) and cerebral toxoplasmosis (n = 48; 24.7%). ART was made with the combination of TDF + FTC + EFV (n = 79; 40.7%). The observation was poor in 33% (n = 64) and unfavourable outcome in 47.4% (n = 92). These were IRIS (n = 5; 2.6%) and death (n = 85; 43.8%), due to anaemic shock (n = 17; 20%), septic shock (n = 8; 9.4%). Marital status (P = 0.04), WHO stage (p = 0.02), and non-compliance treatment (p = 0.0001) could have the link with the death patients. Conclusion: HIV infection in people over 50 years is relatively common at Brazzaville University Hospital, especially among single women. The lethality remains high, unrelated to an opportunistic infection but rather with the notion of non-compliance with treatment and the advanced stage of HIV infection according to the WHO classification. This shows the interest in raising awareness among this population for early detection and the treatment of HIV.

Efficacy of different nucleoside analog rescue therapies for entecavir-resistant chronic hepatitis B patients

BackgroundEntecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue.MethodsPatients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups.ResultsThe rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups.ConclusionsTDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.

Tenofovir plus entecavir combination therapy for chronic hepatitis B with nucleos(t)ide analogue failure

Objectives: Currently, both entecavir (ETV) and tenofovir (TDF) are recommended first-line therapy for chronic hepatitis B treatment due to good tolerance, lower side-effect profile and high genetic barrier. However, mutations that may develop in the polymerase gene during treatment may result treatment failure. In this study, we aimed to evaluate the efficacy and virologic response of ETV plus TDF combination therapy in chronic hepatitis B patients with suboptimal response to nucleos(t)ide analogues (NAs) monotherapy. Methods: A total of 813 patients who were followed-up with the diagnosis of chronic hepatitis B and who were treated with TDF or ETV monotherapy were screened. Patients who had a partial or non response to monotherapy during at least 12 months and who was the presence of serum HBV-DNA levels ≥ 2000 IU/mL at the time of initiation of the ETV plus TDF combination therapy were included. Results: Ten (1.2%) patients (9 TDF, 1 ETV) were identified to have had partial response (50%) or breaktrough (40%) or virologic rebound (10%) to monotherapy. The median age was 36.8 years (range, 22-55 years), and 5/10 (50%) patients were male. Of 10 patients, nine of achieved undetectable HBV-DNA (< 15 IU/mL) levels (50% of in 6 months and 90% of in 18 months) with combination therapy. One patient showed no response. Conclusions: Our results suggest that combination therapy is superior to the antiviral change in treatment failure with NAs. In addition, it is important to conduct HBV drug resistance analyzes to prevent false drug change in treatment.

Hepatitis B virus seromarkers among HIV infected adults on ART: An unmet need for HBV screening in eastern Ethiopia.

Progression of chronic HBV to cirrhosis, end-stage liver disease (ESLD), and hepatocellular carcinoma (HCC) is more rapid in HIV positive individuals than those with HBV alone; however, the distribution of HBV seromarkers in HIV infected individuals on antiretroviral therapy (ART) is not well described. To address this problem, we assessed the distribution of hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) and hepatitis B surface antibody (anti-HBs) among HIV infected adults on ART in Eastern Ethiopia. A cross-sectional study was conducted from September 2017 to February 2018. Socio-demographic, behavioral and health related factors, and clinical data were collected using questionnaire and checklist. Plasma samples were tested for HBsAg, anti-HBc and anti-HBs seromarkers using ELISA. Data were double entered into EpiData 3.1, cleaned, exported to and analyzed using STATA 13. Descriptive and logistic regression analysis were conducted and statistical significance was decided at p≤0.05. A total of 901 participants were included and the prevalence of HBsAg was found to be 11.7% [95%CI (10, 14)]. Among the co-infected, 47.6% were also positive for anti-HBc, of which 58% were on an ART containing tenofovir (TDF). Among those screened for the three seromarkers, 38.1% were negative for all and 21% were positive only for anti-HBc (IAHBc). Being single, history of genital discharge and taking ART with TDF combination were significantly associated with HBV co-infection (p≤0.05). There is high burden HBV co-infection among individuals on ART. The unmet need of HBV screening prior to ART initiation leaves many co-infected individuals without appropriate management including therapy, close monitoring or vaccination when indicated, impacting disease prevention.

Tenofovir and telbivudine combination therapy rapidly decreases viral loads in immune-tolerant chronic hepatitis B patients awaiting assisted reproduction: an open-label, randomized, controlled study.

Immune-tolerant chronic hepatitis B (CHB) patients awaiting assisted reproduction (AR) are required to initiate antiviral therapy because of laboratory safety concerns. The antiviral therapy in this group has not been well assessed. We sought to explore the efficacy and safety of the combination therapy (COM) of tenofovir (TDF) and telbivudine (LdT). In this open-label, randomized, controlled study, we enrolled and randomized hepatitis B virus e-antigen (HBeAg)-positive CHB patients awaiting AR into the study COM group and the control (TDF) group. The COM group received combination therapy of TDF and LdT, and the TDF group received a single treatment of TDF. The patients were followed up for at least 48 weeks. The primary endpoint was the proportion of patients with undetectable HBV DNA level at week 12. A total of 121 patients were recruited into the COM group (n=60) and the TDF group (n=61). The percentages of patients with undetectable HBV DNA levels were 90.0% (54/60) in the COM group and 67.2% (41/61) (P=0.002) in the TDF group at week 12; the percentages were 96.6% (58/60) in the COM group and 85.2% (52/61) in the TDF group at week 48 (P=0.028), respectively. HBeAg seroconversion occurred in 5/60 (8.3%) patients in the COM group and 2/61 (3.3%) patients in the TDF group at week 48 (P=0.233). TDF and LdT combination therapy shows a rapid antivirological response in immune-tolerant CHB patients awaiting AR, which provide an alternative for this group at AR centers. However, the HBeAg seroconversion rate is unsatisfactory in the short term.

Hepatitis B virus coinfection is associated with high early mortality in HIV-infected Tanzanians on antiretroviral therapy

There is limited data on the effect of antiviral therapies on clinical outcomes in HIV and hepatitis B virus (HBV)-infected individuals in sub-Saharan Africa. Single center, prospective longitudinal cohort study at Management and Development for Health supported HIV Care and Treatment clinics in Dar es Salaam, Tanzania. Between April 2014 and December 2015, HIV-infected, HBV-infected and HIV/HBV-coinfected, treatment naïve, Tanzanian adults more than 18 years of age were eligible for enrollment and followed for 10-18 months after initiating antivirals. All HIV-infected and HIV/HBV-coinfected participants received tenofovir, lamivudine and efavirenz; HBV-infected participants received lamivudine. Multivariate regression models were constructed to identify factors associated with mortality in HIV-infected and HIV/HBV-coinfected participants. A total of 265 HIV-infected, 165 HBV-infected and 64 HIV/HBV-coinfected participants were analyzed. At baseline, HBV-infected participants were younger and had a higher BMI than HIV-infected and HIV/HBV-coinfected participants. After a median of 371 (interquartile range 50) days on treatment, there were 40 deaths. Mortality was significantly higher among HIV/HBV-coinfected participants compared with HIV and HBV-infected participants [HIV/HBV-coinfected 12 of 64 (19%) vs. HIV-infected 26 of 265 (10%) and HBV-infected two of 265 (1%), P < 0.01]. High baseline HIV RNA and low hemoglobin levels, but not HBV coinfection were independently associated with early mortality in multivariate analyses of HIV-infected participants. High rates of early mortality were observed after treatment initiation in HIV/HBV-coinfected individuals compared with participants with HIV or HBV alone, despite robust aspartate aminotransferase to platelet ratio index declines and high rates of virologic suppression. HIV rather than HBV-related factors are more important contributors to mortality in these individuals.

Profile Of Antiretroviral Side Effects On Hiv In Rspi Prof. Dr. Sulianti Saroso Jakarta

Symptoms of Acquired Immuno Deficiency Syindrome (AIDS) is a militia or disease caused by me infection of Human Immunodeficiency immune deficiency due to Antiretroviral. Due to Virus (HIV). The therapy used is a drug that the use of Antretroviral is the appearance of unwanted reactions or side effects will appear. The objectives of the study were to analyze the side effects of antiretroviral therapy in HIV / AIDS patients in RSPI Sulianti Saroso, North Jakarta, January-June 2016 period. The sample was 95 patients. The research was done by retrospective method, data analysis desknptif data presented in tabular form and presented with pie chart. The result of the research is the combination of TDF + 3TC + Efavirenz Tenofovir-Lamivudin-Efavirenz) as much as 73,68% (0 person). There were 94.73% (90 people had mild adverse reactions and 5.27% (5 people) severe side effects.

Antiretroviral therapy as a risk factor for chronic kidney disease: Results from traditional regression modeling and causal approach in a large observational study.

ObjectiveWe investigated whether patients receiving selected antiretroviral combinations had a higher risk of chronic kidney disease (CKD) using traditional regression modeling and a causal approach in a large prospective cohort.Patients and methodsFor the purpose of this study, we selected 6301 patients who (i) started their first antiretroviral regimen after 1st January 2004, (ii) had at least one serum creatinine measurement within 6 months before ART initiation (study entry), and (iii) had at least two measurements after study entry. Baseline eGFR was defined from the last serum creatinine measurement before study entry. All eGFR values were calculated using the Modification of Diet and Renal Disease (MDRD) equation. Both traditional Cox proportional hazards model and Cox marginal structural models were applied. Distinct coding for antiretroviral therapy exposure were investigated as well as double robust estimators.ResultsOverall we showed that patients receiving tenofovir (TDF) with a ritonavir boosted protease inhibitor (rbPI) exhibited a higher risk of CKD compared with patients who received TDF with a non-nucleosidic reverse transcriptase inhibitor (NNRTI). Such an increased risk was observed considering both initial and current regimens. Our analysis revealed a clinician-driven switch away from TDF among persons experiencing a decline in renal function while receiving this drug.ConclusionOur results show that combination of TDF and boosted protease inhibitor is associated with a higher CKD risk than TDF and a NNRTI.

Baseline HBsAg and HBcrAg titres allow peginterferon-based 'precision medicine' in HBeAg-negative chronic hepatitis B patients.

Quantitative hepatitis B core-related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon-alpha-2a (PegIFN)-based therapy. Sixty-two HBeAg-negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut-offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log10 IU/mL and 3.450 log10 U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post-treatment follow-up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI [0.578, 0.855]) for HBsAg and 0.668 (95% CI [0.524, 0.811]) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590-0.947), 0.714(0.533-1.000) and 0.800(0.611-1.000), and NPVs for AUCs(95%CI) were 0.756(0.660-0.899), 0.718(0.630-0.857) and 0.765(0.675-0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log10 IU/mL and qHBcrAg 3.450 log10 U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN-based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN-based 'precision therapy'. Our results emphasize that the combination of PegIFN alpha-2a plus TDF with 53% of SR might be an alternative to finite therapy.

Toxicological Impact of Co-treatment with Rifampicin and Tenofovir on the Renal Function of Male Albino Rats

This experimental study comparatively evaluated the toxicological effects of treatment with tenofovir, rifampicin and tenofovir- rifampicin (TDF-RIF) combination on kidney function and histology of male albino rats. Male albino rats used in this study were divided into five (5) groups A-E of sixteen (16) animals each. Animals in group A, (placebo control) were treated orally with normal saline, group B (solvent control) were treated orally with 0.1% ethanol while groups C-E were treated orally with 80 mg/kg of RIF, 32 mg/kg of TDF and a combination of TDF- RIF for 2-8 weeks respectively. Animals were sacrificed at the end of drug therapy, blood sample was collected, centrifuged and serum extracted for creatinine, urea and, uric acid evaluation. Kidney was harvested, weighed and examined for histopathological changes. Treatment with tenofovir-rifampicin combination had no significant (p 0.05) time-dependent increases in serum creatinine, urea and uric acid levels were observed in animals treated with tenofovir-rifampicin combination when compared with treatment using individual doses of these drugs . Acute tubular necrosis, enlarged glomeruli and obliteration of the Bowman's capsule were observed in the kidneys of rats treated with tenofovir, rifampicin and a combination of tenofovir-rifampicin. This result shows that treatment with tenofovir-rifampicin combination in the management of human immunodeficiency virus /tuberculosis (HIV/TB) co-infection may not be associated with synergistic renal toxicity at the dose level used in this study.

Comparative Meta-Analysis of Tenofovir Disoproxil Fumarate versus Emtricitabine and Tenofovir Disoproxil Fumarate as Treatments for Patients with Chronic Hepatitis B

Tenofovir disoproxil fumarate (TDF) monotherapy has proven superior antiviral efficacy in chronic hepatitis B (CHB) patients; however, whether the combination of TDF and emtricitabine (FTC) exerts a significant advantage remains controversial. A meta-analysis was performed to comprehensively compare the therapeutic effects of FTC/TDF combination with TDF alone in CHB patients. Five studies involving 614 patients were identified, and subgroup analysis was performed based on the nucleos(t)ide treatment history. Our results revealed that in patients with nucleos(t)ide-naïve treatment, there were no significant differences between the treatment groups with TDF alone and FTC/TDF combination after 12 and 24 weeks; however, the FTC/TDF combination showed better viral suppression efficacy versus TDF alone after 48 (OR = 2.16, 95% CI = 1.06–4.41, P = 0.03), 96 (OR = 2.76, 95% CI = 1.29–5.92, P = 0.009) and 192 weeks (OR = 2.60, 95% CI = 1.21–5.56, P = 0.01). In patients with nucleos(t)ide treatment history, no differences were noted between the two treatment groups after 12, 24, 48 and 96 weeks. Our results indicated that FTC/TDF combination showed better viral suppression efficacy versus TDF alone in CHB patients with nucleos(t)ide-naïve treatment, while both treatments provided similar viral suppression efficacy in CHB patients with nucleos(t)ide treatment history.

Tenofovir-based rescue therapy in chronic hepatitis B patients with suboptimal responses to adefovir with prior lamivudine resistance.

We evaluated the efficacy of tenofovir (TDF)-based rescue therapy and compared the outcomes of TDF monotherapy and TDF-based nucleoside analog (NA) combination therapy in patients with suboptimal response (SOR) to adefovir (ADV) with or without NAs in lamivudine (LAM)-resistant chronic hepatitis B. All study subjects received ADV with or without NAs due to prior LAM resistance, and were then switched to TDF-based rescue therapy due to SOR (hepatitis B virus DNA >20 IU/ml after at least 6 months of therapy). A total of 125 patients were eligible. The overall cumulative proportion of complete virologic response (CVR) was 64 of 74 patients (86.5%) at 48 weeks of treatment. During the follow-up period of 48 weeks, there was no significant difference in CVR rate (P = 0.750) between the TDF monotherapy (n = 18) and the TDF with NA groups (n = 107). Patients with ADV genotypic mutations showed inferior antiviral responses to TDF compared with the patients without ADV genotypic mutations, but this was not statistically significant (P = 0.069). Partial virological response to prior ADV therapy showed higher CVR rates compared to patients with non-response at 12 weeks (P = 0.013), but there was no significant difference after 24 (P = 0.076) and 48 weeks (P = 0.198) of treatment. TDF monotherapy is as effective as TDF plus NA combination therapy in patients with SOR to ADV-based rescue therapy and LAM resistance. TDF, with or without NAs, was effective even in cases of ADV resistance.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial

ObjectiveLittle clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV.DesignIn this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL...

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial

ObjectiveLittle clinical data are available regarding the optimal treatment of patients who harbour entecavir (ETV)-resistant HBV.DesignIn this multicentre randomised trial, patients who had HBV with ETV resistance-associated mutations and serum...

Effects of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen-Positive Patients With Normal Levels of Alanine Aminotransferase and High Levels of Hepatitis B Virus DNA

Little is known about the benefit of antiviral therapy for hepatitis B e antigen (HBeAg)-positive patients with high viral load and normal levels of alanine aminotransferase. We evaluated the effects of single and combination therapies in immune-tolerant patients with chronic hepatitis B. In a double-blind study, nucleos(t)ide-naïve patients with high levels of hepatitis B virus (HBV) DNA who were positive for HBeAg and had normal levels of alanine aminotransferase were randomly assigned to groups given either oral tenofovir disoproxil fumarate (TDF, 300 mg) and placebo (n = 64) or a combination of TDF (300 mg) and emtricitabine (200 mg, n = 62) for 192 weeks. The primary end point was proportion of patients with serum levels of HBV DNA <69 IU/mL at week 192. The study population (mean age was 33 years; 89% were Asian) was predominantly infected with HBV genotypes B and C (93%), 99% were HBeAg positive with a mean baseline level of HBV DNA of 8.41 log10 IU/mL. At week 192, 55% of patients (35 of 64) in the TDF+placebo group and 76% of patients (47 of 62) in the TDF+emtricitabine group had levels of HBV DNA <69 IU/mL (P = .016). No patients were found to have viral resistance to therapy. HBeAg seroconversion occurred in 3 patients (5%), all in the TDF+placebo group; no patient had loss of hepatitis B surface antigen. In multivariate analysis, female sex (odds ratio = 7.05; P = .002) and TDF+emtricitabine treatment (odds ratio = 3.9; P = .01) were associated with a favorable response. Both regimens were well tolerated. In HBeAg-positive patients with chronic HBV infection, high viral loads, normal levels of alanine aminotransferase, and therapy with the combination of TDF and emtricitabine provided better viral suppression than TDF alone, although rates of HBeAg seroconversion and hepatitis B surface antigen loss were low.

Maintenance of Complete Viral Suppression (CVS) with Tenofovir (TDF) Monotherapy Following CVS with Entecavir (ETV)+TDF Combination in Patients with Prior ETV Partial Response

Purpose: Recent studies indicated that ETV partial responders (PR) can attain CVS with ETV+TDF combination therapy. However, it is not clear if ETV PR can continue to maintain CVS after achieving CVS with combination therapy. Our goal was to examine virologic outcomes of ETV PR treated with ETV or TDF monotherapy following CVS with combination therapy. Methods: We retrospectively studied 57 consecutive patients with ETV PR who subsequently achieved CVS (undetectable HBV DNA PCR) with ETV+TDF combination therapy at 3 U.S. liver clinics. Patients with confirmed antiviral resistance were excluded. HBV polymerase mutation analysis was performed in all patients prior to initiation of combination therapy. Virologic breakthrough was defined as an increase of HBV DNA by ≥1 log IU/mL from nadir. Results: The majority of patients were Asian (96%), male (65%) and HBeAg-positive (95%) with a median age of 38 (22-67) years. A few patients (28%) had previous exposure to lamivudine (16%) or adefovir (19%) prior to initial ETV monotherapy. All patients achieved CVS with ETV+TDF combination after a median of 5 (2-26) months. Following CVS with combination therapy, 13 patients were switched to ETV monotherapy and 20 patients were switched to TDF monotherapy, while 24 patients remained on combination therapy. Cumulative incidence of virologic breakthrough was significantly higher in patients who returned to ETV monotherapy at 6 months (69% vs. 41%, p<0.0001) and 12 months (92% vs. 54%, p<0.0001) compared to patients who switched to TDF monotherapy (Figure 1). Five patients (21%) experienced virologic breakthrough while continuing on combination therapy. Four patients achieved CVS again, suggesting possible medication nonadherence. The other patient admitted to being nonadherent at time of virologic breakthrough.Figure 1: Incidence of cumulative virologic breakthrough with monotherapy following complete viral suppression with ETV and TDF combination therapy.Conclusion: For patients with prior PR to ETV but achieved CVS with combination therapy, TDF monotherapy may be a reasonable option in half of the patients. The economic savings and convenience advantage can be considerable for those who can maintain CVS solely on TDF monotherapy instead of combination therapy. Nonadherence also appears to be a significant issue with combination therapy. Disclosure: Kevin T. Chaung - No financial relationship with a commercial interest; Nghiem B. Ha - No financial relationship with a commercial interest; Kevin C. Kin - No financial relationship with a commercial interest; Huy Trinh - Consultant: Bristol-Myers Squibb, Grant/Research Support: Gilead Sciences Inc., Roche, Stockholder/Ownership Interest: Gilead Sciences Inc., Bristol-Myers Squibb, Advisory Committee/Board Member: Bristol-Myers Squibb, Gilead Sciences Inc.; Huy Nguyen - Speaker's Bureau: Gilead Sciences Inc.; Mindie Nguyen - Consultant: Bristol-Myers Squibb, Gilead Sciences Inc., Bayer, Grant/Research Support: Bristol-Myers Squibb, Novartis Pharmaceuticals, Gilead Sciences Inc.; Roche, Gilead Sciences Inc.

Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

BackgroundHumanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient.Methods/Principal FindingsNOD/shi-scid/γcnull (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir.Conclusions/SignificanceThis report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.

Pre-exposure chemoprophylaxis of HIV infection: Quo vadis?

The pre-exposure chemoprophylaxis (now commonly referred to as PrEP) of HIV infection has gained increased momentum, concomitantly with the successful use of combination drug regimens for the treatment of AIDS. A pivotal component in the current drug combination regimens for the treatment of AIDS as well as the ongoing PrEP trials is tenofovir disoproxil fumarate (TDF, Viread ®) and its combination with emtricitabine (FTC). The combination of TDF with FTC has been marketed as Truvada ®. TDF and TDF/FTC has proven effective, if orally administered daily or intermittently, in the prevention of rectal simian human immunodeficiency virus (SHIV) infection in macaques. Topical tenofovir gel has proven effective in the prevention of HIV infection in women in South Africa. Oral TDF/FTC has proven effective in the prevention of HIV infection in men having sex with men, and recent press releases divulged that oral TDF/FTC is also effective in preventing HIV infection in serodiscordant couples in Botswana, Kenya and Uganda. Other PrEP studies are still ongoing. Available data point to the efficacy and safety of TDF with or without FTC in the prophylaxis of HIV infection (AIDS).