Nucleoside Combination Research Articles

Strategies for managing coinfection with hepatitis B virus and HIV

Hepatitis B virus (HBV) infection is more aggressive in individuals coinfected with human immunodeficiency virus (HIV): in the presence of HIV, HBV carrier rates and viremia levels are higher, episodes of activation are more frequent, cirrhosis progresses more quickly, and hepatocellular carcinoma occurs more often than with HBV infection alone. As in HBV monotherapy, the objective of treatment is suppression of viral replication. Standard or pegylated interferon may be appropriate treatment for chronic HBV infection for patients who have not yet started highly active antiretroviral therapy (HAART) for their HIV. When treatment is required for both diseases, the use of a combination of nucleoside and nucleotide analogues is prudent, with careful selection of therapy to reduce the risk of antiviral resistance--a particular concern for patients receiving antiretroviral therapy for both HIV and HBV. HBV DNA levels should be monitored every 3 months; the frequency can be extended to every 6 months once the viral load becomes stable or undetectable.

Management of Hepatitis B in the peri-transplant period

Hepatitis B virus (HBV) infection is an important indication for liver transplantation worldwide. The most important concern is the prevention of viral recurrence in the post transplant period. With the introduction of Hepatitis B immunoglobulin, there has been a significance reduction in the rate of HBV recurrence with improved patient & graft survival rates. The combination of oral nucleosides along with Hepatitis B immunoglobulin has further reduced the rate of HBV recurrence, and currently the outcome of liver transplantation for HBV infection is comparable to other indications for liver transplantation.

Eficacia de atazanavir en pacientes naïve

The characteristics of atazanavir (convenient doses, good tolerance, and excellent lipid profile) makes it an attractive drug to be included in initial regimes. Clinical trials have been performed on patients with no previous antiretroviral treatment, either atazanavir without boost (400 mg once per day) or atazanavir boosted with ritonavir (400/100 mg). Although atazanavir without boost is effective, there is a tendency for a higher number of failures and a higher development of resistant mutations than in patients who fail with boosted atazanavir. Therefore, it is recommended to use boosted atazanavir in patients that start on treatment. In clinical studies, boosted atazanavir can be used with any nucleoside analogue. No pharmacokinetic or pharmacodynamic interaction problems have been detected with the two nucleoside combinations at fixed doses (tenofovir/FTC, abacavir/3TC). Randomised clinical studies have been carried out that compared atazanavir with other boosted protease inhibitors. In the comparative study with lopinavir/ritonavir administered two times a day, atazanavir/ritonavir once per day demonstrated noninferiority, with a similar efficacy regardless of the patient baseline viral load. The atazanavir/ritonavir virological efficacy did not appear to be affected by the baseline immunological status of the patients, which did influence the lopinavir/ritonavir response. Atazanavir/ritonavir is a useful drug combination in the initial treatment of HIV infected adult patients. Its increased virological and immunological efficacy, together with its ease of administration, good tolerance and excellent lipid profile makes it a PI of choice in these patients.

Chemoimmuno-Therapy with Fludarabine, Cyclophosphamide and Alemtuzumab in Patients with Relapsed/Refractory CLL: Interim Analysis of the CLL2L Trial of the German CLL Study Group

Introduction: Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. As alemtuzumab has proven to be the most effective antibody in CLL treatment, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly scheduleMethods: Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 – 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals.Results: A total of 55 patients of a planned sample size of 61 patients were included in this phase-II study so far, of which 24 patients are evaluable for response and safety analysis. Median age is 63 (range 47–78) years with a medium number of 1 prior regimen; 19/24 patients completed at least four cycles with a median number of 5 cycles. Pretreatment consisted of fludarabine (8/24), fludarabine and cyclophosphamide (13/24) or rituximab combinations (3/24). Thrombocytopenia and neutropenia were the most serious side effects and detailed data will be presented. 3 CMV-reactivations, 1 Herpes-zoster-reactivation and 12 fever of unknown origin have been reported. The overall response rate was 83% with 9 CR(6 CRu) (38%), 9 PR (46%), 3 SD and 1 PD, response was independent of FISH status. A correlation of response with prior treatment was observed, with 100% ORR for fludarabine pre-treatment versus only 77% for those patients pretreated with fludarabine and cyclophosphamide. Updated data of 30 patients and MRD data will be presented.Conclusions: The concomitant application of fludarabine, cyclophosphamide and alemtuzumab appears as a safe and effective approach for patients with relapsed CLL.

Treatment of patients with relapsed/refractory CLL using a combination of fludarabine, cyclophosphamide and alemtuzumab: First safety analysis of the CLL2L trial of the German CLL Study Group

7053 Background: Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. As alemtuzumab has proven to be the most effective antibody in CLL treatment, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly schedule. Methods: Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 - 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals. Results: A total of 39 patients of a planned sample size of 61 patients were included in this phase-II study so far, of which 20 patients are evaluable for response and safety analysis. Median age is 64 (range 48–78) years with a medium number of 1 prior regimen; 14/20 patients completed at least four cycles with a median number of 4.5cycles. Pretreatment consisted of fludarabine (8/20), fludarabine and cyclophosphamide (12/20) or rituximab combination (1/20). Thrombocytopenia and neutropenia were the most serious side effects and detailed data will be presented. 2 CMV-reactivations, 1 Herpes-zoster-reactivation and 12 fever of unknown origin have been reported. The overall response rate was 70% with 5 CR (25%), 9 PR (45%), 2 SD and 2 PD. All complete responders became MRD negative in peripheral blood or bone marrow; response was independent of FISH status. A correlation of response with prior treatment was observed, with 88% ORR for fludarabine pre-treatment versus only 65% for those patients pretreated with fludarabine and cyclophosphamide. Conclusions: The concomitant application of fludarabine, cyclophosphamide and alemtuzumab appears as a safe and effective approach for patients with relapsed CLL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Schering AG, Schering AG Schering AG

Long-term safety and efficacy of nevirapine (NVP)-based antiretroviral therapies

of results 229 patients (pts) were included. Mean age was 37 years. Most pts (54%) were former intravenous drug users. 135 individuals were co-infected with HCV. Median time on NVP was 72.6 months. The main reasons to use NVP were: second or third-line therapy (40%), simplification (30%), first-line therapy (19%), and efavirenz intolerance (10%). Combinations of nucleosides most widely used were: ABC+3TC (25%), AZT+3TC (23%) and TDF+3TC (14%). HDL-cholesterol and GGT increased from baseline to >4year timepoint (48 mg/dl to 62 mg/dl and 58 U/l to 145 U/l, respectively). LDL-cholesterol, triglycerides and alkaline phosphatase showed decreasing values at follow-up (135 mg/dl to 109 mg/dl, 216 to 153 mg/dl, and 177 to 92, respectively). Total cholesterol and liver function tests had no significant changes. CD4 cell counts increased from 439/mm3 at baseline to 628/mm3 at the last available visit. 172 out of 184 pts who remained on NVP-based therapy at last visit maintained viral load values below limit of detection. NVP was stopped or withdrawn in 43 patients due to virological failure (13 pts), toxicity (five pts), virological resistance (four pts), therapy interruption (three pts), death (two pts), dyslipidemia (one pt), simplification (one pt) or unknown reasons (14 pts). Adverse events were reported in 40 patients but none was directly attributed to NVP. The reported follow-up pattern of laboratory tests was also found in the subset of HCV coinfected patients by comparing men and women and stratifying patients with a CD4 cell count cut-off value of 250/mm3.

Nursing Guidelines for Managing Infections in Patients With Chronic Lymphocytic Leukemia

Infections are a primary cause of death in patients with chronic lymphocytic leukemia (CLL). Such individuals are particularly susceptible to infectious complications stemming from immune deficits associated with the primary disease process and with immunosuppression secondary to treatment. Although the recent availability of new treatment modalities and more aggressive therapies are improving outcomes for patients with CLL, standardized approaches are needed so that nurses can monitor for and manage infections. The aim is overall reduction in morbidity and mortality, as well as improvement in quality of life. The current pharmacologic therapies for CLL are alkylating agents, purine nucleoside analogs, monoclonal antibodies, and combinations of those therapies, which may present their own unique risks for and different spectra of infectious events. This article provides an overview of the known risks for developing infections in CLL, as well as nursing guidelines for monitoring and managing patients with CLL.

Early Results of Pentostatin, Cytoxan, Rituximab (PCR) Followed by CAMPATH-H (CA) for the Treatment of Relapse/Refractory Chronic Lymphocytic Leukemia (CLL) in ECOG Protocol E2903.

Purine nucleoside combination therapy, with and without immunotherapy has become the standard treatment approach to CLL. Past approaches, other than stem cell transplantation, have not been successful in curing the disease. Inherent resistance of CLL precursors, impaired immune surveillance (T-cells, NK cells) and microenvironmental abnormalities may all play a role in the ability to effectively eradicate leukemia. PCR has been successfully employed for previously treated (Lamanna 2006) and previously untreated (Kay 2007) patients with CLL. In addition, CA has been added to FCR (Wierda 2006) to treat relapsed/refractory CLL disease. We designed a study to evaluate PCR followed by CA for relapsed/refractory CLL. This ECOG study includes, in addition to response criteria, molecular correlates (FISH anomalies and CpG karyotype), risk parameters analysis, including CD38, ZAP-70 and IgVH mutational status. We assessed the baseline and sequential changes in the angiogenic status of patients by measuring plasma VEGF, bFGF, thrombospondin and their immune status via T-cell repertoire. From September 2004 to September 2006, 32 patients with relapsed/refractory CLL were enrolled in the protocol. The protocol combined 2 regimens (PCR and CA). Step 1, PCR, was planned for 6 monthly cycles. Steps 2 and 3 consisted of short term CA (4 weeks) or standard CA (18 weeks) depending upon Step 1 response. There were 3 ineligible, 1 not evaluated, and 28 evaluable patients. FISH anomalies revealed that 8 patients had a homozygous or heterozygous 13q-defect, 9 had complex FISH defects (more than one FISH anomaly), 5 patients had FISH anomalies that included del(17p13.1), 4 patients had FISH anomalies that included 6q-and 3 had FISH anomalies that included 11q-. CD38 was positive in 10 patients, 11 were ZAP-70 positive and 12 of 19 patients tested had unmutated type clones. The planned 6 cycles of Step 1 (PCR) was administered to 14/32 patients (44%), the others receiving 0–5 cycles. All responses were considered partial responses (11/29; 37.9%), with 2 patients (6.9%) demonstrating progressive disease. However, patients receiving the planned 6 cycles of PCR, achieved a partial response of 71% (10/14) with 2 cases of tumor lysis syndrome. Toxicity (Step 1-PCR) was predominately myelosuppressive (Grade 1–4). A case of chronic idiopathic polyneuropathy and a case of “paraneoplastic pemphigus” were reported. There were 4 deaths. CMV reactivation was diagnosed in 2 patients, neither of which was fatal. During Step 2 (CA), short-term administration in one patient led to grade 3 skin toxicity, which limited administration. During long-term administration of CA (PR, PD, SD) (n=7), infectious complications occurred in 6 patients all of whom developed grade 4 lymphopenia. The median survival for the entire group was 15 months. In conclusion, a significant number of heavily pre-treated and poor prognosis patients with CLL will respond to PCR. Further analysis will determine whether a significant number of patients will achieve a higher level of response and longer survival after CA administration. Studies of association of outcome with the risk parameters are ongoing and will be presented with the clinical response data.

La transplantation hépatique chez les patients co-infectés VIH/VHC et VIH/VHB

Human immunodeficiency virus infection (HIV) has been considered until recently as a contraindication for liver transplantation. This was due to the poor spontaneous prognosis of HIV infection. The advent of highly active antiretroviral drugs (HAART) was a therapeutic breakthrough, and the prognosis has been dramatically improved. 30 % and 10 % of HIV infected patients are coinfected with hepatitis C virus (HCV) and with hepatitis B virus (HBV), respectively. The progression of chronic hepatitis B and C seems more rapid in coinfected patients, and a high number of patients will develop life-threatening liver cirrhosis. There are numerous potential problems raised by liver transplantation in HIV infected patients: (1) the potential risk of needlestick injury during this type of hemorrhagic surgery at high risk of bleeding; (2) the timing for liver transplantation; (3) the risk of interference between HAART and calcineurin inhibitors; (4) The risk of HBV and HCV recurrence post-transplant. Since 1999, a program of liver transplantation has been started in patients coinfected with HIV and HBV or HCV with the support of the Agence Nationale de Recherche contre le Sida et les Hépatites virales (ANRS). The first results showed that liver transplantation in HIV-HCV and HIV-HBV infected patients is feasible, achieving 2-year survival of 70 % and 100 %, respectively. There was no acceleration of HIV disease after transplantation. HBV recurrence was well prevented by the combination of anti-HBs immunoglobulins plus nucleoside and nucleotide analogues effective against HBV. The main problem is HCV recurrence, which is more rapid and more severe in HIV coinfected patients than in HCV monoinfected patients. Understanding HCV recurrence mechanisms, and preventing and treating of HCV recurrence are major future challenges.

Evolution of a novel 5-amino-acid insertion in the β3–β4 loop of HIV-1 reverse transcriptase

HIV-1 isolates harbouring an insertion in the β3–β4 loop of reverse transcriptase (RT) confer high-level resistance to nucleoside analogues. We have identified a novel 5-amino-acid insertion (KGSNR amino acids 66–70) in a patient on prolonged nucleoside combination therapy (didanosine and stavudine) and investigated which factors were responsible for its outgrowth. Remarkably, only small fold increases in drug resistance to nucleoside analogues were observed compared to wild type. The insertion variant displayed a reduced replicative capacity in the absence of inhibitor, but had a slight replicative advantage in the presence of zidovudine, didanosine or stavudine, resulting in the selection and persistence of this insertion in vivo. Mathematical analyses of longitudinal samples indicated a 2% in vivo fitness advantage for the insertion variant compared to the initial viral population. The novel RT insertion variant conferring low levels of resistance was able to evolve towards a high-level resistant replication-competent variant.

Paradoxical CD4+ T-Cell Decline in HIV-Infected Patients With Complete Virus Suppression Taking Tenofovir and Didanosine

Purpose of the Study. Tenofovir and didanosine are adenosine analogs commonly used in highly active antiretroviral therapy combinations. Although virologically effective, this combination is theoretically associated with pharmacokinetic interactions and increased risks of pancreatitis and hyperglycemia. The study examined the CD4+ T-cell effects of the use of these 2 drugs as part of a highly active antiretroviral therapy regimen. Methods. Data from 570 individuals were analyzed retrospectively according to the nucleoside analog “backbone” of protease inhibitor–containing regimens: tenofovir + didanosine in 298 subjects, didanosine in 88, tenofovir in 44, and neither didanosine nor tenofovir in 140. Results. Significant CD4+ T-cell declines were noted in patients taking the combination of tenofovir + didanosine relative to all other nucleoside analog combinations including didanosine or tenofovir only. Patients exposed to higher didanosine doses showed a more pronounced CD4+ T-cell decline, and plasma levels of didanosine correlated with the extent of T-cell loss. Conclusions. Although patients receiving tenofovir + didanosine–based combinations generally achieved excellent viral suppression, their CD4+ T cells often paradoxically declined. This effect generally progressed over time. It is hypothesized that the use of these 2 agents together results in a condition that metabolically resembles purine nucleoside phosphorylase deficiency, a rare but well-described primary immunodeficiency syndrome. Reviewer Comments. Tenofovir and didanosine frequently are the only nucleoside analog agents available to patients with drug-resistant virus. This combination with either a nonnucleoside reverse transcriptase inhibitor or a protease inhibitor is often effective in suppressing virus in patients with limited options. However, the paradoxical decline in T-cell numbers is of great concern. Patients on this regimen must be monitored carefully for this potential complication.

Relative replication fitness of efavirenz-resistant mutants of HIV-1: Correlation with frequency during clinical therapy and evidence of compensation for the reduced fitness of K103N + L100I by the nucleoside resistance mutation L74V

Efavirenz resistance during HIV-1 treatment failure is usually associated with the reverse transcriptase mutation K103N. L100I, V108I, or P225H can emerge after K103N and increase its level of efavirenz resistance. K103N + L100I is the most drug-resistant of the double mutants but is the least common clinically. We hypothesized that differences in replication efficiency, or fitness, influence the relative frequencies of these secondary efavirenz resistance mutations in clinical isolates. We measured fitness of each secondary mutant introduced into HIV NL4-3, alone and in combination with K103N, using growth competition assays in H9 cells. In the absence of efavirenz, the fitness of V108I was indistinguishable from wild type. K103N, L100I, and P225H were minimally, but consistently, less fit than wild type. K103N + L100I had a greater reduction in fitness and was less fit than K103N + V108I and K103N + P225H. The fitness defect of K103N + L100I relative to K103N was completely compensated for by the addition of the nucleoside resistance mutation L74V. In the presence of efavirenz, L100I was less fit than K103N, and K103N + L100I was more fit than K103N + V108I . Our studies suggest the primary driving force behind the selection of secondary efavirenz resistance mutations is the acquisition of higher levels of drug resistance, but the specific secondary mutations to emerge are those with the least cost in terms of replication efficiency. In addition, nucleoside and NNRTI resistance mutations can interact to affect HIV replication efficiency; these interactions may influence which mutations emerge during treatment failure. These studies have important implications for the design of more durable NNRTI–nucleoside combination regimens.

Review article: hepatitis B and liver transplantation

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re-infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome. The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re-infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so-called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission). Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.

Indinavir/ritonavir 800/100 mg bid and efavirenz 600 mg qd in patients failing treatment with combination nucleoside reverse transcriptase inhibitors: 96‐week outcomes of HIV‐NAT 009

Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9-4.7) years; baseline median viral load was 4.09 log(10) HIV-1 RNA copies/mL (range 3.75-4.61 log(10) copies/mL); baseline median CD4 count was 169 cells/microL (range 60-277 cells/microL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was -2.1 (0.7) and -2.1 (0.8) log(10) copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA <50 copies/mL. Sixteen per cent of patients permanently ceased therapy and 26% underwent temporary drug interruptions because of study drug-related adverse events. Fasted-lipid values rose significantly over the 96 weeks of study, as did median blood glucose and median serum creatinine levels. Twelve (20%) patients underwent IDV dose reduction, mainly because of nephrotoxicity (nine of 12 patients). Blood pressure values deteriorated following switch, but markers of nucleoside toxicity improved. IDV/r 800/100 mg bid+EFV 600 mg qd gave a potent, durable response in these NRTI failures and was reasonably well tolerated. However, we observed adverse effects on renal, metabolic and blood pressure parameters. Lower doses of boosted IDV might improve toxicity while maintaining efficacy, and this possibility warrants further investigation.

Predictors of selection of K65R

Over the past 5 years, 1846 HIV-infected patients underwent drug resistance testing at our institution. None out of 216 drug-naive subjects showed K65R. However, it was recognized in 53 out of 1630 antiretroviral-experienced patients (3.3%), of whom 10 had never been exposed to tenofovir. The rate of K65R increased from 0.6% in 1999 to 11.5% in 2004. The recognition of K65R correlated negatively with the presence of thymidine analogue mutations but positively with Q151M.

Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non-Hodgkin's lymphoma of elderly patients

High and intermediate grade non-Hodgkin's lymphomas (NHL) require treatments with aggressive chemotherapy schedules. However, low grade NHLs display a low chemoresponsiveness and patients aged >65 years often do not tolerate anthracycline and corticosteroid-containing chemotherapy regimens. Therapeutic options in this subset of patients are watchful waiting, oral alkylating agents, purine nucleoside analogues, combination chemotherapy, interferon and monoclonal antibodies. The approval of rituximab, an unconjugated chimeric antibody against the CD20 antigen for the treatment of B-cell NHL marked a milestone in the development of antibody treatment. Moreover, promising results have also been found with oxaliplatin in patients with NHL and reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. On the basis of these considerations we have performed a feasibility study in NHL in patients aged >65 years using as schedule: 130 mg/m2 oxaliplatin every 21 days and 375 mg/m2 rituximab weekly. We have enrolled 8 patients, 2 males and 6 females (mean age 69.2+/-3.1 years; median, 67 years) affected by intermediate or high grade stage III/IV NHL. Six patients have cardiac abnormalities (myocardial function between 45 and 50%) and 1 increase of transaminasemia due to active chronic hepatitis. All the patients included in the study were treated for at least 3 cycles and 31 cycles were completed. We have recorded grade I/II (CTC) neurotoxicity in 30%, grade I anemia in 25% and grade I neutropenia in 20% of the patients. No infusional reactions, liver or renal toxicity neither nausea and/or vomiting were recorded. One complete response, 3 partial response and 3 minimal response were obtained at 11 months of median time follow-up. These results demonstrate the feasibility of this schedule which offers a suitable alternative regimen to treat elderly patients with NHL and shows a good efficacy and an acceptable toxicity profile.

Which nucleoside and nucleotide backbone combinations select for the K65R mutation in HIV-1 reverse transcriptase.

The K65R mutation has been reported to be associated with the use of abacavir, didanosine and tenofovir. With the advent of tenofovir we have assessed the change in the prevalence of this mutation. The prevalence of the K65R mutation remains low, but has significantly increased over a 2-year period. Although not associated with a specific drug, it is associated with the dual use of tenofovir, didanosine and the triple combination of tenofovir, didanosine and abacavir.

Thymalfasin for the treatment of chronic hepatitis B

Chronic hepatitis B virus infection is a serious problem because of its worldwide distribution and possible adverse chronic sequelae, such as cirrhosis and hepatocellular carcinoma. Chronic hepatitis B infection is a dynamic state of interactions between the virus, hepatocyte and host immune response. Interferon-Α and direct antiviral agents, such as lamivudine (Epivir®, GlaxoSmithKline), are effective in the therapy of chronic HBV infection but the efficacy is far from satisfactory. Thymalfasin (thymosin Α1; TΑ1, Zadaxin™, SciClone Pharmaceuticals, Inc.) is a 28-amino acid polypeptide produced synthetically but originally isolated from thymosin fraction 5, a bovine thymus extract containing a number of immunologically active peptides. In vitro studies have shown that TΑ1 can influence T-cell production and maturation, stimulate production of Th1 cytokines such as interferon-Γ and interleukin-2, and activate natural killer cell-mediated cytotoxicity. Seven randomized controlled studies on TΑ1 monotherapy in patients with chronic hepatitis B showed that 6 months treatment with TΑ1 (1.6 mg twice-weekly) resulted in a significantly higher sustained response rate than untreated controls. The benefits of TΑ1 therapy is usually not immediately apparent during therapy. There is a trend for complete virological response to increase or accumulate gradually after the end of thymosin therapy. The results of TΑ1 and interferon combination therapy in two open-label trials were also promising. In terms of the mechanisms of action, a combination of TΑ1 and nucleoside or nucleotide analogs is a logical approach in the control of chronic HBV infection and a randomized control study is ongoing.

Another Take on Triple NRTIs

Triple nucleoside combinations are convenient, leave more options for salvage therapy, and are usually associated with a low pill burden. On the

Predictive Factors and Selection of Thymidine Analogue Mutations by Nucleoside Reverse Transcriptase Inhibitors According to Initial Regimen Received

Thymidine analogue mutations were determined and compared in patients who received zidovudine monotherapy and added didanosine or zalcitabine, and in patients who started with one of these dual nucleoside combinations. Although patients who started in the era of zidovudine monotherapy had a longer duration of therapy compared with the other group, there was no statistical difference in the number of mutations between the two groups. However, thymidine analogue mutations were more frequent in patients who added didanosine to zidovudine monotherapy compared with those who added zalcitabine. Patients who started with a dual nucleoside combination developed 215Y/F first, followed by 215Y/F+41L, then 215Y/F+41L+210W, then 215Y/F+67N+70R+41L or 219Q/E, and then 215Y/F+41L+67N+70R+219Q/E. Patients who started with zidovudine monotherapy had a different pathway with the mutation at codon 70 appearing first, followed by 215Y/F+70R or 210W, then 215Y/F+41L+210W, then 215Y/F+67N+70R+219Q/E, and then 215Y/F+41L+67N+70R+210W. Medication adherence was associated with the number of mutations in both groups of patients. Two distinct mutational patterns were noted. The first pattern involved mutations at codons 41, 210 and 215, while the second involved mutations at codons 67, 70 and 219.