Combination Of Abacavir Research Articles

Human adenovirus DNA polymerase is evolutionarily and functionally associated with human telomerase reverse transcriptase based on in silico molecular characterization that implicate abacavir and zidovudine.

Human adenoviruses (HAdVs) are non-enveloped, small double stranded DNA (dsDNA) viruses that cause asymptomatic infections, clinical syndromes and significant susceptibility to infections in immunocompromised people. The aim of the present study was to identify critical host proteins and HAdV hypothetical proteins that could be developed as potential host-viral targets for antiHAdV therapy. Here, the function of selected hypothetical proteins of HAdV based on phylogenetic relationship with the therapeutic targets of antiretroviral drugs of human immunodeficiency virus (HIV) was predicted computationally, and characterized the molecular dynamics and binding affinity of DNA polymerase of HAdV. Thirty-eight hypothetical proteins (HPs) of human adenovirus (HAdV) were used in this study. The results showed that HAdV DNA polymerase (P03261) is related to Human TERT (O14746) and HLA-B (P01889) genes. The protein-protein interaction of human five molecular targets (PNP, TERT, CCR5, HLA-B, and NR1I2) of ARVDs are well-coordinated/networked with CD4, AHR, FKBP4, NR3C1, HSP90AA1, and STUB1 proteins in the anti-HIV infection mechanism. The results showed that the free energy score of abacavir and zidovudine binding to HAdV DNA polymerase are -5.8 and -5.4kcalmol-1 respectively. Also, the control drug, cidofovir and ganciclovir have less binding affinity for DNA polymerase of HAdV when compare to that of abacavir and zidovudine. Similarity was observed in the binding of abacavir and zidovudine to HAdV DNA polymerase (ASP742, ALA743, LEU772, ARG773 and VAL776). In conclusion, combination of abacavir and zidovudine was predicted to be potential therapy for controlling HAdV infection targeting HAdV DNA polymerase.

Effects of Reverse Transcriptase Inhibitors on Proliferation, Apoptosis, and Migration in Breast Carcinoma Cells.

High telomerase activity in human breast cancer is associated with aggressive tumors resulting in decreased survival. Recent studies have shown that telomerase inhibitors may display anticancer properties in some human cancer cell lines. In the present study, we examined the effects of 4 reverse transcriptase inhibitors (RTIs), used for the treatment of HIV; Abacavir (AC), Lamivudine (LV), Stavudine (SV), and Tenofovir (TF) on proliferation, apoptosis, and migration in the normal human mammary epithelial cell line, hTERT-HME1, and the human breast cancer cell line, MCF-7. Cells were treated with AC, LV, SV, or TF alone or in combination with paclitaxel (PAC), a known drug used to treat breast cancer. Conduct of the thiazolyl blue tetrazolium bromide assay demonstrated that AC, SV, and TF had stronger cytotoxic effects on MCF-7 cells than in hTERT-HME1 cells. The combined treatment of RTIs and PAC caused high rates of cell death in MCF-7 and low rates of cell death in HTERT-HME1 by apoptosis. The percentages of apoptotic cells in the treatment of AC and SV in combination with PAC for 48 and 72 hours were higher than PAC. Significantly increased apoptosis and decreased migration levels were found in MCF-7 cells treated with AC and co-treatment of AC+PAC or SV+PAC than HME1 cells. These treatments can also prevent migration capacity more than PAC. Therefore, a combination strategy based on telomerase inhibitors such as AC or SV and anticancer drugs may be more effective in the treatment of certain breast cancers.

ANALYSIS OF MIXED COMBINATIONS OF MEDICINAL PRODUCTS BASED ON ABAKAVIR, LAMIVUDIN, ZIDOVUDIN USING THE METHOD OF MICROCOLONIES LIQUID CHROMATOGRAPHY

Aim.To develop a technique for the detection and separation of abacavir, lamivudine, zidovudine, both individually and combined with adaptol, azaleptin, analgin, amitriptyline, haloperidol, melipramine, neuleptil, phenobarbital, fluoxetine, and chlorprotixen using high performance liquid chromatography (HPLC).Materials and methods. A column filled with ProntoSIL-120-5-C18 AQ was used, eluting with A [0.2 M lithium perchlorate − 0.005 M perchloric acid] − water (5: 95); eluent B is acetonitrile. Chromatography conditions: a linear gradient of the solvent is 3700 μl from 5 to 70% at a flow rate of 100 μl / min. The temperature of the column was 40°C. The results were processed with the help of the computer program MultiChrome (ZAO Ampersend, Moscow).Results. The method of separation and detection of combinations of abacavir, lamivudine, zidovudine with adaptol, azaleptin, analgin, amitriptyline, haloperidol, melipramine, neuleptil, phenobarbital, fluoxetine and chlorprotixene by reversed-phase high-performance liquid chromatography was developed.Conclusion. The developed technique allows detecting abacavir, zidovudine, lamivudine with the help of the HPLC method after isolation from urine separately or at combined poisonings with adaptolom, azaleptinom, dipyrone, amitriptilinom, galoperidolom, melipraminom, neuleptilom, phenobarbital, fluoxetine and hlorprotiksenom

Abacavir/lamivudine + unboosted atazanavir in routine clinical practice: Twelve years experience

ObjectiveTo describe the experience using the combination abacavir, lamivudine plus non-boosted atazanavir (ABC/3TC+ATV) in a group of pretreated patients. Patients and methodsWe performed a retrospective observational study to describe baseline characteristics and the evolution of patients who had received or were treating with ABC/3TC+ATV, from November 2004 and June 15th 2015, in the clinical setting. ResultsOverall, 236 patients were included in the study. Median age (IQR) was 45 (42–50) years and 69% were male. The main reasons for using this combination were previous toxicity in 130 patients (56%), simplification in 60 (20%) and virologic failure in 29 (14%). Previous treatment was based in boosted protease inhibitor in 115 patients (48.7%), 3 analogs in 56 (28%) and non-analogous based in 19 (8.1%). Median treatment length was 2.2 years (IQR 0.8–5.3). A total of 66 (28%) patients continue receiving ABC/3TC+ATV (median time 5.7, IQR 2.2–8.3), treatment was changed in 170 patients (72%) (median time 1.6 years, IQR 0.7–3.6), and 22 (9.3%) patients were lost. Virological failure was assessed in 30 patients. ConclusionIn selected patients, ABC/3TC+ATV is a durable and attractive therapeutic alternative.

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and C\xf4te d\u2019Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial

BackgroundThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.MethodsThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).ResultsBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.ConclusionsAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.Trial registrationClinicalTrial.gov registry n°NCT01127204, 19 May 2010.

Abacavir/lamivudina + atazanavir no potenciado en la práctica clínica diaria: doce años de experiencia

ObjectiveTo describe the experience using the combination abacavir, lamivudine plus non-boosted atazanavir (ABC/3TC+ATV) in a group of pretreated patients. Patients and methodsWe performed a retrospective observational study to describe baseline characteristics and the evolution of patients who had received or were treating with ABC/3TC+ATV, from November 2004 and June 15th 2015, in the clinical setting. ResultsOverall, 236 patients were included in the study. Median age (IQR) was 45 (42-50) years and 69% were male. The main reasons for using this combination were previous toxicity in 130 patients (56%), simplification in 60 (20%) and virologic failure in 29 (14%). Previous treatment was based in boosted protease inhibitor in 115 patients (48.7%), 3 analogs in 56 (28%) and non-analogous based in 19 (8.1%). Median treatment length was 2.2 years (IQR0.8-5.3). A total of 66 (28%) patients continue receiving ABC/3TC+ATV (median time 5.7, IQR2.2-8.3), treatment was changed in 170 patients (72%) (median time 1.6 years, IQR0.7-3.6), and 22 (9.3%) patients were lost. Virological failure was assessed in 30 patients. ConclusionIn selected patients, ABC/3TC+ATV is a durable and attractive therapeutic alternative.

A simultaneous determination of related substances by high performance liquid chromatography in a drug product using quality by design approach

The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high quality assurance. For NOR establishment, Monte Carlo simulation was performed on the basis of which process capability index (Cpk) was derived. Finally, the selectivity issue problem faced due to the pH dependency and the dissimilar pH needs of the two critical responses was resolved by introducing pH gradient into the program. This new ternary gradient program has provided a single robust method. Thus, two HPLC methods for the analysis of the combination drug product have been replaced with a selective, robust, and cost effective single method.

Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study

The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily, with similar tolerability. We present secondary efficacy and safety results analysed at 96 weeks. FLAMINGO was a multicentre, open-label, phase 3b, non-inferiority study of HIV-1-infected treatment-naive adults. Patients were randomly assigned (1:1) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg, with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment. The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety. The non-inferiority margin was -12%. If the lower end of the 95% CI was greater than 0%, then we concluded that dolutegravir was superior to ritonavir-boosted darunavir. This trial is registered with ClinicalTrials.gov, number NCT01449929. Of 595 patients screened, 488 were randomly assigned and 484 included in the analysis (242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir). At 96 weeks, 194 (80%) of 242 patients in the dolutegravir group and 164 (68%) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 12·4, 95% CI 4·7-20·2; p=0·002), with the greatest difference in patients with high viral load at baseline (50/61 [82%] vs 32/61 [52%], homogeneity test p=0·014). Six participants (three since 48 weeks) in the dolutegravir group and 13 (four) in the darunavir plus ritonavir group discontinued because of adverse events. The most common drug-related adverse events were diarrhoea (23/242 [10%] in the dolutegravir group vs 57/242 [24%] in the darunavir plus ritonavir group), nausea (31/242 [13%] vs 34/242 [14%]), and headache (17/242 [7%] vs 12/242 [5%]). Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir. Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients. ViiV Healthcare and Shionogi & Co.

Antiretroviral Prophylaxis and the Risk of Cleft Lip and Palate: Preliminary Signal Detection in the Food and Drug Administration's Adverse Events Reporting System Database

Antiretroviral prophylaxis has been found to be effective in preventing vertical HIV transmission to the offspring of infected mothers. Because medicine and the art of public health require benefits to outweigh any plausible risks, our study aimed to explore and quantify preliminary associations between antiretroviral medications and clefting. We analyzed 5 years of available data from the Food and Drug Administration's Adverse Events Reporting System (Medwatch program) and calculated reporting odds ratios (RORs) and their associated 95% confidence intervals (CIs). The medications with the highest effects were efavirenz with an ROR of 196 (95% CI, 86 to 447), lamivudine with an ROR of 60.2 (95% CI, 14.25 to 148), the combination abacavir sulfate/lamivudine/zidovudine with an ROR of 59.3, and nelfinavir with and ROR of 50.5, followed by nevirapine, lopinavir/ritonavir, and lamivudine/zidovudine. Given the multifactorial etiology of cleft lip and palate, further studies are needed to assess the relative safety of antiretroviral prophylaxis and the specific conditions or potential synergies that might lead to the development of this defect.

Raltegravir-associated perihepatitis and peritonitis: a single case report

Raltegravir, the first approved HIV integrase inhibitor, has demonstrated an excellent safety and tolerability profile in several clinical trials [1] and is currently used widely as one of the key components of salvage regimens. However, the duration of clinical use is relatively short, and unknown adverse effect may occur. Here, we report one case of peritonitis associated with use of raltegravir. Abdominal symptoms appeared within 2 weeks of commencement of treatment, and raltegravir had to be stopped due to worsening of clinical condition. Case report The patient was a 49-year-old Japanese hemophiliac coinfected with HIV and hepatitis C virus (HCV). HIV-RNA was undetectable, and CD4+ cell count was above 500 cells/μl for more than 5 years under the combination of abacavir, nevirapine and lopinavir/ritonavir. In January 2009, lopinavir/ritonavir was replaced with raltegravir because of bleeding tendency related to the use of a protease inhibitor. Abacavir and nevirapine were continued, and no other drugs were modified. The patient visited the hospital on day 18 after the use of raltegravir, complaining of a gradually worsening pain in the right upper abdomen and lower chest wall for 3 days. A nonsteroidal anti-inflammatory drug was not effective, and a computed tomography (CT) scan performed 11 days after the onset of the symptom revealed contrast enhancement of the liver surface (Fig. 1a) and fatty stranding of the greater omentum (Fig. 1b), which are findings compatible with perihepatitis and peritonitis. Oral prednisone (60 mg/day for 3 days, then 30 mg/day for 3 days) was prescribed, and all the symptoms resolved immediately. However, abdominal symptoms developed again after withdrawal of prednisone, necessitating its reintroduction on day 31 at 30 mg/day. Attempts to taper prednisone led to worsening of abdominal pain and development of stomatitis, resulting in continuation of treatment at 20 mg/day. Raltegravir was switched to lopinavir/ritonavir 11 weeks after the onset of abdominal pain and, finally, all antiretroviral drugs were terminated 4 days later because of diarrhea and bleeding related to lopinavir/ritonavir. Abdominal symptoms gradually improved, and prednisone could be tapered to 10 mg/day within 2 weeks. A CT scan performed 10 days after cessation of antiretroviral therapy showed an improvement of perihepatic enhancement. C-reactive protein levels increased to 1.42 mg/dl during raltegravir use and fell to normal levels 6 days after discontinuation of raltegravir. Other laboratory data including transaminase levels showed no changes, and CD4+ cell count and HIV-RNA were stable throughout the course.Fig. 1: A computed tomography scan performed 11 days after the onset of the symptoms. A computed tomography scan shows contrast enhancement around the liver surface (a) and fatty stranding of the greater omentum (b).This is the first reported case of severe peritonitis associated with raltegravir use. Although not described here, we have experienced several other cases with similar abdominal symptoms that disappeared after raltegravir termination. Several case reports have recently described previously unknown adverse effects related to raltegravir, such as rhabdomyolysis [2] and exacerbation of depression [3]. However, to our knowledge, raltegravir-associated peritonitis has not been reported. In the BENCHMRK (Blocking integrase in treatment Experienced patients with a Novel Compound against HIV: MeRcK, MK-0518) study [1], abdominal symptoms, such as diarrhea and nausea, were noted in patients on raltegravir, and some of which might be associated with mild peritonitis. Fortunately, raltegravir-associated peritonitis seemed reversible, at least to some extent. However, the longer use of raltegravir after onset of symptoms may lead to irreversible and lethal sequelae. Cessation of antiretroviral therapy as a result of severe abdominal symptoms is a potential risk for re-emergence of acute retroviral syndrome or the further accumulation of HIV-resistant mutations. Whether the described side effects are universal or related to Asians, hemophiliacs or those who have underlying liver disease is unknown at present. Careful monitoring of abdominal symptoms and the consideration of an appropriate radiographic examination are warranted after commencement of raltegravir-containing regimens. Acknowledgements The authors thank all clinical staff of the AIDS Clinical Center. All authors contributed to the conception, design and performance of this submission. This study was supported in part by the Ministry of Health, Labour, and Welfare of Japan. All authors report no potential conflict of interests.

Twenty‐four‐week safety and tolerability of nevirapine vs. abacavir in combination with zidovudine/lamivudine as first‐line antiretroviral therapy: a randomized double‐blind trial (NORA)*

ObjectiveTo compare the safety/tolerability of abacavir and nevirapine in HIV-infected adults starting antiretroviral (ARV) therapy in Uganda.MethodsTwenty-four-week randomized double-blind trial conducted with 600 symptomatic ARV-naive adults with CD4 <200 cells/mm3 allocated to zidovudine/lamivudine plus 300 mg abacavir (A) and nevirapine placebo (n = 300) or 200 mg nevirapine (N) and abacavir placebo (n = 300) twice daily. The primary endpoint was any serious adverse event (SAE) definitely/probably or uncertain whether related to blinded nevirapine/abacavir. Secondary endpoints were adverse events leading to permanent discontinuation of blinded nevirapine/abacavir, and grade 4 events.ResultsSeventy-two per cent participants were women; 19% had WHO stage 4 disease; the median age was 37 years (range 18–66); the median baseline CD4 count was 99 cells/mm3 (1–199). Ninety-five per cent completed 24 weeks: 4% died and 1% were lost to follow-up. Thirty-seven SAEs occurred on blinded drug in 36 participants. Twenty events [6 (2.0%) abacavir, 14 (4.7%) nevirapine participants] were considered serious adverse reactions definitely/probably/uncertain whether related to blinded abacavir/nevirapine [HR = 0.42 (95% CI 0.16–1.09) P = 0.06]. Only 2.0% of abacavir participants [six patients (0.7–4.3%)] experienced a suspected hypersensitivity reaction (HSR). In total 14 (4.7%) abacavir and 30 (10.0%) nevirapine participants discontinued blinded abacavir/nevirapine (P = 0.02): because of toxicity (6A, 15N; P = 0.07, all rash/possible HSR and/or hepatotoxicity), anti-tuberculosis therapy (6A, 13N), or for other reasons (2A, 2N).ConclusionsThere was a trend towards a lower rate of serious adverse reactions in Ugandan adults with low CD4 starting ARV regimens with abacavir than with nevirapine. This suggests that abacavir could be used more widely in resource-limited settings without major safety concerns.

Abacavir sulfate/lamivudine/zidovudine fixed combination in the treatment of HIV infection

Treatment of HIV infection has typically been carried out using two nucleoside analogs and a protease inhibitor. Such regimens can be complex and have high pill burdens. Use of alternative regimens, such as triple nucleoside-based regimens, can improve adherence and decrease toxicities associated with protease inhibitor therapy. A formulation of abacavir sulfate/lamivudine/zidovudine allows a dosing schedule of one pill twice daily. The components have performed favorably compared with protease inhibitor-based regimens, such as indinavir. Compared with efavirenz-based regimens, abacavir sulfate/lamivudine/zidovudine has not performed as well. The combination is being studied as a cornerstone for induction maintenance strategies, in which switching a patient to abacavir sulfate/lamivudine/zidovudine has been associated with similar virologic outcomes as continuing with either protease inhibitor- or efavirenz-based regimens. Administration of abacavir sulfate/lamivudine/zidovudine also avoids side effects of antiretroviral therapy, such as hyperlipidemia, but its use is associated with a hypersensitivity reaction in a small number of patients. The combination of abacavir sulfate/lamivudine/zidovudine is an important part of the HIV armamentarium. Its potency and ease of administration make it worth consideration in the treatment of HIV, either by itself or in combination with other agents.

Abacavir/lamividune combination in the treatment of HIV-1 infection: a review

Consensus guidelines for the management of HIV infection recommend the use of two nucleoside analogues in combination with either a non-nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in therapy-naive patients. As adherence is crucial for treatment success, regimens with fewer pills, simpler dosing schedules and fewer adverse events have become the first choice for antiretroviral therapy. Fixed-dose combinations further improve the convenience of therapy. There are three dual-nucleoside fixed-dose combinations licensed for treating HIV-infected individuals, which include a combination of abacavir and lamivudine. This article reviews the pharmacology, efficacy, resistance profiles, safety and tolerability of abacavir focussing on its use in combination with lamivudine and discusses the role of this nucleoside backbone in antiretroviral therapy.

Early Virologic Failure and Rescue Therapy of Tenofovir, Abacavir, and Lamivudine for Initial Treatment of HIV-1 Infection: TONUS Study

Background: To assess the efficacy and safety of the triple NRTI combination of abacavir (ABC), lamivudine (3TC), and tenofovir (TDF) in a once-daily regimen. Method: 38 HIV-naive patients (pts) were treated in a prospective open-arm study over 48 weeks (W48). Virological failure was defined as never achieving plasma HIV-1 RNA <400 copies/mL or rebound of ≥0.7 log10. Results: 12/36 (33%) pts had virologic failure at W24 and 10 additional pts had HIV RNA >50 copies/mL at W12 or W24. There was a significant association between baseline viral load (VL) and virologic failure in 0%, 29%, and 64% pts with baseline VL levels <4, 4-5, and >5 log10 copies/mL, respectively (p = .014). 76% of pts developed K65R and M184V/I mutations by W24, and 19% developed M184V/I alone. At W4, 86% of pts had adequate plasma Cmin for the 3 drugs. 14 pts with K65R and M184V/I were given a rescue therapy with a successful outcome (<50 copies/mL; median follow-up 48 weeks). Conclusion: Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.

Fixed dose combination abacavir/lamivudine in the treatment of HIV-1 infection

The fixed dose combination of abacavir with lamivudine represents a new treatment option for patients infected with HIV. Fixed dose combination abacavir/lamivudine has the convenience of one pill and once-daily dosing. It achieves comparable suppression of plasma HIV RNA with the pill’s individual components dosed twice daily and with thymidine analogs combined with lamivudine. The combination is well tolerated, with the potential advantages of less lipoatrophy and fewer metabolic perturbations. However, the abacavir component may cause hypersensitivity reactions, which are reported in up to 8% of patients, and are potentially life threatening. Fixed dose combination abacavir/lamivudine should be considered as a viable treatment option for HIV-infected patients, particularly for those who have otherwise limited nucleoside reverse transcriptase inhibitor choices.

Pharmacokinetics and Pharmacodynamics of Low Dose Mycophenolate Mofetil in HIV-Infected Patients Treated with Abacavir, Efavirenz and Nelfinavir

The use of mycophenolate mofetil in combination with highly active antiretroviral therapy (HAART) has been proposed in order to inhibit HIV replication. Due to the low doses involved, pharmacokinetic-pharmacodynamic monitoring is recommended. The aim of this study was to characterise the pharmacokinetic and pharmacodynamic monitoring of low doses of mycophenolate mofetil (0.25 g twice daily) in HIV-infected patients treated with HAART and after programmed discontinuation of HAART, in order to assess whether low doses of this immunosuppressive agent provide a biological effect. Mycophenolic acid (MPA) plasma levels (assessed by high-performance liquid chromatography) and the capacity of patients' sera to inhibit CEM cell line proliferation (assessed by (3)H-thymidine uptake) were measured post-dose at 0, 20, 40 minutes and 1, 2, 4, 6, 8, 10 and 12 hours in nine HIV-infected patients treated with a combination of abacavir, nelfinavir and efavirenz (HAART) and mycophenolate mofetil 0.25 g twice daily at days 7, 28, 120 and 150 (30 days without HAART) after the treatment initiation. A control group of eight patients was treated with HAART alone. In the 35 post-dose curves analysed, no differences were found in MPA levels between days 7, 28, 120 and 150: area under the plasma concentration-time curve - mean value 15.3 mg . h/L, range 10.4-24.4 mg . h/L; minimum plasma concentration - mean value 0.60 mg/L, range 0.20-4.67 mg/L; maximum plasma concentration mean value 2.60 mg/L, range 0.94-7.98 mg/L. Pretreatment patients' sera did not inhibit CEM proliferation. Post-treatment patients' sera inhibited CEM proliferation to <40% in 25 of 35 curves at 0 hours (six of nine patients), in 34 of 35 curves at 1 hour, in 32 of 35 curves at 2 hours, in 22 of 35 curves at 4 hours, and in 8 of 35 curves at 12 hours. The MPA level versus CEM proliferation inhibition had a concentration that produces 50% of the maximum drug effect (EC(50)) of 0.33 mg/L. Viral load at day 150 was >200 copies/mL in all control patients and in three of nine patients receiving mycophenolate mofetil. These three patients were the only ones repeatedly unable to inhibit pre-dose CEM proliferation to <40%. Mycophenolate mofetil pharmacokinetic profiles in HIV patients under HAART are not significantly different from those found in transplant patients. Sera from the majority of patients receiving low doses of mycophenolate mofetil inhibited lymphocyte proliferation during most of the inter-dose interval, despite low MPA plasma levels. For some patients, higher doses may be necessary: the capacity of sera to inhibit CEM proliferation may help to identify these patients.

Efficacy and Safety of Abacavir Plus Lamivudine Versus Didanosine Plus Stavudine When Combined with a Protease Inhibitor, a Nonnucleoside Reverse Transcriptase Inhibitor, or Both in HIV-1 Positive Antiretroviral-Naive Persons

Purpose: The combination of abacavir + lamivudine (ABC+3TC) versus didanosine + stavudine (ddI+d4T), each combined with other classes of antiretrovirals (ARVs) in ARV-naive patients, was compared for the combined endpoint of time to plasma HIV RNA >50 copies/mL (at or after the 8-month visit) or death (primary endpoint) in a nested substudy of an ongoing multicenter randomized trial. Method: The substudy enrolled 182 patients; mean HIV RNA and CD4+ cell counts at baseline were 5.1 log10 copies/mL and 212 cells/mm3, respectively. Results: After a median follow-up of 28 months, rates of primary endpoint were 57.2 and 67.8 per 100 person-years for the ABC+3TC and ddI+d4T groups (hazard ratio [HR] = 0.81, 95% confidence interval [CI] 0.58-1.14, p = .23). Conclusion: There was a trend for treatments containing ABC+3TC to be better than treatments containing ddI+d4T with respect to HIV RNA decreases, CD4+ cell count increases, and tolerability.

Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients

Data from 20 highly drug-experienced HIV-infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation.

A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir

Objectives (1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome. Design and methods A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D. Results At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels ≤15000 copies/ml versus those with &gt;15000 copies/ml (42 vs 79%, P&lt;0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses ( P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels ≤15000 copies/ml had a significantly better virological response than those with &gt;15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.

K65R with and without S68: A New Resistance Profile in Vivo Detected in Most Patients Failing Abacavir, Didanosine and Stavudine

Antiretroviral treatment with three nucleoside reverse transcriptase inhibitors (NRTIs) is widely used, but the combination of abacavir, didanosine and stavudine has never been investigated. We describe the surprising and consistent genotypic and phenotypic outcome in patients failing this combination. As part of a Danish multicentre study, 60 antiretroviral-naive patients were randomized to treatment with abacavir, didanosine and stavudine. Failure was defined as one HIV-1 RNA >400 copies/ml. Genotyping was performed using TrueGene HIV-1 assay (Visible Genetics, London, UK). Phenotypic susceptibilities were determined with the Virco Antivirogram assay. Eight patients failed treatment with a median viral load of 2.980 copies/ml (range 478-5.950). At baseline, five patients were wild-type. Three patients harboured nucleoside excision mutations (NEMs), but phenotypic susceptibilities were within normal range. All five patients with wild-type virus developed K65R and four of these patients also acquired the S68G mutation. Phenotypic susceptibility decreased towards abacavir (median 8.9-fold) and didanosine (median 3.2-fold), while susceptibility towards stavudine was unchanged (median 0.8-fold). Susceptibility towards lamivudine and tenofovir decreased median 14.2- and 4.0-fold, respectively. In two patients with baseline resistance mutations, further accumulation of NEMs and V75T or L74V was observed. One patient developed Q151M. Failure of a triple NRTI regimen is possible and frequent with only the K65R mutation. Under adequate selection pressure K65R can easily emerge in vivo and may compromise several future treatment options including newer NRTIs. The unexpected high incidence of S68G suggests a functional role of this mutation in viruses harbouring K65R.