In vitro analysis of synergism and antagonism of different nucleoside/nucleotide analogue combinations on the inhibition of human immunodeficiency virus type 1 replication

In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T‐cell lines. PBMCs were infected with a full‐length HIV‐1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV + d4T), lamivudine + abacavir (3TC + ABC), lamivudine + didanosine (3TC + ddI), lamivudine + stavudine (3TC + d4T), tenofovir + stavudine (TDF + d4T), tenofovir + didanosine (TDF + ddI), tenofovir + abacavir (TDF + ABC), tenofovir + lamivudine (TDF + 3TC), tenofovir + zidovudine (TDF + ZDV), stavudine + didanosine (d4T + ddI), zidovudine + lamivudine (ZDV + 3TC), abacavir + didanosine (ABC + ddI), zidovudine + didanosine (ZDV + ddI), and abacavir + stavudine (ABC + d4T). The effect of combining two drugs was evaluated with a quantitative method based on the median‐effect principle of Chou and Talalay. A synergistic effect was observed with combinations containing TDF and ZDV or d4T, d4T and ddI and ZDV plus 3TC. In contrast, combinations including TDF + ddI, 3TC + ddI, ABC + ddI, and ZDV + ddI showed an antagonistic effect on the inhibition of viral replication at all levels of inhibition tested. Lower antagonistic effect was also found in drug combinations that included 3TC + ABC, 3TC + TDF, 3TC + d4T, and TDF + ABC. In conclusion, the method developed allows to measure in vitro the effect of different combinations of two NRTIs on HIV replication. The results suggest that combined therapy including TDF with thymidine analogues may be considered for future therapeutic options in contrast to clearly antagonistic combinations such us TDF plus ddI or 3TC plus ddI, that would explain virological failure in clinical studies when these combinations were used. J. Med. Virol. 81:211–216, 2009. © 2008 Wiley‐Liss, Inc.     

Comparison of Two Once-Daily Regimens with a Regimen Consisting of Nelfinavir,Didanosine, and Stavudine in Antiretroviral Therapy-Naïve Adults: 48-Week Results from the Antiretroviral Regimen Evaluation Study (ARES)

Abstract

Background: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. Method: HIV-1-infected, antiretroviral drug-naïve adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). Results: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL) <50 copies/mL by intention-totreat analysis was 42.3%, 50.0%, and 56.5% for regimens A (n = 26), B (n = 22), and C (n = 23), respectively. The time to a pVL <50 copies/mL for the first time was significantly shorter in regimen C, and there was significantly more progression to CDC events in regimen B. These differences are possibly due to differences in baseline characteristics. Adverse events were lowest for regimen C; more signs associated with mitochondrial toxicity occurred in regimen A. Increase in CD4 count was comparable between arms. Conclusion: No statistically significant difference in efficacy was found between the two investigated once-daily dosed treatment regimens (B and C) and the reference (A). Regimen C possibly had a better virological response and less toxicity than regimens A and B.     

No Virological Failure in Semen During Properly Suppressive Antiretroviral Therapy Despite Subtherapeutic Local Drug Concentrations

Abstract

Purpose: The aim of the study was to investigate whether drug resistance occurs earlier in seminal than in blood plasma with the use of such HAART regimens, of which only the two NRTIs achieve therapeutic concentrations in seminal plasma. Method: Seminal and blood plasma of 12 patients, for 48–96 weeks on suppressive first-line therapy with saquinavir/ritonavir/didanosine/lamivudine, nelfinavir/didanosine/stavudine, or efavirenz/lamivudine/zidovudine were prospectively evaluated for HIV-1-RNA resistance mutations and drug concentrations. Results: Saquinavir, nelfinavir, and efavirenz blood plasma concentrations were in the therapeutic range. Nelfinavir and efavirenz seminal plasma concentrations were below the limit of quantification. In only 2 of 9 seminal plasma samples, from 1 of 6 patients, the saquinavir concentration was above the minimum therapeutic level. The seminal plasma HIV-1-RNA concentration remained undetectable in all patients up to 96 weeks, and therefore drug resistance could not be demonstrated. Thus, despite suboptimal local drug concentrations, no virological failure occurred in seminal plasma after prolonged first-line HAART. Conclusion: This finding supports the hypothesis that the source of HIV in semen is a spillover from the blood/extraluminal tissue and that therefore seminal plasma drug levels may not be critical for viral suppression within the lumen of the male genital tract.     

Antiviral drugs: current state of the art.

The chemotherapy of virus infections has definitely come of age. There are now 15 antiviral agents that have been formally licensed for the treatment of human immunodeficiency virus infections (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir) and several others, such as tenofovir disoproxil, emtricitabine, capravirine, emivirine, T-20 (pentafuside) and AMD3100 (bicyclam) are under clinical development. Lamivudine has been approved, and several other compounds (such as adefovir dipivoxil, emtricitabine and entecavir) are under clinical development, for the treatment of hepatitis B virus infections. Among the anti-herpesvirus agents, aciclovir, valaciclovir, penciclovir, famciclovir, idoxuridine, trifluridine and brivudin are used in the treatment of herpes simplex virus and varicella-zoster virus infections, and ganciclovir, foscarnet, cidofovir, fomivirsen and maribavir (the latter in the developmental stage) are used in the treatment of cytomegalovirus infections. Following amantadine and rimantadine, the neuraminidase inhibitors, zanamivir and oseltamivir, have now become available for the therapy and prophylaxis of influenza virus infections, and so is ribavirin for the treatment of respiratory syncytial virus infections and the combination of ribavirin with interferon-alpha for the treatment of hepatitis C virus infections.     

Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides. Dual X-ray absorptiometry results from A5005s, a substudy of Adult Clinical Trials Group 384

BACKGROUND: Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials. METHODS: Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis. RESULTS: Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03). CONCLUSIONS: Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms.     

Antiviral activity of enteric-coated didanosine,stavudine, and nelfinavir versus zidovudine plus lamivudine and nelfinavir

OBJECTIVE: To assess and compare the activity and safety of capsules containing enteric-coated beadlets of didanosine given once daily with stavudine and nelfinavir with that of a standard reference triple drug regimen of zidovudine plus lamivudine and nelfinavir. DESIGN: Multinational, 49-site, prospective, open-label, randomized, two-arm comparison study. PARTICIPANTS: HIV-infected subjects with limited or no previous antiretroviral therapy who had plasma HIV RNA levels of >or=2000 copies/mL and CD4 cell counts of >or=200/mm3 (511 were randomized to treatment groups, and 352 completed the study). INTERVENTIONS: Triple antiretroviral therapy for 48 weeks: didanosine EC (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg three times daily) or a twice-daily coformulation of zidovudine (300 mg) plus lamivudine (150 mg) and nelfinavir (750 mg three times daily). MAIN OUTCOME MEASURE: Proportion of subjects with HIV RNA levels of <400 copies/mL at week 48 based on an "intent-to-treat, missing = treatment failure" analysis. RESULTS: The two treatment groups were similar in the proportion of treatment responders (i.e., HIV RNA level of <400 copies/mL), with 54% of subjects in the didanosine EC and zidovudine plus lamivudine treatment groups responding at week 48. Results of other analyses supported those of the primary analysis. The two study regimens were associated with similar numbers of adverse events. CONCLUSIONS: The antiviral efficacy of a triple combination regimen containing once-daily didanosine EC is similar to that of a reference triple combination regimen.     

Pilot Study of Once-Daily Simplification Therapy with Abacavir/Lamivudine/Zidovudine and Efavirenz for Treatment of HIV-1 Infection

Abstract

Objective: The purpose of this pilot study was to explore the efficacy and safety of the abacavir/lamivudine/zidovudine fixed-dose combination tablet administered as two tablets once daily (qd) versus one tablet twice daily (bid) in combination with efavirenz (EFV). Method: This was a prospective, randomized, open-label, multicenter study with a 24-week treatment period in 7 outpatient HIV clinics in the United States. Patients currently receiving an initial regimen of abacavir/lamivudine/zidovudine bid plus EFV qd for at least 6 months with HIV-1 RNA <50 copies/mL for at least 3 months and a screening CD4+ cell count ≥200 cells/mm³ were eligible. Thirty-six patients enrolled, and 35 (97%) completed the study. Participants were randomized to switch to 2 tablets of abacavir/lamivudine/zidovudine qd plus EFV qd (QD arm) or continue current treatment (BID arm) for 24 weeks. Results: Efficacy, safety, and adherence were evaluated. Median baseline CD4+ cell count was 521 cells/mm³. At week 24, HIV-1 RNA <50 copies/mL was achieved for 94% of participants in the QD arm and 89% in the BID arm by intent-to-treat, missing = failure analysis (95% confidence interval for difference: ≥0.29 to +0.18, p = 1.000). At week 24, median CD4+ cell count change from baseline was +26 cells/mm³ for the QD arm and –39 cells/mm³ for BID arm. One patient randomized to the QD arm met virologic failure criteria (confirmed HIV-1 RNA >120 copies/mL) at week 20 and viral genotype showed M184V. After failure, this patient revealed he never took EFV throughout the entire study after randomization, effectively receiving only abacavir/lamivudine/zidovudine qd alone. Median adherence was slightly higher in the QD arm, although both arms had broad variability and overlapping interquartile ranges. Adverse events were infrequent and occurred with similar frequency between arms; treatment-related adverse events were abdominal pain, flatulence, nausea, headache, and abnormal dreams (1 patient [3%] for each adverse event). No patients withdrew due to adverse events, and no abacavir hypersensitivity reactions were reported. Conclusion: In this pilot study of patients suppressed on abacavir/lamivudine/zidovudine bid plus EFV, 94% of participants switching to abacavir/lamivudine/zidovudine qd plus EFV maintained virologic suppression, compared to 89% of participants continuing abacavir/lamivudine/zidovudine bid plus EFV.