Lamivudine combination studies

Genel, F., Unal, F., Ozgenc, F., Aksu, G., Aydogdu, S., Kutukculer, N., Yagci, R.V. Decreased ratio of CD4 / CD8 lymphocytes might be predictive for successful interferon alpha and lamivudine combined therapy in childhood chronic hepatitis B infection A preliminary study. X. Gastroenterol. Hepatol. 2003 18 645-650... 

A few studies have evaluated standard lFN-a2a and -a2b combined with lamivudine, whereas more recent trials tested pegylated IFN-a combined with nucleo-side/nucleotide analogues. The aim was to determine whether combination therapy... 

Santantonio T, Niro GA, Sinisi E, Leandro G, Insalata M, Guastadisegni A, Facciorusso D, Gravinese E, Andriulli A, Pastore G (2002) Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients a controlled pilot study. J Hepatol 36 799-804... 

The effects of the protease inhibitor indinavir and the NNRTI efavirenz on lipid concentrations have been compared in a large comparative randomized study (154). Each of the two comparison drugs were used in one arm (with a zidovudine + lamivudine backbone) and the combination of the two drugs in a third arm. Zidovudine and lamivudine did not play a role in the lipid changes. However, both of the comparison drugs significantly increased cholesterol concentrations. 

Support for the hypothesis of a casual relation between stavudine and lipodystrophy comes from another randomized study in which stavudine-containing HAART regimens were switched to a combination of zidovudine, lamivudine, and abacavir (157). Eight patients were randomized to continue stavudine and 14 patients switched to the triple combination. Imbalance in the treatment arms resulted from exclusion of patients who maintained treatment for a minimum of 6 months of follow up. Over 48 weeks after randomization, the average leg and arm fat mass fell in the continuation arm but increased in the switch arm. One patient in the switch arm, who had previously taken zidovudine and lamivudine, had a therapeutic failure. 

Mayers D, Jemesk J, Eyster E, et al. In A double-blind, placebo-controlled study to assess the safety, tolerability and antiretroviral activity of efavirenz (EFV DMP 266) in combination with open-label zidovudine (ZDV) and lamivudine (3TC) in HIV infected patients (DMP 266-004)38th Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego). Washington DC American Society for Microbiology, 1998 22340. 

Combination therapy The combination of IFNa + lamivudine is superior to the corresponding monotherapy and it yielded considerably better results in patients who were resistent to IFN. (164, 166, 186, 195, 196) Likewise Peg-IFNa + lamivudine were applied with success. (182) A combination of lamivudine + ADV led to a virological and biochemical improvement during treatment up to 52 weeks (191, 192). In another study, however, therapy with IFNa + lobucavir (2 x 200 mg/day) had only little success. A combination of lamivudine + famciclovir sometimes produced a certain positive effect. (198) In the same way, IFNa + famciclovir improved initial values in some cases. (183) A combination of famciclovir + thymosin activates T-cell response in the immunotolerance phase. (174) The possibility that IFNa + acyclovir are synergistic in HBV infection has been suggested (S.w. ScHALM et al., 1985) acyclovir as monotherapy (45 mg/kg BW/day, i.v. infusion for 28 days) showed no benefit in chronic HBV carriers with stable disease. (152)... 

Mutimer, D., Naoumov, N., Honkoop, R, Marinos, G., Ahmed, M., de Man, R., McPhillips, R, Johnson, M., Williams, R., Elias, E., Schalm, S. Combination alpha-interferon and lamivudine therapy for alpha-interferon resistant chronic hepatitis B infection results of a pilot study. X Hepatol. 1998 28 923-929... 

Katlama C, Fenske S, Gazzard B, Lazzarin A, Clumeck N, MaUolas J, LafeuiUade A, Mamet JP, Beauvais L AZL30002 European study team. TRIZAL study switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet) 48 weeks efficacy, safety and adherence results. HTV Med 2003 4(2) 79-86. 

In patients with dual HIV and lamivudine-resistant HBV infections, adefovir dipivoxil (10 mg/day) significantly reduces HBVDNA levels and also has been used successfully in patients with lamivudine-resistant HBV infections both before and following liver transplantation. The optimal duration of treatment in different populations, possible long-term effects on HBV complications, and combined use with other anti-HBV agents are under study. 

In contrast, a study found no evidence of any change in the pharmacokinetics of methadone in HIV-positive patients taking methadone 14 days after they started zidovudine 200 mg every 4 hours. No methadone withdrawal symptoms occurred. Another study in 16 patients taking methadone found that a single-dose of a fixed combination of zidovudine 300 mg with lamivudine 150 mg (Combivir) had no effect on the pharmacokinetics of methadone, and there was no evidence of withdrawal or toxicity. ... 

In a placebo-controlled, crossover study in healthy subjects maraviroc 300 mg twice daily had no clinically relevant effect on the pharmacokinetics of zidovudine/lamivudine (Ctmbivir) 300/150 mg twice daily, when they were given together for one week. For the effect of other NRTIs in combination with protease inhibitors or NNRTIs on maraviroc, see CYP3A4 inhibitors , (p.780) and CYP3A4 inducers , (p.780), and for the effect of tenofovir, see Drugs that affect renal clearance , (above). 

Lamivudine 300 mg twice daily was given to 12 HIV-positive patients for 5 doses, with a 200-mg dose of zidovudine with the last dose. No major changes in the pharmacokinetics of the zidovudine occurred and it was concluded that dosage adjustments are not needed if these two drugs are given concurrently. Another study found the same results, and an extensive study in over 200 patients has shown that combined use can he safe and effective. ... 

Indinavir. A study found that when zidovudine 200 mg every 8 hours and indinavir 1 g every 8 hours were given together for a week the AUC of zidovudine was increased by 17% and the AUC of indinavir was increased by 13%. In another study, combined use of indinavir and zidovudine with lamivudine increased the zidovudine AUC by 39% but did not change indinavir pharmacokinetics. These changes are not clinically relevant. 

Furthermore, a once daily combination of tenofovir disoproxil fumarate 300 mg, enteric-coated didanosine 250 mg and lamivudine 300 mg was unexpectedly associated with a high rate of treatment failure (early viro-logical non-response) in a clinical study in treatment-naive patients. Similarly, other studies have shown a high rate of treatment failure with a once daily combination of tenofovir disoproxil fumarate 300 mg, enteric-coated didanosine 250 mg and either efavirenz or nevirapine in treatment-naive patients with high baseline viral loads and low CD4 counts. A poor immune response (lack of increase in CD4 cell counts) has also been seen with full-dose didanosine plus tenofovir regimens in treatment-experienced patients. ... 

Time course Rifampicin induces CYP3A4 at about 15 days, and interaction studies have generally started treatment with protease inhibitors within 15 days of the start of rifampicin therapy. Furthermore, pharmacological tolerance to effects can occur. The problems of variations in pharmacokinetics with time have been illustrated by a study of the effects of rifampicin on the pharmacokinetics of nevirapine in 16 patients coinfected with HTV-1 and tuberculosis [39"]. They took standard antituberculosis therapy and a fixed-dose combination of stavudine, lamivudine, and nevirapine. The median AUC of nevirapine was reduced by rifampicin by 26% at 4 weeks, but by only 7.5% at 10 weeks. The median Crm was reduced by 20% at 4 weeks and by 7.1% at 10 weeks. The authors concluded that the effect of rifampicin on the pharmacokinetics of nevirapine substantially decreases over time. 

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