Immune reconstitution in severely immunosuppressed antiretroviral-naive HIV type 1-infected patients using a nonnucleoside reverse transcriptase inhibitor-based or a boosted protease inhibitor-based antiretroviral regimen: three-year results (The Advanz Trial): a randomized, controlled trial.

Late diagnosis of HIV-1 infection is quite frequent in Western countries. Very few randomized clinical trials to determine the best antiretroviral treatment in patients with advanced HIV-1 infection have been performed. To compare immune reconstitution in two groups of very immunosuppressed (less than 100 CD4(+) cells/microl), antiretroviral-naive HIV-1-infected adults, 65 patients were randomly assigned in a 1:1 ratio to receive zidovudine + lamivudine + efavirenz (group A, 34 patients) or zidovudine + lamivudine + ritonavir-boosted indinavir (group B, 31 patients). The median (interquartile range) CD4(+) cell increase after 12 and 36 months was +199 (101, 258) and +299 (170, 464) cells/microl in the efavirenz arm and +136 (57, 235) and +228 (119, 465) cells/microl in the ritonavir-boosted indinavir arm (p > 0.05 for all time points). The proportion (95% confidence interval) of patients achieving HIV-1 RNA levels under 50 copies/ml was significantly greater in the efavirenz arm at 3 years by the intention-to-treat analysis [59% (41%, 75%) vs. 23% (10%, 41%)], whereas no differences were found in the on-treatment analysis. Immune activation (CD8(+)CD38(+) and CD8(+)CD38DR(+) T cells) was significantly lower for the efavirenz arm from month 6 to month 24. Adverse events were more frequent in the ritonavir-boosted indinavir arm. Almost all cases of disease progression and death were observed in the first year of treatment, with no significant differences between the two arms (p = 0.79 by the log-rank test). At 1 and 3 years, the immune reconstitution induced by an efavirenz-based regimen in very immunosuppressed patients was at least as potent as that induced by a ritonavir-boosted protease inhibitor-based antiretroviral regimen.

[Clinical and pharmacokinetic interactions between methadone and nelfinavir (Nemesia study)]. / Interacciones clínicas y farmacocinéticas entre metadona y nelfinavir (estudio Nemesia).

BACKGROUND AND OBJECTIVE: Patients on methadone maintenance therapy who are administered nelfinavir show a decrease in methadone plasma levels. However, the clinical relevance of this fact is seldom significant because it does not correlate with the appearance of opioid withdrawal symptoms (OWS). The objective of this study was to assess the clinical and pharmacokinetic interactions between methadone and nelfinavir. PATIENTS AND METHOD: A prospective multicenter study of human immunodeficiency virus (HIV) positive patients on stable methadone therapy who initiated nelfinavir was performed. To determine the presence of OWS, 2 questionnaires, objective and subjective, were administered at weeks 1, 2, 3 and 4. A pharmacokinetic study measuring the minimal plasmatic concentration of methadone was done at baseline and at week 4. RESULTS: 29 patient were included. In 7 patients who underwent pharmacokinetic studies, the minimal plasmatic concentration of methadone decreased after 4 weeks of nelfinavir treatment from 6.889 ng/ml to 4.354 ng/ml (37%; p = 0.046). However the results of the questionnaires did not show the significant OWS, which precluded an increase in the dose of methadone. CONCLUSIONS: In patients under stable methadone treatment, antiretroviral therapy including nelfinavir does not require any significant modification of methadone dose. The decrease in methadone plasmatic levels does not correlate with OWS.

Interacciones clínicas y farmacocinéticas entre metadona y nelfinavir (estudio Nemesia) / Clinical and pharmacokinetic interactions between methadone and nelfinavir (Nemesia study)

Fundamento y objetivo: En los pacientes tratados con nelfinavir y metadona disminuyen los valores plasmáticos de ésta, lo que clínicamente no suele ser importante, ya que no aparecen síntomas de abstinencia a opiáceos (SAO). Nuestro objetivo ha sido evaluar las interacciones clínicas y farmacocinéticas entre la metadona y el nelfinavir. Pacientes y método: Estudio prospectivo y multicéntrico con pacientes infectados por el virus de la inmunodeficiencia humana en tratamiento estable con metadona que iniciaban nelfinavir. La presencia de SAO se averiguó mediante sendos cuestionarios, objetivo y subjetivo, en las semanas 1, 2, 3 y 4. En un subgrupo de pacientes se midió la concentración mínima plasmática de metadona basalmente y a la cuarta semana de tratamiento. Resultados: Se incluyó a 29 pacientes y en 7 se realizó estudio farmacocinético. La concentración mínima plasmática de metadona disminuía a la cuarta semana de recibir nelfinavir desde 6,889 hasta 4,354 ng/ml (37%; p = 0,046). Los cuestionarios no detectaron SAO de forma significativa, por lo que no fue necesario cambiar significativamente las dosis de metadona. Conclusiones: La administración de nelfinavir en pacientes en tratamiento estable con metadona no precisa de modificaciones significativas de la dosis de ésta, ya que el descenso producido en sus valores plasmáticos no provoca la aparición de SAO

Background and objective: Patients on methadone maintenance therapy who are administered nelfinavir show a decrease in methadone plasma levels. However, the clinical relevance of this fact is seldom significant because it does not correlate with the appearance of opiod withdrawal symptoms (OWS). The objective of this study was to assess the clinical and pharmacokinetic interactions between methadone and nelfinavir. Patients and method: A prospective multicenter study of human immunodeficiency virus (HIV) positive patients on stable methadone therapy who initiated nelfinavir was performed. To determine the presence of OWS, 2 questionnaires, objective and subjective, were administered at weeks 1, 2, 3 and 4. A pharmacokinetic study measuring the minimal plasmatic concentration of methadone was done at baseline and at week 4. Results: 29 patient were included. In 7 patients who underwent pharmacokinetic studies, the minimal plasmatic concentration of methadone decreased after 4 weeks of nelfinavir treatment from 6.889 ng/ml to 4.354 ng/ml (37%; p = 0.046). However the results of the questionnaires did not show the significant OWS, which precluded an increase in the dose of methadone. Conclusions: In patients under stable methadone treatment, antiretroviral therapy including nelfinavir does not require any significant modification of methadone dose. The decrease in methadone plasmatic levels does not correlate with OWS

Polymorphism of RANTES chemokine gene promoter is not associated with long-term nonprogressive HIV-1 infection of more than 16 years.

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions -28C>G, -109T>C, and -403G>A were assessed. The prevalence of the CCR5Delta 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the chi2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for -28G; 4%, 2%, and 2% for -109C; and 18%, 18%, and 18% for -403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Delta32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.

Vitamin B-12 metabolism in HIV-infected patients in the age of highly active antiretroviral therapy: role of homocysteine in assessing vitamin B-12 status.

BACKGROUND: Before the advent of highly active antiretroviral therapy (HAART), 20% and 10% of HIV-infected patients had low vitamin B-12 and red blood cell folate (RBCF) concentrations, respectively. However, few patients had real vitamin B-12 deficiency. OBJECTIVE: We evaluated the prevalence of low vitamin B-12 and RBCF concentrations in HIV-infected patients receiving HAART and the usefulness of serum homocysteine (sHcy) for differentiating patients with deficiency from those with harmlessly low vitamin B-12. DESIGN: The prevalence of low vitamin B-12 and RBCF was evaluated in 126 HIV-infected patients receiving HAART. Moreover, sHcy concentrations were evaluated in 40 HIV-infected patients with low vitamin B-12 and in 37 HIV-infected patients with low RBCF and were compared with those in 128 HIV-infected patients with normal vitamin B-12 and RBCF. sHcy was used to monitor treatment with vitamin B-12 and folic acid in 28 patients (24 with low vitamin B-12 and RBCF and 4 with hyperhomocysteinemia but normal vitamin B-12 and RBCF). RESULTS: The prevalence of low vitamin B-12 was significantly lower in patients receiving HAART than in previously studied patients who did not receive HAART (8.7% compared with 27%). Nine of the 40 patients (22.5%) with low vitamin B-12 (< or = 200 pmol/L) had hyperhomocysteinemia (> 17.5 micromol homocysteine/L). Nineteen (51.4%) of the 37 patients with low RBCF (< or = 580 nmol/L, percentile 10) had hyperhomocysteinemia. Among the 9 patients with an RBCF concentration < or = 450 nmol/L (percentile 2.5), all had hyperhomocysteinemia. The treatment with vitamin B-12 and folic acid normalized sHcy concentrations. CONCLUSIONS: The prevalence of low vitamin B-12 decreased after the introduction of HAART. The study of sHcy is useful for detecting HIV-infected patients with low vitamin B-12 and real deficiency.