Renal safety of coformulated tenofovir/emtricitabine vs other nucleoside analogues in combination therapy in antiretroviral-naive patients aged 50 years or older in Spain: The TRIP study.

OBJECTIVES: Our aim is to describe the impact of emtricitabine (FTC)/tenofovir (TDF) versus other nucleoside reverse transcriptase inhibitor (NRTIs)-based regimens on renal function of human immunodeficiency virus (HIV) naïve patients >50 years old who started combination antiretroviral therapy (cART). DESIGN: National, retrospective cohort analysis of patients >50 years old when they started cART (January 1, 2006-December 31, 2009). METHODS: We compared renal safety (changes in estimated glomerular filtration rate [eGFR] during the first year, and time to renal events during 4 years of follow-up) in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitors vs non-nucleoside reverse transcriptase inhibitors and Lopinavir/ritonavir vs Efavirenz. RESULTS: We included 103 patients: median age: 54.9 years, 84% males, median CD4 count 247 cells/µl, median viral load 4.7 log; median follow up 18 months (max: 48 months); 73 started with FTC/TDF and 30 with other NRTIs. Change in eGFR was significantly worse for ritonavir-boosted lopinavir (LPV/r) vs efavirenz (EFV) users in the FTC/TDF group (71.2 vs 98.9 ml/min/1.73 m(2) at month 12, P < 0.05). The risk of renal events (progression to an Chronic Kidney Disease Epidemiology Collaboration value < 60 ml/min/1.73 m(2) in subjects with baseline values >60) was comparable for FTC/TDF users and non users, but was higher and almost significant for LPV/r as compared to EFV users in the FTC/TDF group (adjusted hazard ratio 6.1, 95% CI 0.8-45.5). CONCLUSIONS: In our study with a population of HIV infected subjects ≥ 50 years old, renal safety was similar for FTC/TDF and other NRTI-based regimens, but worse for LPV/r as compared to other regimens.

[Consensus statement on metabolic disorders and cardiovascular risks in patients with human immunodeficiency virus]. / Documento de consenso sobre alteraciones metabólicas y riesgo cardiovascular en pacientes con infección por el virus de la inmunodeficiencia humana.

OBJECTIVE: This consensus document is an update of metabolic disorders and cardiovascular risk (CVR) guidelines for HIV-infected patients. METHODS: This document has been approved by an expert panel of GEAM, SPNS and GESIDA after reviewing the results of efficacy and safety of clinical trials, cohort and pharmacokinetic studies published in biomedical journals (PubMed and Embase) or presented in medical scientific meetings. Recommendation strength and the evidence in which they are supported are based on the GRADE system. RESULTS: A healthy lifestyle is recommended, no smoking and at least 30min of aerobic exercise daily. In diabetic patients the same treatment as non-HIV infected patients is recommended. HIV patients with dyslipidemia should be considered as high CVR, thus its therapeutic objective is an LDL less than 100mg/dL. The antihypertensive of ACE inhibitors and ARAII families are better tolerated and have a lower risk of interactions. In HIV-patients with diabetes or metabolic syndrome and elevated transaminases with no defined etiology, the recommended is to rule out a hepatic steatosis Recommendations for action in hormone alterations are also updated. CONCLUSIONS: These new guidelines update previous recommendations regarding all those metabolic disorders involved in CVR. Hormone changes and their management and the impact of metabolic disorders on the liver are also included.

Executive summary of the consensus document on metabolic disorders and cardiovascular risk in patients with HIV infection.

The importance of the metabolic disorders and their impact on patients with HIV infection requires an individualized study and continuous updating. HIV patients have the same cardiovascular risk factors as the general population. The HIV infection per se increases the cardiovascular risk, and metabolic disorders caused by some antiretroviral drugs are added risk factors. For this reason, the choice of drugs with a good metabolic profile is essential. The most common metabolic disorders of HIV infected-patients (insulin resistance, diabetes, hyperlipidemia or osteopenia), as well as other factors of cardiovascular risk, such as hypertension, should also be dealt with according to guidelines similar to the general population, as well as insisting on steps to healthier lifestyles. The aim of this document is to provide a query tool for all professionals who treat HIV-patients and who may present or display any metabolic disorders listed in this document.

Safety, efficacy, and persistence of emtricitabine/tenofovir versus other nucleoside analogues in naive subjects aged 50 years or older in Spain: the TRIP study.

OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naïve patients who are ≥50 years. DESIGN: National, retrospective cohort analysis of patients who were ≥50 years old when they began the first cART (January 1, 2006 to December 31, 2009). METHODS: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. RESULTS: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/µL, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event ≥grade 3, 5.6% interrupted cART due to adverse events,19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non-FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% CI, 1.34-3.29). CONCLUSIONS: In a population of HIV-infected subjects who were ≥50 years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens.

Dyslipidaemia in HIV-infected women on antiretroviral therapy. Analysis of 922 patients from the Spanish VACH cohort.

BACKGROUND: Information concerning lipid disturbances in HIV-infected women on antiretroviral therapy (ART) is scarce. The objective of the study is to describe the lipid profile in a large cohort of HIV-infected women on contemporary ART and analyse differences between regimes and patient's characteristics. METHODS: Observational, multicentre, cross-sectional study from the Spanish VACH Cohort. 922 women on stable ART without lipid-lowering treatment were included. RESULTS: Median age was 42 years, median CD4 lymphocyte count was 544 cells/mm3, and 85.6% presented undetectable HIV-1 viral load. Median total cholesterol (TC) was 189 mg/dL (interquartile range, IQR, 165-221), HDL cholesterol 53 mg/dL (IQR, 44-64), LDL cholesterol 108 mg/dL (IQR, 86-134), and triglycerides 116 mg/dL (IQR, 85-163). Mean accumulated time on ART was 116 months; 47.4% were on NNRTI-based regimes, 44.7% on PI, and 6.7% on only-NRTI therapy. 43.8% were also hepatitis C (HCV) coinfected. Patients on PI treatment presented higher TC/HDL ratio than those on NNRTI (p < 0.001). Significantly higher HDL values were observed in NNRTI-treated patients. HCV-coinfected patients presented lower TC/HDL ratio than the non HCV-coinfected. In multivariate analysis, factors independently associated with TC/HDL ratio were age, triglyceride levels and HCV co-infection. PI treatment presented a non-significant association with higher TC/HDL ratio. CONCLUSIONS: In HIV-infected women, the NNRTI-based ART is associated with a better lipid profile than the PI-based. Factors unrelated to ART selection may also exert an independent, significant influence on lipids; in particular, age, and triglyceride levels are associated with an increased TC/HDL ratio while HCV co-infection is associated with a reduced TC/HDL ratio.

Effect of TNF-alpha genetic variants and CCR5 Delta 32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards.

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is thought to be involved in the various immunogenetic events that influence HIV-1 infection. METHODS: We aimed to determine whether carriage of the TNF-alpha-238G>A, -308G>A and -863 C>A gene promoter single nucleotide polymorphisms (SNP) and the CCR5 Delta 32 variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). TNF-alpha SNP and the CCR5 Delta 32 allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the chi 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis. RESULTS: The distribution of TNF-alpha-238G>A, -308G>A and -863 C>A genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: -238G>A, p = 0.7 and p = 0.3; -308G>A, p = 0.05 and p = 0.07; -863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three TNF-alpha genetic variants assessed was non-significantly different between TP and LTNP: -238G>A, p = 0.35 and p = 0.7; -308G>A, p = 0.7 and p = 0.6: -863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the TNF-alpha-238A variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The CCR5 Delta 32 distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively). CONCLUSIONS: In our cohort of Caucasian Spaniards, TNF-alpha genetic variants could be involved in the vulnerability to HIV-1 infection. TNF-alpha genetic variants were unrelated to disease progression in infected subjects. The -238G>A SNP may modulate the control of viremia in LTNP. Carriage of the CCR5 Delta 32 variant allele had no effect on the risk of infection and disease progression.

Characteristics and outcome of HIV infection in gypsies in the Spanish VACH Cohort.

OBJECTIVE: To study the characteristics of HIV infection in the gypsy (Roma) population in Spain, as compared with those of the Caucasian, non-gypsy majority. DESIGN: Cross-sectional, historical cohort study from the Spanish VACH Cohort. METHODS: Patients attending VACH clinics between 1 June 2004 and 30 November 2004 were classified according to their racial and ethnic origin as "gypsies", Caucasian non-gypsy Spanish natives (CNGN), and "other" (the last being excluded from this study). Their sociodemographic and clinico-epidemiological characteristics were compared, as well as the Kaplan-Meier curves of time to AIDS, or death, or disease progression (either of the 2 outcomes). RESULTS: 4819 (48%) of 10,032 cases included in the VACH database were eligible: 210 (4.2%) were gypsies and 4252 (84.8%) were CNGN. Differences were observed in age, household, academic, inmate, marital, and employment history. Injecting drug use had been the most frequent mechanism of transmission in both groups, but to a greater extent among gypsies (72% versus 50%; P<0.000). Sex distribution, CD4 cell counts, and viral loads at the first visit were similar in the 2 groups, as was the percentage of patients with previous AIDS, percentage receiving antiretrovirals, and percentage subsequently starting antiretroviral therapy. Up to 1 April 2005, 416 new AIDS cases and 85 deaths were recorded. The percentage of these outcomes did not differ between groups, but log-rank test showed a shorter time to AIDS and disease progression among gypsies. CONCLUSIONS: The sociodemographic characteristics of gypsies, the largest minority in the VACH Cohort, show differences relative to those of CNGN. HIV-related outcomes suggest that gypsies have a poorer prognosis.

Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients.

Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays. Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity. Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14). Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (-17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity. Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.

Saquinavir exposure in HIV-infected patients with chronic viral hepatitis.

OBJECTIVES: The aim of this study was to assess the influence of hepatitis B virus or hepatitis C virus co-infection and the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics in HIV-infected subjects without liver function impairment. METHODS: A cross-sectional, comparative study enrolling HIV-infected adults receiving saquinavir/ritonavir 1000/100 mg twice daily or 1500/100 mg once daily was conducted. Patients with chronic viral hepatitis (HEP+) were grouped as having advanced liver fibrosis (HEP+/FIB+) or not (HEP+/FIB-) based on the FIB-4 index. Saquinavir and ritonavir trough concentrations (C(trough)) in plasma were determined by HPLC. The geometric mean ratio (GMR) was used to compare saquinavir and ritonavir C(trough) between HEP- and HEP+ patients, and the influence of the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics was explored using analysis of variance. RESULTS: One hundred and thirty-eight patients on twice-daily saquinavir/ritonavir (67 HEP-, 71 HEP+) and 36 patients on once-daily saquinavir/ritonavir (12 HEP-, 24 HEP+) were included. Saquinavir C(trough) was comparable between HEP- and HEP+ patients receiving either saquinavir/ritonavir 1000/100 mg twice daily [GMR 0.91, 95% confidence interval (CI) 0.60-1.37; P = 0.655] or 1500/100 mg once daily (GMR 0.88, 95% CI 0.39-1.97; P = 0.752). Similarly, ritonavir C(trough) was also comparable between HEP- and HEP+ patients. The extent of liver fibrosis was not significantly related to saquinavir or ritonavir C(trough) in patients receiving either of the two studied doses. CONCLUSIONS: Saquinavir C(trough) was not increased in HIV-infected patients with chronic viral hepatitis in the absence of liver function impairment. These results confirm that no specific dose modification of saquinavir/ritonavir should be recommended in this setting.

Effectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohort.

BACKGROUND: Preliminary data suggest that a once-daily combination of lamivudine, didanosine and efavirenz is an effective alternative regimen for antiretroviral-naive HIV-1-infected patients. However, data from randomized trials comparing this combination versus standard first-line regimens are not available yet. In an observational study, we analyse the efficacy and tolerability of didanosine plus lamivudine and efavirenz versus zidovudine plus lamivudine and efavirenz in a cohort of therapy naive patients. METHODS: We performed an observational study on prospectively collected data from patients participating in a multicentre Spanish treatment-naive cohort (VACH cohort). Efficacy was assessed comparing time to therapeutic failure and CD4 cell recovery. Safety was analysed comparing the proportion of patients who discontinued therapy for toxicity or any other reason. RESULTS: Overall, 219 patients treated with once-daily didanosine/lamivudine/efavirenz and 409 patients receiving twice-daily zidovudine/lamivudine (Combivir) plus efavirenz were evaluated. By intent-to treat analysis (non-completers and therapeutic change=failure), time to treatment failure was similar in both groups of treatment: 40.0 months (95% CI 23.3-56.8 months) among patients on didanosine/lamivudine/efavirenz and 33.3 months (95% CI 25.6-41.1 months) in patients treated with zidovudine/lamivudine/efavirenz (P=0.253). The risk of failure due to treatment change was almost double among patients treated with zidovudine/lamivudine/efavirenz compared with those who received didanosine/lamivudine/efavirenz. CONCLUSIONS: Our data suggest that didanosine/lamivudine/efavirenz is a combination with an efficacy comparable to zidovudine/lamivudine/efavirenz as first-line therapy for HIV infection. The risk of treatment change was significantly higher among patients treated with zidovudine/lamivudine/efavirenz than in those starting therapy with didanosine/lamivudine/efavirenz.

Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903.

BACKGROUND: The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. METHODS: We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log(10) or > or =5.0 log(10) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of <50 copies/mL at week 48, determined by intention-to-treat analysis. RESULTS: Three hundred sixty-nine patients were randomized: 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment. Both groups were well matched in terms of baseline characteristics; 19.3% of patients received a Centers for Disease Control and Prevention assessment of clinical category C, median HIV RNA level was 5.0 log(10) copies/mL, and median CD4(+) cell count was 208 cells/microL. At week 48, by intention-to-treat analysis, 70% of patients in the ddI/3TC/EFV group and 63% of patients in the COM/EFV group had an HIV-1 RNA level of <50 copies/mL (treatment difference, 7.1%; 95% confidence interval, -2.39% to 16.59%). Fourteen patients (8%) in the ddI/3TC/EFV arm (not the COM/EFV arm) and 26 patients (14%) in the COM/EFV arm (not the ddI/3TC/EFV arm) [corrected] discontinued the study medication because of adverse events (P = .046). One patient (1%) in the ddI/3TC/EFV arm and 11 patients (6%) in the COM/EFV arm discontinued medication because of hematological toxicity (P = .003). CONCLUSIONS: At week 48, ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment. A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events, mainly because of hematological toxicity. CLINICAL TRIALS REGISTRATION: NCT00256828.

Three-year follow-up of protease inhibitor-based regimen simplification in HIV-infected patients.

Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were randomly assigned to switch the PI to nevirapine (n = 155), efavirenz (n = 156), or abacavir (n = 149) and were followed for at least 3 years regardless of the discontinuation of assigned therapy. There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir. In contrast, abacavir showed a lower incidence of adverse effects leading to drug discontinuation.

Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection.

BACKGROUND: We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved. METHODS: We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter. RESULTS: At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients. Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups. CONCLUSIONS: When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.

[Efficacy and safety of a reduced-dose of stavudine in HIV-infected patients under immunological and virological stable conditions]. / Impacto de la reducción de dosis de estavudina en su perfil de eficacia/seguridad en pacientes con infección por el virus de la inmunodeficiencia humana inmunológica y virológicamente estables.

BACKGROUND AND OBJECTIVE: Stavudine (d4T) has shown a favourable short and long-term tolerability profile. Nevertheless, its usage is currently decreasing due to some safety concerns. We aimed to evaluate the efficacy and safety of d4T low-dose-based regimens. PATIENTS AND METHOD: This was a multicenter and retrospective review chart of patients receiving standard doses of d4T for > or = 6 months (weight > 60 kg: 40 mg/12 h; weight < 60 kg: 30 mg/12 h) and having undetectable viral load for at least 3 months before the d4T dose reduction (weight > 60 kg: 30 mg/12 h; weight < 60 kg: 20 mg/12 h). Immunological and viral parametres, lipid profile and side effects were determined. RESULTS: A total of 982 patients were included. The main reason for reducing the dose was prevention of toxicity (76%). After 6 months of follow-up, 97% and 84% patients had less than 400 and 50 cp/ml, respectively, and the CD4 cell count increased by 38 cel/ml. Lipids, lipodystrophy and peripheral polineuropathy improved but there was no statistical significance. CONCLUSIONS: A d4T dose reduction in an immuno-virologically stable population does not affect treatment efficacy. Longer follow-ups are required to confirm improvements in the safety profile.

Short communication metabolic and mitochondrial effects of switching antiretroviral-experienced patients to enfuvirtide, tenofovir and saquinavir/ritonavir.

OBJECTIVE: Investigate the metabolic and mitochondrial effects of switching a highly active antiretroviral therapy (HAART) regimen with a high mitochondrial toxicity profile to a HAART with a theoretically low mitochondrial toxicity. PATIENTS AND METHODS: Six consecutive HAART-experienced patients receiving at least one dideoxy-nucleoside reverse transcriptase inhibitor (NRTI) switched to enfuvirtide plus tenofovir plus saquinavir/ritonavir (T20+TDF+SQV/r). Blood samples were collected at baseline, 12 and 24 weeks after the switch, and viral load (VL) and lymphocyte CD4+ T-cell count were determined. Metabolic parameters consisted of fasting serum triglycerides, cholesterol (total and fractions), glucose, insulin, C-peptide and lactate. Mitochondrial assessment consisted on mitochondrial DNA (mtDNA) quantification, COX-II mitochondrial protein expression rate, mitochondrial respiratory chain complex III and IV activities, and oxygen consumption in peripheral blood mononuclear cells. For baseline mitochondrial comparisons, we included six HIV-infected patients naive for ART. RESULTS: Switched patients exhibited a mean increase of 26 CD4+ T-cells/mm3 and a mean decrease of 1.1 log in VL (P = NS for both). Lactate, lipids and glycaemia remained stable during the study; only insulin levels increased significantly (P < 0.05). Switched patients exhibited, at baseline, low mitochondrial measurements, being significant only for complex III and IV activities with respect to naive patients (P < 0.05 for both). MtDNA content did not rise significantly during the study. However, we observed increases in COX-II mitochondrial protein synthesis (124%, P < 0.05), complex III activity (127%, P < 0.05), complex IV activity (86%, P = 0.37) and oxygen consumption (194%, P < 0.05). CONCLUSION: Switching a HAART-containing dideoxy-NRTI to T20+TDF+SQV/r minimally alters metabolic parameters and exerts beneficial effects on mitochondrial function at 24 weeks. Mitochondrial improvement should be considered as an additional advantage of this rescue therapy.

Results of a study of prolonging treatment with pegylated interferon-alpha2a plus ribavirin in HIV/HCV-coinfected patients with no early virological response.

OBJECTIVE: To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR). METHODS: Patients received pegylated interferon (peg-INF)-alpha2a 180 microg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm). RESULTS: One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%. CONCLUSIONS: This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.

Long-term safety and efficacy of nevirapine-based approaches in HIV type 1-infected patients.

Using a multicenter, cross-sectional, observation study, the long-term safety, metabolic profile, and viral efficacy of nevirapine (NVP)-based approaches in HIV-1-infected patients treated for at least 2 years were assessed. For 4 months, all consecutive HIV-1-infected patients who had been receiving an NVP-containing regimen for at least 2 years were recruited. A total of 613 patients were included with a median follow-up period of 43 months (IQR: 31-51). At baseline, 24.5% (150 patients) were treatment naive, 41.5% (254 patients) switched for simplification purposes, and 34% (209 patients) were failing HAART. Increases by five times or more in AST/ALT values were observed in fewer than 2% of patients. Only 5.7% of all adverse events reported during the investigation were attributable to NVP. The percentage of patients with normal HDL cholesterol levels rose from 17.7% at baseline to 35.4% at the last visit. At the latest time point available for analysis, 76% of naive and 74% of those who had switched had HIV-1 RNA loads of <50 copies/ml, while 59% of salvage patients achieved this level of viral suppression. Factors associated with viral suppression at the latest visit were adequate adherence (OR: 2.58, 95% CI: 0.85-7.78, p < 0.001), first-line treatment (OR: 3.02, 95% CI: 1.52-6.00, p = 0.002), and baseline CD4 cells >400 cells/microl (OR: 2.34, 95% CI: 1.22-4.47, p = 0.010). Exposure to nevirapine for up to 4 years is safe. Liver toxicity is infrequent and generally mild. HDL cholesterol levels consistently increase over time and viral suppression is maintained.

[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.