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The aim of this revision is to evaluate ethnicity and gender rate of enrolment in registrative clinical trials of the protease inhibitors (Pls) from 1996 to 2009. Company-sponsored, phase II or III registrative clinical trials of PIs were evaluated. Forty-nine clinical trials were included. Clinical trials were conducted in centres in North America (n = 39), Central-South America (n = 22), Europe (n = 22), Africa (n = 8), Asia (n = 5), Australia (n = 10). Overall mean age was 39.6 years; median proportion of women was 16.3%. The most represented ethnic group was Caucasian. A test for trend over time (1996-2009) shows a significant increase in the proportion of women included (P = 0.012), and a decrease in the proportion of Caucasians included, reaching borderline significance (P = 0.061). An inverse correlation was observed between the proportion of Caucasians and that of women enrolled in each study (r = -0.65, P < 0.0001). Women were less likely to be included in double-blind studies (11.2% versus 17%, P = 0.019). Clinical trials for treatment-naive subjects were more likely to enrol ethnicities other than Caucasian compared with Caucasian (44.7% versus 27.1%, respectively, P = 0.04). Rates of enrolment of minorities in registrative clinical trials for Pls show a positive trend since 1996, mirroring the growing number of people of different ethnic groups accessing ART.

Objective: The primary objective of this study was to investigate the impact of HCV infection and of HCV genotypes on immune restoration in HIV-infected patients on a successful HAART regimen., Methods: Patients from the MASTER Study were included in this current longitudinal study if they met the following criteria: being on any successful HAART, availability of CD4+ cell count and HIV RNA level before starting the suppressive HAART and 12 months after suppressive therapy, availability of HCV antibodies. The primary endpoints of the study were defined as achieving a difference above 100 cell/mmc between CD4+ at baseline and at time of HIV RNA suppression while on therapy (DeltaCD4+early), or 12 month after a suppressive therapy (DeltaCD4+late)., Results: 844 HIV-positive patients were included in the analysis: 673 were HCV-negative and 171 were HCV-positive [92 (53.8%) subjects had HCV genotype 1; 58 (33.9%), genotype 3; 21 (12.3%), genotype 4]. Plasma HIV RNA (both baseline as highest value), nadir CD4+, being naïve, time to reach undetectable plasma HIV RNA, treatment with PI vs NNRTI were associated with an early immunological recovery; the occurrence of previous AIDS event, a history of injection drug use, and HCV infection were associated with failure to achieve an early immunological recovery. Variables associated with DeltaCD4+late immune recovery were baseline CD4+ value, plasma HIV RNA (both baseline as highest value), being naïve and time to reach undetectable plasma HIV RNA. HCV infection per se was not associated with a worse probability to reach late immunologic response, although among HCV infected patients, having a genotype 3 was associated with a worse immune recovery. At multivariable analysis, factors that remained associated with failure to achieve an early immunological response were being HCV infected and history of injection drug use, while those associated with a failure to achieve a late immunological response were being infected with HCV genotype 3 and older age., Conclusions: A blunted early immune recovery was observed in HCV infected patients, compared with HCV negative subjects, while late immune recovery was not different among HCV infected as a whole and not infected subjects; only the subgroup of subjects infected with genotype 3 showed an impaired late immune recovery.

Background: In HIV-1-infected patients harbouring the M184V mutation (M184V), lamivudine monotherapy leads to a smaller decrease in CD4 percentages (CD4%) than treatment interruption, possibly due to the reduced fitness of the mutated virus., Objective: We assessed whether a minimal dose of a cytidine analogue that is theoretically sufficient to maintain M184V (one emtricitabine tablet once-weekly) may be as effective., Study Design: In a proof-of-concept, randomised clinical trial, HIV-1-infected patients with CD4 cells >400/mm(3), failing on lamivudine- or emtricitabine-containing combination antiretroviral therapy (cART), received emtricitabine once-a-week (A), or emtricitabine once-a-day (B), or lamivudine once-a-day (C). The primary endpoint was the proportion of subjects without a 12-week loss in CD4%. The patients resumed cART after 24 weeks or in the case of CD4 cells <350/mm(3)., Results: The 38 enrolled patients had similar baseline characteristics across groups. The primary endpoint was reached by 5/13 patients (38.5%) in arm A, 3/13 (23.1%) in arm B, and 3/12 (25%) in arm C (P=0.644), and respectively 4/13 (30.8%), 4/13 (30.8%) and 5/12 (41.7%) had to resume cART within 24 weeks (P=0.805). The immunological changes over 24 weeks were similar in the three groups, but there was a higher median viral rebound in once-weekly treatment recipients (A) than in once-daily (B+C): 0.97 versus 0.52log(10)copies/ml (P=0.033). M184V was maintained in all the participants., Conclusions: Once-weekly emtricitabine led to a higher viral rebound than once-daily monotherapy, but similar immunological changes, thus suggesting a role of M184V in slowing the decrease in CD4% in treatment failing subjects.

Background: The extent of short-term CD4(+) T-cell recovery in patients tolerating first-line highly active antiretroviral therapy (HAART) and attaining undetectable HIV RNA levels is inadequately defined., Methods: We retrospectively analysed patients in four Italian cohorts who started HAART between January 1996 and September 2006. All patients had known HCV coinfection status, did not modify the regimen for 6 months and had <50 HIV RNA copies/ml at the end of the sixth month., Results: The analysis involved 1,488 patients (1,096 males, 73.7%) with a median age of 43 years (interquartile range [IQR] 39-49); 435 (29.2%) were positive for HCV, 71 (4.8%) were positive for hepatitis B surface antigen (HBsAg) and 76 (5.1%) had experienced a previous AIDS-defining event. At baseline, patient CD4(+) T-cell counts were 226 cells/microl (IQR 99-332), CD4(+) T-cell percentages were 14.7% (IQR 8.7-21.2) and HIV RNA levels were 4.91 log(10) copies/ml (IQR 4.38-5.34). Overall, 24-week CD4(+) T-cell recovery was 144 cells/microl (IQR 70-240). At multivariable analysis, T-cell recovery was positively related to the use of a boosted protease inhibitor (P<0.0001) or thymidine analogues (P<0.0001), baseline HIV RNA levels (P<0.0001), the baseline percentage of CD4(+) T-cells (P<0.0001) and the absence of HCV coinfection (P=0.006). Age, gender, baseline CD4(+)/CD8(+) T-cell ratio and a history of AIDS-defining events had no independent effect on CD4(+) T-cell recovery., Conclusions: Among HIV-infected patients tolerating first-line HAART and with undetectable HIV RNA after 6 months, CD4(+) T-cell recovery is significantly greater in those without HCV coinfection, with a high baseline viral load, a high baseline percentage of CD4(+) T-cells and in those treated with a boosted protease inhibitor.

Objectives: To evaluate changes in resistance to tipranavir/r (TPV/r) and darunavir/r (DRV/r) in patients who had failed a TPV/r-including regimen., Methods: HIV genotypes obtained both at baseline and at tipranavir/r failure (TPVF) were analyzed in 47 HIV-infected patients failing a TPV/r-including regimen. Genotypes were evaluated through the Stanford mutation score: patients were ranked for TPV/r and DRV/r resistance as susceptible (class 1), potential low-level (class 2), low-level (class 3), intermediate-level (class 4), and high-level resistance (class 5). Values are expressed as median (interquartile range) or as frequency (%)., Results: Forty-seven patients were eligible. At baseline (tipranavir initiation), the scoring for TPV/r was: class 3 = 4 (8.5%); class 4 = 31 (66%); and class 5 = 12 (25.5%). Corresponding scores for DRV/r were: class 2 = 1 (2%), class 3 = 12 (25.5%), class 4 = 32 (68%), and class 5 = 2 (4.5%). At TPVF, a shift toward a higher TPV/r scoring class was seen in 16 (34.1%) patients (P = 0.001), whereas a shift toward a higher DRV/r scoring class was observed in 9 (19.2%) patients (P = 0.2381). After TPVF, 25/47 patients (53%) were treated with a DRV/r-containing regimen. After 24 weeks (on-treatment analysis), the median HIV RNA decrease was 3.04 (2.13-3.45) log10 copies per milliliter in DRV/r group versus -0.04 (-0.44; 0.50) log10 copies per milliliter in patients not treated with a DRV/r-containing regimen (P < 0.0001); CD4 increase was 126 (70-169) cells per cubic millimeter in DRV/r group versus -42 (-121; 42) (P < 0.0001)., Discussion: Treatment with TPV/r did not significantly increase the resistance score to DRV/r and did not preclude the efficacy of subsequent treatment with DRV/r.

Background: Etravirine (ETR; also known as TMC125) is a new nonnucleoside reverse-transcriptase inhibitor with activity against wild-type and nonnucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus type 1 (HIV-1)., Methods: This randomized, phase IIb, placebo-controlled, 2-stage, dose-escalating trial evaluated the safety, tolerability, and preliminary efficacy of 3 twice-daily doses of ETR (experimental formulation TF035; compared with placebo), administered with an individually optimized background regimen, in treatment-experienced HIV-1-infected patients. In stage 1 of the trial, 166 patients received ETR (400 mg or 800 mg twice daily) or placebo. In stage 2 of the trial, 74 patients received ETR (800 mg or 1200 mg twice daily) or placebo. The primary objective was to assess the safety and tolerability of the regimens over 48 weeks., Results: Neuropsychiatric adverse events (AEs) of interest occurred in 46.6% of patients in the combined ETR group and in 45.5% of patients in the combined placebo group (P=.89). Clinically relevant hepatic AEs occurred in 3.4% of patients who received ETR and in 6.1% of patients who received placebo (P=.47), and rash occurred in 19.5% and 12.1%, respectively (P=.25). In general, there was no evidence of a relationship between ETR dose and specific AEs. Most AEs were severity grade 1 or 2; the incidence of grade 3 or 4 AEs was comparable between groups (27.0% in the combined ETR group vs. 27.3% in the placebo group). Plasma preparation tubes were used for viral load measurement. In stage 1, there was no statistically significant difference in efficacy between ETR and placebo. In stage 2, the decrease in log10 plasma viral load between baseline and week 24 was statistically significantly greater in patients who received ETR, compared with patients who received placebo; a trend in favor of ETR persisted until week 48., Conclusions: ETR was generally safe and well tolerated during long-term administration in treatment-experienced, HIV-1-infected patients, and it had a safety profile comparable to that of placebo.

The aim of this meta-analysis study was to evaluate the relative risk of death or AIDS-defining events associated to CD4+ guided treatment interruption in patients with chronic HIV infection. A search was conducted using PubMed and Cochrane Library; key words for PubMed were: "antiretroviral therapy and interrupt*" in the full papers from January 1, 2000 up to and including December 31, 2007. To limit the publication bias, clinical trials performed on the topic of the meta-analysis were searched also on http://www.clinicaltrial.gov. Inclusion criteria of studies were: starting a CD4+ guided interruption of HAART in HIV chronically infected patients with CD4+ cell count > 350 cells/mm3, age > 13 years old, and absence of concomitant use of immunomodulatory drugs. Using a conservative approach, to be included in the meta-analysis, studies had to have a follow up period > 100 person years to minimize the bias of a too short observation time. The studies were classified into two categories: randomized clinical trial (one arm stops therapy and other arms continues HAART) and cohort studies. For each study measures of effect (hazard ratio or incidence rate ratio) were reported, when available, uncorrected and corrected for potential confounders. Publication bias was assessed graphically through funnel plot. Pooled relative risk and pooled risk difference were calculated by use of a random effects model following the DerSimonian-Laird method. Observational studies were considered separately and the incidence of primary endpoint was evaluated in each study and the cumulative incidence was calculated. Of the 555 full papers found, all abstracts were screened and 58 full text articles for potential inclusion were retrieved and 18 were retained (seven randomized clinical trials and 11 observational studies). In randomized clinical trials, the meta-analysis showed that the pooled relative risk of AIDS-defining event or mortality was 2.50 (95% CI: 1.87-3.34; p < 0.001); the pooled risk difference of AIDS-defining event or mortality was 0.02 (95% CI: capital ER, Cyrillic0.01-0.05; p = 0.168). The respective values corrected for latest CD4+ value were 1.77 (95% CI: 1.29-2.42; p < 0.001) and 0.01 (95% CI: capital ER, Cyrillic0.01-0.02; p = 0.37). The pooled relative risk of death was 1.8 (95% CI: 1.18-2.77; p = 0.007), and the corresponding pooled risk difference was 0.01 (95% CI: 0.001-0.012; p = 0.03). The risk of death resulted to have increased in patients that interrupted treatment; the corresponding value of risk difference was significant, although it was low (one extra death per 100 person years). Considering that a separate analysis corrected for the latest CD4+ value was not feasible for this endpoint, and that mortality rates in HIV-infected patients are inversely correlated with the CD4+ count, the value reported is extremely conservative. In cohort studies, the cumulative incidence of deaths or AIDS-defining events in the five studies with follow-up > 100 person years, was 0.77 (95% CI: 0.37-1.42 events per 100 person years), ranging in different studies from 0 to 3.2 events per 100 person years. This meta-analysis suggests that in patients undergoing a treatment interruption, there is an increased risk of developing AIDS or death, and that this risk is decreased if a relatively high CD4+ threshold is chosen to reinitiate the treatment, while the risk difference does not reach statistical significance.

Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed for the treatment of HIV-1 infections. The drug was recently approved by the US FDA to be used in combination with other anti-HIV medications. Etravirine is a highly flexible diarylpyrimidine compound, with favorable binding interactions toward mutant HIV strains as well as wild-type virus. This conformation confers an increased genetic barrier to resistance compared with other NNRTIs: multiple mutations are required before there is a decrease in susceptibility to etravirine; whereas, only one mutation (K103N) is typically needed to confer high-level resistance to the first-generation NNRTIs. In vitro, etravirine is predominantly metabolized by cytochrome P450 (CYP)3A4 and CYP2C (2C9, 2C18 and 2C19). In vivo, the most important metabolic pathway for etravirine is methyl hydroxylation, with subsequent glucuronidation of the metabolites. Etravirine is an inducer of CYP3A4 and a weak inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. In Phase II and III trials in treatment-experienced patients, treatment with etravirine led to better virological suppression than placebo. In the DUET I and II trials (Phase III), approximately 60% of the etravirine group achieved a confirmed viral load of less than 50 copies/ml at week 24, compared with approximately 40% in the placebo arm. The mean change in viral load at week 24 was -2.34 (standard deviation: 1.31) and -1.68 (1.40) log(10) copies/ml in the etravirine and placebo groups, respectively. The presence of three or more NNRTI-associated mutations at baseline negatively influenced the outcome. There were no safety concerns and no major differences in frequency or severity of side effects between etravirine and placebo groups, with the exception of rash. Furthermore, the overall rate of discontinuation due to any adverse event was similar between the etravirine and placebo groups. The most common adverse events reported were rash and nausea.

HIV infected patients treated with highly active antiretroviral therapy (HAART) may be at increased risk of cardiovascular events, particularly if based upon the use of protease inhibitors (PI). We investigated the haemostatic markers of cardiovascular risk in 115 HIV infected subjects, divided into four groups : 1) patients naïve to antiretroviral therapy (Naïve; n=34 patients), or subjects that had been on a stable combination therapy for > or =12 months with either: 2) double reverse transcriptase nucleoside analogue inhibitors therapy (2NRTI; n=26), 3) 2NRTI backbone plus a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI; n=27), and 4) on a PI based regimen (PI; n=28). Forty-four healthy subjects were included as controls. Naïve as well as 2NRTI and NNRTI differed from controls for higher F1+2 (P<.0001) and FVII (P<.007) levels. When comparing PI patients with controls we observed significantly higher levels of Fbg (P=.035), FVII (P<.0001), TM (P<.0089), vWF (P=.009), and F1+2 (P<.0001). The only difference observed among the 4 groups of HIV infected patients was a significantly lower level of F1+2 in PI as compared with NNRTI patients (P=.05) At least one abnormal result was observed in > or = 90.6% of HIV infects groups, vs 43.2% of controls (P<.0001 in all cases). In conclusion, a) HIV infection per se may alter the haemostatic markers of cardiovascular risk, b) minor differences were observed among the different classes of HIV infected patients, namely between NNRTI and PI treated patients.

Objectives: The purpose of this study was to evaluate the steady-state pharmacokinetics of amprenavir and ritonavir in HIV-infected patients with different degrees of hepatic impairment., Methods: HIV-positive patients receiving fosamprenavir/ritonavir (700/100 mg twice daily) were included. Patients were classified into three groups: (i) chronic hepatitis; (ii) liver cirrhosis; (iii) normal liver function. Serial blood samples for steady-state amprenavir and ritonavir pharmacokinetics (>14 days on treatment) were collected in the fasting state before the morning dose (C(trough)) and then 1, 2, 3, 4, 6, 8, 10 and 12 h after drug intake. Amprenavir and ritonavir plasma concentrations were determined by HPLC., Results: Twenty-one HIV-infected patients were included. Seven had chronic hepatitis, eight had liver cirrhosis and six patients were in the control group. Amprenavir AUC(0-12), AUC(0-infinity), C(max) and C(ss) were increased by 50% to 60% in the cirrhotic group when compared with controls, whereas CL/F was decreased by 40%. Patients with chronic hepatitis showed a significant increase in AUC(0-12), C(max) and C(ss) values when compared with controls. Ritonavir pharmacokinetics was different only in cirrhotic patients when compared with controls. Liver function parameters at weeks 4, 12 and 24 were not different from baseline in any of the groups. Overall, a significant correlation between amprenavir AUC(0-12) and total bilirubin values on the day of pharmacokinetic analysis was found (r = 0.64, P = 0.003)., Conclusions: On the basis of these data and also of data available in the literature, it seems reasonable to adapt the dose of fosamprenavir and/or ritonavir exclusively in the presence of adverse events, possibly related to protease inhibitors (i.e. liver toxicity), in subjects with high drug plasma levels. Therapeutic drug monitoring is advised in the management of these patients.

Acute liver toxicity is a frequent adverse event that occurs during antiretroviral therapy and was observed in 6-30% of the patients on treatment, especially in presence of HCV coinfection (Cooper et al., 2002, Maida et al., 2006, Sulkowski et al., 2000). A correlation between HCV-associated liver-fibrosis severity and the risk of HAART associated hepatoxicity has been demonstrated (Aranzabal et al., 2005, Sulkowski et al., 2004). This high liver toxicity rate might be due to increased drug exposure in patients with liver disease (Veronese et al., 2000). It has been reported that patients with chronic hepatitis C show significantly reduced CPY3A4 and CYP2D6 activity in comparison with healthy volunteers (Becquemont et al., 2002). The aim of this study was to evaluate the liver function tests in HCV-co-infected patients treated with fos-amprenavir and ritonavir.

Objectives: The aim of this study was to evaluate the correlation between liver function markers (necrosis and cholestasis) and plasma lopinavir levels in a cohort of HIV-infected patients treated with lopinavir and ritonavir., Patients and Methods: The blood samples for determining steady-state C(trough) lopinavir levels and analysing liver function were drawn from fasting patients. Steady-state C(trough) lopinavir levels, liver function and immuno-virological markers were assessed on the same day. Plasma lopinavir and ritonavir levels were determined by means of high-performance liquid chromatography., Results: One hundred and forty-nine patients were included in the analysis [57 were HCV co-infected (34%) and 10 were HBV co-infected (6.7%)]; they had been treated with lopinavir/ritonavir for a median of 232 days (range 132-282). All patients received lopinavir/ritonavir [400/100 mg twice daily or 533/133 mg twice daily if amprenavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI) was part of therapy] and concomitant therapy with NRTI(s). Median (interquartile) lopinavir trough levels were 6391 ng/mL (4121-8726), 5662 (3585-8893) and 6819 ng/mL (5324-8726) in the patients with HIV alone and those with HIV/HCV (or HBV) co-infection, respectively (P = not significant). Univariate analysis showed a significant association between the cholestasis markers and C(trough) lopinavir level. Multivariate analysis selected only gamma glutamyltranspeptidase (GGT) (OR = 1.010, 95% CI: 1.002-1.021) as being independently associated with plasma lopinavir levels of >6425 ng/mL; alkaline phosphatase (OR = 1.004, 95% CI: 1.000-1.010; P = 0.08) and total bilirubin (OR = 3.118, 95% CI: 0.980-11.715; P = 0.07) were not associated., Conclusions: Elevated lopinavir concentrations are associated with raised GGT.

Objective: The aim of this pilot study was to examine the pharmacokinetics of atazanavir (ATV) when given in combination with amprenavir (APV) or saquinavir hard-gel capsules (SQV) to human immunodeficiency virus (HIV)-positive patients., Methods: Included in the study were 34 HIV-infected patients enrolled in the ATV Early Access Program, who were treated with unboosted ATV alone (group 1) or with the double protease inhibitor combinations, ATV plus APV (group 2) or ATV plus SQV (group 3). ATV was given at a daily dose of 400 mg q.d. with the morning meal with SQV 1200 mg per day or APV 1200 mg per day. Serial blood samples for steady-state ATV pharmacokinetics were collected before the morning dose and at 1, 2, 3, 6, 8 and 24 h post-dosing. ATV plasma concentrations were measured using a high-performance liquid chromatography method with ultraviolet detection., Results: Of the patients, 12 received ATV as a single protease inhibitor; 12 received ATV in combination with APV; and 10 in combination with SQV. Geometric mean (coefficient of variation) ATV C(trough) was 110 ng/ml (2.38), 86 ng/ml (0.84) and 149 ng/ml (2.01) in groups 1, 2 and 3, respectively. ATV C(trough) in both double protease inhibitor combination regimens was not significantly different from that as a single protease inhibitor [geometric mean ratio (GMR): 0.77; 95% confidence interval (CI): 0.38-1.58, P=not significant for group 2 versus group 1 and 1.34, 0.40-4.49, P=not significant, for group 3 versus group 1). Patients treated with ATV plus APV had a 40.2% lower ATV C(max) and a 30.8% smaller ATV AUC than the reference group treated with unboosted ATV alone: both these differences were statistically significant (GMR, 95% CI: 0.59, 0.41-0.85, P=0.005 and 0.69, 0.48-0.99, P=0.056, respectively). No difference was observed for either C(max) or AUC between the group treated with ATV plus SQV and the reference group (GMR, 95% CI: 0.78, 0.47-1.30, P=not significant and 1.24, 0.73-2.10, P=not significant, respectively)., Conclusion: ATV pharmacokinetics does not seem to be influenced by the concomitant administration of SQV, whereas APV significantly lowers plasma ATV levels.

The redistribution of mutations related to protease inhibitor (PI) resistance after a PI-sparing regimen in human immunodeficiency virus (HIV)-infected, highly PI-experienced patients was prospectively assessed. Twenty-five patients failing a PI-including regimen were given PI-sparing antiretroviral therapy, and then followed for 24 weeks after PI resumption. Genotyping was performed by direct sequencing before and during the PI-sparing regimen. The median (interquartile range, IQR) baseline CD4+ T-lymphocyte count was 198 (120-255) cells/microl, and the median HIV-RNA level was 82,000 (41,000-300,000) copies/ml. Patients had experienced a median of 4.5 (4-5.25) PIs. The median number of PI mutations was eight (6-9). The PI-sparing regimen consisted of a median of three (3-4) drugs and lasted for a median of 53 (24-67) weeks. At the end of the study, the median number of PI mutations was 6.5 (6-9). The median change in the number of PI mutations was -1 (IQR from -1 to 0). A reduction from baseline was observed in 13 cases (52%); nine (36%) showed no change and three (12%) showed an increased number of PI substitutions. In highly PI-experienced patients, a PI-sparing regimen may lead to a reduction, no change, or increase in the number of PI mutations. The reduction is negligible in most cases.

Objectives: To characterize osteoprotegerin (OPG) levels, bone remodelling and bone mineral density (BMD) in heavily pretreated HIV-infected patients on antiretroviral therapy, and to evaluate the clinical factors associated with bone density decline., Methods: Heavily pretreated (> 5 years) HIV-positive patients were enrolled in this cross-sectional, observational study, which was based on a total body bone densitometry examination and a comprehensive evaluation of bone and mineral parameters., Results: Sixty-eight patients (55 male and 13 female) with a median age of 41 years (range 25-60 years) were included in the study. Their antiretroviral treatment lasted for 82 months. On the basis of the World Health Organization criteria, nine patients (13.2%) were osteoporotic [T-score < -2.5 standard deviation (SD)] and 19 patients (27.9%) were osteopenic (T-score between -1 and -2.5). The principal outcomes associated with the presence of a low BMD were high OPG and lysylpyridinoline/creatinine ratio (Dpd) values. Most of the patients (39 of 48; 81.25%) showed vitamin D insufficiency [Vitamin D (25(OH)D) < 18 ng/mL] with secondary hyperparathyroidism (13 of 50 patients: 26%), which proved to be correlated to osteocalcin (BGP) levels [parathyroid hormone (PTH) vs. BGP: r = 0.34; P < 0.01]. There was an inverse correlation between T-scores and serum osteocalcin and alkaline phosphatase (AP) levels, on one hand, and Dpd, on the other. High AP and Dpd values were associated with relative risks of 4.1 [95% confidence interval (CI) = 1.01-17.6] and 7.2 (95% CI = 1.67-31.03), respectively, of a pathological T-score. Multivariate analysis revealed that the factors associated with the presence of osteopenia or osteoporosis were older age and lower body mass index., Conclusions: About 40% of our heavily pretreated subjects with advanced HIV infection had a low BMD, and 56% (24 of 44 patients) showed a high bone turnover rate with marked osteoclast activation. High OPG levels may protect against bone resorption.

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.

Background: HIV-specific cytotoxic T-cell (CTL) responses are defective in HIV-infected patients undergoing antiretroviral therapy (ART). This defect has been attributed to the decreased antigenic burden secondary to ART-associated suppression of HIV-replication, and is responsible for the rebounds of viraemia that occur when patients interrupt therapy. CTL are stimulated by type 1 cytokines and can kill targets via granule-dependent (perforin and granzymes) and -independent (tumour necrosis factor-alpha, CD95) mechanisms., Methods: Granule-dependent and granule-independent mechanisms of CTL killing, as well as type 1 cytokine production by CD4 T cells, were analysed in 57 chronically HIV-infected ART-treated or ART-untreated individuals., Results: The results can be summarized as follows: the frequency of gp160 (env)-specific interferon-gamma-secreting CD8 T lymphocytes correlates positively with HIV viraemia in ART-treated and -untreated patients; Env-specific perforin- and granzymes-expressing CD8 T lymphocytes, and Env-stimulated perforin and granzymes mRNA, are reduced in ART-treated patients independently of HIV viral load and of type 1 cytokine production; tumour necrosis factor-alpha production is increased in ART-treated individuals; and Env-specific immature CD8+28+27+ cells are only marginally augmented in ART-treated patients, Similar results are observed in cytomegalovirus-specific CD8 T cells and peripheral blood mononuclear cells., Conclusions: A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.

Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.

Background: Control of HIV replication can be observed in highly active antiretroviral therapy (HAART)-treated and, occasionally, in HAART-naive patients. The immunological correlates of these situations were examined in a longitudinal study., Design: A prospective study. Immunovirological analyses in 16 chronically HIV-infected, HAART-naive patients (time 0) who started HAART. Fifteen patients (short-term HAART) were re-evaluated after 24 months (time 1). Results were compared with those of 30 patients who received HAART for more than 12 months before the study period (long-term HAART) and were analysed at the same timepoints. Fifteen patients who were antiviral therapy naive (naive) at both timepoints were also studied., Results: Over a 24-month period CD4 and CD8 cell counts and viraemia remained unchanged in naive and long-term HAART patients; CD4 cell counts increased and viraemia diminished in short-term HAART individuals. Antigen-stimulated proliferation was unmodified in naive and short-term HAART patients, but improved in long-term HAART individuals. Gp160-stimulated IL-2 and IFN-gamma production was augmented in long-term HAART patients and marginally modified in other patients. IL-7 production was unmodified in naive individuals, augmented in short-term HAART patients, and diminished in long-term HAART patients. Chemokine production was similar in all patients. Naive patients showed the highest CD8 cell counts at both timepoints., Conclusion: HAART has a major impact on the outcome of HIV infection, even if functional immune modulation in HAART-treated patients is evident only after long periods of therapy. Low but detectable HIV replication in HAART-naive patients with preserved immune functions might not be associated with CD4 cell reduction, functional immune defects, or changes in viraemia., (Copyright 2002 Lippincott Williams & Wilkins)

The prevalence of lipodystrophy in an HIV-infected population and the risk factors associated with body shape changes were analysed in this study. Five hundred and four subjects were included. Among these, 201 (39.9%) had features of lipodystrophy syndrome (cases); 303 (60.1%) constituted the control group. Compared with the control group, the lipodystrophy subjects were different in age (P = 0.01); duration of antiretroviral therapy (P < 0.001); length of exposure to nucleoside reverse transcriptase inhibitors (NRTIs) (P < 0.001) and to protease inhibitors (P < 0.001); nadir of CD4 cell count (P < 0.001); and value of plasma HIV-RNA before antiretroviral therapy (P = 0.008). In a multivariate analysis, length of therapy and a nadir CD4 cell count below 250 cell/microl were associated with an increased risk of lipodystrophy. Among patients with lipodystrophy, isolated fat loss was observed in 46 (23%); isolated fat accumulation in 40 (20%); mixed (loss and accumulation) syndrome in 50 (25%); and isolated metabolic changes in 65 (32%). Subjects with morphological alterations displayed a greater cumulative time of exposure to NRTIs and to protease inhibitors than patients with isolated metabolic alterations. Patients with lipoatrophy had had a greater exposure to stavudine.

Analysis of the virologic and immunomodulatory effects of an association of efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) was performed in 18 human immunodeficiency virus (HIV)-infected and highly active antiretroviral therapy (HAART)-experienced patients who failed multiple therapeutic protocols. Patients (<500 CD4(+) cells/ micro l; >10,000 HIV copies/ml) were nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive and were treated for 10 months with EFV (600 mg/day) in association with NFV (750 mg three times daily) and d4T (30 or 40 mg twice daily). Measurement of HIV peptide- and mitogen-stimulated production of interleukin-2 (IL-2), gamma interferon (IFN-gamma), IL-4, and IL-10 as well as quantitation of mRNA for the same cytokines in unstimulated peripheral blood mononuclear cells were performed at baseline and 2 weeks (t1), 2 months (t2), and 10 months (t3) into therapy. The results showed that HIV-specific (but not mitogen-stimulated) IL-2 and IFN-gamma production was augmented and IL-10 production was reduced in patients who received EFV, NFV, and d4T. Therapy was also associated with a reduction in HIV RNA in plasma and an increase in CD4(+) cell count. These changes occurred in the first year of therapy (t2 and t3) and were confirmed by quantitation of cytokine-specific mRNA. Therapy with EFV, NFV, and d4T increases HIV-specific type 1 cytokine production as well as CD4 counts and reduces plasma viremia. This therapeutic regimen may be considered for use in cases of advanced HIV infection.

Purpose: To study whether and under what circumstances HIV can be controlled in chronically infected patients., Method: Nine patients treated with hydroxyurea and didanosine (PANDAs) were compared with 7 patients on highly active antiretroviral therapy (HAART) during an 8-week treatment interruption. Both groups had similar baseline viral load, CD4 count, and length of treatment. Treatment was resumed if viral rebound >10,000 copies/mL (virological failure) or CD4 count decrease below 200 cells/mm(3) (immunological failure) occurred in two consecutive measurements., Results: None of the PANDAs failed. Viral rebound was spontaneously contained, and CD4 count remained stable. Four out of 7 patients in the HAART group failed to control HIV by week 6 and had to restart therapy due to either viremia rebound or CD4 decrease. Before therapy interruption, the PANDAs had a vigorous HIV-specific T cell immune response (median CD4VIR 1.2%), while the HAART-treated patients did not (median CD4VIR 0.2%) (CD4VIR represents the percentage of HIV-specific CD4 subpopulation expressing IFN-gamma within the total CD4 population [CD3+, CD4+, IFN-gamma+]). This difference was statistically significant (p =.002)., Conclusion: This study shows that HIV can be controlled during therapy interruption in patients with established infection, and that control of viral replication correlates with vigorous anti-HIV specific immune responses.

Highly active antiretroviral therapies (HAART) represent a major advance in the treatment of HIV infection. Although with HAART a substantial suppression of viral replication can be obtained, eradication of the virus from the body cannot be achieved. Therefore, HIV-infected subjects have to be treated for the rest of their lives. Long term treatment will increase the frequency of: i) drug-related side effects; ii) onset of drug-resistant viral strains; iii) non-adherence of the patients to the treatment. Structured treatment interruptions (STI)-HAART might represent a feasible alternative and preliminary studies have shown that STI-HAART might induce immune control in patients treated in the early stage of infection. This regimen does not produce similar effects in patients treated during the chronic phase of the infection. However, there are some clinical data suggesting a possible role of hydroxyurea (HU) in inducing control of HIV replication in patients with established infection. In this manuscript in vitro and in vivo data indicating that HU might play a major role in the setting of STI-HAART will be presented.

Nelfinavir is a novel protease inhibitor that exhibits good inhibitory activity against human immunodeficiency virus type 1 (HIV-1) and is currently used in combination with reverse transcriptase inhibitors for the management of HIV infection. In this study we analysed the pharmacokinetic profile of nelfinavir after multiple oral doses in 18 HIV-infected patients during a combination regimen of nelfinavir plus efavirenz and stavudine. Patients who received the study drug for >/=4 weeks were considered for pharmacokinetic evaluation. Blood samples were obtained at the following times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h after administration. Nelfinavir plasma concentrations were analysed by a specific and validated HPLC assay with ultraviolet detection. Nelfinavir concentration-time data were analysed by compartmental and non-compartmental techniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between individuals in nelfinavir plasma concentrations. The mean average drug plasma concentration was 2.22 +/- 1.25 mg/L and the mean AUC during the dosing interval was 17.7 +/- 10.0 mg*h/L. The mean nelfinavir trough plasma concentration was 1.58 +/- 1.0 mg/L. A good relationship was found between AUC(0-8h) and the plasma concentrations measured at 6 h, and the trough plasma concentrations made total body exposure for nelfinavir less predictable. Alternatively, a 2 h abbreviated AUC provides a good estimate of the full AUC(0-8h). Comparing the pharmacokinetic parameters obtained in our patients with those reported for patients receiving nelfinavir monotherapy or nelfinavir combined with nucleoside analogues, one observes substantial overlap with nelfinavir concentrations achieved without efavirenz.

Background: Suppression of human immunodeficiency virus (HIV) replication can be obtained in chronically infected individuals by highly active antiretroviral therapy (HAART) and can also be observed in antiretroviral-naïve patients. The immunological correlates of these two situations were examined., Design and Methods: Cross-sectional study involving 32 HIV-infected patients with undetectable HIV plasma viraemia (< 500 copies/ml) and either antiretroviral-naive (n = 14) or undergoing HAART therapy with two nucleoside reverse transcriptase inhibitors (NRTI) plus one (n = 13) or two (n = 5) protease inhibitors (PI). CD4 counts, disease duration, and CDC clinical stage were comparable between the two groups of individuals. Immune parameters (antigen- and mitogen-stimulated proliferation and cytokine production; cytokine mRNA; beta chemokine production; HIV coreceptors mRNA) were analysed in all patients., Results: Results showed immune profiles to be profoundly different in antiretroviral-naive in comparison with HAART-treated patients. Thus: (1) T-cell proliferation to HIV-specific and HIV-unrelated antigens is potent in antiretroviral-naive but suppressed in HAART-treated individuals; (2) interleukin-(IL)2, IL-12 and interferon gamma (IFNgamma) production is robust in naive patients; and (3) a high CCR5/low CXCR4 pattern of HIV coreceptors-specific mRNA is observed in naive but not in HAART-treated patients. In contrast with these observations, no clear differences were detected when beta chemokine production by either peripheral blood mononuclear cells or purified CD8+ T-cells was analysed. Results from HAART-treated patients undergoing therapy with one PI and two NRTI or two PI and two NRTI were in very close agreement., Conclusions: These data suggest that control over HIV replication can be independently achieved by pharmacological or immunologic means. HAART is associated with weaker HIV-specific and -non-specific immune responses.

Tolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1-infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+ count was 204 cells/microl (both mean values); patients had received a mean of 3.1 different treatments (range, 2-5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8%) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+ count increased to 324 cells/microl (+/-59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10 in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked interindividual variability in NFV plasma concentrations, producing in 4 of 18 patients (22%) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95% inhibitory concentration (IC95) determined by phenotyping.

Aims: To define the pharmacokinetic profile of efavirenz (EFV) in HIV-1 infected patients, when administered alone or with nelfinavir (NFV)., Methods: Eleven HIV-positive patients, in steady-state treatment with EFV and 11 patients in steady-state treatment with EFV+NFV, were evaluated. Blood samples for pharmacokinetic analysis were obtained during a dosage interval. Plasma concentrations of EFV were determined by h.p.l.c., Results: No significant difference was found between the principal pharmacokinetic parameters of EFV when administered alone or in combination with NFV (mean AUC: 57.1-7727.3 vs 60.9+/-12.3 microg ml-1 h; mean CL/F: 0.18+/-0.072 vs 0.16+/-0.04 l h-1 kg-1; mean Cmax: 4.0+/-1.7 vs 4.3+/-1.2 microg ml-1, and mean tmax: 4.1+/-1.7 vs 3.5+/-0.5 h) Mean trough plasma concentrations (C0) of EFV were 1.64+/-0.93 microg ml-1, with and without NFV. A good correlation was found between C0 and AUC(0,24h) (r=0.96; P<0. 01)., Conclusions: Despite the common metabolic pathway, there was no significant influence of NFV on the pharmacokinetics of EFV. EFV exhibits a relatively low interindividual variability and a dosing regimen of 600 mg day-1 assures plasma concentrations that are adequate for inhibition of viral replication.

Hydroxyurea and didanosine treatment suppressed HIV replication for more than 2 years, in the absence of viral breakthrough, in chronically infected patients. The profile of viral load reduction was unusual for a two-drug combination, since a continuous gradual decrease in viremia persisted despite residual viral replication. The increase in CD4+ T cell counts was not robust. However, unlike those of patients treated by other therapies, CD4+ T lymphocytes were functionally competent against HIV, mediating a vigorous HIV-specific helper T cell response in half of these patients. In addition, the percentages of naive CD4+ and CD8+ T lymphocytes were not different from those in uninfected individuals. These results demonstrate that prolonged antiretroviral therapy with a simple, well-tolerated combination of two affordable drugs can lead to sustained control of HIV, normalization of immune parameters, and specific anti-HIV immune response.

Objective: To characterize the antiviral effect and tolerability of higher dose (HD, 600 mg two times daily) and lower dose (LD, 400 mg two times daily) combination regimens of ritonavir and saquinavir in British Columbia (BC), Canada., Design: Intent-to-treat analysis with suppression of plasma viral load to levels below 500 copies/ml as the main outcome measure., Patients: Adult human immunodeficiency virus (HIV)-positive individuals in the province of British Columbia prescribed ritonavir and saquinavir in combination between 1 September 1996 and 30 June 1997, with a minimum of two plasma viral loads, one at baseline and one after the initiation of therapy., Results: A total of 84 participants [27 HD (32%) and 57 LD (68%)] were prescribed ritonavir and saquinavir. There was no difference at baseline in the two groups with respect to age (P=0.466), CD4 cell count (P=0.373) and baseline plasma viral load (P=0.656). However, LD were more likely to have had prior protease experience than HD participants (65 versus 40%, P=0.037). The median follow-up time was 9 months. A total of 44 (52%) subjects demonstrated a decrease in plasma viral load to levels <500 copies/ml. After adjusting for length of follow-up, baseline CD4 cell count and prior AIDS diagnosis, HD participants were as likely to be suppressed to <500 copies/ml as LD individuals (P=0.760). HD participants did report more adverse effects (P=0.042) than LD subjects., Conclusion: Our results provide confirmatory evidence that lower doses of ritonavir and saquinavir in combination are better tolerated and as effective as the standard doses of these drugs. This response, however, is seriously compromised by prior exposure to protease inhibitors.

The incidence and spectrum of primary AIDS-defining illnesses in human immunodeficiency virus-positive patients receiving antiretroviral drugs may have changed since the introduction of newer antiretroviral agents. We performed a retrospective analysis of patients enrolled in the British Columbia Drug Treatment Program who were ever prescribed antiretroviral drugs between 1 January 1994 and 31 December 1996. Rates were calculated on a 6-month basis. There were 344 AIDS cases diagnosed among 2,533 participants between 1994 and 1996. The incidence of primary AIDS diseases decreased from 1994 to 1996, with a sharp decline in 1995 and 1996. There was no statistically significant change in the incidence of primary AIDS diagnoses relative to one another, and Pneumocystis carinii pneumonia and Kaposi's sarcoma remain the most common AIDS index diagnoses. In patients receiving antiretroviral therapy in the modern era, the incidence of AIDS-defining illnesses has decreased substantially, but the spectrum of AIDS-defining illnesses remains unchanged.

The costs of four algorithms for monitoring plasma human immunodeficiency virus type 1 RNA were compared. For patients with strong virologic responses, the use of Ultra Direct exclusively was the cheapest strategy. For patients with weak virologic responses, small savings could be obtained by using Amplicor and retesting only samples with values below 500 copies/ml with Ultra Direct.

Diplopia is one of the neuro-ophthalmic manifestations that can be observed during HIV-infection. The etiologic agents of diplopia in HIV-positive patients can be identified with HIV itself or opportunistic pathogens or other related conditions. We reviewed the clinical records of 13 HIV-positive patients with mono or bilateral diplopia, focusing on etiologic agents, clinical evaluation and prognosis. This review encompassed all cases observed from January 1992 to June 1995 at the Infectious Diseases Department, Policlinico S. Matteo, University of Pavia. All patients underwent a complete ophthalmologic examination, including visual acuity, anterior segment evaluation with biomicroscopy, dilated indirect ophthalmoscopy and ocular motility evaluation (with Cover test and Hess-Lancaster test). If requested by clinical findings, radiologic (TC and/or MRI) and cerebrospinal fluid examination were performed in some patients. The most common causes of diplopia-CNS lesions or ocular diseases-, resulted in agreement with those reported in the literature (T. gondii, C. neoformans, non-Hodgkin lymphomas, HIV, JC virus, CMV). We were able to confirm, according to our experience, that diplopia occurrence is often a negative prognostic factor, since it is commonly associated with CNS conditions. In most cases diplopia can herald a near demise (8 patients on 13 died with 60 days from diplopia onset). In those cases where a treatment was available (2 cases of cryptococcosis, 1 case of neurotoxoplasmosis and 1 case of CMV retinitis) a complete resolution of neuro-ophthalmic symptoms was achieved.

The number of subjects with HIV infection or full-blown Acquired Immunodeficiency Syndrome (AIDS) is increasing throughout the world and the range of related opportunistic conditions (infections, neoplasms or degenerative disorders) is also increasing. Consequently, AIDS patients are likely to be prescribed a great number of different drugs. HIV infection is a progressive phenomenon, characterized by inevitable and often irreversible changes which may influence drug disposition, enhancing the risk of toxic adverse effects and drug interactions. One of the stages for the development of new agents and the establishment of an effective therapy is to conduct pharmacokinetic studies. Even though such studies are difficult to realize in AIDS subjects, the knowledge of altered pharmacokinetics of a drug in disease states offers an unique approach for improving and perhaps optimizing the therapeutic management. The purpose of this article is to review our current understanding of how HIV infection influences the various processes of drug disposition (i.e. absorption, distribution, metabolism and excretion).