Efficacy, adherence and tolerability of once daily tenofovir DF-containing antiretroviral therapy in former injecting drug users with HIV-1 receiving opiate treatment: results of a 48-week open-label study.

OBJECTIVE: To assess efficacy, adherence and tolerability of once daily antiretroviral therapy containing tenofovir disoproxil fumarate (DF) 300 mg in HIV-1-infected former injecting drug users receiving opiate treatment (IVDU). METHODS: European, 48-week, open-label, single-arm, multicenter study. Patients were either antiretroviral therapy-naive, restarting therapy after treatment discontinuation without prior virological failure or switching from existing stable treatment. RESULTS: Sixty-seven patients were enrolled in the study and 41 patients completed treatment. In the primary analysis (intent-to-treat missing=failure) at week 48, 34% of patients (23/67; 95% CI: 23%-47%) had plasma HIV-1 RNA <50 copies/mL. Using an intent-to-treat missing=excluded approach, the week 48 proportion of patients with plasma HIV-1 RNA <50 copies/mL increased to 56% (23/41; 95% CI: 40%-72%). Mean (standard deviation) increase from baseline in CD4+ cell count at week 48 was 176 (242) cells/mm(3). Although self-reported adherence appeared high, there were high levels of missing data and adherence results should be treated with caution. No new safety issues were identified. CONCLUSIONS: Levels of missing data were high in this difficult-to-treat population, but potent antiretroviral suppression was achieved in a substantial proportion of HIV-infected IVDU-patients.

Mutations in the C-terminal region of the HIV-1 reverse transcriptase and their correlation with drug resistance associated mutations and antiviral treatment.

OBJECTIVE: replication of HIV-1 after cell entry is essentially dependent on the reverse transcriptase (RT). Antiretroviral drugs impairing the function of the RT currently aim at the polymerase subunit. One reason for failure of antiretroviral treatment is the evolvement of resistance-associated mutations in the viral genome. For RT inhibitors, almost all identified mutations are located within the polymerase; therefore, general genotyping confines to investigate this subunit. Recently several studies have shown that substitutions within the RNase H and the connection domain increase antiviral drug-resistance in vitro, and some of them are present in patient isolates. AIM: the aim of the present study was to investigate the prevalence of these substitutions and their association with mutations in the polymerase domain arising during antiretroviral treatment. MATERIAL AND METHODS: we performed genotypic analyzes on seventy-four virus isolates derived from treated and untreated patients, followed at the HIV Centre of the Johann Wolfgang Goethe University Hospital (Frankfurt/Main, Germany). We subsequently ana?lysed the different substitutions in the c-terminal region to evaluate whether there were associations with each other, n-terminal substitutions or with antiretroviral treatment. RESULTS: We identified several primer grip substitutions, but almost all of them were located in the connection domain. This is consistent with other in-vivo studies, in which especially the primer grip residues located in the RNase H were unvaried. Furthermore, we identified other substitutions in the connection domain and in the RNase H. Especially E399D seemed to be associated with an antiretroviral treatment and N-terminal resistance-delivering mutations. CONCLUSION: some of the identified substitutions were associated with antiviral treatment and drug resistance-associated mutations. Due to the low prevalence of C-terminal mutations and as only a few of them could be associated with antiviral treatment and N-terminal resistance-delivering mutations, we would not recommend routinely testing of the C-terminal RT region.

Human immunodeficiency virus type-1 group M quasispecies evolution: diversity and divergence in patients co-infected with active tuberculosis.

The evolution of intra-host human immunodeficiency virus type 1 (HIV-1) quasispecies prior and after treating active tuberculosis (TB) with chemotherapy in HIV-1/TB patients was assessed. Two time points HIV-1 quasispecies were evaluated by comparing HIV-1-infected patients with active tuberculosis (HIV-1/TB) and HIV-1-infected patients without tuberculosis (HIV-1/non-TB). Plasma samples were obtained from the Frankfurt HIV cohort, and HIV-1 RNA was isolated. C2V5 env was amplified by PCR and molecular cloning was performed. Eight to twenty-five clones were sequenced from each patient. Various phylogenetic analyses were performed. We found a significant increase in diversity and divergence in HIV-1/TB compared to the HIV-1/non-TB. For HIV-1/TB, the average rate of evolution of C2V5 env was higher than previous reports (2.4 × 10(-4) substitution/site/day). Two groups of HIV-1/TB were observed based on the rate of HIV-1 evolution and coreceptor usage: A fast evolving R5-tropic dominating group and a relatively slowly evolving X4 group. The results demonstrated that active TB has an impact on HIV-1 viral diversity and divergence over time. The influence of active TB on longitudinal evolution of HIV-1 may be predominant for R5 viruses.

Intensification of a failing regimen with zidovudine may cause sustained virologic suppression in the presence of resensitising mutations including K65R.

OBJECTIVES: The reverse transcriptase (RT)-mutation K65R limits further therapeutic options and has been selected by unfavorable RT-combinations, e.g. tenofovir in combination with abacavir and/or didanosine. METHODS: We identified HIV-1 infected patients from a large treatment cohort who experienced virological failure (HIV-1 RNA >1000 copies/mL) with evidence of resistance mutations including the K65R, but without thymidine analogue mutations (TAMs) in genotypic resistance assay. Phenotype was performed from previously collected frozen plasma. The patients were followed for clinical and resistance outcome after treatment intensification with only zidovudine. RESULTS: Five patients had experienced antiretroviral treatment failure on various nucleoside analogue combinations, containing abacavir, didanosine, lamivudine, nevirapine, reverset and/or tenofovir. RT-sequence revealed mutations at position K65R in combination with other non-TAMs. The patients' median viral load prior to zidovudine intensification was 3.551 Log10 (range 3.053-4.681) and despite evidence for resistance to the failing drug regimen, all responded within 4 weeks to undetectable levels (<1.699 Log10 or <50 copies/mL) and remained virologically suppressed during follow-up (20 months through 6.5 years). CONCLUSIONS: In virologically failing patients due to K65R- and other non-thymidine-mutations, simple regimen intensification with zidovudine resulted in sustained HIV-1 suppression. The finding of re-sensitized HIV-1 in patients may be clinically relevant.

The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive Individuals.

OBJECTIVE: This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated. METHODS: Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2). RESULTS: 168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209). CONCLUSIONS: Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.

Factors associated with viral rebound among highly treatment-experienced HIV-positive patients who have achieved viral suppression.

OBJECTIVE: More and more highly treatment-experienced patients are achieving viral suppression. However, the durability of suppression remains unclear. METHODS: Patients from Royal Free Hospital (London, UK) and JW Goethe University Hospital (Frankfurt, Germany) who had failed > or = 1 antiretroviral (ARV) regimen in all three main drug classes and > or = 3 previous ARV regimens and subsequently achieved viral load < 50 HIV-1 RNA copies/mL were included. They were followed until stopping pre-combination antiretroviral therapy, end of follow-up or viral rebound (two viral loads >400 copies/mL). RESULTS: Two hundred and forty-seven patients contributed 723 person-years and 114 viral rebounds [rate=15.8 per 100 person-years; 95% confidence interval (CI) 12.9-18.7]. More recent calendar years of viral suppression [relative risk (RR)=0.90 per year later; 95% CI 0.81-1.00; P=0.05] and greater number of ARVs in the regimen not previously failed (RR=0.78 per 1 ARV more; 95% CI 0.65-0.95; P=0.01) were associated with lower viral rebound rates. At 0-1, 1-2, 2-3 and > 3 years after achieving suppression, the rebound rates were 30.9, 9.2, 4.3 and 3.5 per 100 person-years, respectively. Compared to 0-1 years, the adjusted RRs (95% CIs) after 1-2, 2-3 and > 3 years were 0.33 (0.18-0.58), 0.21 (0.09-0.48) and 0.14 (0.06-0.33), respectively (P<0.0001). CONCLUSIONS: Although rebound rates are high, especially in the first year after viral suppression, this risk reduces substantially if highly treatment-experienced patients can maintain viral suppression.

Switch to efavirenz (EFV) after protease-inhibitor (PI)-failure: explorative analysis of outcome by baseline viral VS tolerability failure.

The aim of this database analysis was to investigate the efficacy and safety of efavirenz (EFV)-based highly active antiretroviral therapy (HAART) after switching from failed protease inhibitor (PI)- and boosted PI (PI/r)-based regimens. Data were analyzed from 17 adult patients previously treated with a PI-based HAART with substitution of PI with EFV because of virologic failure and from 14 patients previously treated with a PI-based HAART, with substitution of PI due to tolerability issues. Of 17 patients who switched therapy because of virologic failure, 5 patients maintained EFV-therapy for more than 1 year. In 11/17 patients, EFV-based HAART was discontinued during follow-up and one patient was lost to follow-up. Reasons for discontinuation were: virologic failure in 4, adverse events in 6 (5 CNS-adverse events and 1 rash) and non-compliance in 1 of 17 patients. Of 14 patients who stopped PI-therapy and switched to EFV due to tolerability issues, 6 patients maintained EFV-therapy for more than 1 year. In 8/14 patients EFV-based HAART was discontinued during follow-up. Reasons for discontinuation were: virologic failure in 3, adverse events in 3 (2 CNS-adverse events and 1 patient had rash) and non-compliance in 2 of 14 patients. Instable switch to an EFV-based regimen due to virologic failure or toxicity reasons with a boosted or unboosted PI does not show significant differences but outcome was worse than had been described previously for stable switch settings, likely due to multiple prior virologic failures in many patients.

Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis.

OBJECTIVE: There is controversy over whether or not chronic HIV infection contributes to atherosclerosis. We investigated the relationship between HIV infection, antiretroviral medication and ultrasound evidence of early atherosclerosis in the context of vascular risk factors. DESIGN: A case-control design with 292 HIV-positive subjects and 1168 age- and sex-matched controls. METHODS: We assessed vascular risk factors, blood pressure, serum lipids and carotid intima media thickness (IMT) in cases and controls. With multivariate regression models, we investigated the effects of HIV status and antiretroviral medication on IMT. RESULTS: The common carotid artery (CCA) IMT value was 5.70% (95% confidence interval [3.08-8.38%], p<0.0001) or 0.044 mm [0.021-0.066 mm] (p=0.0001) higher in HIV-positives, adjusted for multiple risk factors. In the carotid bifurcation (BIF), the IMT values were 24.4% [19.5-29.4%] or 0.250 mm [0.198-0.303 mm] higher in HIV patients (p<0.0001). An investigation of antiretroviral substances revealed higher CCA- and BIF-IMT values in patients receiving combination antiretroviral therapy (HAART). CONCLUSIONS: HIV infection and HAART are independent risk factors for early carotid atherosclerosis. Assuming a risk ratio similar to that in large population-based cohorts, the observed IMT elevation suggests that vascular risk is 4-14% greater and the "vascular age" 4-5 years higher in HIV-positive subjects. The underlying mechanisms remain to be clarified.

A standardized, comprehensive magnetic resonance imaging protocol for rapid and precise quantification of HIV-1-associated lipodystrophy.

OBJECTIVES: Although multiple methods have been proposed, there is no current gold standard for assessing HIV-1-associated lipodystrophy. METHODS: HIV-1-infected participants were randomly enrolled and surveyed about changes in the abdomen, thigh, cheek and neck areas. Magnetic resonance imaging (MRI) sequences of these sites were obtained. Participants were grouped according to survey results, and the MRI measurements were compared between groups. RESULTS: One hundred participants were included in the study, of whom 79% reported any body fat changes. Persons reporting increased abdominal girth had higher visceral ([mean+/-standard deviation] 142+/-75 vs. 59+/-48 cm2; P<0.0001) and total abdominal adipose tissue than those reporting no change (344+/-119 vs. 201+/-95 cm2; P<0.0001). The amount of localized fat was less for persons reporting sunken cheeks and reduced diameter of the legs compared with those who noted no changes (5.9+/-3.6 vs. 9.3+/-3.8 cm2; P<0.0001, and 35+/-28 vs. 112+/-56 cm2; P<0.0001). Participants reporting increased neck girth had a thicker fat layer in the dorsocervical region compared with those reporting no change (4.0+/-1.8 vs. 2.3+/-1.4 cm; P<0.0002). CONCLUSIONS: MRI is a precise method for rapidly surveying body regions affected by HIV-1-associated lipodystrophy. Our proposed protocol provides a rapid, comprehensive survey of these areas, without the need to combine multiple modalities or to expose subjects to radiation.

First case of successful allogeneic stem cell transplantation in an HIV-patient who acquired severe aplastic anemia.

We report on the first successful allogeneic stem cell transplantation (SCT) in an HIV-infected patient with severe aplastic anemia (SAA) per- formed at a tertiary care institution. Highly active antiretroviral therapy (HAART) was administered until transplantation and restarted 34 days later with sustained virological response. The patient did however develop a rapid rise in HIV load during the interruption of HAART associated with an acute febrile illness. Due to the extended period between the onset of SAA until SCT, the posttransplant course was complicated by bacterial infections. Stage two skin GvHD, but no AIDS-defining opportunistic diseases were experienced. Neutrophils recovered to >0.5/nL on day +18 and the CD4 count reached 250/microL on day +71 and >500/microL on day +182. The patient is in good condition with an ECOG score of 0 twelve months after transplantation. This report demonstrates the feasibility of allogeneic stem cell transplantation in the HIV setting.

Consensus recommendation from a group of German experts for the use of enfuvirtide in heavily pretreated HIV patients.

BACKGROUND: The EU approval of enfuvirtide (Fuzeon) was granted in May 2003 on the basis of the 48-week data from the TORO 1 and TORO 2 studies. Enfuvirtide is licensed for use in pretreated HIV patients experienced with three classes of drugs who exhibited treatment failure or who have shown intolerance to previous antiretroviral treatment regimens. Recent studies with the new protease inhibitors tipranavir and darunavir (RESIST and POWER studies) showed that a high proportion of heavily pretreated HIV patients achieve a viral load reduction to below the limit of detection when treated with enfuvirtide plus one of these new ritonavir-boosted protease inhibitors and an optimised background treatment regimen. The International AIDS Society (IAS-USA Panel) has recently updated its treatment guidelines in view of these new data and recommends the use of an antiretroviral treatment regimen containing at least two active drugs, one of which that has a new mechanism of action, for HIV patients who have been heavily pretreated. A new treatment goal has also emerged for heavily pretreated patients with advanced HIV disease: reduction of the viral load to below the detection limit of 50 copies/ml. The IAS concluded that the likelihood of achieving this treatment goal is higher when enfuvirtide is selected as one of the two active drugs. OBJECTIVE: A panel of German experts convened to discuss the currently available data and to incorporate them into the updated German consensus recommendations for the use of enfuvirtide when switching treatment in heavily pretreated HIV patients. METHODS: The consensus recommendations are based on published data from controlled, randomised clinical studies and on the expert opinions of the discussants. RESULTS AND CONCLUSIONS: The consensus recommendations were developed to provide practice-relevant standardised recommendations for selecting suitable candidates for enfuvirtide therapy and for their management. Aspects including predictive prognostic factors, disease stage, selection of the optimised background regimen, early indicators of a response to enfuvirtide, as well as accompanying educational measures treatment were considered. New protease inhibitors or other remaining active drugs should be used together with enfuvirtide in heavily pretreated patients in order to enable at least two active drugs to be included in such a salvage regimen.

Dose reduction effective in alleviating symptoms of saquinavir toxicity.

Gastrointestinal intolerance is a limitation of boosted saquinavir antiretroviral treatment. We present three HIV-infected individuals whose severe toxicity symptoms started directly after initiation of a standard dose saquinavir hard-gel capsule-containing regimen (saquinavir/ritonavir 1000/100 mg). All patients underwent immediate 12 h pharmacokinetic (PK) assessment and showed extraordinarily high saquinavir plasma exposure. All three patients did not recover until the saquinavir exposure was decreased. This pilot case study anticipates a new concept of 'direct PK'-guided individual dose interventions under close viral load monitoring. Two major reasons for symptomatic saquinavir overexposure were defined: impaired liver function in a chronic hepatitis C virus co-infected individual at normal liver performance parameters and a delayed cytochrome p450 enzyme autoinduction. Overexposure seems to be an independent intolerance factor. Although delayed autoinduction is not well established as a reason for adverse events in saquinavir therapy, this observation may be confirmed in the near future by increased use.

A randomized, open-label study to compare the effects of two different doses of recombinant human growth hormone on fat reduction and fasting metabolic parameters in HIV-1-infected patients with lipodystrophy.

BACKGROUND: Several studies have shown beneficial effects of recombinant human growth hormone (r-hGH) in reducing visceral adipose tissue (VAT) in HIV-1-infected patients with lipodystrophy. METHODS: Patients were randomized to r-hGH 4 mg daily (group A) or three times per week (group B) over 12 weeks, followed by a 2 mg daily maintenance dose for 12 weeks. Magnetic resonance imaging (MRI) scans were performed to assess body composition. RESULTS: A total of 26 subjects were included in the study. VAT was reduced overall by 35.1 cm(2) (29.5%) at week 12 and by 49 cm(2) (39.9%) at week 24, respectively, compared with baseline (P<0.001 for both comparisons). By week 12, VAT was reduced by 27 and 29% (A vs B; P=0.47) while facial fat was reduced by 3.3 and 2.6 cm(2) in groups A and B, respectively (P=0.96). Over 24 weeks, VAT was reduced by 42 and 38% (P=0.35) and facial fat by 3.2 and 2.4 cm(2) in groups A and B, respectively (P=0.91), compared with baseline. There was a greater increase in high-density lipoprotein (HDL) in group A than in group B (4.9 vs 2.4 mg/dL in week 12 and 7.1 vs -0.4 mg/dL in week 24; P=0.03). Fasting insulin levels increased, whereas glucose and insulin measured in oral glucose tolerance tests remained unchanged. Drug-related side effects were transient and reversible, but more common in group A (67%) than in group B (29%). CONCLUSIONS: This study confirms reports that r-hGH effectively reduces VAT, with a relatively small reduction of facial and limb fat.

Pharmacokinetics and tolerability of a combination of indinavir, lopinavir and ritonavir in multiply pretreated HIV-1 infected adults.

OBJECTIVES: The authors evaluated the pharmacokinetics and tolerability of indinavir/lopinavir/ritonavir in a protease inhibitor only combination. METHODS: Plasma drug levels of patients taking indinavir/lopinavir/ritonavir 800/400/100mg twice daily (n = 24, group 1) were compared to patients taking either lopinavir/ritonavir 400/100mg (n = 35, group2) or indinavir/ritonavir 800/100mg (n = 33, group3) twice daily plus nucleos(t)ide reverse transcriptase inhibitors (NRTI). Steady-state drug concentrations were measured by LC/MS/MS. Minimum and maximum concentrations (C subsetmin, C subsetmax), area under the concentration-time curve (AUC subset0-12h), total clearance (CL subsettot) and half-life (t1/2) were calculated. HIV viral load, CD4 cell count and adverse events causing early termination of therapy were correlated over a period of 48 weeks. RESULTS: Plasma levels of lopinavir/ritonavir were significantly enhanced when combined with indinavir compared to a regimen of lopinavir/ritonavir+NRTI: Mean lopinavir AUC subset(0-12h) 80,912 ng*h/mL vs. 60,548 ng*h/mL; C subsetmin 4,633 ng/mL vs. 3,258 ng/mL; C subsetmax 8,023 ng/mL vs. 6,710 ng/mL. Mean ritonavir AUC(0-12h) 6,907 ng*h/mL vs. 3,467 ng*h/mL; Cmin 220 ng/mL vs. 125 ng/mL; C subsetmax 1,059 ng/mL vs. 522 ng/mL. Indinavir levels were comparable for both indinavir containing regimen. A significantly smaller number of patients stopped indinavir/lopinavir/ritonavir therapy (group1: 16.7%) than indinavir/ritonavir + NRTI treatment (group3: 45.5%) due to adverse events. Virological failure was the main reason for early termination of treatment with indinavir/lopinavir/ ritonavir before week 48 (group1: 50%). CONCLUSIONS: indinavir/lopinavir/ritonavir 800/400/ 100mg twice daily represents a therapy option with an adequate safety but only short term efficacy for extensively pretreated patients.

The feasibility of clinical endpoint trials in HIV infection in the highly active antiretroviral treatment (HAART) era.

BACKGROUND: Planning clinical-endpoint trials in patients with HIV remain difficult as long-term follow-up of many patients is required. Cohort studies of patients with HIV can provide key estimates of the likely disease progression, required sample size and follow-up. OBJECTIVES: To verify the assumptions used in designing ESPRIT, a large randomized clinical trial assessing the clinical benefit of interleukin-2 treatment in patients with HIV infection, to use EuroSIDA to mimic the inclusion criterion of ESPRIT in order to compare the observed event rate in ESPRIT with the projected rate in EuroSIDA, and to project the required length of ESPRIT. METHODS: Patients in EuroSIDA who satisfied the ESPRIT recruitment criteria were selected. Patients were followed from baseline to new AIDS or death. RESULTS: The incidence of clinical progression in the selected EuroSIDA patients (N = 4482) was 1.5 per 100 PYFU (95% CI 1.3-1.7), and did not increase with increasing time from baseline, contrary to what was assumed in the design of the ESPRIT trial. In ESPRIT (N = 4150), for which the comparative data remain blinded, the incidence was 1.1 per 100 PYFU (95% CI 0.9-1.3), with no increase over time. The average follow-up required to complete ESPRIT and accrue the 320 events required by protocol would be seven years, 10 months using the projected rates from the EuroSIDA study, and seven years, 11 months if the observed event rate in ESPRIT continued unchanged. LIMITATIONS: Differences between patients recruited to observational studies or clinical trials cannot always be adjusted for. CONCLUSIONS: Event rates in EuroSIDA were similar in the first two years to those used in the design of ESPRIT, but did not increase over time, leading to an increase in the expected duration of ESPRIT. Clinical endpoint trials in HIV infection remain feasible, and large cohort studies are critical to the planning and ongoing assessment of design assumptions in such trials. The underlying assumptions of the clinical trial should be re-examined to ensure the original trial assumptions remain valid.

["State of the HAART". Current strategies for antiretroviral therapy]. / "State of the HAART". Aktuelle Strategien zur antiretroviralen Therapie.

The goal of antiretroviral therapy is to interrupt the disease progression and to approach normal life expectancy for individuals with HIV. The condition for this is to deter the emergence of resistant HIV. This aim is achieved by improved patient drug adherence, sufficient enteral resorption and the control of interactions, as well as good tolerability and full antiviral activity. An insufficient drug exposure for protease inhibitors is overcome by the use of a booster agent. Emerging HIV-resistance can be described in a phase model:Phase 1:replication of wild-type HIV under incomplete suppressive therapy. Phase 2:transformation of wild-type into resistant HIV through accumulation of mutations. A preventive, resistance-guided switch of therapy preserves therapeutic options for the future. Phase 3:replication of resistant HIV (no more mutations possible).a)stable immunity: continue with failing therapy.b)threatening disease progression: resistance-guided switch to a salvage-regimen.

Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group.

OBJECTIVE: The purpose of the present study was to determine the prevalence and incidence of virological triple drug-class failure (TCF) and to summarize the clinical outcome for patients who started receiving highly active antiretroviral therapy (HAART). METHODS: The present study is an observational longitudinal study of 3496 treatment-experienced (TE) and treatment-naive (TN) patients monitored from the time they started receiving HAART (baseline) until TCF occurred (as determined on the basis of viral loads), until AIDS was newly diagnosed, or until death. RESULTS: Four hundred forty-five patients (12.7%) had TCF; 370 (16.6%) of 2230 patients were TE, and 75 (5.9%) of 1266 patients were TN. At 6 years after starting HAART, 21.4% of TE and 11.2% of TN patients had TCF (P<.0001). The prevalence of TCF at or after 2002 was 15.5% in TE patients and 4.8% in TN patients. TN patients had a 32% annual increase in the incidence of TCF (95% confidence interval [CI], 14%-54%; P<.0001); at 5 years after starting HAART, the rate was comparable for TE and TN patients (3.3 and 3.4 cases/100 person-years of follow-up [PYFU], respectively). The incidence of new cases of AIDS or death was 2.7 cases/100 PYFU in patients who did not experience TCF and 5.0 cases/100 PYFU in patients who did experience TCF, an estimated 36% increase with each category of TCF (95% CI, 19%-56%; P<.0001). CONCLUSION: The prevalence of TCF was low after patients started receiving HAART, particularly among TN patients. Despite the influx of patients who had started receiving HAART more recently, the prevalence of TCF increased over calendar time. Patients with TCF had a higher incidence of newly diagnosed AIDS or death. Treatment of patients with TCF deserves further investigation.

Updated European recommendations for the clinical use of HIV drug resistance testing.

In most European countries, HIV drug resistance testing has become a routine clinical tool. However, its practical implementation in a clinical context is demanding. The European HIV Drug Resistance Panel was established to make recommendations to clinicians and virologists on this topic and to propose quality control measures. The panel recommends resistance testing for the following indications: i) drug-naive patients with acute or recent infection; ii) therapy failure, including suboptimal treatment response, when treatment change is considered; iii) pregnant HIV-1-infected women and paediatric patients with detectable viral load when treatment initiation or change is considered; and iv) genotype source patient when post-exposure prophylaxis is considered. In addition, for drug-naive patients with chronic infection in whom treatment is to be started, the panel suggests that resistance testing should be strongly considered and recommends testing the earliest sample for drug resistance if suspicion of resistance is high or prevalence of resistance in this population exceeds 10%. The panel does not favour genotyping over phenotype, however it is anticipated that genotyping will be used more often because of its greater accessibility, lower cost and faster turnaround time. For the interpretation of resistance data, clinically validated systems should be used to the greatest extent possible. It is mandatory that laboratories performing HIV resistance tests take regular part in quality assurance programs. Similarly, it is necessary that HIV clinicians and virologists take part in continuous education and meet regularly to discuss problematic clinical cases. Indeed, resistance test results should be used in the context of all other clinically relevant information for predicting therapy response. The panel also encourages the timely collection of epidemiological information to estimate the impact of transmission of resistant HIV and the prevalence of HIV-1 non-B subtypes in the different European countries.

Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies.

BACKGROUND: We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART. METHODS: We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months. FINDINGS: During 13408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/microL, adjusted hazard ratios for AIDS or death were 0.55 (95%CI 0.32-0.96) for 25-49 cells/microL, 0.62 (0.40-0.96) for 50-99 cells/microL, 0.42 (0.28-0.64) for 100-199 cells/microL, 0.25 (0.16-0.38) for 200-349 cells/microL, and 0.18 (0.11-0.29) for 350 or more cells/microL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0.59 (0.41-0.86) for 10000-99999 copies/mL, 0.42 (0.29-0.61) for 500-9999 copies/mL, and 0.29 (0.21-0.39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2.4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum. INTERPRETATION: At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.

Limited effect of food composition on the pharmacokinetics of nelfinavir administered twice daily.

UNLABELLED: The objective of the study was to investigate the effect of two different breakfasts on the pharmacokinetics of nelfinavir under steady state conditions. METHODS: Twenty-four healthy male volunteers were evaluated in a 17 days open labeled one sequence crossover study evaluating the effect of a 'light' breakfast (350 kcal) compared to a standard breakfast (800 kcal) on the pharmacokinetics of nelfinavir at steady state during 1250 mg twice daily (BID) administration. RESULTS: After administration with a standard breakfast higher concentrations of nelfinavir were observed during the terminal phase than after administration with a 'light' breakfast. The comparison of the log subset 10 transformed parameters C subset 1-hr-postdose, AUC subset 0-12h, C subset max, and C subset 12 hours, showed that the AUC subset 0-12h was decreased by 13% (P = 0.01) after administration with the 'light' breakfast. Nelfinavir 1250 mg BID was well tolerated. CONCLUSIONS: Although drug intake with a 'light' breakfast' showed a statistically significant decrease for nelfinavir AUC subset 0-12h, this marginal 13% reduction is not considered clinically relevant. No significant effects of the two different breakfasts were found for the remaining three parameters tested C subset 1-hr-postdose, C subset max, and C subset 12 hours.