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. (C) 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

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 ≥1 antiretroviral (ARV) regimen in all three main drug classes and ≥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.

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.

Objective Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options. Design Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV. Methods Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV). Results Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A (n=4) characterized by M184V without further regimen-associated mutations, group B (n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C (n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options. Conclusions Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.

Background: Triple-combination antiretroviral therapy ( CART) for human immunodeficiency virus infection has been in use for almost a decade, but the extent to which treatment success has changed is uncertain. We examined risk of initial virological failure of CART according to the year of starting therapy.Methods: We included subjects from 5 complete clinic cohorts in Europe and Canada who started CART without previous antiretroviral therapy from 1996 to 2002 with 1 or more pre-CART viral load(VL) measurement and CD4 count. Based on the first VL measurement from 6 to 12 months after CART initiation, virological failure was defined as a VL of more than 500 copies/mL. We used the following 3 inclusion strategies: ( 1) including all subjects, with missing VL measurement counted as virological failure (n= 3825; strategy A); ( 2) including all subjects with VL measurement ( n= 3120; strategy B); and ( 3) including all subjects receiving antiretroviral therapy at VL measurement ( n= 2890; strategy C).Results: From 1996 to 2002, risk of virological failure fell from 38.9% to 24.8% for strategy A, 28.4% to 12.0% for strategy B, and 22.8% to 8.2% for strategy C. Estimated relative reductions in risk (95% confidence interval) over the 7-year period, adjusted for cohort, demographic factors, pre-CART VL and CD4 count, and previous AIDS, were 48% (39%-56%), 64%(53%-73%), and 79%(69%-85%) for strategies A, B, and C, respectively. Reductions in risk were greatest from 1996 to 1999, with weaker trends subsequently. Trends remained but were attenuated after further adjustment for the starting regimen.Conclusions: Over a 7-year period of CART use in clinical practice, risk of initial virological failure of treatment has halved at least. These data suggest the trend is due to improvements in CART regimens and greater effectiveness of their use.

BACKGROUND:We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. METHODS:We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS-free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. RESULTS:During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4+ count at the time of HAART initiation (relative rate per log2 cells/microL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4+ count (relative rate per log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. CONCLUSION:The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.

Objectives The aim of the study was to evaluate the safety and efficacy of abacavir (ABC) and efavirenz (EFV) instead of a protease inhibitor (PI) in HIV-1-infected subjects treated with two nucleoside reverse transcriptase inhibitors (NRTIs) and one PI with undetectable viral loads (< 50 HIV-1 RNA copies/mL). To be eligible for inclusion, patients had to have a history of viral load < 400 copies/mL for at least 3 months and had to be naive to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed.Design An open-label, single-centre pilot study of duration 48 weeks was conducted. ABC was added to the original treatment with two NRTIs and one PI at baseline, and at week 6 the PI was replaced by EFV. At each study visit, CD4 cell count, viral load [measured by polymerase chain reaction (PCR)] and clinical chemistry were measured. Fasting blood samples were taken at baseline and at weeks 12, 24, 36 and 48 to measure levels of cholesterol [high-density lipoprotein (HDL)/low- density lipoprotein (LDL)], triglycerides, insulin and C-peptide. Additionally, an oral glucose tolerance test (OGTT) was performed. A bioelectric impedance analysis (BIA) and a single slice abdominal and mid-thigh computed tomography (CT) scan were carried out to assess changes in body composition.Results Thirty patients were included in the study. Three patients experienced ABC-hypersensitivity and one patient demonstrated virological failure caused by nonadherence. At week 48, all remaining patients had viral loads < 50 copies/mL with stable CD4 counts. The fasting metabolic parameters and abdominal fat distribution remained unchanged.Conclusions In heavily pretreated patients, ABC and EFV in combination provide an effective, simplified and well-tolerated alternative to PI treatment.

Background For HIV patients who have lost treatment options with reverse transcriptase inhibitors(RTI), a PI-only regimen is a therapy alternative. Objective: To investigate the potential pharmacokinetic interaction of a boosted double PI-only regimen of Lopinavir and Ritonavir(LPV/RTV) plus Indinavir(IDV). Methods: We determined plasma drug levels of LPV, RTV and IDV in 19 HIV 1-infected adult patients, taking IDV800mg and LPV400/RTV100mg BID only and compared the results to control groups of patients with IDV800mg/RTV100mg BID(+2 or 3RTI) or LPV400/RTV100mg BID(+2 or 3RTI). PK analysis based on a non-compartmental model. Results (see table): Conclusion The addition of LPV to IDV/RTV does not affect the IDV AUC under steady state conditions (group 1 vs 3). LPV plasma levels remain unchanged, except a 33%- elevated LPV Cmin (group 1 vs 2). Significantly lower RTV plasma levels (group 1/2 vs 3*) sufficiently booster IDV/LPV. Clinical Pharmacology & Therapeutics (2004) 75, P65–P65; doi: 10.1016/j.clpt.2003.11.245 Treatment group n AUCss (ng12h/ml) Median (range) Cmax (ng/ml) Median (range) Cmin (ng/ml) Median (range) IDV 1 16 35065(12729–55675) 5555(2620–10600) 727(119–1350) LPV 16 71043(32655–117200) 6995(3510–11500) 4495(1400–6830) RTV 16 4515(1737–13657)* 597(194–2680)* 165(36–389)* LPV 2 17 66660(30295–158000) 6800(3650–16300) 3070(946–9460) RTV (+2or3RTI) 17 3309(853–5723)* 428(94–831)* 107(44–224)* IDV 3 23 43132(16803–63320) 6050(5130–7840) 702(247–3390) RTV (+2or3RTI) 23 12990(6578–39220)* 1580(493–4340)* 367(124–2040)* * Absolute difference of RTV:Group 1 vs 3:p<0,006;group 2 vs 3:p<0,001(Mann-Whitney U-test).

Objective To evaluate the difference in pharmacokinetics (PK) of responders vs. non-responders to a boosted double PI-therapy of SQV+LPV/RTV in an open label cohort study. Methods 29(24male) patients with antiretroviral therapy (ART) failure due to RTI resistance or toxicity were switched to a regimen of SQV 1000mg +LPV/RTV 400/100mg BID and completed a PK profile. PK analysis was performed after at least 2 weeks on therapy. Results (see Table 1Table 2) No difference was found between the RTV PK data of both groups. Conclusion SQV+LPV/RTV may be a salvage therapy option for patients with RTI resistance or toxicity. It may not be suitable for patients with a low CD4 cell count at baseline. Despite no statistical significance, plasma drug levels of SQV/LPV show a mentionable difference in both groups. Therefore TDM is recommended. Clinical Pharmacology & Therapeutics (2004) 75, P65–P65; doi: 10.1016/j.clpt.2003.11.244 clinical data (median) responders (n=20) non-responders (n=9) Baseline: Cumulative time on ART months 76 91 CD4 cell count (/μl) 301 >62 Viral Load log10 cop./ml 5,15 5,29 Week 24: CD4 cell count (/μl) 358 51 Viral Load log10 cop./ml 1,69 4,94 non-compartm. PK data drug responders (n=20) median (range) non-responders (n=9) median (range) difference in % (U-test*) AUCss LPV ng12h/ml 68750(19743–143100) 53911(31580–119000) −22 (p=0,32) Cmin ng/ml 3490(812–9970) 2380(736–4878) −32 (p=0,23) Cmax ng/ml 7060(3450–14200) 7560(4580–14100) +10 (p=0,98) AUCss SQV ng12h/ml 17830(3977–62075) 9502(2812–26105) −47 (p=0,09) Cmin ng/ml 569(151–2940) 285(73–700) −50 (p=0,18) Cmax ng/ml 2445(667–6890) 1720(618–4020) −30 (p=0,1) * acc.to Mann-Whitney.

Early prediction of suboptimal viral response to highly active antiretroviral therapy (HAART) is vital to prevent early development of drug resistance. We used logistic regression to predict the odds of achieving virologic suppression (<50 copies/mL) after 24 weeks of HAART in 656 antiretroviral-naive patients starting HAART at the J.W. Goethe University, Chelsea and Westminster, and Royal Free Hospitals according to their week 4 viral load. Therapy changes involving the switch of a single antiretroviral were assumed to have occurred for toxicity reasons and ignored. Because complete regimen changes or additions of new antiretrovirals could be due to virologic failure, patients were counted as virological failures at week 24. Three hundred sixty (84%) of 430 patients with viral loads of <1000 copies/mL, 106 (61%) of 175 with viral loads between 1001 and 10,000 copies/mL, 11 (37%) of 30 with viral loads between 10,00 1 and 100,000 copies/mL, and 5 (24%) of 21 with viral loads of >100,000 copies/mL at week 4 subsequently attained virologic suppression at 24 weeks. The odds of attaining virologic suppression at 24 weeks was 65% lower for every 1-log higher viral load at week 4 (odds ratio, 0.35; 95% confidence interval, 0.27-0.45). The proportion of patients with an undetectable viral load at 24 weeks among those who have not attained a viral load of <1000 copies/mL by 4 weeks is quite low. We suggest that this group of patients should be particularly closely monitored.

Objective: To assess the pharmacokinetic interaction of saquinavir and lopinavir/ritonavir. Design: Patients from the Frankfurt HIV cohort with limited reverse transcriptase inhibitor (RTI) options received the protease inhibitor (PI) combination of saquinavir (soft-gel capsules, 1000 mg twice a day) plus lopinavir/ritonavir (400/100 mg twice a day), without RTI (LOPSAQ group). A control group received the same doses of saquinavir and ritonavir plus two to three RTI (RITSAQ group). A steady-state 12 h pharmacokinetic assessment was performed. Methods: Plasma levels of saquinavir, ritonavir and lopinavir were determined by liquid chromatography–tandem mass spectrophotometry. Minimum and maximum plasma concentrations (Cmin and Cmax), the clearance (Cltot) and the area under the concentration time curve (AUC) were calculated. Results: Data were collected from 45 patients (LOPSAQ) and 32 patients (RITSAQ). There was no significant difference between the groups for median saquinavir Cmin, Cmax, Cltot and AUC (LOPSAQ: 543 ng/ml, 2300 ng/ml, 1020 ml/min and 16 977 ng*h/ml; RITSAQ: 427 ng/ml, 2410 ng/ml, 1105 ml/min and 15 130 ng*h/ml). Median ritonavir Cmin, Cmax and AUC were lower, the Cltot was higher in the LOPSAQ group (78 ng/ml, 428 ng/ml and 2972 ng*h/ml, 551 ml/min) compared with RITSAQ (194 ng/ml, 683 ng/ml and 6506 ng*h/ml, 266 ml/min; P < 0.001). Lopinavir levels were similar to historical data. Conclusion: Effective plasma levels of both saquinavir and lopinavir can be achieved by the co-administration of saquinavir soft-gel capsules and lopinavir/ritonavir. This boosted double PI combination could be an effective option for patients with limited RTI options.

Definition of the time of loss of virological response is important when designing a viral load endpoint for trials of antiretroviral drugs. We assessed whether, in patients who achieved a viral load below 50 copies/ml, two consecutive values above 50 copies/ml was really indicative of loss of response. It was common for the viral load to return to below 50 copies/ml with no change in regimen, suggesting that a higher threshold for defining the loss of response is required.