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.

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.

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.

The Protease Inhibitor Transfer Study (PROTRA 1): abacavir and efavirenz in combination as a substitute for a protease inhibitor in heavily pretreated HIV-1-infected patients with undetectable plasma viral load.

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.