Monica Airoldi

Similar Adherence Rates Favor Different Virologic Outcomes for Patients Treated with Nonnucleoside Analogues or Protease Inhibitors

BACKGROUND This prospective study verified the effect of adherence on the risk of virologic failure. METHODS At enrollment in the study, a total of 543 patients who were following a steady (duration, >or=6 months) and effective (viral load, <50 human immunodeficiency virus [HIV] RNA copies/mL) regimen of highly active antiretroviral therapy (HAART) completed a self-reported questionnaire derived from the Adult AIDS Clinical Trials Group Adherence Follow-up Questionnaire. Patients were followed up for the subsequent 6 months to document virologic failure, which was defined as 2 consecutive viral load measurements of >500 HIV RNA copies/mL. RESULTS Only the type of treatment and the adherence rate at baseline were significantly associated with the virologic end point. Among patients who reported an adherence rate of <or=75%, the rate of virologic failure was 17.4%; this rate decreased to 12.2% for patients whose adherence rate was 76%-85%, to 4.3% for patients whose adherence rate was 86%-95%, and to 2.4% for patients whose adherence rate was >95%. When analysis was adjusted according to the type of regimen received, patients who were receiving protease inhibitor (PI)-based HAART and who had an adherence rate of up to 85% had a virologic failure rate of >20%, whereas, only for patients who were receiving nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based HAART and who had an adherence rate of <or=75%, the virologic failure rate was >10%. For the comparison of NNRTI-treated patients and PI-treated patients with an adherence rate of 75%-95%, the odds ratio was 0.157 (95% confidence interval, 0.029-0.852). The number of pills and daily doses received correlated with the reported adherence rate. CONCLUSIONS Patients receiving NNRTIs report a higher rate of adherence than do patients receiving PIs. Adherence is significantly influenced by the number of pills and daily doses received. Low adherence is a major determinant of virologic failure; however, different therapies have different cutoff values for adherence that determine a significant increment of risk.

Effect of Adherence to HAART on Virologic Outcome and on the Selection of Resistance-Conferring Mutations in NNRTI- or PI-Treated Patients

Abstract Background: The effect of adherence on the risk of virologic failure and mutations selection was verified in a prospective study. Method: At baseline, all patients had a viral load (VL) <50 copies/mL and completed a self-reported questionnaire. Patients were followed for the subsequent 4 months to document virologic rebound (VL > 50 copies/mL). Results: 1,133 patients completed 2,240 questionnaires/follow-up (non-nucleoside reverse transcriptase inhibitor [NNRTI] = 1,479; single protease inhibitor [PI] = 200; boosted PI = 561). Only the type of treatment and the baseline adherence rate were significantly associated with the virologic endpoint. A viral rebound rate >10% was observed in patients treated with single PI (14.7%) or boosted PI (11.7%) up to an adherence rate of 95%, whereas a similar (17.6%) rebound rate was observed only in NNRTI-treated patients with very low adherence (<55%). After adjustment for other baseline predictors of adherence, patients on NNRTIs showed a higher adherence rate than those on PIs but not higher than those on boosted PIs. The same adherence rate did not have the same result, in terms of virologic rebound, in patients on the same HAART for shorter or longer periods of time. Overall, the risk of virologic rebound for patients with >95% adherence rate was 6.2% in the first 6 months of therapy, lowered to 5.0% in the following 6 months, and was 3.2% thereafter. The risk of selecting for resistance-inducing viral mutation for NNRTI-treated patients was higher (4.9%) at very low adherence rates (<75%); the opposite was true for single PI-treated patients (4.2% for adherence >95%). Boosted PI-treated patients showed an intermediate pattern, even if at a much lower level of risk. Conclusion: Low adherence is a major determinant of virologic failure, however different therapies have different adherence cutoffs determining a significant increment of risk.

One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects

Objective: The aim of the ADONE (ADherence to ONE pill) study was to verify the effect of a reduced number of pills on adherence and quality of life (QoL) in HIV-infected patients on highly active antiretroviral therapy (HAART). Design: Prospective, multicenter, study. Methods: Patients chronically treated with emtricitabine (FTC) + tenofovir (TDF) + efavirenz (EFV) or lamivudine (3TC) +TDF +EFV and with a HIV-RNA < 50 copies/mL were switched to the single-pill fixed-dose regimen (FDR) of FTC +TDF +EFV. Data were collected with SF-36 using visual analog scales. Results of the final (6 months) primary as-treated analysis are reported. Results: 212 patients (77.4% males) of mean age 45.8 years were enrolled; 202 completed the study. One month post switch to FDR the adherence rate increased significantly to 96.1% from a baseline value of 93.8% (P < 0.01). The increase was steadily maintained throughout the study (96.2% at 6 months). QoL improved over time from 68.8% to 72.7% (P = 0.042) as well, and was significantly associated with the perception of health status, presence of adverse events (AEs) and number of reported AEs (P < 0.0001). QoL significantly influenced adherence (P < 0.0001). During FDR use the mean CD4 count increased from 556 to 605 cells/μL (P < 0.0001). At the end of follow-up 98% of patients maintained HIV-RNA level < 50 copies/mL and 100% <400 copies/mL. Four patients stopped therapy because they were lost to follow-up and 6 because of AEs (insomnia/nervousness 4, allergy 1, difficulties swallowing pills 1). Conclusion: By substituting a one-pill once-a-day HAART, we observed an improvement of both adherence and QoL while maintaining high virologic and immunologic efficacy. HAART simplicity is an added value that favors adherence and may improve long-term success.

Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer.

Background:Adequate antiretroviral exposure during pregnancy is critical to prevent the vertical transmission of HIV and for maternal health. Pregnancy can alter drug kinetics. We assessed the pharmacokinetics of atazanavir/ritonavir (300/100 mg a day) during pregnancy. Methods:An intensive steady-state 24-h pharmacokinetic profile of atazanavir was performed in the third trimester of pregnancy and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured atazanavir by reverse-phase high-performance liquid chromatography. Results:Seventeen women completed the study. Antepartum, the atazanavir geometric mean area under the plasma concentration-time curve from 0 to 24 h (AUC0–24) was 28 510 ng·h/l, the maximum observed plasma concentration (Cmax) was 2 591 ng/ml and the 24-h postdose concentration (Ctrough) was 486 ng/ml. The same postpartum parameters were 30 465 ng·h/l, 2 878 ng/ml and 514 ng/ml, respectively. The antepartum to postpartum ratio for AUC0–24 was 0.94 and for Ctrough was 0.96, indicating equivalence, whereas Cmax values were slightly although not significantly lower. The ratio of cord blood/maternal atazanavir concentration in 14 paired samples was 0.13. Conclusion:Atazanavir exposure during the third trimester of pregnancy is similar to that observed in the non-pregnant period. Over the whole dosing interval, therapeutic drug concentrations well above the wild-type HIV 90% inhibitory concentration are maintained. Atazanavir crosses the placenta, potentially providing further protection for the newborn. As pregnancy does not appear to alter atazanavir exposure, no dose adjustment is required in pregnant women. Results suggest that atazanavir is a reasonable component of HAART during pregnancy.

CD4 cell-guided scheduled treatment interruptions in HIV-infected patients with sustained immunologic response to HAART.

OBJECTIVE To compare continuous HAART with a CD4 cell-driven scheduled treatment interruption (STI) strategy. METHODS LOng Term Treatment Interruption study is a randomized, controlled, prospective trial. Patients with CD4 cell counts more than 700 cells/microl were eligible, and the immunologic threshold to resume HAART was 350 cells/microl. The primary end point was the development of an opportunistic disease, death from any cause or the occurrence of diseases, other than opportunistic, requiring hospital admission. Secondary end points were major adverse effects, virologic failures and therapeutic costs. RESULTS Three hundred and twenty-nine patients were randomized 1: 1. Total follow-up was 1388 person-years (mean 4.2 years). Patients in the STI group stopped therapy for a total of 241 STI cycles, their mean off-therapy period was 65.3% of the follow-up. The primary end point occurred in 12.1% of patients on STI and in 11.6% of controls [odds ratio 1.05; 95% confidence interval 0.54-2.05]. A higher proportion of patients in the STI arm were diagnosed with pneumonia (P = 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P < 0.0001) more frequent among controls. Eight patients (4.8%) in the STI group and 11 (6.7%) controls developed viral resistance [odds ratio 0.79, 95% confidence interval 0.27-1.81]. The mean daily therapeutic cost was 20.29 euro for controls and dropped to 9.07 euro in the STI arm (P < 0.0001). CONCLUSION The two strategies may be considered clinically equivalent. CD4 cell-guided STIs seem a possible alternative for chronically infected individuals responding to HAART provided that CD4 cell decrements would be steadily maintained above a safe threshold.

Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients.

BACKGROUND Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells. METHODS A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays. RESULTS No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus. CONCLUSIONS An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.

Prediction of Virologic Outcome of Salvage Antiretroviral Treatment by Different Systems for Interpreting Genotypic HIV Drug Resistance

The authors assessed the predictive capacity of 3 rule-based algorithms (Bergamo, Stanford University, Rega Institute) for HIV genotypic interpretation. A total of 1132 postgenotypic regimens in 533 patients were considered. The genotypic sensitivity score (GSS) was strongly associated (P < .0001) with the virologic outcome (1 log HIV-RNA reduction). The 3 algorithms had a highly significant prediction efficiency. The Bergamo algorithm receiver-operating characteristic curve area under the curve (AUC) for the prediction of ≥1 log HIV-RNA reduction was 0.753 (95% confidence interval, 0.725-0.781), testifying that the prediction was significantly different (P < .0001) from simple chance. The AUCs obtained by the 2 other systems were similar (0.752 Stanford; 0.741 Rega). The predictive capacity of the algorithms was not influenced by the type of antiviral drugs used. The 3 considered rule-based algorithms for the interpretation of HIV genotypic resistance yield congruent results and may effectively predict the virologic outcome of rescue therapy. Their use may help clinicians in interpreting mutational patterns and in making therapeutic choices.

Resistance Costs and Future Drug Options of Antiretroviral Therapies: Analysis of the Role of NRTIs, NNRTIs, and PIs in a Large Clinical Cohort

Abstract Objective To investigate future drug options (FDOs), resistance cost (RCVF), and virologic response to genotypic-driven rescue highly active antiretroviral therapy (HAART), according to type of therapy. Method This was a retrospective analysis in naïve or antiretroviral-experienced patients. Virologic response was defined as HIV RNA <50 copies. Results There were 108 patients failing first-line HAART; there were 328 experienced patients. FDOs were reduced in subjects failing a thymidine-analogue (TA) regimen (median 3.65, IQR 1.29 ) compared to patients without TA (median 3.82, IQR 1.12) (p = .011). FDOs after first failure were higher for patients with non-nucleoside reverse transcriptase inhibitor (NNRTI; median 3.82; IQR 1.24) than with protease inhibitor (PI; median 3.64, IQR 1.15) (p = .027). In experienced patients, FDOs were much higher for TA (p = .005). Patients responding to genotypic-modified regimens had higher FDOs (median 3.9 4, IQR 2.53) than patients not responding (median 2.18, IQR 3.65) (p > .0001). Switching from an NNRTI-based HAART to a boosted PI had a higher chance (48.1%) of achieving a full virologic suppression, compared to switching from PI to NNRTI (21.4%, p < .0001). Conclusion FDOs and RCVF are parameters that can quantify the therapeutic choices at virologic failure. Different drugs induce different FDOs and RCVF. In successive-line regimens, the higher antiviral effect and genetic barrier of boosted PIs may overcome the limits of using nucleoside reverse transcriptase backbones, with only partial effectiveness.

Back to the ring: knocking-out headache.

On October 2010, a 32-year-old Albanian man, living in Italy since 2001, came to the emergency department of our hospital reporting a several months history of persistent sub-continuous occipital headache unresponsive to pharmacological therapy. He worked as bricklayer and he used to go back to Albany every 4 months; the last visit to his country had occurred 1 month before. The patient was apparently in good health, with no remarkable history for relevant diseases. He denied smoking, alcohol or drug use. His mother and his two brothers were apparently in good health too; his father had died of gastric cancer. On physical examination the patient was afebrile, without lymphadenopathy, fully conscious, orientated and showed no overt neurological abnormalities. Haematology and basic blood chemistry tests gave no pathological results; he was negative for HIV infection. A contrast-enhanced CT scan of the brain revealed a hyperdense parafalcial posterior single lesion with ring enhancement, initially interpreted as a possible meningioma. The patient was admitted to the Neurology ward and a brain MRI showed three small rounded lesions in the right hemisphere, all with a vivid gadolinium peripheral enhancement (the largest lesion within the superior frontal gyrus is shown in Fig. 1a).

Lung cryptococcosis in a treated HIV-1-infected patient with suppressed viral load and past disseminated cryptococcosis: relapse or late IRIS?

Sir, Early initiation of combination antiretroviral therapy (cART) in AIDS presenters reduces mortality, but seems to worsen survival in cryptococcal meningitis, probably because of immune reconstitution inflammatory syndrome (IRIS), with fatal cerebral complications. Timing of cART initiation is not clearly defined, ranging from 2 to 10 weeks. Strategies aiming at reducing the risk of IRIS are lacking. We report a case of pulmonary and mediastinal lymph node cryptococcosis occurring late after immune reconstitution and fluconazole prophylaxis discontinuation in a patient with previous AIDS-presenting disseminated/meningeal cryptococcosis. A Pakistani man in his mid-forties presented with AIDS and disseminated/meningeal cryptococcosis (CD4 count 16 cells/mm, plasma HIV-1 RNA 191100 copies/mL and blood and CSF cultures positive for Cryptococcus neoformans). He was treated with a standard amphotericin B course, followed by secondary fluconazole prophylaxis; cART was introduced 1 month later with co-formulated zidovudine/lamivudine and lopinavir/ritonavir, achieving virological suppression and immune restoration (Figure 1). The nucleoside backbone was switched to tenofovir/emtricitabine after 1 month, because of bone marrow toxicity (haemoglobin 8.3 g/dL, white blood cells 1910/mm and neutrophils 390/mm). Lumbar puncture performed at baseline and after 3 months showed a decrease in HIV-1 RNA in the CSF, although the CSF/plasma viral load ratio did not decrease accordingly (2867/191100 copies/mL1⁄40.02 at baseline versus 123/ 314 copies/mL1⁄40.39 at month 3). In the absence of new clinical symptoms, cryptococcal soluble antigen titre in the CSF increased from 1:512 at baseline to 1:2048 at month 3, but culture was negative; no other neurotropic viruses (herpes viruses 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein–Barr virus or JC virus) were detected by PCR. A viral blip at month 5 (HIV-1 RNA 1170 copies/mL) was not confirmed (HIV-1 RNA ,50 copies/mL after 2 weeks); lopinavir/ ritonavir trough concentrations were adequate (5931 ng/dL/ 306 ng/dL). Fluconazole prophylaxis was stopped after 8 months of cART and CD4 count .200 cells/mm, according to guidelines. Nine months later, the patient presented with cough, malaise, weight loss, anorexia and severe dysphagia. Endoscopy revealed extrinsic oesophageal compression. A whole-body CT scan showed enlargement of mediastinal lymph nodes and bilateral apical pulmonary solid infiltrations. Sputum smears were negative for acid-fast bacilli (even by PCR) and other microbes; T cell