Franco Maggiolo

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.

Dolutegravir in Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week Results of the Phase III VIKING-3 Study

Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

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.

Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial

Objective: To compare continuous highly active antiretroviral therapy with a CD4 cell count-driven structured treatment interruption (STI) strategy. The primary end-point was the proportion of subjects maintaining CD4 cell count > 400 × 106 cells/l. Secondary end-points were to identify the dynamic and predictive variables of CD4 cell loss. Methods: The BASTA study is a randomized, controlled, prospective trial. Patients with CD4 cell counts > 800 × 106 cells/l were enrolled and the immunological threshold to resume therapy was set to the lower normal limit of CD4 cells for HIV-uninfected adults. Results: Sixty-nine patients were randomized and followed for 64 weeks. At baseline, all had undetectable plasma HIV RNA and their mean CD4 cell count was 1077 × 106 cells/l. None of the patients showed a disease progression or any AIDS-defining event. At each time point, the proportion of subjects in the STI group that had a CD4 cell count < 400 × 106 cells/l was not statistically different from the control group. In all cases, the 95% confidence interval for this difference was smaller than ±10%. However, 57% of patients with nadir CD4 cell count 200–350 × 106 cells/l reached a CD4 cell count < 400 × 106 cells/l. This was statistically different (P = 0.02) from the nearly 90% of patients with a nadir CD4 cell count 350–500 × 106 cells/l who maintained a CD4 cell count of > 400 × 106 cells/l. Conclusions: Prolonged STI in patients with fully suppressed virus and marked immune reconstitution is generally safe. The main predictor of CD4 cell decline is the nadir CD4 cell count. Pulse therapy warrants further careful prospective evaluation to investigate virological and clinical outcomes over a very long period.

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.

Efavirenz: a decade of clinical experience in the treatment of HIV

Efavirenz, a non-nucleoside reverse transcriptase inhibitor, has been an important component of the treatment of HIV infection for 10 years and has contributed significantly to the evolution of highly active antiretroviral therapy (HAART). The efficacy of efavirenz has been established in numerous randomized trials and observational studies in HAART-naive patients, including those with advanced infection. In the ACTG A5142 study, efavirenz showed greater virological efficacy than the boosted protease inhibitor (PI), lopinavir. Efavirenz is more effective as a third agent than unboosted PIs or the nucleoside analogue abacavir. Some, but not all, studies have suggested that efavirenz (added to two nucleoside reverse transcriptase inhibitors) is more effective than nevirapine. Virological and immunological responses achieved with efavirenz-based HAART have been maintained for 7 years. Dosing convenience predicts adherence, and studies have demonstrated that patients can be switched from PI-based therapy to simplified, once-daily efavirenz-based regimens without losing virological control. The one-pill, once-daily formulation of efavirenz plus tenofovir and emtricitabine offers a particular advantage in this regard. Efavirenz also retains a role after failure of a first PI-based regimen. Efavirenz is generally well tolerated: rash and neuropsychiatric disturbances are the most notable adverse events. Neuropsychiatric disturbances generally develop early in treatment and they tend to resolve with continued administration, but they are persistent and troubling in a minority of patients. Efavirenz has less effect on plasma lipid profiles than some boosted PIs. Lipodystrophy can occur under treatment with efavirenz but it may be reduced if the concurrent use of thymidine analogues is avoided. Efavirenz resistance mutations (especially K103N) can be selected during long-term treatment, underscoring the importance of good adherence. Recent data have confirmed that efavirenz is a cost-effective option for first-line HAART. In light of these features, efavirenz retains a key role in HIV treatment strategies and is the first-line agent recommended in some guidelines.

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.

Factors associated with the failure of HIV-positive persons to return for scheduled medical visits

Abstract PURPOSE: To assess in an HIV-positive cohort the cumulative probability of failing to return for scheduled medical visits and to address the factors associated with follow-up discontinuation. METHOD: This was a hospital-based cohort study conducted from January 1985 through September 1999. Out of 3,300 HIV-1 infected patients, 1,680 patients with CD4 count <500 cells/mL or with AIDS diagnosis were included in the analysis because they received scheduled medical visits for follow-up at our center. Baseline visit was the first visit when patients met the criteria for enrollment. The main outcome measure was failure to return for scheduled medical visits for at least 12 consecutive months. RESULTS: The probability of returning decreased rapidly in the first months after the baseline visit. After 1 year since enrollment, 25% of patients failed to return and after 2 years 34% of patients failed to return. Most patients who failed to return for visits (78%) discontinued their follow-up within 6 months since enrollment. In multivariate analysis, patients in the intravenous drug use (IDU) category were most likely to fail to return for scheduled appointments, as were patients with higher CD4 count (CD4 >50 cells/μL) or patients without AIDS diagnosis. Patients with shorter follow-up had a higher risk of failing to return (odds ratio [OR]: 0.12, 0.36, 0.45, and 0.74 for >36, 24-36, 12-24, and 6-12 months of follow-up respectively vs. <6 months). Patients who were enrolled in more recent years had a higher compliance to follow-up visits (OR: 0.33, 0.63, and 0.61 for ≥1997, 1995-1996, and 1988-1994 vs. <1988). CONCLUSION: Patients in the IDU category, patients without AIDS diagnosis, or patients with higher CD4 counts are more likely to miss medical appointments and discontinue their follow-up. More recently enrolled patients have a lower risk of failing to return. It is possible that the recent and more effective anti-HIV treatment played a major role in increasing adherence to follow-up.

Ultrasensitive assessment of residual low-level HIV viremia in HAART-treated patients and risk of virological failure.

Background:Low-level viremia (LLV) is measurable, with enhanced assays, in many subjects with HIV RNA levels <50 copies per milliliter. The clinical consequences of LLV are unknown. Methods:In a prospective study in HIV-1–infected adults, HIV RNA levels were determined with an ultrasensitive test (3 copies/mL) based on a real time polymerase chain reaction. The primary end point was to evaluate LLV prediction of virological failure, defined as a confirmed plasma HIV RNA level >50 copies per milliliter. Results:One thousand two hundred fourteen patients were followed for (mean) 378 days. At baseline, 71.5% were <3 copies per milliliter below the limit of detection (BLD). The risk of failing highly active antiretroviral therapy in the following 4 months for patients BLD was 0.4% compared with a 3.2% risk for those with LLV (P < 0.0001; odds ratio: 7.52). There was a significant (P < 0.0001) linear relationship between the HIV RNA and the risk of virologic failure. LLV receiver operating curve analysis showed an area under the curve of 0.76 (95% confidence interval: 0.68 to 0.84) that significantly (P < 0.0001) predicted the risk of failure. The risk of an unconfirmed viral blip was higher in patients with LLV (3.9%) than in those BLD (1.1%) (P < 0.0001; odds ratio: 3.56). Longer exposure to antiretrovirals, current use of nonnucleoside reverse transcriptase inhibitors, longer time BLD, and current HIV RNA <3 copies per milliliter were independent predictors of a positive outcome. Interpretation:Viral replication may be the cause of LLV, at least in some patients. A LLV >3 copies per milliliter is linked to a significant increment of risk of virological failure leading to drug resistance. Patients with measurable LLV should be managed to better evaluate, over time, the risk of failure and to limit its consequences.

Prevalence of Hypovitaminosis D and Factors Associated With Vitamin D Deficiency and Morbidity Among HIV-Infected Patients Enrolled in a Large Italian Cohort

Background: A high prevalence of hypovitaminosis D (hypD) in HIV-infected patients has been reported, but reasons are unclear. Methods: The 25 hydroxy vitamin D (vitD) concentration was measured in a sample of HIV-positive patients from Italy enrolled in the Icona Foundation Study. The change in absolute levels of vitD pre/post combination antiretroviral treatment was modelled by linear regression controlling for confounders and seasonality. Factors associated with hypD were identified using logistic regression analysis, and survival analysis was employed to evaluate the prognostic value of vitD concentration to predict severe diseases (diabetes, cardiovascular, renal), AIDS, and death. Results: We studied 810 patients contributing 1408 vitD measures. Median age was 36 years (range: 20-69). VitD insufficiency (30-75 nmol/L) and deficiency (<30 nmol/L) were found in 47% and 6% of the measures. Factors independently associated with vitD deficiency were African or Centre/South American nationality [odds ratio (OR): 4.16 vs. European, P = 0.04], the sample being collected in spring (OR: 11.27, P = 0.001) or in winter (OR: 4.22, P = 0.03) vs. summer, and a previous history of severe diseases (OR: 5.43, P = 0.03) or AIDS (OR: 2.44, P = 0.04). Over a median follow-up of 6.3 years, patients with vitD insufficiency were at higher risk of subsequent severe diseases than those with normal levels (relative hazard = 1.60, P = 0.05). Conclusions: Our analysis shows that despite the relatively young age of our HIV-infected population, the prevalence of hypD was high. Classic risk factors for hypD in the general population were confirmed in this setting. HypD seems to be moderately associated with the risk of severe disease, AIDS, and death.