Sara Melzi

Treatment-related factors and highly active antiretroviral therapy adherence.

Summary: Adherence to highly active antiretroviral therapy (HAART) plays a critical role in the effectiveness of HIV treatment. Nevertheless, the complexity of regimens and frequent side effects make HAART extraordinarily difficult to take, and many HIV‐infected persons fail to adhere. The current study offers an overview of the relationship between adherence and antiretroviral treatment‐related variables. As for other chronic diseases, medication regimen complexity also has an impact on adherence in the management of HIV infection. In particular, the authors discuss the effect of pill burden, dosing frequency, dietary instructions, number and type of different medications prescribed, short‐ and long‐term side effects, convenience, and ability to incorporate the treatment regimen into a daily routine. Medication side effects are common in HAART‐treated persons and are associated with concurrent and future nonadherence. Simplification of regimens, adjustment of the drug schedule to the patients specific lifestyle, and anticipation and self‐management of side effects are treatment‐based strategies to optimize HAART adherence and ensure the most effective, convenient, safe, and well‐tolerated antiretroviral treatment.

Patient-reported and physician-estimated adherence to HAART. Social and clinic center-related factors are associated with discordance

AbstractOBJECTIVES: To evaluate the rate of discordance between patients and physicians on adherence to highly active antiretroviral therapy (HAART) and identify factors related to discordance in these two assessments. DESIGN: Prospective, multicenter, cohort study (AdICONA) nested within the Italian Cohort Naïve Antiretrovirals (ICONA) study. SETTING: Tertiary clinical centers. PARTICIPANTS: The patients filled out a 16-item self-administered questionnaire on adherence to HAART. At the same time, physicians estimated the current HAART adherence of their patient. MAIN OUTCOME MEASURE: Discordance between patient and physician on adherence to antiretroviral therapy. RESULTS: From May 1999 to March 2000, 320 paired patient-physician assessments were obtained. Patients had a mean plasma HIV RNA of 315 copies/ml (64% had undetectable HIV RNA) and a mean CD4+ cell count of 577 cells × 106/L. Nonadherence was reported by 30.9% of patients and estimated by physicians in 45.0% cases. In 111 cases (34.7%), patients and physicians were discordant on adherence to HAART. Kappa statistics was 0.27. Using patient-assessed adherence as reference, sensitivity, specificity, positive predictive value, and negative predictive value of physician-estimated adherence were 64.7%, 66.6%, 81.2%, and 45.8%, respectively. On multivariable analysis, low education level, unemployment, absence of a social worker in the clinical center, and unavailability of afternoon visits were significantly correlated with patient-physician discordance on adherence to antiretrovirals. CONCLUSIONS: Physicians did not correctly estimate patient-reported adherence to HAART in more than one third of patients. Both social variables and factors related to the clinical center were important predictors of discordance between patients and physicians. Interventions to enhance adherence should include strategies addressed to improve patient-physician relationship.

Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens.

The difference between adherence to non- nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens was investigated. Better adherence was found in NNRTI-treated patients, especially when efavirenz was included in the regimen, compared with single PI-treated patients and in those with CD4 cell counts less than 200 x 10(6)/l. By contrast, younger age, self-report of active drug use, fatigue or vomiting negatively affected adherence. Self-reported sexual dysfunction was significantly associated with non-adherence only in PI-treated individuals.

Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy.

Summary: The outcome of second‐line protease inhibitor (PI)‐containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA <1 log10 copies/ml after ≥2 months) and discontinuation due to intolerance/toxicity. During a median follow‐up of 483 days (33‐1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Coxs model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus ≥6 months: 95% confidence interval [CI], 1.08‐2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04‐2.30); the negatively associated factors were advanced age (HR 0.61 >34 years versus ≤34 years: 95% CI, 0.42‐0.88), a saquinavir‐containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34‐0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35‐0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02‐3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22‐0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second‐line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI‐containing regimen are at risk of toxicity to other PIs and should be addressed to PI‐sparing HAART.

96 Week Follow-Up of HIV-Infected Patients in Rescue with Raltegravir Plus Optimized Backbone Regimens: A Multicentre Italian Experience

Background Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. Methods Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. Results Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm3; 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm3, respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. Conclusions In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Predictive role of the three-month CD4 cell count in the long-term clinical outcome of the first HAART regimen.

The aim was to evaluate whether the three-month CD4 cell counts are a reliable predictor of the long-term clinical outcome of HAART-treated patients, by an observational study of 585 patients initiating HAART in a clinical setting. Clinical failure was defined as the occurrence of new or recurrent AIDS-defining events or death, and was analysed by means of intention-to-treat, univariate and multivariate analyses. An adjusted Cox regression model was used to evaluate the effect of three-month CD4+ counts on clinical outcome. Clinical failure occurred in 65 patients (11.1%) during a median follow-up of 31 months (1-65) as a result of new AIDS-defining events (ADEs) in 48 patients, ADE recurrence in six, and death in 11. The mean (median; range) CD4+ counts were 156/microL (155; 4--529) in patients with and 362/microL (326; 18--1162) in patients without clinical failure (P < .0001). Moreover, the proportion of patients with mean CD4+ counts < 200 microL was higher in those experiencing subsequent clinical failure (chi2: 41.11; P< .00001). Multivariate analysis showed that baseline CD4+ counts < 50 microL, HIV-RNA > 100,000 copies/mL and AIDS at baseline predicted failure; after adjusting for three-month CD4+ counts, this marker was the only one independently associated with clinical failure (HR 2.93; 95% Cl: 1.16--7.38). The three-month immunologic response is a reliable predictor of long-term clinical outcome.