Maria Paola Trotta

Self-reported symptoms and medication side effects influence Adherence to highly active antiretroviral therapy in persons with HIV infection

Objectives: To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self‐reported symptoms or medication side effects are related to adherence. Design: Cross‐sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods: Participants receiving HAART completed a 16‐item self‐administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV‐ and HAART‐related symptoms experienced during the last 4 weeks. Results: From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA <500 copies/ml (odds ratio = 0.51; 95% confidence interval: 0.31‐0.85). Frequency of moderate/severe symptoms or medication side effects in nonadherent participants ranged from 3.6% to 30%. On univariate analysis, nausea, anxiety, confusion, vision problems, anorexia, insomnia, taste perversion, and abnormal fat distribution were significantly associated with nonadherence. Nonadherent persons had a higher mean overall symptom score (12.3 ± 9.2 versus 8.1 ± 6.6; p < .001) and mean medication side effect score (2.9 ± 2.7 versus 1.9 ± 1.9; p < .001) when compared with adherent participants. In the multivariate analysis, nausea (p = .003); anxiety (p = .006); younger age (p = .007); unemployment (p < .001); not recalling name, color, and timing of drugs (p = .009); running out of pills between visits (p = .002); and being too busy (p = .03) were independently associated with nonadherence in the last 3 days. Conclusions: In addition to patient characteristics, medication‐related variables, and reasons for nonadherence, patient‐reported symptoms and medication side effects were significantly associated with adherence to HAART.

Depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy.

Summary: Affective disorders have been reported as the most common mental health problem in persons with HIV infection. Depression has a significant impact on the quality of life of persons living with HIV and AIDS and is associated with HIV disease progression and mortality, even after controlling for sociodemographic and clinical characteristics and substance abuse. Depression has been also reported as one of the main causes of poor adherence with antiretroviral regimens. However, no published investigation has specifically focused on the relationship between depression and adherence to antiretroviral therapy. Nonetheless, information on the association between depressive symptoms and adherence may be gathered from investigations carried out to explore determinants of adherence with antiretroviral therapy. Findings from available studies show a substantial and consistent relationship between adherence to antiretroviral regimens and depression. Early recognition and proper management of depressive comorbidity could be an effective intervention strategy to improve adherence and may make a difference in the quality of life, social functioning, and disease course of people with HIV.

Cross-Resistance among Nonnucleoside Reverse Transcriptase Inhibitors Limits Recycling Efavirenz after Nevirapine Failure

Heterogeneity in genotype mutations associated with resistance of HIV to nonnucleoside reverse transcriptase inhibitors (NNRTIs) should allow identification of patients failing nevirapine (NVP) who might benefit from efavirenz (EFV)-containing salvage regimens. To establish the feasibility of recycling EFV after failure of NVP-containing regimens genotypic data on 103 NVP-failed patients were analyzed to evaluate the prevalence of EFV resistance-conferring mutations. A clinically significant resistance to EFV was found in 50 of 103 (58%) of NVP-failed subjects. Furthermore, the 3-month virological response to salvage regimens containing EFV was assessed in patients previously treated with NVP and carrying single mutations conferring resistance to this drug. A proportion of HIV RNA less than 500 copies/ml at 3 months was obtained only in 2 of 12 (17%) of EFV-treated subjects compared with 35 of 67 (52%) of those without NNRTI mutations (OR, 0.18; 95% CI, 0.03-0.79). The median HIV-1 RNA decrease after 3 months was -0.63 log(10) among patients carrying single NNRTI-associated mutations compared with -1.32 log(10) among those without any NNRTI mutations. No virological response was observed in six patients harboring a single Y181C/I mutation. On the basis of the present data, sequential use of NNRTIs should be avoided in the management of treatment failure.

Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

Objective:To evaluate the effect of drug class-wide resistance (CWR) on survival in HIV-infected individuals who underwent genotypic resistance test after antiretroviral failure. Design:Observational, longitudinal cohort study. Methods:HIV-infected individuals experiencing treatment failure were enrolled at first genotypic resistance test. End-points were death for any cause, AIDS-related death and AIDS-defining event/death. CWR was defined according to the International AIDS Society consensus. Survival analysis was performed with Coxs model. Results:Among 623 patients enrolled and followed for a median of 19 months (interquartile range, 12–29), Kaplan–Meier analyses for end-points at 48 months in patients with no CWR, one CWR, two CWR or three CWR were 8.9, 11.7, 13.4 and 27.1%, respectively, for death; 6.1, 9.9, 13.4 and 21.5%, respectively, for AIDS-related death; and 16.0, 17.7, 19.3 and 35.9%, respectively, for new AIDS event/death. In a multivariate Coxs model, higher HIV RNA level, previous AIDS and detection of three CWR (hazard ratio, 5.34; 95% confidence interval, 1.76–16.24) were all significantly associated with increased risk of death, while higher CD4 cell count and use of a new boosted protease inhibitor drug after identifying genotypic resistance were associated with reduced risk. Detection of three CWR was also significantly associated with higher risk of AIDS-related death and new AIDS event/death. Conclusions:Even in the late era of highly effective antiretroviral treatments, detection of CWR, particularly if extended to all three drug classes is related to poorer clinical outcome and represents a risk-marker of disease progression and death.

Variable Prediction of Antiretroviral Treatment Outcome by Different Systems for Interpreting Genotypic Human Immunodeficiency Virus Type 1 Drug Resistance

To determine the variability of genotypic human immunodeficiency virus (HIV) type 1 drug-resistance interpretation by available expert systems and its clinical implications, 261 subjects for whom a potent antiretroviral regimen was failing who were starting salvage therapy were evaluated. The association of the genotypic susceptibility score (GSS) of the salvage regimen, according to 11 interpretation systems, with HIV RNA outcomes for 6 months was examined. GSS was highly variable, as determined by the different interpretation systems, and showed independent correlation with changes from baseline HIV RNA levels at 6 months with 5 systems--Stanford hivdb, GuideLines 3.0, Retrogram 1.4, HIVresistanceWeb, and São Paulo University. Most GSSs predicted virologic response in regimens containing stavudine, lamivudine, efavirenz, or indinavir. Selected systems predicted response in regimens containing didanosine, abacavir, or nelfinavir, and no system predicted outcome of boosted protease inhibitors. GSSs predicted changes in HIV RNA levels better in adherent patients than in nonadherent individuals. Interpretation may be improved, and knowledge should be used uniformly throughout different expert systems.

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.

Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors

ABSTRACT Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naïve patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 Å of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naïve patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs.

Virologic correlates of adherence to antiretroviral medications and therapeutic failure

Summary: Adherence to antiretroviral therapy affects the pharmacokinetics of antiviral drugs and activates a cascade of events ultimately leading to therapeutic success or failure. An optimal adherence usually affords minimal rounds of virus replication and rare spontaneous mutations, which are unable to be fixed in the genome because of the competition of wild‐type (more fit) strains. Therefore, adherence‐based therapeutic success is mostly accompanied by the prevalence of wild‐type strains. In case of poor adherence, virus replication is substantial, and mutations randomly occurring tend to be fixed within the genome. Under these conditions, mutated‐resistant strains will outgrow wild‐type virus (sensitive to antivirals and thereby unable to compete enough with resistant strains for cellular targets): thus, therapeutic failure occurs, and mutated resistant strains are predominant. In the case of very low or absent adherence, virologic failure occurs, although wild‐type virus (whose replication is not significantly affected by antivirals) is not outgrown by mutated strains randomly produced but unable to be fixed within the genome. Taken together, these events and their consequences strongly support the relevance of a tight and continuous monitoring of adherence to antiretroviral drugs to prevent the risk of development of mutated strains often cross‐resistant to the majority of antiretroviral drugs currently available.