Neurocognitive impairment in HIV-infected naïve patients with advanced disease: the role of virus and intrathecal immune activation.

OBJECTIVE: To investigate intrathecal immune activation parameters and HIV-RNA in HIV-associated neurocognitive disorders (HAND) of advanced naïve HIV-infected patients and to evaluate their dynamics before and after initiation of antiretroviral therapy (ART). METHODS: Cross-sectional and longitudinal analysis of HIV RNA, proinflammatory cytokines (IL-6, IL-10, INF-γ, TNF-α, TGF-ß1, and TGF-ß2) and chemokines (MIP-1α, MIP-1ß, and MCP-1) in plasma and cerebrospinal fluid (CSF) of HIV-infected patients with CD4 <200/µL. RESULTS: HAND was diagnosed at baseline in 6/12 patients. Baseline CSF HIV-RNA was comparable in patients with or without HAND, whereas CSF concentration of IL-6 and MIP-1ß, proinflammatory cytokines, was increased in HAND patients. CSF evaluation at 12 weeks was available in 10/12 cases. ART greatly reduced HIV-RNA in all patients. Nevertheless, IL-6 and MIP-1ß remained elevated after 12 weeks of therapy in HAND patients, in whom CSF HIV RNA decay was slower than the plasmatic one as well. CONCLUSION: Immune activation, as indicated by inflammatory cytokines, but not higher levels of HIV-RNA is observed in advanced naïve HIV-infected patients with HAND. In HAND patients, ART introduction resulted in a less rapid clearance of CSF viremia compared to plasma and no modifications of intratechal immune activation.

Resistance costs and future drug options of antiretroviral therapies: analysis of the role of NRTIs, NNRTIs, and PIs in a large clinical cohort.

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.

Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients.

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.

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 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 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.

Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects.

Shared epidemiological risks have resulted in HIV-infected populations having a high prevalence of hepatitis B virus (HBV) co-infection. Several prospective studies have investigated the impact of HBV co-infection on HIV disease progression; most of them were negative. On the contrary, there is evidence that HIV may modify the natural history of HBV infection. HIV positive subjects have higher rates of HBV chronification, higher HBV replication, lower ALT levels and lower rates of seroconversion to anti-HBe and anti-HBs. The impact of HIV co-infection on the outcome of HBV infection is still controversial, even if some studies have shown an accelerated progression towards decompensated cirrhosis in HIV co-infected subjects. HBV co-infection is a risk factor for severe hepatotoxicity during HAART. Vaccination for HBV is mandatory in nonimmune HIV subjects, however its efficacy in immunosuppressed patients is still controversial. HIV co-infection decreases the effectiveness of Interferon in the treatment of HBV infection. Because of its activity against both HBV and HIV, lamivudine is used in HIV-HBV co-infected patients at doses of 300 mg/daily and as part of an antiretroviral regimen, but the rate of sustained response is poor and HBV strains with mutations associated with lamivudine resistance occur at a rate of 20% per year. Trials of new drugs with activity against HBV, some of them with activity also against HIV, and some of them without cross-resistance with lamivudine, are now underway. Highly Active Anti-Hepatitis B Therapy will probably soon come of age.

Clinical experiences with interferon as monotherapy or in combination with ribavirin in patients co-infected with HIV and HCV.

Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.

CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals.

Mechanisms by which HIV affects the thymus are multiple and only partially known, and the role of thymic dysfunction in HIV/AIDS immunopathogenesis remains poorly understood. To evaluate the effects of HIV infection on intra-thymic precursors of T cells in HIV-infected adults, we conducted a detailed immunophenotypic study of thymic tissue isolated from 7 HIV-infected and 10 HIV-negative adults who were to undergo heart surgery. We found that thymuses of HIV-infected individuals were characterized by a relative depletion of CD4+ single positive T cells and a corresponding enrichment of CD8+ single positive T cells. In addition, thymocytes derived from HIV-infected subjects showed increased levels of activated and proliferating cells. Our analysis also revealed a decreased expression of interleukin-7 receptor in early thymocytes from HIV-infected individuals, along with an increase in this same expression in mature double- and single-positive cells. Frequency of regulatory T cells (CD25+FoxP3+) was significantly increased in HIV-infected thymuses, particularly in priorly-committed CD4 single positive cells. Our data suggest that HIV infection is associated with a complex set of changes in the immunophenotype of thymocytes, including a reduction of intrathymic CD4+ T cell precursors, increased expression of activation markers, changes in the expression pattern of IL-7R and enrichment of T regulatory cells generation.

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/muL (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.

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.

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.

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.

Reasons for discontinuation of nevirapine-containing HAART: results from an unselected population of a large clinical cohort.

OBJECTIVES: To evaluate the frequency of and predictive factors for nevirapine-based highly active antiretroviral therapy (HAART) discontinuation. METHODS: All patients receiving nevirapine as a component of HAART at our centre were retrospectively evaluated for efficacy and tolerability. Logistic regression was used to evaluate the influence of baseline characteristics on the outcome and Kaplan-Meier (KM) estimates to evaluate time-dependent variables. RESULTS: Between January 1999 and June 2006, 582 patients (72% males) received 744 nevirapine-based HAART regimens. Naive patients counted for 83 of these regimens; of the remaining 661 regimens administered to experienced patients, 306 were failing virologically and 355 were undergoing simplification strategies. A once-a-day schedule was used in 136 patients. The likelihood of maintaining the nevirapine-based regimen was statistically (P < 0.0001 in both cases) influenced by the patient's status (mean KM estimate of 812 days for virological failures, 1294 for naive patients and 1657 for treatment simplifications) and by the dosing schedule (once-daily 1315 days; twice-daily 1198 days). The most frequent reason for treatment discontinuation was resistance (17.5%) followed by reduced tolerability (16.3%), patient's decision (14%) and treatment strategies such as structured treatment interruptions (13.8%). During 10.2% of treatments, a grade 3 or greater increase in aminotransferase levels was observed, reflecting an overall incidence rate equal to 5.3 cases per 100 person-years. This lead to treatment discontinuation in 3.9% of cases. CONCLUSIONS: Nevirapine, especially when used in simplification strategies, enables doctors to extend the use of HAART over a long period of time. The risk of drug-induced hepatotoxicity is low, but nevirapine should be used with caution in patients co-infected with hepatitis C virus or with elevated liver function tests. As with any decision to prescribe a drug, a careful evaluation of the potential risks and benefits of using nevirapine must be made for each individual.

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.

Genotype resistance profiles in patients failing an NNRTI-containing regimen, and modifications after stopping NNRTI therapy.

Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) develops quickly and independently if they are used in combination with NRTIs or protease inhibitors (PIs) as rescue therapy, mainly due to the low genetic barrier of this class of drugs. In this study we examined clinical, therapeutic, and virologic characteristics in 88 patients with mutations conferring resistance to NNRTIs, and in 11 patients 1 year after stopping NNRTI therapy. Between patients administered Nevirapine (NVP) and those taking Efavirenz (EFV), no statistical differences were found in CD4 cell count, HIV viral load, time on NNRTI therapy, or number of PIs administered previously. A slow decline in the detectability of mutations encoding NNRTI resistance was found.