Teresa Bini

Clinical outcome and predictive factors of failure of highly active antiretroviral therapy in antiretroviral-experienced patients in advanced stages of HIV-1 infection

Objective:To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting. Design:Observational study. Methods:Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome. Results:During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 × 106/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20–5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months. Conclusions:HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.

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.

AIDS-defining diseases in 250 HIV-infected patients; a comparative study of clinical and autopsy diagnoses

ObjectiveTo evaluate the correlation between clinical and autopsy findings in 250 AIDS patients. MethodsClinical and autopsy diagnoses of AIDS-defining diseases in 250 AIDS patients who died in Milan between May 1984 and February 1991 were compared. ResultsPneumocystis carinii (PCP) and oesophageal candidiasis were the most frequent clinical diagnoses, while cytomegalovirus (CMV) infection was observed in almost half of the autopsies. Forty-seven per cent of the diseases found at autopsy had not been diagnosed during life; CMV infection, mycoses, HIV-specific brain lesions, cerebral lymphomas and progressive multifocal leukoencephalopathy (PML) had a higher rate of non-diagnosis in life. CMV visceral infection accounted for the majority of the diseases not recognized in life. In contrast, clinically diagnosed PCP, oesophageal candidiasis and, to a lesser degree, brain toxoplasmosis were often not found at autopsy, possibly indicating a significant rate of recovery and prevention of relapse. Finally, bacterial pneumonia and sepsis, although not AIDS indicator diseases, were observed in approximately one-third of the autopsies. ConclusionConsiderable differences in the frequency and type of the AIDS-defining diseases diagnosed during life and at post mortem were found.

CD4 cell counts at the third month of HAART may predict clinical failure.

OBJECTIVE To evaluate the influence of immunological and virological markers on clinical outcome in patients receiving their first highly active antiretroviral therapy (HAART) regimen. DESIGN AND METHODS 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 3-month CD4 cell counts on clinical outcome. RESULTS Clinical failure occurred in 55 patients (9.4%) during a median follow-up of 483 days (range 33-1334 days): 45 new AIDS-defining events (ADEs) in 38, ADE recurrence in six, and death in 11. Twenty-four of the 45 new ADEs (53.4%) occurred during the first 3 months of HAART, and 11 of 45 (24.4%) in the presence of CD4 cell counts > 200 x 10(6) cells/l. The mean (median, range) CD4 counts were 144 x 10(6) cells/l (128, 4-529) in patients with and 322 x 10(6) cells/l (288, 14-1162) in patients without clinical failure (P < 0.0001). Moreover, the proportion of patients with mean CD4 cell counts < 200 x 10(6) cells/l was higher in those experiencing subsequent clinical failure (X2 test: 26.75; P < 0.00001). Multivariate analysis showed that baseline CD4 cell counts < 50 x 10(6) cells/l and AIDS at enrolment predicted failure; after adjusting for 3-month CD4 cell counts, this marker was the only one independently associated with clinical failure (hazard risk, 4.79; 95% confidence interval, 1.40-16.47). CONCLUSIONS The 3-month immunological response is a reliable predictor of long-term clinical outcome.

Protease inhibitors and erectile dysfunction.

Increasing numbers of HIV-positive men receiving protease inhibitors (PI) complain of erectile dysfunction (ED). Through the analysis of 334 HIV-1-infected male outpatients, this study shows homosexuality, CD4 cell count, viral load, and indinavir treatment to be independent variables predictive of ED. Furthermore, a neuropathy of the sacral region was detected in 12 patients with ED who underwent diagnostic investigations. For the first time, a PI-containing regimen has been associated with peripheral neuropathy causing ED.

Lopinavir/ritonavir treatment in HIV antiretroviral-experienced patients: evaluation of risk factors for liver enzyme elevation

To evaluate the risk factors for lopinavir/ritonavir (LPV/r)‐related liver enzyme elevation (LEE) in HIV antiretroviral‐experienced patients.

Predictors of cytomegalovirus disease, natural history and autopsy findings in a cohort of patients with AIDS.

Objective:To identify the predictors of acquiring cytomegalovirus (CMV) disease, and to describe natural history, therapeutic management and autopsy findings in affected patients. Design:Observational study of a consecutive cohort of AIDS patients diagnosed and followed in the same institution. Methods:All of the patients with CMV disease were included. Statistical analyses were performed to establish the risk of acquiring the disease at or after AIDS presentation, survival, and the occurrence and time of relapses in relation to maintenance therapy. The presence of CMV infection at autopsy was also investigated. Results:CMV disease was diagnosed in 304 (24.8%) out of 1227 patients, its incidence increasing according to the year of AIDS diagnosis. Women, homosexual men, patients given zidovudine and Pneumocystis carinii pneumonia (PCP) prophylaxis before AIDS, and severely immunodepressed patients were at higher risk for the disease. CMV disease was an independent factor of worse survival (hazard ratio, 1.7 versus PCP; 95% confidence intervals, 1.28–2.13). Patients untreated during the acute phase had a 4.3 higher risk of dying than those treated. Relapses occurred less frequently and later in patients given continuous maintenance treatment (23 out of 113; 17 months) than in untreated patients (13 out of 16; 3 months) or those given discontinuous therapy (22 out of 40; 7 months), whereas survival was independent from treatment. CMV infection was found in 97 out of 134 patients at autopsy, but was unassociated with relapse. Conclusions:CMV is a severe disease whose frequency is higher in severely immunodepressed patients. Continuous treatment leads to a lower relapse rate even if it does not change survival or eradicate the infection.

Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: A randomized trial by the CIOP Study Group

This subgroup analysis assessing secondary prophylaxis for Pneumocystis carinii pneumonia (PCP) describes a multicenter, open-labeled, randomized, controlled trial evaluating the discontinuation of PCP prophylaxis. The main inclusion criterion was a history of PCP and an increase in the CD4 cell count to >200 cells/microL associated with receipt of highly active antiretroviral therapy for >or=3 months. The primary end point was the development of definitive or presumptive PCP. A total of 146 patients were enrolled (77 in the treatment discontinuation arm). After >2 years, 1 definitive and 1 presumptive case of PCP were observed, both of which occurred in patients who discontinued therapy. In most patients, secondary prophylaxis for PCP can be safely discontinued after potent antiretroviral therapy is initiated, but the threshold of >200 CD4 cells/microL may not be considered absolutely safe. Patients who present with symptoms after discontinuation of secondary prophylaxis should be evaluated for PCP despite high CD4 count and complete virus suppression.

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.

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.