Efficacy and safety of dolutegravir/rilpivirine in real-world clinical practice. GeSIDA study 1119.

INTRODUCTION: Dolutegravir/rilpivirine (DTG/RPV) is an effective antiretroviral (ART) regimen endorsed by clinical trials as a switch therapy. The aim of our study was to analyse the efficacy and safety of DTG/RPV in real-world clinical practice. METHODS: Observational, multicentre study of patients who started DTG/RPV. Efficacy, adverse events and metabolic changes at 48 weeks were analysed. RESULTS: A total of 348 patients were included; median time of HIV infection was 21.1 years, 33.7% were AIDS cases; median nadir CD4 was 160 cells/µL; 90.5% had received ≥3 lines of ART and 179 (53.8%) had prior virological failure. Convenience (43.5%), toxicity/intolerance (28.4%) and interactions (17.0%) were the main reasons for starting DTG/RPV. Previous regimens were protease inhibitors (PI) (31.6%), non-nucleoside reverse transcriptase inhibitors (NNRTI) (20.4%) and integrase strand transfer inhibitors (INSTI) (14.9%). Efficacy (HIV-RNA <50 copies/mL) at 48 weeks was 89.7% (95% CI 86.1-92.6) by intention-to-treat (ITT) and 94.2% (95% CI 91.3-96.4) by on treatment (OT); 10 patients (3.1%) were not suppressed (3 had abandoned ART). There was a mean decrease in triglycerides, total cholesterol, low-density lipoprotein-cholesterol, glutamic-pyruvic transaminase (GPT), gamma-glutamyl transferase (GGT) and alkaline phosphatase; creatinine increased with a decrease in glomerular filtration rate. CONCLUSIONS: This study confirms the effectiveness, tolerability and safety of DTG/RPV in real-world clinical practice in a different population from clinical trials, with many years of infection, low CD4 nadir, several previous treatment lines, more than half with virological failures, and one-third diagnosed with AIDS. The switch to DTG/RPV was safe with few discontinuations due to adverse effects. Modifications of the lipid and liver profiles were favourable. There were no relevant changes in kidney function.

Evaluation of kidney function in HIV-infected patients receiving an antiretroviral regimen containing one or two inhibitors of the tubular secretion of creatinine.

OBJECTIVES: The aim of this study was to determine the evolution of renal function in patients receiving one or two inhibitors, according to different baseline factors. Some antiretroviral drugs such as rilpivirine (RPV), dolutegravir (DTG), or cobicistat (COBI), interact with the tubular secretion of creatinine, but there are no data about their impact in renal function evaluation in patients with renal disease or when these drugs are used concomitantly. METHODS: A prospective cohort study was carried out in HIV-infected patients who switched to a dual regimen including DTG, RPV or darunavir/COBI, separately or in combination. The primary endpoint was the evolution of the serum creatinine-based estimated glomerular filtration rate (eGFR-scr). A control group not receiving any transporter inhibitor was included. RESULTS: A total of 288 patients on different dual regimens were included (DTG + RPV, 92; DTG + darunavir/COBI, 23; DTG, 26; COBI, 19; control group, 128). In patients receiving two transporter inhibitors, eGFR-scr decreased by a mean of -8.4 mL/min/1.73 m2 , similar to that observed with the separate use of DTG or COBI (mean of both groups, -8.6 mL/min/1.73 m2 ), while eGFR-scr improved in the control group. Similar evolution of proteinuria and tubular dysfunction was observed in all the groups, and there were no significant changes in the cystatin C-based eGFR. Mean eGFR-scr change inversely correlated with baseline eGFR-scr value (r = -0.39; P < 0.01), with a lower eGFR-scr decrease in patients with chronic kidney disease. CONCLUSIONS: Similar eGFR-scr decreases were observed in patients using different antiretroviral drugs inhibiting the tubular transport of creatinine, separately or in combination, with no alterations in proteinuria or cystatin C-based eGFR. The lack of additional changes when the drugs were used in combination, and the lower impact in cases of previous chronic kidney disease, suggest that there are compensatory mechanisms for creatinine secretion.

Switching to dual antiretroviral regimens is associated with improvement or no changes in activation and inflammation markers in virologically suppressed HIV-1-infected patients: the TRILOBITHE pilot study.

OBJECTIVES: While the use of dual antiretroviral therapies could reduce the toxicity of antiretroviral treatment in treatment-experienced HIV-1-infected patients, it is crucial to know if reducing the number of drugs could lead to an adverse increase in inflammation and activation markers. METHODS: This was a cross-sectional pilot study conducted at the HIV-1 Unit at the Tertiary University Hospital in Madrid, Spain, evaluating biomarkers of activation [interferon-γ-induced protein 10 (IP10), high-sensitivity C-reactive protein (hs-CRP), soluble CD14 (sCD14) and sCD163], inflammation [interleukin-6 (IL-6)], blood coagulation (d-dimer), and immune response [interferon (IFN)-γ, tumour necrosis factor (TNF)-α and IL-4] in three groups of suppressed HIV-1-infected patients: patients continuing on triple therapy (26 patients), and patients who switched from triple to dual therapy, at 24 or 48 weeks after switching (13 and 36 patients, respectively). RESULTS: Demographic and immunovirological parameters were similar in the three groups of patients. IL-6 and sCD14 levels were lower in patients at 48 weeks after switching to dual therapy compared with those found in patients who continued to receive triple therapy (P = 0.012 and P = 0.001, respectively), with no differences in the levels of the remaining biomarkers. Among patients with nadir CD4 count ≤ 200 cells/µL, sCD14 levels were lower in patients who had been on dual therapy for 48 weeks (14 patients) compared with those found in patients who received ongoing triple therapy (11 patients; P = 0.029), with no differences in the levels of the other biomarkers. CONCLUSIONS: HIV-1-infected patients receiving dual regimens showed similar or even lower levels of inflammatory and activation markers compared with those found in patients who received ongoing triple therapy. Of note, similar data were obtained in patients with low nadir CD4 count.

Switching to abacavir versus use of a nucleoside-sparing dual regimen for HIV-infected patients with tenofovir-associated renal toxicity.

OBJECTIVES: We investigated the reversibility of tenofovir disoproxil fumarate (TDF)-associated renal decline and tubular dysfunction using different antiretroviral strategies. METHODS: A successive evaluation of renal [estimated glomerular filtration rate (eGFR)] and tubular (phosphataemia, proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria and tubular proteinuria) parameters was performed in 231 patients, before and after switching from TDF to abacavir (n = 60), using dual therapy (n = 49), or continuing the same regimen including TDF (n = 122). RESULTS: In a successive evaluation after a median of 8.86 months, or less time if treatment was switched (4.8 months vs. 13.3 months to second evaluation; P < 0.01), a significant improvement in eGFR (median change +0.3 vs. -2.91 mL/min/1.73 m2 in patients who did not discontinue TDF; P = 0.04) and tubular dysfunction (median change -40% vs. +30%, respectively; P < 0.01) was observed. Lineal regression showed that age (ß = -0.14; P = 0.04), previous eGFR decline (ß = -0.42; P < 0.01), and time on TDF (ß = -0.19; P = 0.04) were associated with impaired eGFR recovery. There were no differences in eGFR slopes between patients using abacavir instead of TDF and those using a dual therapy, who showed similar improvement in proteinuria (-22% vs. -19%, respectively), phosphaturia (+10.1% vs. +9.4%, respectively), and urinary beta-2-microglobulin (-9% vs. -15%, respectively; P > 0.1 for all), although patients receiving the dual regimen were more heavily pretreated. A eGFR decrease (-6.17 mL/min/1.73 m2 ) was observed in patients taking dolutegravir or rilpivirine, but with similar improvement to that observed in the rest of switching patients in tubular abnormalities. CONCLUSIONS: Tenofovir disoproxil fumarate discontinuation was associated with a rapid and significant improvement in eGFR and tubular abnormalities, regardless of whether abacavir or dual therapy was chosen. Switching to a regimen that included dolutegravir and/or rilpivirine was associated with a eGFR decrease without differences in the rate of tubular dysfunction improvement in comparison with the rest of patients who discontinued tenofovir.

Liver toxicity and risk of discontinuation in HIV/hepatitis C virus-coinfected patients receiving an etravirine-containing antiretroviral regimen: influence of liver fibrosis.

OBJECTIVES: The aim of the study was to establish the risk of liver toxicity in HIV/hepatitis C virus (HCV)-coinfected patients receiving etravirine, according to the degree of liver fibrosis. METHODS: A prospective cohort study of 211 HIV-infected patients initiating an etravirine-containing regimen was carried out. HCV coinfection was defined as a positive HCV RNA test, and baseline liver fibrosis was assessed by transient elastography. Hepatotoxicity was defined as clinical symptoms, or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value > 5-fold higher than the upper limit of normal if baseline values were normal, or 3.5-fold higher if values were altered at baseline. RESULTS: Overall, 145 patients (69%) were HCV coinfected, with a lower nadir (165 versus 220 cells/µL, respectively; p = 0.03) and baseline (374 versus 498 cells/µL, respectively; p = 0.04) CD4 count than monoinfected patients. Etravirine was mainly used with two nucleoside reverse transcriptase inhibitors (129; 61%) or with a boosted protease inhibitor (PI) (28%), with no significant differences according to HCV serostatus. Transient elastography in 117 patients (81%) showed a median (range) stiffness value of 8.25 (3.5-69) kPa, with fibrosis stage 1 in 43 patients (37%) and fibrosis stage 4 in 28 patients (24%). During an accumulated follow-up time of 449.3 patient-years (median 548 days), only one patient with advanced fibrosis (50.8 kPa) had grade 3-4 liver toxicity (0.7%). Transaminases changed slightly, with no significant differences compared with baseline fibrosis, and nine and six patients had grade 1 and 2 transaminase increases, respectively. Also, HCV coinfection was not associated with a higher risk of discontinuation (25% discontinued versus 21% of monoinfected patients; p = 0.39, log-rank test) or virological failure (8% versus 12%, respectively; p = 0.4). CONCLUSIONS: Our data suggest that etravirine is a safe option for HIV/HCV-coinfected patients, including those with significant liver fibrosis.

The influence of patient beliefs and treatment satisfaction on the discontinuation of current first-line antiretroviral regimens.

OBJECTIVES: Large cohort studies have shown a high rate of first-line combination antiretroviral therapy (cART) regimen discontinuation in HIV-infected patients, attributed to characteristics of the cART regimen or toxicity. METHODS: A cohort study of 274 patients receiving a first-line regimen was carried out. Patients' perceptions and beliefs prior to initiation were assessed using an attitude towards medication scale (0-15 points), and their satisfaction during therapy was assessed using an HIV treatment satisfaction questionnaire (HIVTSQ). Treatment discontinuation was defined as any switch in the cART regimen. RESULTS: During 474.8 person-years of follow-up, 63 (23%) patients changed their cART regimen, mainly because of toxicity/intolerance (42; 67%). The overall rate of change was 13.2 per 100 patient-years [95% confidence interval (CI) 11.1-16.4 per 100 patient-years]. An efavirenz (EFV)-based single tablet regimen showed the highest rate of adverse events (27%), but the lowest rate of change (16%; 7.44 per 100 patient-years). Cox regression revealed a decreased hazard of first regimen termination with better initial attitude towards drugs [hazard ratio (HR) 0.76; 95% CI 0.62-0.93; P < 0.01] and higher satisfaction (HR 0.94; 95% CI 0.89-0.99; P = 0.01), and an increased hazard of termination with the presence of adverse events (HR 7.7; 95% CI 2.4-11.6; P < 0.01). One-third of patients (18 of 59; 31%) with mild/moderate adverse events (which were mainly central nervous system symptoms) continued the regimen; these patients, compared with those discontinuing therapy, showed better perception of therapy (mean score 14.4 versus 12.1, respectively; P = 0.05) and greater satisfaction during therapy (mean score 50.6 versus 44.6, respectively; P = 0.04). CONCLUSIONS: Patients' beliefs and satisfaction with therapy influence the durability of the first antiretroviral regimen. These patient-related factors modulate the impact of mild adverse events, and could explain differences in the rate of discontinuation.

Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy.

BACKGROUND AND PURPOSE: Progressive multifocal leucoencephalopathy-associated immune reconstitution inflammatory syndrome (PML-IRIS) is the paradoxical worsening or unmasking of preexisting infection with JC virus attributable to a rapid recovery of the immune system after highly active antiretroviral therapy (HAART) initiation. We investigated the incidence and factors associated with PML-IRIS in HIV-infected patients. We also studied its influence on mortality of PML and the effect of corticosteroid therapy. METHODS: Single-center retrospective analysis of HIV-infected patients diagnosed with PML from 1996 to 2012 who received HAART. RESULTS: Among 59 PML patients treated with HAART, 18 (30.51%) developed PML-IRIS (five delayed PML-IRIS, 13 simultaneous PML-IRIS). Patients who developed IRIS had lower CD4 counts prior to treatment (102 vs. 68.5, P < 0.05) and experienced a greater decline in HIV-RNA levels in response to HAART (2.5log vs. 2.95log, P < 0.05). Gadolinium enhancement on MRI was observed in 31.25% of PML-IRIS cases versus 2.56% of PML non-IRIS (P < 0.01). Survival rates were higher in patients with PML-IRIS compared to those with PML non-IRIS. Eight patients received corticosteroids, five of which had a good outcome. Patients who died were severely ill when treatment was initiated whereas patients who survived were treated before major neurological deterioration occurred. CONCLUSIONS: Nearly one-third of HIV-infected patients with PML develop IRIS after initiating HAART. Patients severely immunocompromised who experience a rapid virological response to HAART have a higher risk for PML-IRIS. There was a trend for lower mortality in patients with IRIS. Early treatment with corticosteroids might be useful.

Visceral leishmaniasis as an independent cause of high immune activation, T-cell senescence, and lack of immune recovery in virologically suppressed HIV-1-coinfected patients.

OBJECTIVES: Different immune alterations have been described in HIV-infected patients with visceral leishmaniasis (VL). We aimed to identify the immunological factors involved in the lack of immunological recovery and VL relapses in HIV-infected patients with VL, by comparison with other HIV-infected patients. METHODS: We carried out a cross-sectional study of 55 patients receiving suppressive combination antiretroviral therapy (cART) for at least 1 year: nine with previous relapsing VL, 20 with an immunodiscordant response (IDR) to cART (CD4 count < 200 cells/µL) and no previous VL, and 26 with a concordant response (CR) to cART (CD4 count > 350 cells/µL) without VL. Immunosenescence was investigated by analysing CD57(+) CD28(-) levels, immune activation by analysing CD38(+) HLA-DR(+) levels, inflammation by analysing interleukin (IL)-6 levels, and microbial translocation by analysing lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels. RESULTS: In VL patients, the median time since VL diagnosis was 42 months, and all patients had had at least one relapse despite suppressive cART for a median time of 43 months. Patients with previously diagnosed VL had a higher CD8 T-cell activation level (P < 0.001) than those with IDR. Also, levels of IL-6, LPS and especially sCD14, associated with bacterial translocation and additional monocyte activation, were significantly increased in patients with previous VL compared with patients with IDR (P = 0.048, P = 0.049 and P < 0.001, respectively). In addition, patients with previous VL had higher levels of CD8 T-cell senescence. Notably, the levels of immune activation and inflammation in patients with previous VL were not related to the time of VL diagnosis, the number of VL relapses, or hepatitis C virus (HCV) coinfection. CONCLUSIONS: Our data demonstrate that VL patients had an even worse immunological status than patients with IDR, which was probably associated with increased microbial translocation and additional monocyte/macrophage activation. These data explain the observed lack of immunological recovery and the occurrence of VL relapses in HIV-infected patients with previous VL.

High levels of CD4⁺ CTLA-4⁺ Treg cells and CCR5 density in HIV-1-infected patients with visceral leishmaniasis.

Visceral leishmaniasis (VL) in HIV-1-infected patients has been associated with poor immunological recovery and frequent disease relapses. The aim of this study was to analyse the role of T cell populations, Treg cells and CCR5 density in patients with VL compared to HIV-1-infected patients without leishmaniasis. A cross-sectional study of nine Leishmania-HIV-1-coinfected (LH) patients with VL receiving suppressive cART for at least 1 year were compared to 16 HIV-1-infected patients with non-immunological response (NIR, CD4 count below 250 cells/mm(3)) and 26 HIV-1-infected patients with immunological response (IR, CD4 count above 500 cells/mm(3)) without leishmaniasis. LH patients had a deep depletion of naïve T cells (p = 0.002), despite similar levels of effector T cells compared to NIR patients. CD4 Treg cells were similar compared to NIR patients, but higher compared to IR patients (p < 0.001). Interestingly, CD4 Treg CTLA-4(+) cells were higher in LH patients compared to either NIR or IR patients (p = 0.022 and p < 0.001, respectively), and the CD4 Treg/TEM ratio was similar to NIR patients, but higher compared to IR patients (p = 0.017). CCR5(+) T cell levels were higher compared to IR patients (p < 0.001), while CCR5 density on T cells were higher compared to both NIR and IR patients (p < 0.005 in both cases). Higher levels of CD4(+) CTLA-4(+) Treg cells and CCR5 density on CD8(+) T cells are strongly associated with VL in HIV-1-infected patients. Also, these patients have a poor immunological profile that might explain the persistence and relapse of the pathogen.

Prevalence of causes of secondary osteoporosis and contribution to lower bone mineral density in HIV-infected patients.

SUMMARY: Eighty-one percent of human immunodeficiency virus (HIV)-infected patients had one or more of seven evaluated causes of secondary osteoporosis, and this rate increases with age. The type and number of causes were associated with a lower bone mineral density (BMD), and with an increased rate of osteopenia/osteoporosis, regardless of age and body mass index. INTRODUCTION: The objective of this study was to determine whether factors of secondary osteoporosis were associated with lower BMD in HIV. METHODS: This was a cross-sectional study of 285 HIV-infected patients (25 % females) evaluating the impact of seven different factors of reduced BMD: hyperthyroidism, diabetes, chronic viral hepatitis, chronic kidney disease (CKD), hypovitaminosis D, secondary hyperparathyroidism, and hypogonadism. Dual-energy X-ray absorptiometry scan of the femoral neck was obtained at the clinical visit. RESULTS: Mean age was 45.7 years; osteopenia and osteoporosis were diagnosed in 38 and 6 %, respectively. Overall, 230 patients (81 %) had secondary factors; 107 (38 %) had only 1 cause, 94 (33 %) had 2, and 28 (10 %) had 3 or more, predominantly vitamin D deficiency in 61 %, hepatitis C virus coinfection in 45 %, and secondary hyperparathyroidism in 27 %. The number of secondary factors was closely related to a lower BMD, which is statistically significant for patients having ≥2 causes (0.77 vs 0.73 g/cm(2), p = 0.02). The rate of osteopenia ranged from 36 % without any cause to 57 % with three or more, osteoporosis from 0 to 19 %, and Z-score <-2 SD from 0 to 27 %, respectively. In a multivariate linear regression, adjusting by age, body mass index, and HIV-related factors, the number of secondary factors was independently associated with a lower BMD (ß coefficient -0.134; p = 0.02), mainly due to patients with hepatitis C virus (HCV) coinfection, secondary hyperparathyroidism, and CKD. CONCLUSIONS: A high prevalence of secondary causes of osteoporosis is observed in HIV-infected patients, and its type and cumulative number determine a lower BMD, after adjusting by age and body mass index.

Continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in HIV/AIDS patients in the current era.

To evaluate the situation and perspectives of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected patients, we investigated changes in the incidence, causes, and long-term outcome of this disease in 72 acquired immunodeficiency syndrome (AIDS) patients who were diagnosed with PML from 1996 to 2011. Patients were classified according to the date of diagnosis in the first (1996-2000, n = 35), second (2001-2006, n = 26), and recent or third highly active antiretroviral therapy (HAART) period (2007-2011, n = 11). Overall, the incidence of PML decreased from 14.8 cases/1,000 patients/year in 1996 to 2.6 in 2005 and 0.8 in 2011, and nearly two-thirds of recent cases (64 %) were observed in HIV patients not attending clinical visits. The baseline median CD4+ count was higher in recently PML-diagnosed patients (77 vs. 86 vs. 101 cells/mm(3); p < 0.01), and this fact was associated with a cerebrospinal fluid (CSF) inflammatory profile (from 11 to 31 to 55 %, p = 0.007) and with a significantly longer survival (attributable death, 54 vs. 35 vs. 36 %, respectively, p < 0.01). Thus, the overall 1-year and 3-year survival rates were 55 and 50 %, respectively, increasing to 79 % at 1 year for patients with CD4+ count above 100 cells/mm(3) at diagnosis. In a Cox regression analysis, an older age (hazard ratio, HR 0.76), a baseline CD4+ count above 100 cells/mm(3) (HR 0.33), and a CSF inflammatory profile (HR 0.12) were significantly associated with a longer survival. The clinical presentation and outcome of PML in AIDS patients continue to change dramatically. Now, a declining incidence and long-term survival is observed.

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection.

There are few data about the long-term histological outcome of HIV-/HCV-coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow-up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow-up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log-rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33-7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05-1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow-up after SVR to interferon therapy in HIV-/HCV-coinfected patients.

Severe sirolimus-related inflammatory state anemia in an HIV+ liver transplant patient with calcineurin inhibitor renal insufficiency: a case report.

Although multifactorial anemia is common following orthotopic liver transplantation (OLT), the late introduction of sirolimus (SRL) has been associated with high rates of anemia, whose pathogenic mechanisms have not been fully studied. Herein we have described a case of severe anemia in an HIV+ OLT patient who was switched from calcineurin inhibitors (CNI) to SRL due to severe nephrotoxicity. After 22 weeks of SRL, hemoglobin levels dropped 4 g/dL to a nadir of 6.5 g/dL. After discarding other causes for anemia, we concluded that it displayed the features of anemia of a chronic inflammatory state (ACIS): decreased mean corpuscular volume (MCV), low serum iron despite high ferritinemia, and elevated fibrinogen and C-reactive protein (CRP) levels. SRL trough levels were never above the therapeutic range. After blood transfusions and erythropoietin (EPO) use, SRL was maintained within the lower range of therapeutic levels, with significant improvement in renal function. As described among kidney transplant recipients, SRL-related anemia in this HIV+ patient with CNI nephrotoxicity after OLT showed features of ACIS. Blood transfusions and EPO use allowed SRL maintenance.

Increased prevalence of asymptomatic vertebral fractures in HIV-infected patients over 50 years of age.

The prevalence of asymptomatic vertebral fracture in HIV-infected patients over 50 was 20%, associated with older age, male sex, longer time since HIV diagnosis, and tubular renal alterations. Vertebral fractures were independent of osteoporosis at lumbar spine, and were not predicted by the use of the FRAX equation. PURPOSE: Vertebral fractures (VF) are the hallmark of osteoporotic fractures. Our objective was to determine the prevalence of asymptomatic VF and associated factors in HIV-infected patients over 50 years, and the role of FRAX equation. METHODS: In a cross-sectional study, a diagnosis of VF was established by the semiquantitative method of Genant in thoracic and lumbar radiographs. Simultaneously, a dual X-ray absorptiometry (DXA), bone and kidney-related analytical, calcium intake, physical exercise, HIV-related factors, and FRAX estimation were evaluated. RESULTS: Overall, 128 patients (35 women, 27%) were included. Mean age was 57 years. Hypophosphatemia and tubular renal dysfunction were observed in 13 and 21%. DXA scan showed osteopenia and osteoporosis at hip in 65 and 7% of patients, and in spine in 39 and 34%, respectively. VF were observed in 26 patients (20%), with a trend to be associated with lower serum phosphate, increased alkaline phosphatase, and with lower daily calcium intake. In a multivariate analysis, older age (OR 1.2 per year; 14% of VF at 50-55; 44% at 65-70), male sex (26 vs 6%), longer time since HIV diagnosis, and renal and tubular dysfunction were the associated factors. VF were not related with osteoporosis at lumbar spine, and could not be predicted by the FRAX equation. CONCLUSIONS: The prevalence of asymptomatic vertebral fractures is high in HIV-infected patients older than 50 years, and is not identified by the presence of osteoporosis in spine neither predicted by the FRAX equation. Spine and lumbar X-rays should be routinely performed in this aging population.

Limitations of a simplification antiretroviral strategy for HIV-infected patients with decreasing adherence to a protease inhibitor regimen.

PURPOSE: To determine the long-term efficacy of a simplification strategy in the clinical setting when used to improve adherence. METHOD: Prospective study of 70 patients included in a regimen with ddI plus 3TC plus an NNRTI, after viral suppression with a PI-containing regimen, due to decreasing adherence. Adherence to PI was calculated as the percentage of doses taken last week before inclusion, and patients were stratified as high and low adherence (95% and <95% of doses). RESULTS: Overall, 19 patients (27%) related adherence to PI <95% at inclusion (6 patients [9%], with adherence <80%). Mean adherence improved, with only 8% of patients presenting values <95%. At 104 weeks, 88% of patients on therapy had viral load suppression, but only 43% by ITT analysis. The main cause of therapy change or withdrawal was toxicity or drug interactions (26%). Notably, 16% of patients were lost to follow-up or left therapy, especially in the group of initially low adherent (26% vs. 12%, p = .02). CONCLUSION: The use of a simplification strategy could be associated with long-term high risk of treatment failure, when used to improve adherence in the clinical setting.

Predictors of long-term response to protease inhibitor therapy in a cohort of HIV-infected patients.

OBJECTIVE: To assess the rate of long-term effectiveness and factors associated with response to protease inhibitor therapy in a cohort of HIV-infected patients. DESIGN AND SETTING: Prospective, non-randomized study in a tertiary care centre. PATIENTS: A total of 400 HIV-infected patients who started on protease inhibitor therapy (saquinavir, 28%; ritonavir, 26%; indinavir, 46%) from March 1996 to March 1997. MAIN OUTCOMES MEASURES: Long-term virological and immunological effectiveness were defined as HIV RNA levels below 200 copies/ml and CD4+ cell count increase greater than 100 x 10(6)/l, respectively, after 12 months of therapy. RESULTS: Fifty-seven per cent of patients had a prior AIDS-defining illness, and 91% had received nucleoside analogues for a median time of 28 months. Median CD4+ count was 86 x 10(6) cells/l and HIV RNA level was 4.46 log10 copies/ml. The global rate of virological and immunological effectiveness at 1 year was 45 and 59%, respectively. In a logistic regression analysis, treatment failure was associated with higher baseline HIV load [relative risk (RR), 2.10; P<0.01], prior antiretroviral therapy (RR, 2.07; P<0.01), and use of saquinavir (RR, 1.55; P = 0.03), whereas a reduction of more than 1 log10 in HIV load within the first 3 months on therapy was strongly associated with response (RR, 0.65; P<0.01). There was no strict correlation between virological and immunological effectiveness (r = -0.35; P = 0.01). CONCLUSIONS: Nearly half of the patients maintain undetectable HIV load after 1 year of therapy, although important immunological benefit can be obtained in a greater proportion of patients. These data suggest the use of the most potent antiretroviral therapy in pretreated patients with high HIV load, and the capacity of initial virological decline to predict the long-term outcome.

Incidence and risk factors for developing cytomegalovirus retinitis in HIV-infected patients receiving protease inhibitor therapy. Spanish CMV-AIDS Study Group.

OBJECTIVE: To assess the incidence and risk factors for cytomegalovirus (CMV) retinitis in HIV-infected patients who initiated protease inhibitor-containing antiretroviral therapy. DESIGN AND SETTING: Prospective, multicentre study. PATIENTS: A cohort of 172 HIV-infected patients with a CD4 cell count below 100x10(6) cells/l at the time of protease inhibitor introduction. MAIN OUTCOME MEASURES: Confirmed CMV retinitis and mortality, according to CD4 cell count, HIV load, and CMV viraemia. RESULTS: The cumulative incidence of CMV retinitis was 5% at 1 year and 6% at 2 years. Only a positive CMV polymerase chain reaction (PCR) test at therapy initiation was significantly associated with the development of disease (relative hazard, 4.41; 95% confidence interval, 2.12-8.93; P<0.00001). The 12-month Kaplan-Meier CMV retinitis event rate was 38% in patients who were CMV PCR-positive compared with 2% in those who were CMV PCR-negative (P<0.001). Mean CMV load was significantly higher in those individuals who went on to develop CMV retinitis (3700 versus 384 copies/ml, P = 0.002). Only 2% of patients remained CMV PCR-positive after 3 months of protease inhibitor therapy, and CMV viraemia was not associated with a worse therapy response or shorter survival. Transient CMV positivity without a higher risk of disease was observed in 7% of patients at the first month on therapy. CONCLUSIONS: Protease inhibitor-containing antiretroviral therapy significantly reduces the incidence of CMV viraemia and disease. Although a positive CMV PCR test identifies those patients on therapy at highest risk of CMV retinitis, it is not associated with an increased risk of death or a worse response to protease inhibitor therapy.

Phenotypic testing predicts virological response in successive protease inhibitor-based regimens.

OBJECTIVE: To evaluate the importance of the number of active drugs, as determined by phenotypic resistance testing, in achieving virological response in successive salvage regimens. DESIGN: Phenotypic study of 57 plasma samples corresponding to 24 patients who had sequentially received three protease inhibitor-containing regimens. Phenotypic susceptibility to a drug (active drug) was defined as less than a four-fold-increase in the IC50 in comparison with the wild type. MAIN OUTCOME MEASURE: Virological response according to the number of active drugs (three versus two or fewer), HIV load, length of antiretroviral exposure, and line of protease inhibitor-based therapy (first, second and third regimen). RESULTS: Before the first protease inhibitor-based therapy, the median time on antiretroviral treatment was 42 months, and before the second and third protease inhibitor-salvage regimens it was 10 and 8 months, respectively. The number of patients receiving three active drugs simultaneously was 24, 35 and 31% in each line of therapy. At week 12, a close correlation was found between the presence of three active drugs in the antiretroviral regimen and the rate of virological response, in comparison with those patients receiving two or fewer active drugs [76 versus 45%, relative risk (RR), 1.7; 95% confidence interval (CI) 1.1-2.6; P = 0.028]. In a multivariate analysis, the use of two or fewer active drugs was an independent predictor of lack of response, regardless of HIV load, length of previous antiretroviral exposure and line of salvage therapy (RR, 4.5; 95%CI, 1.1-18.3; P = 0.03). Of note, a higher rate of response was observed in patients receiving the first protease inhibitor-containing regimen in comparison with those in subsequent protease inhibitor-based salvage regimens (83 versus 50 versus 28%, P < 0.01), even when only those patients receiving three active drugs were included (100 versus 71 versus 60%). CONCLUSIONS: This data confirm the usefulness of phenotypic testing in guiding antiretroviral therapy in heavily pretreated patients. The number of active drugs and the line of salvage therapy are independent predictors of virological response, regardless of HIV load and the length of antiretroviral exposure.

Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen.

OBJECTIVE: To determine the rate of nevirapine resistance in patients failing a nevirapine plus protease inhibitor (PI)-based regimen, and whether these isolates remain susceptible to other non-nucleoside reverse transcriptase inhibitors (NNRTI). DESIGN AND SETTING: A retrospective cohort study in two tertiary university hospitals. PATIENTS: Eighty-eight HIV-infected, NNRTI-naive patients receiving nevirapine plus PI as a rescue regimen after PI treatment failure. MAIN OUTCOME MEASURES: Genotypic and phenotypic resistance data at inclusion (73 and 60 plasma samples, respectively) and after 24 weeks (53 and 42 samples). RESULTS: Baseline phenotypic susceptibility to nevirapine was found in 70% of patients, and similar data were observed for efavirenz (91%) and delavirdine (71%). NNRTI resistance-associated mutations were found in 11 patients (12.5%). At 24 weeks, resistant isolates to nevirapine were found in 92% of patients, and correlated with similar resistance to efavirenz (68%) and delavirdine (73%). In the genotypic analysis, the Y181 C mutation was observed in 76% of mutants, and the most common changes were a combination of mutations at positions Y181C/K103N (23%) and the single mutation Y181C (15%). The development of nevirapine resistance was associated with baseline resistance to PI included in the regimen (P= 0.01). For isolates containing the single amino acid substitution Y181C, 29% remained fully susceptible to efavirenz, whereas 14% showed intermediate resistance to efavirenz and delavirdine. CONCLUSION: The failure of a nevirapine plus PI-containing regimen is associated with nevirapine resistance in most patients, with the most common mutation occurring at amino acid residue 181. Although there is a high degree of cross-resistance among NNRTI, nearly one third of resistant isolates carrying the single Y181C mutation remain susceptible to efavirenz.