Search

Tenofovir disoproxil fumarate (TDF) is an adenine analogue reverse transcription inhibitor widely used in first-line treatment of human immunodeficiency virus (HIV) infection and also in hepatitis B virus infection. Its use has been linked to sporadic Fanconi syndrome, renal failure and bone disease. We present the clinical characteristics of tenofovir-induced osteomalacia, discuss bone biopsy findings, describe predisposing factors and compare our results with other reported cases. We describe five cases of hypophosphatemic osteomalacia induced by TDF and recorded at the rheumatology service of a university hospital between 2010 and 2014. We also report the characteristics of bone biopsies of this pathology, which have not been previously described. We include a review of published cases of proximal renal tubulopathy (PRT) and osteomalacia induced by TDF (PubMed 1995–2014; keywords: osteomalacia, tenofovir, Fanconi syndrome, hypophosphatemic osteomalacia, proximal renal tubulopathy, bone biopsy). Five HIV patients who developed hypophosphatemic osteomalacia under TDF treatment (>5 years) presented increasing bone pain and a progressive inability to walk without assistance as a result of multiple insufficiency fractures. Bone biopsy performed in three patients after tetracycline labelling showed increased osteoid thickness, confirming osteomalacia. A literature review retrieved 17 publications on this condition, including 53 cases: 26 patients developed isolated PRT, 25 presented PRT and with multiple insufficiency fractures and two presented isolated bone disease, including osteomalacia and osteoporosis. Rheumatologists should be alert to this complication in patients receiving tenofovir. The main complaint reported by these patients is diffuse pain, predominantly in the lower limbs, indicating multiple stress fractures. Serum phosphate and appropriate screening for abnormal proximal tubule function should be monitored. Bone scintigraphy should be carried out in cases of limb pain before the occurrence of more severe complications.

Infection with HIV-1 frequently results in the loss of specific cellular immune responses and an associated lack of antibodies. Recombinant growth hormone (rGH) administration reconstitutes thymic tissue and boosts the levels of peripheral T cells, so rGH therapy may be an effective adjuvant through promoting the recovery of lost cellular and T-cell-dependent humoral immune responses in immunosuppressed individuals. To test this concept, we administered rGH to a clinically defined group of HIV-1-infected subjects with defective cellular and serological immune responses to at least one of three commonly employed vaccines (hepatitis A, hepatitis B or tetanus toxoid). Of the original 278 HIV-1-infected patients entering the trial, only 20 conformed to these immunological criteria and were randomized into three groups: Group A (n = 8) receiving rGH and challenged with the same vaccine to which they were unresponsive and Groups B (n = 5) and C (n = 7) who received either rGH or vaccination alone, respectively. Of the eight subjects in Group A, five recovered CD4 cellular responses to vaccine antigen and four of these produced the corresponding antibodies. In the controls, three of the five in group B recovered cellular responses with two producing antibodies, whereas three of the seven in Group C recovered CD4 responses, with only two producing antibodies. Significantly, whereas seven of ten patients receiving rGH treatment in Group A (six patients) and B (one patient) recovered T-cell responses to HIVp24, only two of six in Group C responded similarly. In conclusion, reconstitution of the thymus in immunosuppressed adults through rGH hormone treatment restored both specific antibody and CD4 T-cell responses.

Objective: The ability of a prolonged antiretroviral treatment interruption to reverse mitochondrial toxicity was evaluated in a sub-study of TIBET, a prospective trial examining antiretroviral treatment interruption guided by CD4+ cell count. Patients and Methods: The study population was composed of patients from the TIBET study who had been followed for ≥96 weeks and whose peripheral blood mononuclear cells (PBMCs) had been collected at baseline and throughout the study period. Of the 201 patients included in the TIBET study, 38 were selected for the mitochondrial sub-study; 18 patients discontinued antiretroviral therapy for ≥96 weeks and 20 maintained therapy. Mitochondrial DNA (mtDNA) and RNA (mtRNA) were measured in PBMCs using real-time polymerase chain reaction, and mitochondrial function relative to mitochondrial content was assessed using the cytochrome c oxidase and citrate synthase ratio (COX/CS). Results: Whereas mtDNA content showed a similar progressive decrease throughout the study period in both arms, the mtRNA amount remained stable in both groups and the COX/CS ratio improved significantly in patients who interrupted therapy. Conclusions: Mitochondrial function improved during a prolonged antiretroviral treatment interruption despite a decrease in mtDNA levels in PBMCs, probably because of the existence of a mitochondrial transcriptional and translational upregulation mechanism or the reversion of mitochondrial toxicity by a mechanism that is independent of DNA polymerase gamma. The reduction in virus-related mitochondrial damage should be considered another relevant benefit of antiretroviral therapy.

An unexplained resurgence of Group A streptococci (GAS) infections has been observed since the mid-1980s in the United States and Europe, particularly among intravenous drug users (IDUs). Several risk factors have been identified. Mutations in the capsule synthesis regulator genes (csrRS) have been associated with an increase in virulence. From January 1998 to December 2003, we conducted a prospective and retrospective descriptive analysis of invasive GAS soft-tissue infections in IDUs in Barcelona, Spain. Clinical features were collected, and we conducted a surveillance study to identify risk factors associated with GAS soft-tissue infections. We analyzed chromosomal DNA by low cleavage restriction enzymes and used pulsed-field gel electrophoresis (PFGE) and variable gene sequence typing (VGST) of the emm gene to disclose the epidemiologic relationship between the strains. We analyzed the influence of clonality (M-type) and mutations in csrRS genes of these strains on clinical features. We identified 44 cases, all of which were grouped in 3 clusters: fall 2000, fall 2002, and fall 2003. Cellulitis with or without abscesses (75%) and fever (90.9%) were the most common clinical manifestations. Distant septic complications were infrequent (18.2%). Although all patients had severe infections (mainly bacteremic needle abscesses), their outcome with antibiotic therapy, usually beta-lactam, was successful in all cases. However, surgery was needed in 40.9% of patients. Through the surveillance study we found that infected patients had a higher number of drug injections per day (odds ratio [OR], 18.84; 95% confidence interval [CI], 4.83-79.4; p

The influence of previous structured treatment interruptions (STIs) on the length of time off therapy when highly active antiretroviral treatment (HAART) is discontinued in chronically HIV-infected subjects was assessed. A comparative, retrospective clinical cohort study included patients with plasma viral load (VL)50 copies/ml and CD4 cell count500 cells/mm(3) who interrupted HAART. Fifteen patients interrupted HAART after six 2-weeks-off-/4-weeks-on therapy cycles (STI group) and 30 subjects discontinued HAART without previous STIs (NSTI group). The criteria for treatment resumption were development of AIDS-defining clinical events, VL100,000 copies/ml or CD4350 cells/mm(3). Median (IQR) time off therapy was 48 (29-56) weeks in the STI group and 31 (8-77) weeks in the NSTI group (p0.15). After 48 weeks, 46% of the patients in the STI group and 40% in the NSTI group remained off HAART (p0.74). No patient developed AIDS-defining events and all but one achieved virological control after treatment resumption. The CD4 nadir was 341 (298-464) cells/mm(3) among patients who reinitiated HAART and 560 (364-682) cells/mm(3) in those who remained off therapy by week 48 (p0.01). Likewise, CD4 count prior to treatment interruption was 902 (806-1040) cells/mm(3) and 1123 (924-1234) cells/mm(3) in subjects resuming and remaining off HAART, respectively (p = 0.03). No relationship between treatment resumption and pre-ART VL or with the time with undetectable VL before enrollment was found. CD4 nadir was a significant predictor for treatment reinitiation in a multivariate analysis. Previous STIs do not influence time off therapy when HAART is definitively discontinued in chronically HIV-infected subjects. CD4 nadir is an important factor in the treatment discontinuation decision.

BACKGROUND Simpler and less toxic antiretroviral strategies are needed to maximize treatment compliance without sacrificing potency, at least for drug-experienced HIV-infected patients currently on regimens containing protease inhibitors (PIs). Small nonrandomized studies have suggested a beneficial role of PI-sparing regimens on lipodystrophy. OBJECTIVES To assess the virologic, immunologic, and clinical benefit of switching the PI to nevirapine in patients with HIV-associated lipodystrophy and sustained viral suppression before entry in the study. DESIGN Open-labeled, prospective, randomized, multicenter study. SETTING Seven reference inpatient centers for HIV/AIDS in Spain. PATIENTS One hundred six HIV-infected adults with clinically evident lipodystrophy who sustained HIV-RNA suppression for at least 6 months with PI-containing antiretroviral combinations. INTERVENTION Replacement of the PI with nevirapine during 48 weeks (Group A) versus continuing the prior PI (Group B). MEASUREMENTS Several virologic and immunologic analyses, standard and specific biochemical tests, and anthropometric and dual X-ray absorptiometry measurements. RESULTS At week 48, an HIV-1 RNA level

Combined highly active anti-retroviral therapy (HAART) with protease and reverse transcriptase inhibitors has modified the natural history of opportunistic infections and neoplasms in human immunodeficiency virus (HIV)-infected patients. We analysed the influence of HAART on the response to treatment and survival in a series of 58 patients with acquired immune deficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL) treated with CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone). Two groups of patients were included: (i) forty-one patients diagnosed with NHL between 1988 and 1996 who were not treated with HAART; (ii) seventeen patients diagnosed since 1996, who were receiving or commenced HAART when NHL was diagnosed. The response rate to CHOP was higher in group 2 (13 out of 17 cases; 75%) than in group 1 (14 out of 41 cases; 34%) (P = 0.003). The 2-year probability of event-free survival (EFS) [95% confidence interval (CI)] for group 1 was 0.5 (0.24-0.74), whereas for group 2 it was 0.85 (0.61-0.90) (P = 0.024). The lymphoma-free survival (LFS) was also significantly different for both groups (2-year LFS probability 0.53 vs. 1.0, P = 0.04). The median (95% CI) overall survival (OS) for group 1 was 7 months (range, 3-10.8 months), whereas it was not reached in group 2 (P = 0.0015). In the multivariate analysis for remission attainment, the only variables with a higher probability to achieve complete remission (CR) were HAART (P = 0.01) and International Prognostic Index score 1 (P = 0.02). The only statistically significant variable in the multivariate analysis for EFS was HAART (P = 0.049) and the variables with prognostic value for OS in the multivariate analysis were B symptoms (P = 0.01) and HAART (P = 0.003). Patients with AIDS-related NHL treated with CHOP and HAART had a higher CR rate than those treated only with CHOP. In this study, HAART was an independent prognostic factor for CR, OS and EFS in patients with AIDS-related NHL.

Background: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long-term period of therapy are necessary. Methods: This is a prospective, randomized, two-arm controlled study including patients starting their first- or second-line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow-up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long-term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long-term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self-reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of ≥95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. Results: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence ≥95% (p =.008); 89% of patients in the EG versus 66% controls had HIV-1 RNA levels

Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA5000-10000 copies/ml and CD4 cells500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or whether it is better to delay the initiation to more advanced stages.To study the immunological and virological benefits of starting antiretroviral therapy at these early stages.A total of 161 HIV-infected asymptomatic patients with CD4 cell count500 x 10(6) cells/l and viral load10000 copies/ml were randomly assigned to one of five treatment groups: no treatment, twice daily zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The endpoints were progression to350 x 10(6) cells/l CD4 cells, to500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load0.5 log10 copies/ml above baseline, or to AIDS or death. In various substudies, the lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to mitogens and cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers were also analysed.Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P0.001). The peak mean viral load decrease was greater in the three-drug group when compared with any of the three groups with a two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; Por = 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 33 patients in the three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change the therapy as a result of adverse events. Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue HIV RNA was measured in seven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was20 copies/ml at 1 year. It was 15151 and 133333 copies/mg tissue in the two patients from the two-drug group,40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase of 4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/-3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving antiretroviral therapy, response to HIV-1 p24 antigen was not detected in any patient in either treatment group.This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 disease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated patients at 8 months of follow-up. Some immune system parameters improved toward normal values after 1 year of antiretroviral therapy, but the proliferative response of CD4 T lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antiretroviral t

The first stereoselective synthesis of (3 R ,4 E )-19-methylicos-4-en-1-yn-3-ol, an immunosuppressive and antitumoral metabolite isolated from the Caribbean sponge Cribrochalina vasculum , has been achieved and its stereostructure has been confirmed. The key step of the synthesis involves a borane-mediated reduction of the parent ( E )-19-methyl-1-trimethylsilylicos-4-en-1-yn-3-one in the presence of a chiral oxazaborolidine.

Seven AIDS patients who were receiving suppressive therapy for previously diagnosed cytomegalovirus (CMV) retinitis were offered treatment with protease inhibitors (PIs). Secondary prophylaxis for CMV was discontinued after 3 months of therapy with PIs if patients had150 CD4 cells/mm3 and a human immunodeficiency virus (HIV) load of200 copies/mL and if they were negative for CMV as determined by qualitative CMV polymerase chain reaction (PCR). Ophthalmologic exams were done periodically. After a median follow-up of 9 months (range, 9-12), no new episodes of CMV retinitis were observed. CD4 cell counts were150 cells/mm3 in all cases, HIV loads were200 copies/mL, and results for qualitative CMV PCRs remained negative. These observations suggest that for selected patients with healed CMV retinitis who have immunologic and virologic evidence of a clinical response to potent combination antiretroviral therapy, temporary discontinuation of a chronic anti-CMV suppressive therapy may not result in further retinal necrosis. However, the long-term immunologic benefit of PIs and hence the safety of prolonged withdrawal of anti-CMV therapy is unknown.

We conducted a pilot study to assess the effect of atorvastatin on HIV replication. Patients with stable HAART-controlled infection interrupted therapy and were randomly assigned to a control group or to start atorvastatin 40 or 80 mg/day. Statin groups showed lower serum cholesterol but similar viral loads and CD4 T-cell counts to the control group at weeks 4 and 12. Paradoxically, baseline serum cholesterol, but not atorvastatin, influenced viral rebound at week 4.

Objective : To analyse plasma HIV-1 RNA levels as a marker of clinical stability and survival in a cohort of HIV-infected patients whose time of seroconversion is unknown. Design : Retrospective cohort study. Setting : Retrovirology laboratory and AIDS Unit in a teaching hospital. Patients : A total of 916 samples from 302 patients, most on antiretroviral therapy, were analysed. Mean initial CD4 cell counts and HIV-1 RNA were 299x10 6 /l (range : 0-1600) and 134 261 copies/ml (range : < 200-4 300 000), respectively. Sixty-six cases had been diagnosed previously with AIDS. Methods : Analysis of progression to AIDS and survival, according to initial and longitudinal viral load (VL) and CD4 cell count measurements was performed by Kaplan-Meier test. Relative risks were calculated by Cox's proportional hazards model. Results : During a mean follow-up of 444 ± 309 days, 29 patients developed AIDS and 21 died. Relative risk (RR) of progression related to the group with VL < 35 000 was : 10.4 when CD4 ≥ 250x10 6 /l and VL ≥ 35 000 (P 0.001) ; and 45.3 when CD4 < 250x10 6 /l and VL ≥ 35 000 (P < 0.0001). Cumulative probability of progression was : 0%, 0% and 12.3%, at the first, second and third year respectively, for patients with all their sequential VL determinations < 60 000 ; and 13.3%, 34.7% and 79.3% for patients who did not maintain VL values always < 60 000 (RR = 23 ; P < 0.0001). The minimum value of VL that reached statistical significance for the survival analysis was 100 000 copies/ml (P < 0.0001). Conclusions : VL ≥ or < 35 000 is a better discriminant for progression than a CD4 cell count ≥ or < 250x10 6 /1. Sequential VL determinations < 60 000 are associated with a better prognosis.

Background The aim of this study was to assess the short-term and long-term consequences of stopping antiretroviral therapy (ART) in patients with preserved immune function. Methods This was a randomized 144-week follow-up CD4+ T-cell-count-guided treatment-interruption trial. HIV-1-infected adults with plasma HIV-1 RNA+ T-cell count >500 cells/ml and nadir CD4+ T-cell count >100 cells/ml were randomized to continuous treatment (CT) or treatment interruption (TI) until CD4+ T-cell count decreased to + T-cell count Results A total of 106 patients were included, 50 in the CT arm and 56 in the TI arm. A trend to a higher rate of primary end points was observed in the TI group (26.8% versus 14%, difference 12.8%, 95% CI -2.3, 27.8; P=0.105). In addition, 10 patients presented clinical events related with HIV rebound, including 8 cases of thrombocytopaenia. The CD4+ T-cell count significantly decreased in the TI group (even in patients with persistently high CD4+ T-cell counts and no clinical events) versus the CT group (median change -408 cells/ml versus -21.5 cells/ml; P+ T-cell count was observed (256 cells/ml versus -59 cells/ml; P+ T-cell counts. Conclusions Discontinuation of ART in patients with preserved immune function is followed by significant immunological impairment even in those with no clinical events, and may be associated with an increased risk of HIV-related complications. Hence, patients who stop ART voluntarily should be closely monitored, regardless of their CD4+ T-cell count.

OBJECTIVE: To report a clinically severe interaction between ritonavir (RTV) and acenocoumarol resulting in a decrease in the anticoagulant effect severe enough to eventually preclude RTV administration. CASE SUMMARY: An asymptomatic, HIV-infected, 46-year-old man with mitraortic prosthetic valves receiving acenocoumarol therapy started stavudine, lamivudine, and RTV 600 mg twice daily. His international normalized ratio (INR) decreased dramatically (the opposite of what should be expected). Although the acenocoumarol dose was progressively increased to 3 × the original dose, it was impossible to achieve the previous INR and RTV was withdrawn. DISCUSSION: RTV is an inducer of the hepatic isoenzymes CYP1A2, CYP1A4, and CYP2C9/19 and leads to extensive metabolism of acenocoumarol that cannot be balanced by dose increases. This effect is the opposite of what was expected to occur, considering that RTV is also a strong inhibitor of most hepatic isoenzymes. CONCLUSIONS: RTV severely decreases the anticoagulant effect of acenocoumarol. It must be added to the list of drugs that affect the action of oral anticoagulants, and it probably should be avoided in patients receiving acenocoumarol.

The epidemiology of HIV infection in Spain has changed during the past decade. Surveillance of HIV infection occurs in 15 of the country’s 17 regions, and 2,264 new HIV infections were diagnosed in 2009 (Ministerio de Sanidad y Politica Social, Ministerio de Ciencia e Innovacion, 2010). As previously reported (Hernandez-Aguado, 1999), the HIV epidemic in Spain has been largely driven by injecting drug users (IDUs). Reductions in the rates of new infections among drug users were reported a decade ago for the first time since the beginning of the epidemic (Castilla, 2006). In 2009, 77.0% of new infections were acquired through sexual transmission, and IDUs represented less than 10% of reported cases (Ministerio de Sanidad y Politica Social, Ministerio de Ciencia e Innovacion, 2010). The HIV epidemic among IDUs continues to develop heterogeneously across different parts of Europe. In the European Union, the reported rates of newly diagnosed cases of HIV infection in IDUs are mostly stable or in decline (European Monitoring Centre for Drugs and Drug Addiction, 2009). Data on newly reported cases of HIV infection in IDUs for 2007 suggest that rates of infection are still declining in Europe following a peak in 2002, which was caused by outbreaks in Estonia, Latvia and Lithuania. In 2007, the overall rate of newly reported infections of HIV among IDUs in the 24 EU member states for which national data

Background Structured antiretroviral therapy interruption (TI) is discouraged because of poorer AIDS and non-AIDS-related outcomes, but is often inevitable in clinical practice. Certain strategies could reduce the emergence of resistance mutations related to TI. Methods A total of 106 HIV-1-infected patients on stable HAART with undetectable plasma viral load were randomized to therapy continuation ( n=50) or CD4+ T-cell-guided TI ( n=56). Staggered interruption involved stopping non-nucleoside reverse transcriptase inhibitors (NNRTIs) 7 days before the nucleoside backbone. Genotypic resistance testing (GRT) was performed on proviral DNA from peripheral blood mononuclear cells (PBMCs) at baseline and before each TI, and on plasma RNA after each TI. Results At baseline, GRT on PBMCs detected mutations in nine patients and only two major mutations were identified. GRT on plasma samples performed after TIs showed nucleoside reverse transcriptase inhibitors (NRTI), NNRTI and protease inhibitor major resistance associated mutations in 10/56, 3/46 and 1/8 patients receiving these drugs, respectively. Only in two patients had the same mutations been observed in GRT on PBMCs at baseline. Three patients presented virological failure after resumption of therapy, all receiving NNRTIs. In one of them, resistance mutations detected at failure had been also observed previously in GRT on plasma after TI. Conclusions Staggered interruption of NNRTIs 7 days before the nucleoside backbone does not avoid resistance emergence completely, but does not necessarily lead to virological failure after treatment resumption. Plasma HIV-1 RNA genotype after the interruption and the patient's treatment history seem to be more useful than baseline proviral DNA genotype to assess the risk of virological failure after restarting therapy.

A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects.

Fundamento El uso del tratamiento antirretroviral de gran actividad (TARGA) (highly active antiretroviral therapy) ha conducido probablemente a la reduccion de las infecciones hematogenas en pacientes infectados por el virus de la inmunodeficiencia humana (VIH). Pacientes y metodo Se han estudiado todas las infecciones hematogenas, incluidas micobacteriemias y fungemias, ocurridas en pacientes infectados por el VIH y se han estratificado en dos periodos ( I: 1995-1996, y II: 1997-1998) para evaluar los cambios atribuibles al TARGA. Resultados Se atendieron 226 episodios (incidencia: 38,8 en el periodo I y 15,3 en el periodo II; p Conclusiones La infeccion hematogena en pacientes infectados por el VIH ha disminuido de forma significativa tras el uso generalizado del TARGA.

The first stereoselective synthesis of (3 R ,4 E )-19-methylicos-4-en-1-yn-3-ol, an immunosuppressive and antitumoral metabolite isolated from the Caribbean sponge Cribrochalina vasculum , has been achieved and its stereostructure has been confirmed. The key step of the synthesis involves a borane-mediated reduction of the parent ( E )-19-methyl-1-trimethylsilylicos-4-en-1-yn-3-one in the presence of a chiral oxazaborolidine.

Dear Sir, Tumour necrosis factor (TNF) plays an important role in HIV infection, allowing an intracellular reservoir of the virus.1 For this reason, TNF was considered an appealing therapeutic target in HIV-infected patients; however, the use of anti-TNF agents only achieves a transient decrease in TNF levels, with no changes in CD4 count and viral load.2 TNF is also a key cytokine in the pathophysiology of inflammatory bowel disease (IBD), and anti-TNF agents have become a cornerstone in its management. A major drawback in the use of anti-TNF in IBD is the risk of developing severe infectious complications, but no recommendations for those patients with immunosuppressive conditions other than …

BACKGROUND Human cytomegalovirus (HCMV) infection has been strongly associated to HIV-1 progression. We have investigated whether the magnitude of the overall peripheral blood mononuclear cell responses to HCMV stimulation correlated with HIV-1 progression. METHODS Blood samples were collected from 75 HIV-1-positive individuals on highly active antiretroviral therapy with CD4 count>500 cells per cubic millimeter and undetectable HIV RNA just before interrupting treatment. Specific interferon-gamma (IFN-gamma) HCMV cell responses were measured by an enzyme-linked immunospot (ELISPOT) assay. The results were analyzed by Kaplan-Meier survival curves, contingency tests, and the Cox proportional hazard models to evaluate the predictive value of peripheral blood responses to HCMV and the length of time that patients were off treatment. RESULTS Patients were stratified into those with weak ( 500 spot-forming units) IFN-gamma responses to HCMV. During the 3-year follow-up, 51% of patients with strong responses remained untreated compared with 14% of patients with weak HCMV responses (P=0.0015). Length of time without therapy was also longer in patients with stronger responses (hazard ratio=2.08; P=0.001). HCMV responses were still predictive of restarting therapy after adjusting for the CD4 nadir counts. CONCLUSION Specific IFN-gamma responses to HCMV may be employed as a predictive useful marker for the evolution of HIV-1 infection.

Introduction The objective is to show how disease and clinical trial modeling can be applied to estimate the success probability, duration and cost that resulting from a certain trial design or from similar decisions. Methods Multidisplinar team has participated in the construction of the general simulation model of clinical trials. This model is constructed splitting the whole process into two main parts. The first part represents the recruitment sub-model aiming at estimating the time and the number of included patients. The second part is based on the follow-up sub-model represented by disease progression. Results The model is applied to retrospective clinical trial. Conclusion Simulation modelling will optimise clinical trials whenever information from different disciplines, such as clinics, statistics, economics and informatics is integrated and used properly. Keywords: clinical trials; disease; modelling and simulation; optimal design; net benefit

We evaluated the safety of CD4 cell count and plasma HIV-1 RNA (pVL)-guided treatment interruptions (GTI) and determined predictors of duration of treatment interruption.Chronically HIV-1-infected adults with sustained CD4 cell counts500 cells/microl and pVL50 copies/ml were randomly assigned to either continue with standard antiretroviral therapy (control group, n = 101) or to interrupt therapy aimed at maintaining CD4 cell counts350 cells/microl and pVL100,000 copies/ml (GTI group, n = 100). Both groups were followed for 2 years.There were no AIDS-defining illnesses or deaths in either group. Compared to controls, subjects interrupting therapy reduced treatment exposure by 67%, but suffered significantly more adverse events related to the intake of medication or to therapy interruption [relative hazard, 2.71; 95% confidence interval (CI), 1.64-4.49; P0.001), mainly due to an excess in mononucleosis-like symptoms. While GTI subjects demonstrated improvements in the psychosocial spheres of quality of life and pain reporting, GTI had no effect on the physical aspects of quality of life. Although both groups had a similar hazard for developing CD4 cell count200 cells/microl; at least 10% of subjects on GTI had CD4 cell counts350 cells/microl at every time point. Drug resistance mutations were detected in 36% of subjects but were selected de novo only in subjects interrupting non-nucleoside reverse transcriptase inhibitor therapy. Lower CD4 cell count nadir, higher set-point pVL and prior exposure to suboptimal regimens were all independent predictors of the need to reinitiate treatment.Overall, GTI were not as safe as continuing therapy. Despite achieving some improvements in quality of life, GTI did not reduce the overall rate of management-related adverse events.

An increase in the levels of naive T cells after the administration of HAART is an indicator of the quality of immune reconstitution. We investigated whether levels of naive CD4 T cells (CD4(+)/CD45RA(+)) and of recent thymic emigrants (RTEs; CD4(+)/CD45RA(+)/CD31(+)) achieved in chronically treated HIV-infected patients could predict the length of time patients could interrupt antiretroviral treatment before their CD4 counts reached valuesor =350 cells/mm(3) or HIV-1 RNA levels increased toor =100,000 copies/ml (Tibet cohort). Serial measurements revealed that the level of naive CD4 T cells among patients was extremely variable (5-95%), but the values for each patient remained stable throughout the study. We then focused on those patients who showed percentages of naive CD4 T cells above 60% or below 30%. The levels of naive T cells, RTEs, mononuclear cells containing T cell receptor excision circles (TRECs), and the strength of CD4 helper responses to HIV p24 antigen during treatment failed to predict the duration of treatment interruptions. In contrast, the median survival time of patients with a CD4 nadiror =350 cells/mm(3) was 2-fold higher than that of patients with a CD4 nadir350. However, the probability of restarting therapy in these two groups of patients was independent of the levels of naive T cells, RTEs, or TRECs.

We have retrospectively studied the influence of highly active antiretroviral therapy (HAART) on the outcome of AIDS-related lymphomas (ARL) as well as the possible influence of the virological response to HAART on complete response (CR) rate and survival in our series of ARL treated with CHOP. Two groups of patients were studied: (1) 44 patients who did not take HAART when the lymphoma was diagnosed, and (2) 26 patients treated with HAART concomitantly and after chemotherapy. There were 4 (9%) women in group 1 versus 11 (42%) in group 2 (P = 0.01), and serum lactate dehydrogenase (LDH) level was lower in group 2. The response rate to CHOP was higher in group 2 patients (15 out of 23, 65%) than in those of group 1 (16 out of 44, 36%) (P = 0.025). The factors associated with improvement of CR in the multivariate analysis were the administration of HAART (P = 0.004) and International Prognostic Index (IPI) scoreor = 2 (P = 0.006). Among group 2 patients, those with a virological response to HAART and with IPI scoreor = 2 had better response rate to chemotherapy (odds ratios 9.3 and 11.8, respectively). The median (95% CI) overall survival (OS) for group 1 patients was 7 (3-11) months, whereas it has not been reached for group 2 (P = 0.002). The only parameters influencing OS in the multivariate analysis were HAART (0.003), as a protective factor and IPI score2 (P = 0.015) with negative influence. Among patients treated with HAART, those with virological response had higher OS probability (P = 0.004), whereas those with IPI score2 had an unfavorable prognosis (P = 0.014). The only variable with statistical significance for disease free survival (DFS) in the univariate and multivariate analyses was HAART (P = 0.0168 and P = 0.028, respectively). We conclude that HAART is an independent prognostic factor for CR attainment, OS and DFS in patients with ARL treated with CHOP. Those patients with virological response to HAART had a better survival.

We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n=24 patients) or after 12 weeks of STI (interruption [I] group; n=22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads

We assessed the impact of an efavirenz-containing regimen versus a protease inhibitor-containing regimen on quality of life, emotional status, and adherence of HIV-1-infected patients. In addition, we sought to define the adverse events associated with these treatments, with a special focus on central nervous system disorders in the efavirenz treatment group. This prospective, randomized, two-arm, controlled study included 100 patients for whom initial treatment with a protease inhibitor-containing regimen failed. Patients were randomized to start treatment with two nucleoside retrotranscriptase inhibitors plus efavirenz (group 1; 51 patients) or two nucleoside retrotranscriptase inhibitors plus one or more new protease inhibitors (group 2; 49 patients). Quality of life was assessed by a five-point item adapted from the HIV questionnaire of the Medical Outcomes Study, emotional status was evaluated by the Profile of Mood State questionnaire, and patients self-reported adherence. Data were analyzed by both an as-treated method and an intention-to-treat-last observation carried forward method. Patients in group 1 reported the following findings at week 4: dizziness (66%), abnormal dreaming (48%), light-headedness (37%), and difficulty sleeping (35%). At week 24, dizziness (13%; p

Structured treatment interruption strategies may help overcome problems of highly active antiretroviral therapy, but might also represent a cause of stress. We present data that indicate a psychological benefit from structured treatment interruption. Although some disturbances appear at the resumption of therapy, no definitive problems are found that preclude such therapeutic approaches from a psychological perspective. However, a close follow-up of patients during interruption periods is advisable to avoid difficulties reported at treatment resumption presenting a risk to patients' health.

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.

To investigate the virological and immunological impact of a structured treatment interruption (STI) in a cohort of HIV-1 chronically infected patients with a further long-lasting effective virus suppression.Twelve HIV-1 chronically infected adults who had maintained viral suppression (20 copies/ml) for more than 2 years, as well as a CD4:CD8 ratio1 for a median time of 22 months, were included in the study. Participants interrupted their antiretroviral treatment during a maximum period of 30 days or until a viral load rebound3000 copies/ml was detected. The same prior antiretroviral regimen was resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days during the treatment interruption period. Flow cytometry and cell proliferation assays were performed before and after STI. Genotypic resistance was assessed at the time of treatment resumption.No adverse events occurred during the interruption period. In two patients no viral rebound was detected after 30 days of treatment interruption. In the remaining 10 patients, viral load became detectable (20 copies/ml) at a median time of 14 days after treatment interruption. Afterwards, viral load increased exponentially with a mean t1/2 of 1.6 days. Treatment was successfully resumed in all patients. No resistance-conferring mutations associated with the pre-interruption antiretroviral regimen were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the STI period; however, the level of expression of T-cell activation antigen CD38 on CD8 T cells increased significantly in response to viral rebound. Four patients gained T-helper cell responses to recall antigens (tuberculin and tetanus toxoid), two of who developed an HIV-specific response to p24.STI in chronically HIV-1-infected patients is not associated with reductions in CD4 T lymphocytes or to clinical complications in this group of patients after 2 years of effective plasma viral suppression. Viral load rebounds in most but not all patients, without evidence of selection of resistance-conferring mutations. Thereafter, viraemia can be effectively controlled by antiretroviral agent reintroduction. HIV-specific T-helper cell responses may be achieved after one cycle of treatment interruption suggesting some degree of immune-stimulation. These data do not discard consecutive cycles of STI as a therapeutic strategy to boost HIV-specific immunity in order to maintain viral replication under effective control.

Objectives: To evaluate the safety and effectiveness of once-daily didanosine and nevirapine plus twice-daily stavudine versus twice-daily administration of all three drugs. Methods: This open-label, randomized, multicentre study enrolled 94 antiretroviral-naive patients with chronic HIV infection, CD4+ cell counts > 500 × 10 6 cells/l, and viral loads > 5000 copies/ml. Patients were treated with either 40 mg stavudine (twice daily) plus 400 mg didanosine (once daily) and 400 mg nevirapine (once daily) or 40 mg stavudine (twice daily) plus 200 mg didanosine (twice daily) and 200 mg nevirapine (twice daily). Results: After 12 months, 68% of patients who received twice-daily didanosine and nevirapine had viral loads < 200 copies/ml in the intention-to-treat and 79% in the on-treatment analysis, respectively. The corresponding values for patients treated with didanosine and nevirapine, taken once-daily, were 73 and 85%. The percentages of patients in each group with viral loads < 5 copies/ml at 12 months were 40% (once daily ) and 45% (twice daily) for the intention-to-treat analysis. Five of 11 patients (45%) with plasma viral loads < 5 copies/ml at 12 months had detectable virus in tonsillar tissue. Genotypic resistance to nevirapine was noted in seven of the 14 patients with detectable viral load at month 12. Mean changes in CD4+ cell counts for patients treated with stavudine plus once- or twice-daily didanosine and nevirapine were 154 and 132 × 10 6 cells/I, respectively. Treatment was interrupted due to adverse events in seven patients (8%) (four who received once-daily didanosine and nevirapine and three treated with twice-daily doses). Conclusions: The combination of twice-daily stavudine plus once-daily didanosine and nevirapine was as safe and well tolerated as twice-daily administration of all three agents. Both regimens were equally effective in reducing viral loads and in increasing CD4+ cell counts.

Objective: To assess HIV-1 RNA levels in cerebrospinal fluid (CSF) and their potential correlation with plasma viral load and central nervous system (CNS) HIV-1 infection markers in stable asymptomatic patients with a CD4 T cell count > 500 × 10 6 cells/l. Patients and methods: Consecutive patients screened for two trials were eligible for lumbar puncture assessment. At day 0, simultaneous samples of CSF and plasma were obtained and levels of total proteins, albumin, IgG, antibodies against HIV-1 p24 antigen, HIV-1 RNA (using the polymerase chain technique) and white cells were measured. Results: The integrity of the blood-brain barrier was preserved (albumin index ≥ 7) in 59 out of 70 patients (84%). Intrathecal production of antibodies against HIV-1 p24 antigen was demonstrated in 55 out of 70 individuals (78%). Viral load in CSF was significantly lower than plasma values (3.13 ± 0.95 versus 4.53 ± 0.53, P = 0.0001). HIV-1 RNA was not detected in CSF in only three of the 70 patients (4%). Overall, there was a significant correlation between plasma and CSF HIV-1 RNA levels (r = 0.43, P = 0.0001); however, in 29 patients (41%) there were significant differences (> 1.5 log 10 copies/ml) between the viral loads in plasma and CSF. In the multivariate analysis, a high level of protein and white cells in CSF, but not the HIV-1 RNA plasma level, were factors independently associated with a higher level of HIV-1 RNA in CSF (P = 0.0001). Conclusions: HIV-1 RNA can be detected almost always in CSF of asymptomatic patients in early stages of HIV-1 infection including those with a preserved integrity of the blood-brain barrier. The important discrepancies between plasma and CSF viral load, and the independent association between CSF abnormalities and CSF viral load, support the hypothesis of local production of HIV-1.

The objective of this study was to assess the value of quantitative HIV-1 RNA as a predictor for the short-term risk of developing AIDS-defining events in comparison with CD4 cell counts. A total of 1,028 samples from 324 patients were analysed. Median initial CD4 cell counts and HIV-1 RNA were 249 x 10(6)/l (range 0-1400 x 10(6)/l) and 4.5 log copies/ml (range: 2.3-6.4 log copies/ml). CD4 cell counts and viral load (VL) values obtained the year before a single AIDS-indicator disease were selected to define the risk of developing that event. Cox regression models with CD4 cell counts and VL values treated as time-dependent covariates were performed to analyse the risk for developing certain events. Receiver operating characteristic (ROC) curves were used to compare CD4 cell counts and VL values as predictive markers for progression. During a median follow-up of 870 d (range 30-1381 d), 132 patients developed AIDS. Median log VL values during the year before the event were 3.6 for non-progressors and 5.2 for those who developed AIDS (p < 0.0001). Minimum log VL threshold values for developing diseases were 2.3 for tuberculosis, 3.8 for Candida esophagitis, 4.4 for wasting syndrome, 4.5 for CMV disease and 4.7 for PCP. VL values were not, however, a better predictive marker for developing specific events than were CD4 cell counts. Although we have identified VL thresholds for the risk of developing certain AIDS-indicator diseases, the indication for starting prophylactic regimens may still be based on CD4 cell counts.

The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with/=250 CD4 cells/microL and plasma HIV-1 RNA levels/=500 copies/mL for24 weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with their previous antiretroviral regimen (n=13) or to continue with the same treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105+/-65/microL; P.05) but not in the control group (30+/-78/microL). Memory T cells initially contributed to the CD4 T cell increase at week 4 (P.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became statistically significant at week 24 compared with the control group (28+/-27/microL; P.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection.

Our case illustrates the first report of an HIV-infected patient with a nasopharyngeal squamous cell carcinoma with viremia by one Epstein-Barr virus (EBV) and seropositivity by two high risk oncogenic human papilloma viruses (HPV)-types (HPV-16 and HPV-33), previous to his death. This patient presented a fatal fast-evolution. CASE REPORT A 38 year-old man diagnosed with HIV in 1987 (dis- seminated tuberculosis) and HCV, who was an ex-IDU, smoker (30 cigarettes per day), and alcohol consumer (30 g/day), with poor HAART adherence, and a CD4 nadir of 6 cells/mm 3 in 2005, was seen on April 20 th 2006 in a routine HIV control. He reported having an oppressive headache in the last week. The exploration only showed hypoesthesia in the right side of the face. A small ulcer in the cavum and an exophytic polypoid lesion in the back and upper area of the right nostril were observed by nasopharyngoscopy. Com- puted tomography visualized a mass in the cavum. A biopsy diagnosed a moderately differentiated squamous cell cancer. P.E.T. showed a hypermetabolic mass from the skull base to the right jawbone (Fig. 1). In addition, P.E.T. also showed infiltration in the latero-cervical, supra clavicular and para- oesophagus nodes, in C3 and C6 (cervical vertebras), and in the liver (not shown). The patient restarted HAART on May 9 th and was discharged. The patient was readmitted to the hospital on June 6 th and he died one week later because of liver failure. The patient signed the informed consent to study HPV (June 6 th ) and his family authorized to publish this event.

Hodgkin's lymphoma (HL) is one of the most frequent neoplasias in human immunodeficiency virus (HIV) infection [1]. Interfollicular Hodgkin's lymphoma (IFHL) is a peculiar pattern of lymph node inv...

To address the question of whether individuals with chronic HIV-1 infection have a stable viral load set-point and to assess the influence of host and viral factors on the evolution of viral load in a subset of stable asymptomatic patients with a baseline viral load below 5000 copies/ml and CD4+ T-cell count above 500 x 10(6)/l.Medical visits were performed at least every 6 months including routine blood analysis, viral load and CD4+ T-cell count. HIV-1 RNA was measured in frozen (-70 degrees C) plasma samples using PCR. Patients were classified into three groups according to baseline viral load: group A,200 copies/ml (undetectable); group B, 201-2000 copies/ml; group C, 2001-5000 copies/ml. A survival analysis and a Cox regression model were performed to assess the influence of viral and host factors in the increase of baseline viral load. The endpoint was the time to increase viral load to a stable level0.5 log10 copies/ml above baseline viral load in groups B and C and to a stable detectable viral load (200 copies/ml) in group A.A cohort of 114 patients with viral load below 5000 copies/ml was followed for a median of 12 months (6-42 months). Overall, 22 (19%) out of 114 patients had an increase0.5 log10 copies/ml of baseline viral load. Baseline viral load increased in two (5%) out of 37 patients in group A, four (12%) out of 33 patients in group B, and 16 (36%) out of 44 patients in group C (survival analysis, P0.002). Patients of group C had a eightfold higher risk of increasing baseline viral load than patients in the other two groups pooled together (hazards ratio, 8.28; 95% confidence interval, 1.78-38; P = 0.006). Patients with an increase of viral load to the virological endpoint had a threefold higher risk of decreasing baseline CD4+ T-cell counts100 x 10(6)/I than patients with stable viral load (hazards ratio, 2.78; 95% confidence interval, 1.12-14; P = 0.03).In our cohort of chronically HIV-1-infected asymptomatic patients with a baseline viral load5000 copies/ml and CD4+ cell count500 x 10(6)/l, a true viral load set-point did not seem to exist. Patients with baseline viral load of 2000-5000 copies/ml had an eightfold higher risk of increasing the level of viral load than patients with a baseline viral load below 2000 copies/ml.

Patients with HIV infection were studied to assess the efficacy of octreotide, a somatostatin analogue, in the long-term management of refractory diarrhoea. Dosage of subcutaneous octreotide was increased progressively at 48 h intervals from 150 to 300, 750 and 1500 micrograms/day according to response. Twenty-nine patients, 21 with Cryptosporidium enteritis, one with Isospora belli enteritis and seven with no identifiable pathogen were selected for the study; four of these were excluded from the study because of death during the first month (two cases), abdominal pain and acute pancreatitis (one case each). Twenty-five patients were evaluable for response. Ten patients (four with Cryptosporidium enteritis, five without an identifiable pathogen and one with I. belli enteritis) achieved a complete response (40%) and nine cases (all with cryptosporidial enteritis) had a partial response (36%). Patients with higher weight and Karnofsky performance status and non-cryptosporidial enteritis had a better response to treatment. Mean durations of treatment and response were 4.2 +/- 4.2 and 4.4 +/- 4.5 months, respectively. In the absence of specific agents for cryptosporidial enteritis and HIV enteropathy, octreotide was found to be useful in the management of chronic diarrhoea in AIDS patients.

A case of recurrent multisystemic infection due to Rhodococcus equi in a patient with antibody to the human immunodeficiency virus (HIV) but without AIDS is reported. This case, which occurred in a woman with a history of alcohol and drug abuse, is, to our knowledge, the first such case described. The infection involved the lungs, kidneys, brain, and bloodstream. Despite several courses of therapy with antibiotics to which her isolates of R. equi were susceptible in vitro, the patient experienced multiple relapses before her death. On the basis of this case and a few others reported in HIV-infected patients, we recommend an initial antibiotic course at least 6-8 weeks in duration, and we suggest that combination antibiotic treatment be considered. We also suggest that infection with R. equi be included in the diagnostic criteria for AIDS.

The year-long antiviral efficacy of a high-dose salvage regimen consisting of saquinavir (800 mg twice daily) plus ritonavir (400 mg twice daily) was evaluated in 58 HIV-positive patients who had seen no improvement under first-line protease inhibitor-containing regimens, nor in baseline predictors of virologic response. The efficacy of therapy was determined by CD4+/CD8+ and HIV-1 RNA values. The primary endpoint of our study was the percentage of patients with HIV-1 RNA levels200 copies/ml (virologic success) at 6 and 12 months of of follow-up. Secondary endpoints were log10 reduction in HIV-1 RNA levels and CD4+ increases through follow-up. Surrogate markers related with a lower HIV-1 RNA area under the curve were identified at baseline. Kaplan-Meier analysis and Cox proportional hazards models were applied to identify baseline predictors of achieving viral suppression at200 copies/ml. All analyses were intention to treat-last observation carried forward. Patients achieved a median HIV-1 RNA level reduction of0.5 log through 1 year (-0.59 log10 at 12 months), as well as CD4+ counts increased significantly (89 cells/mm3 at 12 months). Overall, 53% of patients were likely to achieve HIV-1 RNA levels200 copies/ml at 6 months. Seventy-six percent of patients who started therapy at HIV-1 RNA levels5000 copies/ml but only 42% with baseline viral load of 5000 to 30,000 copies/ml and 18.7% with baseline viral load30,000 copies/ml were likely to achieve viral suppression at 6 months (p.001, log-rank test). Patients with baseline HIV-1 RNA levels between 5000 and 30,000 copies/ml (relative hazard [RH], 0.39; 95% confidence interval [CI], 0.01 to 0.98; p = .0396) and patients with baseline HIV-1 RNA levels30,000 copies/ml (RH, 0.20; 95% CI, 0.07-0.61; p = .0040) were less likely to reach undetectable HIV-1 RNA levels than those with baseline HIV-1 RNA levels5000 copies/ml. Salvage highly active antiretroviral therapy (HAART) strategies including saquinavir (SQV) at high doses plus ritonavir (RTV) exert a significant long-term efficacy in more than half of PI-experienced patients without significant additional toxicity. This therapeutic efficacy is strongly implemented by a switch at the lower HIV-1 RNA levels.