Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen for HIV post-exposure prophylaxis.

Objectives: To assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies. Methods: A prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical trials.gov number: NCT08431173. Results: Median age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP. Conclusions: A higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.

Improvement of lipoatrophy by switching from efavirenz to lopinavir/ritonavir.

OBJECTIVE: To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy. METHODS: Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed. RESULTS: Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm. CONCLUSIONS: Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study.

INTRODUCTION: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Influence of human immunodeficiency virus 1 infection and degree of immunosuppression in the clinical characteristics and outcome of infective endocarditis in intravenous drug users.

BACKGROUND: Immunosuppression caused by human immunodeficiency virus 1 (HIV) infection appears to modify the clinical characteristics and to increase the severity of several bacterial infections. The impact of HIV infection and the degree of immunosuppression on the clinical characteristics and outcome of infective endocarditis (IE) in intravenous (IV) drug users has not been well characterized. METHODS: Prospective cohort study among 292 consecutive IV drug users with IE diagnosed in 2 academic institutional hospitals in Barcelona, Spain, from January 1, 1984, to October 31, 1995. Serostatus of HIV infection was documented in 283 patients. We measured demographics, clinical and biological data, cause, echocardiographic findings, HIV serostatus and classification, CD4 cell count, complications, and mortality. RESULTS: Among the 283 episodes of IE, 216 (76.3%) were in HIV-infected patients and 67 (23.7%) in non-HIV-infected patients. Rate of IE per 1000 admissions ranged from 0.17 to 0.82 per year, peaking in 1989. Characteristics of IE independently associated with HIV infection were right-side involvement (odds ratio [OR], 7.6; 95% confidence interval [CI], 3.5-16.7), a micro-organism different from viridans streptococci (OR, 2.5; 95% CI, 1.1-5.9), duration of drug abuse longer than 5 years (OR, 5.0; 95% CI, 2.4-10.3), and white blood cell count of no more than 10 X 10(9)/L (OR, 2.2; 95% CI, 1.1-4.2). There were no significant differences in mortality due to IE according to HIV serostatus. Among the 216 patients with HIV infection, the variables independently associated with worse outcome were CD4 cell count lower than 0.200 x 10(9)/L and left-sided or mixed IE. CONCLUSIONS: Although there is a difference in clinical presentation in IE in IV drug users, outcome was similar according to their HIV status. However, among HIV-infected patients, severe immunosuppression and mixed or left-side valvular involvement were strong risk factors for mortality.

Lack of evidence of a stable viral load set-point in early stage asymptomatic patients with chronic HIV-1 infection.

OBJECTIVE: 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. METHODS: 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 level > 0.5 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. RESULTS: 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 increase > 0.5 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, P<0.002). 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 counts > 100 x 10(6)/I than patients with stable viral load (hazards ratio, 2.78; 95% confidence interval, 1.12-14; P = 0.03). CONCLUSIONS: In our cohort of chronically HIV-1-infected asymptomatic patients with a baseline viral load < 5000 copies/ml and CD4+ cell count > 500 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.

Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy.

BACKGROUND: This study addresses the dynamic of viral load rebound and immune system changes in a cohort of eight consecutive HIV-1-infected patients in very early stages [all the patients were taking highly active antiretroviral therapy (HAART} and were recruited in the coordinating center from a larger study] who decided to discontinue HAART after 1 year of treatment and effective virologic response. The safety of this procedure and the outcome with reintroduction of the same treatment was also investigated. METHODS: Plasma, cerebrospinal fluid (CSF), and lymphatic tissue viral loads were measured at baseline; lymphocyte immunophenotyping and CD4 lymphocyte proliferative responses to mitogens and specific antigens were assessed. The same antiretroviral therapy was reintroduced as soon as plasma viral load became detectable (above 200 copies/ml). RESULTS: At day 0, plasma viral load was below 20 copies/ml in all eight patients (and below 5 copies/ml in five of eight patients). A rebound in plasma viral load was detected in all patients from day 3 to day 31 with a mean doubling time of 2.01 (SE 0.29) days. Three out of eight patients achieved a peak plasma viral load at least 0.5 log10 above baseline, pretreatment values. Mutations associated with resistance to reverse transcriptase or protease inhibitors were not detected. After 31 days off therapy, CD4 lymphocytes decreased [mean 45% (SE 4) to 37% (SE 3); P = 0.04], CD8+CD28+ lymphocytes decreased [mean 59% (SE 5) to 43% (SE 4); P = 0.03], and CD8+CD38+ lymphocytes increased [mean 55% (SE 3) to 66% (SE 4); P = 0.009]. Mean stimulation indices of lymphocytes treated with phytohemagglutinin (PHA) and CD3 decreased from day 0 to day 31 from 34% (SE 8) to 17% (SE 9) (P = 0.06) and from 24% (SE 8) to 5% (SE 2) (P = 0.02), respectively. These changes were mainly contributed by the group of five patients with plasma viral load below 5 copies/ml at day 0. Viral load dropped below 20 copies/ml in all patients after 1 month of restarting the same antiretroviral regimen. CONCLUSIONS: Discontinuation of HAART after 1 year of successful treatment is followed by a rapid rebound of viral load; this rapidly returns to undetectable levels following reintroduction of the same treatment. In patients with more effective control of virus replication (viremia below 5 copise/ml), discontinuation of treatment was associated with more severe impairment of immunologic parameters.

Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection.

OBJECTIVES: To assess whether an almost complete restoration of immune system can be achieved when antiretroviral therapy is initiated at very early stages of asymptomatic chronic HIV-1 infection. DESIGN: T cell subsets and cell-mediated responses were analysed at baseline and after 12 months of either a double or a triple antiretroviral therapy in 26 asymptomatic HIV-1-infected patients with CD4 T cell counts > 500 x 10(6) cells/l and a baseline plasma viral load > 10000 copies/ml. RESULTS: Triple therapy was significantly more effective in reducing plasma HIV RNA to undetectable levels, in returning CD4:CD8 ratio to nearly normal levels, in reducing activated cells (CD38) and in increasing naive (CD45RA+CD45RO-) and memory (CD45RA-CD45RO+) CD4 cells. Both double and triple therapies caused a clear decrease in memory (CD45RA-CD45RO+) CD8 cells as well as a significant increase in the CD28 subset of CD8 cells. At baseline, there was an important increase in cells producing interferon-gamma (IFNgamma) with no significant abnormalities in T lymphocytes producing interleukin 2 (IL-2), tumour necrosis factor alpha and interleukin 4. Both types of therapy reduced IFNgamma- and IL2-producing CD4 T lymphocytes while IFNgamma-producing CD8 cells remained increased. Even before therapy, these HIV-1-positive patients lacked significant abnormalities in the T cell responsiveness to polyclonal stimuli as well as in the secretion of CCR5 chemokines by peripheral blood mononuclear cells. CONCLUSIONS: Initiating highly active antiretroviral therapy at very early stages of chronic HIV-1 infection allows rapid and almost complete normalization of T cell subsets and preservation of T cell functions. These early-treated patients could be excellent candidates for receiving additional HIV-specific immune-based therapies, which might be essential for the control of HIV infection.

The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection.

BACKGROUND: Some individuals with chronic HIV-1 infection have discontinued their drug therapy with consequent plasma virus rebound. In a small number of patients, a delayed or absent rebound in plasma virus load has been noted after drug cessation, apparently associated with prior drug interruptions and autologous boosting of HIV-1 specific immune responses. We hypothesized that cyclic structured treatment interruptions structured treatment interruptions (STI) could augment HIV-1 specific immune responses in chronic HIV-1 infection, which might help to control HIV-1 replication off therapy. METHODS: We initiated an STI pilot study in 10 antiretroviral treatment-naive HIV-1 chronically infected subjects with baseline CD4 T-cell counts > 500 x 10(6) cells/l and plasma viral load > 5000 copies/ml who received highly active antiretroviral therapy (HAART) for 1 year with good response (plasma viral load < 20 copies/ml for at least 32 weeks). Three cycles of HAART interruption were performed. RESULTS: In all of the patients viral load rebounded, but doubling times increased significantly between the first and third stops (P = 0.008), and by the third stop, six out of nine subjects had a virological set-point after a median 12 months off therapy that was lower than baseline before starting HAART (ranging from 0.6 log(10) to 1.3 log(10) lower than baseline) and in four it remained stable below 5000 copies/ml. Those subjects who controlled viral replication developed significantly stronger HIV-1 specific cellular immune responses than subjects lacking spontaneous decline (P < 0.05). During viral rebounds no genotypic or phenotypic changes conferring resistance to reverse trancriptase inhibitors or protease inhibitors was detected, but mean absolute CD4 T-cell counts declined significantly, although never below 450 x 10(6)/l and the mean value at 12 months off therapy was significantly higher than the pre-treatment level (P = 0.004). CONCLUSIONS: Our findings suggest that STI in chronic HIV-1 infection might augment HIV-1-specific cellular immune responses associated with a spontaneous and sustained drop in plasma viral load in some subjects but at the potential cost of lower CD4 T-cell counts.

Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy.

OBJECTIVES: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine. DESIGN: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000. METHOD: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values. RESULTS: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4--14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan--Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity. CONCLUSIONS: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.

Comparison of twice-daily stavudine plus once- or twice-daily didanosine and nevirapine in early stages of HIV infection: the scan study.

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 x 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 x 10(6) cells/l, 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.

A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study.

BACKGROUND: Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells > 500 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. OBJECTIVE: To study the immunological and virological benefits of starting antiretroviral therapy at these early stages. METHODS: A total of 161 HIV-infected asymptomatic patients with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 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 to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 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. RESULTS: 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; P < 0.001). 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; P < or = 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 was < 20 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. CONCLUSIONS: 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

[A study of 30 patients with bacteremia due to Campylobacter spp]. / Estudio de 30 pacientes con bacteriemia por Campylobacter spp.

BACKGROUND: To get better knowledge about clinical and bacteriological features in Campylobacter spp. bacteremia. PATIENTS AND METHODS: Over a period of 8 years (1987-1994) we prospectively analyzed underlying diseases, predisposing factors, clinical manifestations, complications and outcome of patients with Campylobacter spp. bacteremia. The study took place in an urban third-level teaching hospital. Antibiogram was tested in all the strains isolated. RESULTS: We identified 30 cases of Campylobacter spp. bacteremia (26 due to C. jejuni and 4 due to C. fetus). Seventy-three percent of the patients were male and the mean age +/- SD of all the patients was 52 +/- 19 years. Ninety percent of patients had some kind of immunodepression related to immunosuppressive therapy or to underlying diseases, especially liver cirrhosis and HIV infection. All patients had fever and 40% complained of intestinal symptoms before bacteremia. Mortality rate in patients with C. jejuni bacteremia was 30.8% (8 patients) during the admission, the death was directly related to bacteremia in 11.5% (3 patients). In all the fatal cases C. jejuni was resistant to empirical antibiotherapy instituted. In contrast, none of the patients with C. fetus bacteremia died. We detected an increasing ciproflaxin resistance in C. jejuni strains during this period which reached to 75% in the last years. Antimicrobial susceptibility to erythromycin and aminoglucosids was kept in all the strains. CONCLUSIONS: Campylobacter spp. bacteremia has a remarkable mortality rate, probably related to immunosuppressive underlying diseases in affective patients. In our institution we detected an increasing fluoroquinolone resistance over the years while susceptibility to erythromycin and aminoglucosids was maintained.

[138 episodes of bacteremia or fungemia in patients with solid organ (renal or hepatic) transplantation]. / Estudio de 138 episodios de bacteriemia o funguemia en pacientes con trasplante de órgano sólido (renal o hepático).

BACKGROUND: To study the bacteremias and fungemias of the patients with solid organ transplantation (kidney or liver) and analyze the differences according to the type of graft. METHODS: A prospective study included in a control program of bacteremias of a 1000-bed hospital and a follow up study of the infections of the patients who had undergone kidney transplantation (KT) (1985-1991) and liver transplantation (LT) (1988-1991) were carried out. RESULTS: One hundred thirty-one bacteremias and 5 fungemias, 75 in 62 patients with KT out of a total of 568 transplantations (11%) and 63 out of 54 patients with LT out of a total of 185 transplantations (29%) were identified. The prevalence of bacteremia in LT was greater (p < 0.001). The origin was nosocomial in 95% in LT and 70% in KT (p < 0.001). Around 50% of the bacteremias occurred during the first month post LT and KT. The microorganisms isolated were: Staphylococcus sp. (21 in KT and 30 in LT), with greater incidence in LT (p < 0.05); Enterococcus sp. (9 and 5, respectively), enterobacterias (12 and 12, respectively), Pseudomonas sp. (14 and 6, respectively), Candida sp. (2 and 3, respectively) with similar rates in both transplants. The origin of bacteremia was; renal and urinary tract, most frequent in KT (21 and 2 respectively) (p = 0.001). The origin of bacteremia was: renal and urinary tract, most frequent in KT (21 and 2 respectively) (p < 0.001), intraabdominal and biliary tract, most frequent in LT (4 and 14, respectively) (p = 0.007); intravenous catheter, most frequent in LT (16 and 24 respectively) (p < 0.05); lung, most frequent in LT although without statistical significance (3 and 8, respectively), (p = NS), and finally, surgical wound (4 and 1, respectively) (p = NS). Seventeen patients died (14 with LT and 3 with KT). CONCLUSIONS: The incidence of bacteremia and the mortality related, was greater in LT than that observed in KT. The most frequent origin in KT was the kidney and urinary tract and the biliary and intraabdominal organs and the intravenous catheter were most prevalent in liver transplants. Staphylococcus sp was the most frequent germ in both types of transplantation and polymicrobian infection in liver transplants. Gram-negative germs caused higher mortality in liver transplantation.

A randomized trial comparing the efficacy and tolerability of two HAART strategies at two years in antiretroviral naive patients.

BACKGROUND: The use of HAART combining 2 nucleoside analogues reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor (PI) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) has shown comparable efficacy. The study was designed to compare long term (2 years) effectiveness of two antiretroviral (ARV) treatment strategies in patients not previously treated: starting with a nelfinavir based HAART switching to nevirapine in case of failure or side effects or the reverse sequence. METHODS: This multicenter, randomized, open label clinical trial enrolled ARV-naïve HIV patients with CD4 counts below 500 cells/mm3. They were randomly assigned to start ddI + d4T + nelfinavir (switching to ZDV + 3TC + NEV in case of failure or toxicity) (PI-NEV arm) or ddI + d4T + nevirapine, switching to ZDV + 3TC + NFV in case of failure or toxicity (NEV-PI arm). The primary study endpoint was the Kaplan-Meier estimates of the time to failure after switching to second regimen if necessary (considering failure as two consecutive plasma HIV-1 RNA determinations above 200 copies/mL, death, a new category C event or toxicity leading to treatment discontinuation of the second regimen) after a minimum follow-up of two years. RESULTS: A total of 137 patients were evaluable (67 and 70 in the PI-NEV and NEV-PI arms respectively). Baseline characteristics did not differ among groups. Kaplan-Meier estimates of time to failure did not show differences between the two arms neither in the on-treatment (OT) analysis (log rank test, p = 0.81) nor in the intent-to-treat (ITT) analysis (p = 0.58). At 24 months, the estimated proportion of patients free of failure were 72% and 66% respectively in the PI-NEV and NEV-PI arms OT analysis (p = 0.54) and 73% and 64% in the PI-NEV and NEV-PI arms in the ITT analysis (p = 0.49). The difference in the median in CD4+ lymphocyte count at 24 months was not significantly different in the two groups: 393 and 307 CD4 cells/mm3 in the PI-NEV and NEV-PI arms respectively (p = 0.167). The incidence of adverse events (AEs) in the two arms was very similar: 50 (75%) in the PI-NEV and 54 (70%) in the NEV-PI group, as it was for grade 3-4 AEs leading to drug switching. CONCLUSION: At two years both treatments strategies (PI-NEV vs NEV-PI) had a high and comparable efficacy and were generally well tolerated.

Residual low-level viral replication could explain discrepancies between viral load and CD4+ cell response in human immunodeficiency virus-infected patients receiving antiretroviral therapy.

We report the evolution of chronic infection with human immunodeficiency virus type 1 (HIV-1) in a patient treated with stavudine plus didanosine, whose CD4+ lymphocyte count progressively decreased, despite a sustained plasma viral load <20 copies/mL. After 12 months of therapy, treatment was switched to zidovudine plus lamivudine plus nelfinavir. CD4+ T cell count decreased from 559 x 10(6)/L at month 0 to 259 x 10(6)/L at month 12. Plasma viral load decreased from 21,665 HIV-1 RNA copies/mL at baseline (month 0) to <20 copies/mL after 1 month of therapy with stavudine plus didanosine, and remained below 20 copies/mL until month 12, but always >5 copies/mL. Viral load in tonsilar tissue at month 12 was 125,000 copies/mg of tissue. After the change to triple-drug therapy, the plasma viral load decreased to 5 copies/mL, the CD4+ T cell count increased to 705 x 10(6)/L, and the viral load in tonsilar tissue decreased to <40 copies/mg of tissue at month 24. A low level of HIV-1 replication could explain the lack of immunologic response in patients with apparent virological response.

Predictive factors influencing peak viral load drop in response to nucleoside reverse transcriptase inhibitors in antiretroviral-naive HIV-1-infected patients.

Therapy with two nucleoside reverse transcriptase inhibitors (NRTI), the backbone of triple combinations, is still widely used in early stages of HIV-1 disease. However, factors influencing virologic response need to be further analyzed, to test the hypothesis that the reduction of plasma RNA viremia with NRTI may be greater in patients with higher baseline viral load (BVL) and to analyze the predictive factors of viral load drop below detection (200 HIV RNA copies/ml of plasma). Selected for the study were 169 HIV-1-infected antiretroviral therapy-naive patients with CD4+ T-lymphocyte counts ranging from 6 to 1040/microl coming from three randomized studies comparing the efficacy of monotherapy (zidovudine [ZDV], 250 mg every 12 hours; N=40) versus two-drug therapy consisting of ZDV (250 mg every 12 hours) with dideoxycytidine (ddC, 0.75 mg every 8 hours) or didanosine (ddI, 200 mg every 12 hours; N=129). Viral load was measured at 1, 3, and 6 months by polymerase chain reaction (PCR). A linear regression model was used to analyze the relation between BVL and the peak reduction of plasma RNA viremia. The variables included in a logistic regression model to determine the likelihood of VLs dropping below detection levels were age, gender, risk group for HIV-1 infection, baseline CD4+ lymphocyte count, BVL, clinical status (AIDS versus non-AIDS), HIV-1 phenotype (syncytium-inducing [SI] versus non-syncytium-inducing [NSI]) and type of treatment (monotherapy versus double therapy). The peak reduction of VL was related to baseline level following a linear model in both monotherapy and double-therapy regimens. In the subgroup of patients treated with two NRTIs, the regression line that fitted best with the data was log10 (peak reduction)=1.8-0.36 log10 (BVL) (F=23.5; p < .0001). This indicates that for every increase of 1 log10 of BVL, the peak reduction would be of 0.64 log10 greater. Forty-nine (29%) of the 169 patients dropped to <200 copies/ml. The likelihood of dropping below detection level was significantly greater in those receiving double therapy versus monotherapy (odds ratio [OR]=16.1; 95% confidence interval [CI], 2-128), in those with baseline CD4+ lymphocyte count >350/microl (OR=2.28; 95% CI, 1.1-4.9) and in those with BVL <10,000 HIV-1 RNA copies/ml (OR= 2.25; 95% CI, 1.1-6.1). None of the 13 patients with an SI phenotype at baseline dropped below detection levels. The reduction of VL in response to two NRTIs was greater in those patients with a higher level of BVL. In conclusion, peak reduction below detection in response to NRTI can be predicted and is associated with double therapy, with a baseline CD4+ cell count >350/microl and with a BVL <10,000 RNA copies/ml.

Dose-finding study of once-daily indinavir/ritonavir plus zidovudine and lamivudine in HIV-infected patients.

BACKGROUND: Strategies for treatment of HIV need to be considered in terms of combining potency, safety, and convenience of dosage. However, regimens including once-daily protease inhibitors are not yet available. We have performed a pilot study to determine an indinavir/ritonavir (IND/RTV) regimen for once-daily dosing, by monitoring plasma levels. METHODS: Antiretroviral-naive HIV-infected adults were eligible. Therapy was zidovudine/lamivudine 1 pill twice daily plus IND/RIT (liquid formulation) 800/100 mg twice daily with food. At 4-week intervals, plasma levels were measured and dosage of IND/RIT switched to 1000/100 mg daily and then 800/200 mg daily. If 12-hour minimum concentrations (Cmin12h) of IND were too low (<0.1 microg/ml) with IND/RIT 1000/100 mg once daily in the first half of the patients, it was planned to switch directly to 800/200 mg once daily in the other half. RESULTS: In all, 27 patients were recruited. Mean baseline CD4+ lymphocyte count was 107 x 106/L (range, 4-623 x 106/L). Eleven patients (40%) discontinued the study medication within the first 4 weeks due to clinical progression (n = 3) or grade 1-2 RTV related side effects (n = 8). Nine patients (group A) switched from 800/100 mg twice daily to 1000/100 mg once daily and then to 800/200 mg once daily. Seven patients (group B) switched directly to 800/200 mg once daily. At week 32, viral load was <5 copies/ml in 15 of 16 patients (94%). RTV levels were always <2.1 microg/ml. The mean and 95% confidence interval for IND Cmin and Cmax in microg/ml was: using IND/RTV 800/100 mg twice daily (n = 16) 1.4 (0.5-2.3) and 6.7 (4.4-9.1), respectively; using IND/RTV 1000/100 mg once daily (n = 9) 0.18 (0-0.41) and 8.6 (3.3-14), respectively; and using 800/200 mg once daily (n = 16) 0.38 (0-0.9), and 7.5 (0.8-14.8). For all 16 patients who received IND/RTV 800/100 mg twice daily, the Cmin value for IND was >/=0.1 microg/ml. Conversely, IND Cmin was <0.1 microg/ml in 4 of 9 receiving 1000/100 mg once daily but in only 1 of 16 receiving 800/200 mg once daily. CONCLUSION: Once-daily regimen of IND/RIT is feasible and deserves further evaluation in larger randomized trials. Liquid formulation of RIT was not well tolerated by our antiretroviral-naive patients despite lower than suggested doses.