Tenofovir plasma concentrations according to companion drugs: a cross-sectional study of HIV-positive patients with normal renal function.

As the risk of tenofovir-associated renal toxicity has been found to be proportional to the drug plasma concentration, our aim was to measure the determinants of tenofovir plasma exposure in HIV-positive patients with normal renal function. A cross-sectional analysis was conducted in HIV-positive patients chronically receiving tenofovir-containing highly active antiretroviral therapies (HAARTs). Patients on tenofovir-containing antiretroviral regimens, presenting 22 to 26 h after drug intake, having estimated glomerular filtration rates above 60 ml/min, reporting high adherence to antiretroviral medications (above 95% of the doses), and signing a written informed consent were included. Plasma tenofovir concentrations were measured through a validated high-performance liquid chromatography-mass spectrometry (HPLC/LC-MS) method. The tenofovir trough concentrations in 195 patients (median, 50 ng/ml, and interquartile range, 35 to 77 ng/ml) were significantly associated with the estimated glomerular filtration rate, body mass index, and third-drug class (protease-containing versus protease-sparing regimens) (with the highest exposure in unboosted-atazanavir recipients). The results of multivariate analysis showed that the third-drug class and the weight/creatinine ratio were independent predictors of tenofovir trough concentrations. This cross-sectional study shows that tenofovir trough concentrations are predicted by the weight/creatinine ratio and by the coadministered antiretrovirals, with protease inhibitors (whether boosted or unboosted) being associated with the highest plasma exposure. These data, previously available in healthy subjects or for some drugs only, could be useful for designing strategies to manage tenofovir-associated toxicity, since this toxicity has been reported to be dose dependent.

Tuberculosis in HIV-infected persons in the context of wide availability of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV-infected persons. Nonetheless, HIV-associated tuberculosis continues to occur in countries where HAART is widely used. To identify the characteristics of HIV-infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999-2000. These patients represent 0.7% of the 40,413 HIV-infected patients cared for in the clinical units participating in this current study. From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells x mm(-3) versus 100 cells x mm(-3), and 109 cells x mm(-3), respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded. Failure of tuberculosis control interventions (e.g. noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV-associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment.

Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy.

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor-containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P= .04, chi(2) test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30-3.75; P= .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy.

Incidence of Kaposi's sarcoma and HHV-8 seroprevalence among homosexual men with known dates of HIV seroconversion. Italian Seroconversion Study.

OBJECTIVES: To evaluate temporal trends of Kaposi's sarcoma (KS) and of the KS-related human herpesvirus (HHV-8) among homosexual men who seroconverted for HIV between 1984 and 1997. METHODS: The study participants were 387 homosexual men. Changes over a period of time were assessed by estimating KS incidence rates per 1000 person-years for the periods 1984-1989, 1990-1992, 1993-1995, and 1996-1997. The proportional incidence of KS as the AIDS-defining disease for the same periods was also calculated. To evaluate a cohort effect of calendar period, Kaplan-Meier curves were used to estimate the risk of KS by period of HIV seroconversion [i.e. before 1990 (median year of seroconversion) versus later]. Relative hazards for the four periods were estimated using competitive-risks models. We also estimated HHV-8 seroprevalence over the study period. RESULTS: Forty-eight participants developed KS. Between 1984 and 1995, the incidence rate of KS per 1000 person-years increased from 3.9 to 32.8, whereas the proportional incidence decreased from 33.3 to 24.3%. The risk of developing KS after HIV seroconversion did not change when comparing the seroconversion periods (i.e. before 1990 versus later). HHV-8 seroprevalence also remained stable. The rates of KS and the relative hazards dramatically decreased after 1995. CONCLUSIONS: Although KS incidence rates increased up to 1995, the proportional incidence decreased, due to the higher increase in rates of other AIDS-defining diseases. The finding that the risk of developing KS after HIV seroconversion remained stable over time is consistent with the stable trend of HHV-8 seroprevalence. The dramatic decrease in KS incidence rates after 1995 coincides with combined antiretroviral therapy.

Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases.

BACKGROUND: The incidence of Kaposi's sarcoma (KS) is increased severalfold in individuals infected with human immunodeficiency virus-1 (HIV). Human herpesvirus 8 (HHV8) has also been implicated in KS. We investigated several factors that may determine the onset of KS, particularly HHV8 infection in individuals after becoming seropositive for HIV. METHODS: We studied 366 individuals belonging to different HIV-exposure categories (i.e., homosexual activity, intravenous drug use, and heterosexual contact) for whom a negative HIV serologic test and then a positive HIV serologic test were available within a 2-year period. HHV8 antibody testing was performed by use of an immunofluorescence assay on the first serum sample available after the first positive HIV test. Actuarial rates of progression of KS and of other acquired immunodeficiency syndrome (AIDS)-defining diseases were estimated by use of time-to-event statistical methods. All statistical tests were two-sided. RESULTS: Twenty-one of the 366 study participants developed AIDS-related KS, and 83 developed AIDS without KS. One hundred forty (38.3%) participants had detectable anti-HHV8 antibodies. The actuarial progression rate to KS among persons co-infected with HIV/HHV8 was nearly 30% by 10 years after HIV seroconversion. Increasing HHV8 antibody titers increased the risk of developing KS (for seronegative versus highest titer [1:125 serum dilution], adjusted relative hazard [RH] = 51.82; 95% confidence interval [CI] = 6.08-441.33) but not of other AIDS-defining diseases (adjusted RH = 1.14; 95% CI = 0.72-1.80). HHV8-seropositive homosexual men compared with HHV8-seropositive participants from other HIV-exposure categories showed an increased risk of KS that approached statistical significance (adjusted RH = 6.93; 95% CI = 0.88-54.84). CONCLUSIONS: Approximately one third of individuals co-infected with HIV/HHV8 developed KS within 10 years after HIV seroconversion. Progression to KS increased with time after HIV seroconversion. Higher antibody titers to HHV8 appear to be related to faster progression to KS but not to other AIDS-defining diseases.

Serum IgG antibodies to human herpesvirus-6 (HHV-6) do not predict the progression of HIV disease to AIDS. Italian Seroconversion Study group.

OBJECTIVES: To evaluate if different levels of human herpesvirus 6 (HHV-6) antibodies can predict HIV disease progression. DESIGN: Longitudinal study of individuals with a documented date of HIV seroconversion. SETTING: Clinical centers located throughout Italy. PATIENTS: Individuals who serconverted for HIV between 1983 and 1995 in Italy. METHODS: Sera were tested for IgG antibodies to HHV-6 using a commercial enzyme immunoassay. A serum sample with an optical density (OD) > or =242 (i.e. the mean value of 10 negative controls +4x standard deviation) was considered as HHV-6 positive; the progression of HIV disease was evaluated estimating the relative hazards (RH) of AIDS (by Cox models) for individuals with higher levels vs. lower levels of HHV-6 antibodies or considering levels of antibodies based on 10% increase of the distribution (deciles). Rates of CD4 decline fitting linear regression were also estimated. RESULTS: A total of 381 persons were followed for a median time of 4 years (range: 0.15-9 years) following the date of collection of the serum sample. The median OD value of HHV-6 antibodies was 306, with an interquartile range of 241-440 and a range of 48-2330. A slight inverse correlation was found between HHV-6 antibody levels and age of the individual at the time of serum collection (Spearman rank correlation coefficient, -0.16; p = 0.0013). No association was found between HHV-6 and CD4 level or between HHV-6 and CD8 level at the date of serum collection. The unadjusted RH of progression to AIDS was 0.63 (95% CI: 0.42-0.96) for HHV-6 positive individuals vs. HHV-6 negative; when adjusting for possible confounders (CD4, age, pre-AIDS HIV-related pathologies at the date of sera collection, and previous anti-herpes treatment), the RH of AIDS increased to 0.80 (95% CI: 0.51-1.23). No particular association with HIV disease progression was found when using the deciles of the distribution of HHV-6 antibodies. The median CD4 cell loss was 5.0x10(6) cells/l per month among HHV-6 positive individuals and 5.7x10(6) cells/l per month among the others. CONCLUSIONS: The presence of high levels of HHV-6 antibodies does not seem to predict the clinical or immunologic progression of HIV disease.

Coinfection and superinfection of hepatitis B virus in patients infected with human immunodeficiency virus: no evidence of faster progression to AIDS.

The influence of hepatitis B virus (HBV) on the natural history of human immunodeficiency virus (HIV) infection was evaluated in a prospective study of 347 HIV-positive, AIDS-free individuals infected through injecting drug use and sex and with known seroconversion dates. End points were CD4+ cell count < 200 x 10(6) cell/L and AIDS diagnosis. At entry, 229 had seromarkers to HBV; during the study, 107 had a CD4+ cell count < 200 x 10(6) cells/L and 66 developed AIDS. HBsAg chronic carriers, HBV infection-free subjects and those with baseline evidence of prior HBV infection did not differ in rates of progression to end points. Sexual transmission of HIV was significant predictor of CD4+ cell decline to < 200 x 10(6) cells/l [Hazard ratio (HZ): 1.56, 95% confidence interval (CI): 1.06-2.29, p = 0.0232] and progression to AIDS (HZ: 1.91, CI: 1.17-3.11, p = 0.0091). 15 HIV-positive and HBV infection-free patients had HBV seroconversion. They did not differ from those who remained HBV infection-free in rates of progression to end points, but 40% of them became HBsAg chronic carriers. These results suggest that HBV has no influence on progression of HIV disease, but that patients who have HIV before their HBV infection are more likely to become HBsAg chronic carriers than those who are infected with HBV before HIV.

Asymptomatic women at high risk of vertical HIV-1 transmission to their fetuses.

OBJECTIVE: To identify how reliably CD4+ (helper) lymphocyte count and p24 antigenaemia can predict mother-to-infant transmission of human immunodeficiency virus type 1 (HIV-1). DESIGN: Prospective study. SETTING: University of Turin Center for Intravenous Drug Users (IVDU) and/or HIV-1 seropositive pregnant women. SUBJECTS: Twenty-nine infants born to asymptomatic seropositive women from November 1985 to June 1991. RESULTS: Seven children (24%) developed symptomatic infection, while 22 healthy seronegative children at the age of 18 months were considered uninfected. A CD4+ lymphocyte count persistently < 500/mm3 during pregnancy was associated significantly with the child's infection status with a relative risk (RR) of 11.4. (CI 1.58-82.05). A marked association (RR 13.6) (CI 1.93-95.72) was similarly detected between maternal antigenaemia and the risk of the child being infected. In a multivariate logistic analysis, crude and adjusted odds ratios (OR) of transmission were 27.0 (95% CI 2.5-291.2) and 35.6 (1.1-1159) for low CD4+ counts; 64 (3.2-1261) and 51.6 (2.5-1058) for p24 antigenaemia. CONCLUSIONS: Asymptomatic HIV positive women with a CD4+ count below 500/mm3 or p24 antigenaemia are about ten times as likely to transmit the virus to their children. CD4+ lymphocytes decrease during pregnancy and a low CD4+ cell count early in pregnancy remains low up to delivery. Therefore knowledge that they have a low CD4+ lymphocyte count early in pregnancy may help women to decide whether or not to continue their pregnancy.

Serological diagnosis of hepatitis B and delta virus (HBV/HDV) coinfection.

Diagnosis of acute hepatitis B virus/hepatitis delta virus (HBV/HDV) coinfection is currently based on detection of anti-HD, however this antibody may be undetectable during the acute phase of hepatitis. To evaluate the entity of misdiagnosis of HBV/HDV coinfection in acute HBsAg-anti-HBc IgM positive hepatitis we examined sera from 245 consecutive patients obtained at admission and day 30, 60, 120, 210 and 400 of their follow-up. Anti-HD was detected in the serum of 26 out of 245 patients (10.6%). In 15% of cases it was present at admission, while in 92% it was found after 30 days. The combined detection of HDV-RNA, HDAg and IgM anti-HD in acute phase sera allowed a correct etiologic diagnosis in 69% of the cases. These findings suggest that the prevalence of HBV/HDV coinfection is underestimated when anti-HD is the only marker to be detected during the acute phase of disease. A correct etiologic diagnosis can only be made by testing acute phase sera for all the available markers of HDV. However, the best cost-effective procedure is to test any patient with HBV markers at presentation for anti-HD, 30-40 days after the onset of symptoms.

Risk of AIDS in HIV seroconverters: a comparison between intravenous drug users and homosexual males.

A multicentre cohort study was conducted in Italy to estimate the risk of developing AIDS in 261 intravenous drug users and 89 homosexual males for whom the seroconversion period was known. Four years after HIV seroconversion, AIDS incidence, estimated by Kaplan-Meier survival technique, was 13.8% for intravenous drug users and 16.2% for homosexual males; the difference was not statistically significant. These findings suggest that four years after seroconversion the risk of developing AIDS in HIV seropositive intravenous drug users is no higher than that of subjects who acquired HIV infection through sexual contact.

[Infection monitoring in orthopedics]. / La sorveglianza infettivologica in ortopedia.

The results of infection surveillance in orthopaedics are reported: the high incidence of hospital infections in patients undergoing major surgery, the paucity of microbiological data and the failure to standardise prophylaxis protocols were the most significant findings as well as providing a point of departure for programming future fields of intervention and for redefining the operating framework for continuous infection surveillance.

The natural history of HIV infection in intravenous drug users: risk of disease progression in a cohort of seroconverters.

A multicentre cohort study was carried out to estimate the incidence of AIDS and HIV-related conditions in newly infected intravenous drug users (IVDU). The enrollment criteria included the identification of the seroconversion time. Two hundred and five subjects entered the study, and were followed for a mean of 26 months. Twelve subjects developed clinical AIDS over a 4-year period. The actuarial incidence of AIDS estimated by Kaplan-Meier survival technique was 17.8% by 4 years since seroconversion. The risk of developing AIDS increased significantly after 24 months from seroconversion. Relatively small figures accounted for the lack of statistical association between the risk factors investigated and the disease status.

PIP: The natural course of HIV infection in 205 intravenous drug users (IVDU) presenting at 11 centers in Italy was followed since 1983. Criteria for entering the study were spontaneous attendance at the clinic from January 1983-April 1988; history of IVDU; dated negative HIV test and a positive test not over 18 months later. 13 of the 205 subjects developed AIDS by 30 April 1988, a total of 447.25 person-years, for an overall incidence of AIDS of 2.9% person-years. The clinical presentation was opportunistic infections in 7, wasting syndrome in 5, and encephalopathy in 1. No Kaposi's sarcoma was seen. The incidence of AIDS was 1.5% in the 1st year; 2.9% after 2 years; 9.9% after 3 years and 17.9% after 42-48 months. The risk of AIDS increased significantly 24 months after seroconversion. 11 others developed AIDS-related complex (ARC) in the 4-year period, an incidence of 3.4% person-years. The minor opportunistic infections seen were zona (4 cases), oral candidiasis (2), and hairy leukoplakia (1). 2 subjects had myelopathy. 87 others developed persistent generalized lymphadenopathy (PGL). 45.8% of the group remained asymptomatic. The subjects mean age was 26, and the sex ratio was 4:1 overall, but 12:1 among the AIDS group. The natural history of AIDS in this series closely resembled other reports on male homosexuals.

[Hospital infections in an emergency surgery ward]. / Infezioni ospedaliere in un reparto di chirurgia d'urgenza.

A study was conducted on hospital infections in an emergency surgery ward. The survey lasted one year and confirmed the higher incidence of infections after contaminated and dirty operations. Rates of infection were also high after clean operations due to the large number of subjects at risk among the group examined. The most commonly encountered micro-organisms in the infections of surgical wounds were, in order, E. coli, Str. faecalis and Staph. aureus, the latter being only minimally responsive to the standard antibiotics. Several proposals are advanced for prophylaxis in the attempt to halt the circulation of strains with a multiple resistance to antibiotics.

[Cefotiam, a new cephalosporin. Microbiological research, preliminary evaluation of its effect on phagocytosis and clinical multicenter research]. / Cefotiam, nuova cefalosporina. Ricerca microbiologica, valutazione preliminare dell'interferenza sulla fagocitosi e ricerca clinica policentrica.

After a brief review of the data on cefotiam in the literature the report presents the results of microbiological research, a preliminary study into the drug's possible actions on phagocytosis and a polycentric clinical study of 93 cases of broncho-pleuro-pulmonary pathology and one sinusitis of the jaw. In vitro cefotiam was found to have an excellent inhibitory effect on gram positive and gram negative bacteria with MICs50 and 90 respectively 0.2 and 0.8 mcg/ml V. Staph. aureus, Str. pyogenes. E. Coli, K. pneumoniae and Pr. mirabilis. A dose-dependent increase in phagocytosis was noted. The clinical response was excellent with 90.43% (88/94) of the cases achieving clinical and radiological cure or very much improved. Cefotiam was very well tolerated with the appearance of 2/94 skin rashes (2.12%). The liver and kidney parameters showed no change at the end of treatment. No increase in enzymuria was noted during treatment with cefotiam.

[Case reports of 77 HTLV III/LAV-positive patients observed during one-year period. Preliminary note]. / Su di una casistica di 77 soggetti HTLV III/LAV positivi osservata nell'arco di un anno. Nota preventiva.

Three hundred and forty-four patients at risk for HTLV/LAV infection were examined and seventy-seven were positive at the HTLV III/LAV Ab test. The clinical and laboratory study permitted to diagnose one case of AIDS, 26 cases of ARC and 50 cases of simple positivity at the HTLV III/LAV Ab test.

[Bacampicillin vs amoxicillin in respiratory pathology]. / Bacampicillina vs amoxicillina in patologia respiratoria.

Clinical research was conducted to evaluate the comparative therapeutic efficacy in respiratory pathology of 800 mg X 2 per diem bacampicillin v. 1000 mg X 2 per diem amoxicillin, both orally administered. The results were more or less identical and are interpreted as indicating the better constant absorption of the precursor, hence its higher concentration gradient that produces a higher antibiotic concentration in the lungs.

[Cephalosporins and enzymuria]. / Cefalosporine ed enzimuria.

Urinary enzyme excretion was studied in 56 patients treated with cephalosporins in order to evaluate their potential nephrotoxicity. Only in 4 out of 56 patients (7%) was increased NAG, gamma-GT, AlP excretion seen. A rapid return to normal values was observed just after the end of the therapy.