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OBJECTIVES: To assess the efficacy and tolerance of chemoprophylaxis with cotrimoxazole compared with placebo among HIV-1-infected adults. DESIGN: Randomized, double-blind, placebo-controlled clinical trial in the urban community of Dakar, Senegal. METHODS: Eligibility criteria were age greater than 15 years, HIV-1 or HIV-1 and HIV-2 dual seropositivity, CD4 cell count lower than 400 copies/mm3, no progressive infection, no previous history of intolerance to sulphonamide, lack of severe anemia or neutropenia, and renal or hepatic failure. Written informed consent was obtained. Recruited patients received 80 mg of trimethoprim and 400 mg of sulphamethoxazole daily or a matching placebo. The main outcomes were survival and the occurrence of clinical events defined as Pneumocystis carinii pneumonia, cerebral toxoplasmosis, bacterial pneumonia, infectious enteritis, bacterial meningitis, urinary tract infection, bacterial otitis and sinusitis, and pyomyositis. RESULTS: Between September 1996 and March 1998, 297 patients were screened, and 100 were randomized in the study. Demographic, clinical, and biological characteristics of the two groups were similar as was the mean length of follow-up (7.7 months for the cotrimoxazole group vs. 8.0 months for the placebo group). There was no significant difference between the two groups in survival (hazard ratio = 0.84; 95% confidence interval [CI]: 0.36-1.94) in the probability of severe event occurrence, defined as death or hospital admission (hazard ratio = 1.10; 95% CI: 0.57-2.13), or in the probability of clinical event occurrence (hazard ratio = 1.19; 95% CI: 0.55-2.59). Adjustment for initial CD4 cell count did not change these results. A low dose of cotrimoxazole was tolerated well clinically as well as biologically; only one treatment interruption occurred as the result of a moderate cutaneous eruption (grade 2). CONCLUSION: Our study does not show a beneficial effect of chemoprophylaxis with low-dose cotrimoxazole on survival or occurrence of opportunistic or nonopportunistic infections for HIV-1-infected patients in Dakar, Senegal.
The incidence and risk factors for Pneumocystis carinii pneumonia (PCP) recurrence were evaluated in 451 HIV-infected patients enrolled in the French Hospital Database on HIV who started highly active antiretroviral therapy (HAART) while receiving secondary PCP prophylaxis after a first episode occurring between January 1995 and December 1998. There were 18 episodes of recurrent PCP. On HAART, the CD4+ cell count increased to above 200 x 106/L in 274 patients, 51 of whom stopped PCP prophylaxis. None of these patients had PCP recurrences during 363 person-years (PY) of follow-up after the CD4+ cell count had reached 200 x 106/L (incidence rate [IR], 0.00 cases/100 PY; 95% confidence interval [CI], 0.00-0.82), and 37 PY of follow-up after the CD4+ cell count had reached 200 x 106/L and PCP prophylaxis had been discontinued (IR, 0.00 cases/100 PY; 95% CI, 0.00-7.84). The CD4+ cell count remained < 200 x 106/L in 177 patients; 9 patients stopped PCP prophylaxis, and 6 of these had a disease recurrence. Multivariate Cox analysis (time censored when CD4+ cell count > 200 x 106/L) showed that discontinuation of secondary prophylaxis (relative hazard [RH], 25.95; p <.0001) was associated with recurrence, whereas higher CD4+ cell counts during follow-up (RH, 0.39/50 x 106/L increment; p <.002) were protective.
Medicinal products of biological origin still carry a specific iatrogenic risk, mainly because of their starting material, mode of preparation and variability. Careful postmarketing surveillance systems are therefore necessary. To assess the long-term safety of haemophilia treatment with plasma-derived and recombinant clotting factor products, a cohort study was set up in France in 1994. Participants were patients with haemophilia A and B, with or without previous clotting factor therapy. Clinical events, treatments, biological data and adverse events were recorded on standard forms. Blood samples were separated into serum, plasma and peripheral blood mononuclear cells, frozen, and banked in a central laboratory. The same data and samples were collected at yearly follow-up visits. As of December 1999, 1234 haemophiliacs were enrolled in 39 haemophilia centres. At enrollment, 50.2% of patients were under 15 years of age, and the cumulative number of days of exposure to the product was below 50 in 35.1% of cases. The median duration of follow-up was 26.9 months, with a total of 2729 patient-years (135,947 days of exposure and 211 million units of factor VIII or IX). To date, only 17 patients were lost to follow-up. The initial results show good compliance with this health-watch policy among patients and clinicians specializing in haemophilia. The regular follow-up data and centralized sample bank will serve to investigate rapidly any suspected outbreaks as soon as reliable biological tests become available in the future.
The distribution of telomeric sequence (TTAGGG)n in the genomes of Chondrichthian species at different stages of evolution was investigated both by DNA genomic hybridization, and by fluorescence in-situ hybridization (FISH) of metaphase chromosomes. The sequence is highly conserved in all the species examined. FISH revealed a label uptake only by the telomeres in Raja asterias. However, in Torpedo ocellata, we revealed pericentromeric and interstitial sequence localization on some chromosome pairs in addition to the hybridization signal on telomeres. These findings confirm that the karyotype evolution of these fish began by Robertsonian fusion.
BACKGROUND AND OBJECTIVES: To assess the cost and effectiveness of adding a system of polymerase chain reaction (PCR) testing to the current enzyme-linked immunosorbent assay (ELISA) screening for hepatitis C virus (HCV) in blood donations. MATERIALS AND METHODS: We performed a cost-effectiveness analysis comparing three HCV screening strategies in French blood donors: detection of antibodies against HCV by an ELISA on blood donations (the current policy) vs. ELISA and PCR either on each blood donation or on blood pools. We combined national surveillance data on HCV antibody-positive blood donors with a literature review in a Markov model for natural history of HCV disease and its treatment. RESULTS: PCR testing performed in parallel with ELISA will potentially add less than 1 year of life for all French recipients compared to ELISA screening alone. The incremental costs per life year saved were, respectively, epsilon84.6 million with ELISA and PCR testing of blood pools, and epsilon891.1 million with testing of individual blood donations. CONCLUSION: PCR testing performed in parallel with antibody screening, either on pools or on single donations is not currently a cost-effective option for the detection of HCV RNA virus in blood donors.
OBJECTIVES: Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine. METHODS: We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. RESULTS: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M. CONCLUSIONS: Our study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24-48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.
BACKGROUND: The prognostic value of discordant immunologic (CD4 cell increase) and virologic (plasma HIV RNA level decrease) responses to antiretroviral treatment is not known. OBJECTIVE: To study the relation between clinical outcome of HIV-infected patients receiving highly active antiretroviral therapy (HAART) and early immunologic and virologic responses to such therapy. DESIGN: Prospective cohort study. SETTING: 68 hospitals in France. PATIENTS: 2236 protease inhibitor-naive patients. INTERVENTION: Initiation of HAART with one protease inhibitor and two nucleoside analogues between July 1996 and March 1997. MEASUREMENTS: Immunologic and virologic response at 6 months. Multivariate Cox models were used to assess the relation between these responses and progression to a new AIDS-defining event or death. RESULTS: On the basis of 6-month immunologic and virologic responses, patients were classified into four groups: complete response (47.5%), complete nonresponse (16.2%), immunologic response only (19.0%), and virologic response only (17.3%). After month 6 and within a median of 18 months, 69 patients died and 123 experienced a new AIDS-defining event. After adjustment, complete nonresponders and those with only a virologic response had significantly higher risks for clinical progression at 6 months (relative risk, 3.38 [95% CI, 2.28 to 5.02] and 1.98 [CI, 1.26 to 3.10], respectively) than complete responders. The difference between complete responders and those with only an immunologic response at 6 months was weaker and nonsignificant (relative risk, 1.55 [CI, 0.96 to 2.50]). CONCLUSIONS: Immunologic response after 6 months of HAART indicates a favorable clinical outcome in HIV-infected patients regardless of virologic response. This suggests that both immunologic and virologic markers should be used in clinical practice to evaluate treatment response.
OBJECTIVE: To compare the antiviral activity, effect on CD4 cell count, and tolerability of didanosine (ddI) administered once daily and twice daily in HIV-1-infected patients receiving ddI with stavudine or zidovudine, with or without a protease inhibitor. The study was designed to demonstrate that once-daily dosing of ddI was not inferior to twice-daily dosing. DESIGN: Randomized, open-label, multicenter, two-arm study. PATIENTS AND METHODS: 121 HIV-1-infected adults on a stable regimen including ddI (twice daily) during the previous 3 months with a stable viral load <10,000 copies/ml started therapy. Of these, 62 were randomized to switch to a combination that included ddI once daily and 59 to continue with ddI twice daily. The ddI dose was 400 mg/day (250 mg/day if body weight was <60 kg). The primary efficacy analysis compared the time-averaged difference (TAD) between the two treatment regimens in change from baseline log10 plasma HIV-1 RNA levels over 24 weeks of therapy, with an equivalence margin between the two treatment groups of <0.5 log10 copies/ml. RESULTS: At week 24, the mean plasma HIV-1 RNA level had increased by 0.31 and 0.17 log10 copies/ml in the ddI once-daily and ddI twice-daily groups, respectively. The time-averaged difference between the two groups in change from baseline plasma HIV-1 RNA levels over 24 weeks was (0.05 log10 copies/ml (95% confidence interval, -0.21 to +0.12 log10 copies/ml), indicating that the antiviral activity of ddI once daily is similar to that of ddI twice daily. After 24 weeks of treatment, changes from baseline in CD4 cell counts were similar in the two groups. Both regimens were generally well-tolerated. CONCLUSIONS: Once-daily and twice-daily ddI are equally effective at reducing plasma HIV-1 RNA levels when used in a combination regimen with stavudine or zidovudine, with or without a protease inhibitor.
OBJECTIVE: To study the natural history and the current risk factors for cytomegalovirus (CMV) disease in the context of highly active antiretroviral therapy (HAART). SETTING: Prospective multicentre cohort in 15 university hospitals in France. METHODS: A group of 198 patients with CD4 cell count < 100 x 10(6) cells/l (or < 200 x 10(6) cells/l under HAART for at least 2 months), no previous CMV disease and CMV-positive serology were followed every 4 months clinically and for virological testing including HIV RNA and CMV blood markers (culture, pp65 antigenaemia, plasma CMV DNA and CMV late mRNA by the polymerase chain reaction). RESULTS: At inclusion, median CD4 was 77 x 10(6) cells/l (0-308) and 85% of the patients received protease inhibitors. The percentage of patients receiving HAART reached 99% at 12 months. After a follow-up of 23.6 months, the incidence of CMV disease was 3.2/100 patient-years [95% confidence interval (CI) 1.3-5.0]. In univariate Cox models, all the CMV markers, a CD4 cell count remaining < 75 x 10(6) cells/l and an HIV viral load > 100,000 copies/ml were predictive for CMV disease. The hazard ratios for CMV disease were 11 for blood culture; 14 and 70 for pp65 antigenaemia of > or = 1 and > or = 100 nuclei/200,000 cells, respectively; 35 for plasma CMV DNA; 6 for CMV mRNA; 29 for CD4 < 75 x 10(6) cells/l; and 12 for HIV RNA > 100,000 copies/ml. In a stepwise multivariate analysis, only three covariates were independently associated with the occurrence of a disease: plasma CMV DNA, pp65 antigenaemia > or = 100 nuclei/200,000 cells and a CD4 count < 75 x 10(6) cells/l. CONCLUSION: CMV blood markers and CD4 count < 75 x 10(6) cells/l remain risk factors for CMV disease in patients receiving HAART. Analysis of plasma CMV DNA by the polymerase chain reaction is a reproducible and standardized tool that could be used as a decision marker for initiating CMV pre-emptive therapy.
OBJECTIVE: To evaluate the efficacy and safety of the foscarnet-ganciclovir combination in induction therapy (IT) and maintenance therapy (MT) for cytomegalovirus (CMV) central neurological disorders in HIV-infected patients. DESIGN: An open pilot non-comparative multicentre study. METHODS: Thirty-one patients with acute CMV encephalitis (CMVe) (n = 17) or CMV myelitis (CMVm) (n = 14) during the era before highly active antiretroviral therapy (HAART) received intravenous IT with foscarnet 90 mg/kg plus ganciclovir 5 mg/kg twice a day followed by MT. The primary endpoint was clinical efficacy, assessed at the end of the induction phase. RESULTS: The foscarnet-ganciclovir combination in IT resulted in a 74% (23 out of 31 patients) clinical improvement or stabilization. Eight patients did not respond clinically. Side-effects leading to drug discontinuation occurred in 10 patients during IT. Among the 23 patients who qualified for the maintenance phase, CMV disease progressed in 10, with a median time to the first relapse of 126 days (range 64-264 days). Overall, the median survival time was 3 months [95% confidence interval (CI), 2-4 months]. CONCLUSION: The combination of foscarnet and ganciclovir can safely be used for CMV central nervous system (CNS) infection, with an improvement or stabilization in 74% of patients. Life-long MT with this combination is recommended as long as the immune system is profoundly impaired.
Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS.
OBJECTIVE: To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy. METHODS: From the French Hospital Database on HIV, 1402 protease inhibitor-naive patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes. RESULTS: During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naive patients. CONCLUSION: In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.
BACKGROUND: The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4+ cell counts greater than 100/microL. PATIENTS AND METHODS: We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4+ and CD8+ cell counts, plasma HIV load, p24 antigenaemia, beta2-microglobulinaemia and immunoglobin A and G serum levels. RESULTS: During a median follow-up of 22 months (3-81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9-126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression (P < 0.05). Previous and concomitant opportunistic diseases (P = 0.003) and low CD4+ cell counts (P = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival. CONCLUSION: Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4+ cell count).
OBJECTIVE: To estimate the completeness of the French mandatory AIDS surveillance system (Declaration Obligatoire DO) over the 1990-1993 period using a capture-recapture approach, by matching the mandatory reports with the AIDS cases present in the French Hospital Database on HIV infection (FHDH). METHODS: An anonymous record-linkage algorithm was developed to identify those cases common to both anonymous surveillance systems. The linkage was based on sex, date of birth, and infection risk group, all strictly matched, and on the dates of AIDS diagnosis and of death, the places of diagnosis and residence, and the AIDS-defining diseases at diagnosis. The total number of AIDS cases and completeness of both surveillance systems were estimated using a capture-recapture approach, assuming independence of the ascertainment sources. RESULTS: The completeness of the mandatory reporting was estimated at 83.6% (95% CI: 82.9-84.3), and that of the FHDH at 47.6% (95% CI: 46.9-48.3) for the surveillance of AIDS cases diagnosed among adults in France between 1990 and 1993. The completeness of the system based on FHDH increased over the study period as more hospitals joined the project, while the completeness of the DO surveillance system remained stable. CONCLUSION: This approach was useful in estimating the underreporting of AIDS cases in France. Regularly performed, it will allow the impact of underreporting to be monitored over time.
Over the last years, mathematical models have been applied in HIV infection to investigate the population dynamics of HIV-1 and cells of the immune system in infected hosts. They have contributed to a better understanding of the pathogenesis of AIDS. Among the model-based works, the quantitative studies carried out by two teams, during the years 1995, 1996 and 1997, have brought important results on HIV infection dynamics, reminding that HIV belonged to the lentivirus family, which had not been integrated in research of the previous years. In the studies on HIV dynamics, solutions of mathematical models were fitted to viral and/or immunological markers data in order to estimate the parameters of the viral and cellular production kinetics in infected patients. The present paper is a critical review of these studies. The methods and the most important results are presented. We explain why their impact was so considerable, but also show how the simplicity of modelling could result in conceptual errors. We finally discuss the contribution and the limits of mathematical models in the analysis of experimental data.
OBJECTIVES: It is important to assess the extent of bias when comparing the clinical efficacy of antiretroviral regimens in observational databases because, with the current lack of planned large trials, such analyses may represent the only means of assessing the risk of serious clinical events associated with new regimens. We aimed to compare the results from observational databases with those from randomized trials. METHODS: Three treatment comparisons from randomized trials [Delta, AIDS Clinical Trials Group (ACTG) 175, Community Programs for Clinical Research on AIDS (CPCRA) 007 and ACTC 320] were mimicked in cohorts: (i) zidovudine monotherapy versus combination regimens of two nucleoside analogues; (ii) zidovudine combined with either didanosine or zalcitabine; and (iii) a dual combination versus a triple regimen including a protease inhibitor. Data for over 10 000 patients from the French Hospital Database on HIV, the EuroSIDA study and the Swiss HIV cohort study were analysed for each of the comparisons. Progression to AIDS disease or death was analysed in Cox models, adjusting for baseline differences, and results compared with randomized trials. RESULTS: For comparison (i) the adjusted relative risk estimates from cohorts were between 0.61 and 0.84, favouring combinations over monotherapy, compared with 0.57 to 0.63 for trials. For comparison (ii) relative risk estimates from cohorts ranged from 0.81 to 1.01 compared with 0.77 to 0.92 for trials. For comparison (iii), two of the cohorts showed similar results to the ACTG 320 trial but one indicated a higher risk of progression on triple therapy [relative risk 1.20, 95% confidence interval (CI) 1.01-1.441, in direct contrast to the trial result (relative risk 0.50, 95% CI 0.33-0.76). CONCLUSION: Serious biases can be present when comparing outcomes from the use of antiretroviral regimens in observational studies. However, such bias is not inevitable and careful interpretation of the results from several observational studies considered together is likely to be informative, guiding the design of new trials.
OBJECTIVE: To estimate the statistical distribution of the incubation period of Creutzfeldt-Jakob disease (CJD) in human growth hormone (hGH) recipients in France. BACKGROUND: Published papers suggest that the median incubation period of hGH-related CJD is approximately 15 years, but there are as yet no statistical data that support this assertion. METHODS: Of the 1,361 hGH recipients who were included in this study, 55 had developed CJD at the time of the study. Individual data on hGH treatment history were available. Different mathematical models were used to estimate the statistical distribution of the incubation period. One main feature of the models was to take into account the occurrence of future CJD cases. RESULTS: Models showed that the mean incubation period was 9 to 10 years, and the 95th percentile of the distribution was 15 to 16 years. Data and models indicated that the incubation period was significantly shorter in homozygotes at codon 129 of the prion protein gene than in heterozygotes. CONCLUSIONS: The short mean incubation period of CJD in French hGH recipients may be due to high infectivity in hormone lots. Estimates of the 95th percentile indicate that the number of hGH-related CJD cases may continue to increase in the coming years.