[Liposomal amphotericin B in secondary prophylaxis of visceral leishmaniasis in HIV-infected patients: report of five clinical cases]. / L'amphotéricine B liposomale en prophylaxie secondaire chez les patients VIH+ atteints de leishmaniose viscérale: à propos de cinq cas.

Treatment of visceral leishmaniasis in HIV patients encounters inefficacy and relapse due to drug resistance, toxicity and immunodepression. Our goal was to evaluate treatment of these patients by liposomal amphotericin B (L-AmB). Since 1998, five clinical files were exploitable out of 13 patients. Protocols used bolus doses ranging between 2.9 and 4.1 mg/kg dispatched on 5-24 days, followed by maintenance dose ranging from 2.7 to 3.8 mg/kg every 15 days. Attack treatment involved high bolus dose (cumulated doses ranging from 60 to 86 mg/kg at day 30) and allowed favorable clinical and biological results with healing in four patients. Secondary prophylaxis with L-AmB has been efficacious and well tolerated in three patients. Although literature and study results cannot indicate a standard therapeutic care in these patients, an initial treatment by L-AmB at doses higher than marketing-approved doses with a secondary prophylaxis by L-AmB associated with an antiretroviral treatment seem to be major asset in order to obtain healing. Expanding this study to a multicenter trial should allow to better define the frequency and duration of the secondary prophylaxis and to evaluate the risk of therapeutic escape as well as the life-span increase.

Polymorphism and drug-selected mutations in the protease gene of human immunodeficiency virus type 2 from patients living in Southern France.

The susceptibility of human immunodeficiency virus type 2 (HIV-2) to protease inhibitors (PI) is largely unknown. We studied HIV-2 protease genes from 21 HIV-2-infected patients who were exposed or not exposed to PI. The aim of this study was (i). to characterize the polymorphism of HIV-2 protease in the absence of drug, (ii). to know whether the HIV-2 protease gene naturally harbors HIV-1 drug resistance codons, and (iii). to identify mutations emerging under PI-selective pressure. Sixty-five HIV-2 RNA or proviral DNA samples were directly sequenced from the plasma or peripheral blood mononuclear cells of 8 patients who had received PI and 13 patients who had never received any antiretroviral. In untreated patients, the highest amino acid variability in HIV-2 protease was observed at positions 14, 40, 43, 46, 65 and 70, and seven codons (10V, 32I, 36I, 46I, 47V, 71V, and 73A) associated with drug resistance in HIV-1 were highly prevalent. In addition, at six positions (positions 7, 46, 62, 71, 90, and 99), the amino acid variability or the amino acid frequencies or both differed significantly in PI-treated and untreated patients, suggesting that mutations 7K-->R, 46V-->I, 62V-->A/T, 71V-->I, 90L-->M and 99L-->F were occurring under PI-selective pressure. At these positions, at least one sample simultaneously harbored both wild-type and mutated codons, while substitutions at positions 62, 71, 90, and 99 were confirmed in a longitudinal analysis. Moreover, the presence of codons 46I and 99F in the absence of drug in HIV-2 subtype B proteases may reflect natural resistance to PI. In conclusion, the present study revealed that HIV-2 strains harbor specific patterns of natural polymorphism and resistance.

Highly active antiretroviral treatment does not increase sexual risk behaviour among French HIV infected injecting drug users.

STUDY OBJECTIVE: This study examined the impact of highly active antiretroviral therapies (HAART) on sexual risk behaviours of HIV infected injecting drug users (IDUs) included in the French MANIF 2000 cohort study. DESIGN: Longitudinal analysis including baseline and last follow up characteristics using generalised estimating equations (GEE). SETTING: Hospital departments for specialist AIDS care in south eastern France and inner suburbs of Paris. PATIENTS: All patients antiretrovial treatment naive, who reported being sexually active at enrollment, and who had at least one follow up visit in the cohort between October 1996 and May 1998 (n=188). MAIN RESULTS: Of the 188 HIV infected IDUs who were antiretroviral treatment naive at enrollment, 34 were prescribed HAART during follow up. Proportion of patients who reported at least one episode of unprotected sexual intercourse in the previous six months only significantly decreased in the HAART treated group (from 47.1% to 23.5%, p=0.008, compared with 43.5% to 35.7% in the rest of the sample, p=0.10). GEE multivariate model confirmed that prescription of HAART was associated with reduced sexual risk. CONCLUSIONS: The concern that HAART might result in clinical improvement leading to resumption of high risk activities that could inadvertently result in HIV transmission was not supported by these data. Reasons for further reductions in HIV risk with taking HAART remain to be clarified.

Highly active antiretroviral therapy (HAART) and circulating markers of immune activation: specific effect of HAART on neopterin.

The circulating levels of immune activation markers, including neopterin, tumor necrosis factor receptor type II, and interleukin-2 receptors, are increased in human immunodeficiency virus-infected patients. We show here that highly active antiretroviral therapy significantly decreased neopterin levels. This effect is reversible, since neopterin levels increased after the arrest of treatment. Their determination may be useful in the evaluation of the efficacy of antiretroviral therapy.

Rickettsia mongolotimonae: a rare pathogen in France.

We report a second case of laboratory-confirmed infection caused by Rickettsia mongolotimonae in Marseille, France. This rickettsiosis may represent a new clinical entity; moreover, its geographic distribution may be broader than previously documented. This pathogen should be systematically considered in the differential diagnosis of atypical rickettsioses, especially rashless fevers with lymphangitis and lymphadenopathy, in southern France and perhaps elsewhere.

Use of buprenorphine in HIV-infected injection drug users: negligible impact on virologic response to HAART. The Manif-2000 Study Group.

Some HIV-infected injecting drug users (IDUs) on drug abuse maintenance treatment have access to highly active antiretroviral therapy (HAART); this raises questions about the effects of individual treatments on the efficacy of HAART. The French Cohort Study of HIV-infected IDUs - MANIF-2000 - allowed one to assess whether buprenorphine differentially impacts efficacy of HAART. Of the 103 HAART-treated patients, (excluding active IDUs and patients on methadone), 20 were on buprenorphine substitution treatment and 83 were ex-IDUs. A linear regression model used the differences in viral load titre before and after treatment initiation, as a dependent variable, and showed that buprenorphine treatment was not significantly associated with viral load trend. This was also the case when adjusting for other potential confounders, and suggests that there is no major short-term influence of buprenorphine on HIV viral load in HAART-treated patients.

Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection.

Baseline genotype resistance analysis was carried out in 48 adults with primary HIV-1 infection between 1995 and 1998 before starting early combination therapy. Seventeen percent (8/48) of the isolates displayed key mutations conferring resistance to reverse transcriptase (RT) inhibitors such as amino acid substitutions 215Y/F (5/48,10%), 70R (3/48, 6%), 184V (2%). Two percent (1/48) had a major mutation associated with resistance to protease inhibitors (D30N). Other mutations at positions 10, 15, 20, 33, 36, 46, 63, 71, 77, 82, 93 of the protease gene were frequent (73%). Among the 46 patients who were given antiretroviral combination therapy and who responded durably to treatment after 6 and 12 months, there was no significant difference between those harboring RT mutant strains (Group I) and those with wild-type isolates (Group II). No significant difference was found at months 6 and 12 between the two groups in terms of CD4+ cell counts. These findings suggest that the presence of drug-resistant strains at the time of primary HIV-1 infection does not necessarily predict drug failure. Other factors, such as adherence to treatment, tolerance and pharmacokinetics parameters are probably major determinants of virological response in patients with early therapeutic intervention.

Impact of highly active anti-retroviral therapy (HAART) on cytokine production and monocyte subsets in HIV-infected patients.

HIV infection is associated with cytokine production by monocytes and expansion of a monocyte subset that expresses high levels of CD16. Our study was designed to investigate the effects of anti-retroviral therapies on these immune parameters. Four groups of HIV+ patients were included in the study. The first group comprised drug-naive patients (n = 20); the second included patients who received two inhibitors of HIV reverse transcriptase (n = 45); the third group received a therapy combining these two inhibitors and one inhibitor of HIV protease (HAART) (n = 35); the fourth consisted of patients who had stopped their treatment (n = 20). The release of inflammatory cytokines (tumour necrosis factor, IL-1beta, IL-6) and immunoregulatory cytokines such as IL-10 by monocytes was determined by ELISA. The monocyte subsets expressing low or high levels of CD16 were studied by flow cytometry. Monocytes from patients naive of treatment released higher amounts of inflammatory cytokines and IL-10 than HIV- individuals. Each anti-retroviral therapy restored a normal pattern of cytokine secretion. Nevertheless, the release of cytokines increased again after the arrest of the treatment. The expansion of the monocyte subset that expresses high levels of CD16 was significantly decreased by HAART but not by the treatment including two inhibitors of reverse transcriptase. These results suggest that only HAART controls monocyte activation in the treatment of HIV infection.

Mutation patterns of the reverse transcriptase and protease genes in human immunodeficiency virus type 1-infected patients undergoing combination therapy: survey of 787 sequences.

The aim of the present study was to evaluate the resistance-associated mutations in 302 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving combination therapy and monitored in Marseille, France, hospitals from January 1997 to June 1998. In the reverse transcriptase (RT) gene, the most frequent mutations were found at codons 215 (53%), 41 (34%), and 67, 70, 184, and 210 (>20%). One deletion and two insertions in the beta3-beta4 hairpin loop of the finger subdomain (codon 69) were detected. Interesting associations and/or exclusions of specific mutations were observed. In 96% of RT genes, a mutation at codon 70 (most frequently, K70R) was associated with a wild-type genotype at position 210 (P < 10(-5)). Similarly, a mutation at codon 210 (most frequently, L210W) was generally associated with mutations at codons 41 (92%) and 215 (96%) but not at codon 219 (16%) or codon 70 (4%) (P < 10(-5)). In the protease gene, the most prevalent mutations were at codons 63 (84%), followed by codons 10, 36, 71, 77, and 93 (ca. 20%). As for RT, pairwise associations of mutations were observed. Analysis of the mutation patterns for patients with undetectable HIV-1 loads revealed a high proportion (65%) of wild-type RT genotypes but only 18% wild-type protease genotypes. For patients with high viral loads (>100,000 copies/ml), more than 50% of the RT and protease genes displayed three or more mutations. The significant correlation between the level of viremia in plasma and the number of resistance mutations in the protease (P = 0.007) and RT (P = 0.00078) genes strengthens the importance of defining the genotype of the predominant HIV-1 quasispecies before initiating antiretroviral therapy.

[Multiple and bilateral nodular opacities revealing primary pulmonary lymphoma of the Burkitt-like type in AIDS]. / Opacités nodulaires multiples et bilatérales révélatrices d'un lymphome pulmonaire primitif de type Burkitt-like au cours du SIDA.

We report the observation of AIDS patient with a history of cough, dyspnea, fever, cachexia and bilateral nodular opacities at the chest X-ray. Infectious etiologies were initially suspected but the recovery was not obtained with their treatment. Only lung biopsy established the precise diagnosis of primary pulmonary Burkitt's-like lymphoma (BBL). The sole extranodal site of BBL at the lungs is an unusual finding. Generally, this lymphomatous proliferation is observed at the early period of the HIV infection. Immunodepression and Epstein-Barr virus (EBV) infection are the major pathogenic basis for BL as indicated by the high prevalence of EBV genomes found in malignant cells. The lack of EBV sequences in a significant proportion of Burkitt's lymphoma or BBL and AIDS-associated non-Hodgkin malignant lymphoma suggest that alternative pathogenic mechanisms may be involved. This observation permit to show the difficulties observed before the multiple and bilateral opacities whom the etiologies are varied. The prognosis of AIDS-associated BLL is very severe.

Differential regulation of killer cell Ig-like receptors and CD94 lectin-like dimers on NK and T lymphocytes from HIV-1-infected individuals.

NK and T lymphocytes share various cell surface receptors, including NK receptors for MHC class I molecules (NKR). NKR include killer cell Ig-like receptors (KIR) and lectin-like dimers which are composed of the invariant CD94 associated with a variety of NKG2 molecules. The combination of KIR and CD94/NKG2 dimers expressed on NK and T cell subsets defines a repertoire of MHC class I recognition. Engagement of NKR by cognate MHC class I molecules governs T and NK cell activation. We investigated the NKR distribution on NK and T cell subsets from uninfected and HIV-infected individuals, according to the clinical status, the absolute numbers of CD4+ T cells as well as the plasmatic viral load of the patients. We show that the KIR distribution on NK cells is not affected by HIV-1 infection, whereas the absolute numbers of T cells expressing specific KIR members (CD158b, p70) transiently increase in early stages of HIV infection. By contrast, the percentages of NK and T cells which express CD94 dimers increase in parallel with the disease. These results document a differential regulation of KIR and CD94 lectin-like dimers during the course of a chronic viral infection in humans and further suggest that both types of NKR are independently regulated.

Pregnancy and contraception in a French cohort of HIV-infected women. SEROCO Study Group.

OBJECTIVE: To describe the impact of HIV diagnosis on contraception, incidence of pregnancy and live-births among HIV-infected women in France. DESIGN: Follow-up of women included in a French cohort of HIV-infected adults (SEROCO). METHODS: In 17 hospital-based units and one private practitioners' network in the Paris area and south-east region of France, 412 HIV-infected women (volunteers) were enrolled from 1988 to 1993, shortly after HIV diagnosis (median, 3 months), and followed for a median of 3 years. The main outcome measures were incidence and outcome of pregnancy, proportions of women sexually active and methods of contraception. RESULTS: The incidence of pregnancy decreased significantly from 20.4 per 100 person-years in the year preceding HIV diagnosis to 7.9 per 100 person-years after HIV diagnosis (P < 0.001), whereas the proportion of pregnancies voluntarily interrupted doubled (63 versus 29%). The proportion of women who were sexually inactive increased from 5% before HIV diagnosis to 20% thereafter. During followup, 80% of sexually active women were using contraceptive methods. CONCLUSIONS: The study supports an association between the discovery of HIV infection and a decrease in the proportion of women who are sexually active, a decrease in the incidence of pregnancy in general and live-births in particular, and an increase in the proportion of pregnancies voluntarily interrupted. Nevertheless, 24% of the women became pregnant and around 20% of sexually active women were not using any contraception. The high rate of voluntary abortion may indicate that many of these pregnancies were unplanned and could have been prevented.

Acceptability and impact of zidovudine for prevention of mother-to-child human immunodeficiency virus-1 transmission in France.

We studied the propagation and the impact of zidovudine prevention on the human immunodeficiency virus-1 transmission rate from infected mothers to their infants in the French nationwide prospective cohort. Infection was diagnosed in the children on the basis of at least two positive human immunodeficiency virus-1 polymerase chain reaction tests, culture, or both. The transmission rate among treated women was compared with that among untreated women during the same period and with that among women enrolled in the cohort since 1986. The impact of zidovudine was analyzed according to the women's clinical and biologic characteristics, the mode of delivery, and use of zidovudine therapy before the pregnancy. Nearly 90% of women were treated as soon as the second half of 1994. In 1994 and 1995, 80% of mother-child pairs received at least one of the three phases of preventive treatment. Among the 663 mothers enrolled during these 2 years, only six refused the treatment. Zidovudine treatment was associated with a reduction in the transmission rate of nearly two-thirds, from 14% +/- 6% to 5% +/- 2% (p < 0.01). The degree of reduction was not influenced by the maternal CD4+ cell count or p24 antigenemia at delivery. Zidovudine treatment of the mother before the pregnancy considerably reduced the impact of preventive therapy; the transmission rate was significantly higher among pretreated mothers (20% versus 5%, p < 0.01) even after adjusting for maternal CD4+ cell count. Zidovudine prevention is now widely used in France and has had a major impact on the epidemiology of mother-child human immunodeficiency virus transmission. This justifies a policy of offering human immunodeficiency virus screening to all women before or shortly after the diagnosis of pregnancy.

Ethical dilemmas in care for HIV infection among French general practitioners.

A survey was carried out in May-June 1992, in the city of Marseille (South-Eastern France), to analyze attitudes towards ethical issues associated with the care of HIV-infected patients in a random sample of general practitioners (GPs) (telephone interviews; answer rate = 78.6%; n = 313). A total of 70.6% were consulted by HIV carriers and 48.9% regularly took care of these patients over the past year. Multi-dimensional analysis showed that support for HIV mandatory screening was related to lack of knowledge and experience with HIV infection, high perception of risks associated with HIV care, and the individual characteristics of GPs, such as religious beliefs and intolerance to uncertain situations. GPs with experience of regular care of HIV carriers had the same opinions than the rest of the sample about 'creation of specialized hospitals for AIDS patients' and similar attitudes toward HIV testing 'without patients' consent' or breaching of confidentiality of HIV diagnosis. Debates on ethical issues among GPs cannot be reduced to a simplistic division of a 'liberal group' highly involved in prevention and HIV care and a 'conservative' majority more or less inclined to stigmatize HIV-infected patients. Ambiguous messages on these issues from health authorities and professional ethical bodies may have very negative impacts on the attitudes of primary care physicians regarding the acceptability of HIV-infected patients.

[Evaluation of medication costs in hospitalization of AIDS patients]. / Evaluation du coût médicamenteux des séjours d'hospitalisation chez des malades atteints de sida.

The aim of this study was to examine the global pharmaceutical cost of AIDS patients hospitalized in a ward of infectious diseases in Marseille. They were 209 patients at various clinical stages of HIV infection receiving or not AZT or another specific drugs. All of the 319 hospitalization stays entailed a pharmaceutical cost of 1,065,593 FF for year 1990. A detailed analysis of the therapies, excepted for AZT, determined very large expenses of anti-infectious, hypnotics and other patent drugs of gastroenterology, pneumology, stomatology and toxicology. The study showed that the total drug cost increased with the hospitalization duration.

[Familial deficiency of C7 associated with adrenomyeloneuropathy]. / Déficit familial en fraction C7 du complément associé a une adrénomyéloneuropathie.

A 24-year old man presented with recurrent meningitis resulting from familial deficiency of a late component of the complement system (C7). Five years later, he developed gait disturbance, mental impairment and loss of hearing. Adrenomyeloneuropathy was diagnosed by a raised plasma long chain fatty acids level.