Hepatitis B virus DNA sequences in lymphoid cells from patients with AIDS and AIDS-related complex.

A lymphotropic virus HTLV-III/LAV was recently identified as the etiologic agent of the acquired immune deficiency syndrome (AIDS). In a study of concomitant hepatitis B infections in patients with AIDS or the AIDS-related complex, DNA sequences of hepatitis B virus (HBV) were found in fresh and cultured lymphocytes from patients with AIDS even in the absence of conventional HBV serological markers. Furthermore, the restriction DNA pattern was consistent with the integration of the viral DNA. These results should prompt additional studies to reevaluate a possible role of HBV as a cofactor in AIDS in addition to the HTLV-III/LAV causal agent.

Qualitative and quantitative analysis of human cytotoxic T-lymphocyte responses to HIV-1 proteins.

OBJECTIVE: To study the degree of immunogenicity of each HIV-1 protein. DESIGN: In most viral systems, antiviral cytotoxic T-lymphocytes (CTL) from a given donor preferentially recognize only one or a small number of viral proteins. METHODS: Anti-HIV CTL were generated by in vitro stimulation of peripheral blood mononuclear cells from seropositive donors and tested against multiple HIV-1 proteins or groups of proteins encoded by seven genes (env, gag, pol, nef, rev, tat and vif). Using autologous target cells infected with recombinant vaccinia viruses expressing one of the HIV-1LAI proteins, we compared the cytolytic activities obtained from bulk culture with those found in limiting dilution analysis (LDA). RESULTS: Our results were noteworthy for the following reasons. (1) Each responding donor reacted simultaneously to multiple proteins; this is very unusual in other viral systems. Anti-Gag CTL were detected in most, and anti-Pol in approximately three-quarters, of the patients, together with very high amounts of the corresponding CTL precursors in LDA. CTL against Env and Nef were found in two-thirds of the patients, while Vif- and Rev-specific CTL were less frequent. Finally, Tat was seldom recognized by CTL, but its antigenicity was revealed in LDA. (2) All responding cells revealed in bulk cultures as well as in LDA were CD8+ T-cells, and their in vitro differentiation did not require the help of CD4+ T-cells. (3) Proteins from the HIV-1LAI isolate were recognized with high frequency by CTL from seropositive donors, most certainly being infected by other isolates, which suggests that relatively conserved epitopes are predominant targets of CTL. CONCLUSION: Taken together, these results are encouraging for vaccine purposes, since anti-HIV-1 CTL stimulation is thought to be a requirement for such a vaccine.

Phase II study of liposomal encapsulated daunorubicin in the treatment of AIDS-associated mucocutaneous Kaposi's sarcoma.

OBJECTIVE: To evaluate the efficacy and safety of liposomal encapsulated daunorubicin (DaunoXome) in the treatment of AIDS-associated mucocutaneous Kaposi's sarcoma. DESIGN: A Phase II, multicentre, European, non-comparative, open study to assess the use of DaunoXome in patients with no prior anthracycline chemotherapy for Kaposi's sarcoma. The response rate, time to disease progression, and the incidence and severity of adverse events were documented. SETTING: Hospital-based HIV units. PATIENTS: Thirty HIV-seropositive patients with mucocutaneous Kaposi's sarcoma were enrolled and treated. INTERVENTIONS: Treatment with DaunoXome at a dose of 40 mg/m2 intravenously once every 2 weeks. Treatment with antiretroviral agents and prophylaxis of opportunistic infections where indicated. RESULTS: Of the 30 evaluable patients, 22 patients (73%) achieved a partial response. Median time to treatment response was 30 days (range, 15-202). For patients with a partial response, median time to treatment failure was 153 days (range, 15-558). Patients received a median of 10 cycles (range, 1-44). Adverse events were minimal. The most common side effect was granulocytopenia in 16 patients (53%). CONCLUSION: DaunoXome is an effective and well-tolerated treatment for AIDS-associated mucocutaneous Kaposi's sarcoma and can be administered for prolonged periods. The myelosuppression can be managed by dose reductions and dose not preclude the concurrent use of antiretroviral therapies.

Changes in blood CD8+ lymphocyte activation status and plasma HIV RNA levels during antiretroviral therapy.

OBJECTIVE: To analyse the relationship between CD8+ lymphocyte phenotype alterations and plasma HIV RNA levels in HIV-infected patients treated with the zidovudine-didanosine combination. METHODS: A total of 30 HIV-infected patients who had never received antiretroviral therapy and who were starting treatment with a combination of zidovudine and didanosine were prospectively studied. Multiparameter flow cytometric analysis of CD8+ lymphocytes and plasma HIV RNA determination were performed on day 0, day 15 and monthly from months 1 to 6. RESULTS: Patients were divided into three categories according to the time-course of plasma HIV RNA levels. In 14 patients, an early and sustained fall in plasma HIV RNA to below the detection limit (500 copies/ml) was observed; in 10 patients, the fall was transient; in six patients, plasma HIV RNA was always detectable (non-responders). The mean CD4+ lymphocyte gain was 120 x 10(6)/l at month 6 in sustained and transient responders, and 55 x 10(6)/l in non-responders. A significant fall in the proportion of CD8+ lymphocytes with an activated phenotype was observed only in the two groups of responders, and was higher in the sustained responders (CD38+HLA-DR+, -56.8%; CD38+CD45RO+, -54.0%; HLA-DR+CD45RO+, -48.4%; CD38+CD28-, -47.3%). CONCLUSION: A fall in the proportion of activated CD8+ lymphocytes is associated with the disappearance of HIV RNA from plasma during antiretroviral therapy. Undetectable plasma HIV RNA is not associated with a return to normal CD8+ lymphocyte activation status after 6 months of treatment, suggesting that viral replication persists in lymphoid tissues.

T cell changes after combined nucleoside analogue therapy in HIV primary infection.

OBJECTIVE: To characterize the immune changes after treatment of acute HIV-1 infection with triple nucleoside analogue therapy. DESIGN: Immunological and virological parameters were monitored from day 0 to weeks 36-44 in eight patients [median CD4 cells = 451 cells/microl (range: 149-624), viral load = 4.8 log10 copies/ml (range: 6.5-3.3)] who started at time of primary HIV infection (PHI) a therapy including zidovudine (ZDV), didanosine (ddl), and lamivudine (3TC). METHODS: Lymphoid subsets were evaluated on peripheral blood lymphocytes by four-colour flow cytometry using a panel of mAbs directed against differentiation and activation markers. RESULTS: We observed a median -2.1 (range: -1; -3.3) log10 copies/ml viral load decrease and a median +158 cells/microl (range: +7 to +316) CD4 cell count increase at week 4 reaching normal CD4 cell count values of 761 CD4 cells/microl (range: 389-1153) at weeks 36-44. Virus undetectability was obtained at week 24 for all subjects. A rapid CD4 T cell amplification involved both memory and naive CD4 T cells. This was associated with a very rapid and significant decrease in activation markers [human leukocyte antigen-DR (HLA-DR), CD38] on both CD4 and CD8 T cell subsets together with a CD8+CD28+ cell increase as early as week 4. CONCLUSIONS: These results show that early therapy with nucleoside analogues can correct the immunological abnormalities observed in CD4 and CD8 T cell subsets at the time of PHI. This early kinetics in T cell recovery appears to be faster than in established disease.

Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous therapy.

Thirty-five patients with the acquired immunodeficiency syndrome (AIDS) and central nervous system toxoplasmosis, seen over a 30-month period, were treated with the combination pyrimethamine/sulfadiazine. All patients had clinical and computed tomographic scan findings consistent with active neurotoxoplasmosis. Mean duration of total therapy was six months. During the first two months of therapy, four patients died of acute neurotoxoplasmosis and 31 showed improvement. Of the 24 patients evaluable for long-term therapy, 14 (58 percent) achieved complete resolution and 10 had late clinical (n = 7) and/or computed tomographic scan (n = 6) sequelae. Six patients experienced 10 relapses, which occurred within six weeks of treatment discontinuation in seven of 10. Reintroduction of the combination led to complete resolution of the relapse in eight cases. These clinical results were correlated with brain anatomic findings in the 15 autopsied cases. Side effects, noted in 25 of 35, were mainly hematologic toxicity (n = 21) and cutaneous rash (n = 12). However, the combination had to be definitively stopped in only two cases and sulfadiazine alone had to be withdrawn in eight other cases. These data suggest that pyrimethamine/sulfadiazine is highly efficacious in neurotoxoplasmosis and that life-long therapy is needed to prevent relapses in patients with AIDS.

Clinical and echocardiographic observations in pulmonary valve endocarditis.

Clinical and echocardiographic data from 12 patients with pulmonary valve endocarditis are described. Seven patients had isolated pulmonary endocarditis and in 5 patients other valves were infected (aortic, tricuspid, mitral or all 3). Two patients were heroin addicts and 4 had underlying heart disease (congenital heart disease in 3 and aortic regurgitation in 1 patient). The organisms involved were alpha streptococci in 3 patients (all with underlying heart disease), Staphylococcus aureus in 4, Streptococcus D bovis in 1 patient and Candida guillermondii in 1. M-mode and 2-dimensional echocardiography was performed in 10 patients and revealed vegetations in 8. Pulsed Doppler echocardiography was performed in 6 patients and revealed pulmonary regurgitation in all 6. Seven patients had pulmonary emboli. Four patients underwent surgery. Four patients died, including 1 after cardiac surgery. Five patients, including the patient infected with Candida guillermondii, recovered with antibiotic treatment.

Frequency of cytokine-producing T cells in HIV-infected patients treated with stavudine, didanosine, and ritonavir.

To assess prospectively the influence of the control of viral replication on the frequency of cytokine-producing T cells, and to correlate these changes with immune activation, we conducted a 15-month follow-up study of IFN-gamma- and IL-2-producing CD4+ and CD8+ T cells at a single-cell level in 12 previously untreated patients receiving highly active antiretroviral therapy (HAART). At baseline we observed a strikingly high proportion of IFN-gamma-producing CD8+ T cells. The treatment-induced decrease in the proportion of IFN-gamma-producing CD8+ T cells ran parallel to the decrease in HLA-DR+ and CD38+CD8+ T cell subsets and was associated with the reduction in HIV RNA level. IL-2-producing cells were mainly CD4+. As a consequence of CD4+ T cell loss, the number of IL-2-producing CD4+ T cells was lower in patients than in control subjects (52 vs. 171 cells/microl), but the proportion of these cells was unchanged (22.4 vs. 19.3). During therapy the proportion of CD4+ IL-2-producing cells was initially stable and then fell markedly at month 5, followed by a gradual return to previous values. The reduction in viral load was associated with the fall in the proportion of CD4+ activated subsets. Intracellular cytokine assays are a new approach to the assessment of T cell function in HIV infection. Our results suggest that the functional capacity of CD4+ T cells is probably less severely altered than previously thought on the basis of conventional assays. CD8+ T cells exhibit an increased capacity to produce IFN-gamma that is associated with an increase in activation marker expression. These alterations decrease partially and in parallel under treatment.

Immunohistochemical evidence for human immunodeficiency virus-1 infection of liver Kupffer cells.

To investigate the possibility of human immunodeficiency virus-(HIV) 1 infection of liver cells, liver samples from 17 patients with either acquired immunodeficiency syndrome (AIDS, 13), AIDS-related complex (ARC, 3), or lymphadenopathy syndrome (LAS, 1) were studied. A monoclonal antibody directed against the p24 gag HIV-1 protein was used in an immunoperoxidase assay and yielded positive results in seven out of 17 samples. Staining by anti-p24 antibody was of three types: diffuse in Kupffer cells of most samples, inside granuloma in cells that were probably histiocytes, and in some sinusoidal cells whose origin was difficult to ascertain. Attempts to locate the CD4 membrane antigen showed that it was mainly present on endothelial sinusoidal cells. These results indicate that liver cells, including Kupffer cells, might be infected by HIV-1, and that these cells might be involved in certain liver lesions observed during HIV-1 infection, particularly sinusoidal abnormalities.

Treatment of imported cases of falciparum malaria in France with halofantrine.

Halofantrine is a 9-phenanthrenemethanol which is effective against multi-drug resistant strains of Plasmodium falciparum. It has been shown to be highly effective and extremely well tolerated in the treatment of imported cases of falciparum malaria in France. A total of 1,500 mg administered in three 500 mg doses at six-hour intervals results in a 100% cure rate in semi-immune subjects. This dosage should be repeated after 14 days to obtain the same cure rate in non-immune patients. Minor clinical side effects included epigastric pains, nausea and, in one case, a skin rash.

[Digestive manifestations of the acquired immunodeficiency syndrome (AIDS): study in 26 patients]. / Manifestations digestives du syndrome d'immunodéficience acquise (SIDA): étude chez 26 patients.

We studied the gastrointestinal manifestations in 26 cases of AIDS. The patients belonged to two different epidemiological groups: the first group included thirteen french homosexual men, the second group included 6 Haitians, 6 Africans and a Pakistanian, none of them admit homosexual activity. The clinical manifestations were: chronic watery diarrhea in 17 cases, bloody diarrhea in 2 cases; loss of weight in the 26 cases; dysphagia in five cases; jaundice in one patient (due to Kaposi sarcoma of the ampulla of Vater). The digestive lesions found, alone or associated, were necrotizing enteritis (2), ulcerative colitis (1), pseudomembranous colitis (1), Candida esophagitis (10), erythematous duodenitis (6), proctitis (4), Kaposi sarcoma (3), diffuse (2) or localized (1). Thirteen patients out of the 26 presented opportunistic digestive infections due to one or several germs. These were 10 cases of esophageal infection (due to Candida albicans) and 8 cases of enterocolonic infection due to Cytomegalovirus (3 cases), Cryptosporidium (3 cases), Mycobacterium avium intracellulare (1 case), Cryptococcus neoformans (1 case). The other digestive infections cases were due to non-opportunistic pathogens: Entamoeba histolytica (3 cases); Giardia lamblia (3 cases); Strongyloides stercoralis (2 cases); Salmonella typhi (2 cases); Shigella (1 case); Herpes simplex virus (1 case). No difference was noticed between the homosexual and the heterosexual groups with respect to the nature and the frequency of the digestive infections.

[Anxious-depressive state and cognitive deficit in HIV infection]. / Statut anxio-dépressif et déficit cognitif au cours de l'infection par le VIH.

UNLABELLED: This study tries to demonstrate the importance of using follow-up trials and taking anxio-depressive status into account while interpreting cognitive impairment in HIV-infected subjects. Subjects included were: 18 HIV carriers, mostly homosexual, belonging to CDC groups II (4), III or IVC2 (7) and IV (7), selected within a cohort of 63, as having been assessed 3 times, with no focal or identified brain disease at entry. Our methods were: 1) psychiatric interview based on DSM III-R criteria, clinical scales (Spielberger's STAXI and the MADRS) and cognitive questionnaires; 2) neuropsychological evaluation including 16 subtests screening attention, memory, visuo-spatial function, motor dexterity, psychomotor speed, and language; 3) repeated assessment within a period ranging from 6 to 21 months. RESULTS: At entry, cognitive status was impaired for 14 subjects (2 II, 5 III or IVC2, 7 IV). Disorders had disappeared for 7 subjects (2 II, 2 IVC2 and 3 IV) at following assessments allowing us to conclude on a psychogenic origin. For 7 subjects, cognitive status had either remained constant (3 III and 2 II) or had worsened within 7 to 17 months (2 IV), whereas psychiatric symptoms had decreased, implying HIV encephalopathy. Follow-up trials including 3 neuropsychological and psychiatric assessments and neuroimagery, if necessary, were required to ascertain the causes of cognitive impairment consequently attributed to anxio-depressive symptoms or HIV encephalopathy in 14 subjects.

[Treatment of CMV retinitis with intravitreal foscarnet]. / Traitement de la rétinite à CMV par foscarnet intravitréen.

PURPOSE: To assess the tolerability and efficacy of intravitreal injections of foscarnet in cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome (AIDS). METHODS: Patients with CMV retinitis resistant and/or intolerant to intravenous foscarnet and ganciclovir and resistant to intravitreal ganciclovir were included. The induction therapy consisted of intravitreal injections of 2,400 micrograms of foscarnet twice a week. The assessment was performed by clinical examination and photographies of the fundus. RESULTS: Three patients (four eyes) have been included. Three eyes were administered seven and one eye eight intravitreal injections. The tolerability was good, but the efficacy was mere: the retinal lesions became less edematous, but they still extended. CONCLUSION: In these four eyes with CMV retinitis resistant to intravitreal ganciclovir, intravitreal injections of foscarnet were well tolerated but did not stop the progression of the retinitis.

[Pneumocystis carinii pneumonia in HIV infection. Diagnosis, prognostic factors and curative treatment]. / Pneumopathie à Pneumocystis carinii au cours de l'infection à VIH. Diagnostic, facteurs pronostiques et traitement curatif.

The diagnosis of Pneumocystis carinii pneumonia (PCP) rests on the isolation of this micro-organism in patients whose latest blood count, less than 2 months old, shows less than 250 CD4 lymphocytes per cubic mm and who present with signs of impaired lung function. Bronchoalveolar lavage (BAL) is the reference diagnostic method, but induced expectoration may be the initial examination, in which case BAL is performed only when the latter fails or gives negative results. Prognostic factors are those of any interstitial pneumonia plus those specific to PCP and those associated with HIV infection. It is only when no initial severity factor is present that cure can be contemplated, provided the effectiveness of treatment is evaluated daily. Cotrimoxazole is the reference drug for comparisons with all new treatments; the indications of corticosteroid therapy and the necessity of intensive care techniques are now better determined. The frequency of PCP and its mortality rate should be reduced, and one may look forward to a time when this disease will be rare and atypical, thereby raising other diagnostic and therapeutic problems.

[Pulmonary cryptococcosis during HIV infection. 15 cases]. / Cryptococcose pulmonaire au cours de l'infection à VIH. 15 observations.

We reviewed the records of 15 Human Immunodeficiency Virus (HIV) infected patients with pulmonary cryptococcosis (PC). PC was the first AIDS-defining manifestation in nine patients. HIV infection was identified simultaneously with the onset of PC in 4 patients. The CD4+ lymphocyte count was low in all cases (median, 24/m3). Chest radiography showed interstitial infiltrates in 13 instances, associated with pleural effusion in 5 cases and hilar adenopathy in 2 cases. In one case, chest-X-ray showed isolated pleural effusion and was normal in one patient. For 11 of 12 patients, bronchoalveolar lavage fluid culture was positive for Cryptococcus neoformans. Seven of 15 patients had evidence of extrapulmonary cryptococcal disease with positive cerebrospinal fluid culture. Serum cryptococcal antigen was detected in all 15 patients. Concomitant lung infection with Pneumocystis carinii was diagnosed in 4 patients. First-line regimen was fluconazole in 10 patients and amphotericin B in 4 patients. Fluconazole has been prescribed in 7 patients as a permanent suppressive therapy and should be continued indefinitely.

[Buccopharyngeal Kaposi's sarcoma in AIDS. Apropos of 51 cases]. / Le sarcome de Kaposi buccopharyngé au cours du SIDA. A propos de 51 cas.

The authors present a series of 51 cases of buccopharyngeal Kaposi's sarcoma observed in patients with AIDS. The diagnosis of Kaposi's sarcoma is generally obvious due to its appearance, its constantly violaceous colour and its site, especially palatine and velar. When Kaposi's sarcoma is the first manifestation of the disease, it appears to be associated with a relatively favourable pejorative connotation when the nevertheless extremely modest median survival of these patients is compared with that of patients who initially presented with an opportunistic infection not associated with Kaposi's sarcoma. Buccopharyngeal Kaposi's sarcoma is usually only an epiphenomenon. It is rare that the local course requires any tumour reduction treatment. When such treatment is required, radiotherapy with 35 Gys is currently considered to be the best solution.

[Acquired immunodeficiency syndrome in the adult. Its value in tropical medicine]. / Le syndrome d'immuno-dépression acquise de l'adulte. Interêt en médecine tropicale.

In the temperate climate countries, AIDS is defined as the occurrence of opportunistic infections and/or Kaposi's sarcoma in adults, mostly homosexuals. It can be preceded by a related state of asthenia, loss of weight, adenopathies, diarrhoea, but which is far from always developing into AIDS. The immune syndrome is specified by cutaneous anergy , lymphopenia with an elective decrease of OKT4. The etiology is not known and, if one often refers to retro-viruses (specific disease), the role of multiple and repeated infections ( plurifactorial syndrome) can not be discarded. Cases of AIDS exist in Haiti and possibly in Equatorial Africa, the latter may be different from the occidental cases. The planning for a survey in Africa is suggested.

[Prophylaxis and maintenance treatments of opportunistic infections in adults]. / Prophylaxies et traitements d'entretien des infections opportunistes de l'adulte.

Primary prophylaxis against opportunistic infections is a capital advance in the management of HIV-infected patients. In cases with pneumocystosis prophylaxis is recommended when the number of T4 cells reaches 200/mm3 or 15 to 20% and constitutes a major incitation to apply for detection of seropositivity. It can be predicted that other prophylaxis of this type will be available for other main opportunistic infections whose proportion is increasing due to extension of the patient's life expectation (e.g. toxoplasmosis). Research in this field relies on new drugs, on the use of older drugs, and above all on experimental models providing a good preclinical evaluation. The development of combined prophylactic treatments against several opportunistic infections is a priority target. Maintenance treatments are systematically given after a first opportunistic infection.