The changing face of HIV/AIDS in treated patients.

The spectrum of complications emerging in successfully treated HIV-infected patients has dramatically changed since the advent of HAART. Typical AIDS-defining illnesses have been substituted by new comorbid conditions that threaten even those patients who maintain virologic suppression. Proper management of cardiovascular risk, and early diagnosis of AIDS-related and, particularly, non-AIDS-related malignancies (including papilomavirus-related neoplasms) must be introduced into the routine of care. Hot areas of investigation include HIV-associated neurocognitive disorders, hepatitis B and C coinfection, non-alcoholic fatty liver disease, progressive multifocal leukoencephalopathy and tuberculosis. Bone and kidney long-term toxicities and lipoatrophy remain as issues of paramount importance. The identification and early treatment of immune reconstitution disease is also of major interest, specially in those patients starting their antiretroviral treatment with severe CD4 cell depletion. The present review focuses on these twelve areas of increasing interest for physicians currently facing successfully treated HIV+ patients.

Passive immunotherapy in advanced HIV infection and therapeutic plasmapheresis in asymptomatic HIV-positive individuals: a four-year clinical experience.

We have been treating patients with advanced HIV disease using passive immunotherapy (PIT). Earlier studies of PIT which have been published concerned relatively short periods of treatment: our study is by far the longest and reports also on the long-term effects of plasmapheresis on healthy HIV-infected individuals. Fifty-nine patients with an average CD4+ T-cell count of 55 per cu.mm. at baseline were transfused at monthly intervals with 500 ml of hyperimmune plasma. No disease progression or death occurred among the 8 asymptomatic patients under the treatment, which lasted for 36.25 months on average. Seven of the 15 ARC patients progressed to AIDS but none died in an average period of 25.9 months. Seven of the 36 symptomatic AIDS patients with advanced disease died in an average period of 19.6 months. PIT appears to be nontoxic and to have beneficial effects lasting at least four years under continuous treatment. It probably delays disease progression in ARC and AIDS patients, and almost certainly does so in asymptomatic late HIV infection with a very low CD4+ T-cell count. None of the 51 donors suffered adverse effects, nor did any progress to ARC or AIDS in an average period of 30.1 months. Their laboratory parameters indicated a nearly stable condition: in particular, their average CD4+ T-cell count rose from 478 to 498. The study of our plasma donors indicated that repeated and frequent plasma donation by asymptomatic HIV-infected individuals could delay disease progression, although further studies are needed to investigate this.

Concurrent Sweet's syndrome and Löfgren's syndrome.

Concurrent Sweet's syndrome and acute sarcoidosis (Löfgren's syndrome) has been reported in 4 cases. We describe a 40-year-old woman with biopsy confirmed lesions of Sweet's syndrome and erythema nodosum together with arthritis and hilar and mediastinal adenopathy. We review the association of Sweet's syndrome and malignancy or hematologic disorders, and the need to exclude malignancy when hilar adenopathy is found. Aggressive diagnostic procedures can be avoided with prompt recognition of Löfgren's syndrome.

A study of the reliability, validity and responsiveness of the HIV overview of problems evaluation system (HOPES) in assessing the quality of life of patients with AIDS and symptomatic HIV infection.

The objective of this study was to evaluate the feasibility, reliability, validity and responsiveness of the HIV Overview of Problems Evaluation System (HOPES) in a Dutch sample. The HOPES was administered three times in a one-year period to a sample of 106 outpatients with a symptomatic HIV-infection (n = 23) or AIDS (n = 83). The HOPES is a self-report HIV-specific quality of life (QOL) questionnaire including five scales: physical, psycho-social and sexual functioning, medical interaction and partner relationship. QOL was also assessed with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), a 30-item self-report instrument. Clinical data included Centers for Disease Control and Prevention (CDC) stage, date of diagnosis and CD4 cell count. Patients needed approximately 20-30 minutes to complete the questionnaire. The five scales had good internal consistency reliability. Multitrait scaling analysis provided moderate support for item discriminant and convergent validity. The HOPES exhibited adequate levels of construct validity: (1) the inter-scale correlations and correlations with the EORTC QLQ-C30 were in the predicted direction; (2) it discriminated clearly between patients with AIDS and ARC and (3) it was able to document changes in QOL over time. Moreover, the HOPES was responsive to changes in clinical status over time as indicated by CD4 counts. This study provides further evidence of the reliability and validity of the HOPES and shows that this instrument is responsive to changes in CD4 cell counts.

Preliminary results in HIV-1-infected patients treated with transfer factor (TF) and zidovudine (ZDV).

The efficiency of HIV-1 specific transfer factor (TF) administration, combined with Zidovudine (ZDV), in asymptomatic persistent generalised lymphadenopaty, or AIDS related complex (ARC) patients was evaluated. Twenty patients were randomly assigned to receive only ZDV (1st group) or ZDV together with HIV-1-specific TF (2nd group). HIV-1-specific TF was administered orally at 2 x 10(7) cell equivalent daily for 15 days, and thereafter once a week for up to 6 months. There were no significant differences between the two groups in clinical evolution, red blood cells, haemoglobin, lymphocytes, CD20 subset, transaminases, beta-2-microglobulin, p24 antigen. White blood cells, CD8 lymphocytes as well as IL-2 levels increased in the second group, while the CD4 subset increased in the first group. The combination treatment with ZDV and TF appeared to be safe and well tolerated. Furthermore, levels of serum cytokines were investigated in 10 patients (8 asymptomatic and 2 ARC) treated with ZDV, and compared with 5 patients of the 2nd group (3 asymptomatic and 2 ARC) treated with ZDV plus HIV-1-specific TF. Peripheral lymphocytes, CD4, CD8 subsets, IL-2, TNF alpha, IL-6, p24 antigen, IL-2 soluble lymphocyte receptors (sR), CD4sR, CD8sR and beta-2-microglobulin were evaluated at the baseline and at the 3rd month. The CD4 subset was not significantly different in the two groups, whilst IL-2 increased in the 2nd group receiving ZDV plus TF, suggesting an activation of the Th1 secretion pattern.

Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex.

To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

[HIV infection in servicemen (the work experience of a specialized hospital department)]. / VICh-infektsiia u voennosluzhashchikh (po opytu raboty spetsializirovannogo otdeleniia gospitalia).

PIP: In 1987, under the aegis of the governmental campaign against AIDS, military hospitals in Moscow established a department for the diagnosis and treatment of HIV-infected and AIDS patients among the military and their families. Clinical and laboratory examinations showed that 96 people out of 130 examined either were positive for HIV or were suffering from symptoms of AIDS. 77 were military from African countries, 15 from Russia, and 4 were their family members. Out of these 15 patients from Russia, 8 had been infected via sexual intercourse: 1 via homosexual and 7 via heterosexual intercourse. In 10 patients, HIV infection had been diagnosed 1-2 years after being infected, in 3 patients 3-6 years later, and in 2 patients more than 10 years afterwards. Every other patient exhibited symptoms of the second stage of AIDS: persistent generalized lymphadenopathy. 4 patients had lost body weight, 8 patients had prolonged fever, 2 had diarrhea, 4 had various dermatological symptoms, 4 had opportunistic infections, 5 had other infections (viral hepatitis, acute pneumonia, and salmonella), and 3 patients had other ailments (paranephritis, salpingoophoritis, endometritis, purulent otitis). The cases of 3 patients are described in detail. 4 out of 5 patients who were transferred to this special department demonstrated severe inflammatory processes as a consequence of their HIV-infection: paranephritis, pneumonia, purulent cholangitis, and salmonella. All patients also evinced damage to their immune system: the reduction of T-lymphocyte count and T-helper cells and the reduction of the index of T-helper/T-suppressor cells (to 0.31 from the norm of 1.1-2.2). The treatment of AIDS patients consisted of the use of azidothimidine, which inhibits the activity of reverse transcriptase; the stimulation of the immune system by means of timalin (10 mg for 5 days im); and treating secondary fungal infections (up to 8 million IU of nystatin/day, up to 4 million IU of levorin, and up to 200 mg of diflucan).^ieng

Predictive ability of acute physiology and chronic health evaluation II scoring applied to human immunodeficiency virus-positive patients.

OBJECTIVE: To evaluate the predictive ability of the Acute Physiology and Chronic Health Evaluation II (APACHE II) prognostic scoring system when applied to human immunodeficiency virus (HIV) seropositive patients in the medical intensive care unit (ICU). DESIGN: A retrospective chart review. SETTING: An urban university hospital serving the local community population and also functioning as a tertiary care referral center. PATIENTS: All HIV-positive patients who were discharged from the Yale-New Haven Hospital medical ICU between October 1, 1986 and September 30, 1991. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: APACHE II scoring significantly underestimated the mortality rate in our patient population (n = 161) (35.5% estimated vs. 44.1% observed, p < .025). When patients were evaluated according to total lymphocyte count, APACHE II scores accurately predicted the mortality rate of all patients with a total lymphocyte count of > or = 201 cells/mm3 (n = 112) (32.6% estimated vs. 33.0% observed). However, APACHE II scoring significantly underestimated the mortality rate in the group of patients with a total lymphocyte count of < or = 200 cells/mm3 (n = 36) (44.2% expected vs. 61.1% observed, p < .05), particularly those patients with pneumonia or sepsis (n = 14) (50.5% expected vs. 85.7% observed, p < .01). CONCLUSION: APACHE II scoring significantly underestimates mortality risk in HIV-positive patients admitted to the medical ICU with a total lymphocyte count of < or = 200 cells/mm3. This finding is particularly true regarding patients admitted due to pneumonia or sepsis.

[In vitro synergic lymphocyte stimulation in HIV-1 infected patients using inosine derivatives and radio-detoxified endotoxin]. / HIV-1 fertözöttek lymphocytáinak in vitro együttes serkenthetösége inozin származékokkal és sugárdetoxikált endotoxinnal.

Restoration of immune functions through promoting cell cycle might delay acquired immunodeficiency syndrome development. Therefore, stimulation of peripheral lymphocytes of human immunodeficiency virus-1 infected patients in successive clinical stages was studied by phytohaemagglutinin and other stimulants. In vitro blastogenesis was quantitated by 3H-thymidine uptake. Stimulation by phytohaemagglutinin decreased in patients with AIDS related complex to 63.1%, with AIDS to 13.6% of control values. Small amount of recombinant interleukin-2 or indomethacin solely not promoting lymphocytes, increased response to phytohaemagglutinin minimally. Alone ineffective methyl-ester and methyl-phosphonate inosine derivatives augmented phytohaemagglutinin-response of controls and patients with AIDS related complex by approx. 1.5-fold, but the effect in the case of AIDS patients was minimal. Radio-detoxified endotoxin alone or in combination with phytohaemagglutinin stimulated lymphocytes of both controls and patients with AIDS related complex slightly. Lymphocyte stimulation of patients with AIDS related complex was augmented in concentration-dependent manner, and by synergic effect it approached phytohaemagglutinin-stimulated blastogenesis of controls. Anergy due to human immunodeficiency virus-1 infection damages synchronisation of secondary messenger systems induced on cell surface receptors, therefore their selective influence by recombinant interleukin-2 or indomethacin is less efficient. Inosine derivatives promote cell cycle by inhibiting cyclic adenosine 3',5'-monophosphate production. In the early stage of virus infection, radio-detoxified endotoxin might bind to receptors of immature T cells and facilitate cell cycle through cyclic guanosine 3',5'-monophosphate stimulation. The clinical trials of radio-detoxified endotoxin (Tolerin) have already been launched.

Whole body hyperthermia associated with beta-carotene supplementation in patients with AIDS.

The objective of this work was to check possible additive beneficial effects of whole body hyperthermia (WBH) associated with beta-carotene (BC) supplementation in patients with AIDS. In a pilot study, 10 HIV positive patients, (8 with AIDS and 2 with AIDS related complex, ARC), after AZT or DDI discontinuation, were first treated with one single session of WBH applied with a non-invasive procedure at 42 degrees C core temperature for one hour, and subsequently supplemented with BC 120 mg daily continuously. All patients well tolerated the non-invasive WBH as well as the high dose BC supplementation. Apart from one patient who died after 4 months, all the others underwent an HIV burden diminution, clinical improvement and amelioration of laboratory data, along with an subjective improvement of their life quality. With reference to control groups, namely (a) only WBH applied with extracorporeal procedure to 31 AIDS patients, and (b) only BC supplementation at high dosage applied to 64 ARC patients, the combined physical and BC supplemental treatments clearly showed a better and longer lasting response.

[The in vitro potentiation of LAK cell cytotoxicity in cancer and aids patients induced by F3--a fractionated extract of Astragalus membranaceus].

The in vitro induction of LAK cell activity was studied in cancer and AIDS patients. F3, an immuno-regulatory component of Astragalus membranaceus was shown capable of potentiating the LAK cell inducing activity of rIL-2. The killing activity against Hs294T melanoma cell line of LAK cells induced by 50 U/ml rIL-2 in the presence of F3 (55 micrograms/ml) reached 64% which was comparable to that (60%) induced by 500 u/ml of rIL-2 alone. With F3 plus rIL-2, the effector to target cell ratio could be reduced to one-half in order to obtain an equivalent level of cytotoxicity when rIL-2 was used alone. In some patients, whose peripheral blood lymphocytes were relatively inert to rIL-2, F3 could make them responsive to rIL-2. These results imply that F3 may be useful to potentiate LAK cell activity, reduce the amount of rIL-2 and thus minimize the later's toxic side effects when used in vivo.

[Intravenous immunoglobulin substitution in patients with ARC and AIDS (WR 3-6)]. / Intravenöse Immunglobulinsubstitution bei Patienten mit ARC und AIDS (WR 3-6).

HIV-infected patients acquire a profound dysfunction in humoral and cellular immunity. This immunological impairment causes a markedly increased incidence of recurrent infections. While effective prophylaxis of Pneumocystis carinii pneumonia is available, infections with other microorganisms still cause a high rate of morbidity and mortality. Preliminary results of our randomized outpatient trial to evaluate the efficacy of intravenous immunoglobulin (IVIG) in adults demonstrate that IVIG reduces the episodes of fever, diarrhea, and the duration of hospitalization. We also found a significant reduction of mortality due to infection.

Phase I/II vaccination study of recombinant peptide F46 corresponding to the HIV-1 transmembrane protein coupled with 2.4 dinitrophenyl (DNP) Ficoll.

In order to evaluate tolerance, toxicity, and in vivo antigenicity, 29 HIV-1-infected patients (eight with ARC and 21 with AIDS) were vaccinated with a synthetic peptide derived from the gp41 transmembrane protein of the HIV-1. This peptide had been coupled with 2.4 dinitrophenyl-Ficoll (F46), a T-cell independent adjuvant. The patients received a single intradeltoid injection of either 0.1 or 0.3 mg of F46. Five of the individuals with AIDS were boostered, four of them twice. Anti-F46 antibody titers were measured before vaccination, and on days 7, 14, 21, 28, 90, 180 and 270 after vaccination. Anti-F46 titers rose at least twofold over prestudy values in 10/21 individuals with AIDS and in 1/8 individuals with ARC at least once during the observation period. The overall response, however, consisted of only weak antibody production that was independent of the dose or patient characteristics. No signs of toxicity or of clinical progression related to the vaccination were observed in this phase I/II trial of a T-cell independent therapeutic vaccine.

Care requirements of people with ARC/AIDS in Rome: non-hospital services.

In Italy, care for people with AIDS (PWA) is centred on hospital services. However, other services are beginning to develop, both in the form of residential facilities and of home care. It seems, therefore, important to define the type of non-hospital services that should be supplied on the basis of AIDS patients' real needs. The aim of this paper is to contribute to the definition of care requirements by administration to 92 persons with ARC/AIDS of a questionnaire on Functional Multidimensional Evaluation to assess the demand for services in relation to the state of health and socio-economic situation of those interviewed. The pattern that emerged was one of severe socio-economic difficulties (most of the patients were drug addicts) and of major functional impairment (about 60% of those interviewed were not self-sufficient as far as Instrumental Activities of Daily Living were concerned). Among the main problems: difficulties of finding accommodation (almost 9% of those interviewed have no fixed abode) and economic difficulties; the demand for services was characterized by a lack of self-sufficiency. The most frequently required social services were help with preparation of meals, household chores and assistance with transport; the most frequently required health service was physiotherapy, which is also the least available. The study supplies useful information for the planning of non-hospital services in Italy and in other western countries with similar epidemiological situations.

Effects of adoptive immunotherapy with autologous CD8+ T lymphocytes on immunologic parameters: lymphocyte subsets and cytotoxic activity.

CD8+ cytotoxic T lymphocytes (CTL) may be an important parameter of host resistance to HIV infection. The present study determined whether CD8+ cells could be purified and propagated in vitro to enhance anti-HIV CTL activity, and the immunologic effects of infusion of these cells into autologous, HIV-infected patients as a potential immunotherapy for AIDS and AIDS-related complex (ARC). CD8+ lymphocytes from five AIDS and ARC patients were purified from leukapheresis preparations in cell culture flasks coated with CD8-specific monoclonal antibodies and propagated in vitro for 3 weeks. The ex vivo propagated cells were 98% (+/- 1%) CD8+ and 43% (+/- 6%) HLA-DR+. The majority of the CD8+ cell preparations had increased lytic activity against autologous B lymphoblastoid cells infected with vaccinia virus vectors expressing HIV-IIIb structural proteins gag, pol, or env, relative to that of fresh blood mononuclear cells tested prior to purification and culture. The results also show for the first time that CD8+ CTL from HIV-infected patients can lyse cells expressing the HIV regulatory protein, tat. Enhanced expression of CD56 (natural killer cell marker) and lytic activity against vaccinia virus control vector-infected, autologous targets were also noted in the CD8+ cell preparations. Infusion of the CD8+ CTL into autologous patients was well-tolerated and resulted in low but discernible, temporal increases in circulating cytotoxic activity against the HIV gene-expressing targets.

Splenectomy in patients with AIDS and AIDS-related complex.

OBJECTIVE: To study the effect of splenectomy in HIV-infected patients. DESIGN: A retrospective chart review of patients admitted to St Vincent's Hospital who had splenectomies and were HIV-positive. SETTING: All patients were treated at St Vincent's Hospital, New York City, New York, USA. PATIENTS: Only patients who were HIV-positive and who had had a splenectomy at St Vincent's Hospital were included. INTERVENTION: All patients had a splenectomy. MAIN OUTCOME MEASURES: The effect of the splenectomy in these HIV-positive patients was studied with respect to their operative morbidity and mortality, platelet counts, overall survival and the development of new opportunistic infections. RESULTS: All patients who did not have AIDS but did have thrombocytopenia responded to splenectomy in terms of their thrombocytopenia. None of them had an accelerated progression to AIDS. Most patients with AIDS and thrombocytopenia responded to splenectomy in terms of correcting their thrombocytopenia. CONCLUSIONS: Splenectomy as a treatment for thrombocytopenia is successful not only in HIV-positive patients without AIDS, but also in AIDS patients. However, in patients with disseminated Kaposi's sarcoma or Mycobacterium avium intracellulare, splenectomy may not be a factor for survival.

Generation and characterization of ex vivo propagated autologous CD8+ cells used for adoptive immunotherapy of patients infected with human immunodeficiency virus.

Cytolytic T lymphocytes play an important role in host defense against viral infections, including human immunodeficiency virus (HIV). In a phase I clinical trial (protocol 080 of the AIDS Clinical Trials Group), generation of CD8+ effector cells from peripheral blood of patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS and safety of autologous adoptive transfer of these cells were evaluated. For therapeutic infusions, CD8+ T cells were purified by positive selection on anti-CD8 monoclonal antibody-coated flasks from leukapheresed peripheral blood of seven patients. These CD8+ T cells were cultured in the presence of interleukin-2 and phytohemagglutinin for up to 3 weeks to obtain cells sufficient for therapeutic infusions (10(8) to 10(10)). All 31 cell cultures established from the seven patients and used for therapy were highly enriched in CD8+ (mean, 97%), CD8+HLA-DR+ (50%), cytotoxic CD8+CD11b- (82%), and memory CD29+ (78%) T lymphocytes. In vitro expanded CD8+ cells had excellent cytotoxic function at the time they were used for therapy, including HIV-specific activity against autologous targets infected with vaccinia vectors expressing HIV-IIIb antigens, gag, pol, and env. Anti-HIV activity of cultured CD8+ cells was significantly higher than that of autologous fresh peripheral blood lymphocytes. Our results show that CD8+ T lymphocytes obtained from peripheral blood of symptomatic HIV-infected patients can be purified, cultured to obtain large numbers of cells with enhanced anti-HIV activity, and safely infused into patients with AIDS as a form of immunotherapy.