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.

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.

[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.

[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.

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.

A phase 1 study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS.

Based on preclinical studies showing that CD8+ T lymphocytes of human immunodeficiency syndrome (HIV)-infected subjects have anti-HIV activities, a phase 1 study was undertaken to determine the safety and feasibility of infusing in vitro purified, activated, and expanded CD8+ cells as a therapeutic measure in seven patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS. Autologous CD8+ cells were first selectively isolated in monoclonal antibody-coated flasks from peripheral blood mononuclear cells recovered by leukapheresis. They were then cultured and expanded with phytohemagglutinin and recombinant interleukin-2 (rIL-2) before infusion. Five cycles of isolations and infusions of increasing numbers of CD8+ T cells were achieved in five of seven subjects. Five cycles could not be completed in two subjects with AIDS whose CD4+ cell counts were < or = 48/microliters. Infusions of CD8+ cells alone were well tolerated. Four patients received rIL-2 by continuous infusion for 5 days with their final cycle of CD8+ cells. All developed reversible adverse effects attributable to rIL-2. After infusion, 111In-labeled CD8+ cells quickly accumulated in the lungs, with less than 10% of the labeled cells remaining in the circulation. After 24 hours, labeled CD8+ cells were reduced in the lungs, but increased and persisted in liver, spleen, and bone marrow. Four of five patients who were treated with multiple infusions of CD8+ cells have improved or remained clinically stable, and the fifth developed Pneumocystis carinii pneumonia but recovered. This study demonstrated that infusion of autologous, in vitro expanded and activated CD8+ cells was feasible and clinically well tolerated in five of seven subjects with advanced HIV infections.

AIDS-related complex treated by antiviral drugs and allogeneic bone marrow transplantation following conditioning protocol with busulphan, cyclophosphamide and cyclosporin.

A 26-year-old man with AIDS-related complex (ARC) was treated with high-dose busulphan and cyclophosphamide, followed by allogeneic bone marrow transplantation. For 3 months before transplantation he received a combination of four drugs considered active against human immunodeficiency virus (HIV) to reduce the viral burden: zidovudine, acyloguanosine, fusidic acid and phenylidantoin. Although in reduced doses in coincidence with marrow engraftment, zidovudine therapy was scheduled after transplantation in order to protect donor cells from infection with HIV. Engraftment rapidly occurred and was documented by cytogenetic analyses. The post-transplant course was characterized by severe acute GvHD with irreversible hepatorenal failure. The patient died on day 48 after transplantation. Polymerase chain reaction analyses for detecting HIV DNA showed the persistence of positivity at day +30 and +45 after transplantation. Antibodies to specific HIV proteins evaluated with Western blot testing also persisted at days +21 and +35 after transplantation. Circulating immunocomplexes disappeared on day +31, and an increase in the CD4/CD8 ratio occurred. The short survival of the patient, affected by chronic hepatitis too, does not allow final conclusions about the role of BMT in HIV disease.

Value of lymph node biopsy in the treatment of patients with the human immunodeficiency virus.

The indications and value of lymph node biopsy in patients infected with the human immunodeficiency virus (HIV) are not clearly defined. We reviewed 29 consecutive lymph node biopsies performed on 24 patients with the HIV over a 4-year period. Indications for biopsy included: (1) new or worsening medical symptoms with no detectable etiology in patients with lymphadenopathy, (2) disproportionately larger or enlarging lymph node in patients with generalized adenopathy, and (3) exclusion of concomitant disease in patients with previously defined infectious or neoplastic processes. The biopsy samples exhibited a diversity of histologic appearances including atypical and reactive hyperplasia, malignancy, and infection. Nineteen biopsies (64%) resulted in the institution or alteration of treatment. The absolute number of T-helper cells prior to biopsy was significantly lower in patients with a diagnosis of malignancy or infection (p < 0.05), as well as in those who eventually died (p < 0.05). Four (14%) minor complications resulted from lymph node biopsy. Based on our results, we conclude that lymph node biopsy is indicated in the above three subsets of HIV-infected patients. Biopsy can be performed with minimal morbidity and significantly alters therapy in the majority of patients.

Viral-specific immunization in AIDS-related complex by photopheresis.

The potential for therapeutic intervention in 7 patients with AIDS-related complex (ARC) was evaluated through the use of photopheresis. The rationale for the study was based on: 1. the demonstration that psoralen and UVA could inactivate HIV/virus in vitro; 2. CD4 cells are the primary target population effected by HIV and photopheresis; and 3. reinfusion of inactivated virus and cell-associated virus might serve to engender an immune response. Preliminary results in 7 patients with ARC over 6 to 18 months revealed a virus-specific response with an elevation of HIV antibodies, while EBV and CMV titers remained unchanged. The immunologic results revealed an increase in the CD8 lymphocyte population, stable activation markers (B2 microglobulin neopterin), a decrease in p24 antigen titers and inability to culture HIV virus in 3 patients. All of these results were in the context of a stable or increasing CD4+ percent. Six patients did not reveal a generalized inhibition of other immune responses as demonstrated by recovery of DTH. In addition, the resolution of lymphadenopathy, night sweats, fever and weight loss, paralleled the immunologic response.

Major salivary gland lymphoepithelial lesions and the acquired immunodeficiency syndrome.

Presently, there is no consensus regarding the most appropriate diagnostic and therapeutic approach to patients with human immunodeficiency virus (HIV)-associated lymphoepithelial lesions of the major salivary glands. A retrospective review of 60 consecutive patients with lymphoepithelial lesions is presented. Thirty-eight cases were associated with HIV infection. Lesions associated with HIV infection were usually bilateral, multiple, cystic, and associated with lymphadenopathy. In contrast, in those cases without HIV infection, the lesions tended to be solitary and solid. In the HIV-infected group, treatment included surgery, radiotherapy, zidovudine (AZT), and/or cyst aspiration. All therapeutic regimens, other than aspiration alone, were found to be effective. Eighteen of the patients with HIV infection developed the acquired immunodeficiency syndrome (AIDS) during the study period. Surgical treatment is probably not necessary in the majority of HIV-associated cases. Depending upon individual circumstances, treatment with AZT or low-dose radiotherapy is recommended. A diagnostic and therapeutic algorithm is presented as a guide to the management of future cases.

Recombinant alpha-2a interferon treatment in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC): clinical and immunological evaluation.

We evaluated clinical efficacy and tolerability of recombinant alpha 2a interferon (IFN), in a group of 16 patients with AIDS and ARC, including 3 children. All patients were followed up monthly for clinical and immunological studies. The frequency of oportunistic infections (OI) in AIDS, and the following symptoms in all patients were studied: fever, night sweats, fatigue, diarrhoea, weight loss. Immunological parameters (CD3+, CD4+, CD8+ lymphocytes, skin tests to recall antigens, NK activity, lymphoproliferative response to PHA) were also evaluated. Adult patients were treated with 3-6 million IU of r-alpha 2a IFN daily im for 3 months and the 3 times weekly up to 12 months. Pediatric cases were treated with lower doses of 0.5-1.5 million IU using the same time schedule. We observed clinical improvement and reduction of severe infections in 10/15 evaluable patients (4/4 ARC and 6/11 AIDS). Immunological parameters were transiently improved in one third of cases. We observed only mild side effects in r-alpha IFN treatment. We suggest therapy with r-alpha 2a IFN at low dosage should be tried in patients with AIDS for its beneficial effects on OI development.

Clinical benefits and recovery of delayed-type hypersensitivity in patients with AIDS-related complex treated with IMREG-1 or placebo.

IMREG-1, an immunomodulatory biological therapeutic, was studied in a placebo-controlled, double-blind, six-month trial in 45 anergic patients with AIDS-related complex (ARC) and 4 with Kaposi's sarcoma, which was followed by compassionate IMREG-1 administration to all subjects. The IMREG-1 group had significantly less AIDS-defining events compared with the placebo group during the randomized trial (6.9 events per 100 person-years vs 43.7 events per 100 person-years, P = 0.018, relative risk 6.33) and the total observation period. Patients receiving IMREG-1 significantly improved their work performance. Nine (41%) of 22 patients in the IMREG-1 group, compared with one (14%) of seven in the placebo group, recovered cutaneous reactivity to tetanus toxoid. At the end of the six-month trial, CD4+ counts were 0.429 x 10(9)/l in the IMREG-1 group and 0.304 x 10(9)/l in the placebo group (P = 0.04). IMREG-1 is a promising therapeutic for HIV-infected patients with symptoms of ARC.

Red cell transfusion therapy for anemia in patients with AIDS and ARC: incidence, associated factors, and outcome.

The records of the San Francisco General Hospital (SFGH) Blood Bank were reviewed, and 263 likely AIDS and AIDS-related complex (ARC) patients were identified, who received 1545 units of packed red cells (PBRCs) between July 1, 1987, and June 30, 1988. A probability sample of 80 of these patients was selected randomly for detailed chart review. Of this sample, 78 (98%) were confirmed to have AIDS (86%) or ARC (14%). On the basis of the yearly census of the SFGH AIDS clinic, a transfusion incidence of 0.89 PRBC units per patient per year for patients with AIDS and 0.27 PRBC units per patient per year for those with ARC was estimated. Whereas 26 percent of the 177 transfusions studied in detail involved more than one associated (possibly causative) factor, antimicrobial drug therapy, zidovudine therapy, and disseminated Mycobacterium avium complex (MAC) infection were the sole associated factors in 20, 14, and 12 percent of the transfusions, respectively. To assess the role of MAC, the 263 transfused patients were compared with the 574 patients whose blood was submitted to the SFGH Mycobacteriology Laboratory during the same period. Patients whose blood yielded MAC had a relative risk of 5.2 for transfusion-requiring anemia. In 80 percent of cases, the patient returned home after transfusion. Most PRBC transfusions administered to AIDS or ARC patients were optimal therapy.

Major histocompatibility complex class I to III allotypes in patients with AIDS-related complex/Walter-Reed 5, disseminated Kaposi's sarcoma and in normal controls. The ARC-IVIG Study Group.

In HIV-infected patients major histocompatibility complex (MHC) class I and II (= HLA-A, B, C, DR) association has been controversial. Of the MHC class III coded complement components C2, BF, C4A/C4B especially C4 allotypes appear of major immunogenetic relevance for their potential differences in virus neutralizing potency and immune complex formation. In the present study 29 patients with AIDS-related complex and Walter-Reed 5 ARC/WR5), 35 patients with disseminated Kaposi's sarcoma (KS), and 160 HIV-negative control individuals were compared for MHC class I to III allotypes. Diagnosis of ARC and KS (WR criteria) was done by clinical and laboratory parameters, MHC testing, by standard procedures. An increase in frequency (p less than or equal to 0.05) was observed between ARC/WR5 patients and controls for HLA-B35/CW4, DRW14, a decrease for B16, CW6/DR7. However, values were not significant if corrected for the number of tested antigens. No significant differences were seen between KS and ARC patients or controls for class III allotypes, nor for previously reported associations, e.g. for B8, DR2, DR3, and especially DR5, including the DR5 splits DRW11, 12. The results indicate the lack of a strong MHC association with the investigated antigens in West German Caucasoids, and support the hypothesis of ethnic dependence of HIV-related diseases. The HLA-B35/CW4 increase, also associated with the duplicated C4 A*3 A*2 and the silent C4B*Q0, was more pronounced in ARC patients with progression to AIDS-OI. The increased frequency of C4B*Q0 alleles in these patients was thought to be secondary to a hypothetical increase in 'converted' and dysregulated C4 genes not seen to be associated in this study.