History Of Opportunistic Infections Research Articles

Phase III Vehicle-Controlled, Multi-Centered Study of Topical Alitretinoin Gel 0.1% in Cutaneous AIDS-Related Kaposi??s Sarcoma

This randomized, double-blind and vehicle-controlled phase III study was conducted to evaluate the efficacy and safety of alitretinoin gel 0.1% for the topical treatment of the cutaneous lesions of AIDS-related Kaposi's sarcoma (KS). Patients received treatment with alitretinoin gel (n = 62) or vehicle gel (n = 72) twice daily for 12 weeks. The primary efficacy endpoint was the cutaneous KS tumor response rate according to AIDS Clinical Trials Group (ACTG) objective criteria applied to topical therapy, with the patient as the unit of analysis. Treatment of patients with alitretinoin gel resulted in a significant antitumor effect. The overall patient response rate (complete plus partial response) was 37% (23 of 62) for the alitretinoin-treated patients and 7% (5 of 72) for the vehicle-treated patients (p = 0.00003). The difference in response rates for the 2 treatment groups remained significant even after taking into consideration numerous variables, including age (p = 0.00001), Eastern Cooperative Oncology Group (ECOG) status (p = 0.00002), CD4+ cell count (p = 0.00002), history of opportunistic infection (p = 0.00002), aggregate area of indicator lesions (p = 0.00005), number of raised indicator lesions (p = 0.00002), prior therapy for KS (p = 0.00003), and number of drugs (p = 0.00002) used in concomitant antiretroviral therapy. Generally, treatment with alitretinoin gel was well tolerated. The overall incidence of adverse events was similar for the 2 treatment groups. Adverse events related to treatment with alitretinoin gel tended to be mild to moderate in severity and limited to the site of application. The most frequent adverse event occurring at the application site following alitretinoin gel treatment was irritation coded as rash (32%). The results of this study provide convincing evidence of the superiority of alitretinoin gel over vehicle gel for the treatment of the cutaneous lesions of AIDS-related KS.

Management of AIDS-related non-Hodgkin's lymphomas.

The incidence of non-Hodgkin's lymphoma in individuals infected with HIV is approximately 60- to 100-fold increased over the general population. The majority of patients with AIDS-related lymphoma (ARL) present with stage III-IV disease and with B-symptoms. They often have multiple extranodal localisations, with a high incidence of central nervous system involvement. Histologically, most tumours are either diffuse large cell lymphomas or Burkitt lymphomas. Several factors, such as disrupted immune surveillance, Epstein-Barr virus infection, chronic antigenic stimulation, cytokine dysregulation and the acquisition of genetic lesions, are thought to contribute to the pathogenesis. Patients with ARL have a poor prognosis: overall survival ranges from 1.5 to 18 months. The most important adverse prognostic factors are poor performance status, a low CD4+ cell count and a history of opportunistic infections. Results of treatment with polychemotherapy compare unfavourably to results in patients without HIV infection. Since the advent of highly active antiretroviral therapy (HAART), there appears to be a decrease in the incidence of ARL. In addition, the use of HAART in combination with chemotherapy and the use of new treatment modalities may improve the outcome of this disease.

Dehydroepiandrosterone sulfate (DHEAS) and testosterone: relation to HIV illness stage and progression over one year.

This study explored associations between serum dehydroepiandrosterone sulfate (DHEAS), free and total testosterone levels, and HIV illness markers, including viral load, and the behavioral problems of fatigue and depressed mood. Subjects were 169 HIV-positive men evaluated at baseline, 6, and 12 months for levels of DHEAS, total and free testosterone, HIV RNA, CD4, HIV symptoms, opportunistic illnesses, fatigue, and depression. Men with AIDS (N = 105), compared with men with less advanced illness, had lower mean levels of DHEAS. Baseline DHEAS was positively correlated with CD4 count, HIV symptom severity, and was inversely correlated with HIV RNA. Baseline DHEAS below the laboratory reference range (96 microg/dl) was associated with history of opportunistic infections and malignancies (adjusted odds ratio [OR], 4.4; 95% confidence interval [CI], 1.9-10.4) and with incidence of these complications or death over 1 year (adjusted OR, 2.6; 95% CI, 1-7.2). Initiating protease inhibitor combination therapy was associated with an increase in DHEAS over 6 months. Free testosterone was inversely correlated with HIV RNA, but there were no other significant associations between testosterone and HIV illness markers. No hormone was related to fatigue or depression. This study confirms that low serum DHEAS is associated with HIV illness markers, including viral load, and carries negative prognostic value. Further, protease inhibitor therapy may result in increased circulating DHEAS.

Palliative treatment of epidemic Kaposi sarcoma of the feet.

Limited information is available in the medical literature on epidemic Kaposi sarcoma (EKS) of the foot. Patients with EKS of the foot can experience severe discomfort that makes it difficult to ambulate and even wear shoes. Between 1985 and 1996, 36 patients with EKS of the foot were treated with palliative intent. Most patients were referred for radiation therapy because of foot discomfort or marked difficulty with ambulation. From the pool of 36 patients, data were available at completion of treatment for 46 sites, and at 1 month for 44 sites. Morbidity was assessed for 35 sites. The median follow-up time for the 44 sites with at least 1 month follow-up was 8 months. The most frequently used regimen was a novel fractionation schedule of three fractions a week at 3.5 Gy/fx to a total dose of 21.0 Gy. The overall response rate and complete response rate for the 44 sites with at least 1 month follow-up were 91% and 80%, respectively. The 46 treated sites evaluated at the completion of treatment had a complete response rate of only 13% and an overall response rate of 63%. Of the 35 sites assessed for acute toxicity, 63% experienced discomfort related to the radiation therapy. This discomfort usually resolved without intervention within 2 weeks of completion of radiation therapy. For patients with and without a history of opportunistic infections, complete responses were observed in 8 of 12 sites (67%) and 25 of 27 sites (93%), respectively (p = 0.06). Radiation therapy for EKS of the foot yields excellent response rates, comparable with responses seen in other cutaneous sites with EKS. Appropriate patient education and support are needed because initial responses to radiation therapy are often disappointing and pedal discomfort can be exacerbated transiently. However, the discomfort resolves and complete response occurs in most patients. The 3.5-Gy triweekly fractionation schedule is a convenient and effective regimen and minimizes treatment visits for patients with ambulatory discomfort. A history of opportunistic infections appears to be a poor prognosticator of response to radiation treatments.

Correlation between plasma levels of cytokines and HIV-1 RNA copy number in HIV-infected patients.

The plasma levels of HIV-1 RNA, tumor necrosis factor alpha (TNF-alpha), soluble receptors type II of TNF-alpha (sTNF-alpha RII), soluble receptors of interleukin-4 (sR IL-4), interleukin-6 (IL-6), soluble receptors of interleukin-6 (sR IL-6), granulocyte macrophage colony stimulating factor (GM-CSF), soluble receptors of GM-CSF (sR GM-CSF), RANTES, MIP-1 alpha and MIP-1 beta were measured in 80 HIV-infected patients. All patients had not been treated previously with antiretroviral drugs and did not present a recent history of opportunistic infection. A statistically significant correlation was found between HIV-1 RNA and TNF-alpha (p = 0.005) or sTNF-alpha RII levels (p < 0.001). RANTES and MIP-1 alpha levels did not correlate with HIV-1 RNA. MIP-1 beta levels were correlated with plasma RNA titers in patients with CD4+ T cells < 200 x 10(6)/l (p = 0.03). MIP-1 alpha and sR IL-4 levels were significantly different according to the CD4+ T cell range (p = 0.003 and p = 0.0002, respectively). GM-CSF and sR GM-CSF were undetectable in each case. These data confirm that HIV-1 replication in the plasma is correlated with TNF-alpha levels, but do not show a clear correlation with levels of the chemokines studied.

Secondary colony formation after long-term bone marrow culture using peripheral blood and bone marrow of HIV-infected patients.

To determine if defective bone marrow function in HIV infection is associated with decreased numbers of progenitor cells or defective stromal cell function. Defective bone marrow function may in part be responsible for the cytopenias so frequently seen in patients with AIDS. Although a number of investigators have reported impaired growth of committed hematopoietic progenitor cells in HIV-1-infected patients, few studies have examined the most primitive hematopoietic stem cells. Our study was designed to determine the function and quality of the most immature hematopoietic progenitor and stem cells in the peripheral blood and bone marrow of HIV-1-infected patients and to assess stromal cell function. For quantification of these cells we used a modified long-term culture-initiating cell (LTCIC) assay in which the number of secondary colony-forming cells after 5 weeks of stromal culture served as a measure of LTCIC. Stromal cells from normal controls and HIV-1-infected patients were used for cross-matching experiments. Normal CD34+ cells or those derived from HIV-infected patients were plated and colony growth assessed. We found that HIV-1-infected patients had a mean of 0.8 secondary colony-forming cells/10(5) peripheral blood mononuclear cells (PBMC), whereas normal controls showed 1.2 secondary colony-forming cells/10(5) PBMC (P = not significant) after long-term culture. Asymptomatic patients showed well preserved numbers of secondary colony-forming cells after long-term culture of PBMC, but a significant reduction was seen in patients with a history of opportunistic infections (P < 0.01), low CD4+ cell count (< 200 x 10(6)/l; P < 0.05), or leukopenia (P < 0.05). Decreased numbers of secondary colony-forming cells have also been found in bone marrow of HIV-1-infected patients with advanced disease. When normal CD34+ cells were cultured on stromal layers from bone marrow of HIV-1-infected patients or normal controls, no differences in the numbers of surviving progenitor cells were found. Our data indicate that the hematopoietic defect in HIV-1 infection involves the most immature hematopoietic cells and becomes evident in advanced disease. Stromal function of HIV-infected patients appears normal.

Overshoot of HIV-1 viraemia after early discontinuation of antiretroviral treatment.

To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time. Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations. After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal. Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.

Role of Fas Ligand and Receptor in the Mechanism of T-Cell Depletion in Acquired Immunodeficiency Syndrome: Effect on CD4+ Lymphocyte Depletion and Human Immunodeficiency Virus Replication

AbstractDirect killing of CD4+ lymphocytes by human immunodeficiency virus-1 (HIV-1) probably cannot account for the magnitude of the loss of these cells during the course of HIV-1 infection. Experimental evidence supports a pathophysiologic role of the apoptotic process in depletion of CD4 cells in acquired immunodeficiency syndrome (AIDS). The Fas-receptor/Fas-ligand (Fas-R/Fas-L) system mediates signals for apoptosis of susceptible lymphocytes and lympoblastoid cell lines. A number of investigators have recently reported increased expression of the Fas receptor in individuals with HIV infection, along with increased sensitivity of their lymphocytes to anti-Fas antibody mimicking Fas ligand. We attempted to determine the role of Fas-mediated apoptosis in disease progression and viral replication. Increased Fas-receptor (CD95) expression on CD4+ and CD8+ lymphocytes was found in a large group of HIV-1–infected patients compared with normal controls; individuals with a diagnosis of AIDS and a history of opportunistic infection had significantly more Fas receptor expression than did asymptomatic HIV-infected persons and normal blood donor controls (P < .01). Triggering of the Fas-R by agonistic anti-Fas monoclonal antibody, CH11, was preferentially associated with apoptosis in the CD4+ cells; this effect was more pronounced in lymphocytes derived from HIV+ individuals. Soluble and membrane-bound forms of Fas-L were produced in greater amounts in peripheral blood mononuclear cells (PBMC) cultures and in plasma obtained from HIV-1–infected persons than from normal controls. Furthermore, triggering of lymphocytes from HIV-infected persons by CH11 increased levels of interleukin-1β converting enzyme (ICE), a protein associated with apoptosis. When PBMC were cultured in the presence of CH11, p24 production per number of viable cells was decreased as compared with the same PBMC without CH11 (P < .01). These findings suggest that multiple mechanisms, including increased production of Fas-L by infected PBMC, increased Fas-R expression, and induction of a protease of ICE family, may play roles in the apoptotic depletion of CD4+ cells in HIV infection.

Cytomegalovirus as a Primary Pulmonary Pathogen in AIDS

In patients with AIDS, isolation of cytomegalovirus (CMV) from respiratory secretions is common. It is often found with other pathogens, which has led to debate regarding its role as a primary pulmonary pathogen. A retrospective investigation of patients with AIDS and CMV as a sole pulmonary isolate was performed in an attempt to describe their clinical presentation and course. All patients admitted to the hospital with pneumonia and with BAL or transbronchial biopsy (TBB) specimen positive for CMV between 1991 and 1994 were identified through a review of inpatient records. Inclusion criteria included positive CMV cultures from BAL, cytomegalic inclusion bodies from BAL or TBB, and thorough documentation of the absence of other pulmonary pathogens. Nine patients met the inclusion criteria for CMV pneumonitis. Seven were male and two were female, ages 26 to 44 years, and all had a history of opportunistic infections. Typical clinical presentation was characterized by increased respiratory rate, hypoxemia, and diffuse interstitial infiltrates. The mean CD4 count was 29.6 (+/- 22) cells per cubic millimeter, mean lactate dehydrogenase level was 414 (+/- 301) IU/L, and in seven patients in whom CMV antigen was measured it was greater than 50 positive cells per 200,000 WBCs. Three untreated patients died of respiratory failure and three had autopsy confirmation of CMV pneumonia. Five patients were treated with anti-CMV therapy for at least 2 weeks, and all demonstrated improvement in symptoms, oxygen saturation, and chest radiograph. At 3 months follow-up, all five patients were asymptomatic with no pulmonary symptoms. At 6 months follow-up, three of the five patients remained asymptomatic; the other two died of other opportunistic infections. In at least these nine patients, CMV represented a primary pulmonary pathogen. Patients who were treated responded quickly and were able to be discharged home from the hospital with marked improvement in their symptoms. We recommend that clinicians consider this diagnosis in the proper setting and consider treatment with anti-CMV therapy.

Human Immunodeficiency Virus Infection: Complications and Outcome of Orthopaedic Surgery.

Orthopaedic surgeons practicing in areas with a high prevalence of human immunodeficiency virus (HIV) infection may expect that up to 7% of their patients who undergo emergent procedures and 1% to 3% of those who undergo elective surgery will be HIV-positive. Although basic science studies have demonstrated impairment of defenses to routine orthopaedic pathogens as well as to opportunistic organisms, clinical studies have shown that this impairment has not resulted in an increased incidence of postoperative infections or failure of wound healing in the asymptomatic HIV-positive patient. Even for the symptomatic patient, current medical management appears adequate to reduce the risk of early postoperative infection. The HIV-positive patient with a pros-thetic implant may be at increased risk for late hematogenous implant infection as host defenses diminish. Regular medical attention, prophylactic antibiotic therapy before dental work and invasive procedures, and early evaluation and treatment of possible infections are especially important in this setting. Decisions regarding elective surgery should be made on a risk-benefit basis. Because the risk of surgical complications increases with progression of the dis-ease, guidelines for elective surgery should include an assessment of the HIV-positive patient's immune status, including the CD4 lymphocyte count, history of opportunistic infection, serum albumin level, the presence of skin anergy, and the state of nutrition and general health.

Overview of the Management of AIDS-Related Kaposi's Sarcoma

To review the epidemiology, pathogenesis, clinical presentation, diagnosis, and staging of Kaposi's sarcoma (KS), as well as the current role of local and systemic therapies in the management of AIDS-related KS (AIDS-KS). MEDLINE and CANCERLIT searches of the English-language medical literature were conducted. Emphasis was placed on studies published since the onset of the AIDS epidemic in the early 1980s. A manual review of selected bibliographies was also completed. AIDS-KS is a disease with a heterogeneous presentation that affects approximately 20% of patients with AIDS. Although the proportion of AIDS patients developing this disease during the course of their illness is declining, the actual number of AIDS-KS cases is increasing. The etiology of AIDS-KS is not clear, but a sexually transmitted cofactor has been implicated. Recent reports demonstrate that a herpes-like virus may be responsible for the development of KS in patients with and without AIDS. Furthermore, the cellular origin of KS has not been identified and questions remain about whether KS represents a true malignancy. The system used in staging patients with AIDS-KS has changed dramatically since initial therapeutic trials were conducted; this may account for observed differences in outcome among trials. The immunologic status of patients is now included as part of the staging system, since it has prognostic significance. Since specific therapy for AIDS-KS is not curative and does not prolong survival, it should be directed at improving patient cosmesis and palliation of disease-related symptoms. Local therapy, such as radiation, cryotherapy, and intralesional chemotherapy, is recommended for the management of limited disease. Systemic interferon alfa or chemotherapy is indicated for disseminated disease. Interferon alfa is useful in patients with predominantly mucocutaneous disease and is most effective in patients with good prognostic factors, such as absence of B symptoms, no history of opportunistic infections, and a CD4 count of more than 200 cells/mm3. Interferon alfa alone or in combination with zidovudine produces responses in approximately 30% of AIDS-KS patients with good prognostic factors. Single-agent or combination chemotherapy is indicated for rapidly progressive or advanced AIDS-KS. Commonly used agents include doxorubicin, daunorubicin, bleomycin, vincristine, and vinblastine. Responses can be expected in at least 50% of patients treated with single-agent or combination chemotherapy. However, many patients are unable to tolerate the toxicity associated with systemic AIDS-KS therapy. Future research will focus on therapies that target the underlying pathogenesis of this disease. The optimal therapy for patients with AIDS-KS has not been determined. Treatment is appropriately directed at palliation of disease-related symptoms as no therapy has been unequivocally proven to impact survival. Local therapies should be used in the management of localized disease, while systemic therapy is appropriate for disseminated disease. Interferon alfa is useful in patients with primarily mucocutaneous disease or asymptomatic visceral involvement. Chemotherapy is indicated in patients who have rapidly progressive or advanced disease. Therapy must be individualized according to the patient's disease course and other patient-specific factors.

Decreased Frequency of Functional Natural Interferon-Producing Cells in Peripheral Blood of Patients with the Acquired Immune Deficiency Syndrome

Deficient in vitro production of interferon-α (IFN-α) in response to herpes simplex virus (HSV) occurs in patients infected with the human immunodeficiency virus (HIV), with the most deficient responses associated with opportunistic infections (OI). The peripheral blood mononuclear cells (PBMC) which produce IFN-α in response to HSV are light density, HLA-DR + cells lacking any unique surface markers and have been termed "natural interferon-producing cells" (NIPC). In this study, IFN-α responses were measured and the ELISpot assay was utilized to determine the frequency of NIPC in response to HSV. As expected, HIV-infected patients had depressed IFN-α production. In the ELISpot assay, healthy controls had a mean frequency of 1:703 NIPC among PBMC; each NIPC made approximately 2 international units (IU) of IFN-α. HIV-infected patients on average had fourfold less NIPC than controls and produced 1 IU IFN-α/NIPC; the plaque size for patient samples was often smaller than that for controls. NIPC frequency and IFN-α production were lowest in patients with a history of OI. In conclusion, deficient IFN-α production by AIDS patients results from reductions in both the frequency and the activity of NIPC, probably reflecting a gradual turning off of IFN-α production.

History of opportunistic infection in the immunocompromised host.

pire where it was used to describe exemption from service or duty. The earliest medical use was in the first century A.D. to describe resistance to snake bite. Before this, however, the phenomenon of immunity was well described during the golden age of Greece. The earliest and most eloquent description of immunity was written by Thucydides in History of the Peloponnesian War [1 ]. The following quote is from his account of the plague of Athens, an epidemic of unknown etiology that occurred in 430 B.C.:

Anxiety, depression and HIV related symptomatology across the spectrum of HIV disease.

Levels of anxiety and depression were assessed for 207 HIV seropositive homosexual/bisexual men (AIDS = 34, ARC = 72, asymptomatic HIV infection = 101), and 36 seronegative controls. Lymphocyte subset enumeration, history of opportunistic infections, and occurrence of HIV-related symptoms were recorded at the time of assessment. No differences between groups were found on age, educational level, state/trait anxiety or depression scores. Neither the number of symptoms reported, their duration, severity, frequency of occurrence, nor the proportion of patients who reported a specific symptom was different between the three HIV seropositive groups. Severity of anxiety and depression was related to the magnitude of symptomatology, but not associated with either degree of immunodeficiency, number of opportunistic infections or diagnostic group. Principal component analysis extracted five symptom factors (cognitive, affective, psychosocial, neurological and physical), none of which predicted state anxiety scores. However, affective and psychosocial symptom factors predicted trait anxiety and depression scores. The results indicate that ratings of anxiety and depression are independent of stage of HIV infection, may be in part mediated by constitutional and physical symptoms of HIV disease, but are primarily associated with the presence of psychological and psychosocial symptoms.

The Baron Has AIDS: A Case of Factitious Human Immunodeficiency Virus Infection and Review

A 31-year-old cachectic intravenous drug user received treatment at in- and outpatient AIDS care facilities for almost one year before the diagnosis of Munchausen syndrome was established. Cases of factitious AIDS have been reported with increasing frequency since the onset of the AIDS epidemic. Patients typically give a complex history of opportunistic infections and present with acute neurological or psychiatric complaints. Few of these patients have a history of Munchausen syndrome. Most are members of groups at high risk for human immunodeficiency virus (HIV) infection and are thus at risk for actually developing the conditions they feign. As multidisciplinary care of HIV-infected patients becomes increasingly broad-based, technical, and expensive, health care providers should be aware of the phenomenon of factitious AIDS. Judicious confirmation of medical history and HIV serologic test results should not be overlooked in clinical facilities that are oriented toward treatment of HIV-infected patients.

A Growing Spectrum of Surgical Disease in Patients With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

One hundred twenty major general surgical procedures were performed on 88 adult patients harboring the human immunodeficiency virus. Fifty-eight (48%) of the procedures were performed on patients who fulfilled the criteria for acquired immunodeficiency syndrome. The patients were predominantly male (94%). Single risk factors included homosexuality (73% of cases), intravenous drug abuse (8%), and previous blood transfusions (8%). Four patients (5%) had multiple risk factors; risk factors were denied by seven patients (8%). The mean age at surgery was 41.6 years (range, 22 to 67 years). Surgical conditions that rarely affect the population without the human immunodeficiency virus presented diagnostic challenges. Altered physiologic responses to even routine conditions were observed. Thirty-day morbidity rates for emergency (group A) and elective (group B) procedures were 19% and 9%, respectively. This included seven surgical deaths (13%) in group A and one in group B (2%). Patients undergoing 92 of 112 procedures (82%) not associated with surgical mortality were followed up. Patients who were dead at follow-up had mean procedure-survivals of 19 weeks (group A) and 21 weeks (group B) for 33 procedures. Those who remained alive had a mean procedure-survival of 86 weeks for 59 procedures. No single prognosticator could be correlated with outcome, although the combination of hypoalbuminemia with a history of opportunistic infection(s) was associated with short survival. Emergency and elective procedures can be performed in the patient with human immunodeficiency virus/acquired immunodeficiency syndrome with acceptable morbidity and mortality. Procedures are indicated to extend patient life or to improve quality of life.

Interferon-??2a in the Treatment of Acquired Immunodeficiency Syndrome-Related Kaposi??s Sarcoma

In a series of studies, recombinant interferon-alpha 2a (rIFN alpha 2a, Roferon-A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Patients were treated with daily doses of rIFN alpha 2a ranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFN alpha 2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.

Bronchoalveolar Lavage Findings in Patients Seropositive for the Human Immunodeficiency Virus (HIV)

To evaluate bronchoalveolar lavage (BAL) findings in patients infected with human immunodeficiency virus (HIV), 39 patients seropositive for the virus but with no history of opportunistic infection were studied. Opportunistic organisms such as Pneumocystis carinii were not found in any of the 35 BAL fluids sent for special stains and cultures. Three of 16 (18 percent) BAL fluids sent for HIV culture were positive compared with a 60.9 percent blood HIV culture positivity in the same group. To evaluate cellular recovery, the patients were divided into Walter Reed (WR) groups 1 and 2 (blood CD4 greater than or equal to 400/cu mm) and WR3 to WR5 (blood CD4 less than 400/cu mm). Compared with ten nonsmoking healthy controls, the WR1 and WR2 group had a greater overall cellular recovery but this was not statistically significant when the smokers were excluded. There was no difference in macrophage or lymphocyte percentages in either patient group compared with controls. T-cell subset analysis of a small group of WR1 to WR5 patient BAL fluids revealed no difference in CD4 numbers or the CD4/CD8 rate between WR1 and WR2 and WR3 to WR5 patients. We conclude that opportunistic pulmonary infection is unlikely in HIV-seropositive patients with normal chest roentgenograms despite symptoms of dyspnea on exertion. Also, HIV can be isolated from BAL fluid from these patients although not as often as from blood. Finally, there appears to be no distinct progression in BAL cellular findings before the onset of acquired immunodeficiency syndrome.

Recombinant human gamma interferon enhances in vitro activation of lymphocytes isolated from patients with acquired immunodeficiency syndrome

Decreased responses to antigens and lectins are a characteristic feature of peripheral blood lymphocytes isolated from patients with the acquired immunodeficiency syndrome (AIDS). The in vitro addition of recombinant gamma interferon (IFN-gamma) to cultures of peripheral blood lymphocytes obtained from patients with AIDS resulted in an augmented proliferative response [( 3H]thymidine uptake) to phytohemagglutinin (PHA) and an enrichment in CD4+ and CD8+ T lymphocytes. In AIDS cultures stimulated with PHA, IFN-gamma increased the release of T-cell growth factors and enhanced the expression of interleukin-2 receptors on activated lymphocytes. Responsiveness to PHA was augmented, albeit to a lesser extent, by IFN-gamma in cultures derived from normal donors. Proliferation to microbial antigens including herpes simplex virus, cytomegalo virus, and Candida albicans was increased by IFN-gamma in cultures established from a group of AIDS patients with Kaposi's sarcoma who had no history of opportunistic infection.

High levels of oral yeasts in early HIV-1 infection.

Ten human immunodeficiency virus-1 (HIV-1) infected homosexual or bisexual individuals (ages 24-45) with no history of opportunistic infection were examined, by culture, for the presence of yeasts in whole saliva and on oral mucosa. All were HIV-1 antibody-positive men, non-smokers, non-denture wearers, and taking no medication. The mean salivary level of yeast was four logs higher in the HIV-1 infected group compared to a control group of normal, unmedicated, non-smoking men (ages 20-41) who denied any risk behavior for HIV-1 infection. Identification of the yeast in these HIV-1 positive individuals established that Candida albicans was the predominant species found in whole saliva and on buccal mucosa and tongue. Distinct hyphae were observed with only one mucosal sample. No significant correlation was found between whole saliva yeast concentration and the T4/T8 lymphocyte ratios or absolute number of T4 cells. No correlation was observed between oral yeast concentration and anti-C. albicans IgA titers. The high level of oral yeast in these individuals prior to the development of opportunistic infections is consistent with the suggestion that oral defense mechanisms are compromised in individuals following HIV-1 infection.