HIV viral load markers in clinical practice.

Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?

Mortality associated with mode of presentation in the acquired immune deficiency syndrome.

A population-based survival study was done for all cases of the acquired immune deficiency syndrome diagnosed in the city of San Francisco through May 1983. Follow-up was obtained for 165 of 173 diagnosed cases. Median survival among 75 patients presenting with Kaposi's sarcoma (KS) alone was 21 months. Median survival among 90 patients presenting with opportunistic infections, primarily Pneumocystis carinii pneumonia, was 9 months; survival at 21 months was zero. Survival among patients presenting with both KS and opportunistic infections was not statistically different from survival among patients presenting with opportunistic infections only. When cases were divided into those diagnosed before and after May 1982, there was no significant improvement in survival from diagnosis in the more recently diagnosed cohort.

The HIV epidemic: medical and social challenges.

The sudden appearance, rapid spread, and devastating clinical impact of HIV infection in Africa, Europe and North America has created a medical problem unprecedented in the modern era. HIV is sexually transmitted, afflicts sexual and racial minorities in developed countries, and appears likely to be fatal and incurable in a majority of infected people. Its epidemiology (transmission and natural history) and clinical manifestations have been well described, but treatment of HIV remains minimally effective, creating only a short respite from progressive deterioration. In the absence of effective vaccination, HIV will continue to spread, abetted by a long period of asymptomatic carriage during which carriers are infectious. It has spread internationally to most undeveloped countries aided by fear and ignorance. The problem will resist simple technological solutions and adversely impact the lives of tens of millions of people in these areas over the next several decades. In developed countries HIV will strain medical resources and kill several million people before the end of the century. Despite the tremendous problems created by the AIDS epidemic, it has driven a remarkable expansion of virologic and immunologic understanding which promises to ultimately lead to control of not only AIDS, but a variety of other serious diseases. The following reviews of pivotal issues in AIDS research document this progress.

Clinical and virologic effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma: results of a randomized trial.

Thirty patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL) receiving chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were randomized to receive either subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) or no additional therapy. Recombinant rGM-CSF (at a dose of 10-20 micrograms/kg/d) was given on days 1 to 10 (early rGM-CSF) to the first five patients, but was changed to days 4 to 13 (delayed rGM-CSF) of each chemotherapy cycle in subsequent patients. Compared with the control group (N = 10), the delayed rGM-CSF group (N = 11) had higher mean nadirs of the absolute neutrophil count (0.36 v 0.89 x 10(9)/L; P = .009), shorter mean durations of neutropenia (4.9 v 1.3 days; P = .02), fewer chemotherapy cycles complicated by neutropenia and fever (67% v 27%; P = .001), fewer days hospitalized for fever and neutropenia (4.9 v 1.8; P = .004), fewer reductions in chemotherapy dosages, and less frequent delays in chemotherapy administration. No significant differences were observed between patients in the control group and those in the early rGM-CSF group (N = 5). Median levels of serum HIV-1 p24 antigen decreased to 18% and 17% of baseline values in control (N = 4) and rGM-CSF groups (N = 6), respectively, 1 week following administration of the first cycle of chemotherapy. In the third week after chemotherapy, median antigen levels remained below baseline in the control group, but rose to 243% of baseline values in the rGM-CSF group (P = .01), suggesting stimulation of HIV replication. The effect of this change in HIV activity on clinical outcome of treated patients could not be determined, and therefore the clinical significance of this finding remains unclear. Complete response rates of 67%, 70%, and 60% were observed in the control, delayed rGM-CSF, and early rGM-CSF groups, respectively, with corresponding survival times of 9.0, 11.4, and 8.0 months.

Toxic effects of zidovudine in asymptomatic human immunodeficiency virus-infected individuals with CD4+ cell counts of 0.50 x 10(9)/L or less. Detailed and updated results from protocol 019 of the AIDS Clinical Trials Group.

BACKGROUND: Protocol 019 of the AIDS Clinical Trials Group is a multicenter, double-blind, placebo-controlled trial of zidovudine (3'-azido-3'-deoxythymidine; formerly AZT) in human immunodeficiency virus-infected asymptomatic individuals. The initial results in the stratum of subjects entering with CD4+ cell counts of 0.50 x 10(9)/L or less have been reported, but without a detailed analysis of toxic effects. METHODS: This detailed and updated report analyzes the toxic effects that occurred in 1567 subjects (91% men; 89% white) in this stratum of protocol 019 who received placebo (494 subjects), a 500-mg daily dose of zidovudine (544 subjects), or a 1500-mg daily dose of zidovudine (529 subjects). Hematologic, hepatic, and renal effects and patient-reported symptoms and clinical signs were monitored. RESULTS: Severe anemia (hemoglobin level, < 80 g/L) was associated with both the 500-mg zidovudine group and the 1500-mg group compared with placebo. The estimated 18-month risks of severe anemia were 0.4%, 2.0%, and 9.7% for the placebo, 500-mg zidovudine, and 1500-mg zidovudine groups, respectively. Predictive baseline measures were lower hemoglobin level in the 1500-mg group and the two zidovudine groups combined and lower platelet count in the 500-mg zidovudine group. The risk of a first severe anemia developing was greatest in months 3 through 8 of treatment. Of the 44 subjects with severe anemia in the zidovudine groups, 18 (41%) progressed from mild anemia (hemoglobin level, 95 to 109 g/L) to severe anemia on consecutive visits (usually 2 to 4 weeks apart). Severe neutropenia (absolute neutrophil count, < 750 x 10(6)/L) did not occur significantly more often in the 500-mg zidovudine group but did in the 1500-mg zidovudine group. Moderate neutropenia (absolute neutrophil count, < 1300 x 10(6)/L) did develop significantly more often in the 500-mg zidovudine group (165 subjects) than in the placebo group (71 subjects). Mild (or worse) elevations of bilirubin levels were uncommon but occurred more often with zidovudine. Severe nausea (and/or vomiting) was rare (2.8% of subjects) but was associated with zidovudine. Milder patient-reported events were common, and a number were associated with zidovudine. CONCLUSION: Zidovudine at the 500-mg/d dosage appears to be tolerable in many patients with asymptomatic human immunodeficiency virus infection and CD4+ cell counts of 0.50 x 10(9)/L or less. Increased clinical surveillance for anemia may be warranted in certain patients.

Advances in the medical management of patients with HIV-1 infection: an overview.

New guidelines for the management of patients with HIV-1 infection emphasize early aggressive treatment using multi-drug combination regimens. Accurate assessment of the effectiveness of these treatments and their potential (small as it now seems) to eradicate HIV-1 infection requires testing for viral levels in the blood, and in other compartments that may serve as long-term viral reservoirs, using the most sensitive assays. At present, most of our information regarding triple-drug combination therapies (usually two nucleosides and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor) has come from the assessment of viral levels in blood. Available results strongly support the virologic superiority of such treatments over monotherapy and two-drug combinations. There are important questions that remain to be answered regarding these highly effective therapies. Questions regarding the durability of these treatments in preventing the evolution of drug resistance can be addressed by using sensitive reverse transcription/polymerase chain reaction assays to assess treatment response. Others, such as how best to treat patients who have failed potent drug therapy, await results from new, large-scale, clinical trials. An important concern with respect to newer antiretroviral therapies is their complexity and thus the increased risk for non-compliance and resultant viral resistance. In addition, longer-term side-effects are increasingly recognized. Programs that enhance compliance with these treatments will increase the probability that they will provide durable suppression of viral replication and arrest the clinical progression of HIV disease.

The safety and pharmacokinetics of GLQ223 in subjects with AIDS and AIDS-related complex: a phase I study.

A phase I dose-escalation study was performed to evaluate the safety and pharmacokinetics of a single intravenous infusion of GLQ223 in subjects with AIDS and AIDS-related complex (ARC). The active ingredient in GLQ223 is trichosanthin. Trichosanthin, imported from China, is the active drug in community-initiated treatment programs for patients with HIV infection. Eighteen subjects were enrolled, 10 with AIDS and eight with ARC. All subjects were monitored for tolerance and toxicity. Immunological and virological parameters were also followed. GLQ223 administration was not associated with notable toxicity with the exception of one subject who experienced a severe neurological adverse reaction. No consistent or sustained changes in CD4+ lymphocyte populations or HIV antigen levels were observed. Serum concentrations of GLQ223 that were comparable to concentrations shown to have antiviral activity in vitro were achieved transiently but may not have been maintained for a sufficient duration to exert antiretroviral effects. Further studies are indicated to determine pharmacodynamic properties of GLQ223, its optimal dosing schedule, and whether GLQ223 or related molecules will be useful in the treatment of HIV infection.

Interferon-alpha 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.

Findings in psychiatric consultations with patients with acquired immune deficiency syndrome.

Thirteen of 40 patients with acquired immune deficiency syndrome (AIDS) admitted to the wards of a large city hospital were seen by the staff of a psychiatric consultation service. Eleven were gay men and two were bisexual men. "Depression" was the stated reason for referral of 10 patients; of these, two met DSM-III criteria for major depression, one had dysthymic disorder, and seven had adjustment disorder with depressed mood. Recurrent psychological themes of the 13 patients were: dealing with a life-threatening illness, uncertainty about the implications of an AIDS diagnosis, social isolation, and guilt over their previous life style. The role of the primary physician and of the mental health professional in the psychological care of AIDS patients is discussed.

HIV antigen variability in ARC/AIDS.

To define the natural variability of human immunodeficiency virus p24 antigen (HIV Ag) over time in untreated HIV-infected patients, we analyzed the percentage change of serum HIV Ag in 40 antigenemic ARC/AIDS subjects receiving placebo in a 24 week clinical trial. When grouped by month of observation, no differences in HIV Ag change were seen among all five 1 month observation periods (p greater than 0.4). After all 105 monthly changes (median of 3 per subject) were pooled, the mean monthly HIV Ag change was 0% change (standard deviation: 77% increase, 44% decrease). Furthermore, HIV Ag changes did not differ among all lengths of observation (from 1 to 5 months using all possible pairwise combinations of HIV Ag levels, p greater than 0.4). CD4 T-cell changes over the whole study did not correlate with HIV Ag changes over the same period. Knowledge of this broad HIV Ag variability should be useful in calculating sample size and in choosing categorical responses unlikely to occur spontaneously in clinical trials of antiviral agents where HIV Ag changes are used as surrogate markers of efficacy.

Kaposi's sarcoma involving the lung in patients with the acquired immunodeficiency syndrome.

To determine the distinguishing features of pulmonary Kaposi's sarcoma (KS) in patients with the acquired immunodeficiency syndrome (AIDS), we compared three groups of patients, 16 with endobronchial KS, 15 with endobronchial KS and an opportunistic lung infection, and 40 with Pneumocystis carinii pneumonia (PCP) without concomitant pulmonary KS. The majority of pulmonary KS patients had extensive cutaneous disease at the time of pulmonary diagnosis, and the diagnosis of pulmonary KS was easily established by the characteristic appearance of the endobronchial lesions. Dyspnea, fever, and cough were common presenting symptoms, but occurred more commonly in association with accompanying opportunistic infection. Diffuse interstitial infiltrates were observed in most patients in both groups, but the findings of nodular parenchymal densities or pleural effusion were more commonly observed in patients with pulmonary KS than in those with PCP alone. Pulmonary uptake of gallium-67 citrate or a diffusing capacity less than 80% were unusual in patients with pulmonary KS alone, but common in those with accompanying opportunistic infection or with PCP alone. Median survival in patients with pulmonary KS was only 2 months, and most patients had complicating opportunistic infections at the time of death. Pulmonary KS is generally a late and often preterminal manifestation of AIDS. Chest radiographs, gallium lung scans, and pulmonary function testing may provide diagnostic information that is helpful in distinguishing pulmonary KS from opportunistic lung infections.

Cryotherapy for cutaneous Kaposi's sarcoma (KS) associated with acquired immune deficiency syndrome (AIDS): a phase II trial.

To assess the response and toxicity of liquid nitrogen cryotherapy for cutaneous lesions of Kaposi's sarcoma (KS) associated with AIDS, we evaluated 20 subjects with biopsy-proven KS in a phase II clinical trial. Subjects had two to four cutaneous KS indicator lesions treated with liquid nitrogen cyrotherapy. Treatment was repeated at 3 week intervals, allowing adequate healing time. On average, subjects received three treatments per lesion with a mean follow-up time of 11 weeks (range of 6-25 weeks). One treatment consisted of two freeze-thaw cycles, with thaw times ranging from 11 to 60 s per cycle. A complete response was observed in 80% of treated KS lesions and lasted a minimum of 6 weeks following the completion of therapy. Greater than 50% cosmetic improvement of KS was observed. Histopathology of treated lesions correlated poorly with cosmetic improvement. Response was not predicted by tolerance to zidovudine therapy, CD4+ cell count, presence of B symptoms, or previous chemotherapy. Subjects without prior history of opportunistic infection (OI) were more likely to have a better response than those with a prior history of OI. Subjects tolerated cryotherapy well. Blistering occurred frequently, but local pain was limited and relieved by acetaminophen. Secondary infection did not occur. Based on this study, we recommend cryotherapy to subjects with cutaneous KS lesions. Liquid nitrogen cryotherapy is easily applied as a primary therapy, and may also have a role in the treatment of cutaneous KS lesions that respond slowly or show incomplete cosmetic improvement with systemic therapies.

Intralesional recombinant tumor necrosis factor-alpha for AIDS-associated Kaposi's sarcoma: a randomized, double-blind trial.

The effect of recombinant tumor necrosis factor-alpha (rTNF), injected directly into the tumor, was evaluated in a Phase I/II study of 27 patients with AIDS-associated Kaposi's sarcoma (KS). The maximally tolerated intralesional dose was less than 100 micrograms/m2 and the recommended intralesional dose was 25 micrograms/m2. In a double-blind, randomized, placebo-controlled study, rTNF reduced the cross-sectional area of 15 of 16 (94%) of the injected KS lesions and caused complete disappearance of 3 of 16 (19%) lesions. Only injected lesions showed a response. Rigors and fever were common dose-dependent side effects and were attenuated by meperidine. There were no changes in human immunodeficiency virus (HIV) activity as determined by serum p24 antigen levels. While biologically active, the systemic toxicity of rTNF as well as the lack of distant antitumor effects in noninjected lesions limits its clinical usefulness under the conditions employed in this trial.

Weekly doxorubicin in the treatment of patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group.

Fifty-three patients with AIDS-related Kaposi's sarcoma and no previous treatment with cytotoxic chemotherapy enrolled in a phase II multicenter study to evaluate the safety and efficacy of weekly doxorubicin treatment. Doxorubicin was given intravenously at a dose of 15 mg/m2. Patients were stratified for purposes of analyses by tumor burden and coexistence of HIV-associated signs and symptoms; stratum I included patients with cutaneous disease alone and no symptoms, and stratum II included patients with visceral disease, tumor-associated edema, a previous opportunistic infection, or systemic symptoms. Fifty-one patients were evaluable for toxicity and 50 for tumor response. Five patients had a partial response (10%); 32, a minor response (64%); 12, no change (24%); and one, progression (2%) as the best measurable response. Partial response durations ranged from 4 to 14 weeks. Fifteen patients subsequently showed progression while on treatment. A significantly greater number of patients in stratum I (20.1%) had a partial response compared with those in stratum II (0%, p = 0.009). The major toxicities included nausea (37%), stomatitis (9.8%), mucositis (13.7%), and moderate to severe neutropenia (71%). Neutropenia was dose limiting and resulted in discontinuation of doxorubicin in 18% of the patients. Two patients developed cardiac toxicity. In conclusion, doxorubicin treatment induced relatively few tumor responses and remission durations were short. Treatment was limited by a high rate of toxicity.

The role of chemotherapy for epidemic Kaposi's sarcoma.

Studies of classic, and especially African, Kaposi's sarcoma in the 1970s showed that both forms of the disease respond to cytotoxic chemotherapy. The agents that had proven effective against these forms of neoplasm were among the first to be tried for managing epidemic Kaposi's sarcoma (EKS). Thus far, single-agent regimens using either vinblastine, vincristine, or etoposide have apparently shown the greatest efficacy in AIDS-associated Kaposi's sarcoma, with overall response rates of up to nearly 90% in some trials. Various combination regimens have been studied with a view to reducing side effects, particularly immune suppression, while maintaining overall efficacy. Thus far, only an alternating regimen of vinblastine and vincristine shows promise. Despite intrinsic shortcomings, chemotherapy, using cytotoxics alone or in combination with biologic response modifiers and other modalities, will play a role in managing EKS, even as the search for the optimal regimen continues.

Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome-related Kaposi's sarcoma.

Acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma (KS) is more virulent than previously reported cases of KS and affects a much younger population. The cell of origin is lymphatic endothelium, with the histopathology characterized by a proliferation of small vessels with abnormal endothelial cells, extravasated erythrocytes, and spindle-shaped-cell infiltration. Clinical manifestations are pigmented, nodular lesions affecting the skin, mucous membranes, lymph nodes, and/or visceral organs. The head and oral cavity, uncommon sites in other KS populations, are frequently involved. Pain is not an early part of the clinical picture. AIDS-related KS is often widespread and rapidly progressive. However, the cause of death in most cases is attributed to opportunistic infection, which is believed to increase as a result of conventional cytotoxic chemotherapy. Recombinant interferon alpha has been the most thoroughly tested of immune-stimulating or nonimmunosuppressive drugs for the treatment of AIDS-related KS. An objective antineoplastic response rate (25% to 60%) comparable to single-agent chemotherapy with vinblastine or VP-16 has been demonstrated in several trials. Response rates to interferon alpha may be enhanced by such factors as absence of lymphoma-like B symptoms, low levels of circulating acid-labile interferon alpha, and absent history of recent serious infection. Varied drug dose, schedule, and route of administration have been employed; doses equal to or greater than 30 million U/day administered intravenously or intramuscularly appear to give the best results. Daily dosing regimens may induce tolerance for subjective toxicities (eg, fever, asthenia, and anorexia), which are often dose limiting. Direct immune stimulation following treatment with interferon alpha has not been conclusively established, but evidence suggests that respondents have low rates of opportunistic infection. Other recent studies demonstrate interferon alpha inhibiting activity against the AIDS-associated retrovirus in vitro and trials in vivo are in progress to define the clinical relevance of this observation.

Alpha interferon therapy of AIDS-associated Kaposi's sarcoma.

Alpha interferon has been the most widely studied biologic response modifier for the treatment of Kaposi's sarcoma (KS) associated with acquired immune deficiency syndrome (AIDS). At San Francisco General Hospital's AIDS Clinic, three sequential trials of recombinant interferon alfa-2b (Intron A) were conducted between August 1982 and April 1984. In the first study, ten patients with early KS were randomized to receive either low-dose (1 MU/m2) subcutaneous (SC) or high-dose (50 MU/m2) intravenous (IV) treatment 5 days per week, every other week, for eight weeks. A perceived advantage of the latter regimen led to a subsequent trial in which 20 subjects received high-dose IV therapy. A 32% objective response rate was achieved, despite the fact that these patients had less favorable disease status and more constitutional symptoms than those in the first trial and had also experienced previous opportunistic infections (OIs). A final 8-week investigation evaluated the use of 30 MU/m2 three times per week in 30 subjects. Drug-related toxicity seemed more pronounced with this regimen, but overall objective responses were identical to those seen in the high-dose IV study. None of the trials produced evidence of immune reconstitution on laboratory evaluation. The patients were not protected from developing AIDS-related OI either during or following interferon therapy, although OI was diagnosed less frequently in responders, who also displayed a distinct survival advantage over those with progressive disease. These trends remained evident when the data from the three studies were pooled with those from three parallel trials conducted at the University of California, Los Angeles (UCLA). Studies evaluating the combined use of alpha interferon and chemotherapeutic agents known to be active against AIDS-related KS (such as VP-16 and vinblastine) have thus far failed to demonstrate a synergistic antitumor effect, while toxicity has increased. In light of in vitro evidence that alpha interferon suppresses the AIDS retrovirus and has clinical efficacy in KS comparable to that of cytotoxic agents, additional investigations, focusing on maximizing therapeutic potential, are warranted.

Alpha interferon therapy of AIDS-associated Kaposi's sarcoma.

Alpha interferon has been the most widely studied biologic response modifier for the treatment of Kaposi's sarcoma (KS) associated with acquired immune deficiency syndrome (AIDS). At San Francisco General Hospital's AIDS Clinic, three sequential trials of recombinant interferon alfa-2b (Intron A) were conducted between August 1982 and April 1984. In the first study, ten patients with early KS were randomized to receive either low-dose (1 MU/m2) subcutaneous (SC) or high-dose (50 MU/m2) intravenous (IV) treatment 5 days per week, every other week, for eight weeks. A perceived advantage of the latter regimen led to a subsequent trial in which 20 subjects received high-dose IV therapy. A 32% objective response rate was achieved, despite the fact that these patients had less favorable disease status and more constitutional symptoms than those in the first trial and had also experienced previous opportunistic infections (Ols). A final 8-week investigation evaluated the use of 30 MU/m2 three times per week in 30 subjects. Drug-related toxicity seemed more pronounced with this regimen, but overall objective responses were identical to those seen in the high-dose IV study. None of the trials produced evidence of immune reconstitution on laboratory evaluation. The patients were not protected from developing AIDS-related OI either during or following interferon therapy, although OI was diagnosed less frequently in responders, who also displayed a distinct survival advantage over those with progressive disease. These trends remained evident when the data from the three studies were pooled with those from three parallel trials conducted at the University of California, Los Angeles (UCLA). Studies evaluating the combined use of alpha interferon and chemotherapeutic agents known to be active against AIDS-related KS (such as VP-16 and vinblastine) have thus far failed to demonstrate a synergistic antitumor effect, while toxicity has increased. In light of in vitro evidence that alpha interferon suppresses the AIDS retrovirus and has clinical efficacy in KS comparable to that of cytotoxic agents, additional investigations, focusing on maximizing therapeutic potential, are warranted.

Lack of response to suramin in patients with AIDS and AIDS-related complex.

Forty-one homosexual men with the acquired immune deficiency syndrome (AIDS) or AIDS-related complex were treated with 0.5, 1.0, or 1.5 g of suramin weekly for up to six months. In no patient was evidence of symptomatic improvement or regression of Kaposi's sarcoma shown. Opportunistic infections developed in 16 patients during therapy. Only six patients (15 percent) became human immunodeficiency virus (HIV) culture-negative during treatment, despite documentation of adequate serum suramin levels. All but one of these six have had disease progression. Decreases in the numbers of total T4 cells with time were observed in both AIDS and AIDS-related complex subgroups. Toxicity was significant and consisted of fatigue, fever, and hepatic and renal dysfunction, all of which were observed most frequently with the 1.0 or 1.5 g dosages. Fatal hepatic failure developed in two patients, and adrenal insufficiency was documented in eight patients. Suramin is a toxic agent that shows no virologic, immunologic, or clinical benefit in patients with HIV-related disease.

A phase I study of HGP-30, a 30 amino acid subunit of the human immunodeficiency virus (HIV) p17 synthetic peptide analogue sub-unit vaccine in seronegative subjects.

HGP-30-KLH vaccine in alum at doses of 10, 25, 50, and 100 micrograms/kg administered intramuscularly at weeks 0, 4, and 10 appear well-tolerated clinically. Local pain at the injection site, appears to be the main clinical toxicity. Laboratory parameters are not affected by administration of the vaccine candidate except for perhaps mild urinalysis abnormalities at the highest dose. This vaccine candidate has no apparent immunotoxicity and does not appear to affect lymphocyte populations or T-cell functional studies. Low levels and transient antibodies develop in a minority of subjects early after immunization with the vaccine candidate. These responses were observed in the lowest dose range. Higher doses, and longer follow-up will be needed to confirm this observation. T-cell proliferative responses to KLH and KLH-HGP-30 are consistent and may not be dose dependent, but the proliferative responses are variable and more data need to be accumulated. Preliminary, there appears to be an HGP-30-induced CTL response of HGP-30-coated EBV-transformed autologous B cell lines. This study was approved under an IND for the California Department of Health Services' Food and Drug Branch. They have provided excellent support and regulatory guidelines for this project. Future work will extend and confirm these initial observations.