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Multiple mutations were found in the human immunodeficiency virus pol gene following treatment of an AIDS patient with antiretroviral drugs. After approximately 2.5 years of monthly alternating therapy with 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), most of the pol sequences amplified from the patient's peripheral blood mononuclear cell DNA contained known AZT resistance mutations at codons 41, 67, and 215 and a putative ddC resistance mutation at codon 69 as well as other novel mutations. These mutations persisted for 6 months after the patient was switched to 2',3'-dideoxyinosine monotherapy. Mutations known to be associated with 2',3'-dideoxyinosine resistance did not occur during this time. Antiviral susceptibility testing of point mutants, introduced into the genetic background of laboratory strain NL4-3, showed that the codon 41 mutation antagonized ddC resistance when present with the codon 69 mutation. However, this antagonism was not found with a chimeric mutant containing the patient's pol gene sequence from codons 25 to 218, implying that other mutations compensated for the antagonism. Thus, alternating therapy with AZT and ddC resulted in the selection of viruses resistant to both drugs.

Objective: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone., Design: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared., Setting: Outpatient clinics of 12 AIDS Clinical Trials Units., Patients: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL)., Intervention: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine., Measurements: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks)., Results: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels., Conclusions: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

To identify candidate interferons (IFNs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection and to investigate sequence-function relationships, the antiviral activities of nine species of recombinant IFN-alpha [IFN-alpha A, IFN-alpha B, IFN-alpha C, IFN-alpha D, IFN-alpha J, [Ser116]IFN-alpha J1, IFN-alpha K, IFN-alpha J/C(Fnu4HI), and IFN-alpha A/D(BglII)] were evaluated against HIV-1. MT-2 cells were exposed to various concentrations of each IFN and were then infected with HIV. Protective effect was determined by cell viability using a tetrazolium dye assay. Activity against vesicular stomatitis virus (VSV) was assessed on MDBK and WISH cells. The 50% inhibitory concentration against HIV was 37 +/- 14 pg/ml for IFN-alpha A, and ranged from 15 +/- 3 pg/ml for IFN-alpha J/C(Fnu4HI) to > 90,000 pg/ml for IFN-alpha D. In general, relative activity against HIV was similar to relative activity against VSV on WISH cells. IFN-alpha D was notable for its decreased activity on human cells. The observations suggest that it may be possible to produce IFNs-alpha with more favorable therapeutic indices than currently available IFNs. Furthermore, the anti-HIV activity of IFNs-alpha is not determined solely by their linear amino acid sequence.

Salmonella bacteremia is being identified with increasing frequency in persons infected with the human immunodeficiency virus. Salmonellosis may occur in patients with an established diagnosis of acquired immunodeficiency syndrome (AIDS), or it may be the first manifestation of this disorder. In patients with AIDS, salmonellosis is characterized by recurrent bacteremia despite treatment and a relative paucity of gastrointestinal manifestations. Treatment regimens may be limited by antimicrobial resistance, poor penetration of antibiotics into phagocytes, and drug intolerance; optimal therapy remains to be established. Possible mechanisms to account for this increased frequency and severity of salmonellosis include altered cell-mediated immunity, hemolysis, prior use of antibiotics, and increased exposure to the pathogen. Salmonellae should be considered among the pathogens associated with human immunodeficiency virus infection.