S. A. Danner

Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection : a composite of redistribution and proliferation

The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.

Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs.

To investigate the effect of persistent HIV infection on the immune system, we studied leukocyte functions in 14 asymptomatic homosexual men (CDC group II/III) who were at least two years seropositive, but who still had normal numbers of circulating CD4+ T cells. Compared with age-matched heterosexual men and HIV-negative homosexual men, the CD4+ and CD8+ T cells from seropositive men showed decreased proliferation to anti-CD3 monoclonal antibody and decreased CD4+ T-helper activity on PWM-driven differentiation of normal donor B cells. Monocytes of HIV-infected homosexual men showed decreased accessory function on normal T cell proliferation induced by CD3 monoclonal antibody. The most striking defect in leukocyte functional activities was observed in the B cells of HIV-infected men. B cells of 13 out of 14 seropositive men failed to produce Ig in response to PWM in the presence of adequate allogeneic T-helper activity. These findings suggest that HIV induces severe immunological abnormalities in T cells, B cells, and antigen-presenting cells early in infection before CD4+ T cell numbers start to decline. Impaired immunological function in subclinically HIV-infected patients may have clinical implications for vaccination strategies, in particular the use of live vaccines in groups with a high prevalence of HIV seropositivity.

Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection.

ObjectiveTo investigate the risk of hepatotoxicity after initiation of protease inhibitor-containing highly active antiretroviral therapy (HAART) for HIV-1 infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection. DesignRetrospective study with 394 HIV-1-infected patients initiating HAART at a single university clinic. MethodsLiver enzyme elevation (LEE) was defined as alanine aminotransferase or aspartate aminotransferase at least five times the upper limit of normal and an absolute increase of > 100 U/l. Relative risks for time to LEE were estimated using Cox proportional hazards models. ResultsOf 394 patients 7% were hepatitis B surface antigen (HBsAg)-positive and 14% were anti-HCV-positive. Patients with chronic hepatitis had a higher risk for LEE compared with patients without co-infection: 37% versus 12% respectively. After adjustment for higher baseline transaminases, the presence of HBsAg or anti-HCV remained associated with an increased risk of LEE – relative risk 2.78 (95% confidence interval, 1.50–5.16) and 2.46 (95% confidence interval, 1.43–4.24) respectively. In patients with LEE, transaminases declined whether HAART was continued or modified. Of patients with chronic HBV infection 38% lost HBeAg or developed anti-HBe after initiation of HAART, and one seroconverted from HBsAg-positive to anti-HBs-positive. However, there was no clear relationship with LEE. ConclusionsHIV-1-infected patients co-infected with HBV or HCV were at considerably higher risk of developing LEE when HAART was initiated compared with patients without co-infection, but it is usually not necessary to modify antiretroviral therapy.

Persistent HIV antigenaemia and decline of HIV core antibodies associated with transition to AIDS.

Sequential serum samples from 13 homosexual men who seroconverted for antibodies to human immunodeficiency virus (HIV) were tested for HIV antigen. In one of these men, who developed the acquired immune deficiency syndrome (AIDS), HIV antigenaemia preceded the onset of AIDS by more than a year and persisted throughout the course of the disease. This antigenaemia was accompanied by the disappearance of IgG antibody reactivity to the major HIV core protein p24. In none of the 12 others, who all remained without serious disease, were serum concentrations of HIV antigen detected, except on one occasion in one man. All their serum samples showed strong IgG antibody reactivity to p24. Nine children who were infected with HIV in 1981 by plasma transfusion from a single donor were also followed up for HIV antigenaemia. HIV antigen was almost constantly present in the serum (26 of 28 samples) of five children who developed AIDS related complex or AIDS and less often in the serum (four of 10 samples) of four children who remained free of symptoms. The two children who developed AIDS showed a virtual absence of antibody reactivity to p24. These results indicate that increased HIV gene expression is a contributing factor to the development of AIDS and also provide evidence for a switch from latent to active HIV infection.

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment

OBJECTIVE--To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment. DESIGN--Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988. SETTING--An academic centre for AIDS. PATIENTS--196 Patients with AIDS and neurological symptoms examined from 1982 to 1988. INTERVENTIONS--Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D). MAIN OUTCOME MEASURES--Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid. RESULTS--The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive. CONCLUSIONS--The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.

Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine

Objectives: Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment. Design: Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later. Methods: Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction. Results: Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 × 106/l and median plasma viral RNA levels decreased by at least 2.87 log10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log10 copies/g at baseline, was markedly reduced with at least 2.1 log10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed. Conclusions: Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.

CLINICAL AND VIROLOGICAL EFFECTS OF HIGH-DOSE RECOMBINANT INTERFERON-α IN DISSEMINATED AIDS-RELATED KAPOSI'S SARCOMA

Abstract The effectiveness and antiretroviral activities of interferon-α in AIDS-related Kaposis sarcoma was assessed in a non-randomised, phase-II clinical trial. 28 patients were treated with high-dose (27-36 MU) human recombinant interferon-α 2a subcutaneously every day for 8 weeks. In patients with stable disease or showing a response, treatment was continued three times weekly until a complete response was achieved or there was progression. 12 of the 26 evaluable patients achieved a major response; 5 of these showed histologically confirmed complete responses. There was a significant increase in OKT4-positive cells in the responders and a significant decrease in HIV antigen (HIV-Ag) in the 7 responders with initially detectable HIV-Ag. Interferon-α is thus an effective treatment. The increase in OKT4-positive cells and the decrease in HIV-Ag seem to be significantly related to patients with tumour responses.

Distinct IgG recognition patterns during progression of subclinical and clinical infection with lymphadenopathy associated virus/human T lymphotropic virus

Longitudinal IgG recognition patterns of viral proteins were studied in 15 men who had seroconverted for lymphadenopathy associated virus/human T lymphotropic virus (LAV/HTLV-III). Antibodies to the major viral core protein p24, which is a cleavage product of the gag gene encoded precursor protein pr55, appeared first. These were soon followed by antibodies to pr55 and more gradually by antibodies to the other gag gene encoded cleavage product p18, the env gene encoded transmembrane glycoprotein gp41, the env gene encoded glycoproteins gp65 and gp110, and the putative pol gene product p33. In 13 subjects who remained healthy the reactivity to the different proteins increased or stabilised with time, while in two men who developed acquired immune deficiency syndrome (AIDS) the reactivity, most noticeably to gag encoded proteins, diminished before or at the onset of symptoms.

Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy

Objective:To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs. Design:Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study. Methods:Participants with ≥ 10 000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers. Results:The elimination rate constants for HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens. Conclusion:With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs

OBJECTIVE To identify genotypic drug resistance patterns of HIV-1 in patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral combination therapy. METHODS Drug susceptibility of the viruses was tested by a phenotypic recombinant virus assay. Genotypic analysis of HIV resistance was performed by sequencing of the amino-terminal part of the corresponding reverse transcriptase (RT) gene (amino acids 1-280) for serum-derived and recombinant viruses. RESULTS Among viruses from 92 patients studied, three (3%) viruses contained a T215Y amino-acid change as well as a previously unseen combination of an amino-acid change at codon 67 (N-->E/S) and a two amino-acid insertion between codons 68 and 69 of the RT gene of HIV-1. Phenotypic resistance analysis showed high levels of resistance to zidovudine, lamivudine and stavudine (in all patients) and moderate levels of resistance to didanosine and zalcitabine (in two patients), whereas neither serum-derived nor recombinant viruses contained previously known amino-acid changes conferring resistance to didanosine, zalcitabine, lamivudine and stavudine. However, all recombinant viruses contained an insertion of two amino acids between codons 68 and 69 of RT as well as an amino-acid change at codon 67, as was seen in the serum-derived viruses. CONCLUSIONS Antiretroviral therapy including zidovudine may yield replicating viruses with a two amino-acid insertion in RT in combination with amino-acid changes at codons 67 and 215, which are highly resistant to lamivudine and stavudine on top of zidovudine and have unpredictable susceptibility to didanosine and zalcitabine despite lack of previously reported corresponding resistance-associated amino-acid changes. It is currently unknown what regimens can induce the emergence of this type of multidrug-resistant viruses. This will only be elucidated when resistance assays are capable of detecting these mutants.