Gilbert R. Kaufmann

Immune Reconstitution in HIV-Infected Patients

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of potent antiretroviral therapies (ARTs), which have enabled sustained suppression of HIV replication and recovery of CD4 T cell counts. Knowledge of the function of CD4 T cells in immune reconstitution was derived from large clinical studies demonstrating that primary and secondary prophylaxis against infectious agents, such as Pneumocystis jirovecii (Pneumocystis carinii), Mycobacterium avium complex, cytomegalovirus, and other pathogens, can be discontinued safely once CD4 T cell counts have increased beyond pathogen-specific threshold levels (usually >200 CD4 T cells/mm3) for 3-6 months. The downside of immune reconstitution is an inflammatory syndrome occurring days to months after the start of ART, with outcomes ranging from minimal morbidity to fatal progression. This syndrome can be elicited by infectious and noninfectious antigens. Microbiologically, the possible pathogenic pathways involve recognition of antigens associated with ongoing infection or recognition of persisting antigens associated with past (nonreplicating) infection. Specific antimicrobial therapy, nonsteroidal anti-inflammatory drugs, and/or steroids for managing immune reconstitution syndrome should be considered.

Characteristics, Determinants, and Clinical Relevance of CD4 T Cell Recovery to <500 Cells/µL in HIV Type 1—Infected Individuals Receiving Potent Antiretroviral Therapy

BACKGROUND The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.

Immunological recovery and antiretroviral therapy in HIV-1 infection

Potent antiretroviral therapy has dramatically improved the prognosis of patients infected with HIV-1. Primary and secondary prophylaxis against Pneumocystis carinii, Mycobacterium avium, cytomegalovirus, and other pathogens can be discontinued safely once CD4 cell counts have increased beyond pathogen-specific thresholds. Approximately one-third of individuals receiving antiretroviral therapy will not reach CD4 cell counts above 500 cells per muL after 5 years despite continuous suppression of plasma HIV-1 RNA. Whether this failure represents a risk factor for the long-term incidence of opportunistic diseases--eg, tuberculosis or malignancies--remains uncertain. We describe the time course of CD4 cell concentrations in patients whose plasma HIV-1 RNA is durably suppressed by antiretroviral therapy, in patients with incomplete suppression of plasma HIV-1 RNA, and during treatment interruptions. In addition, immune reconstitution disease, an inflammatory syndrome associated with immunological recovery occurring days to weeks after the start of antiretroviral therapy, is briefly described.

The extent of HIV-1-related immunodeficiency and age predict the long-term CD4 T lymphocyte response to potent antiretroviral therapy.

Objective To study the long-term immunological recovery in HIV-1-infected individuals receiving potent antiretroviral therapy (ART). Design Prospective, observational study. Methods Plasma HIV-1 RNA, CD4 and CD8 T lymphocyte counts were determined at 3–6 monthly intervals in 95 HIV-1-infected subjects receiving ART who suppressed plasma HIV-1 RNA to levels below 400 copies/ml during a median observation period of 45 months. Results The median CD4 cell count rose from 325 to 624 cells/μl at 48 months, increasing by 22.6 cells/μl per month in the first 3 months, 8.1 cells/μl per month from months 3 to 12, 6.8 cells/μl per month in the second year, 3.3 cells/μl per month in the third, and 1.7 cells/μl per month in the fourth year. At 48 months, 98% of subjects reached CD4 cell counts > 200 cells/μl, 86% > 350 cells/μl, and 74% > 500 cells/μl. A higher nadir CD4 cell count and younger age were independently associated with greater increases in CD4 cell counts, and higher absolute CD4 cell counts at 48 months. Poor immunological responders who did not reach 500 CD4 lymphocytes/μl at 48 months showed lower nadir and baseline CD4 cell counts than good responders (99 versus 300 cells/μl and 160 versus 373 cells/μl, respectively). Conclusion The recovery of CD4 T lymphocytes occurs mainly in the first 2 years after the initiation of ART, and is associated with age and the pre-existing degree of HIV-1-related immunodeficiency, suggesting that the long-term exposure to HIV-1 infection has caused damage to the immune system that is difficult to correct.

Potent Antiretroviral Therapy of Primary Human Immunodeficiency Virus type 1 (HIV-1) Infection: Partial Normalization of T Lymphocyte Subsets and Limited Reduction of HIV-1 DNA Despite Clearance of Plasma Viremia

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy.

ObjectiveTo determine the long-term T-lymphocyte response to highly active antiretroviral therapy (HAART) and to define predictors of the immunological response. DesignCohort study, including 135 HIV-1-infected subjects at a city general practice who commenced HAART between 1996 and 1998. MethodsCollection of plasma HIV-1 RNA, CD4+ and CD8+ T-lymphocyte data at 3-6 monthly time intervals over 2 years. ResultsSeventy-three subjects (54%) achieved suppression of plasma HIV-1 RNA to levels below 400 copies/ml during the observation period, 31 individuals (23%) had detectable plasma HIV-1 RNA below 10 000 copies/ml and 31 subjects (23%) had virological failures with viral loads above 10 000 copies/mL. Median CD4+ T lymphocytes increased from 246 to 463 × 106 cells/l , showing a median rise of 20 × 106 cells/l per month in the first 3 months and 7 × 106 cells/l per month thereafter. The proportion of individuals who reached CD4+ cell counts above 500 × 106 cells/l increased from 8% at baseline to 54% at 2 years. Treatment-naïve individuals, subjects with a large reduction of HIV-1 RNA or a large early CD8+ increase had better early CD4+ responses. Long-term CD4+ T-cell increases were inversely correlated with mean plasma HIV-1 RNA levels. Baseline CD4+ T-cell count was the most important determinant of reaching CD4+ cell counts above 500 × 106 cells/l. Nineteen per cent of subjects had no further CD4+ T-cell increases in the second year of therapy despite undetectable viral load. ConclusionsImmune reconstitution is a slow process, showing a large individual variability. The virological response to HAART was the most important determinant of the immunological short- and long-term response.

Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection

ObjectiveTo compare the effect of highly active antiretroviral therapy on immune reconstitution in subjects with acute and chronic HIV-1 infection. DesignProspective study including 58 treatment-naive subjects who commenced indinavir or nelfinavir and two nucleosides during primary (PHI; n = 28) or chronic HIV-1 infection (CHI; n = 30). MethodsNaive (CD45RA+62L+), memory (CD45RA−) and activated (CD38+HLA-DR+) T cell subsets were quantified at 1–2 monthly time intervals using 4-colour flow cytometry. ResultsAt 1 year, HIV-1 RNA declined in both cohorts to undetectable levels (< 50 copies/ml), while median CD4 lymphocyte count increased from 470 to 758 × 106 cells/l in PHI and from 204 to 310 × 106 cells/l in CHI, reaching > 500 × 106 cells/l in 93% of PHI, but only in 37% of CHI subjects (P < 0.001). Naive CD4 lymphocytes increased from 106 to 176 × 106 cells/l in PHI and from 41 to 44 × 106 cells/l in CHI (PHI versus CHI at 12 months:P = 0.003), while memory cells rose from 368 to 573 × 106 cells/l in PHI and from 148 to 223 × 106 cells/l in CHI (P < 0.001). Early increases (< 3 months) of CD4 lymphocytes were larger in subjects with PHI, consisting of naive CD45RA+CD62L+ as well as memory CD45RA−CD62L+ cells (P = 0.001). CD4 activation declined from 5 to 2% in PHI and from 13 to 6% in CHI (P = 0.001), while CD8 cell activation was reduced from 33 to 15% in PHI and from 42 to 19% in CHI (P = 0.02). ConclusionImmune reconstitution was more complete, occurred earlier and comprised both naive and memory CD4 T lymphocytes in subjects who commenced antiretroviral therapy during primary HIV-1 infection.

Patterns of Viral Dynamics during Primary Human Immunodeficiency Virus Type 1 Infection

This study used curve-fitting techniques to detail the dynamics of human immunodeficiency virus (HIV)-1 and its relationship to circulating T lymphocyte changes in a cohort of 41 male patients (mean age 36+/-7 years) infected with HIV-1. The following characteristics of viral kinetics were obtained: virus load peak, 6. 35+/-0.71 log10 RNA copies/mL at 12.2+/-7.1 days; virus load drop from peak, 2.02+/-0.93 log10 copies/mL; viral decay rate from peak, 0.071+/-0.042 log10 RNA copies/mL/day; and steady state virus load, 4.57+/-0.68 log10 copies/mL at 135+/-81 days. Analysis of individual virus load curves revealed highly variable viral kinetics. Although these could be grouped into three distinct patterns, virus load and CD4 lymphocyte counts were similar in all patterns at 12 months, but the interval from infection to achievement of steady state virus load varied significantly.

Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty

Analysing T‐cell receptor excision circle numbers in healthy individuals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for individuals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older individuals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half‐life of approximately 50 days before this change occurs, and that either the life‐span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T‐cell receptor excision circle levels for individuals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T‐cell production and that this percentage decreases with the 15.7 year half‐life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.

Treatment response and durability of a double protease inhibitor therapy with saquinavir and ritonavir in an observational cohort of HIV-1-infected individuals.

Objective:To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine. Design:Observational cohort of HIV-positive individuals. Methods:Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1–3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures. Results:A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10 HIV RNA copies/ml from baseline (interquartile range: 1.49–2.46) and became undetectable (< 400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction < 0.5 log10 copies/ml) and 23% were incomplete responders (nadir of HIV RNA > 400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 × 106 to 418 × 106 cells/l (range, 241–537 × 106 cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%. Conclusion:Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy.