Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma

OBJECTIVE: To determine the effects of highly active antiretroviral therapy (HAART) on survival in AIDS-related primary central nervous system lymphoma (PCNSL). METHODS: Survival in consecutive patients with PCNSL at a large county teaching hospital from 1995 to 2001 were analyzed by the log rank test and Cox proportional hazards ratios (HR) were calculated for factors potentially affecting survival. RESULTS: During the study period, 25 patients were diagnosed with PCNSL: 19 definite and 6 probable. At diagnosis, median CD4 cell count was 12 x 10(6) cells/l (range 1-151) and median HIV viral load was 5.3 log(10) copies/ml (range 3.9-5.9). Sixteen patients died (median survival 87 days; range, 0 to > 2112). Longer survival was noted for patients who received HAART after diagnosis [HR for death, 0.06; 95% confidence interval (CI), 0.01-0.48]. Six of seven HAART-treated patients were alive versus 0/18 untreated patients at a median follow-up time of 667 days (P = 0.0007 by log rank test). A survival benefit was seen for patients who had >/= 0.5 log(10) copies/ml decrease in HIV viral load after diagnosis (n = 6; HR, 0.07; 95% CI, 0.01-0.55) and for patients with a significant CD4 cell rebound (increase >/= 50 x 106 cells/l) in response to HAART (n = 6): all survived versus 0/19 survived (P = 0.0003). Cranial radiation therapy (n = 13) prolonged survival (HR, 0.20; 95% CI, 0.07-0.58). Median survival was only 29 days for 11 patients who received neither radiation nor HAART. CONCLUSIONS: Receipt of HAART after diagnosis is associated with a significantly longer survival in patients with AIDS-related CNS lymphoma.     

Metabolic syndrome associated with HIV and highly active antiretroviral therapy

The introduction of highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of HIV disease with increased survival rates. However, some HAART regimens, especially those including protease inhibitors, have been shown to cause in a high proportion of HIV-infected patients metabolic (dyslipidemia, insulin resistance) and somatic (lipodystrophy/lipoatrophy) changes that are associated with an increased risk of cardiovascular disease (coronary artery disease and stroke). The pathogenesis of HAART-associated metabolic syndrome and of its atherogenic profile is complex, and several factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, activation of proinflammatory cytokines, and mitochondrial dysfunction. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients facing long-term HAART.     

Factors associated with poor immunologic response to virologic suppression by highly active antiretroviral therapy in HIV-infected women

Virologic response to highly active antiretroviral therapy (HAART) typically results in a substantial rise in CD4 cell counts. We investigated factors associated with poor CD4 response among HIV-infected women followed at 6-monthly intervals in the Women's Interagency HIV Study. Women with nadir CD4 counts < 350 cells/mm3 who achieved at least 6 months of plasma HIV RNA < 400 copies/ml were studied. Demographic, clinical, and treatment factors were compared between immunologic nonresponders, defined as the lower quartile of CD4 count change after two visits with virologic suppression (< 56 cell/mm3; n = 38), and the remaining group of responders (n = 115). Immunologic nonresponders had lower baseline HIV RNA levels and higher CD4 counts, more frequently used HAART 6 months prior to achieving consistent viral suppression, and more commonly had HIV RNA levels > 80 but < 400 copies/mL at both suppressive visits (21 vs. 7.8%, p = 0.024). In multivariate analysis, higher CD4 count and lower HIV RNA level at the last presuppressive visit were associated with immune nonresponse. We conclude that higher baseline CD4 count and lower HIV RNA level were associated with poor immunologic response to HAART in women with virologic suppression for at least 6 months. Persistent low level viremia may also contribute.     

Highly active antiretroviral therapy is associated with improved survival among patients with AIDS-related primary central nervous system non-Hodgkin's lymphoma

Highly active retroviral therapy (HAART) has been in widespread use in the United States since 1996. We sought to determine how the use of HAART influenced survival among patients with acquired immunodeficiency syndrome (AIDS) and primary central nervous system (CNS) non-Hodgkin's lymphoma (NHL). We used the population-based San Diego and Orange County cancer registry to identify 94 patients with both AIDS and CNS NHL diagnosed 1994-1999, of whom 31 were diagnosed 1996-1999. We performed Kaplan-Meier analyses to compare survival between patients who received HAART at NHL diagnosis or thereafter versus untreated patients and Cox proportional hazard models for adjusted survival. Among the patients diagnosed with NHL in 1996-1999, seven (23%) were taking HAART at the time of NHL diagnosis. Median survival was eight months for those who received HAART at the time of lymphoma diagnosis or after, versus one month for untreated patients. HAART, radiation therapy, and better performance status were associated with improved survival. We conclude that HAART prolongs survival in AIDS-related CNS NHL.     

HIV infection, highly active antiretroviral therapy and the cardiovascular system

Cardiovascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in peripheral artery and coronary artery diseases. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients candidate to antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines.     

Rapid reconstitution of humoral immunity against cytomegalovirus but not HIV following highly active antiretroviral therapy

OBJECTIVE: To determine the kinetics of reduction in human cytomegalovirus (HCMV) load and specific anti-glycoprotein B (gB) immune responses in patients with concurrent HCMV DNAaemia following the initiation of highly active antiretroviral therapy (HAART). DESIGN: Sequential analysis of eleven patients with HCMV DNAaemia who received HAART and eleven control patients with HCMV DNAaemia. METHODS: HCMV load was measured by quantitative competitive polymerase chain reaction and anti-gB, anti-HIV Env and Gag responses by an end-point dilution immunofluorescence assay using recombinant antigens expressed in insect cells. Estimates of the efficacy of the reconstituting immune system at controlling HCMV replication were based on previous dynamic models. RESULTS: In patients initiating HAART, HCMV DNA levels in blood declined rapidly, with a median half-life of 5.2 days, consistent with an efficacy of the reconstituting immune system at inhibiting HCMV replication of 52.8-85% (median, 61%). Commensurate with this decrease, a significant increase in anti-gB titres was observed in the post-HAART period (corresponding to an average fourfold increase in titre by 1 month rising to an eightfold increase at month 3; = 0.01). No changes in titre were observed in the control group or for anti-HIV Gag antibody levels, while anti-HIV Env antibody levels decreased after HAART. CONCLUSIONS: In patients with HCMV DNAaemia, reconstitution of humoral immunity to HCMV gB occurs rapidly following the initiation of HAART. These changes contrast with the patterns observed for anti-HIV humoral immune responses.     

Immune activation in patients infected with HIV type 1 and maintaining suppression of viral replication by highly active antiretroviral therapy

Immune activation associated with HIV infection declines after highly active antiretroviral therapy (HAART), but may persist or recur in some patients. It is not clear whether this reflects a resurgence of HIV replication or another cause of immune activation, such as inflammatory reactions to opportunistic pathogens (immune restoration disease [IRD]). Here, we studied plasma and cellular immune activation markers in adult HIV-1 patients who had received HAART for >12 months and maintained plasma HIV RNA levels of <400 copies/ml for >6 months. Plasma interleukin 1 receptor antagonist and tumor necrosis factor receptor I levels were similar in patients and HIV-negative control subjects, but the highest levels occurred mainly in patients with a history of IRD. In contrast, expression of HLA-DR and CD38 on monocytes and of HLA-DR on CD8(+) T cells was higher in patients than in control subjects. Thus, cellular markers of immune activation are abnormal in some patients with a good virological response to HAART, and abnormalities of plasma immune activation markers correlate with a history of IRD.     

Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) effectively reduces human immunodeficiency virus (HIV) RNA in cerebrospinal fluid (CSF), as well as in plasma. The effect on intrathecal immunoactivation is less well studied. We had earlier found that a substantial number of patients still have evidence of intrathecal immunoactivation after up to 2 years of treatment. We identified 15 patients treated with HAART for > or =4 years who had plasma HIV-RNA levels of <50 copies/mL for > or =3.5 years. CSF samples were available from 10 patients before treatment. We measured white-blood-cell count, HIV-RNA level, neopterin level, and IgG index. During treatment, all patients had HIV-RNA levels of <50 copies/mL in plasma and CSF. In CSF, both neopterin level and IgG index decreased significantly. After 4 years, 9 (60%) of the 15 patients still had neopterin levels in CSF that were above the upper normal reference value (5.8 nmol/L). During HAART, 9 (60%) of the 15 patients had an abnormal IgG index (>0.63). HAART significantly decreases intrathecal immunoactivation, but, despite effective treatment for >4 years, with HIV-RNA levels <50 copies/mL for > or =3.5 years, a substantial proportion of patients continue to show signs of macrophage/microglia activation and intrathecal immunoglobulin production in the CNS.     

A delay in CD4 cell response after initiation of highly active antiretroviral therapy is associated with the presence of anti-cytomegalovirus but not with anti-herpes simplex virus antibodies

After the successful initiation of highly active antiretroviral therapy (HAART) in HIV-1-infected patients, the mean CD4 cell response was lower in cytomegalovirus (CMV)-seropositive patients than in CMV-seronegative patients (P < 0.05). The difference between the mean CD4 cell counts of CMV-seronegative and CMV-seropositive patients was maximal (163 x 10(6)/l) at 76 weeks after the start of HAART, and decreased gradually thereafter. No association was found between herpes simplex virus types 1 and 2 serostatus and CD4 cell response.     

Defective hepatitis B virus DNA is not associated with disease status but is reduced by polymerase mutations associated with drug resistance

Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA (% dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90% of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the % dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated liver cirrhosis, genotype, or drug treatment. However, the % dDNA was significantly lower in individuals infected with lamivudine-resistant (LMV-R) HBV compared with wild-type HBV (P < 0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results. CONCLUSION: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.     

Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy

Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of-life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients.     

Immune reconstitution after receipt of highly active antiretroviral therapy in children with advanced or progressive HIV disease and complete or partial viral load response

We assessed CD4 cell recovery in 175 children with advanced human immunodeficiency virus disease who had received a 4-drug antiretroviral regimen and were categorized as viral load (VL) responders (VLRs), partial VLRs, or non-VLRs. Median CD4 cell counts increased from baseline to week 48, and, among children with maximal follow-up, increases in CD4 cell counts were sustained to week 96 among VLRs and partial VLRs but not among non-VLRs. For VL rebounders still in the study, CD4 cell counts remained increased for 32 weeks after VL rebound. Sustained immunologic benefits can be achieved even with partial VL response in children with advanced disease.