Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters

Although continuous highly active antiretroviral therapy (HAART) is effective for many HIV-infected patients, it can be toxic and prohibitive in cost. By decreasing the total amount of time patients receive medications, intermittent HAART could reduce toxicity and cost. Therefore, we initiated a pilot study in which 10 HIV-infected individuals receiving effective therapy that resulted in levels of HIV RNA <50 copies per ml of plasma and CD4(+) T cell counts >300 cells per mm(3) of whole blood received repeated cycles of 7 days on HAART followed by 7 days off of HAART. Patients maintained suppression of plasma viremia for 32-68 weeks. There was no significant increase in HIV proviral DNA or replication-competent HIV in peripheral CD4(+) T cells or HIV RNA in peripheral blood or lymph node mononuclear cells. There was no significant change in CD4(+) T cell counts, no significant increase in CD4(+) or CD8(+) T cells expressing activation markers or producing IFN-gamma in response to HIV, no increase in CD4(+) T cell proliferation to p24 antigen, and no evidence for the development of resistance to HAART medications. There was a significant decrease in serum cholesterol and triglyceride levels. Thus, in this proof-of-concept study, short-cycle intermittent HAART maintained suppression of plasma viremia as well as HIV replication in reservoir sites while preserving CD4(+) T cell counts. In addition, there was a decrease in serum cholesterol and triglyceride levels. Intermittent therapy may be an important strategy to reduce cost and toxicity for HIV-infected individuals.     

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy

Objective

The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART.

Methods

Ferritin levels were retrospectively determined in stored plasma from 138 HAART‐naïve, moderately immunosuppressed HIV‐infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time‐points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption.

Results

At baseline, 31% and 16% of the HIV‐infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety‐five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (−8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/μL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05–3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C‐reactive protein were not elevated in patients with either high or low ferritin levels.

Conclusions

Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV‐positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART.

     

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.     

Metabolic and cardiovascular complications of highly active antiretroviral therapy for HIV infection

Highly active antiretroviral therapy (HAART) regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease. A careful stratification of the cardiovascular risk of HIV-infected patients under HAART is needed according to the most recent clinical guidelines.     

Osteoarticular complications related to HIV infection and highly active antiretroviral therapy.

With the significant increase in life expectancy for HIV-infected patients in the era of high potency antiretroviral therapy, major metabolic changes have been observed due to the prolonged period of the viral infection and the treatment itself. Osteoarticular changes resulting from these processes are mainly reported in long term HIV-infected patients receiving high potency antiretroviral therapy and include osteopenia/osteoporosis, osteonecrosis, carpal tunnel syndrome and adhesive capsulitis of the shoulder.     

Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: effects on drug toxicity and on immunologic and virologic parameters

We evaluated the effect of long-cycle structured intermittent therapy (SIT; 4 weeks without highly active antiretroviral therapy [HAART] followed by 8 weeks with HAART) versus continuous HAART. The study was prematurely terminated to new enrollment because of the emergence of genetic mutations associated with resistance to antiretroviral drugs in 5 patients. After 48 weeks, there was no significant difference between groups in lipid, hepatic transaminase, and C-reactive protein levels in 41 patients. Although there were no differences in CD4(+) or CD8(+) T cell counts or the percentage of cells that were CD4(+)CD25(+), CD8(+)CD25(+), or CD4(+)DR(+), patients who received SIT had a significantly higher percentage of CD8(+)CD38(+) and CD8(+)DR(+) cells. There was no clear autoimmunization effect by immunologic or virologic parameters. There was no benefit to long-cycle SIT versus continuous HAART with regard to certain toxicity, immunologic, or virologic parameters.     

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy

BACKGROUND: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SETTING: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. METHOD: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. RESULTS: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. CONCLUSIONS: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.     

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.     

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.     

HIV infection in the era of highly active antiretroviral therapy: the Malaga Study

We analyse the characteristics of patients diagnosed with HIV infection in the highly active antiretroviral therapy era in the southeast of Spain. Data were collected on 470 HIV patients diagnosed between January 1997 and December 2002. The number of cases fell over recent years and HIV transmission was sexual in 70.5%. The mean CD4 lymphocyte count was 302.1 x 10(6)/L and the mean viral load 4.70 log(10). Diagnosis of HIV coincided with an AIDS-defining opportunistic illness in 30.6% of patients and a late diagnosis (CD4 < 200 x 10(6)/L) was made in 48.3% of patients. A late diagnosis was related to male gender (OR 2.50; 95% CI 1.20-5.12; P < 0.001) and AIDS case (OR 18.80; 95% CI 10.50-33.80; P < 0.00001). These results suggest that there has been a progressive reduction in new cases of HIV-infected patients, with the main route of transmission being sexual and that the diagnosis was late in almost half the patients.     

HIV infection with negative serological tests: development of seropositivity in association with highly active antiretroviral therapy

A 19-year-old woman with well-documented HIV-1 infection had persistently negative enzyme immunoassay (EIA) and Western blot serological tests. She has plasma HIV-1 RNA levels of > 480,000 copies/mL and T-helper cell counts of approximately 100/mm3. When treated with highly active antiretroviral therapy (HAART), the viral load became undetectable (< 400 copies/mL), the T-helper cell count increased to > 500/mm3 and EIA and Western blot tests became positive.     

Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma

Twenty-eight HIV patients either naive or failing highly active antiretroviral therapy (HAART)with moderate-advanced Kaposi's sarcoma (KS)were randomly chosen to initiate a new HAART regimen plus pegylated liposomal doxorubicin(PLD) or the new HAART regimen alone. After 48 weeks, better response rates were observed in the HAART plus PLD group (76% versus 20%).In HIV-infected patients with moderate-advanced KS, HAART alone may not be enough for KS response.     

Meta-analysis of adherence to highly active antiretroviral therapy in patients with HIV infection in China

With the widespread implementation of antiretroviral therapy in many countries, the HIV/AIDS epidemic has declined. However, little is known about the prevalence of adherence rate to Highly Active Antiretroviral Therapy (HAART) in patients with HIV infection in China. This is the first meta-analysis of cross-sectional studies of treatment adherence (≥ 95%) to HAART in Chinese patients. Both English (PubMed, PsycINFO, EMBASE, and Web of Science) and Chinese (WanFang, CNKI, and SinoMed) databases were systematically and independently searched by three investigators. Studies with adherence rate estimates of HAART were included. Adherence rate estimates of each eligible study were extracted and pooled using the random-effects model. A total of 40 studies conducted in China were eligible and analyzed. The mean rate of?≥?95% adherence to HAART was 81.1% (95%CI: 75.1%–88.0%, I²?=?97.3%) at one week, 80.9% (95%CI: 74.7%–85.9%, I²?=?96.6%) at one month, and 68.3% (95%CI: 46.1%–84.4%, I²?=?97.1%) at 3 months or longer. Subgroup analyses revealed that samples with no gender predominance, low education level, middle economic region, rural area, older age (42.3 years), and recent publication (2013 or later) were correlated to higher HAART adherence. The average rate of HAART adherence was relatively high in China, which indicates effective HIV/AIDS policy, prevention and control measures. However, the HAART adherence rate decreased over the study time period.     

Intensive care in patients with HIV infection in the era of highly active antiretroviral therapy

STUDY OBJECTIVES: The use of highly active antiretroviral therapy (HAART) has dramatically improved morbidity and mortality in patients with HIV infection. The types of critical illness and their outcomes in HIV-infected patients in recent years is unknown. DESIGN: We reviewed the medical records of all patients admitted to the Medical ICU of Beth Israel Medical Center, NY, from January to June 2001 and compared their characteristics with patients admitted to the same unit from November 1991 to October 1992. RESULTS: Of 441 admissions in the first half of 2001, 63 admissions (14%) were in 53 HIV-seropositive patients. There were 65 admissions to the Medical ICU during the 1-year period spanning 1991 to 1992. Compared with the earlier period, the 2001 patients were more likely to be black (52% vs 26%, respectively; p < 0.01) and injection drug users (75% vs 48%, respectively; p < 0.01), and were less likely to be white (11% vs 23%, respectively; difference not significant) and homosexual men (6% vs 26%, respectively; p < 0.01). In 2001, patients were less likely to be admitted with respiratory failure (22% vs 54%, respectively; p < 0.01) and with Pneumocystis jiroveci pneumonia (formerly referred to as Pneumocystis carinii) [3% vs 34%, respectively; p < 0.001], and were more likely to be admitted with non-HIV-related diseases (67% vs 12%, respectively; p < 0.001). Overall survival was much higher in the later period (71% vs 49%, respectively; p < 0.01). CONCLUSIONS: In the era of HAART, more patients with HIV infection were admitted to the ICU over a 12-month period than were 10 years previously. Patients were more likely to be injection drug users and were more likely to be admitted to the ICU because of non-HIV-associated conditions.     

Timing of highly active antiretroviral therapy and chemotherapy for Kaposi's sarcoma in patients with HIV infection

Highly active antiretroviral therapy (HAART) is an important part of the treatment of Kaposi's sarcoma (KS) in HIV-infected patients. We describe two cases of KS, which worsened on HAART.