Comparative response of African HIV-1-infected individuals to highly active antiretroviral therapy

OBJECTIVE: Few data exist on the virological response to antiretroviral therapy of individuals infected with African HIV-1 subtypes. Our objective was to compare the response, in our clinic, of African HIV-1-infected patients with their British and European contemporaries treated with the same regimes. DESIGN: The St Mary's Hospital HIV database was used to identify drug-naive African and European patients starting a highly active antiretroviral therapy (HAART) regimen. METHODS: HIV-1 subtype was determined by phylogenetic analysis of pol sequences. Kaplan-Meier survival analysis was used to estimate the proportion of patients achieving undetectable viral loads (< 500 copies/ml). The longer-term response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. RESULTS: A total of 265 patients were classified as 'European' and 97 as 'African', confirmed by sequence. The time to first undetectable viral load was similar for the two groups (P = 0.9). Although there were no statistically significant differences in the CD4 cell count responses (P = 0.11), there was evidence of an increase in viral load after 9 months for the African group, resulting in a widening viral load gap between the two cohorts; the effect of ethnic group was statistically significant (P < 0.001). CONCLUSION: The initial virological and immunological responses of the African and European cohorts to HAART were similar; although the longer-term virological response was poorer in the African cohort, which may be related to adherence. On the basis of these findings, there is no justification for withholding HAART from Africa on virological grounds.     

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients

Background

We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV‐1.

Methods

A multicentre retrospective study of 23 multidrug‐resistant paediatric patients (five children and 18 adolescents) enrolled in the study from 1 September 2007 to 28 February 2010 was carried out. We performed a longitudinal analysis of immunological, virological and clinical data.

Results

The median age of the patients was 14.2 years [interquartile range (IQR) 12.5–15.8 years]. At baseline, the median HIV‐1 RNA was 29 000 (4.5 log₁₀) HIV‐1 RNA copies/mL (range 4300‐83 000 copies/mL), the median CD4 T‐cell count was 445 cells/μL (range 221–655 cells/μL) and the median CD4 percentage was 19.6% (IQR 13.0‐31.0). Remarkably, 16 of 23 patients (70%) harboured one or more etravirine‐associated resistance mutations. The backbone regimen included at least two fully active drugs in 91% of patients. After etravirine‐based therapy, 20 patients (87%) achieved HIV‐1 RNA<400 copies/mL and 18 of 23 (78%) achieved HIV‐1 RNA<50 copies/mL: three (13%) within the first month, seven (30%) within the first 4 months, and six (26%) between the 5th and 8th months. CD4 T‐cell recovery was observed in 19 patients (83%). The median follow‐up time was 48.4 weeks (IQR 35.7–63.4 weeks); four patients (17%) were exposed to etravirine for >120 weeks. Three mild/short‐term and two moderate skin rashes were observed in the adolescents. Laboratory abnormalities included hypercholesterolaemia (11 of 23 patients), hypertriglyceridaemia (eight of 23 patients), and reduced high‐density lipoprotein cholesterol (10 of 23 patients). Adherence was complete in seven patients (30%). No patients showed complete resistance to etravirine after follow‐up. However, three of 21 patients (14%) who initially showed intermediate resistance interrupted etravirine treatment because of virological failure.

Conclusions

We observed a sustained antiviral response and improved immunological parameters in multidrug‐resistant paediatric patients, most of whom had received etravirine as part of salvage regimens with at least two fully active drugs.     

Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients.

OBJECTIVE: To assess the impact of long-term virus suppression on the peripheral blood CD4 T cells integrated and total HIV-1 DNA loads in patients receiving highly active antiretroviral therapy (HAART). METHODS: A total of 10 HIV-1-infected patients receiving a triple combination therapy (two nucleoside analogues and one protease inhibitor) were longitudinally studied to compare integrated and total HIV-1 DNA loads. HIV-1 DNA quantification was performed using a quantitative nested polymerase chain reaction (PCR) on genomic peripheral blood mononuclear cell (PBMC) DNA obtained at baseline and at 48 weeks of HAART. RESULTS: All the study patients showed an early and sustained decrease in plasma HIV-1 RNA to below the limit of detection (200 copies/ml). Concordant with the plasma viral decline, a significant increase in the CD4 T cell count was observed (P = 0.007). A statistically significant fivefold decrease in total HIV-1 DNA was detected after 48 weeks of HAART (P = 0.005). However, no statistically significant change was noted after the therapy when the integrated HIV-1 DNA copy number was compared (P = 0.333). Taken together, these results suggest that in the patients analysed the integrated HIV-1 DNA does not decay rapidly after HAART. CONCLUSION: Within the study cohort the total amount of PBMC HIV-1 DNA decreased drastically after 48 weeks of HAART. Nevertheless, the integrated HIV-1 DNA did not significantly decay during this period. Although the data presented here are limited by the number of patients analysed, our findings suggest that 48 weeks of HAART does not significantly reduce the integrated HIV-1 proviral DNA load in the latently infected CD4 T cell reservoir.     

Once-a-day highly active antiretroviral therapy in treatment-naive HIV-1-infected adults in Senegal

OBJECTIVES: To study the effectiveness, adherence and tolerance of a once-a-day highly active antiretroviral therapy regimen in adults in Senegal. DESIGN AND METHODS: In a prospective, open-label one-arm study, 40 treatment-naive HIV-1-infected patients took the following three drugs once a day at bedtime: didanosine, lamivudine and efavirenz. The primary endpoint was the percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months. The analysis was done on an intent-to treat basis. RESULTS: Eighty-five per cent of patients were at Centers for Disease Control and Prevention stage B or C and the plasma HIV RNA level was 5.4 +/- 0.4 log(10) copies/ml at baseline. The percentage of patients with plasma HIV-1 RNA below 500 copies/ml at 6 months was 95% [95% confidence interval (CI), 83-99]. The proportions of patients with plasma HIV-1 RNA below 50 copies/ml at months 3, 6, 9, 12 and 15 were 26% (n = 39; 95% CI, 12-39), 78% (n = 40; 95% CI, 65-90), 70% (n = 40; 95% CI, 56-84), 77% (n = 39; 95% CI, 64-90) and 69% (n = 39; 95% CI, 55-84), respectively. The CD4 cell count was 164 +/- 75 x 106/l at baseline and increased by a mean of 199 +/- 101 x 106/l at month 15. Permanent treatment discontinuation was never necessary for serious adverse effects. Adherence was excellent, as shown by plasma drug concentrations and according to the results of the questionnaire. CONCLUSIONS: The once-daily regimen of didanosine, lamivudine and efavirenz was safe, easy-to-take and demonstrated strong antiretroviral and immunologic effects in African patients with advanced HIV infection.     

Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy

PURPOSE: To review reported inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) in persons infected with HIV-1 and to explore the mechanisms leading to these reactions. DATA SOURCES: MEDLINE search of biomedical literature reporting inflammatory reactions after HAART. Bibliographies of retrieved reports were also reviewed. STUDY SELECTION: Articles describing patients infected with HIV-1 who had immunologic and virologic responses to HAART and subsequently developed inflammatory reactions. DATA EXTRACTION: Data on the immune status, clinical characteristics, and therapeutic management of patients who were seropositive for HIV-1 and had inflammatory reactions after HAART. DATA SYNTHESIS: Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced reductions in plasma HIV-1 viral load and increases in CD4(+) T-lymphocyte counts. Clinical presentation was often atypical of that in patients with untreated HIV-1 infection, probably because of restored immunity. Most cases improved despite continuation of HAART, although some patients required anti-inflammatory drugs or specific antimicrobial agents. CONCLUSIONS: Clinicians caring for patients who are infected with HIV-1 and receiving HAART must be aware of this new and diverse clinical syndrome. As more HAART recipients are studied, new presentations will probably be observed.     

Decreased apoptosis of bone marrow progenitor cells in HIV-1-infected patients during highly active antiretroviral therapy

Impaired haematopoiesis during HIV-1 infection may be caused by the overproduction of inflammatory cytokines by immune cells at the bone marrow level inducing Fas-mediated apoptosis of stem progenitors. In this study, we evaluated the effects of highly active antiretroviral therapy on apoptosis of CD34+ stem cells derived from the bone marrow of HIV-1-infected patients, and observed decreased Fas expression on progenitor cells, in parallel with the diminution of TNF-alpha levels and the amelioration of clonogenic parameters.     

Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients

OBJECTIVE: Unusual clinical inflammatory syndromes associated with underlying previously unrecognized opportunistic infections are increasingly being noted shortly after starting highly active antiretroviral therapy (HAART). This study examined the possible relationship between such unexpected disease manifestations and in vitro parameters of microbial antigen-specific immune reactivity in patients infected with HIV-1 who had a Mycobacterium avium intracellulare or Mycobacterium xenopi infection. DESIGN: In vitro T-cell proliferation experiments were performed after specific stimulation of a patient's peripheral blood mononuclear cells (PBMC) with M. avium and M. xenopi antigen and non-specific stimulation with phytohaemagglutinin (PHA). The results were compared with appropriate controls. PATIENTS: Five patients who presented with unusual clinical syndromes associated with M. avium or M. xenopi infection within weeks of experiencing large rises in CD4+ cell counts following the initiation of antiretroviral therapy. RESULTS: In all patients except one, mycobacteria-specific lymphoproliferative responses rose significantly following HAART; this was temporally associated with elevations in CD4+ cell counts and the occurrence of clinical disease. The patient with M. xenopi infection appeared to clear his infection subsequently without antimycobacterial therapy. In three of the four patients with M. avium infection, antimycobacterial treatment could be stopped without recurrence of infection. CONCLUSION: Our findings support the hypothesis that HAART may lead to clinically relevant inflammation as a result of restoration of specific immune reactivity against microbial pathogens that are subclinically present at the time treatment is initiated. Continuation of HAART may subsequently result in protective immunity and clearance of infection.     

Long-term decay of the HIV-1 reservoir in HIV-1-infected children treated with highly active antiretroviral therapy

To investigate the decay of the human immunodeficiency virus type 1 (HIV-1) reservoir in children receiving highly active antiretroviral therapy (HAART), we measured HIV-1 DNA in peripheral blood mononuclear cells from 14 children who achieved and maintained suppression of plasma viremia up to 48 months after the initiation of HAART. Levels of intracellular unspliced and multiply spliced HIV-1 RNA were used as markers of residual viral replication. During the first month of HAART, there were significant decays in levels of both plasma HIV-1 RNA and multiply spliced HIV-1 RNA, yet unspliced HIV-1 RNA persisted in most of the children. Greater HIV-1 DNA decay during the first month of HAART correlated with a higher concomitant increase in CD4(+) cell counts (P=.028) and a smaller subsequent HIV-1 DNA decay (P=.0012). Furthermore, HIV-1 DNA decayed faster from 1 to 9 months of HAART (median half-life, 5 months) than during the subsequent follow-up period (median half-life, 30 months). Moreover, after 9 months of HAART, HIV-1 DNA tended to decay more slowly in children with detectable levels of unspliced HIV-1 RNA. These findings suggest that clearance of the viral reservoir in HAART-treated children may be influenced by immune repopulation and residual viral replication and may help in refining long-term treatment strategies.     

Hyperglycosylated ferritin in sera of HIV-1-infected patients treated with highly active antiretroviral therapy

A study was conducted to determine the relationship between ferritin and glycosylated isoforms of ferritin and insulin resistance in 69 HIV-infected men receiving HAART. Ferritin levels were significantly correlated with aspartate aminotransferase, alanine aminotransferase, bilirubin and with insulin resistance. The ferritin isoelectric focusing patterns of five insulin-resistant HIV-infected patients under HAART showed large amounts of hyperglycosylated isoforms, which was not found in 56 control subjects and 46 untreated HIV-1-infected patients.     

Metabolic complications associated with the use of highly active antiretroviral therapy in HIV-1-infected adults

The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic declines in morbidity and mortality in patients infected with human immunodeficiency virus-1 (HIV-1). However, the success of HAART has been tempered by the recognition of adverse metabolic effects clearly associated with its use. These "metabolic complications" include dyslipidemia, changes in body fat distribution, insulin resistance and glucose intolerance, metabolic bone disease, and lactic acidosis. Guidelines to assist clinicians in the management of these complications have been put forth by various organizations, including the International AIDS Society, the HIV Medicine Association of the Infectious Disease Society of America, and the Adult AIDS Clinical Trials Group.     

Serum leptin concentrations and fat redistribution in HIV-1-infected children on highly active antiretroviral therapy

OBJECTIVES: HIV-related lipodystrophy is a syndrome of adipose tissue redistribution, dyslipidaemia and insulin resistance. Combination antiretroviral therapy (CART) is a key risk factor. We hypothesized that fat redistribution in HIV-infected children is related to altered endocrine function of adipose tissue, namely leptin secretion. METHODS: Serum leptin and fat redistribution were measured in 104 HIV-infected children in a prospective observational study from 2003 to 2004. Fat redistribution was defined by clinical observation. Body fatness was estimated using body mass index and four skinfold measurements. Serum leptin was determined using an enzyme-linked immunosorbent assay (Quantikine; R&D Systems, Abingdon, UK). Linear analogue models were used to adjust the leptin concentration for body fatness. RESULTS: There was no significant difference in serum leptin among children treated with protease inhibitors (PIs), children on non-PI CART and children not treated with CART (P>0.05). When leptin concentrations were adjusted for body fatness, there was again no difference among PI-treated, non-PI-treated and untreated children. Categorization of CART exposure as never, current or past did not change these results. CONCLUSIONS: There is no evidence that leptin plays any role in lipodystrophy other than reflecting body fatness.     

T-cell repopulation and thymic volume in HIV-1-infected adult patients after highly active antiretroviral therapy

The origin of T cells after highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus 1 (HIV-1) is now under discussion. The possibility of renewed lymphopoiesis in aged thymuses is still controversial. In this work we combine the analysis of na?ve T cells, T-cell receptor excision circles (TRECs), and computed tomography scanning of thymic tissue to further assess whether the thymus is involved in immune reconstitution. Fifteen antiretroviral-na?ve HIV-1-infected patients were evaluated during 48 weeks of HAART. At baseline, significant correlation was present among age and both thymic volume and TRECs, and between na?ve T cells and TRECs. After starting HAART, there was a significant increase at week 12 in na?ve CD4(+) and CD8(+) T cells, TRECs, and thymic volume. The initial net increases in na?ve T cells and TREC counts were significantly correlated. Changes in thymic volume and TRECs were also indirectly related; splitting the population into 2 groups of high and low baseline TREC levels, only the group with low TREC levels had significant increases in both TRECs and thymic volume. Thus, the increase in thymic volume might be functional, in response to depleted TREC levels. Taken together, our data strongly suggest a thymic role in immune reconstitution, at least in patients with depleted baseline TREC levels. (Blood. 2002;99:3702-3706)     

Comparison between HIV-1-infected hemophiliacs and non-hemophiliacs on survival and clinical courses after starting highly active antiretroviral therapy

In order to investigate the long-term prognosis and clinical efficacy of highly active antiretroviral therapy (HAART) in HIV-1-infected hemophiliacs, we compared clinical courses of 69 HIV-1-infected hemophiliacs and 29 non-hemophiliacs all of whom were asymptomatic between 1990 and 1993. Changes of CD4 count during 1990 through 2000 in both groups were not significantly different. The time to death due to AIDS in both groups were also not significantly different. The major causes of death not related to AIDS in hemophiliacs were bleeding, liver cirrhosis, and liver cancer. A total of 55 (39 hemophiliacs and 16 non-hemophiliacs) out of 98 patients survived in 1997. Since then, the 28 hemophiliacs and the 12 non-hemophiliacs received HAART. Although the percentage of patients whose viral loads (VL) decreased to below undetectable level (VL < 400 copies/ml) by the initial HAART regimens without saquinavir were not significantly different, continuation of the same regimens in the hemophiliacs were significantly longer than non-hemophiliacs (84 weeks vs. 51 weeks, p < 0.05). From starting HAART to July 2000, 35.7% of the hemophiliacs were changed regimens three times or more. That is higher prevalence comparing with non-hemophiliacs of 16.7%. This study suggests that there might be the patient group who have to been changed HAART regimens frequently in the hemophiliacs.