Preserved CD4 Cell Counts Research Articles

Quadrivalent HPV vaccine in HIV-1-infected early adolescent girls and boys in Kenya: Month 7 and 12 post vaccine immunogenicity and correlation with immune status

IntroductionIn sub-Saharan Africa, a generation of HIV-1-infected children is approaching the age of sexual debut and becoming at risk for HPV infection and its sequelae. We assessed safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in HIV-1-infected adolescents. MethodsIn an open-label trial among Kenyan, HIV-1-infected adolescents aged 9–14 years, we administered the qHPV vaccine at 0, 2 and 6 months and measured antibody titers to HPV-16, 18, 6 and 11 at month 7 and 12 post-vaccination. Measures of immunogenic response from HIV-1-negative historical cohorts from Africa and HIV-1 positive adolescent cohorts from the USA were used for comparison. ResultsWe enrolled 100 girls and 80 boys with a median age of 12 years and median baseline CD4 cell count of 684 (IQR 478, 935) cells/µL. One hundred and fifty four (86%) were receiving antiretroviral therapy for a median of 4.5 (IQR 2.3, 6.3) years; 110 (71%) had <400 copies of plasma HIV-1 RNA/mL. Of 189 enrolled children, 179 received all three doses. Two hundred and eighty five (64%) of 445 adverse events were injection site reactions; none were greater than grade 2. Of 6 Serious Adverse Events (SAEs), none were considered vaccine related. Seroconversion to HPV-18, 16, 11, 6 at month 7 occurred in 93.3%, 98.3%, 97.2% and 99.6% of vaccine recipients; similar rates have been reported in historical controls. The mean log10 HPV antibody titer measured at month 7 increased with each log10 increase in CD4 by 1.4 (95% CI: 1.1–1.7) for HPV-18; 1.2 (0.9–1.4) for HPV-16; 1.1 (0.8–1.3) for HPV-11; 0.7 (0.5–1.0) for HPV-6 (all p < 0.0001). ConclusionAlmost all Kenyan HIV-1-infected adolescents mounted an immune response comparable to other immunized populations. HPV antibody titers were higher in those with preserved CD4 cell counts. Longer term-follow up will determine sustainability of the immune response.ClinicalTrials.gov number, NCT00557245.

Immune activation despite preserved CD4 T cells in perinatally HIV-infected children and adolescents.

BackgroundHIV disease progresses more rapidly in children than adults with mortality rates exceeding 50% by 2 years of age without antiretroviral therapy (ART) in sub-Saharan Africa. Recent World Health Organization (WHO) guidelines recommend universal treatment for all living persons with HIV, yet there is limited supporting evidence in pediatric populations. The objective of this study was to determine whether CD4 cell counts reflect immunological markers associated with disease progression in ART naïve perinatally-infected HIV+ children and adolescents and their response to ART.MethodsPBMC and plasma samples were collected from 71 HIV negative and 132 HIV+ children (65 ART naïve and 67 on ART) between ages 1–19 years from Mombasa, Kenya. Untreated HIV+ subjects were sub-categorized by high or low CD4 T cell counts. Immune activation markers CD38, HLA-DR and Ki67 were analyzed by flow cytometry. Plasma soluble CD14 (sCD14) was quantified by ELISA.ResultsHIV-infected children and adolescents with preserved CD4 cell counts had depleted CD4 percentages and CD4:CD8 ratios, and high immune activation levels. ART initiation rapidly and persistently reversed T cell activation, but failed to normalize CD4:CD8 ratios and plasma sCD14 levels.ConclusionsDiminished CD4 percentages and CD4:CD8 ratios along with profound immune activation occur independent of CD4 cell count thresholds in ART naïve HIV+ children and adolescents. Immediate ART initiation, as recommended in the most recent WHO guidelines may protect them from pathologic sequelae associated with persistent inflammation.

First Report of AIDS-Related Burkitt's Lymphoma Presenting as Bilateral Orbital Masses.

Burkitt's lymphoma (BL) is an aggressive B-cell non-Hodgkin's lymphoma and one of the fastest growing tumors in humans. It is an acquired immunodeficiency syndrome- (AIDS-) defining disease and occurs with relatively preserved CD4 cell counts. It rarely affects the orbital region in the setting of AIDS. We report unusual presentation of a fatal case of AIDS-associated BL in a 42-year-old female patient with severe CD4 cell depletion who presented with dramatic fast growing (within days) bilateral orbital masses leading to striking facial deformities. To the best of our knowledge, this is the first report of bilateral orbital involvement in AIDS-associated BL.

Pandemic (H1N1) 2009 and HIV Infection

Pandemic (H1N1) 2009 and HIV Infection

Do nevirapine and efavirenz affect vitamin D homeostasis similarly?

Pasquet and colleagues observed, in keeping with previous studies [1–5], an association between exposure to non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral therapy and vitamin D deficiency in their cross-sectional cohort study [6]. Their study was insufficiently powered to look at individual NNRTI, and no significant association between vitamin D deficiency and either efavirenz or nevirapine was observed. However, comparable crude and adjusted coefficients for efavirenz and nevirapine led the authors to question whether the observed association between vitamin D deficiency and NNRTI reflects an NNRTI class effect rather than a phenomenon restricted to efavirenz as reported by ourselves [2]. An increasing body of evidence supports an association between efavirenz and 25-hydroxy-vitamin D [25(OH)D] deficiency [2,7,8]. Initiation of efavirenz appears to be consistently associated with reductions in 25(OH)D levels [5,6,9], and preliminary data suggest that etravirine and efavirenz may have similar effects on 25(OH)D homeostasis [10]. Although we found an association between efavirenz use and severe 25(OH)D deficiency [adjusted odds ratio (aOR) 2.0 (1.5, 2.7)] as well as raised alkaline phosphatase levels [aOR 1.6 (1.02, 2.4)], nevirapine use appeared to be protective against 25(OH)D deficiency [aOR 0.6 (0.3, 1.5)] and raised alkaline phosphatase [aOR 0.5 (0.3, 0.9)] in multivariate models adjusted for sex, ethnicity, season and CD4 cell count [2], and no association between nevirapine and 25(OH)D deficiency or insufficiency was observed in the SUN cohort [7]. Whilst comparable reductions in 25(OH)D have been observed in patients initiating efavirenz and nevirapine [5], the small sample size of this study precluded inclusion of individual NNRTI in multivariate analyses. Furthermore, no significant reductions in 25(OH)D from baseline were observed in 18 patients who initiated zidovudine, lamivudine and nevirapine [11] and in 27 patients who commenced nevirapine together with ritonavir-boosted lopinavir [12]. Whereas the effects of antiretroviral treatment-associated reductions in 25(OH)D on bone remain to be defined, a trend toward lower bone mineral density (BMD) with efavirenz and higher BMD with nevirapine has been reported in HIV infected children [13]. In clinical practice, efavirenz and nevirapine are preferentially used in some patients and avoided in others; associations with either NNRTI in observational cohort studies may thus be subject to channelling bias. For example, nevirapine may be the drug of choice for premenopausal African women with low CD4 cell counts and efavirenz for white men with preserved CD4 cell counts. As black ethnicity, female sex and low nadir CD4 cell count were all independently associated with severe vitamin D deficiency in our study [2], an inability to adjust for these factors may lead to a spurious association between nevirapine and vitamin D deficiency in cross-sectional studies. On the contrary, 61% of our patients were black, and it is possible that the effects of nevirapine on 25(OH)D homeostasis differ by ethnicity [14]. Of note, the two studies that reported a decline in 25(OH)D with nevirapine or an association between nevirapine and vitamin D deficiency predominantly included white men with preserved CD4 cell counts, did not adjust for sex, ethnicity and nadir CD4 cell count, and showed that 25(OH)D levels in black patients were minimally affected by antiretroviral treatment [5,6]. The consistent finding that vitamin D deficiency is very common in HIV-infected patients raises more important questions than which antiretroviral drug(s) may be implicated, namely what is the clinical significance of low 25(OH)D and is there any benefit from vitamin D supplementation? Vitamin D deficiency in the general population has been associated with numerous adverse health outcomes including cardiovascular disease, cancer, infection, osteopenia and fractures [15]. HIV infection is associated with an increased risk of (opportunistic) infections, cancer [16] and low BMD [17], and exposure to antiretroviral therapy with an increased risk of cardiovascular events [18] and further reductions in BMD [19]. As the greatest reductions in BMD are observed in patients who initiate antiretroviral therapy [12,20–21], the contribution of vitamin D deficiency and the potential of vitamin D supplementation to reduce this initial bone loss deserve further study. An effect of ethnicity and specific antiretrovirals, especially efavirenz and tenofovir, should be considered in the design of these studies. Acknowledgements None of the authors has any financial or personal relationships with people or organizations that could inappropriately influence this work, although all authors have, at some stage in the past, received funding from a variety of pharmaceutical companies for travel grants. In addition, F.A.P. has received research funding, speaking engagements or consultancy fees from GlaxoSmithKline, ViiV, Tibotec, Bristol-Meyers Squibb and Gilead Sciences.

It is safe to stop antiretroviral therapy in patients with preantiretroviral CD4 cell counts >250 cells/microL.

To study clinical, immunologic, and virologic outcomes in patients who stop antiretroviral therapy (ART) with relatively preserved CD4 cell counts. Patients with a documented CD4 cell count >250 cells/microL who stopped ART for any reason for at least 5 weeks were studied. Relevant clinical and laboratory data were collected using a standardized data collection form. Patients were monitored for outcomes including Centers for Disease Control (CDC) category B or C events, time to restarting ART, and time to reaching a CD4 cell count of < or = 250 cells/microL. A total of 107 patients were included. The median time on ART was 45 months and median number of antiretroviral medications was 4. The median pre-ART CD4 cell count and HIV viral load were 463 cells/microL and 4.35 log copies/mL, respectively. The median CD4 cell at time of ART stop was 739 cell/microL. The slope of the CD4 decrease was 65 cells/mo in the first 2 months, which was greater than the subsequent decline of 8 cells/mo thereafter (P < 0.01). Similarly the median viral load increase was 2.54 log copies/mL in the first 2 months after stopping and was unchanged after that point. Two patients experienced the retroviral rebound syndrome after ART cessation but no CDC category B or C events were observed during 10 months of follow-up. The median time from stopping ART to reaching the combined endpoint of CD4 <250 or restarting ART was 8.9 months. In multivariate analysis, pre-ART CD4 cell count >250 was protective of reaching the combined endpoint (odds ratio = 0.156, P = 0.03). Other predictors of reaching the combined endpoint in multivariate analysis were older age and number of prior ART agents. Patients who restarted ART had a favorable virologic and immunologic response. Patients with relatively high CD4 cell counts prior to starting ART did well after stopping ART. Pre-ART CD4 cell count can be used to predict outcomes after ART cessation.

Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes.

To evaluate CD4 T-cell cytopathicity of protease inhibitor (PI)-resistant isolates from patients with preserved CD4 cell counts after long-term virologic failure. PI-resistant primary isolates from 14 patients with stable or increasing CD4 T-cell counts despite long-term virologic failure during continuous combination therapy were examined. Replication and cytopathicity were assessed in activated peripheral blood mononuclear cell cultures in the presence and absence of PI using titered stocks of primary HIV-1 isolates and during initial viral isolation. Also studied were PI-sensitive isolates from four of these patients after therapy discontinuation and reversion to PI-sensitive virus and from seven antiretroviral drug-naive patients. Coreceptor use, syncytia-inducing (SI) phenotype and protease sequences were determined by standard methods. All isolates obtained during continued therapy showed genetic markers of PI resistance and decreased phenotypic susceptibility. PI-resistant SI isolates were highly to moderately cytopathic whereas non-syncytia-inducing isolates were moderately to weakly cytopathic. PI-susceptible and PI-resistant isolates obtained after discontinuation of therapy were equally cytopathic at similar replication levels. The cytopathicity of PI-resistant isolates was not altered by PI and was similar to that of isolates from untreated subjects. Primary isolates from patients showing virologic rebound without net CD4 T-cell loss during continued therapy are as cytopathic as PI-sensitive isolates with equivalent input infectious titer. As with PI-sensitive isolates, cytopathicity of PI-resistant viruses was determined primarily by coreceptor preference. These results suggest that the sustained immunologic response observed after failure of PI-containing regimens is not due to the emergence of PI-resistant strains that are intrinsically less cytopathic for activated peripheral CD4 lymphocytes.