Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014.

BACKGROUND: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. METHODS: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. RESULTS: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDR-TB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50.7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. CONCLUSION: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment.

Tuberculosis specific responses following therapy for TB: Impact of HIV co-infection.

Characterizing perturbations in the immune response to tuberculosis in HIV can develop insights into the pathogenesis of coinfection. HIV+ TB+ and TB monoinfected (TB+) subjects recruited from clinics in Bamako prior to initiation of TB treatment were evaluated at time-points following initiation of therapy. Flow cytometry assessed CD4+/CD8+ T cell subsets and activation markers CD38/HLA-DR. Antigen specific responses to TB proteins were assessed by intracellular cytokine detection and proliferation. HIV+ TB+ subjects had significantly higher markers of immune activation in the CD4+ and CD8+ T cells compared to TB+ subjects. HIV+ TB+ had lower numbers of TB-specific CD4+ T cells at baseline. Plasma IFNγ levels were similar between HIV+ TB+ and TB+ subjects. No differences were observed in in-vitro proliferative capacity to TB antigens between HIV+ TB+ and TB+ subjects. Subjects with HIV+ TB+ coinfection demonstrate in vivo expansion of TB-specific CD4+ T cells. Immunodeficiency associated with CD4+ T cell depletion may be less significant compared to immunosuppression associated with HIV viremia or untreated TB infection.

Baseline CD4+ T-cell counts predict HBV viral kinetics to adefovir treatment in lamivudine-resistant HBV-infected patients with or without HIV infection.

BACKGROUND: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. METHODS: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. RESULTS: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. CONCLUSION: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV.

CCL5 mRNA is a marker for early fibrosis in chronic hepatitis C and is regulated by interferon-α therapy and toll-like receptor 3 signalling.

Mechanisms causing liver fibrosis during chronic hepatitis C virus infection (cHCV) are not sufficiently understood. This study was aimed to identify biomarkers for early fibrosis (EF) and to investigate their potential role in cHCV-related fibrogenesis. To this end, peripheral whole blood (PB) samples from 36 patients with cHCV recruited from two independent cohorts were subjected to microarray analysis 12 h before initiation of peginterferon-alpha (Peg-IFN-α) and ribavirin therapy. Liver biopsies were evaluated using the Batts-Ludwig staging (BL-S) classification system for fibrosis. We showed that gene expression profiles (N = 8) distinguished between EF (BL-S: 0,1) and late fibrosis (LF; BL-S: 2,3,4) with 88.9% accuracy. Fibrosis-related functional annotations for chemokine-'C-C-motif'' ligand 5 (CCL5) provided foundation for focused investigation, and qRT-PCR confirmed that CCL5 mRNA levels (PB) reliably discriminate EF from LF (accuracy: 86.7%). Positive correlations (P < 0.05) with CCL5 mRNA levels and EF discovered gene expression profiles (PB) reflecting stable expression of IFN-α receptor 1, negative regulation of the MyD88-dependent toll-like receptor (TLR) pathway and decreased expression of TLR3 in vivo. Remarkably, Peg-IFN-α suppressed CCL5 mRNA levels (PB) in EF in vivo. These findings along with results from parallel in vitro investigation into the effect of IFN-α or poly I:C (TLR3-agonist) on CCL5 gene expression in hepatic stellate cells (HSC) attest to the multi-site involvement of these pathways in regulating fibrogenesis. In conclusion, we identified novel, reliable biomarkers for EF and exposed functional properties of the molecular network regulating CCL5 biosynthesis in peripheral or hepatic cell types with key roles in cHCV-related liver and/or immune pathogenesis.

Peripheral expansion of pre-existing mature T cells is an important means of CD4+ T-cell regeneration HIV-infected adults.

The CD4+ T-cell pool in HIV-infected patients is in a constant state of flux as CD4+ T cells are infected and destroyed by HIV and new cells take their place. To study T-cell survival, we adoptively transferred peripheral blood lymphocytes transduced with the neomycin phosphotransferase gene between syngeneic twin pairs discordant for HIV infection. A stable fraction of marked CD4+ T cells persisted in the circulation for four to eighteen weeks after transfer in all patients. After this time there was a precipitous decline in marked cells in three of the patients. At approximately six months, marked cells were in lymphoid tissues in proportions comparable to those found in peripheral blood. In two patients, the proportion of total signal for the transgene (found by PCR analysis) in the CD4/CD45RA+ T-cell population relative to the CD4/CD45RO+ population increased in the weeks after cell infusion. These findings indicate that genetically-marked CD4+ T cells persist in vivo for weeks to months and that the CD4+ T-cell pool in adults is maintained mostly by the division of mature T cells rather than by differentiation of prethymic stem cells. Thus, after elements of the T-cell repertoire are lost through HIV infection, they may be difficult to replace.

Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV.

We examined the effects of human immunodeficiency virus infection on the turnover of CD4 and CD8 T lymphocytes in 17 HIV-infected patients by 30 min in vivo pulse labeling with bromodeoxyuridine (BrdU). The percentage of labeled CD4 and CD8 T lymphocytes was initially higher in lymph nodes than in blood. Labeled cells equilibrated between the two compartments within 24 h. Based on mathematical modeling of the dynamics of BrdU-labeled cells in the blood, we identified rapidly and slowly proliferating subpopulations of CD4 and CD8 T lymphocytes. The percentage, but not the decay rate, of labeled CD4 or CD8 cells in the rapidly proliferating pool correlated significantly with plasma HIV RNA levels for both CD4 (r = 0.77, P < 0.001) and CD8 (r = 0.81, P < 0.001) T cells. In six patients there was a geometric mean decrease of greater than 2 logs in HIV levels within 2 to 6 mo after the initiation of highly active antiretroviral therapy; this was associated with a significant decrease in the percentage (but not the decay rate) of labeled cells in the rapidly proliferating pool for both CD4 (P = 0.03) and CD8 (P < 0.001) T lymphocytes. Neither plasma viral levels nor therapy had an effect on the decay rate constants or the percentage of labeled cells in the slowly proliferating pool. Monocyte production was inversely related to viral load (r = -0.56, P = 0.003) and increased with therapy (P = 0.01). These findings demonstrate that HIV does not impair CD4 T cell production but does increase CD4 and CD8 lymphocyte proliferation and death by inducing entry into a rapidly proliferating subpopulation of cells.

[Depression and neuroplasticity]. / Dépression et neuroplasticité.

The effect of antidepressants cannot be explained by the classical monoaminergic theory. In particular, that model does not explain the delay in clinical response with antidepressants. Many hypotheses have been developed to understand the mechanism of action of antidepressants, each of them involving the regulation of different receptors. In parallel, functional brain imaging and neurobiological techniques have revealed specific neuroanatomical lesions in affective disorders. Depression in particular is associated with a neuronal loss in specific brain regions. These anatomical changes are reduced after antidepressant treatment. In the last decade, a new pathophysiological concept of affective disorders has emerged, integrating preferentially molecular and cellular antidepressant-induced changes leading to rehabilitation of synaptic activity. In the present review, we will summarize recent crucial data that establish the link between depression and neuroplasticity.

Induction of humoral and cell-mediated anti-human immunodeficiency virus (HIV) responses in HIV sero-negative volunteers by immunization with recombinant gp160.

Development of an effective vaccine for prevention of infection with HIV would provide an important mechanism for controlling the AIDS epidemic. In the current study, the first clinical trial of a candidate HIV-1 vaccine initiated in the United States, the safety and immunogenicity of escalating doses (10-1,280 micrograms) of recombinant gp160 (rgp160), were evaluated in 138 HIV-negative volunteers. Maximal antibody responses, as evaluated by ELISA, were seen after immunization with three doses of 1,280 micrograms rgp160. Responses to some specific epitopes of HIV gp160, including the second conserved domain and the CD4 binding site, were seen more frequently than after natural infection. Neutralizing antibodies to the homologous HIV strain, but not heterologous strains, were induced by this regimen. Blastogenic responses to rgp160 were seen in most volunteers receiving at least two doses of > or = 20 micrograms. These envelope-specific T cell responses were also seen against heterologous strains of HIV. No major adverse reactions were seen after immunization. Thus, rgp160 is a safe and immunogenic candidate HIV vaccine; further studies are needed to determine if it will provide any clinical benefit in preventing HIV infection.

Establishing Reference Ranges of Hematological Parameters from Malian Healthy Adults.

INTRODUCTION: Measurement of immuno-hematological parameters has been historically helpful in the diagnosis and treatment monitoring of many infectious diseases and cancers. However, these parameters have not yet been established in many developing countries where patient care strongly relies on such low-cost tests. This study describes the immuno-hematological parameter ranges for Malian healthy adults. METHODS: A cross sectional study was conducted from August 2004 to May 2013. We included 213 healthy volunteers (173 male and 40 female), aged between 18-59 years. Median, 2.5 and 97.5 percentile ranges for each immuno-hematological parameter are presented. RESULTS: In our study population, the hematological parameters' ranges were mostly different to the universal established ranges. We found in our population a Median white blood cell (WBC) count of 5200 cells/µL [3237.5-11900], Red Blood Cell (RBC) count of 4.94 10^6 [3.56-6.17], hemoglobin (Hb) of 14.2 g/dL [12.2-17.38], platelet count (Plt) of 275 10^3/µL [145.4-614.4], lymphocytes 2050/µL [1200-3800], neutrophils 2200/µL [1040-6220]; monocytes 200/µL [100-660]; eosinophils 131/µL [0-1026]; CD4 902 cells/µL [444-1669] and CD8 485 cells/µL [0-1272]. We found significant gender differences in RBC, Hb level and MPV. However, RBC and Hb were higher in males median values compared to females (median values) (p<0.001), whereas the Mean platelet volume lower values (MPV) in males than females (P<0.047). The hemoglobin level for some West African countries (Mali, Burkina Faso, Togo, and Nigeria) ranged from 13.5 to 15.1 g/dL for males and 12 to 13 g/dL for females. However in East and Southern Africa, the values were anywhere from 14.1 to 16.1 for males and 11.2 to 14.4 for females. CONCLUSION: Our data may help physicians to better define hematological abnormalities in patients. They may also be used to define new "normal hematological values" in Malian population or in the whole West African population.

Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali.

OBJECTIVES: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the 'cording' characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method-Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). METHODS AND RESULTS: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517-1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5-11) and 6 days (IQR 5-6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. CONCLUSION: As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB.

Prospects for an emergency department-based adult immunization program.

Immunization of adults has been deficient in the United States. According to interviews conducted during their visits to an emergency room, only 20.1% of 350 patients who fit into high-risk categories for immunization had heard of pneumococcal vaccine, whereas 82.7% had heard of influenza vaccine. Only 8.6% and 47.8%, respectively, had ever been given pneumococcal or influenza vaccine. Previous pneumococcal vaccination was six times more common (10.3% vs 1.6%) and prior influenza vaccination twice as common (52.7% vs 25.4%) in the respondents who could identify a primary care provider or clinic than in those who could not. Of the patients who had not received a specific vaccine, about 60% indicated that they would take pneumococcal or influenza vaccine if it was offered while they were in the emergency room setting. Offering vaccine in an emergency room setting promises to complement other approaches to immunizing adults at high risk for complications of influenza and pneumococcal infections.

Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA.

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.

A dose escalation study to determine the toxicity and maximally tolerated dose of foscarnet.

OBJECTIVE: To determine the maximum tolerated dose of intravenous foscarnet (trisodium phosphonoformate hexahydrate); and to examine antiviral activity at plasma levels shown to inhibit HIV-1. DESIGN: Dose escalation study in three male subjects with AIDS who received foscarnet by continuous intravenous infusion at a dose of 200 mg/kg per day, after a 20 mg/kg loading dose. The dose was increased until a plasma level > 150 micrograms/ml was attained. RESULTS: Foscarnet was discontinued due to progressive renal insufficiency in all three patients (days 11, 19, and 21). Renal function normalized in all three, and no adverse sequelae due to foscarnet were observed at 1 year of follow-up. A seizure was observed in one patient on day 19. Maximum daily doses of foscarnet achieved were 395 mg/kg, 389 mg/kg, and 523 mg/kg. No changes in serum Ca2+, Mg2+, or PO4- were observed. CONCLUSIONS: Renal effects and toxicity of foscarnet in evolving renal insufficiency is self-limiting and reversible when the drug is discontinued. Incremental increases in dose can result in rapid rises in the plasma level with renal failure and may be compounded by concomitant medications and underlying illnesses.

Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients.

OBJECTIVE: To determine some of the factors influencing the time to progression of cytomegalovirus (CMV) retinitis among HIV-infected patients being treated with foscarnet. DESIGN: A retrospective analysis of two open-label Phase I/II studies in multiple university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of the patients in the databases examined, 31 had adequate pharmacokinetic information and 29 had information on outcome and the other patient covariates. INTERVENTION: After induction therapy with foscarnet at a dose of 60 mg/kg three times daily was completed, patients had maintenance therapy with 60-120 mg/kg foscarnet once daily. Doses were subsequently adjusted for changed estimated creatinine clearance. MEASUREMENTS: The measured endpoint was time to progression of CMV retinitis. The independent variables examined to determine influence on time to progression included mean peak foscarnet concentration, mean area under the concentration-time curve (AUC) for foscarnet, the positive or negative outcome of a baseline blood culture for CMV, the initial CD4 cell count for a patient and the peak CD4 cell count observed during maintenance therapy. RESULTS: A wide range (-10-fold) of foscarnet AUC was observed, even though only a fourfold dose range was employed, and doses were altered for changing estimated creatinine clearance. In a multivariate Cox model, only AUC and the status of the baseline CMV blood culture significantly affected the time to progression of the retinitis. CONCLUSION: The AUC produced by a dose of foscarnet has a wide interindividual range. The AUC of foscarnet significantly altered time to progression of the retinitis. However, patients with positive baseline CMV blood cultures had a significantly more shallow dose-response curve. This indicates that the added risk of nephrotoxicity which is present with aggressive foscarnet dosing might be best borne by the subgroup of patients with a positive CMV blood culture at baseline.

Pre-HAART HIV burden approximates post-HAART viral levels following interruption of therapy in patients with sustained viral suppression.

OBJECTIVE: To evaluate the relationship between the HIV viral burden in individuals prior to receiving highly-active antiretroviral therapy (HAART) and the viral burden after withdrawal of HAART. DESIGN AND SETTING: Retrospective cohort study at the National Institutes of Health, Bethesda, Maryland, USA. PATIENTS: Fourteen HIV-infected patients who achieved and maintained viral control on HAART who subsequently discontinued HAART. MAIN OUTCOME MEASURES: Pre- and post-HAART viral loads measured from plasma or serum. RESULTS: Patients achieved viral control (< 500 copies/ml) on HAART in a median 28 days (range, 15-490 days; mean, 72 days), maintained viral control for a median 661 days (range, 53-1067 days; mean, 611 days), and subsequently discontinued HAART for a median 49 days (range, 14-196 days; mean, 73 days). The median difference between the pre- and post-HAART viral loads was 0.16 log10 (range, -0.72 to 1.05 log10; mean, 0.19 log10). The median absolute difference between the pre- and post-HAART viral loads was 0.43 log10 (range, 0.06-1.05 log10; mean, 0.46 log10). Nine individuals had post-HAART values higher than pre-HAART values, five had lower values. Median duration between pre- and post-HAART viral load measurements was 1757 days (range, 117-3177 days; mean, 1756 days), or 4.8 years. CONCLUSIONS: After discontinuing HAART, individuals had rebounds in their viral burdens approximating pre-HAART levels, even after a significant lapse of time approaching 5 years. Our data suggest that an intrinsic viral load set-point may exist, and that a single interruption of an effective regimen with viral suppression for almost 2 years does not significantly alter this set-point.

Rapid activation of lymph nodes and mononuclear cell HIV expression upon interrupting highly active antiretroviral therapy in patients after prolonged viral suppression.

OBJECTIVE: To compare the architecture and HIV-1 RNA and Gag p24 protein expression in lymph nodes (LN) excised from individuals during chronic highly active antiretroviral therapy (HAART) with LN removed from the same patient after plasma virus rebound following the interruption of HAART. MATERIALS AND METHODS: Six HIV-1-infected patients on HAART, with CD4 cell counts greater than 350 cells/microl, and plasma HIV-1 RNA less than 50 copies/ml, underwent inguinal LN excision upon discontinuation of HAART, and again after rebound of plasma virus. Lymph nodes were evaluated by immunohistochemical staining for Gag p24 antigen and Ki67, in-situ hybridization for HIV-1 RNA and H3-histone, and transmission electron microscopy (TEM). RESULTS: LN at baseline were quiescent to mildly hyperplastic and generally contained more primary than secondary follicles. Only one LN had detectable follicular dendritic cell (FDC)-associated p24 antigen, none had HIV RNA. Few mononuclear cells (MNC) expressed RNA or p24 antigen. Plasma virus at the second biopsy ranged from 329 to 3.2 x 10(6) copies/ml. CD4 cell count decline ranged from 5 to 51% during drug hiatus, and was greatest in patients with highest viral rebound. Four of six of the second LN were more hyperplastic than the initial LN, two showed paracortical hyperplasia. MNC expression of HIV RNA in the second LN paralleled the level of plasma viremia. Increased Ki67 and H3-histone signal occurred in the second LN. CONCLUSION: Quiescent LN from individuals on HAART rapidly become hyperplastic and activated within 1-2 months after treatment interruption. As in acute HIV infection, virus expression by LN MNC parallels the rebound in plasma viremia and fall in CD4 cell count.

Lymph node architecture preceding and following 6 months of potent antiviral therapy: follicular hyperplasia persists in parallel with p24 antigen restoration after involution and CD4 cell depletion in an AIDS patient.

OBJECTIVES: To evaluate changes in architecture, viral RNA, and viral protein over 6 months in lymph nodes from retroviral-naïve HIV-infected persons before and after commencing highly active antiretroviral therapy (HAART). METHODS: Nine antiretroviral-naïve HIV-infected persons had lymph nodes excised at baseline and at 2 and 6-8 months after beginning a four-drug combination regimen containing zidovudine, lamivudine, nevirapine, and indinavir. Two patients had AIDS. Lymph nodes were examined by immunohistochemical staining for Gag p24 HIV, CD3, CD21, CD20, HAM 56, and Ki67 antigens and by in-situ hybridization (ISH) for HIV RNA and H3-histone RNA. RESULTS: Eight of nine baseline lymph nodes showed follicular hyperplasia and germinal center and paracortical mononuclear cell activation. At 2 months, the lymph nodes from seven patients, including the AIDS patients, showed more follicular hyperplasia and activation than their baseline specimens but with decreased mononuclear cell activation. By 6 months, seven lymph nodes were less hyperplastic and activated than their corresponding 2 month specimens. Combined ISH/immunohistochemical staining of baseline lymph nodes revealed productively infected T (CD3) and B (CD20) cells and macrophages (HAM56+). HIV RNA-positive mononuclear cells were infrequent at 2 months, and rare at 6 months. HIV RNA was still associated with follicular dendritic cells (FDC) at 2 months, but not at 6 months. HIV p24-positive antigen in germinal centers persisted through all 6, and the one 8 month specimens. The baseline lymph nodes from one of the AIDS patients was involuted and T cell depleted, whereas the follow-up lymph nodes were hyperplastic with normal T cell levels. CONCLUSION: Follicular hyperplasia and cell activation, possibly caused by persistent viral protein in germinal centers, may help explain why HIV viremia rebounds so rapidly after the interruption of HAART. Restoration of architecture may follow the treatment of patients with AIDS who initially had involuted and CD4 cell-depleted lymph nodes.

Foscarnet and ganciclovir in the treatment of cytomegalovirus retinitis.

Induction regimens of foscarnet and ganciclovir are highly effective in arresting cytomegalovirus (CMV) retinitis in patients with AIDS. Chronic maintenance therapy is nonetheless required to forestall progression of disease following induction. In open studies of these two agents in AIDS patients with CMV retinitis at dosages similar to those currently recommended, median times to retinitis progression during maintenance therapy of as long as greater than 100 days have been observed. In a randomized comparative trial of immediate and delayed foscarnet treatment utilizing rigorously defined end points, the mean times to retinitis progression were 13.3 weeks among patients receiving immediate foscarnet therapy and 3.2 weeks among those receiving no treatment. In a similar trial of ganciclovir, the mean times to progression were 68.5 days among patients receiving immediate treatment and 22.9 days among those receiving no treatment. Experience in a number of studies not designed to assess mortality has suggested that specific antiviral treatment for CMV retinitis is associated with prolongation of survival. One retrospective analysis of survival patterns in patients treated with ganciclovir has suggested a significant effect of this agent on survival; another analysis has shown no association between anti-CMV therapy and survival, with the relative hazard of death among patients receiving foscarnet therapy being equivalent to that among patients receiving ganciclovir therapy. In the one randomized study comparing the mortality of patients receiving initial treatment with either foscarnet or ganciclovir, foscarnet-treated patients had a median survival of 12.6 months compared with 8.5 months for ganciclovir-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)