Lars Mathiesen

Latent Tuberculosis in HIV positive, diagnosed by the M. Tuberculosis Specific Interferon-γ test

BackgroundAlthough tuberculosis (TB) is a minor problem in Denmark, severe and complicated cases occur in HIV positive. Since the new M. tuberculosis specific test for latent TB, the QuantiFERON-TB In-Tube test (QFT-IT) became available the patients in our clinic have been screened for the presence of latent TB using the QFT-IT test. We here report the results from the first patients screened.MethodsOn a routine basis the QFT-IT test was performed and the results from 590 HIV positive individuals consecutively tested are presented here. CD4 cell count and TB risk-factors were recorded from patient files.Main findings27/590(4.6%) of the individuals were QFT-IT test positive, indicating the presence of latent TB infection. Among QFT-IT positive patients, 78% had risk factors such as long-term residency in a TB high endemic area (OR:5.7), known TB exposure (OR:4.9) or previous TB disease (OR:4.9). The prevalence of latent TB in these groups were 13%, 16% and 19% respectively. There was a strong correlation between low CD4 T-cell count and a low mitogen response (P < 0.001;Spearman) and more patients with low CD4 cell count had indeterminate results.ConclusionWe found an overall prevalence of latent TB infection of 4.6% among the HIV positive individuals and a much higher prevalence of latent infection among those with a history of exposure (16%) and long term residency in a high endemic country (13%). The QFT-IT test may indeed be a useful test for HIV positive individuals, but in severely immunocompromised, the test may be impaired by T-cell anergy.

Syphilis and human immunodeficiency virus (HIV)-1 coinfection : Influence on CD4 T-cell count, HIV-1 viral load, and treatment response

Objectives: To assess the effect of human immunodeficiency virus (HIV)-1 and syphilis coinfection on HIV-ribonucleic acid (RNA) viral load, CD4 cell count, and the response in rapid plasmin reagin (RPR) to treatment of the syphilis infection. Study Design: Cases of syphilis diagnosed during 1 year in HIV-infected patients in Copenhagen were included. HIV-RNA, CD4 cell counts, and RPR-serology were measured before, during, and after syphilis. Results: Forty-one patients were included. CD4 cell count decreased significantly during infection in patients with primary and secondary stages of syphilis (mean 106 cells/mm3, P = 0.03). Treatment of syphilis was associated with an increase in the CD4 cell count and a decrease in HIV-RNA in the overall group (mean 66 cells/mm3 and −0.261 RNA log10 copies/ml, P = 0.02 and 0.04). The serological response rates for 15 patients treated with penicillin and 25 treated with doxycycline were the same. Conclusion: Syphilis was associated with a decrease in CD4 cell counts and an increase in HIV-RNA levels that both improved after treatment of syphilis.

Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial

OBJECTIVESnTo compare the efficacy and safety of indinavir 800 mg three times a day, ritonavir 600 mg twice a day, and a combination of ritonavir 400 mg twice a day and saquinavir 400 mg twice a day, when administered with two nucleoside analogues.nnnDESIGNnA randomized, open-labelled, controlled trial. Two hundred and eighty-four patients started randomized treatment. The primary end-point was the proportion of patients with HIV RNA of 200 copies/ml or less (Roche Amplicor) and HIV RNA of 20 copies/ml or less (Roche ultradirect assay) at 6 months. Analysis was performed as intent-to-treat, and missing values were accounted for as failures.nnnRESULTSnAs of 1 May 1998, 269 patients should have completed 24 weeks of treatment. The proportion of patients with HIV RNA of 200 copies/ml or less was 71% (indinavir), 67% (ritonavir), and 82% (ritonavir + saquinavir), P = 0.07. In antiretroviral drug-naive patients (n = 119), the corresponding figures were 63, 57, and 89% (P < 0.01), whereas among drug-experienced patients (n = 165) 77, 74, and 77% had HIV RNA of 200 copies/ml or less (P = 0.90). The same pattern was observed in the ultradirect analysis. All three regimens were generally safe, but significantly more patients in the ritonavir group (37%) stopped treatment because of adverse drug reactions compared with the indinavir group (8%) and the ritonavir plus saquinavir group (16%) (P < 0.001).nnnCONCLUSIONSnTreatment with saquinavir plus ritonavir in combination with two nucleoside analogues is generally safe, and has superior short-term antiviral efficacy compared with indinavir and ritonavir also combined with two nucleoside analogues in antiretroviral drug-naive patients. Further follow-up is needed to determine the durability of the viral response.

Highly active antiretroviral therapy normalizes the function of progenitor cells in human immunodeficiency virus-infected patients.

CD34 cells from human immunodeficiency virus (HIV)-infected persons have been described to be impaired in function. The effect of highly active antiretroviral treatment (HAART) on the function of CD34 cells in HIV-infected patients was examined. Numbers and function of CD34 cells from 11 HIV-infected patients were determined prior to HAART and after 2, 4, 8, and 12 weeks of therapy. The mean number of colony-forming units (cells) per milliliter (cfu/mL) was 15.0 prior to HAART vs. 109.8 in healthy controls (P<.001). During HAART, the number of cfu/mL increased to 100.3 (P<.001). This increase in cfu/mL eliminated the differences between HIV-infected patients and controls. Significant increases in numbers of CD34 cells were not detected. Of importance, the cloning efficiency of CD34 cells increased from 1.7% prior to therapy to a peak at 18.7% (P=.003). In conclusion, HAART normalized CD34 cell function in HIV-infected patients and thus might allow de novo production of T lymphocytes from progenitor cells.

Prevalence of Drug Resistance Mutations and Non-B Subtypes in Newly Diagnosed HIV-1 Patients in Denmark

The aim of this study was to monitor the prevalence of drug resistance mutations in newly diagnosed HIV-1 positive individuals in Denmark. In addition we assessed the prevalence of non-B subtypes based on phylogenetic analysis of the pol gene. Plasma samples from 104 newly diagnosed HIV-1 positive patients were obtained in the year 2000. The entire protease gene and 320 amino acids of the reverse transcriptase gene were genotyped. Sequences were obtained from 97 patients. No subjects displayed primary resistance mutations in the protease gene, whereas all carried 1 or more secondary mutations. Resistance mutations in the RT-gene associated with NRTI-resistance were found in 1 patient, who was infected with zidovudine resistant HIV-1 harbouring the M41L mutation in combination with T215S and L210S. The T215S mutation has been showed to be associated with reversion of zidovudine resistance. The T215S mutation was found in 1 additional patient. The subtype distribution was subtype B 59%, C 18%, A 8%, CRF02_AG 5%, CRF01_AE 4%, D 3% and G 2%. We found 2 patients (2%) with mutations associated with resistance in the RT-gene and none in the protease gene indicating a low prevalence of resistant HIV-1 in Denmark in the year 2000.

Serological diagnosis of acute viral hepatitis

Fifty cases of symptomatic acute viral hepatitis presenting at the Washington, D.C., Veterans Administration Medical Center between 1976 and 1977 were tested for serological markers of hepatitis virus infection. The etiology of the acute hepatitis appeared to be hepatitis A virus in 20%, hepatitis B virus in 52%, non-A, non-B agents in 22%, delta hepatitis in 4%, and infectious mononucleosis in 2%. The diagnosis of type B hepatitis was difficult to verify because 10% of cases were seronegative for HBsAg and another 10% were seronegative by conventional testing for IgM antibody to hepatitis B core antigen (a putative marker of acute hepatitis B virus infection). Accurate serodiagnosis of acute viral hepatitis depends upon the correct application of testing for IgM antibody to hepatitis A virus, IgM antibody to hepatitis B core antigen, HBsAg, and tests for syphilis and mononucleosis.

Correlation of increases in 1,25-dihydroxyvitamin D during vitamin D therapy with activation of CD4+ T lymphocytes in HIV-1-infected males.

Abstract Background: In HIV-1–infected individuals, levels of CD4+ T lymphocytes are depleted and regulatory T-lymphocytes (Tregs) are elevated. In vitro studies have demonstrated effects of vitamin D on the growth and differentiation of these cells. We speculated whether supplementation with vitamin D could have an effect on CD4+ T lymphocytes or Tregs in HIV-1–infected males. Methods: We conducted a placebo-controlled randomized study that ran for 16 weeks and included 61 HIV-1–infected males, of whom 51 completed the protocol. The participants were randomized to 1 of 3 daily treatments: (1) 0.5-1.0 µg calcitriol and 1200 IU (30 µg) cholecalciferol, (2) 1200 IU cholecalciferol, (3) placebo. Percentages of the following T-lymphocyte subsets were determined: naïve CD4+ and CD8+ cells, activated CD4+ and CD8+ cells, and CD3+CD4+CD25+CD127low Tregs. Furthermore 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, and parathyroid hormone were measured. Results: No significant changes of the studied T-lymphocyte subsets occurred in the treatment groups compared to the placebo group. Increases in 1,25-dihydroxyvitamin D were associated with increases in activated CD4+ T lymphocytes (P = .001) and Tregs (P = .01) in adjusted models. Changes in parathyroid hormone correlated inversely with Tregs (P = .02). Smokers had higher levels of naïve CD4+ T lymphocytes (37% vs 25%;P = .01), naïve CD8+ T lymphocytes (28% vs 19%; P = .03), and Tregs (9% vs 7%; P = .03). Conclusion: Cholecalciferol and calcitriol administered during 16 weeks did not change the levels of T-lymphocyte fractions compared to placebo. However, increases in 1,25-dihydroxyvitamin D were associated with an expansion of activated CD4+ cells and Tregs.

The naive CD4+ count in HIV-1-infected patients at time of initiation of highly active antiretroviral therapy is strongly associated with the level of immunological recovery.

Current antiretroviral therapy can induce considerable, sustained viral suppression followed by immunological recovery, in which naive CD4+ cells are important. Long-term immunological recovery was investigated during the first 3 y of highly active antiretroviral therapy (HAART) in 210 HIV-1-infected patients. The focus was on the naive CD4+ cell time course and associations between naive CD4+ cell counts and established prognostic markers. Total and naive CD4+ cell counts were measured using flow cytometry. The HIV-RNA detection limit was 20 copies/ml. During 36 months of HAART, the total CD4+ count followed a triphasic pattern, reflecting an initial phase of rapid redistribution from lymphoid tissues, followed by a slow increase, partially due to an increase in naive CD4+ cell count. From Month 18 onwards, both naive and total CD4+ cell counts stabilized, although viral suppression was sustained. There was no association between plasma viral load and the increase in naive CD4+ cell count. Importantly, baseline naive CD4+ cell count was significantly associated with the change in naive CD4+ cell count, suggesting that the naive cell count at baseline does influence the immunological recovery that can be obtained from treatment. Surprisingly, the naive CD4+ cell count tended to stabilize at a subnormal level after 18 months of HAART. This finding merits further investigation.

Effect of Granulocyte Colony-Stimulating Factor (G-CSF) in Human Immunodeficiency Virus-Infected Patients: Increase in Numbers of Naive CD4 Cells and CD34 Cells Makes G-CSF a Candidate for Use in Gene Therapy or to Support Antiretroviral Therapy

The potential of granulocyte colony-stimulating factor (G-CSF) to mobilize CD4 cells and/or CD34 cells for use in gene therapy or to support antiretroviral therapy was examined. Ten human immunodeficiency virus-infected patients were treated with G-CSF (300 microg/day) for 5 days. Numbers of CD4 and CD34 cells were measured. To examine the numbers of naive and memory type CD4 cells, CD4 cell coexpression of CD45RA and CD45RO was measured. Functionality of mobilized CD4 cells was examined by use of the proliferation assay and interleukin-2 ELISA. The number of CD34 cells increased from 1.50 to 20.01/microL (P < .002). The CD4 cell count increased from 236 to 452/microL (P < .002). The CD45RA/CD45RO ratio increased from 0.50 to 0.57 (P < .03). Mobilized CD4 cells were functionally intact. In conclusion, G-CSF induced increases in numbers of CD34 cells and CD4 cells in HIV-infected patients. Furthermore, the fraction of naive CD4 cells increased. These findings have implications for the design of immunotherapy or gene therapy protocols.

Risk of HIV or second syphilis infection in Danish men with newly acquired syphilis in the period 2000–2010

Objectives Risk of subsequent diagnosis of HIV in persons diagnosed with newly acquired syphilis, and syphilis in HIV-infected persons, are of interest as these infections are markers of unsafe sex. Methods From a nationwide register, all Danish men aged >16u2005years diagnosed with syphilis in the period 2000–2010 (n=1217) were identified, and subsequently data on HIV status was extracted from the Danish HIV Cohort Study. We used Kaplan–Meier analysis to estimate the 5-year risk of HIV and second syphilis infection, and Cox regression to determine incidence rate ratios (IRR). Results The 5-year risk of HIV diagnosis was 9.8% (95% CI 7.0% to 12.6%). Those with a second diagnosis of syphilis had a higher risk of being diagnosed with HIV (IRR=3.1, 95% CI 1.2 to 8.0). The 5-year risk for a second diagnosis of syphilis was 14.8% (95% CI 12.1% to 17.4%) and HIV-infected persons had a higher risk of a second syphilis diagnosis (IRR=4.0, 95% CI 2.8 to 5.9). Sixty-five percent of the persons were men having sex with men (MSM). Thirty-four percent of the HIV-infected persons had viral load >1000u2005copies/ml at time of syphilis diagnosis. Conclusions The substantial risks of syphilis and HIV infection in men diagnosed with one of these sexually transmitted diseases indicate a high frequency of unsafe sex in the Danish MSM population. As one-third of the HIV-infected persons diagnosed with syphilis had high viral loads, our data support initiation of antiretroviral therapy in all HIV-infected MSM to reduce HIV transmission.