Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population.

OBJECTIVES: Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). A recent publication found that WLWH in Denmark attend the national ICC screening programme less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark compared with that in women in the general population. METHODS: We studied a nationwide cohort of WLWH and a cohort of 15 age-matched women per WLWH from the general population for the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank, which contains nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology result to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. RESULTS: We followed 1140 WLWH and 17 046 controls with no prior history of ICC or hysterectomy for 9491 and 156 865 person-years, respectively. Compared with controls, the overall incidences of CIN1 or worse (CIN1+), CIN2+ and CIN3+, but not ICC, were higher in WLWH and predicted by young age and a CD4 count < 200 cells/µL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, when we compared subgroups of WLWH and controls where women in both groups were adherent to the national ICC screening programme and had a normal baseline cytology, incidences of CIN and ICC were comparable. CONCLUSIONS: Overall, WLWH developed more cervical disease than controls. Yet, in WLWH and controls adherent to the national ICC screening programme and with normal baseline cytology, incidences of CIN and ICC were comparable.

Is it possible to define an optimal time for chemotherapy after surgery for ovarian cancer?

OBJECTIVE: The aims of this study are to investigate the actual time from primary surgery for epithelial ovarian cancer (OC) to initiation of chemotherapy (TI) amongst Danish women in 2005-2006, and to compare the survival for groups with early initiation (≤median TI) and late initiation of adjuvant chemotherapy (>median TI). METHODS: All Danish women who underwent surgery for OC in the period 1 January 2005 to 31 December 2006 and recorded in the Danish Gynaecological Cancer Database (DGCD) were included. The five-year survival was estimated overall and by TI exposure. The Cox proportional hazard regression analysis was used to compute the adjusted hazard ratio (HR). RESULTS: The median TI was 32days (25-75% quartile: 24days; 41days). The strongest prognostic factors for death were residual tumour and the International Federation of Obstetrics and Gynecology (FIGO) stage. The unadjusted HR for death in patients with TI>32days compared with TI≤32days was 0.85 (95% CI: 0.70; 1.04), p-value 0.12. When adjusted for residual tumour and FIGO-stage the HR was 1.13 (95% CI: 0.92; 1.39), p-value 0.26. The overall five-year survival was 42.8%, (95% CI: 38.9%; 46.5%). CONCLUSIONS: This nationwide population-based cohort study revealed a non-significant increased risk of death for patients with TI>32days compared with the reference TI≤32days. The strongest prognostic factors were residual tumour after surgery and FIGO-stage. The overall five-year survival was 42.8% (95% CI: 38.9%; 46.5%).

Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients.

Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young patients with cystic fibrosis (CF), and several treatment strategies are used to control the infection. However, it is not known whether intensified treatment with antimicrobial agents causes eradication of S. aureus clones. We retrospectively determined the impact of intravenous (IV) antimicrobial agents on the suppression and eradication of S. aureus clones. One thousand and sixty-one S. aureus isolates cultured from 2526 samples from 130 CF patients during a 2-year study period were subjected to spa typing. Intervals between positive samples and the occurrence of clone replacements were calculated in relation to courses of IV antimicrobial agents. Of 65 patients chronically infected with S. aureus, 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6-31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003). When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60-1.61). In conclusion, we show that 2 weeks of IV antimicrobial treatment can significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.

Early treatment with inhaled antibiotics postpones next occurrence of Achromobacter in cystic fibrosis.

OBJECTIVES: In this nationwide retrospective study, we analysed species distribution, antimicrobial susceptibility and time to next occurrence of Achromobacter in Danish cystic fibrosis (CF) patients from 2000 to 2011. METHODS: Thirty-four primary isolates were identified to species level and subjected to antimicrobial susceptibility testing. Effectiveness of early antimicrobial treatment was assessed by a Kaplan-Meier estimation of time to recurrence. RESULTS: Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species accounted for 11 (32%) of the isolates. Meropenem, piperacillin-tazobactam and trimethoprim-sulfamethoxazole were highly active against chemotherapy-naïve Achromobacter, while ceftazidime, colistin and tobramycin were judged adequate for inhalation therapy. Fifty-five percent of 25 patients treated with inhaled ceftazidime, colistin, or tobramycin remained free of Achromobacter three years after acquisition, in contrast to 17% of 22 patients who did not receive inhaled antibiotics (P<0.01). CONCLUSIONS: Early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter in CF patients.

Phylogeny and resistance profiles of HIV-1 POL sequences from rectal biopsies and blood.

The phylogeny and resistance profiles of human immunodeficiency virus type 1 (HIV-1) protease (PR) and reverse transcriptase (RT) sequences were compared among six patients with HIV-1 who had received numerous treatments. RNA and DNA fractions were obtained from concurrent blood and rectal biopsy samples. Phylogenetic trees and resistance profiles showed that the rectal mucosa and the peripheral blood mononuclear cells (PBMCs) harbored different HIV-1 strains. The resistance-associated mutations found in each strain corresponded to the treatment history of the patients. The resistance mutations acquired during earlier treatment regimens were detected in the sequences obtained from the rectal samples and in the PBMCs in several of the patients. Also, differences in the resistance profiles were observed between anatomical sites and between RNA and DNA fractions. Thus, a single sample probably will not be representative of the HIV-1 archived in different sites. Both the resistance profile and phylogeny of HIV-1 often differed in sequences obtained from RNA and DNA from the same site. These findings suggest that additional information regarding the antiviral resistance profile of the patient might be obtained by testing different anatomical sites.

Ten years of extrapulmonary tuberculosis in a Danish university clinic.

The objective of this study was to describe the symptoms, diagnostic measures and outcomes of extrapulmonary tuberculosis (ex-TB) in a Danish university clinic from 1990 to 1999. 48 patients with ex-TB were identified retrospectively and clinical and laboratory data extracted from the patient files. The majority were immigrants from Africa (71%). A direct connection between symptoms on admission and anatomical localization of TB was found in 83%. The main localizations of ex-TB were peripheral lymph nodes (n = 15) and the abdomen (n = 19). In 73% Mycobacterium tuberculosis could be cultured. One culture was resistant to isoniazide and 1 had decreased sensitivity to isoniazide and etambutol. Two patients relapsed with TB. Some pitfalls in diagnosing TB were found, as 13% had a normal erythrocyte sedimentation rate at presentation, 9% had a negative tuberculin skin test and fever was absent in 31% of the cases. The patients' subjective complaints on admission should guide the diagnostic procedures.

The use of calcium carbonate in nelfinavir-associated diarrhoea in HIV-1-infected patients.

OBJECTIVES: To evaluate the efficacy of oral calcium supplements in HIV-infected patients with nelfinavir (NFV)-associated diarrhoea, and to investigate the influence on the pharmacokinetics of nelfinavir and the active metabolite M8. METHODS: An open-label prospective trial with enrolment of 15 patients with NFV-associated diarrhoea. Study subjects received either calcium carbonate or calcium gluconate/calcium carbonate in addition to highly active antiretroviral therapy (HAART), and were randomized to (i) calcium supplements for 14 days followed by 14 without calcium supplements, or (ii) 14 days without calcium supplements followed by calcium supplements for 14 days. Clinical endpoint was the severity of diarrhoea, graded and summarized for the specific 14 day-period. In the pharmacokinetic evaluation concentrations of NFV and M8 were measured before morning dosing, and 3 h after dosing. RESULTS: Nine patients were treated with calcium carbonate, and six with calcium gluconate/calcium carbonate. In the paired analysis, neither of the groups had a significant improvement in diarrhoea score when treated with calcium supplements (P = 0.34 and 0.46, respectively). We found no significant differences in the concentrations of NFV and M8 between the calcium and control periods. CONCLUSIONS: Oral calcium supplements did not significantly improve nelfinavir-associated diarrhoea. In the pharmacokinetic analysis calcium supplements did not induce major alterations in plasma concentrations of NFV and M8.

Changing demographics in an HIV-infected population: results from an observational cohort study in Western Denmark.

We present demographic data from an observational database of HIV and AIDS in the Western part of Denmark, a region with a population of 2,935,156 individuals (55.1% of the population of Denmark). Five centers in the region treat HIV-positive adults; all patients attached to these centers since 1995 are included in this study. In total, 749 adult HIV-infected individuals were enrolled as of 31 December, 1999. Estimates of prevalence and incidence of HIV infection in the area were 25.9/100,000 and 2.6/100,000, respectively, which are lower than average for the country. The number of newly diagnosed HIV-infected patients remained constant during the period 1995-99, with an average of 62 diagnoses per year. The number of HIV-related deaths declined from 43 in 1995 to 15 in 1999. Of the enrolled patients, 70.9% were of Danish origin, 75% were Caucasians, 69.7% were male and 47.2% had heterosexual contact as their primary risk behavior. There seems to have been a shift in the HIV epidemic in recent years, with a higher proportion of newly diagnosed HIV patients having contracted the infection through heterosexual contact, a higher proportion being immigrants from less developed countries and newly diagnosed individuals getting older.

The insufficient suppression of viral load by saquinavir hard gel is reversible: a retrospective cohort study.

PURPOSE: To assess the effect of changing antiretroviral therapy in patients initially treated with saquinavir hard gel capsule (hgc). METHOD: A retrospective cohort study comparing the virological and immunological responses in antiretroviral-naïve patients initially treated with a regimen of saquinavir-hgc, zidovudine, and lamivudine, with patients receiving either ritonavir or indinavir on a background of zidovudine and lamivudine. RESULTS: Twenty-nine patients starting with saquinavir-hgc as the protease inhibitor (PI) component were compared to 58 patients starting with ritonavir (n = 16) or indinavir (n = 42). Median follow-up time was 30 and 33 months, respectively. Twelve, 18, 24, and 30 months after starting a regimen including saquinavir-hgc, 72%, 50%, 4%, and 0% of patients still received this PI. At these time points, 35%, 24%, 59%, and 74% of the patients in the saquinavir group obtained an HIV-RNA <500 copies/mL compared to 76%, 72%, 66%, and 65% in the indinavir/ritonavir group. No significant difference in CD4 count between the two groups was observed. CONCLUSION: We found that saquinavir-hgc, in combination with nucleoside reverse transcriptase inhibitors, suppressed viral load insufficiently in HIV patients naïve to antiretroviral therapy. However, the suboptimal effect of saquinavir-hgc seems reversible after optimizing the antiretroviral regimen, at least for the short term.

Herpesvirus type 1-8 in BAL fluid from HIV-1-infected patients with suspected pneumonia and from healthy individuals.

Pneumonia is still a major problem in human immunodeficiency virus (HIV)-infected patients, and despite extensive investigation the aetiology remains unknown in many cases. The prevalence of the eight human herpesviruses was determined by polymerase chain reaction in 91 samples of bronchoalveolar lavage (BAL) fluid from 72 HIV-infected patients with 91 episodes of suspected pneumonia. The presence of herpesviruses was related to clinical and immunological findings and the prevalence of herpesviruses in HIV-infected patients was compared with the prevalence in BAL fluid from 50 healthy, immunocompetent individuals. Epstein-Barr virus, cytomegalovirus and human herpesvirus-8 (HHV8) were found in 5.5%, 36% and 5.5% of BAL fluid samples from HIV-infected patients. No herpesviruses were detectable in BAL fluid from healthy, immunocompetent individuals. The herpesviruses occurred mainly in patients with CD4+ counts <200 x 10(6) L(-1). All patients with herpesviruses recovered without specific antiviral treatment. Two patients with HHV8 had the diagnosis of Kaposi's sarcoma. It is concluded that cytomegalovirus, Epstein-Barr virus, and human herpesvirus-8 are frequently present in bronchoalveolar lavage fluid from severely immunocompromised human immunodeficiency virus-infected patients with pulmonary symptoms. In bronchoalveolar lavage fluid from healthy, immunocompetent individuals, herpesviruses are absent. Apart from human herpesvirus-8, the present results indicate that the herpesviruses do not play a serious pathogenic role in the development of pulmonary symptoms in human immunodeficiency virus-infected patients.

The effect of nevirapine in combination with nelfinavir in heavily pretreated HIV-1-infected patients: a prospective, open-label, controlled, randomized study.

The purpose of the current study was to determine the efficacy and safety of nevirapine combined with nelfinavir and two nucleoside reverse transcriptase inhibitors (NRTIs) in patients previously exposed to highly active antiretroviral therapy (HAART). In a prospective, open-label, randomized study, 56 HIV-infected adults who had received HAART, including saquinavir hard gel capsule, ritonavir, or indinavir, were randomly assigned to receive nevirapine in addition to nelfinavir and two NRTIs. The proportion of patients who achieved an undetectable viral load (plasma HIV-RNA <200 copies/ml) at weeks 24 and 36 was significantly higher in the nevirapine group than in the control group (55% and 52% vs. 22% and 22%; p =.015 and p =.047). No differences in CD4 cell count or clinical outcome were observed. In the nevirapine group, 17% of patients discontinued treatment because of rashes. We conclude that the addition of nevirapine, when switching from one protease inhibitor-containing regimen to one containing nelfinavir, has a substantial effect on viral suppression.

Saquinavir hard gel suppresses viral load insufficiently in HIV-infected patients naive to anti-retroviral therapy: a retrospective cohort study.

Protease inhibitors are important components in anti-retroviral regimens. In this retrospective study 29 HIV-infected patients treated with a regimen of zidovudine, lamivudine and saquinavir hard gel in 1 centre in Denmark were compared with 58 patients treated with zidovudine, lamivudine and ritonavir or indinavir followed at 5 other centres in Scandinavia. All patients were naive to anti-retroviral therapy prior to institution of the actual anti-retroviral regimen and were followed for a median of 1.3 and 1.4 y respectively. The 2 groups did not differ significantly with respect to age, gender, route of infection, ethnic background, viral load, CD4 count, AIDS at baseline or frequency of clinical controls. Six and 12 months after initiating anti-retroviral therapy, 31% and 34% of the patients on the saquinavir regimen obtained HIV-RNA < or = 500 compared with 76% and 73% in the control group (p < 0.001). In contrast to viral load, the increase in CD4 count did not differ significantly between the 2 groups. In conclusion, we found that with respect to suppression of viral load a regimen of saquinavir, zidovudine and lamivudine seemed to be inferior to a regimen of zidovudine, lamivudine and ritonavir or indinavir.

[Treatment of HIV infections and AIDS with protease inhibitor and two nucleoside analogs]. / Behandling af HIV- og AIDS-patienter med proteaseinhibitor og to nukleosidanaloger.

Until December 31st 1997, 163 HIV/AIDS patients were treated with HAART at the Department of Infectious Diseases, Aarhus University Hospital. The patients mainly received a combination of zidovudine, lamivudine and saquinavir. They were observed for an average period of 375 days. HAART was found to increase the amount of CD4 lymphocytes in peripheral blood and decrease the number of HIV-RNA copies. Both effects were seen to be more pronounced in patients naive to antiretroviral treatment. However, 64 patients had their protease inhibitor changed during the observation period, 53% due to failure of suppression of the viral load, 25% due to adverse events and 22% due to other reasons.