Risk factors during pregnancy and birth-related complications in HIV-positive versus HIV-negative women in Denmark, 2002-2014.

OBJECTIVES: We aimed to compare risk factors for adverse pregnancy outcomes in women living with HIV (WLWH) with those in women of the general population (WGP) in Denmark. Further, we estimated risk of pregnancy- or birth-related complications. METHODS: A retrospective cohort study including all WLWH who delivered a live-born child from 2002 to 2014 and WGP, matched by origin, age, year and parity, was carried out. We compared risk factors during pregnancy and estimated risk of pregnancy- and birth-related complications using multivariate logistic regression. RESULTS: A total of 2334 pregnancies in 304 WLWH and 1945 WGP were included in the study. WLWH had more risk factors present than WGP during pregnancy: previous caesarean section (CS) (24.7% versus 16.3%, respectively; P = 0.0001), smoking (14.2% versus 7.5%, respectively; P = 0.0001) and previous perinatal/neonatal death (2.3% versus 0.9%, respectively; P = 0.03). We found no difference between groups regarding gestational diabetes, hypertensive disorders, low birth weights or premature delivery. More children of WLWH had intrauterine growth retardation (IUGR) [adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.1-3.2; P = 0.02]. Median gestational age and birth weight were lower in children born to WLWH. WLWH had a higher risk of emergency CS (EmCS) (aOR 1.6; 95% CI 1.2-2.1; P = 0.0005) and postpartum haemorrhage (aOR 1.4; 95% CI 1.0-1.9; P = 0.02) but not infection, amniotomy, failure to progress, low activity-pulse-grimace-appearance-respiration (APGAR) score or signs of asphyxia. CONCLUSIONS: WLWH had more risk factors present during pregnancy, similar risks of most pregnancy- and birth-related complications but a higher risk of postpartum haemorrhage and EmCS compared with WGP. Children born to WLWH had lower median birth weights and gestational ages and were at higher risk of IUGR.

Assessment of mode of delivery and predictors of emergency caesarean section among women living with HIV in a matched-pair setting with women from the general population in Denmark, 2002-2014.

OBJECTIVES: We aimed to assess mode of delivery and predictors of emergency caesarean section (EmCS) in women living with HIV (WLWH) in a matched-pair setting with women from the general population (WGP) in Denmark. Further, we analysed birth plan in WLWH. METHODS: All WLWH giving birth to live-born children from 2002 to 2014 were included in the study. Data were retrieved from medical records and national registries. WLWH were matched 1:5 by age, birth year, parity and ethnicity to WGP. Multivariate logistic regression was used to estimate predictors. RESULTS: We included 389 WLWH and 1945 WGP in the study. At delivery, all WLWH were on antiretroviral therapy and 85.6% had HIV RNA <40 HIV-1 RNA copies/mL. Mean age was 32.7 years [95% confidence interval (CI) 32.1-33.2 years]. Mode of delivery differed significantly between WLWH and WGP [vaginal delivery, 33.4% versus 73.3%, respectively; elective caesarean section (ECS), 40.6% versus 9.7%, respectively; EmCS, 26% versus 17%, respectively; P < 0.0001]. Age > 40 years [adjusted odds ratio (aOR) 2.3; 95% CI 1.5-3.5], asphyxia (aOR 3.2; 95% CI 2.4-4.1), delivery during the evening and at night [aOR 2.3 (95% CI 1.7-3.0) and aOR 2.0 (95% CI 1.5-2.7), respectively], preterm delivery (aOR 3.8; 95% CI 2.6-5.6) and premature rupture of membranes (aOR 3.0; 95% CI 2.1-4.4) predicted EmCS. WLWH had a higher risk of EmCS compared with WGP [2002-2006, aOR 2.0 (95% CI 1.2-3.3); 2007-2008, aOR 2.9 (95% CI 1.4-5.9); 2009-2014, aOR 2.6 (95% CI 1.7-3.9)]. After 2007, more than half of WLWH planned to deliver vaginally. Prior caesarean section was associated with ECS (aOR 11.0; 95% CI 4.5-26.8). No mother-to-child transmission occurred. CONCLUSIONS: Increasing numbers of WLWH deliver vaginally. Despite virological suppression, more WLWH plan and deliver by ECS than WGP. WLWH had a twofold higher risk of EmCS compared with WGP.

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.

Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study.

OBJECTIVES: Patients infected with HIV are at increased risk of myocardial infarction (MI). Increased plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased risk of cardiovascular diseases (CVD), including MI in the general population. We tested suPAR as a predictive biomarker of MI in HIV-1-infected individuals. METHODS: suPAR levels were investigated in a nested case-control study of 55 HIV-1-infected cases with verified first-time MI and 182 HIV-1-infected controls with no known CVD. Controls were matched for age, gender, duration of antiretroviral therapy (ART), smoking and no known CVD. suPAR was measured in the four plasma samples available for each patient at different time-points; 1, Before initiation of ART; 2, 3 months after initiation of ART; 3, 1 year before the case's MI; and 4, The last sample available before the case's MI. RESULTS: In unadjusted conditional regression analysis, higher levels of suPAR were associated with a significant increase in risk of MI at all time-points. Patients in the third and fourth suPAR quartiles had a three- to 10-fold higher risk of MI compared to patients in the lowest suPAR quartile at all time-points. suPAR remained a strong significant predictor of MI, when adjusting for HIV-1 RNA, total cholesterol, triglycerides and high-density lipoprotein. CONCLUSION: Elevated suPAR levels were associated with increased risk of MI in HIV-infected patients, suggesting that suPAR could be a useful biomarker for prediction of first-time MI in this patient group, even years before the event.

Long-term follow-up on affinity maturation and memory B-cell generation in patients with common variable immunodeficiency.

PURPOSE: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary immunodeficiency disorders. Immunophenotyping of memory B cells at the time of diagnosis is increasingly used for the classification of patients into subgroups with different clinical prognoses. The EUROclass classification is a widely used method. Levels of somatic hypermutation (SHM) have proven useful as a prognostic marker for recurrent respiratory tract infections. As time of presentation and diagnosis is highly variable in CVID patients, and diagnostic delay is a common problem, it is important to know whether classification parameters are stable over time. The purpose of the study was to address this question in a cohort of 33 CVID patients followed from 3 to 19 years after diagnosis (average follow-up 8.8 years). METHODS: Levels of class-switched memory B cells were analyzed using flow cytometric immunophenotyping, and patients were classified according to the EUROclass criteria. Affinity maturation of B cells was measured using Igκ-REHMA, which assesses somatic hypermutation in kappa light chain transcripts. Clinical manifestations in terms of splenomegaly, autoimmune disease and granulomatous disease were also determined. RESULTS: Switched memory B cells and levels of SHM were not consistently stable markers in a long-term follow-up setting. At a given time during follow-up, 60% of the patients were assigned to the EUROclass group SmB- (less than 2% switched memory B cells), but only 23% were consistently assigned to this group. Associations between clinical manifestations and levels of switched memory B cells or SHM were not observed in our study. CONCLUSION: Based on our findings, we suggest that immunologic characteristics in CVID patients should be evaluated several times after diagnosis using internationally standardized methods.

Unsuccessful treatment of chronic norovirus infection with enteral immunoglobulin in patients with common variable immunodeficiency, case report.

Background: Norovirus gastroenteritis is commonly an acute infection that lasts 2-3 days, but in immunocompromised patients norovirus can cause a chronic gastroenteritis lasting for years. Norovirus replicates in the gastrointestinal tract, but the pathway of viral clearance is not yet known. Promising results of enterally administered immunoglobulin in the treatment of chronic norovirus gastroenteritis in immunocompromised patients have previously been published. Case presentation: We report two individuals with common variable immunodeficiency and chronic debilitating norovirus gastroenteritis. Both patients were treated with enterally administered immunoglobulin via a duodenal feeding tube as other treatment modalities have been unsuccessful. The patients did not experience any immediate or long-term benefit of enterally administered immunoglobulin. Conclusion: Despite previous case reports of successful treatment of chronic norovirus infection among immunocompromised patients with enterally administered immunoglobulin, these two patients experienced no benefit of the treatment. This demonstrates the need for further research in treatment of chronic norovirus infection in immunocompromised patients.

Genetical analysis of all Danish patients diagnosed with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disorder of the innate immune system caused by a defect in NADPH oxidase, leaving the granulocytes unable to kill invading microorganisms. CGD is caused by mutation in one of the five components gp91phox, p22phox, p47phox, p67phox and p40phox, encoded by the X-linked CYBB gene and the autosomal CYBA, NCF1, NCF2 and NCF4 genes respectively. We have collected samples from all Danish patients with known CGD followed in the clinic or newly diagnosed during a 5-year period, a cohort of 27 patients, and characterized them genetically. The cohort includes 10 male patients with X-linked CGD and one female with extremely lyonized expression of a defective CYBB allele. Six patients had mutation in CYBA. Seven of 10 patients with a defect in NCF1 were homozygous for the common GT deletion, one was compound heterozygous for the GT deletion and a splice-site mutation, and two patients were homozygous for a nonsense mutation in exon 7. Three novel mutations were detected, a deletion of exon 6 in CYBA, a duplication of exon 8-13 in CYBB and a splice site mutation in intron 7 of NCF1.

Prevention of mother-to-child transmission of HIV in Denmark, 1994-2008.

OBJECTIVES: The aim of this study was to describe trends in the management of pregnancies in HIV-infected women and their outcomes over a 14-year period in Denmark on a national basis. METHODS: The study was a retrospective cohort study of all HIV-infected women in Denmark giving birth to one or more children between 1 June 1994 and 30 June 2008. RESULTS: We identified 210 HIV-infected women with 255 pregnancies, ranging from 7 per year in 1995 to 39 per year in 2006. Thirty per cent of the women were Caucasian and 51% were Black African. Knowledge of HIV status before pregnancy increased from 8% (four of 49) in 1994-1999 to 80% (164 of 206) in 2000-2008. Only 29% (53 of 183) of the women chose to consult an infectious disease specialist when planning pregnancy, while 14% (27 of 199) received assistance with fertility. The proportion of women on antiretroviral therapy (ART) increased from 76% (37 of 49) in 1994-1999 to 98% (201 of 206) in 2000-2008. Vaginal deliveries ranged from 0 in 2003 to 35% of pregnancies in 2007. Mother-to-child transmission (MTCT) of HIV decreased from 10.4% in 1994-1999 to 0.5% in 2000-2008. All women giving birth to an HIV-positive child were diagnosed with HIV during or after delivery and did not receive prophylactic ART. CONCLUSIONS: The annual number of HIV pregnancies increased fivefold during this 14-year period and substantial changes in pregnancy management were seen. No woman treated according to the national guidelines, i.e. ART before week 22, intravenous zidovudine (ZDV) during labour, neonatal ZDV for 4 to 6 weeks and no breastfeeding, transmitted HIV to her child.

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.

Residual viraemia in HIV-1-infected patients with plasma viral load

Despite undetectable viral load in conventional assays, probably all human immunodeficiency virus (HIV)-1 infected patients have residual viraemia (RV) detectable by ultra-sensitive assays. To study this issue, this study investigated virologic and immunologic consequences of RV in highly active antiretroviral therapy (HAART)-treated HIV-1-infected patients with plasma HIV-1 RNA or=1 episode with TMA-RV whereas 9 patients had undetectable TMA-RV throughout the study-period. Time-points with TMA-RV and PCR-RV were associated with higher circulating sTNFrII (+0.234 ng/ml, P = 0.030) and beta(2)-microglobulin (+22 nmol/l, P = 0.016) and time-points with PCR-RV were also associated with higher IgA (+0.82 micromol/l, P = 0.035) and CD8-count (+1.18-fold, P = 0.001). Patients with TMA-RV in the study-period had higher HIV-1 RNA pre-HAART (P = 0.032). RV was not associated with proviral-HIV-1-DNA, CD4-count, CD4+HLA-DR+, CD8+HLA-DR+CD38+, CD4+CD45RA-CD45RO+, CD8+CD45RA-CD45RO+, CD4+CD45RA+CD62L+, CD8+CD45RA+CD62L+ T cells, IgG or IgM. In conclusion, RV was associated with increased blood levels of soluble immune activation markers in HAART-treated HIV-1-infected patients. The finding that RV was associated with higher pre-HAART plasma viral load suggests that RV is linked to pre-HAART disease progression.

Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study.

BACKGROUND: Predictors of virological response to highly active antiretroviral therapy (HAART) have never been systematically evaluated in a large continental multicenter cohort of unselected human immunodeficiency virus (HIV)-infected people. OBJECTIVE: To determine the factors related to achieving and maintaining undetectable plasma HIV-1 RNA levels among HIV-1-infected patients first starting protease inhibitor- or nonnucleoside retrotranscriptase inhibitor-containing HAART in Europe. DESIGN: Prospective multicenter cohort study. SETTING: Fifty-two clinical centers in 17 European countries included in the EuroSIDA Study Group, from August 1996 to April 1999. PATIENTS: A total of 1469 HIV-positive patients first starting HAART recruited from an unselected cohort of more than 7300 HIV-positive patients. MAIN OUTCOME MEASURE: Detection of factors related to virological success after first starting HAART (baseline) and ensuing failure by standard survival techniques, including Kaplan-Meier techniques and Cox proportional hazards models. All analyses were intention to treat. RESULTS: Most patients (80%) achieved plasma HIV-1 RNA levels of less than 500 copies/mL during follow-up (60.4% at 6 months from the onset of HAART). Patients with higher baseline HIV-1 RNA levels (relative hazard [RH], 0.76 per log higher; 95% confidence interval [CI], 0.69-0.84; P<.001) and those taking saquinavir mesylate hard gel as a single protease inhibitor (RH, 0.62; 95% CI, 0.47-0.82; P<.001) were less likely to reach undetectable HIV-1 RNA levels. Conversely, higher CD4+ lymphocyte counts (RH per 50% higher, 1.09; 95% CI, 1.02-1.16; P = .008) and the initiation of 3 or more new antiretroviral drugs (RH, 1.29; 95% CI, 1.03-1.61; P = .02) were independent predictors of higher success. Once success was achieved, HIV-1 RNA levels rebounded in more than one third of all patients during follow-up (24% at 6 months). Antiretroviral-naive patients (RH, 0.50; 95% CI, 0.29-0.87; P = .01), older patients (RH, 0.86 per year older; 95% CI, 0.75-0.99; P = .04), and those starting a protease inhibitor other than saquinavir hard gel (RH, 0.66; 95% CI, 0.44-0.98; P = .04) were at decreased hazard for virological failure. Higher baseline HIV-1 RNA level (RH, 1.18 per log higher; 95% CI, 0.99-1.40; P = .06) and a longer time to achieve virological success (RH per 12 months, 1.53; 95% CI, 0.99-2.38; P = .06) were marginally significant predictors of a decreased hazard of ensuing virological failure. CONCLUSIONS: HAART is associated with a favorable virological response if started when the baseline HIV-1 RNA level is low, if at least 2 new nucleoside retrotranscriptase inhibitors are added, and if standard doses of saquinavir hard gel capsule are avoided as a single protease inhibitor. Older patients are more likely to achieve virological success. Thereafter, the higher durability of virological response is predicted by an antiretroviral-naive status and by the use of specific regimens. Lower baseline HIV-1 RNA levels and rapid maximal viral suppression seem to be other important factors in the durability of virological response.

Hepatitis A outbreak among MSM linked to casual sex and gay saunas in Copenhagen, Denmark.

During an outbreak of hepatitis A predominantly among men who have sex with men (MSM) in Copenhagen, Denmark, in 2004, we did a case-control study to determine risk factors for infection. A case was an MSM >17 years, living in Copenhagen, with IgM positive hepatitis A infection diagnosed between June and August 2004, and without a household contact with a hepatitis A case before onset of illness. Controls were selected at the Copenhagen Pride Festival. The study included 18 cases and 64 controls. Sixteen of 18 cases and 36/63 controls had sex with casual partners (ORMH 5.6, 95% CI 1.2-26.9). Eleven of 18 cases and 14/62 controls had sex in gay saunas (ORMH 4.2, 95% CI 1.5-11.5). Sex at private homes appeared to be protective (ORMH 0.2, 95% CI 0.1-0.7). Casual sex including sex in gay saunas was an important risk factor for the spread of HAV among MSM in Copenhagen. The results are in accordance with findings in other European outbreaks. As the general immunity to hepatitis A decreases and the outbreak potential increases, we recommend health education and hepatitis A vaccination to all MSM not living in monogamous relationships, especially if they visit gay saunas or other places with frequent partner change. To stop spread of hepatitis A among MSM in Europe, a European consensus on prevention and control measures may be required.

Hepatitis A outbreak among MSM linked to casual sex and gay saunas in Copenhagen, Denmark.

During an outbreak of hepatitis A predominantly among men who have sex with men (MSM) in Copenhagen, Denmark, in 2004, we did a case-control study to determine risk factors for infection. A case was an MSM >17 years, living in Copenhagen, with IgM positive hepatitis A infection diagnosed between June and August 2004, and without a household contact with a hepatitis A case before onset of illness. Controls were selected at the Copenhagen Pride Festival. The study included 18 cases and 64 controls. Sixteen of 18 cases and 36/63 controls had sex with casual partners (ORMH 5.6, 95% CI 1.2-26.9). Eleven of 18 cases and 14/62 controls had sex in gay saunas (ORMH 4.2, 95% CI 1.5-11.5). Sex at private homes appeared to be protective (ORMH 0.2, 95% CI 0.1-0.7). Casual sex including sex in gay saunas was an important risk factor for the spread of HAV among MSM in Copenhagen. The results are in accordance with findings in other European outbreaks. As the general immunity to hepatitis A decreases and the outbreak potential increases, we recommend health education and hepatitis A vaccination to all MSM not living in monogamous relationships, especially if they visit gay saunas or other places with frequent partner change. To stop spread of hepatitis A among MSM in Europe, a European consensus on prevention and control measures may be required.

Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion and clinical outcome.

OBJECTIVE: To investigate the longitudinal changes in serum HIV RNA, and to clarify whether the viral load early in infection has a predictive value for the clinical outcome; also, to correlate viral phenotype at seroconversion and changes in CD4 cell counts with viral burden. DESIGN: Twenty seroconverters with HIV isolates available at seroconversion had HIV RNA quantified by polymerase chain reaction (PCR) at seroconversion and thereafter every 6 months. Mean follow-up time was 65 months. Patients were classified according to viral phenotype at seroconversion, time to AIDS progression, serum viral load within the first year (less or more than 1.5 x 10(4) copies/ml). RESULTS: High viral load at seroconversion was followed by a significant decline within the first months (P < 0.0005). Decline to < 1.5 x 10(4) copies/ml was correlated with slower progression to AIDS (P < 0.05). A correlation between the rate of CD4 decline and the median viral load during the ensuing viral load plateau phase was also shown (P < 0.05). Subsequent to this phase the viral burden increased. Rapid progressors had higher viral load than slow- or non-progressors; this was particularly pronounced late in infection. Harbouring syncytium-inducing (SI) virus at seroconversion was associated with faster progression to AIDS than non-SI (NSI; P < 0.005). The increased in vitro replication rate of SI over NSI was not translated into significantly higher serum HIV RNA. CONCLUSION: Serum HIV RNA is high around the time of seroconversion. A significant decline within the first months hereafter is followed by a plateau phase, which in turn is followed by an increase in HIV RNA. HIV RNA early in infection has a predictive value for the clinical outcome. The increased virulence of SI over NSI virus did not translate into significantly higher HIV RNA values.

Nosocomial HIV-transmission in an outpatient clinic detected by epidemiological and phylogenetic analyses.

OBJECTIVE: To determine if a case of HIV-infection in a patient (GP) with common variable immunodeficiency, and with no known risk factors for HIV-infection, could be due to horizontal nosocomial transmission. METHODS: For determination of time of transmission stored serum-samples from GP were analysed for HIV RNA content. Patient records were used to identify patients, who had received intravenous therapy on the same day as GP. Samples from GP and these possible source patients were identified and phylogenetic analyses of the env, gag and RT-encoding region of pol were performed. Furthermore, routines in conjunction with intravenous therapy were examined. RESULTS: We identified a patient (FDL) harbouring virus almost indistinguishable from the virus isolated from GP. The pairwise nucleotide distance between the C2-V3-C3 region of the env and gag sequences from the two patients were 1.9 and 0.9% respectively. In addition, GP harboured HIV RNA with a foscarnet resistance mutation further lending support to virus from the foscarnet-treated FDL being the source of the infection. Interestingly, GP experienced increases in immunoglobulin production after contracting the HIV-infection, and decreases after antiretroviral-induced viral suppression. A clinical procedure which, under stressful conditions, could lead to breaches in infection control measures was identified. The source of the infection was most likely a contaminated multidose vial. CONCLUSION: Through epidemiological and phylogenetic analyses a case of horizontal nosocomial HIV-transmission was disclosed. Identification of multidose vials as possible vehicles for horizontal nosocomial transmission recently led to the recommendation of restriction of the use of multidose vials, a recommendation supported by the present study. The study underlies the importance of a constant survey of infection control precautions.

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

OBJECTIVES: To 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. DESIGN: A 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. RESULTS: As 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). CONCLUSIONS: Treatment 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.

Changes in use of antiretroviral therapy in regions of Europe over time. EuroSIDA Study Group.

OBJECTIVES: To analyse use of antiretroviral therapy within Europe between 1994 and 1997. DESIGN: From September 1994, the EuroSIDA study (cohorts I-III) has prospectively followed unselected HIV-infected patients from 50 clinical centres in 17 European countries (total, 7230). METHODS: Patients under follow-up at half-year intervals from September 1994 (n=2871) to September 1997 (n=3682) were classified according to number of drugs currently used (none, one, two, three, four or more). Use of antiretroviral therapy was stratified by CD4 cell count (< 200 versus > or = 200 x 10(6)/l) and by region of Europe (south, central, or north). Frequency data were compared by chi2 test and logistic regression modelling. RESULTS: The proportion of patients on antiretroviral monotherapy diminished over time (1994, 42%; 1997, 3%), as did the proportion of patients without therapy (from 37 to 9%). Over time, the proportion of patients on triple (from 2 to 55%) and quadruple (from 0 to 9%) therapy increased, whereas use of dual therapy peaked in 1996 and subsequently fell. In the three regions of Europe, changes in use of antiretroviral therapy differed substantially. However, as of September 1997, only minor differences persisted. The proportion of patients on dual, triple, and quadruple therapy were as follow: south, 33, 52 and 5%, respectively; central, 23, 55 and 14%, respectively; north, 16, 59 and 10%, respectively. In September 1997, odds for use of three or more drugs including at least one protease inhibitor did not differ significantly between regions. CONCLUSIONS: Use of antiretroviral therapy in Europe has changed dramatically towards combination treatment in the last few years. Regional differences in use of antiretroviral therapy have decreased, and by September 1997 only minor differences remained. Antiretroviral therapy with three or more drugs and use of protease inhibitors has become more common in all regions of Europe.

The relative prognostic value of plasma HIV RNA levels and CD4 lymphocyte counts in advanced HIV infection.

OBJECTIVE: It has been suggested that the plasma HIV RNA level is a better predictor of AIDS and death than the CD4 lymphocyte count. We assessed whether the prognostic value of plasma virus levels was different according to the CD4 count. DESIGN: Prospective cohort study of HIV-infected patients followed for a median of 2.91 years (range, 0.02-4.54). SETTING: Department of Infectious Diseases at Rigshospitalet, Copenhagen, Denmark. PARTICIPANTS: A group of 255 HIV-infected individuals with an initial measurement of CD4 lymphocyte count and plasma HIV RNA. MAIN OUTCOME MEASURE: Survival time. RESULTS: The plasma HIV RNA (median 101410 copies/ml; range (range 200-7200000) and the CD4 lymphocyte count (median 250 cells x 10(6)/l; range 1-1247) were negatively correlated (Pearson r = -0.53; P < 0.00001). Of the 255 patients, 110 died during follow-up. Overall, a higher HIV RNA level was associated with increased risk of death, but the association was smaller in patients with lower CD4 lymphocyte counts (test for interaction P < 0.0001). In patients with CD4 count below 50 cells x 10(6)/l the association between HIV RNA and risk of death was not statistically significant (relative hazard per 10-fold higher HIV RNA level was 1.53; P = 0.11; adjusted for age and CD4 count) while that between the CD4 count and risk of death was highly significant (relative hazard per 50% lower CD4 count 1.38; P = 0.005; adjusted for age and HIV RNA level). CONCLUSIONS: Patients were relatively lightly treated with antiretroviral drugs both before and during this study. In this situation, it appears that the HIV RNA level has a relatively weak association with risk of death in patients with advanced HIV infection and that the CD4 lymphocyte count is probably more useful in assessing prognosis.

Quantification of HIV-1 RNA during antiretroviral therapy: association with viral phenotype and development of resistance.

The aim of this study was to analyse the interplay between the treatment responses, as assessed by serum HIV-1 RNA levels and CD4 cell counts, virological phenotype and the development of phenotypic and genotypic resistance. A total of 47 late-stage, HIV-1-infected, antiretroviral-naive patients treated with reverse transcriptase inhibitors (zidovudine or didanosine monotherapy or alternating zidovudine and didanosine) as part of a randomized study and remaining on treatment for a minimum of 1 year were included in the study. Baseline serum HIV-1 RNA levels did not differ between the patients harbouring syncytium-inducing (SI) virus and those harbouring non-syncytium-inducing (NSI) virus (P = 0.66), despite the fact that the group of patients with SI virus had a significantly lower median CD4 cell count (P < 0.00005) and a higher proportion of patients diagnosed with AIDS at study entry (11/19 versus 6/25) than did the group with NSI virus. The patients harbouring SI virus had significantly faster clinical progression than that of the patients harbouring NSI virus (P < 0.001). The patients wit