Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types

BACKGROUND: Standard first-line combination antiretroviral treatment (cART) against human immunodeficiency virus 1 (HIV-1) contains either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Differences between these regimen types in the extent of the emergence of drug resistance on virological failure and the implications for further treatment options have rarely been assessed. METHODS: We investigated virological outcomes in patients from the Swiss HIV Cohort Study initiating cART between January 1, 1999, and December 31, 2005, with an unboosted PI, a PI/r, or an NNRTI and compared genotypic drug resistance patterns among these groups at treatment failure. RESULTS: A total of 489 patients started cART with a PI, 518 with a PI/r, and 805 with an NNRTI. A total of 177 virological failures were observed (108 [22%] PI failures, 24 [5%] PI/r failures, and 45 [6%] NNRTI failures). The failure rate was highest in the PI group (10.3 per 100 person-years; 95% confidence interval [CI], 8.5-12.4). No difference was seen between patients taking a PI/r (2.7; 95% CI, 1.8-4.0) and those taking an NNRTI (2.4; 95% CI, 1.8-3.3). Genotypic test results were available for 142 (80%) of the patients with a virological treatment failure. Resistance mutations were found in 84% (95% CI, 75%-92%) of patients taking a PI, 30% (95% CI, 12%-54%) of patients taking a PI/r, and 66% (95% CI, 49%-80%) of patients taking an NNRTI (P < .001). Multidrug resistance occurred almost exclusively as resistance against lamivudine-emtricitabine and the group-specific third drug and was observed in 17% (95% CI, 9%-26%) of patients taking a PI, 10% (95% CI, 0.1%-32%) of patients taking a PI/r, and 50% (95% CI, 33%-67%) of patients taking an NNRTI (P < .001). CONCLUSIONS: Regimens that contained a PI/r or an NNRTI exhibited similar potency as first-line regimens. However, the use of a PI/r led to less resistance in case of virological failure, preserving more drug options for the future.

[Bisexuality and AIDS. Implications for heterosexual HIV infections in women]

One of the possible pathways into heterosexual population is the transfer of HIV-virus from bisexual men to their female partners. Therefore sexual behaviour of HIV-positive and -negative bisexual men (n = 31) before and after Aids-disease was analysed. Prior to the Aids-epidemic promiscuous behavior towards male partners (about one female partner per year versus 10 male partners per year). Relatively common contacts to woman occurred within steady relationships. After contact with HIV-test and personal counselling sexual practice became significantly different. The number of female and male contacts was markedly reduced, especially female chance acquaintances were avoided; safer sex was preferred and readiness to inform female partners about bisexuality was increased. This study suggests that reduction of risk for HIV-infection of female partners by homosexual men can be achieved by means of a HIV-test and personal counselling, a possibility that should be considered in preventive concepts.

Rapid diagnostic tests for the home-based management of malaria, in a high-transmission area

Rapid diagnostic tests (RDT) are sometimes recommended to improve the home-based management of malaria. The accuracy of an RDT for the detection of clinical malaria and the presence of malarial parasites has recently been evaluated in a high-transmission area of southern Mali. During the same study, the cost-effectiveness of a 'test-and-treat' strategy for the home-based management of malaria (based on an artemisinin-combination therapy) was compared with that of a 'treat-all' strategy. Overall, 301 patients, of all ages, each of whom had been considered a presumptive case of uncomplicated malaria by a village healthworker, were checked with a commercial RDT (Paracheck-Pf). The sensitivity, specificity, and positive and negative predictive values of this test, compared with the results of microscopy and two different definitions of clinical malaria, were then determined. The RDT was found to be 82.9% sensitive (with a 95% confidence interval of 78.0%-87.1%) and 78.9% (63.9%-89.7%) specific compared with the detection of parasites by microscopy. In the detection of clinical malaria, it was 95.2% (91.3%-97.6%) sensitive and 57.4% (48.2%-66.2%) specific compared with a general practitioner's diagnosis of the disease, and 100.0% (94.5%-100.0%) sensitive but only 30.2% (24.8%-36.2%) specific when compared against the fulfillment of the World Health Organization's (2003) research criteria for uncomplicated malaria. Among children aged 0-5 years, the cost of the 'test-and-treat' strategy, per episode, was about twice that of the 'treat-all' (U.S.$1.0. v. U.S.$0.5). In older subjects, however, the two strategies were equally costly (approximately U.S.$2/episode). In conclusion, for children aged 0-5 years in a high-transmission area of sub-Saharan Africa, use of the RDT was not cost-effective compared with the presumptive treatment of malaria with an ACT. In older patients, use of the RDT did not reduce costs. The question remains whether either of the strategies investigated can be made affordable for the affected population.

Variability of anti-PF4/heparin antibody results obtained by the rapid testing system ID-H/PF4-PaGIA

BACKGROUND: Recent studies have shown that a low clinical pretest probability may be adequate for excluding heparin-induced thrombocytopenia. However, for patients with intermediate or high pretest probability, laboratory testing is essential for confirming or refuting the diagnosis. Rapid assessment of anti-PF4/heparin-antibodies may assist clinical decision-making. OBJECTIVES: To evaluate the performance of rapid ID-H/PF4-PaGIA. In particular, we verified reproducibility of results between plasma and serum specimens, between fresh and frozen samples, and between different ID-H/PF4-polymer lots (polystyrene beads coated with heparin/PF4-complexes). PATIENTS/METHODS: The samples studied were 1376 plasma and 914 corresponding serum samples from patients investigated for suspected heparin-induced thrombocytopenia between January 2000 and October 2008. Anti-PF4/heparin-antibodies were assessed by ID-H/PF4-PaGIA, commercially available ELISAs and heparin-induced platelet aggregation test. RESULTS: Among 914 paired plasma/serum samples we noted discordant results (negative vs. low-titre positive) in nine instances (1%; 95%CI, 0.4-1.6%). Overall, agreement between titres assessed in plasma vs. serum was highly significant (Spearman correlation coefficient, 0.975; P < 0.0001). Forty-seven samples tested both fresh and after freezing/thawing showed a good agreement, with one discordant positive/negative result (Spearman correlation coefficient, 0.970; P < 0.0001). Among 1376 plasma samples we noted a strikingly variable incidence of false negative results (none - 82%; 95%CI, 66-98%), depending on the employed ID-H/PF4-polymer lot. Faulty lots can be recognized by titrating commercial positive controls and stored samples of HIT-patients. CONCLUSION: Laboratories performing the assay should implement stringent internal quality controls in order to recognize potentially faulty ID-H/PF4-polymer lots, thus avoiding false negative results.

Is perioperative point-of-care prothrombin time testing accurate compared to the standard laboratory test?

There is no accepted way of measuring prothrombin time without time loss for patients undergoing major surgery who are at risk of intraoperative dilution and consumption coagulopathy due to bleeding and volume replacement with crystalloids or colloids. Decisions to transfuse fresh frozen plasma and procoagulatory drugs have to rely on clinical judgment in these situations. Point-of-care devices are considerably faster than the standard laboratory methods. In this study we assessed the accuracy of a Point-of-care (PoC) device measuring prothrombin time compared to the standard laboratory method. Patients undergoing major surgery and intensive care unit patients were included. PoC prothrombin time was measured by CoaguChek XS Plus (Roche Diagnostics, Switzerland). PoC and reference tests were performed independently and interpreted under blinded conditions. Using a cut-off prothrombin time of 50%, we calculated diagnostic accuracy measures, plotted a receiver operating characteristic (ROC) curve and tested for equivalence between the two methods. PoC sensitivity and specificity were 95% (95% CI 77%, 100%) and 95% (95% CI 91%, 98%) respectively. The negative likelihood ratio was 0.05 (95% CI 0.01, 0.32). The positive likelihood ratio was 19.57 (95% CI 10.62, 36.06). The area under the ROC curve was 0.988. Equivalence between the two methods was confirmed. CoaguChek XS Plus is a rapid and highly accurate test compared with the reference test. These findings suggest that PoC testing will be useful for monitoring intraoperative prothrombin time when coagulopathy is suspected. It could lead to a more rational use of expensive and limited blood bank resources.

Self-reported alcohol consumption and its association with adherence and outcome of antiretroviral therapy in the Swiss HIV Cohort Study

BACKGROUND: Alcohol consumption leading to morbidity and mortality affects HIV-infected individuals. Here, we aimed to study self-reported alcohol consumption and to determine its association with adherence to antiretroviral therapy (ART) and HIV surrogate markers. METHODS: Cross-sectional data on daily alcohol consumption from August 2005 to August 2007 were analysed and categorized according to the World Health Organization definition (light, moderate or severe health risk). Multivariate logistic regression models and Pearson's chi(2) statistics were used to test the influence of alcohol use on endpoints. RESULTS: Of 6,323 individuals, 52.3% consumed alcohol less than once a week in the past 6 months. Alcohol intake was deemed light in 39.9%, moderate in 5.0% and severe in 2.8%. Higher alcohol consumption was significantly associated with older age, less education, injection drug use, being in a drug maintenance programme, psychiatric treatment, hepatitis C virus coinfection and with a longer time since diagnosis of HIV. Lower alcohol consumption was found in males, non-Caucasians, individuals currently on ART and those with more ART experience. In patients on ART (n=4,519), missed doses and alcohol consumption were positively correlated (P<0.001). Severe alcohol consumers, who were pretreated with ART, were more often off treatment despite having CD4+ T-cell count <200 cells/microl; however, severe alcohol consumption per se did not delay starting ART. In treated individuals, alcohol consumption was not associated with worse HIV surrogate markers. CONCLUSIONS: Higher alcohol consumption in HIV-infected individuals was associated with several psychosocial and demographic factors, non-adherence to ART and, in pretreated individuals, being off treatment despite low CD4+ T-cell counts.

Assessment of a real-time PCR test to diagnose syphilis from diverse biological samples

OBJECTIVES: To investigate the contribution of a real-time PCR assay for the detection of Treponema pallidum in various biological specimens with the secondary objective of comparing its value according to HIV status. METHODS: Prospective cohort of incident syphilis cases from three Swiss hospitals (Geneva and Bern University Hospitals, Outpatient Clinic for Dermatology of Triemli, Zurich) diagnosed between January 2006 and September 2008. A case-control study was nested into the cohort. Biological specimens (blood, lesion swab or urine) were taken at diagnosis (as clinical information) and analysed by real-time PCR using the T pallidum 47 kDa gene. RESULTS: 126 specimens were collected from 74 patients with primary (n = 26), secondary (n = 40) and latent (n = 8) syphilis. Among primary syphilis, sensitivity was 80% in lesion swabs, 28% in whole blood, 55% in serum and 29% in urine, whereas among secondary syphilis, it was 20%, 36%, 47% and 44%, respectively. Among secondary syphilis, plasma and cerebrospinal fluid were also tested and provided a sensitivity of 100% and 50%, respectively. The global sensitivity of T pallidum by PCR (irrespective of the compartment tested) was 65% during primary, 53% during secondary and null during latent syphilis. No difference regarding serology or PCR results was observed among HIV-infected patients. Specificity was 100%. CONCLUSIONS: Syphilis PCR provides better sensitivity in lesion swabs from primary syphilis and displays only moderate sensitivity in blood from primary and secondary syphilis. HIV status did not modify the internal validity of PCR for the diagnosis of primary or secondary syphilis.

The effect of an oral glucose load on sodium and water excretion after rapid intravenous infusion of 0.9% (w/v) saline

Previous studies have suggested that oral or intravenous glucose enhances salt and water retention following a saline load. To test this, we studied the effects of an oral glucose load on urinary sodium and water excretion and serum biochemistry in response to a 2l intravenous infusion of 0.9% saline in normal subjects.

Field performance of two rapid screening tests in active surveillance of transmissible spongiform encephalopathies in small ruminants

Recently, screening tests for monitoring the prevalence of transmissible spongiform encephalopathies specifically in sheep and goats became available. Although most countries require comprehensive test validation prior to approval, little is known about their performance under normal operating conditions. Switzerland was one of the first countries to implement 2 of these tests, an enzyme-linked immunosorbent assay (ELISA) and a Western blot, in a 1-year active surveillance program. Slaughtered animals (n = 32,777) were analyzed in either of the 2 tests with immunohistochemistry for confirmation of initial reactive results, and fallen stock samples (n = 3,193) were subjected to both screening tests and immunohistochemistry in parallel. Initial reactive and false-positive rates were recorded over time. Both tests revealed an excellent diagnostic specificity (>99.5%). However, initial reactive rates were elevated at the beginning of the program but dropped to levels below 1% with routine and enhanced staff training. Only those in the ELISA increased again in the second half of the program and correlated with the degree of tissue autolysis in the fallen stock samples. It is noteworthy that the Western blot missed 1 of the 3 atypical scrapie cases in the fallen stock, indicating potential differences in the diagnostic sensitivities between the 2 screening tests. However, an estimation of the diagnostic sensitivity for both tests on field samples remained difficult due to the low disease prevalence. Taken together, these results highlight the importance of staff training, sample quality, and interlaboratory comparison trials when such screening tests are implemented in the field.

Circumcision and HIV infection among men who have sex with men in Britain: the insertive sexual role

The objective was to examine the association between circumcision status and self-reported HIV infection among men who have sex with men (MSM) in Britain who predominantly or exclusively engaged in insertive anal intercourse. In 2007-2008, a convenience sample of MSM living in Britain was recruited through websites, in sexual health clinics, bars, clubs, and other venues. Men completed an online survey which included questions on circumcision status, HIV testing, HIV status, sexual risk behavior, and sexual role for anal sex. The analysis was restricted to 1,521 white British MSM who reported unprotected anal intercourse in the previous 3 months and who said they only or mostly took the insertive role during anal sex. Of these men, 254 (16.7 %) were circumcised. Among men who had had a previous HIV test (n = 1,097), self-reported HIV seropositivity was 8.6 % for circumcised men (17/197) and 8.9 % for uncircumcised men (80/900) (unadjusted odds ratio [OR], 0.97; 95 % confidence interval [95 % CI], 0.56, 1.67). In a multivariable logistic model adjusted for known risk factors for HIV infection, there was no evidence of an association between HIV seropositivity and circumcision status (adjusted OR, 0.79; 95 % CI, 0.43, 1.44), even among the 400 MSM who engaged exclusively in insertive anal sex (adjusted OR, 0.84; 95 % CI, 0.25, 2.81). Our study provides further evidence that circumcision is unlikely to be an effective strategy for HIV prevention among MSM in Britain.

HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5-20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV-infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.

A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients

Because of the large variability in the pharmacokinetics of anti-HIV drugs, therapeutic drug monitoring in patients may contribute to optimize the overall efficacy and safety of antiretroviral therapy. An LC–MS/MS method for the simultaneous assay in plasma of the novel antiretroviral agents rilpivirine (RPV) and elvitegravir (EVG) has been developed to that endeavor. Plasma samples (100 μL) extraction is performed by protein precipitation with acetonitrile, and the supernatant is subsequently diluted 1:1 with 20-mM ammonium acetate/MeOH 50:50. After reverse-phase chromatography, quantification of RPV and EVG, using matrix-matched calibration samples, is performed by electrospray ionization–triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The stable isotopic-labeled compounds RPV-13C6 and EVG-D6 were used as internal standards. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<6.4%), as well as EVG and RPV short and long-term stability in plasma. Calibration curves were validated over the clinically relevant concentrations ranging from 5 to 2500 ng/ml for RPV and from 50 to 5000 ng/ml for EVG. The method is precise (inter-day CV%: 3–6.3%) and accurate (3.8–7.2%). Plasma samples were found to be stable (<15%) in all considered conditions (RT/48 h, +4°C/48 h, −20°C/3 months and 60°C/1 h). Selected metabolite profiles analysis in patients' samples revealed the presence of EVG glucuronide, that was well separated from parent EVG, allowing to exclude potential interferences through the in-source dissociation of glucuronide to parent drug. This new, rapid and robust LCMS/MS assay for the simultaneous quantification of plasma concentrations of these two major new anti-HIV drugs EVG and RPV offers an efficient analytical tool for clinical pharmacokinetics studies and routine therapeutic drug monitoring service.

Prevalence and risk factors of late presentation for HIV diagnosis and care in a tertiary referral centre in Switzerland.

QUESTIONS UNDER STUDY We sought to identify reasons for late human immunodeficiency virus (HIV) testing or late presentation for care. METHODS A structured chart review was performed to obtain data on test- and health-seeking behaviour of patients presenting late with CD4 cell counts below 350 cells/µl or with acquired immunodeficiency syndrome (AIDS), at the Zurich centre of the Swiss HIV Cohort Study between January 2009 and December 2011. Logistic regression analyses were used to compare demographic characteristics of persons presenting late with not late presenters. RESULTS Of 281 patients, 45% presented late, 48% were chronically HIV-infected non-late presenters, and an additional 7% fulfilled the <350 CD4 cells/µl criterion for late presentation but a chart review revealed that lymphopenia was caused by acute HIV infection. Among the late presenters, 60% were first tested HIV positive in a private practice. More than half of the tests (60%) were suggested by a physician, only 7% following a specific risk situation. The majority (88%) of patients entered medical care within 1 month of testing HIV positive. Risk factors for late presentation were older age (odds ratio [OR] for ≥50 vs <30 years: 3.16, p = 0.017), Asian versus Caucasian ethnicity (OR 3.5, p = 0.021). Compared with men who have sex with men (MSM) without stable partnership, MSM in a stable partnership appeared less likely to present late (OR 0.50, p = 0.034), whereas heterosexual men in a stable partnership had a 2.72-fold increased odds to present late (p = 0.049). CONCLUSIONS The frequency of late testing could be reduced by promoting awareness, particularly among older individuals and heterosexual men in stable partnerships.

Higher Risk of Incident HCV-Coinfections in MSM with a Wide HIV Transmission Bottleneck

BACKGROUND  High-risk sexual behaviors have been suggested as drivers of the recent dramatic increase of sexually-transmitted HCV among HIV-infected men who have sex with men(MSM). METHODS  We assessed the association between the HIV-transmission-bottleneck and the prevalence and incidence of HCV-coinfections in HIV-infected MSM from the Swiss-HIV-Cohort-Study(SHCS). As a proxy for the width of the transmission bottleneck we used the fraction of ambiguous nucleotides in Genotypic-Resistance-Tests(GRTs) from recent HIV-infections. We defined a broad bottleneck as a fraction of ambiguous nucleotides exceeding a previously-established threshold(0.5%). RESULTS  From the SHCS, we identified 671 MSMs with available HCV-serologies and with a HIV-GRT sampled during recent infection. Of those, 161(24.0%) exhibited a broad HIV-transmission-bottleneck, 38(5.7%) had at least one positive HCV test, and 26(3.9%) had an incident HCV infection. Individuals with broad HIV-transmission bottlenecks exhibited a twofold-higher odds of having ever experienced an HCV coinfection(OR[95%CI]=2.2[1.1, 4.3]) and a threefold-higher hazard of an incident HCV infection(HR[95%CI]= 3.0[1.4, 6.6]) than individuals with narrow HIV-transmission-bottlenecks. CONCLUSIONS  Our results indicate that the currently occurring sexual spread of HCV is focused on those MSMs that are prone to exhibit broad HIV-transmission-bottlenecks. This is consistent with an important role of high-risk behavior and mucosal-barrier-impairment in the transmission of HCV among MSM.

Hepatitis B und C bei HIV-Koinfektion

Hepatitis B and C virus infections are a leading cause of death in HIV-positive patients. Furthermore, the management of these infections is complicated. Psychosocial problems and comorbidities are frequent barriers to the optimal management of these patients. Furthermore, the rapid changes in treatment strategies particularly in Hepatitis C make it difficult to treat patients outside specialized centers. An improvement in treatment uptake and efficacy can only be achieved through coordinated efforts between private care physicians and specialized centers.