Sexually transmitted diseases in people living with HIV after implementation of cost coverage of HIV pre-exposure prophylaxis by statutory health insurance in Germany.

OBJECTIVES: After pre-exposure prophylaxis (PrEP) was introduced, rates of sexually transmitted infections (STIs) increased among PrEP users. However, data on STI trends in people living with HIV since then are limited. Since September 2019, PrEP has been covered by statutory German health insurance (SHI) in vulnerable groups. This study aimed to determine whether this coverage of PrEP costs affected STI rates in people living with HIV (specifically, men who have sex with men). METHODS: All patients of the HIVCENTER Frankfurt diagnosed with at least one STI within the observation period were retrospectively enrolled in the study. STIs included infection with Treponema pallidum, Chlamydia trachomatis, Neisseria gonorrhoeae, and/or Trichomonas vaginalis. The observation period covered 1 year before and 1 year after the coverage of PrEP costs by German SHI. Data were collected from outpatient clinic records. RESULTS: In total, 143 patients were enrolled in the study. The observation period was September 2018 to August 2019 for group 1 (n = 73) and September 2019 to August 2020 for group 2 (n = 70). The most frequent STIs were syphilis and infections due to chlamydia, gonococci, and trichomonads, in descending order. Infections with T. pallidum occurred more often in group 2 than in group 1 (60.0% vs. 50.7%; p = 0.253) as did chlamydia (37.1% vs. 28.8%; p = 0.286). CONCLUSIONS: A tendency for an increased ratio of STIs in people living with HIV was observed after the introduction of PrEP coverage by German SHI. STIs should be discussed intensively with people living with HIV, since the communities of PrEP users and people living with HIV overlap, and changes in risk behaviour might influence both groups.

[HIV First Diagnoses in Germany in 2014 - A Regional Analysis]. / HIV-Erstdiagnosen in Deutschland im Jahr 2014 ­ eine regionale Analyse.

BACKGROUND: Information on testing units in health care is scarce, particularly the group of late-presenters among the HIV-first diagnoses is still a challenge in Germany. AIM: Analysis of the impact of testing units on and reasons for the prevalence of HIV-first diagnoses and late presentation, taking 2014 for illustrative purposes. MATERIAL AND METHODS: Cross-sectional analysis of all individuals, treated in the Network HIV-Regional who were first diagnosed with HIV in 2014; patient characteristics, demographic and clinical data, including information on HIV testing were collected retrospectively and in a decentralised manner, pseudonymized and statistically evaluated. RESULTS: A total of 971 individuals with HIV-first diagnosis from 31 specialised care centres throughout Germany (15 hospitals, 16 private practices) represented 27.5% of all National HIV-first diagnoses -registrations from Robert Koch Institute for 2014, with similar results for CD4-cell count and HIV-transmission risk. The most common test site was a hospital (34.8%), followed by the office of a family doctor (19.6%) and medical specialist (16.1%). If the first diagnosis was established in hospital, then the patients were on average older than those tested on an ambulant care basis (42 vs. 37 years, p=0.001); moreover, the HI-viral load was higher (585 vs. 270 thousand copies/mL, p<0.001) and the CD4-cell count lower (265 vs. 414/µL, p<0.001). In 208/971 individuals with first diagnosis, at least one AIDS-defining disease was found, most frequently pneumocystis-pneumonia (43.8%), candidiasis (36.5%) and Kaposi sarcoma (10.6%). A regional comparison revealed that in eastern Germany, for first diagnosed HIV-patients were younger, had a higher HIV-RNA viral load and also more often clinical AIDS. CONCLUSION: This analysis of HIV-Regional for 2014 enables a deeper insight into HIV first diagnoses, on the eve of the introduction of important prevention tools in Germany, e. g., HIV home testing and pre-exposure prophylaxis. This cross-sectional analysis was representative for Germany and underscores the importance of specialised hospitals, in particular for eastern Germany, and furthermore the involvement of late-presenters into HIV health care.

[HIV Test in Pregnancy - 100% Not Reached in 2020]. / HIV-Test in der Schwangerschaft ­ 2020 noch nicht bei 100.

INTRODUCTION: In 2019 38 million people were living with HIV worldwide, more than half of them girls and women. Knowledge about maternal HIV status enables HIV transmission prophylaxis, reducing mother-to-child transmission<1%. We aimed to investigate the implementation of the mandatory documentation of counseling and optional HIV testing in the maternity records as recommended in the German maternity guidelines. METHODS: In the Obstetric Department of the University Hospital Bonn, maternity records were reviewed from June to October 2020, and pregnant women were interviewed regarding the patients' recall of counseling and HIV testing as well as their attitude towards a universal screening strategy using an anonymous questionnaire. RESULTS: Documentation was incomplete in 11% of maternal records: in 8% there was neither documentation of counseling nor of HIV testing, in 3% documentation of counseling only. In 291 questionnaires 47% of pregnant women could not recall counselling. 90% of pregnant women were in favor of universal HIV testing in pregnancy, 9% were undecided, and 1% opposed it. 55% would support change from an "opt-in" to an "opt-out" screening policy in pregnancy. SUMMARY: Documentation of counseling and HIV testing was incomplete in 11% of cases, and nearly half of the women could not recall counselling. New strategies from midwives and obstetricians need to be developed to achieve universal HIV testing in pregnant women leading to zero HIV mother-to-child transmissions.

Treatment modification after starting cART in people living with HIV: retrospective analysis of the German ClinSurv HIV Cohort 2005-2017.

OBJECTIVE: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving. METHODS: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan-Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data. RESULTS: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59-66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39-0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011-2017), being on a multi-tablet regimen (MTR). CONCLUSIONS: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.

Influence of tenofovir exposure in utero on primary dentition.

Tenofovir disoxoproxil fumarate (TDF) is recommended for antiretroviral treatment for pregnant women living with HIV. As a comparative method to study bone density, we investigated the influence of in utero tenofovir exposure on the prevalence and distribution of developmental defects of enamel (DDE) in the primary dentition, as the mineralization process in teeth is higher and more complex and thus more vulnerable. HIV-exposed children with in utero exposition to tenofovir were included in this prospective observational single-center study. Dental status and enamel defects were assessed by an experienced dentist following a standardized protocol. Further information was collected using a standardized questionnaire, available in German and English. The prevalence of developmental defects in children with intrauterine tenofovir exposure was compared with literature data from a recent study of 377 healthy children in Germany and literature data from a study of 1221 healthy African children. Thirty-one children (mean age 2.1 ± 0.3 years; 41.9% female) were included. Median tenofovir exposure in utero was 28 weeks (mean ± 10.52 SD). Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children (16.1% vs. 5.3%, p = 0.051 (compared to German cohort); 16.1% vs. 33.3%, p = 0.068 (compared to African cohort)).Conclusion: HIV-uninfected infants with in utero exposure to TDF showed no significant differences in the prevalence of DDE in comparison to cross-sectional data of HIV- and TDF-unexposed children; thus, the in utero exposure to TDF did not negatively influence the prevalence or distribution of DDE. What is Known: • There are no data available on the prevalence of developmental defects of enamel (DDE) in the primary dentition in intrauterine HIV- and tenofovir-exposed children. • Conclusions can be drawn from intrauterine milk tooth development to bone development and mineralization. What is New: • Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children. • Preterm birth and hospitalization did not show a significant association on the prevalence of developmental defects in the primary dentition.

[Treatment of HIV in Pregnancy - Progress Over One Decade]. / Behandlung von HIV in der Schwangerschaft ­ Entwicklung über eine Dekade.

INTRODUCTION: Worldwide, 37 million people are infected with HIV; more than 50% are women. Currently, MTCT (mother-to-child transmission) can be reduced to<1%. The intention of the present study was to analyze the development of (1) the course of pregnancy of HIV-infected women, (2) the mode of delivery and (3) the post-exposure prophylaxis of the newborn over the last decade. METHODOLOGY: In this retrospective study, data from HIV-infected women who between 2005 and 2016 received care at the HIV outpatient department and gave birth at the Department of Obstetrics at University Hospital Bonn was analyzed. Furthermore, neonatal data was collected and HIV-MTCT was evaluated. RESULTS: In the 2005-2016 study period, 87 pregnancies in 61 women were identified. Seventy babies were born alive at the Department of Obstetrics, University Hospital Bonn. 53% of these women were of African origin. The median of CD4+ cell count was 510 cells/ml (IQR 444); however, 32 women (52%) had more than 500 cells/ml. During the antenatal period, the HI viral load had been suppressed completely in 77% of women (<50 HIV-1-RNA copies/ml) and was<400 HIV-1-RNA copies/ml in 92% of women. The elective cesarean section rate fell significantly from 77% in the years 2005-2011 to 58% in 2012-2016. The proportion of deliveries after 37 weeks of gestation increased markedly from 60% to 69% after 2012. Additionally, while between 2005-2011 the birth weight of 78% of the newborns was between the 10th and 90th percentile, this proportion increased to 92% after 2012. Fifty-four of 70 newborns (77%) were classified as having low to normal HIV transmission risk. A vertical HIV transmission from mother to child did not occur (0/70). CONCLUSIONS: Between 2005 and 2016 no vertical HIV transmission from mother to child occurred (0/70). Due to the change in treatment strategy, the elective cesarean section rate fell significantly as well the rate of premature births. An optimal interdisciplinary collaboration builds the basis for successful treatment of HIV in pregnancy.

HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy.

There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV-1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over time impaired HIV-1 suppression in CSF.

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

BACKGROUND: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. METHODS: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. RESULTS: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). CONCLUSIONS: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. CLINICAL TRIALS REGISTRATION: NCT00825929.

Maraviroc Pharmacokinetics in HIV-1-Infected Pregnant Women.

OBJECTIVE: To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. METHODS: HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. RESULTS: Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing. CONCLUSIONS: Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy. CLINICAL TRIALS REGISTRATION: NCT00825929 and NCT000422890.

Identification of a new epitope for HIV-neutralizing antibodies in the gp41 membrane proximal external region by an Env-tailored phage display library.

HIV controllers are a valuable source for the identification of HIV-neutralizing antibodies, as chronic infection over decades allows extensive affinity maturation of antibodies for improved Ag recognition. We analyzed a small cohort of elite controllers (ECs) for HIV-neutralizing antibodies using a panel of standardized HIV-1 pseudovirions on TZM-bl cells. An HIV-1 Env-tailored phage display library was generated to select epitopes targeted by neutralizing antibodies in the EC26 plasma sample showing the broadest neutralizing activity. Selected Env fragments were mostly allocated to the membrane proximal external region of gp41. After preabsorbing the EC26 plasma with the selected phage EC26-2A4, we achieved 50% depletion of its neutralizing activity. Furthermore, antibodies affinity-purified with the EC26-2A4 epitope from EC26 plasma showed neutralizing activity, proving that the selected phage indeed contains an epitope targeted by neutralizing plasma antibodies. Epitope fine mapping of the purified plasma antibodies on peptide arrays identified a new epitope overlapping, but clearly distinct, from the prominent 2F5 epitope. Of note, the purified antibodies did not show autoreactivity with cardiolipin, whereas low reactivity with phosphatidylserine comparable to mAb 2F5 was observed. Thus, this new epitope represents a promising candidate for further analysis in view of HIV vaccine development.

Impact of raltegravir on HIV-1 RNA and DNA forms following initiation of antiretroviral therapy in treatment-naive patients.

OBJECTIVES: The rapid early-phase decay of plasma HIV-1 RNA during integrase inhibitor-based therapy is not fully understood. The accumulation of biologically active episomal HIV-1 cDNAs, following aborted integration, could contribute to antiviral potency in vivo. METHODS: This prospective, controlled clinical observation study explored raltegravir's impact on the dynamics of HIV-1 RNA in plasma, and concentrations of total HIV-1 cDNA, episomal 2-long terminal repeat (LTR) circles and HIV-1 integrants in peripheral blood mononuclear cells (PBMC). Individuals starting therapy with two nucleoside reverse transcriptase inhibitors plus either raltegravir (raltegravir group; n = 10 patients) or boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitor (control group; n = 10 patients) were followed for 48 weeks. RESULTS: Suppression of HIV-1 RNA (<50 copies/mL) was reached earlier (5/10 versus 0/10 at week 4; 8/10 versus 4/10 at week 12) on raltegravir. Significant total HIV-1 cDNA reductions in PBMC were reached by day 99 and persisted until day 330, with median factors of decrease of 7.2 and 8.9, respectively. Broad inter-individual variations, yet no treatment-associated differences, were noted for HIV-1 cDNA concentrations. Despite reductions in HIV-1 RNA (∼3 log) and total HIV-1 cDNA (∼1 log), concentrations of integrants and 2-LTR circles remained largely unchanged. CONCLUSIONS: These results extend the previously reported early benefit of raltegravir on the decline of plasma viraemia to treatment-naive patients. The modest treatment-associated, yet group-independent, decline in total HIV-1 cDNA load and the lack of significant changes in integrated and episomal HIV-1 cDNA suggest that most integrated DNA is archival and targeting of HIV reservoirs other than PBMC may underlie beneficial effects of raltegravir.

Long-term effects of chemoradiotherapy for anal cancer in patients with HIV infection: oncological outcomes, immunological status, and the clinical course of the HIV disease.

BACKGROUND: Despite the increasing evidence for chemoradiotherapy as standard treatment for anal cancer in patients with HIV infection, there is still some uncertainty regarding increased toxicity and adverse effects on the immune status. OBJECTIVE: We report the clinical outcome of 5-fluorouracil/mitomycin C-based concurrent chemoradiotherapy for anal carcinoma in patients with HIV infection with an emphasis on the long-term course of CD4 counts and the HIV-related morbidity during follow-up. DESIGN AND SETTINGS: A retrospective single-institution chart review was performed. PATIENTS: Between 1997 and 2012, 36 HIV-positive patients were treated with standard chemoradiotherapy (median tumor dose, 54 (range, 50.4-60.4) Gy at 1.8 Gy/fraction; 5-fluorouracil, 800-1000 mg/m(2), days 1-4 or 1-5; mitomycin C, 10 mg/m(2), day 1, in the first and fifth week). MAIN OUTCOME MEASURES: A retrospective analysis was performed with respect to tumor response, local control, cancer and overall survival, and toxicity. Immunological parameters, including pre- and posttreatment CD4 counts, viral load, and HIV-specific morbidity were recorded during follow-up. RESULTS: Chemoradiotherapy could be completed in all patients. Acute grade 3 toxicities occurred in 17/36 patients (47%). Complete response was achieved in 31 patients (86%). Five-year local control, colostomy-free, cancer-specific, and overall survival were 72%, 87%, 77%, and 74%. The median pretreatment CD4 count significantly decreased from 367 cells/µL to 139 cells/µL, 3 to 7 weeks after completion of chemoradiotherapy (p < 0.001). Four patients (11%) experienced opportunistic illnesses during the follow-up (median, 66; range, 10-164 months). LIMITATIONS: This study is limited by its retrospective design and its small sample size. CONCLUSIONS: Our data confirm again that, in the highly active antiretroviral therapy era, anal cancer can be treated in HIV-positive patients with standard chemoradiotherapy, with a clinical outcome similar to their HIV-negative counterparts. The chemoradiotherapy-related decline of the CD4 counts, which remain decreased up to 6 years after chemoradiotherapy, was not associated with increased HIV-related clinical morbidity.

Lopinavir/ritonavir pharmacokinetics, efficacy, and safety in HIV and hepatitis B or C coinfected adults without symptoms of hepatic impairment.

OBJECTIVE: Lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors is one standard antiretroviral therapy regimen, both in patients with HIV alone and coinfected with hepatitis B or C. Our objective was to investigate whether hepatitis coinfection without clinical signs of hepatic impairment is a cofactor altering lopinavir pharmacokinetics and influencing therapy outcome. METHODS: Steady-state 12-hour pharmacokinetic profiles of lopinavir/ritonavir were assessed in patients with (group 1, n = 20) or without (group 2, n = 36) hepatitis coinfection, taking lopinavir/ritonavir 400/100 mg twice a day plus nucleoside reverse transcriptase inhibitors, measured by means of high-performance liquid chromatography-tandem mass spectrometry. Demographic (sex, age, weight), pharmacological (formulation, comedication), clinical, and virological/immunologic parameters (HIV-RNA PCR, CD4(+) cell count) were compared between the groups and included in regression analyses for correlations with lopinavir pharmacokinetic parameters (C(min), C(max), AUC, CL, and t(1/2)) and viral load evolution over 48 weeks on therapy. Patient pairs were matched 1:2 for the parameters sex, age, weight, ethnicity, and drug formulation. RESULTS: None of the hepatitis-related cofactors (aspartate aminotransferase, alanine aminotransferase, γGT, HBe Ag, HBsAg, HCV-RNA PCR, HCV-therapy) had an influence on lopinavir pharmacokinetics in this group of patients. Lopinavir C(min) (P = 0.039) and area under the curve (P = 0.038) and ritonavir C(max) (P = 0.049) were significantly enhanced in hepatitis-coinfected patients, but correlated only with drug formulation (ie, soft gel capsule or Meltrex tablet formulation, multivariate regression analysis, P = 0.001), not hepatitis coinfection. CONCLUSIONS: Despite moderately enhanced lopinavir/ritonavir plasma concentrations, regular therapeutic drug monitoring is not to be considered in hepatitis-coinfected patients without hepatic impairment. Antiviral efficacy is comparable between both groups, a less-pronounced CD4(+) cell increase in hepatitis-coinfected patients is in line with previously published data.

Differences in the Course of CD4 and CD8 Cells After Chemoradiotherapy in People Living with HIV with Anal Cancer.

Incidence of anal carcinoma (AC) in people living with HIV (PLWH) is increased compared to the general population. Adverse effects of chemoradiotherapy (CRT) on the immune system are associated with a significant detrimental prognosis on overall survival in patients receiving CRT for solid tumors. The aim of this study was to evaluate immunological factors, in particular the differences in recovery of CD4+ and CD8+ cell counts before and after CRT for AC in PLWH. Retrospective single-center chart review extraction to analyze immunological data collected from PLWH with AC; descriptive statistics were used. Thirty-six PLWH with histologically proven AC were included in the analysis. Absolute CD4 cell count 60 months after CRT was 67.2% of the value at the beginning of CRT, whereas the CD8 cell count reached 82.3%. These differences were statistically significant (p = .048), whereas CD4/CD8-ratio remained stable. The findings of the presented study regarding CD4+ and CD8+ cell recovery after CRT are congruent with results from prior studies in non-HIV infected patients. Although not reaching the level of prior CRT T cell numbers, the ability to generate CD8+ cells seems to be better recovered, while CD4+ regeneration is more impaired. These observations are best explained by faster recovery of CD8+ cells via thymic-independent pathways, which are not available for regeneration of CD4+ cells. Further studies with larger numbers of patients are required to analyze the specific CD4+ and CD8+ cell subsets.

Immune response after two doses of the novel split virion, adjuvanted pandemic H1N1 influenza A vaccine in HIV-1-infected patients.

BACKGROUND: To determine the rate of seroconversion after 2 doses of a novel split virion, inactivated, adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in human immunodeficiency virus type 1 (HIV-1)-infected patients (ClinicalTrials.gov NCT01017172). METHODS: Diagnostic study of adult HIV-1-infected patients scheduled for H1N1 influenza A vaccination. Blood samples where taken before and 21 days after the first dose and 21 days after the second dose of the vaccine. Antibody (AB) titers were determined by hemagglutination inhibition assay. Seroconversion was defined by either an AB titer ≤ 1:10 before and ≥ 1:40 after or ≥ 1:10 before and a ≥ 4-fold increase in AB titer 21 days after vaccination. RESULTS: One hundred thirty-five patients received 2 doses of the H1N1 vaccine and were analyzed. The rate of seroconversion was 68.2% (95% confidence interval, 59.6-75.9) after the first dose and 91.9% (95% confidence interval, 85.9-95.9) after the second dose. Patients who did not seroconvert had a lower mean nadir CD4 cell count (± standard deviation; 81 ± 99 vs 190 ± 148 cells/µL; P = .006), had a longer duration of HIV infection (± standard deviation; 13.1 ± 5.9 vs 8.8 ± 6.8 years; P = .04), and were more likely to have an AB titer ≥ 1:40 before vaccination (4% vs 55%; P < .001) when compared with patients with seroconversion. No other differences were found between the 2 groups, including AIDS status, highly active antiretroviral therapy status, HIV RNA - polymerase chain reaction load <50 copies/mL, CD4 cell count, sex, body mass index, and chronic hepatitis. CONCLUSION: Among HIV-infected patients, the rate of seroconversion after the first dose of an adjuvanted H1N1 influenza A vaccine was 68% and increased to 92% after a second doses.

Evaluation of Platelet Activation by HIV Protease Inhibitors - The HIV-PLA II Study.

BACKGROUND: In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks. METHODS: The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin α-IIb/Integrin ß-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses. RESULTS: CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation. CONCLUSION: CD62P expression, detecting the ɑ-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART. CLINICAL TRIAL REGISTRATION NO: DRKS00000288.

Reasons for Choice of Antiretroviral Regimens in HIV Patients Presenting Late for Initial Treatment in Europe.

The choice of an optimal antiretroviral therapy (ART) in naive patients presenting late for initial therapy with advanced HIV infection, that is, with a CD4 cell count <200/µL and/or an AIDS-defining disease (late presenters, LPs), is still a challenge, even for HIV specialists. At present, there is little information on the decision process and selection criteria that physicians must take into account when choosing the presumably optimal initial ART for LPs. This study analyzes reasons for the individual choice of first-line ART in HIV LPs. We conducted a prospective multi-center study to analyze the decision-making process of physicians treating naive HIV patients presenting with a CD4 cell count <200/µL and/or an AIDS-defining condition. Two European HIV treatment centers based in Frankfurt (Germany) and A Coruna (Spain) participated in the study. Physicians documented the reasons that led to their decision for a specific first-line ART regimen. A questionnaire was designed for the study. Decisions of the participating physicians were evaluated. A total of 52 treatment decisions were analyzed. Evaluation of the choice of antiretroviral treatment demonstrated that for the overall group of physicians, simplicity of the regimen was the most important selection criterion in 34.6% of cases. The presence of comorbidities was given as the decisive selection criterion in 26.9%, followed by experience with the chosen drugs in 21.2% of cases. In the group of physicians choosing an integrase strand transfer inhibitor (INSTI)-based regimen for first-line ART, the same selection criteria were identified as in the overall group; 33.3% of clinicians selected an INSTI-based regimen because of its simplicity. The presence of comorbidities was the second most frequent decisive criterion (31.0%), followed by personal experience with the prescribed ART (23.8%). In the protease inhibitor group, simplicity was also the most common selection criterion with 40%. Results of clinical trials were stated as the most important criterion for the selection of ART in 38% of all cases, followed by the expected adherence of the patient (22%). Among the physicians who used a non-nucleoside reverse transcriptase inhibitor-based regimen, patients' desire to have children was the most frequent criterion for selection of ART (60%). An ongoing pregnancy was the second most frequent selection criterion, followed by ART's simplicity (8%). For patients treated with a single-tablet regimen, simplicity of ART was comprehensibly the most important decisive criterion (54.5%). Experience with the chosen drugs was the decisive selection criterion in 24.2%, followed by comorbidities in 18.2% of cases. Physicians' selection of individual ART in patients presenting late for first-line treatment seems to be predominantly dependent on patient-centered factors such as adherence issues as well as the clinical experience of physicians with the prescribed drugs.

Risk factors for IRIS in HIV-associated Pneumocystis-pneumonia following ART initiation.

BACKGROUND: HIV-infected patients with Pneumocystis-pneumonia (PCP) may develop paradoxical immune reconstitution inflammatory syndrome (IRIS), when combination antiretroviral therapy (cART) is started early during the course of PCP-treatment (PCPT). The aim of this study was to identify risk factors and predictors for PCP-IRIS and to improve individualized patient care. METHODS: An ICD-10 code hospital database query identified all Frankfurt HIV Cohort patients being diagnosed with PCP from January 2010 - June 2016. Patient charts were evaluated retrospectively for demographic, clinical and therapeutic (cART/PCPT) characteristics and incidence of paradoxical IRIS according to French's case definitions. RESULTS: IRIS occurred in 12/97 patients that started cART while on PCPT (12.4%). They had a higher rate of re-hospitalization (41.7vs. 4.7%; odds ratio (OR) 14.46; p = 0.009), intensive care treatment (66.7vs. 30.6%; OR = 4.54; p = 0.018), and longer median hospitalization (48 days vs. 23; p < 0.001). A high HIV-RNA level (> 6Log10/ml) before cART initiation was associated with IRIS development (41.6vs. 15.0%; OR 4.05; p = 0.042). Serum immunoglobulin G-levels (IgG) [mg/dl] were lower (894.0 vs. 1446.5; p = 0.023). CONCLUSION: Higher hospitalization rate and morbidity parameters underscore the clinical importance of PCP-related paradoxical IRIS. A baseline viral load of > 6Log10/ml and serum IgG may help to assess individual risks for PCP-IRIS.