Emerging socio-economic disparities in COVID-19-related deaths during the second pandemic wave in Germany.

Over the course of the second pandemic wave in late 2020, new infections with severe acute respiratory syndrome coronavirus-2 shifted from the most affluent to the most deprived regions of Germany. This study investigated how this trend in infections played out for deaths due to coronavirus disease 2019 (COVID-19) by examining area-level socio-economic disparities in COVID-19-related mortality during the second pandemic wave in Germany. The analysis was based on nationwide data on notified deaths, which were linked to an area-based index of socio-economic deprivation. In the autumn and winter of 2020/2021, COVID-19-related deaths increased faster among residents in Germany's more deprived districts. From late 2020 onwards, the mortality risks of men and women in the most deprived districts were 1.52 (95% confidence interval [CI] 1.27-1.82] and 1.44 (95% CI 1.19-1.73) times higher than among those in the most affluent districts, respectively, after adjustment for age, urbanization and population density. To promote health equity in the pandemic and beyond, deprived populations should receive increased attention in pandemic planning, infection control and disease prevention.

Impact of the COVID-19 pandemic and associated non-pharmaceutical interventions on other notifiable infectious diseases in Germany: An analysis of national surveillance data during week 1-2016 - week 32-2020.

BACKGROUND: The COVID-19 pandemic and associated non-pharmaceutical interventions (NPIs) affect healthcare seeking behaviour, access to healthcare, test strategies, disease notification and workload at public health authorities, but may also lead to a true change in transmission dynamics. We aimed to assess the impact of the pandemic and NPIs on other notifiable infectious diseases under surveillance in Germany. METHODS: We included 32 nationally notifiable disease categories with case numbers >100/year in 2016-2019. We used quasi-Poisson regression analysis on a weekly aggregated time-series incorporating trend and seasonality, to compute the relative change in case numbers during week 2020-10 to 2020-32 (pandemic/NPIs), in comparison to week 2016-01 to 2020-09. FINDINGS: During week 2020-10 to 2020-32, 216,825 COVID-19 cases, and 162,942 (-35%) cases of other diseases, were notified. Case numbers decreased across all ages and notification categories (all p<0•05), except for tick-borne encephalitis, which increased (+58%). The number of cases decreased most for respiratory diseases (from -86% for measles, to -12% for tuberculosis), gastro-intestinal diseases (from -83% for rotavirus gastroenteritis, to -7% for yersiniosis) and imported vector-borne diseases (-75% dengue fever, -73% malaria). The less affected infections were healthcare associated pathogens (from -43% infection/colonisation with carbapenem-non-susceptible Acinetobacter, to -28% for Methicillin-resistant Staphylococcus aureus invasive infection) and sexually transmitted and blood-borne diseases (from -28% for hepatitis B, to -12% for syphilis). INTERPRETATION: During the COVID-19 pandemic a drastic decrease of notifications for most infectious diseases and pathogens was observed. Our findings suggest effects of NPIs on overall disease transmission that require further investigation. FUNDING: The Robert Koch Institute is the National Public Health Institute of Germany, and is an institute within the portfolio of the Federal Ministry of Health.

Socioeconomic inequalities in the prevalence and perceived dangerousness of SARS-CoV-2 infections in two early German hotspots: findings from a seroepidemiological study.

OBJECTIVE: Evidence on socioeconomic inequalities in infections with the novel coronavirus (SARS-CoV-2) is still limited as most of the available studies are ecological in nature and individual-level data is sparse. We therefore analysed individual-level data on socioeconomic differences in the prevalence and perceived dangerousness of SARS-CoV-2 infections in local populations. Data were obtained from a population-based seroepidemiological study of adult individuals in two early German SARS-CoV-2 hotspots (n = 3903). Infection was determined by IgG antibody ELISA, RT-PCR testing and self-reports on prior positive PCR tests. The perceived dangerousness of an infection and socioeconomic position (SEP) were assessed by self-reports. Logistic and linear regression were applied to examine associations of multiple SEP measures with infection status and perceptions of dangerousness. RESULTS: We found no evidence of socioeconomic inequalities in SARS-CoV-2 infections by education, occupation, income and subjective social status. Participants with lower education and lower subjective social status perceived an infection as more dangerous than their better-off counterparts. In successfully contained local outbreaks of SARS-CoV-2 in Germany, infections may have been equally distributed across the socioeconomic spectrum. But residents in disadvantaged socioeconomic groups might have experienced a higher level of mental distress due to the higher perceived dangerousness of an infection.

[COVID-19 patients in Germany: exposure risks and associated factors for hospitalization and severe disease]. / COVID-19-Patientinnen und -Patienten in Deutschland: Expositionsrisiken und assoziierte Faktoren für Hospitalisierungen und schwere Krankheitsverläufe.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spread worldwide in 2020. By the end of June 2021, over 3.7 million people had been infected in Germany. The spread of the infection, however, is not evenly distributed across all parts of the population. Some groups are at a higher risk for SARS-CoV­2 infections or severe coronavirus disease 2019 (COVID-19) trajectories than others.This narrative review provides an overview of the parts of the population in Germany that are most affected by COVID-19. In addition, risk factors associated with hospitalization or severe courses of COVID-19 are identified.SARS-CoV­2 transmission may occur in various locations and settings. Professional settings, e.g., in the meat-processing industry, but also leisure activities and large public events are particularly affected. In the course of the pandemic, certain comorbidities associated with an increased risk for hospitalization or severe courses of COVID-19 have been identified. These include preexisting pulmonary, cardiovascular, and metabolic diseases. Patients with organ transplants and people with Down syndrome (trisomy 21) have the highest risk for hospitalization after SARS-CoV­2 infection.The identified settings that contribute to the spread of SARS-CoV­2 and the knowledge about vulnerable groups with a higher risk for hospitalization or severe disease trajectories form an important evidence base for the planning of prevention strategies and the fight against the pandemic.

[Recording of SARS-CoV-2 laboratory tests in Germany]. / Erfassung der Labortestungen auf SARS-CoV-2 in Deutschland.

The collection of data on SARS-CoV­2 tests is central to the assessment of the infection rate in the context of the COVID-19 pandemic. At the Robert Koch Institute (RKI), data collected from various laboratory data recording systems are consolidated. First, this article aims to exemplify significant aspects regarding test procedures. Subsequently the different systems for recording laboratory tests are described and test numbers from the RKI test laboratory query and the laboratory-based SARS-CoV­2 surveillance as well as accounting data from the Association of Statutory Health Insurance Physicians for SARS-CoV­2 laboratory tests are shown.Early in the pandemic, the RKI test laboratory query and the laboratory-based SARS-CoV­2 surveillance became available and able to evaluate data on performed tests and test capacities. By recording the positive and negative test results, statements about the total number of tests and the proportion of positive test rates can be made. While the aggregate test numbers are largely representative nationwide, they are not always representative at the state and district level. The billing data of the Association of Statutory Health Insurance Physicians can complement the laboratory data afterwards. In addition, it can provide a retrospective assessment of the total number of SARS-CoV­2 numbers in Germany, because the services provided by statutory health insurers (around 85% of the population in Germany) are included. The various laboratory data recording systems complement one another and the evaluations flow into the recommended measures for the pandemic response.

[Adaptation of the routine surveillance system for infectious diseases in 2020 in the context of the COVID-19 pandemic]. / Anpassung des Meldesystems gemäß Infektionsschutzgesetz im Jahr 2020 aufgrund von COVID-19.

In response to the COVID-19 pandemic the routine surveillance system for infectious diseases had to be adapted. The disease was unknown before the first cases were reported under a catch-all notification requirement for new and threatening pathogens and diseases, but specific notification requirements for SARS-CoV­2 detection by laboratories as well as for suspect cases of COVID-19 diagnosed by physicians were soon integrated in the infectious diseases protection act. This article describes how the notification system for infectious diseases was adapted in 2020 to meet the requirements of the COVID-19 pandemic.In addition to the notification requirements, the list of data that is collected through the notification system was also amended. To facilitate the work of laboratories and local health authorities we have established the possibility for electronic reporting.Additionally, the software used for case and contact management within the local health authorities had to be adapted accordingly.COVID-19 notification data is important for the assessment of the current epidemiological situation and daily updated data was published by the Robert Koch Institute. To ensure timely data and good data quality, the IT infrastructure within the public health system has to be further modernized and the electronic notification system should be further strengthened.

[Crisis management at the Robert Koch Institute during the COVID-19 pandemic and the exchange between federal and state governments]. / Das Lagemanagement des Robert Koch-Instituts während der COVID-19-Pandemie und der Austausch zwischen Bund und Ländern.

The Robert Koch Institute (RKI) plays a central role in Germany in the management of health hazards of biological origin. The RKI's crisis management aims to contribute to protecting the health of the population in Germany in significant epidemic situations and to maintain the RKI's working ability over a long period of time even under high load. This article illustrates the crisis management of the RKI in general as well as during the COVID-19 pandemic. The generic RKI crisis management structures and the setup of the RKI emergency operations centre (EOC), their operationalisation in the context of the COVID-19 pandemic and the resulting challenges as of 31 October 2020 are described in this paper. The exchange between the federal and state governments during the pandemic is also described.The COVID-19 pandemic has led to extraordinary circumstances. During the epidemic situation, good communication and coordination has been essential, both within the RKI and with other federal or state authorities and expert groups. Under great pressure, the RKI produces and regularly updates recommendations, statements and assessments on various topics. To provide operational support for all COVID-19 related activities, an EOC was activated at the RKI. During the COVID-19 pandemic, there are various challenges regarding personnel and structures. It became apparent that good preparation (e.g. existing task descriptions and premises) has an important positive impact on crisis management.

Everything counts - a method to determine viral suppression among people living with HIV using longitudinal data for the HIV care continuum - results of two large, German, multi-center real-life cohort studies over 20 years (1999-2018).

BACKGROUND: The aim of this study was to develop a standardized method to reconstruct persons' individual viral load (VL) courses to determine viral suppression and duration of viremia for the HIV care continuum in Germany using longitudinal cohort data. METHODS: We analyzed data from two large, multi-center German cohort studies under the direction of the Robert Koch Institute. We included data from 1999 to 2018 of all diagnosed people and of people who initiated antiretroviral treatment (ART). We developed a model generating virtual VL values and an individual VL course corresponding to real VL measurements with a maximum distance of 180 days, considering ART status and VL dynamics. If the distance between VL measurements was > 180 days, the time between was defined as gap time. Additionally, we considered blips, which we defined as a single detectable VL < 1000 copies/ml within 180 days. RESULTS: A total of 22,120 people (164,691 person-years, PY) after ART initiation were included in the analyses. The proportion of people with viral suppression (VL < 50 copies/ml) increased from 34% in 1999 to 93% in 2018. The proportion of people with VL < 200 copies/ml increased from 47% in 1999 to 96% in 2018. The proportion of people with viremia > 1000 copies/ml decreased from 37% in 1999 to 3% in 2018. The proportion of people with gap time fluctuated and ranged between 18 and 28%. An analysis of the first VL after gap time showed that 90% showed viral suppression, 5% VL between 50- < 1000 copies/ml and 5% VL > 1000 copies/ml. CONCLUSION: We provide a method for estimating viral suppression and duration of viremia using longitudinal VL data. We observed a continuous and remarkable increase of viral suppression. Furthermore, a notable proportion of those with viremia showed low-level viremia and were therefore unlikely to transmit HIV. Individual health risks and HIV drug resistance among those with low-level viremia are problematic, and viral suppression remains the goal. In 2018, 93 and 96% of people after ART initiation showed VL < 50 copies/ml and VL < 200 copies/ml, respectively. Therefore, using the threshold of VL < 200 copies/ml, Germany reached the UNAIDS 95 target of viral suppression since 2017.

Serology- and PCR-based cumulative incidence of SARS-CoV-2 infection in adults in a successfully contained early hotspot (CoMoLo study), Germany, May to June 2020.

Three months after a coronavirus disease (COVID-19) outbreak in Kupferzell, Germany, a population-based study (n = 2,203) found no RT-PCR-positives. IgG-ELISA seropositivity with positive virus neutralisation tests was 7.7% (95% confidence interval (CI): 6.5-9.1) and 4.3% with negative neutralisation tests. We estimate 12.0% (95% CI: 10.4-14.0%) infected adults (24.5% asymptomatic), six times more than notified. Full hotspot containment confirms the effectiveness of prompt protection measures. However, 88% naïve adults are still at high COVID-19 risk.

Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series.

BACKGROUND: In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. METHODS: A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. FINDINGS: Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3-4·3) and the median serial interval was 4·0 days (3·0-5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0-99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2-32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6-8·9; 11 of 217) among non-household, high-risk contacts. INTERPRETATION: Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. FUNDING: All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.

German and international studies on SARS-CoV-2 seroprevalence.

Since the beginning of the year 2020, the SARS-CoV-2 coronavirus has spread globally at a tremendous pace. Studies on the prevalence of SARS-CoV-2 antibodies in the population help estimate the number of people that have already been infected. They also allow an estimate of the number of undetected infections i.e. infections that do not appear in data on officially reported cases. The interpretation of study results needs to consider bias from selective sampling and the diagnostic test properties. To promote networking and co-operation between scientists, the Robert Koch Institute has compiled an overview of the seroepidemiological studies conducted in Germany on its website, which is regularly updated. The RKI conducts searches, for example of press releases, study registry entries or preprint server publications, and contacts the lead investigators of these studies. Of the 40 studies contacted so far, 24 have already provided information (as of 25.06.2020). We can differentiate between studies of the general population, of selected population groups such as healthcare workers, or of ongoing cohorts. This article provides an overview of such studies from Germany, but also of selected international studies. A special focus is set on studies of children and adolescents, which are now of particular interest due to the planned reopening of childcare facilities and schools.

Seroepidemiological study on the spread of SARS-CoV-2 in populations in especially affected areas in Germany - Study protocol of the CORONA-MONITORING lokal study.

At a regional and local level, the COVID-19 pandemic has not spread out uniformly and some German municipalities have been particularly affected. The seroepidemiological data from these areas helps estimate the proportion of the population that has been infected with SARS-CoV-2 (seroprevalence), as well as the number of undetected infections and asymptomatic cases. In four municipalities which were especially affected, 2,000 participants will be tested for an active SARS-CoV-2 infection (oropharyngeal swab) or a past infection (blood specimen IgG antibody test). Participants will also be asked to fill out a short written questionnaire at study centres and complete a follow-up questionnaire either online or by telephone, including information on issues such as possible exposure, susceptability, symptoms and medical history. The CORONA-MONITORING lokal study will allow to determine the proportion of the population with SARS-CoV-2 antibodies in four particularly affected locations. This study will increase the accuracy of estimates regarding the scope of the epidemic, help determine risk and protective factors for an infection and therefore also identify especially exposed groups and, as such, it will be crucial towards planning of prevention measures.

Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort.

The prevalence of transmitted drug resistance (TDR) in antiretroviral therapy (ART)-naïve individuals remains stable in most developed countries despite a decrease in the prevalence of acquired drug resistance. This suggests that persistence and further transmission of HIV-1 that encodes transmitted drug resistance mutations (TDRMs) is occurring in ART-naïve individuals. In this study, we analysed the prevalence and persistence of TDRMs in the protease and reverse transcriptase-sequences of ART-naïve patients within the German HIV-1 Seroconverter Study Cohort who were infected between 1996 and 2017. The prevalence of TDRMs and baseline susceptibility to antiretroviral drugs were assessed using the Stanford HIVdb list and algorithm. Mean survival times of TDRMs were calculated by Kaplan-Meier analysis. The overall prevalence of TDR was 17.2% (95% CI 15.7-18.6, N = 466/2715). Transmitted NNRTI resistance was observed most frequently with 7.8% (95% CI 6.8-8.8), followed by NRTI resistance (5.0%, 95% CI 4.2-5.9) and PI resistance (2.8%, 95% CI 2.2-3.4). Total TDR (OR = 0.89, p = 0.034) and transmitted NRTI resistance (OR = 0.65, p = 0.000) decreased between 1996 and 2017 but has remained stable during the last decade. Viral susceptibility to NNRTIs (6.5%-6.9% for individual drugs) was mainly reduced, while <3% of the recommended NRTIs and PIs were affected. The longest mean survival times were calculated for the NNRTI mutations K103N (5.3 years, 95% CI 4.2-5.6) and E138A/G/K (8.0 years, 95% CI 5.8-10.2 / 7.9 years, 95% CI 5.4-10.3 / 6.7 years, 95% CI 6.7-6.7) and for the NRTI mutation M41L (6.4 years, 95% CI 6.0-6.7).The long persistence of single TDRMs indicates that onward transmission from ART-naïve individuals is the main cause for TDR in Germany. Transmitted NNRTI resistance was the most frequent TDR, showing simultaneously the highest impact on baseline ART susceptibility and on TDRMs with prolonged persistence. These results give cause for concern regarding the use of NNRTI in first-line regimens.

Molecular evolution of HIV-1 integrase during the 20 years prior to the first approval of integrase inhibitors.

BACKGROUND: Detailed knowledge of the evolutionary potential of polymorphic sites in a viral protein is important for understanding the development of drug resistance in the presence of an inhibitor. We therefore set out to analyse the molecular evolution of the HIV-1 subtype B integrase at the inter-patient level in Germany during a 20-year period prior to the first introduction of integrase strand inhibitors (INSTIs). METHODS: We determined 337 HIV-1 integrase subtype B sequences (amino acids 1-278) from stored plasma samples of antiretroviral treatment-naïve individuals newly diagnosed with HIV-1 between 1986 and 2006. Shannon entropy was calculated to determine the variability at each amino acid position. Time trends in the frequency of amino acid variants were identified by linear regression. Direct coupling analysis was applied to detect covarying sites. RESULTS: Twenty-two time trends in the frequency of amino acid variants demonstrated either single amino acid exchanges or variation in the degree of polymorphy. Covariation was observed for 17 amino acid variants with a temporal trend. Some minor INSTI resistance mutations (T124A, V151I, K156 N, T206S, S230 N) and some INSTI-selected mutations (M50I, L101I, T122I, T124 N, T125A, M154I, G193E, V201I) were identified at overall frequencies >5%. Among these, the frequencies of L101I, T122I, and V201I increased over time, whereas the frequency of M154I decreased. Moreover, L101I, T122I, T124A, T125A, M154I, and V201I covaried with non-resistance-associated variants. CONCLUSIONS: Time-trending, covarying polymorphisms indicate that long-term evolutionary changes of the HIV-1 integrase involve defined clusters of possibly structurally or functionally associated sites independent of selective pressure through INSTIs at the inter-patient level. Linkage between polymorphic resistance- and non-resistance-associated sites can impact the selection of INSTI resistance mutations in complex ways. Identification of these sites can help in improving genotypic resistance assays, resistance prediction algorithms, and the development of new integrase inhibitors.

[Surveillance and Monitoring - Results of the Working Group 10 of the Forum Future Public Health, Berlin 2016]. / Surveillance und Monitoring.

Evidence-based health policies and evidence-based measures need comprehensive information on the health of the population. The existing health surveillance system provides reliable answers to many health policy issues. Nonetheless, there are many information gaps not yet covered or are only covered via short-term project solutions. 1. We need to strengthen and expand existing health surveillance and monitoring to continuously collect information on the health status of all population groups, including those that are difficult to reach through the existing surveys and methods, such as people with a migration background, or socially disadvantaged. This information must be regularly available on the national, regional and also on the local level. 2. The use of existing data on health, for example from official statistics or social insurance, must be significantly expanded and strengthened. The infrastructure for scientific analyses of health data as well as the transfer of information to policy makers and the public must be strengthened. Through an expansion of the resources for scientific processing of health-relevant questions, Public Health can make an important contribution to effective health policies.

Surveillance of recent HIV infections among newly diagnosed HIV cases in Germany between 2008 and 2014.

BACKGROUND: The HIV surveillance system in Germany is based on mandatory, anonymous notification of newly diagnosed HIV cases by laboratories. Because the time between HIV infection and the diagnosis of HIV varies widely between persons, it is difficult to determine the number of cases of recent HIV infection among newly diagnosed cases of HIV. In Germany, the BED-capture-enzyme immunoassay (BED-CEIA) has been used to distinguish between recent and long-standing HIV infection. The aim of this analysis is to report the proportion of cases of recent HIV infection among newly diagnosed cases in Germany between 2008 and 2014 and to identify factors associated with recent infections. METHODS: A sample of voluntary laboratories among all HIV diagnostic laboratories was recruited. Residual blood from HIV diagnostic tests was spotted on filter paper as dried serum or dried plasma spots and was sent along with the notification form of the HIV cases. The BED-CEIA test was performed. A case was defined as recent HIV infection with a BED-CEIA test result of less than 0.8 normalized optical density, with the exclusion of CDC stage C. The proportion of recent newly diagnosed HIV infections among different groups (such as transmission groups, gender or age groups) was calculated. We used logistic regression to identify factors associated with recent HIV infection and to identify subpopulations with high proportions of recent HIV infections. RESULTS: Approximately 10,257 newly diagnosed cases were tested for recency using the BED-CEIA. In total, 3084 (30.4%) of those were recently infected with HIV. The highest proportion of recent HIV infections was found among men who had sex with men (MSM) (35%) and persons between 18 and 25 years of age (43.0%). Logistic regression revealed that female German intravenous drug users with a recent HIV infection had a higher chance of being detected than German MSM (OR 2.27). CONCLUSIONS: Surveillance of recent HIV infection is a useful additional tool to monitor the HIV epidemic in Germany. We could observe ongoing HIV transmission in Germany in general and in different subgroups, and we could identify factors associated with recent HIV infection in Germany.

Immunological recovery in tuberculosis/HIV co-infected patients on antiretroviral therapy: implication for tuberculosis preventive therapy.

BACKGROUND: Understanding the immune response to combination antiretroviral therapy (cART) is essential for a clear approach to tuberculosis (TB) preventive therapy. We investigated the immunological recovery in cART-treated HIV-infected patients developing TB compared to those who remained free of TB. METHODS: We extracted data of HIV-infected patients from a multicenter cohort for the HIV clinical surveillance in Germany. No patients included in our study had TB at the beginning of the observation. Using a longitudinal mixed model, we assessed the differences in the mean change of biomarkers (CD4+ cell count, CD8+ cell count, CD4:CD8 ratio and viral load) since cART initiation in patients who remained free of TB vs. those developing TB. To detect the best-fit trajectories of the immunological biomarkers, we applied a multivariable fractional polynomials model. RESULTS: We analyzed a total of 10,671 HIV-infected patients including 139 patients who developed TB during follow-up. The highest TB incidences were observed during the first two years since cART initiation (0.32 and 0.50 per 100 person-years). In an adjusted multivariable mixed model, we found that the average change in CD4+ cell count recovery was significantly greater by 33 cells/µl in patients who remained free of TB compared with those developing TB. After the initial three months of cART, 65.6% of patients who remaining free of TB achieved CD4+ count of ≥400 cells/µl, while only 11.3% of patients developing TB reached this immunological status after the three months of cART. We found no differences in the average change of CD8+ cell count, CD4:CD8 ratio or viral load between the two-patient groups. CONCLUSION: All HIV-infected patients responded to cART. However, patients developing TB showed reduced recovery in CD4+ cell count and this might partly explain the incident TB in HIV-infected patients receiving cART. These findings reinforce the importance of adjunctive TB preventive therapy for patients with reduced recovery in CD4+ cell count.

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.

OBJECTIVE: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. METHODS: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. RESULTS: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. DISCUSSION: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.