HIV Viral load measurement in the Public Health Approach to HIV/AIDS

Background To end AIDS by 2030, the WHO 90-90-90 targets call for 90% virologic suppression in those on ART. In this context, it is crucial to understand which factors drive virologic suppression and how available resources can be targeted most effectively. This thesis evaluates a large HIV treatment program in Tanzania and explores performance and factors associated with treatment outcome on individual and on health system level. It then develops a clinical score to predict virologic failure and optimize patient management. Design This cross-sectional facility-based study assessed 702 patients stratified by time on ART at 7 study sites selected to represent regions of the study area and health care level. Methods Facility and patient-level information were collected during a single study visit. Logistic regression analysis and Generalized Boosted Model Technique derived Propensity Score Methods were used to explore health system and individual-level factors associated with virological failure. Predictive multilevel mixed logistic regression models were developed, externally validated and simplified into a normogram for the clinical score which was then tested against WHO recommended failure criteria using Decision Curve Analysis. Results Within the population on ART, 89% was virologically suppressed below 1000 copies/ml and 86% below 400 copies/ml. Differences could be found between health care levels but not regions. The study site had a direct impact on treatment outcome on the individual and health system level. Performance of the clinical scores was high with a ROC-AUC of 0.8 in the training, and ROC-AUC between 0.7 and 0.8 in the population and the geographic validation dataset. Decision Curve Analysis showed a net benefit against the WHO routine and targeted viral load monitoring strategies. Conclusion To fully reach the “the last 90” health system-level interventions should support sites. On individual level, the clinical score developed could be used to better identify and manage individuals at risk of treatment failure

Gemeinsam gegen AIDS : Klinikpartnerschaft des HIVCENTER mit Lesotho und Südafrika

In einer vernetzten Welt machen Epidemien nicht an Ländergrenzen Halt. Mit der zunehmenden Verfügbarkeit von wirksamen Therapien in Entwicklungsländern wird nun auch das Wissen, das in den Industrieländern durch klinische Forschung gewonnen wurde, für Afrika und Südost-Asien interessant. Das Wissen um eine verbesserte Behandlung HIV-Infizierter mit benachteiligten Regionen in Afrika zu teilen, ist auch das Anliegen einer Klinikpartnerschaft zwischen dem Frankfurter HIVCENTER und der Karabong Klinik des Mafeteng Government Hospitals in Lesotho. Durch die Einbeziehung der Universitätsklinik in Stellenbosch, Südafrika, die eine Hochschulpartnerschaft mit der Universitätsklinik Frankfurt unterhält, soll zudem der Süd-Süd-Austausch zwischen den afrikanischen Partnern gestärkt werden

Lipometabolic side-effects of three ritonavir-boosted double protease inhibitor regimens without reverse transcriptase inhibitors

Poster presentation: Purpose of the study To compare the lipometabolic profiles of three double-boosted protease inhibitor (PI) regimens at standard dose, containing saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) in HIV-positive patients, treated without reverse transcriptase inhibitors (RTI). ..

High turnaround times and low viral resuppression rates after reinforced adherence counselling following a confirmed virological failure diagnostic algorithm in HIV‐infected patients on first‐line antiretroviral therapy from Tanzania

Objective Early identification of confirmed virological failure is paramount to avoid accumulation of drug resistance in patients on antiretroviral therapy (ART). Scale‐up of HIV‐RNA monitoring in Africa and timely switch to second‐line regimens are challenged. Methods A WHO adapted confirmed virological treatment screening algorithm (HIV‐RNA screening, enhanced adherence counselling, confirmatory HIV‐RNA testing) was evaluated in HIV‐infected patients on first‐line ART from Tanzania. The main endpoints included viral resuppression and virological failure rates, retention and turnaround time of the screening algorithm until second‐line ART initiation. Secondary endpoints included risk factors for virological treatment failure and patterns of genotypic drug resistance. Results HIV‐RNA >1000 copies/ml at first screening was detected in 58/356 (16.3%) patients (median time‐on‐treatment 6.3 years, 25% immunological treatment failure). Adjusted risk factors for virological failure were age <30 years (RR 5.2 [95% CI: 2.5–10.8]), years on ART ≥3 years (RR 3.0 [1.0–8.9]), CD4‐counts <200 cells/µl (RR 9.3 [4.0–21.8]) and poor self‐reported treatment adherence (RR 2.0 [1.2–3.4]). Resuppression of HIV‐RNA <1000 copies/ml was observed in 5/50 (10%) cases after enhanced adherence counselling. Confirmatory testing within 3 months was performed in only 46.6% and switch to second‐line ART within 6 months in 60.4% of patients. Major NNRTI‐mutation were detected in all of 30 patients, NRTI mutations in 96.7% and ≥3 thymidine‐analogue mutations in 40%. No remaining NRTI options were predicted in 57% and limited susceptibility in 23% of patients. Conclusion We observed low levels of viral resuppression following adherence counselling, associated with high levels of accumulated drug resistance. High visit burden and turnaround times for confirmed virological failure diagnosis further delayed switching to second‐line treatment which could be improved using novel point‐of‐care viral load monitoring systems

Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri

Background: The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. Methods Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+;71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, alpha(4)beta(7)). Results Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and alpha(4)beta(7)in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32;p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or alpha(4)beta(7)+ CD4 T cells. Conclusion The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women

Evaluation of health research capacity strengthening trainings on individual level: validation of a questionnaire

RATIONALE, AIMS AND OBJECTIVES In the field of global health, research capacity strengthening is becoming a common concept for defining and improving research competencies on individual, organizational, national and supranational level. However, HRCS activities often lack evaluation procedures to measure their impact and to ensure their quality. The aim of this study was to develop and validate a short questionnaire to evaluate trainings in the field of health research capacity strengthening (HRCS). METHOD The questionnaire was developed by an interdisciplinary research team and tested in four different training settings at the Mbeya Medical Research Center and Mbeya Referral Hospital, Tanzania. Construct validity of the questionnaire was tested based on 97 responses of the participants of four trainings. RESULTS Iterative checking of Cronbach's alpha of the subscales and exploratory factor analysis revealed a four-factor solution that differed from the original structure and subscales of the questionnaire. The instrument was adapted accordingly and consists now of four subscales with 19 items, three global impression items, and open questions for participants' comments and recommendations. CONCLUSIONS The result of the study is a short, validated questionnaire for the evaluation of HRCS trainings on the individual level. The tool can be applied both to measure the short-term effects of international health research capacity trainings and to ensure their quality. In the future, after collecting larger sample sizes, a confirmatory factor analysis should be done to further support the four factors

Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients from Tanzania and Cote d'Ivoire

Objective: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. Design: Randomized clinical trial. Methods: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Cote d'Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. Results: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75-1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89-1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharma-cokinetic analysis supported o.d. administration of FZD. Conclusion: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial

Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy: Collaborative Analysis of Cohorts of HIV-1-Infected Patients

Background: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods: We analyzed data on 20,379 treatment-naive HIV-1- infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count 350 cells/μL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART