Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants
. Combinations of drugs ...can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection
. Although anti-HIV-1 antibodies constitute a potential alternative to ART
, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants
. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection
. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC117
and 10-1074
, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg
of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log
copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.
Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic ...suppression in people with HIV-1 through Week 144 in TANGO.
134 centers, 10 countries.
Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196.
Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term.
Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.
Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess ...treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral cART use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio OR 2.89; P < .001), improved PFS (hazard ratio HR 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; “intensive regimens”: HR 0.35; P < .001) and OS (“intensive regimens”: HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.
•Rituximab use is associated with significant improvement in all outcomes for patients with HIV-associated CD20-positive lymphomas.•Infusional EPOCH chemotherapy is associated with better overall survival in patients with AIDS-related diffuse large B-cell lymphoma (DLBCL).
Cryptococcosis is the most prevalent fungal infection of the central nervous system worldwide. We performed a retrospective multicenter cohort study to gain insights into the epidemiology of ...cryptococcosis in Germany. We describe the use of diagnostic tests, clinical management and patient outcome. We included 64 patients with underlying HIV infection (55%) or other predispositions. Molecular typing by MLST documented 20 individual sequence types among 42 typed isolates. A fatal outcome was documented in 14% of patients in the first two months after diagnosis.
Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. ...This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL.
Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD.
Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%).
In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.
Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after ...achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate.
NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like ...receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host
HLA-C
genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between
KIR/HLA
immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific
KIR/HLA-C
combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1
+
individuals. Compared to 60 HIV-1
-
controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C
+
and KIR3DL2
+
NK cell sub-populations from HIV-1
+
individuals was enlarged compared to HIV-1
-
controls. Stratification along
KIR/HLA-C
genotypes revealed a genotype-dependent expansion of KIR2DL1
+
NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host
KIR2DL/HLA-C
genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.
Background
With 1.5 million deaths worldwide in 2018, tuberculosis (TB) remains a major global public health problem. While pulmonary TB (PTB) is the most common manifestation, the proportion of ...extrapulmonary TB (EPTB) is increasing in low-burden countries. EPTB is a heterogeneous disease entity posing diagnostic and management challenges due to the lack of reliable biomarkers. In this study, we prospectively evaluated clinical data and treatment response which were correlated with different biomarkers.
Methods
The study was conducted at the University Hospital of Cologne. 20 patients with EPTB were enrolled. We analyzed plasma interferon-γ-inducible protein 10 (IP-10) levels in plasma by ELISA for up to 12 months of treatment. In addition, the QuantiFERON
®
-TB Gold Plus (QFT
®
Plus) test was performed during the course of treatment. Clinical data were assessed prospectively and correlated with QFT
®
Plus and IP-10 levels.
Results
Plasma IP-10 levels were found to be significantly increased (
p
< 0.001) in patients with extensive disease compared to patients with limited disease (cervical lymph node TB) or healthy controls. In patients with clinically confirmed paradoxical reaction (PR), a further increase of IP-10 was noted. IFN-γ measured by the QFT
®
Plus test did not decrease significantly during the course of treatment. Of note, in four EPTB patients (20%) without radiographic pulmonary involvement, sputum culture was positive for
Mycobacterium tuberculosis
.
Conclusion
Our data demonstrate that IP-10 may be a valuable biomarker for estimation of disease severity in EPTB and monitoring of the disease course in extensive forms. However, IP-10 may be less suitable for diagnosis and monitoring of EPTB patients with limited disease. The QFT
®
Plus test does not appear to be a suitable marker for therapy monitoring. Sputum should be examined in EPTB patients even in case of normal diagnostic imaging of the chest.
While the International Prognostic Index is commonly used to predict outcomes in immunocompetent patients with aggressive B-cell non-Hodgkin lymphomas, HIV-infection is an important competing risk ...for death in patients with AIDS-related lymphomas. We investigated whether a newly created prognostic score (AIDS-related lymphoma International Prognostic Index) could better assess risk of death in patients with AIDS-related lymphomas. We randomly divided a dataset of 487 patients newly diagnosed with AIDS-related lymphomas and treated with rituximab-containing chemoimmunotherapy into a training (n=244) and validation (n=243) set. We examined the association of HIV-related and other known risk factors with overall survival in both sets independently. We defined a new score (AIDS-related lymphoma International Prognostic Index) by assigning weights to each significant predictor age-adjusted International Prognostic Index, extranodal sites, HIV-score (composed of CD4 count, viral load, and prior history of AIDS) with three risk categories similar to the age-adjusted International Prognostic Index (low, intermediate and high risk). We compared the prognostic value for overall survival between AIDS-related lymphoma International Prognostic Index and age-adjusted International Prognostic Index in the validation set and found that the AIDS-related lymphoma International Prognostic Index performed significantly better in predicting risk of death than the age-adjusted International Prognostic Index (P=0.004) and better discriminated risk of death between each risk category (P=0.015 vs. P=0.13). Twenty-eight percent of patients were defined as low risk by the ARL-IPI and had an estimated 5-year overall survival (OS) of 78% (52% intermediate risk, 5-year OS 60%; 20% high risk, 5-year OS 50%).
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