Nadia Valin

Higher efficacy of nevirapine than efavirenz to achieve Hiv-1 plasma viral load below 1 copy/ml

Objectives:To compare the level of HIV-1 residual viremia, defined by a viral load below 50 copies/ml in patients receiving a tenofovir/emtricitabine and nevirapine (NVP) or efavirenz (EFV)-containing regimen. Design:One hundred and sixty-five HIV-1-infected patients were retrospectively included since they achieved virological suppression (viral load <50 copies/ml) for at least 6 months with a tenofovir/emtricitabine and non-nucleoside reverse transcriptase inhibitor-containing regimen (NVP, n = 75 and EFV, n = 90). Methods:Residual plasma viremia was measured using an ultrasensitive assay with a limit of quantification of 1 copy/ml. A Fishers exact test was used to compare the percentage of patients with HIV-1 RNA below 1 copy/ml between the two treatment groups. Logistic regression was used to search for factors associated with a viral load below 1 copy/ml among the different patient characteristics. Results:Patients in the NVP group had more frequently a viral load below 1 copy/ml than patients in the EFV group (81.3 vs. 55.6%, P < 0.001). In multivariate analysis, only NVP vs EFV (P = 0.005) and duration of viral suppression under antiretroviral treatment (P = 0.005) were independently associated with viral load below 1 copy/ml. Conclusions:It is well known that NVP has a good penetration in anatomic compartments that could explain a deep control of virus replication in some compartments and consequently decrease the residual level of viral load. The clinical relevance of having a viral load below 1 copy/ml has now to be studied for example on systemic inflammatory or immune activation markers.

Impact of late presentation on the risk of death among HIV-infected people in France (2003-2009).

Objective:A recent consensus defines “late presentation” (LP) during the course of HIV infection as presentation with AIDS whatever the CD4 cell count or with CD4 <350 cells per cubic millimeter. Here, using this new definition, we examined the frequency and predictors of LP and its impact on mortality. Methods:In antiretroviral-naive patients enrolled in the French Hospital Database on HIV between 2003 and 2009, we studied risk factors for LP by multivariable logistic regression. The impact of LP on mortality was analyzed according to the level of immunodeficiency by using Cox multivariable models adjusted for potential confounders, with follow-up categorized into 0–6, 6–12, and 12–48 months. Results:There were 11,038 (53.9%) late presenters among the 20,496 patients included in the study. Compared with patients presenting for care with CD4 ≥350 cells per cubic millimeter, patients presenting with AIDS had a very high risk of death with crude hazard ratio ranging from 48.3 during the first 6 months of follow-up to 4.8 during months 12–48; the corresponding values among AIDS-free patients with CD4 ⩽200 cells per cubic millimeter were 8.1 and 2.3. Importantly, patients presenting with CD4 between 200 and 350 cells per cubic millimeter also had a significantly increased risk of death beyond 6 months of follow-up (hazard ratio: 3.0 and 1.8 for months 6–12 and 12–48, respectively). Results were similar after adjustment. Conclusions:LP with HIV infection is still very frequent in France and is associated with higher mortality, even among patients with only moderate immunodeficiency. Encouraging early testing and access to care is still urgently needed.

Raltegravir as functional monotherapy leads to virological failure and drug resistance in highly treatment-experienced HIV-infected patients

Abstract The objective of this study was to evaluate the development of resistance to raltegravir (RAL) in patients with viraemia between 40 and 400 copies/ml. All HIV-1-infected patients with multidrug-resistant virus, plasma HIV-1 RNA >1000 copies/ml and starting RAL were enrolled in this observational study and followed up until week 48. Sixty-seven patients with median plasma HIV-1 RNA at 4.3 log10 copies/ml and CD4 at 177 cells/mm3 were included. At week 24, 43 achieved full viral suppression (FVS; plasma HIV-1 RNA <40 copies/ml), 18 had incomplete viral suppression (IVS; plasma HIV-1 RNA 40–≤400 copies/ml) and 6 experienced virological failure (VF; plasma HIV-1 RNA >400 copies/ml). At week 48, all the FVS were sustained, 16 of the IVS patients retained a plasma HIV-1 RNA <400 copies/ml and only 2 of the IVS at week 24 experienced VF. No RAL resistance was detected in the persistent low viraemia. In contrast, integrase mutation was detected in 6 of the patients with VF. A genotypic sensitivity score equal to 0 was associated with plasma HIV-1 RNA >40 copies/ml at week 24 (OR 20.9, 95% CI 2.0–215.1) and with RAL resistance (OR 14.2, 95% CI 2.1–94.7). This study confirmed the high efficacy of a RAL-containing regimen under routine clinical conditions in infections caused by multidrug-resistant virus. If persistent low viraemia is observed over more than 48 weeks without the emergence of resistance, RAL should never be given as functional monotherapy, as it is associated with a maximal risk of VF and the emergence of RAL resistance.

Risk factors for 'unmasking immune reconstitution inflammatory syndrome' presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients.

Objective:To determine characteristics and risk factors for unmasking tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRIS) following initiation of combination antiretroviral therapy (cART) in HIV-infected patients, which have not yet been assessed to date. Design:Retrospective single-center cohort study. Methods:Medical records of HIV-infected patients diagnosed with tuberculosis following cART initiation were reviewed. Cases of unmasking IRIS were identified using provisional consensus definitions. Characteristics of patients with and without unmasking TB-IRIS were compared. A case–control design was used to identify risk factors for unmasking TB-IRIS in patients initiating cART. Results:Among 47 patients on cART at TB diagnosis, 11 experienced unmasking IRIS (23%). They had lower CD4% (9 vs. 14, P = 0.02), higher HIV-RNA load at baseline (5.2 vs. 4.0 log, P = 0.005), and a stronger CD4% increase with HIV-RNA decline after 1 month on cART (+7 vs. +3 log, P = 0.02, and −3.2 vs. −0.8 log, P = 0.005) than the 36 remaining patients without unmasking IRIS. In the case–control study, risk factors for unmasking IRIS were African country of origin (65 vs. 18%, P = 0.007), higher baseline HIV-RNA load (5.2 vs. 4.7 log, P = 0.01), stronger CD4% increase (+7 vs. +2, P = 0.0001), and HIV-RNA decline of more than 3 log after 1 month on cART (73 vs. 27%, P = 0.02). Conclusion:Patients with African origins, advanced HIV infection, or a strong response to cART are at greater risk of unmasking TB-IRIS.

Efficacy and tolerance of telaprevir in HIV-hepatitis C virus genotype 1-coinfected patients failing previous antihepatitis C virus therapy: 24-week results.

The efficacy and tolerance of telaprevir (TVR) was examined in 20 mostly cirrhotic HIV-hepatitis C genotype 1 (HCV-G1)-infected patients failing previous treatment with pegylated-interferon and ribavirin (PR). HCV-RNA less than 12 IU/ml was observed in 35.3% of patients at W2, 55.0% at W4, 65.0% at W12 and 55.0% at W24. All patients with virological failure (n = 9) exhibited V36M/R155K mutations. Early virological response was a determinant of HCV-RNA less than 12 IU/ml at W24 (P < 0.001). No grade 3–4 dermatological side-effects were reported. TVR-PR tritherapy appeared to be rather effective and well tolerated among difficult-to-treat HIV-HCV-G1 patients.

Bipolar hypertrophic herpes: an unusual presentation of acyclovir-resistant herpes simplex type 2 in a HIV-infected patient.

Hypertrophic pseudo tumoral herpetic lesion is an uncommon presentation in immunocompromized hosts that can be refractory to established therapies. We describe bipolar anal and tonsilar herpetic tumoral lesions related to acyclovir-resistant HSV-2 in a human immunodeficiency virus-infected patient. Treatment with valacyclovir, cidofovir, and thalidomide failed and surgical excision was required.

Evaluation of the efficacy and safety of switching to tenofovir, emtricitabine, and rilpivirine in treatment-experienced patients.

Mississippi baby brought additional excitement; however, the re‐emergence of virus in this infant has given pause to hopes for additional functional cures. At the recent IAS conference on HIV/AIDS, Zaunders et al presented on patient C135, one of the delta nef deleted HIV virus recipients in the Sydney blood bank cohort, who is not on antiretroviral medications and in whom infectious virus cannot now be detected. Whether this person is functionally cured or in remission is unknown. C135 has some genetic biomarkers that are associated with slower disease progression: HLA‐B*57 positivity and heterozygosity for the CCR5Delta 32 mutation. As HIV researchers develop strategies for regimens designed toward functional cure, we propose that in HIV-infected persons in whom functional cure regimens are being considered, and in whom therapeutic vaccination is a proposed intervention, immunogenomic approaches are taken into account to prioritize initial studies. For example, those with HLA or KIR alleles associated with slow progression, such as HLA‐B*57, Delta 32CCR5 heterozygosity, overexpression of intrinsic resistance genes, and others, could be candidates prioritized for these studies. We call this identification of “remission ready” patients. Oncologists stage patients based on a number of biomarkers for entry into differential clinical practices. HIV health practitioners enrolling subjects into functional cure regimens that include therapeutic immunizations should consider taking immunogenomics into account when identifying remission ready patients. Although the ultimate goal for HIV research is a universal cure and effective vaccine, this Sydney blood bank cohort subject has shown that genetics is a powerful indicator of viral suppression and potential remission. Immunogenomic profiling can help identify other such “remission ready patients.” This strategy could be described as “test” (immunogenomic profiling), “treat” (provide antiretroviral therapy), and “cure” (augmentative therapies designed for functional cures).

Potential Role of Vδ2+ γδ T Cells in Regulation of Immune Activation in Primary HIV Infection

Although conventional regulatory T cells (Tregs) are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI). Our previous data suggested that double negative (DN) T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI). In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT), we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+) γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro-inflammatory cytokine profile and participate in sustenance of immune activation.