Suppressive Highly Active Antiretroviral Therapy Research Articles

Hepatitis B vaccine responsiveness and clinical outcomes in HIV controllers.

BackgroundHepatitis B virus (HBV) vaccine responsiveness is associated with reduced risk of AIDS or death in HIV-infected individuals. Although HIV controllers (HIC) typically have favorable immunologic and clinical characteristics compared to non-controllers, vaccine responsiveness has not been studied.Methods and FindingsIn the U.S. Military HIV Natural History Study, HBV vaccine response was defined as antibody to hepatitis B surface antigen (anti-HBs) ≥10 IU/L after last vaccination. For determination of vaccine responsiveness, HIC (n = 44) and treatment-naïve non-controllers (n = 476) were not on highly active antiretroviral therapy (HAART) when vaccinated while treated non-controllers (n = 284) received all HBV vaccine doses during viral load (VL)-suppressive HAART. Progression to AIDS or death was also compared for all HIC (n = 143) and non-controllers (n = 1566) with documented anti-HBs regardless of the timing of HBV vaccination. Positive vaccine responses were more common in HIC (65.9%) compared to HAART-naïve non-controllers (36.6%; P<0.001), but similar to non-controllers on HAART (59.9%; P = 0.549). Factors associated with vaccine response for HIC compared to HAART-naïve non-controllers include HIC status (OR 2.65, 95% CI 1.23–5.89; P = 0.014), CD4 count at last vaccination (OR 1.28, 1.15–1.45 for every 100 cells/uL; P<0.001), and number of vaccine doses administered (OR 0.56, 0.35–0.88; P = 0.011). When HIC were compared to non-controllers on HAART, only CD4 count at last vaccination was significant (OR 1.23, 1.1–1.38 for every 100 cells/uL; P<0.001). The rate of AIDS or death per 100 person/years for HIC compared to non-controllers was 0.14 (95% CI 0–0.76) versus 0.98 (95% CI 0.74–1.28) for vaccine responders and 0 (95% CI 0–2.22) versus 4.11 (95% CI 3.38–4.96) for non-responders, respectively.ConclusionsHIC have improved HBV vaccine responsiveness compared to treatment-naïve non-controllers, but similar to those on VL-suppressive HAART. Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIC.

Immune activation despite suppressive highly active antiretroviral therapy is associated with higher risk of viral blips in HIV-1-infected individuals

Viral blips are thought to represent random biological variations around a steady state of residual HIV viraemia and to lack clinical significance. We aimed to assess the association of immune activation and the occurrence of blips. HIV-infected patients from our out-patient cohort who developed a blip after having been on fully suppressive highly active antiretroviral therapy (HAART) for at least 180 days were matched with patients without blips according to duration of complete viral suppression (CVS), age, sex and Centers for Disease Control and Prevention (CDC) stage. Frequencies of CD3(+), CD3(+) CD4(+), CD3(+) CD8(+), CD3(+) HLA-DR(+), CD4(+) CD45RA(+), CD16(+) CD56(+) CD3(-) and CD19(+) cells, as well as C-reactive protein (CRP) levels and clinical parameters, were included in conditional logistic regression models. Adherence to HAART was assessed by measuring prescribed nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) plasma levels in a sample of 57 patients. Eighty-two patients with viral blip were matched with 82 controls from the same cohort. The mean age was 47.2 years [standard deviation (SD) 12.1 years], 80.5% of patients were male and 42.7% had CDC stage C disease. Viral blips occurred after a median of 14 months [interquartile range (IQR) 8-34 months] of CVS. In the logistic regression, activated CD3(+) HLA-DR(+) lymphocytes [odds ratio (OR) 1.25 per 100 cells/μL; 95% confidence interval (CI) 1.02-1.54; P = 0.03] were significantly associated with blips and there was a trend for an association of longer time on HAART with blips (OR 1.31 per year; 95% CI 0.96-1.78; P = 0.09). No between-group difference regarding subtherapeutic drug levels was found (P = 0.46). The occurrence of viral blips after suppressive HAART was associated with elevated markers of T-cell activation. Blips may identify a subset of patients with higher immune activation and increased risk for HIV disease progression.

High CD56++CD16- natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort

BackgroundUp to 40% of HIV-infected individuals receiving Highly Active Antiretroviral Therapy (HAART) have poor CD4+ T-cell recovery. The role of natural killer (NK) cells in immune recovery during HAART is not well understood. We described the profiles of NK cell subsets and their expression of activating receptor, NKG2D and cytotoxicity receptor NKp46 among suboptimal immune responders to despite four years of suppressive HAART.MethodsA case control study utilized frozen peripheral blood mononuclear cells (PBMC) from a cohort of HIV-infected adults that initiated HAART in 2004/5, at CD4 < 200 cells/μl. Cases were ‘suboptimal’ responders; patients within the lowest quartile of CD4+ T-cell reconstitution, with a median CD4 count increase of 129 (-43-199) cells/μl (difference between CD4 count at baseline and after 4 years of HAART) and controls were ‘super-optimal’ responders; patients within the highest quartile of CD4 T-cell reconstitution with a median CD4 count increase of 528 (416-878) cells/μl). Expression of NK cell lineage markers (CD56+/-CD16+/-) and receptors NKG2D and NKp46, was measured among PBMC from 29 cases of ‘suboptimal’ responders’ and 23 controls of ‘super-optimal responders’, and compared among ‘suboptimal’ and ‘super-optimal’ responders. NK cell populations were compared using the Holm Sidak multiple comparison test and p values < 0.05 were considered statistically significant. Data was analyzed using FLOWJO and GraphPad Prism 6.Results‘Suboptimal responders’ had a higher proportion of cytokine producing CD56++CD16+/- (CD56bri) NK cells than the ‘super-optimal responders’ p = 0.017, and CD56neg NK cells were lower among suboptimal than super-optimal responders (p = 0.007). The largest NK cell subset, CD56dim, was comparable among suboptimal responders and ‘super-optimal immune responders’. Expression of NKG2D and NKp46 receptors on NK cell subsets (CD56bri, CD56neg and CD56dim), was comparable among ‘suboptimal’ and ‘super-optimal’ immune responders.ConclusionsThe pro-inflammatory CD56++CD16-- NK cells were higher among ‘suboptimal’ responders relative to ‘super-optimal’ responders, despite four years of suppressive HAART. Alteration of NK cell populations could inhibit host immune responses to infections among suboptimal responders. We recommend further analysis of NK cell function among suboptimal immune responders in order to inform targeted interventions to optimize immune recovery among HAART-treated adults.

Antiretroviral therapy is not associated with reduced herpes simplex virus shedding in HIV coinfected adults: an observational cohort study

ObjectivesHerpes simplex virus types 1 and 2 (HSV-1/2) may have adverse consequences on HIV type 1 infection. We quantified the frequency of HSV reactivations in highly active antiretroviral therapy (HAART)-treated...

Delayed‐type hypersensitivity (DTH) test anergy does not impact CD4 reconstitution or normalization of DTH responses during antiretroviral therapy

IntroductionDelayed-type hypersensitivity (DTH) testing is an in vivo assessment of cell-mediated immunity. Although highly active antiretroviral therapy (HAART) improves immunologic parameters, the relationship between DTH responsiveness and CD4 gains on HAART is not completely understood. We investigated CD4 reconstitution and the change in DTH responses from treatment baseline through 24 months of viral load (VL)-suppressive HAART in the U.S. Military HIV Natural History Study.MethodsTreatment-naïve subjects with VL <400 copies/mL after ≥24 months on HAART were included (n=302). DTH testing consisted of ≥3 recall antigens, and responses were classified by the number of positive skin tests: anergic (0–1) or non-anergic (≥2). Pre-HAART DTH results were compared for the outcome of CD4 reconstitution at 24 months of HAART. Improvement in DTH responses was also analyzed for those anergic before HAART initiation.ResultsNon-anergic responses were observed in 216 (72%) participants, while 86 (28%) individuals were anergic prior to HAART initiation. Demographically there were similar distributions of age at HIV diagnosis and HAART initiation, as well as gender and race or ethnicity. There were no significant differences between non-anergic and anergic participants in pre-HAART CD4 count (409 cells/μL, interquartile range (IQR) 315–517 vs. 373 cells/μL, IQR 228–487; p=0.104) and VL (4.3 log10 copies/mL, IQR 3.4–4.9 vs. 4.4 log10 copies/mL, IQR 3.6–5.0; p=0.292). Median CD4 gains 24 months after HAART initiation were similar between the non-anergic (220 cells/μL, IQR 115–358) and anergic groups (246 cells/μL, IQR 136–358; p=0.498). For individuals anergic before HAART initiation, DTH normalization occurred at 24 months post-HAART in the majority of participants (51 of 86, 59%). Normalization of DTH responses was not associated with CD4 count at HAART initiation (OR 0.73, 95% CI 0.47, 1.09 per 100 cells; p=0.129) nor with AIDS diagnoses prior to HAART (OR 0.34, 95% CI 0.04, 2.51; p=0.283).ConclusionsDTH responsiveness has been shown to predict HIV disease progression independent of CD4 count in untreated individuals. In the setting of HAART, pre-HAART anergy does not appear to impact CD4 gains or the ability to normalize DTH responses after 24 months of VL-suppressive HAART.

Urological aspects of HIV and AIDS

The use of highly active antiretroviral therapy (HAART) in HIV-infected people has led to a dramatic decrease in the incidence of opportunistic infections and virus-related malignancies such as non-Hodgkin lymphoma and Kaposi sarcoma, but not cervical or anal cancer. Advanced-stage cervical cancer is associated with a high incidence of urological complications such as hydronephrosis, renal failure, and vesicovaginal fistula. Adult male circumcison can significantly reduce the risk of male HIV acquisition. Although HAART does not completely eradicate HIV, compliance with medication increases life expectancy. HIV infection or treatment can result in renal failure, which can be managed with dialysis and transplantation (as for HIV-negative patients). Although treatment for erectile dysfunction--including phosphodiesterase 5 inhibitors, intracavernosal injection therapy, and penile prosthesis--can increase the risk of HIV transmission, treatment decisions for men with erectile dysfunction should not be determined by HIV status. The challenges faced when administering chemotherapy to HIV-infected patients with cancer include late presentation, immunodeficiency, drug interactions, and adverse effects associated with compounded medications. Nonetheless, HIV-infected patients should receive the same cancer treatment as HIV-negative patients. The urologist is increasingly likely to encounter HIV-positive patients who present with the same urological problems as the general population, because HAART confers a prolonged life expectancy. Performing surgery in an HIV-infected individual raises safety issues for both the patient (if severely immunocompromised) and the surgeon, but the risk of HIV transmission from patients on fully suppressive HAART is small.

Severe Immune Dysregulation Affects CD4+CD25hiFoxP3+ Regulatory T Cells in HIV-Infected Patients With Low-level CD4 T-Cell Repopulation Despite Suppressive Highly Active Antiretroviral Therapy

We hypothesized that CD4(+)CD25(hi)FoxP3(+) regulatory T cells (Tregs) could be involved in the high immune activation existing in patients with low-level CD4 T-cell repopulation under suppressive high active antiretroviral therapy (hereafter, "LLR patients"). Sixteen LLR patients, 18 human immunodeficiency virus (HIV)-infected controls (hereafter, "HIV controls"), and 16 healthy subjects were included. The frequency of CD4(+)CD25(hi)FoxP3(+) and HIV-specific Treg suppressive function were assessed. Relationships between Treg and CD4/CD8 activation (HLA-DR/CD38) and the frequency of naive CD4 T-cells were assessed. Low-level patients showed a higher Treg frequency but reduced HIV-specific immunosuppressive functions than HIV controls. Whereas in healthy subjects a strong negative correlation between Tregs and activated CD8 T cells emerged (r=-0.75, P<.001), it appeared disrupted in both HIV-infected groups (r=-0.06 and P=.83 for LLR patients; r=-0.11 and P=.68 for and HIV controls). Nevertheless, in LLR patients, Tregs negatively correlated with naive CD4 T cells (r=-0.60, P=.01), whereas there was no such correlation in HIV controls (r=-0.19, P=.46) or healthy subjects (r=-0.10, P=.73). Remarkably, a higher ratio of Tregs to naive CD4 T cells was observed in LLR patients than in HIV controls (P=.001) and healthy subjects (P<.001). We conclude that LLR patients have important alterations in immunoregulation involving CD4(+)CD25(hi)FoxP3(+) Tregs. In this scenario, the role of Tregs seems to be more related to the control of the naive CD4 T-cell homeostatic proliferation, rather than to the immune activation.

Low-level viraemia on HAART

The source, significance and optimal management of low-level viraemia during highly active antiretroviral therapy (HAART) are poorly defined. This review highlights recent observations that have implications for clinical practice. The definition of low-level viraemia remains elusive. Whereas evidence obtained with second-generation viral load assays indicates that confirmed detection of plasma HIV-1 RNA above 50 copies/ml predicts negative outcomes, third-generation assays detect HIV-1 RNA below this threshold. In patients monitored with the Abbott RealTime assay, the cutoff that should trigger confirmation of viraemia and clinical review can be revised to 40 copies/ml. Further data are needed on the cost-effectiveness of intervening when RNA detection is observed below this cutoff. Discrepancies among viral load assays prevent generalization of these observations. To further compound the issue, most patients on stably suppressive HAART show residual viraemia at around 1-10 copies/ml using research-based ultrasensitive assays. The source of residual viraemia remains controversial, but neither short nor long-term HAART intensification with antiretrovirals such as raltegravir reduces the viraemia. A transient effect of intravenous immunoglobulin has been reported, and different regimens may vary in their propensity to allow HIV-1 RNA persistence. Further studies are required to clarify the relationship between low-level viraemia and the size of proviral DNA reservoirs, and the contribution of cellular and tissue compartments and cell-to-cell spread to ongoing virus replication during HAART. Understanding the source and clinical significance of HIV-1 RNA persistence in plasma during HAART is required to guide patient care and inform the design of HIV eradication strategies.

Differential alterations of the CD4 and CD8 T cell subsets in HIV-infected patients on highly active antiretroviral therapy with low CD4 T cell restoration

This study examined the homeostatic parameters possibly related to HIV-infected patients who, despite being under suppressive highly active antiretroviral therapy (HAART), show low-level CD4 T cell repopulation (LLR). Twenty-one LLR individuals, 20 HIV-infected controls with satisfactory CD4 T cell repopulation (R) and 14 healthy subjects were studied. Markers related to activation, senescence and proliferation were analysed for both the CD4 and CD8 T cell subsets. Additionally, soluble CD14 (sCD14) and high-sensitivity C-reactive protein (hsCRP) were measured, and the CD34+ cells and the levels of interleukin-7 (IL-7) receptor were quantified. The frequency of naive CD4 T cells from LLR patients was significantly reduced, and these cells showed increased expression of markers for activation, senescence and proliferation as compared with naive CD4 T cells from R patients. Naive CD8 T cells were also reduced when compared with those from R patients, but did not exhibit an altered phenotype. Moreover, frequencies of effector memory T cells were higher in LLR than R patients. No differences between LLR and R patients were observed for sCD14 levels, CD34+ cells and the IL-7 receptor, although LLR patients showed a tendency toward increased levels of hsCRP >2 μg/mL. Patients with low CD4 T cell restoration under suppressive HAART show significant alterations in T cell homeostasis that do not appear to be related to a reduction in haematopoietic progenitors. sCD14 levels were not specifically altered in these patients. Our results agree with our previously proposed model of premature immunosenescence in LLR patients and further describe homeostatic features associated with poor CD4 recovery.

Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy

Highly active antiretroviral therapy (HAART) dramatically reduces plasma HIV-1 viremia. However, despite completely suppressive HAART, it has been suggested that low-levels of viral replication may persist in the gut mucosa and elsewhere in individuals on long-term HAART. We conducted a double-blind randomized, placebo-controlled trial evaluating whether intensification of HAART in long-term virologically suppressed individuals with raltegravir is associated with a reduction in the level of proviral HIV-1 DNA in CD4(+) T cells in blood and the sigmoid colon (gut). Long-term (>4 years) virologically suppressed HIV-infected individuals on standard HAART were randomized 1 : 1 in a double-blind fashion to receive raltegravir (400 mg twice/day) or placebo for 48 weeks. After week 48, all participants were treated with raltegravir to week 96. Blood and sigmoid biopsies were sampled and the frequency of CD4(+) T cells carrying HIV-1 proviral DNA was determined. Twenty-four study patients were recruited. At 48 weeks, no difference was apparent between participants receiving raltegravir or placebo in blood HIV-1 proviral levels (P = 0.62), CD4(+) T-cell counts (P = 0.25) and gut proviral loads (P = 0.74). Similarly, prolonged raltegravir intensification up to week 96 had no further effect on both blood and gut HIV-1 proviral loads and blood CD4(+) T-cell counts. In long-term virologically suppressed patients on standard HAART, intensification with raltegravir did not result in further decay of CD4(+) T cells carrying HIV-1 proviral DNA in either the blood or gut after 48 or 96 weeks of therapy, or in any increase in CD4(+) T-cell counts.

Disseminated rhodococcus equi infection in HIV infection despite highly active antiretroviral therapy

BackgroundRhodococcus equi (R.equi) is an acid fast, GRAM + coccobacillus, which is widespread in the soil and causes pulmonary and extrapulmonary infections in immunocompromised people. In the context of HIV infection, R.equi infection (rhodococcosis) is regarded as an opportunistic disease, and its outcome is influenced by highly active antiretroviral therapy (HAART).Case presentationWe report two cases of HIV-related rhodococcosis that disseminated despite suppressive HAART and anti-rhodococcal treatment; in both cases there was no immunological recovery, with CD4+ cells count below 200/μL. In the first case, pulmonary rhodococcosis presented 6 months after initiation of HAART, and was followed by an extracerebral intracranial and a cerebral rhodococcal abscess 1 and 8 months, respectively, after onset of pulmonary infection. The second case was characterized by a protracted course with spread of infection to various organs, including subcutaneous tissue, skin, colon and other intra-abdominal tissues, and central nervous system; the spread started 4 years after clinical resolution of a first pulmonary manifestation and progressed over a period of 2 years.ConclusionsOur report highlights the importance of an effective immune recovery, despite fully suppressive HAART, along with anti-rhodococcal therapy, in order to clear rhodococcal infection.

Cardiovascular disease in HIV infection

Highly active antiretroviral therapy (HAART) use has markedly reduced AIDS-related mortality and opportunistic illness. With improved survival, cardiovascular disease (CVD) has emerged as an important noninfectious chronic comorbidity among antiretroviral (ARV)-treated HIV-infected persons. HIV infection can impact CVD and comorbidities known to increase CVD risk. Untreated HIV can cause proatherogenic elevations in serum lipids. Chronic HIV viremia results in increases in systemic inflammation, hypercoagulation, and reductions in endovascular reactivity, all of which are at least partially reversible with virally suppressive HAART. Chronic T-cell activation can also result in adverse vascular effects. Use of some ARV drugs can impact CVD risk by causing pro-atherogenic serum lipid elevations, induction of insulin resistance, increases in visceral adiposity or subcutaneous fat loss. Abacavir use may increase myocardial infarction risk by reducing vascular reactivity and/or increasing platelet activation. Traditional risk factors such as advancing age, smoking, hyperlipidemia, and hypertension remain important predictors of CVD among HAART-treated HIV-infected persons. HIV in the HAART era is a chronic manageable condition. CVD is an important cause of morbidity among HIV-infected persons. Untreated HIV can increase CVD risk in several ways and these effects are at least partially reversible with successful treatment. Use of specific ARVs can adversely impact CVD risk but the multiple long-term benefits of chronic HIV suppression and immune reconstitution achievable with potent HAART outweigh the adverse impact upon CVD risks that they may have. Standard CVD screening and risk-reducing interventions should be routinely undertaken for HIV-infected persons.

Microbial Translocation: A Marker of Advanced HIV-1 Infection and a Predictor of Treatment Failure?

To the Editor—We agree that the issue of whether microbial translocation (MT) is a cause or consequence of human immunodeficiency virus type 1 (HIV-1) disease progression is an important question that can only be addressed through longitudinal analyses of natural history cohorts such as the study by Redd et al [1]. A timely and definitive answer to this question will depend on the availability of archived specimens that have been well characterized and properly stored. Specimen banks of this nature are relatively rare in Africa. However, there are issues of equal importance, namely, whether microbe-associated immune activation persists during highly active antiretroviral therapy (HAART) and whether this has an adverse effect on therapeutic outcome. There is already a growing body of evidence indicating that HAART-treated patients have elevated levels of bacterial DNA and plasma lipopolysaccharide (LPS) for at least 2 years after starting therapy [2], with one North American study showing decreased levels of LPS and CD4 T cell cycling after >5 years of maximally suppressive HAART [3]. There is also increasing evidence that elevated levels of LPS are associated with monocyte-macrophage activation and disease pathology, not only in HIV-1-infected patients with dementia [4] and hepatitis C–related liver disease [5], but also in HIV-1–negative patients with tuberculosis [6] and inflammatory bowel disease [7]. LPS has also been linked to T cell activation and proliferation [3], presumably via secretion of proinflammatory mediators by monocyte-macrophages. However, as emphasized by Redd et al, MT does not account for all aspects of immune activation in patients with late-stage disease. We examined the relationship between plasma LPS, HIV-1 viral load, and immune activation, before and after 1 year of nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART), in Africans with advanced HIV-1 disease and CD4 counts <200 cells/μL [8]. We found that some aspects of monocyte activation (CCL2, CXCL10, the frequency of CD14+CD16+ monocytes) were associated with high levels of HIV-1 RNA, whereas others (tumor necrosis factor [TNF], soluble CD14 [sCD14]) were more closely linked to plasma concentrations of LPS or the presence of opportunistic co-infections (interleukin 6). In addition to being independent of HIV-1 replication, LPS-associated activation, as measured by sCD14 and TNF, was independent of T cell activation and was only partially curtailed after 1 year of successful ART. These findings may help explain the results of Rempel et al [9]. Similar to our study, these investigators found that LPS and sCD14 remained elevated in HAART-treated patients. They also found that monocytes isolated from patients with high levels of residual viremia exhibited different patterns of gene expression after in vitro stimulation with LPS and interferon (IFN)–α. IFN-α activation resembled that observed in patients, while the LPS pattern differed from that normally induced following activation with whole bacteria (interleukin 10) or Fc/complement receptor–mediated phagocytosis (interleukin 6, interleukin 1β), leading to the conclusion that these monocytes were not responsive to LPS. However, LPS induced the up-regulation of a large number of genes (n = 992), a finding that is consistent with the ability of LPS to induce 5 different signaling cascades [10]. Whether these altered LPS patterns are due to a superimposed (or counterbalancing) effect of HIV-1 on monocyte activation or a defect in endotoxin tolerance remains to be determined. Additional studies should include HAART-treated patients with undetectable viremia and be performed using whole bacteria and LPS/LPS-binding protein (LBP) in addition to monomeric LPS. To rule out activation during positive selection with anti-CD14 antibodies, monocytes should be isolated using negative as well as positive selection methods. Additional studies are also needed to unravel the relationships between LPS, sCD14, and immune activation. CD14 binds and presents LBP-bound LPS to its signaling complex, lymphocyte antigen 96 (MD-2)/toll-like receptor 4 (TLR4), triggering monocyte-macrophage activation and the release of sCD14 [11]. sCD14 contributes to cell activation by transferring monomeric LPS to membrane CD14 (mCD14), or directly to the MD-2/TLR4 complex in cells that lack mCD14. However, sCD14 can also induce endotoxin tolerance by removing LPS from mCD14 and diverting it to plasma lipoproteins [11], a process that may decrease CD14 shedding. This is further complicated by studies showing that HIV-1 RNA can enhance TLR4-mediated response to LPS, causing dysregulation of endotoxin tolerance [12]. The complex relationships between HIV-1, MT, and immune activation are likely to depend on the integrity of gastrointestinal epithelium, the level of HIV-1 replication, plasma concentrations of LPS-binding protein and endotoxin core antibody, and the presence/absence and type of opportunistic co-infections, as well as the combined effects of these infections on TLR signaling cascades. Understanding these interactions may be critical to the design of strategies aimed at enhancing therapeutic efficacy in Africa where treatment is often delayed until CD4 counts drop to <200 cells/μL.

Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy

Cerebrospinal fluid HIV-1 virological escape with lymphocytic meningitis under lopinavir/ritonavir monotherapy

HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Higher risk of AIDS or death in patients with lower CD4 cell counts after virally suppressive HAART

The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain. We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/microL before HAART initiation; >or=2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50-1000 copies/mL. One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/microL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs. 39 among those who did not meet either endpoint (P=0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of <or=200 vs. >350 cells/microL was 10.7 (P=0.013), and at CD4 cell count of 201-350 vs. >350 cells/microL was 8.54 (P=0.014). In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.

A Simian Immunodeficiency Virus-Infected Macaque Model To Study Viral Reservoirs That Persist during Highly Active Antiretroviral Therapy

The treatment of human immunodeficiency virus type 1 (HIV-1) infection with highly active antiretroviral therapy (HAART), a combination of three or more antiretroviral drugs, suppresses viremia below the clinical limit of detection (50 HIV-1 RNA copies/ml), but latently infected resting CD4(+) T cells serve as lifelong reservoirs, and low-level viremia can be detected with special assays. Recent studies have provided evidence for additional reservoirs that contribute to residual viremia but are not present in circulating cells. Identification of all the sources of residual viremia in humans may be difficult. These discoveries highlight the need for a tractable model system to identify additional viral reservoirs that could represent barriers to eradication. In this study, simian immunodeficiency virus (SIV)-infected pig-tailed macaques (Macaca nemestrina) were treated with four antiretroviral drugs to develop an animal model for viral suppression during effective HAART. Treatment led to a biphasic decay in viremia and a significant rise in levels of circulating CD4(+) T cells. At terminal infection time points, the frequency of circulating resting CD4(+) T cells harboring replication-competent virus was reduced to a low steady-state level similar to that observed for HIV-infected patients on HAART. The frequencies of resting CD4(+) T cells harboring replication-competent virus in the pooled head lymph nodes, gut lymph nodes, spleen, and peripheral blood were reduced relative to those for untreated SIV-infected animals. These observations closely parallel findings for HIV-infected humans on suppressive HAART and demonstrate the value of this animal model to identify and characterize viral reservoirs persisting in the setting of suppressive antiretroviral drugs.

Potential impact of early antiretroviral therapy on transmission

In this review, we will discuss the potential of early highly active antiretroviral therapy (HAART) to reduce the sexual transmission of HIV on an individual and population level. We will focus on the biological plausibility and behavioural factors associated with HAART use and interventions that might influence such a strategy. Empiric and phylogenetic studies support the view that recent HIV infection is a highly infectious disease stage. Evidence increasingly demonstrates that individuals on fully suppressive HAART are significantly less likely to transmit HIV to sexual partners and some even suggest that such individuals cannot transmit HIV. Changes in risk behaviour are associated with the availability of HAART but behavioural studies offer contradictory observations regarding the direction and magnitude of these changes. This in turn makes the intricate assumptions and therefore outcomes of many complex mathematical modelling studies less secure. Furthermore, there is evidence that it is those individuals with undiagnosed HIV infection who contribute significantly to onward sexual transmission. At an individual level, HAART will reduce viral load and, therefore, infectiousness, although whether to zero or not remains controversial. At a population level, if recent infection and undiagnosed infections continue to drive onward transmission, earlier treatment will only alter the pandemic if accompanied by an improvement in diagnosing the undiagnosed and recognizing recent infection.

Low‐level plasma HIVs in patients on prolonged suppressive highly active antiretroviral therapy are produced mostly by cells other than CD4 T‐cells

The cellular source(s) and the clinical significance of persistent low-level viremia, below 50 HIV RNA copies per ml of plasma, achieved in many patients with high adherence to highly active antiretroviral therapy (HAART) remain unclear. Also, it is not clear if residual plasma HIVs during HAART can become predominant populations in the rebounding plasma viral loads after therapy interruption. Since, different HIV quasispecies tend to compartmentalize in various cell types and tissue locations in patients during chronic infection, the phylogenetic relationships between HIV sequences amplified from residual plasma viruses and CD4 T cells of five patients on long-term suppressive therapy were examined. Three of these patients stopped therapy voluntarily for 3 weeks, but only one of them demonstrated viral load rebound in plasma. In phylogenetic analyses, the residual plasma viruses were found to be distinct genetically from the majority of CD4 T cell-associated virus populations in four of five patients. The compartmental analyses revealed that in all patients, plasma- and CD4 T cell-derived viral sequences were compartmentalized separately. Interestingly, the plasma sequences obtained before and after HAART-off in two patients were produced apparently from the same compartment, which was different from the circulating CD4 T cell-compartment. These results suggest the possibility that residual plasma viruses in patients on long-term suppressive HAART may be produced persistently from a cellular source yet to be identified, and are capable of spreading quickly in vivo, accounting for the rapid rebound of viral loads in plasma after therapy interruption.

Impairment of the intestinal barrier is evident in untreated but absent in suppressively treated HIV-infected patients

Background and aims:Impairment of the gastrointestinal mucosal barrier contributes to progression of HIV infection. The purpose of this study was to investigate the effect of highly active antiretroviral therapy (HAART)...