Osteosclerotic disease and bone cyst in a prehispanic burial from Las Cañadas del Teide (Tenerife, Canary Islands).

Skeletal remains of two prehispanic male adult individuals (antiquity ≈ 550 BP) recovered from a burial cave located in Montaña Blanca (Las Cañadas del Teide) at an altitude of 2450 m above sea level, in the highlands of Tenerife (Canary Islands) showed some unusual features. Femora and tibiae of both individuals showed increased bone density, with irregular thickening of the midshaft diaphyses. One individual showed a cystic lesion in the distal third of the left femoral diaphysis, surrounded by a subtle sclerotic reaction of the spongiosa and a thin cortex that was partially fractured. Periosteal thickening was present, but not around the cystic lesion. A thoracic vertebra with rachischisis was also recovered. The bone density of vertebrae and iliac bones were normal, and one recovered jaw was also normal. The tibiae of one individual showed an abnormal location of the foramen nutritium. Hypoplasia of the lesser trochanter and an abnormally thin left femoral neck were also observed. It is possible that both individuals were affected by diaphyseal dysplasia (possibly Camurati Engelmann or Ribbing disease). One of them also showed a lesion compatible with a unicameral bone cyst. The alternative possibility of a Klippel-Trenaunay-Weber disease, with a bone aneurysmal cyst, also exists.

Smart e-Skin Cancer Care in Europe During and after the Covid-19 Pandemic: a Multidisciplinary Expert Consensus.

INTRODUCTION: Melanoma is the deadliest of all the skin cancers and its incidence is increasing every year in Europe. Patients with melanoma often present late to the specialist and treatment is delayed for many reasons (delay in patient consultation, misdiagnosis by general practitioners, and/or limited access to dermatologists). Beyond this, there are significant inequalities in skin cancer between population groups within the same country and between countries across Europe. The emergence of the COVID-19 pandemic only aggravated these health deficiencies. OBJECTIVES: The aim was to create an expert opinion about the challenges in skin cancer management in Europe during the post COVID-19 acute pandemic and to identify and discuss the implementation of new technologies (including e-health and artificial intelligence defined as "Smart Skin Cancer Care") to overcome them. METHODS: For this purpose, an ad-hoc questionnaire with items addressing topics of skin cancer care was developed, answered independently and discussed by a multidisciplinary European panel of experts comprising dermatologists, dermato-oncologists, patient advocacy representatives, digital health technology experts, and health technology assessment experts. RESULTS: After all panel of experts discussions, a multidisciplinary expert opinion was created. CONCLUSIONS: As a conclusion, the access to dermatologists is difficult and will be aggravated in the near future. This fact, together with important differences in Skin Cancer Care in Europe, suggest the need of a new approach to skin health, prevention and disease management paradigm (focused on integration of new technologies) to minimize the impact of skin cancer and to ensure optimal quality and equity.

A Prehispanic infant from Tenerife with diffuse microporotic lesions.

We describe diffuse microporotic lesions observed in most of the scattered skeletal remains belonging to a ≈ 6 months-old female (genetic sexing) prehispanic (antiquity ≈ 600 years BP) individual recovered from a small recess of a basaltic burial cave in the highlands (2300 m above sea level) of Tenerife. Although sphenoid wings were lacking, microporotic lesions were present in several bones, especially in the hard palate, basilar part of the occipital bone, outer aspect of the maxilla, and proximal half of the right humerus, accompanied by a subtle periosteal reaction. Although non-specific, bone lesions may be compatible with scurvy, possibly in the context of malnutrition, that probably also affected the mother, given the young age of the infant and her dependence on maternal feeding. Pathophysiological connections among iron deficiency, vitamin C deficiency and vitamin D deficiency are discussed. Both observational reports on paleopathological cases of diffuse microporotic lesions as well as experimental studies devoted to discern the relative and combined effects of hypoxia-mediated bone marrow expansion, protein-calorie malnutrition, ascorbate, vitamin D or iron deficiency on such lesions are needed.

Profiling the Effects of Systemic Antibiotics for Acne, Including the Narrow-Spectrum Antibiotic Sarecycline, on the Human Gut Microbiota.

Treatment for moderate-to-severe acne vulgaris relies on prolonged use of oral tetracycline-class antibiotics; however, these broad-spectrum antibiotics are often associated with off-target effects and negative gastrointestinal sequelae. Sarecycline is a narrow-spectrum antibiotic treatment option. Here, we investigated the effect of prolonged sarecycline exposure, compared with broad-spectrum tetracyclines (doxycycline and minocycline) upon the colonic microbiota. Three in vitro models of the human colon were instilled with either minocycline, doxycycline or sarecycline, and we measured microbiota abundance and diversity changes during and after antibiotic exposure. Significant reductions in microbial diversity were observed following minocycline and doxycycline exposure, which failed to recover post antibiotic withdrawal. Specifically, minocycline caused a ~10% decline in Lactobacillaceae and Bifidobacteriaceae abundances, while doxycycline caused a ~7% decline in Lactobacillaceae and Bacteroidaceae abundances. Both minocycline and doxycycline were associated with a large expansion (>10%) of Enterobacteriaceae. Sarecycline caused a slight decline in bacterial diversity at the start of treatment, but abundances of most families remained stable during treatment. Ruminococcaceae and Desulfovibrionaceae decreased 9% and 4%, respectively, and a transient increased in Enterobacteriaceae abundance was observed during sarecycline administration. All populations recovered to pre-antibiotic levels after sarecycline exposure. Overall, sarecycline had minimal and transient impact on the gut microbiota composition and diversity, when compared to minocycline and doxycycline.

Pan-resistant HIV-1 emergence in the era of integrase strand-transfer inhibitors: a case report.

BACKGROUND: In 2019, WHO reported that the prevalence of HIV-1 drug resistance to first-line regimens of non-nucleoside reverse transcriptase inhibitors is increasing in countries with a low number of therapeutic options. This increasing prevalence of drug resistance is an important threat to ending the AIDS pandemic, as it compromises individual clinical outcomes and increases the risk of transmission. In countries with a high number of therapeutic options, little global information is available regarding the prevalence of multidrug-resistant HIV-1 infections, which presents a potential challenge for the clinical management of people with HIV. Even after the approval of two new antiretroviral drug classes in 2007, which were intended to help alleviate this problem, some cases of infection with HIV-1 that show limited susceptibility to the five available antiretroviral classes have been described. We did a thorough in-vitro evaluation of the drug resistance profile of HIV-1 from an observational case to show that five-class pan-resistant clinical cases do exist. METHODS: We investigated a case of a highly treatment-experienced Caucasian male with HIV-1 who had a poor virological response to previous combination antiretroviral therapy (ART) and who was not responding to a dolutegravir-based regimen. For the complete panel of approved antiretrovirals, we examined genotypic resistance using the Stanford HIV Drug Resistance Database interpretation algorithm, and we examined phenotypic resistance using the PhenoSense and Trofile assays. Using viral gp160 sequence analysis, we also explored the potential susceptibility of this virus to novel therapeutic drugs targeting viral envelope binding. FINDINGS: The individual was diagnosed with HIV-1 on Sept 29, 1989. Since starting antiretroviral treatment in 1995, the individual had received more than 14 different antiretroviral drugs over the course of his illness. In November, 2017, a blood sample was collected from the individual and we did drug resistance analysis tests. We found that this individual was infected with a pan-resistant HIV-1 subtype B strain that showed broad genotypic and phenotypic cross-resistance to all approved antiretroviral drugs, including the newest second-generation integrase inhibitors, dolutegravir and bictegravir. With no remaining clinical options available, except for investigational drugs, this case provides evidence that new antiretroviral drugs with different mechanisms of action are needed. INTERPRETATION: Our case report shows that HIV-1 multidrug cross-resistance remains an important concern, despite the extensive number of antiretroviral drugs currently available. Highly treatment-experienced patients, especially those who have been given suboptimal combination ART, can develop highly complex resistance-associated mutation patterns, conferring cross-resistance to all widely available ARTs. The identification and reporting of cases, such as the one described in this report, are needed to increase awareness of emerging trends that have the potential to affect patient management. FUNDING: None.

Impact of prior virological failure and nucleos(t)ide genotypic resistance mutations on the efficacy of switching from ritonavir-boosted protease inhibitors to raltegravir.

BACKGROUND: The virological efficacy of switching from a ritonavir-boosted protease inhibitor (PI/r)- to a raltegravir (RAL)-containing regimen remains controversial according to the results of SWITCHMRK and SPIRAL studies. The aim of this analysis is to assess the impact of prior resistance mutations to nucleos(t)ides and other potential factors on the virological outcome. METHODS: This was a substudy of the prospective, open-label, multicentre SPIRAL study. Demographic, virological variables, prior episodes of virological failures (VF) and archived resistance mutations to nucleos(t)ides were identified from databases and its impact measured by genotypic sensitive scores (GSS) according to the genotypic resistance interpretation algorithm from the Stanford HIV Drug Resistance Database on outcome was analysed. RESULTS: Of 250 patients (128 RAL and 122 PI/r) included in the main SPIRAL study, 74 (30%) had previous VF with prior genotypic resistance tests (GRT). Median time of virological suppression prior to inclusion in SPIRAL study was 63.5 months. GSS for backbone nucleos(t)ides was <1 in 15/38 (39%) in the RAL arm and in 9/36 (25%) in the PI/r arm (P=0.13). Among those with nucleos(t)ides GSS <1, 0/15 (0%) in the RAL versus 2/9 (22%) in the PI/r arm developed VF (P=0.13). Moreover 0/11 subjects with null or residual (GSS≤0.5) backbone activity developed VF in the RAL arm. CONCLUSIONS: The 48-week virological efficacy of switching from a PI/r to RAL in subjects with long-term virological suppression was not compromised by a reduction of the nucleos(t)ide backbone activity.

Raltegravir pharmacokinetics in HIV/HCV-coinfected patients with advanced liver cirrhosis (Child-Pugh C).

OBJECTIVES: To describe raltegravir pharmacokinetics at steady-state in HIV/hepatitis C virus (HCV)-coinfected patients under antiretroviral (ARV) treatment with (n = 5) and without (n = 5) advanced liver cirrhosis (Child-Pugh C). METHODS: This was a non-randomized, Phase I, parallel-assignment, open-label pharmacokinetic study in HIV/HCV-coinfected patients with Child-Pugh grade C hepatic cirrhosis. We recruited clinically stable HIV/HCV-coinfected adult patients with controlled HIV viraemia (<50 copies/mL) for at least 6 months. Raltegravir (400 mg twice daily) was added under fasting conditions for 5 days to the successful ritonavir-boosted protease inhibitor-based ARV regimen. The trial was registered in the ClinicalTrials.gov database (NCT01289951) (LIVERAL). RESULTS: Raltegravir AUC0-12 and C12 were increased 1.72-fold (90% CI, 1.02 to 2.92) and 6.58-fold (90% CI, 2.92 to14.85), respectively, in patients with advanced liver cirrhosis. No safety issues were identified and raltegravir was well tolerated by all patients. CONCLUSIONS: Raltegravir plasma levels are increased in HIV/HCV-coinfected patients with advanced liver cirrhosis (Child-Pugh C). Despite the higher exposure, raltegravir was safe and well tolerated.

Assessment of migration of HIV-1-loaded dendritic cells labeled with 111In-oxine used as a therapeutic vaccine in HIV-1-infected patients.

Monocyte-derived dendritic cells (DCs) loaded with heat-inactivated HIV are used in therapeutic immunizations. It is not known whether they migrate in vivo to lymph nodes. We used an (111)In-oxine-labeled DC (ILDC) method to visualize the migration of DCs. The activity, time and incubation medium were investigated to obtain the highest cellular viability and radiolabeling yield. A trypan-blue exclusion test was used to determine the cellular viability. In five patients, 2 x 10(6) ILDCs were injected subcutaneously in the arm. An initial dynamic study was performed during the first 5 min after injection. This was followed by static acquisitions at several time points, using a high-resolution (general electric) gamma-camera and quantifying the activity at regions of interest drawn on the injection point. The sensitivity of the gamma-camera was evaluated. The highest number of viable DCs (>83%) and the best radiolabeling yield (>70%) were obtained with 1.11 MBq (111)In-oxine, after 10 min of incubation at 37 degrees C in sodium chloride solution 0.9%. We did not observe migration of ILDCs to local lymph nodes in any patient. However, focal uptake at the place of injection continued during the study period. We observed a higher than expected loss of activity from the injection point (median A(t)/A(0) = 0.60 at day 2), which correlated with an increase in total cytotoxic T lymphocytes (CD8(+) and granzyme B(+) cells) in the lypmphoid tissue observed after immunization (R(2) = 0.92, p = 0.03). If more than 20,000 ILDCs had migrated, they could have been detected. In future trials, a higher number of DCs or alternative methods should be used to assess the migration of DCs to lymph nodes.

Immune modulators and treatment interruption.

PURPOSE OF REVIEW: This article reviews the relevance of sudden immune activation in HIV pathogenesis and summarizes the strategies that could prevent the high peaks of viral replication after antiretroviral therapy interruption. RECENT FINDINGS: Systemic immune activation could have both beneficial and harmful effects in chronic infection. Recent findings suggest that in addition to viral replication other factors could drive immune activation. The changes in natural regulatory T cell number or function and microbial translocation have been hypothesized as potential causes. Immune activation after antiretroviral therapy interruption could play a critical role in the increase in the rates of AIDS-defining and non-AIDS-defining malignancies or cardiovascular events between patients on a CD4 T-cell-guided intermittent antiretroviral therapy strategy in the SMART study. SUMMARY: The use of a cytostatic drug would help T lymphocytes to remain quiescent, becoming refractory to productive HIV-1-infection and thus avoiding high peaks of viral replication after antiretroviral interruption without blunting HIV-1 specific immune responses. This has been the rationale for the use of immunomodulators (such as corticosteroids, hydroxyurea, mycophenolate mofetil, thalidomide, and cyclosporin A) as adjuvant to antiretroviral therapy in structured treatment interruption strategies.

Immunological profile of heterosexual highly HIV-exposed uninfected individuals: predominant role of CD4 and CD8 T-cell activation.

BACKGROUND: Altered T cell subset distribution patterns in uninfected individual highly exposed to human immunodeficiency virus (HIV) have been explained either as a consequence of viral exposure or as a surrogate marker of low susceptibility to infection. METHODS: Multiple genetic and immunological parameters were studied prospectively in 21 HIV-serodiscordant heterosexual couples. RESULTS: We found changes of both CD4(+) and CD8(+) T cells in highly HIV-exposed, uninfected individuals, with a lower level of naive and CD28(+) T cells and higher levels of HLA-DR(+) T cells and CD4(+) T cells expressing CCR5 and memory CD4(+) T cells than in control subjects. The changes in memory and activated T cells observed in highly HIV-exposed, uninfected partners were directly correlated with plasma viral load (PVL) of the HIV-1-infected partners, whereas changes in naive and CD4(+) CD28(+) T cells observed in highly HIV-exposed uninfected partners were inversely correlated with PVL of the HIV-1-infected partners. We were only able to detect HIV-1-specific T-cell responses in a few highly HIV-exposed uninfected partners. CONCLUSIONS: These data suggest that the peripheral immune cells of highly exposed, uninfected individuals responded according to the level of HIV exposure from the partner, even though evidence of specific HIV stimulation is rarely seen.

HIV-1 upregulates intercellular adhesion molecule-1 gene expression in lymphoid tissue of patients with chronic HIV-1 infection.

OBJECTIVES: Intercellular adhesion molecule (ICAM)-1 is an adhesion molecule that plays an important role in the transmission of HIV-1 to CD4+ target cells and in the decrease of these cells in lymphoid tissue (LT). Our main objective was to study ICAM-1 expression in LT from HIV-1-infected persons and to correlate this expression with LT viral load and the immunoarchitecture alteration before and after highly active antiretroviral therapy (HAART). METHODS: Tonsillar LT samples from 16 patients with chronic asymptomatic HIV-1 infection were studied before initiating treatment and after 12 months of HAART. ICAM-1 protein expression was studied by immunohistochemistry in all cases, and ICAM-1 messenger RNA (mRNA) was quantified from frozen tissue in 6 patients using quantitative real-time polymerase chain reaction (PCR). LT viral load was determined by PCR. The LT immunoarchitecture, p24 immunoexpression, and CD4+ cell count were assessed from tissue sections. RESULTS: Before initiating HAART, there was high immunohistochemical ICAM-1 expression in follicular dendritic and endothelial cells and high ICAM-1 mRNA quantification. These findings correlated with a high LT viral load, strong p24 expression, and an effacement of LT immunoarchitecture with a low number of CD4+ cells. After HAART, there was a significant decrease of immunohistochemical and gene ICAM-1 expression. These results correlated with a significant decrease of LT viral load and p24 immunoexpression, a recovery of LT architecture, and a significant increase of CD4+ cells. CONCLUSIONS: HIV-1 upregulates ICAM-1 expression in LT. This finding is associated with a marked effacement of LT architecture. HAART produces downregulation of ICAM-1 expression and recovery of LT architecture by reducing LT viral load significantly.

Clinicoimmunological progression and response to treatment of long-term nonprogressor HIV-hepatitis C virus-coinfected patients.

We assess the severity and response to treatment of hepatitis C virus (HCV) infection in a cohort of long-term nonprogressors (LTNP) and analyze whether HCV infection affects the progression of HIV-1 infection. A case-control study comparing coinfected LTNP (n = 28) with coinfected normal progressors (NP) (n = 56) was performed. Signs of hepatopathy, response to HCV treatment, HIV viral load (VL), and lymphocyte T subsets were analyzed. A cohort of LTNP with (n = 28) and without HCV infection (n = 7) was compared to assess the influence of HCV on HIV-1 infection. Liver enzymes were lower in LTNP than in NP. There were no significant differences between LTNP and NP in clinical signs of chronic liver disease at physical examination, echostructure, degree of inflammation, or fibrosis score in liver biopsy. There were no differences in the response to HCV treatment between groups (57% vs. 45%, p = 0.69). LTNP presented a proportionally higher drop of CD4 during HCV treatment, which persisted 2 years after discontinuing treatment [-195, -10, and 30 cells/mm3 HCV-treated LTNP (n = 7), NP (n = 56), and non-HCV-treated LTNP (n = 21), respectively, p < 0.05]. There were no differences in any variables analyzed when coinfected and monoinfected LTNP were compared. LTNP do not seem to have a better outcome or response to HCV treatment than NP. HCV-treated LTNP could have a worse HIV progression than HIV-HCV-treated NP or untreated coinfected LTNP. HCV infection does not have a deleterious effect on the progression of LTNP.

Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine.

OBJECTIVE: To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir. DESIGN AND METHODS: NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements. RESULTS: Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed. CONCLUSIONS: Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection.

Therapeutic immunization with autologous monocyte-derived dendritic cells (DCs) loaded with heat-inactivated autologous human immunodeficiency virus type 1 (HIV-1) in 12 patients with chronic HIV-1 infection who were receiving highly active antiretroviral therapy (HAART) was feasible, safe, and well tolerated. Virus was obtained during an initial interruption of HAART (hereafter, "stop 1") so that DCs could be pulsed. After immunization and a second interruption of HAART (hereafter, "stop 2"), set-point plasma viral load (PVL; 24 weeks after stop 2) decreased > or =0.5 log(10) copies/mL relative to baseline PVL in 4 of 12 patients. We observed a significant lengthening in mean doubling time of PVL rebound and significant decreases in the area under the curve and the mean peak of PVL rebound after stop 2, compared with those after stop 1. This response was associated with changes in HIV-1-specific CD4(+) lymphoproliferative and CD8(+) T cell responses. These changes were not observed in a group of nonimmunized control patients.

Immunoarchitecture of lymphoid tissue in HIV-infection during antiretroviral therapy correlates with viral persistence.

Plasma viral load and T-cell subset determinations in blood are the markers used for monitoring HIV-1 infection. However, key pathogenesis events, viral replication and most immunologic changes occur in the lymphoid tissues. We have studied the tonsillar biopsies of 30 patients in the early stages of the disease, before initiating treatment and after 12 and 36 months of fully effective highly active antiretroviral therapy. We have investigated the HIV RNA by polymerase chain reaction (lymphoid tissue viral load), the immunohistochemical HIV-p24 antigen expression, as well as the lymphoid tissue architecture and lymphoid cell subsets using morphometry. The lymphoid tissue viral load and the immunoexpression of p24, which was found to be mainly associated with follicular dendritic cells, decreased significantly after treatment, but did not disappear in all cases, even after 36 months of treatment. A significant improvement of the lymphoid tissue architecture was also observed after treatment, with recovery of follicular structures. These histological changes correlated with the lymphoid tissue viral load. Moreover, the counts of CD4+ increased whereas CD8+ and cytotoxic lymphocytes (CD8+ granzyme B+) decreased significantly, the latter in both interfollicular and intrafollicular areas. However, these cellular counts after treatment did not reach those of lymphoid tissue of non-HIV-infected patients used as control cases. Naive (CD45RA+) and memory (CD45RO+) cells also improved significantly after treatment. In conclusion, in HIV-infection the impact of treatment can only be assessed completely in the lymphoid tissue reservoir, where most of the virus is stored and associated with follicular dendritic cells. Highly active antiretroviral therapy produces a significant recovery of lymphoid tissue architecture and lymphoid cell subsets, which are associated with the decrease of lymphoid tissue viral load. However, these parameters studied in lymphoid tissue are not re-established completely, even after 36 months of highly active antiretroviral therapy.

Long-term clinical follow-up, without antiretroviral therapy, of patients with chronic HIV-1 infection with good virological response to structured treatment interruption.

The present study assessed the long-term clinical follow-up of 26 of 60 human immunodeficiency virus (HIV)-positive patients who followed structured treatment interruption (STI) protocols and who, because of good virological response, did not resume receipt of highly active antiretroviral therapy (HAART). The plasma viral load (pVL) noted after > or =2 years without antiretroviral therapy remained significantly lower than the pVL noted before initiation of HAART, for 11 of the 26 patients (i.e., for 18% of the 60 patients who had STI performed). The CD4+ T cell count remained stable throughout the study. A low pVL at the end of follow-up was independently associated with a low CD8+CD38+ T lymphocyte count and a high stimulation index to p24 antigen after STI. In conclusion, approximately 2 years after STI, only a low proportion of patients who had a good immunological profile at the end of the STI period still had a good virological response.

Nevirapine-containing regimens in HIV-infected naive patients with CD4 cell counts of 200 cells/microl or less.

We retrospectively evaluated the effectiveness of nevirapine-containing regimens in 118 naive patients initiating highly active antiretroviral therapy with CD4 cell counts S 200 cells/jl. After 24 months, 51% of patients continued nevirapine, 43 and 83% had viral loads < 50 copies/ml by intent-to-treat and on-treatment analyses, and a mean increase of +246 CD4 cells/microl occurred. More than 80% of patients who continued with nevirapine had viral loads < 50 copies/ml and CD4 cell counts > 200 cells/pl.

Relevance of HIV-1-specific CD4+ helper T-cell responses during structured treatment interruptions in patients with CD4+ T-cell nadir above 400/mm3.

OBJECTIVES: To analyze the dynamics of both HIV-1-specific CD4 and CD8 T-cell responses during structured treatment interruptions (STIs) in chronically HIV-1-infected (CHI) patients and to correlate them with the viral set point achieved. METHODS: Forty-five early-stage CHI patients who were on highly active antiretroviral therapy (HAART) for at least 1 year and underwent STI were included. Plasma viral load (VL), peripheral blood mononuclear cell (PBMC) lymphoproliferative (LPR) response to HIV p24 protein, and HIV-1 epitope-specific interferon-gammarelease from CD8 T cells were measured over a minimum study period of 2 years. RESULTS: VL set point during final STI was both significantly lower than, and positively correlated to, baseline VL (P < 0.0001: mean VL reduction 0.77 log10, and r = 0.42, P = 0.004, respectively). CD4 LPRs to p24 increased significantly (P = 0.001) between day 0 of the first STI cycle and 4th STI but decreased thereafter. VL set point during final STI was significantly and negatively correlated with LPRs to p24 at both 2nd STI and 4th STI. Nevertheless, at week 52, 12 weeks after the end of the last STI, LPRs were weak and transient in all patients and were not correlated with VL set point. Moreover, the magnitude and breadth of HIV-1-specific CD8 T-cell responses increased significantly (P < 0.0001) between day 0 and week 52. The largest increases occurred during the final STI. Even though VL reached set point by week 12 of the final STI, HIV-1-specific CD8 T-cell responses did not stabilize but rather increased until the end of the follow-up and did not correlate with plasma VL (r = 0.01, P = 0.88). CONCLUSIONS: STIs do not lead to control of viral replication in CHI patients, probably due to the fact that boosted CTL responses lack strong and durable helper T-cell responses. To reset the VL set point, new approaches that effectively augment and preserve helper T-cell responses should be investigated.

Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study.

The main goal of this study was to assess the role of mycophenolate mofetil (MMF) during interruption of highly active antiretroviral therapy (HAART). Seventeen patients with early-stage chronic HIV type 1 infection were treated with HAART for 12 months. They were then randomized (day 0) to receive MMF (HAART-MMF group, n = 9) or to continue the regimen (HAART group, n = 6) for 120 additional days. At day 120 in the HAART-MMF group, HAART was discontinued, and MMF administration was continued. The primary end point of the study was the number of individuals maintaining a plasma viral load (VL) set point of <200 copies/mL after at least 6 months off HAART. At day 120, all patients in both groups had undetectable plasma VLs. After 6 months off HAART, 5 of 9 patients in the HAART-MMF group versus 1 of 6 patients in the HAART group maintained a plasma VL of <200 copies/mL (P = 0.28). According to the ability of their plasma to inhibit cellular proliferation, patients were reclassified and divided into an inhibition group (n = 6) and a no inhibition group (n = 9). The doubling time of VL rebound was significantly higher in the inhibition group (mean +/- SE, 10.22 +/- 1.3) than in the no inhibition group (mean +/- SE, 4.6 +/- 1.6; P = 0.03). Moreover, 5 of 6 patients in the inhibition group maintained a plasma VL of <200 copies/mL versus 1 of 9 patients in the no inhibition group (P = 0.005) after 6 months off HAART. We found that combining MMF and HAART delayed VL rebound and improved control of viral replication without HAART but only when inhibition of lymphocyte proliferation was achieved.