Interruption Of Highly Active Antiretroviral Therapy Research Articles

Pathophysiology of Adipose Tissue Macrophages indicating a potential reservoir site for HIV infection that might be troublesome to eradicate HIV-1

Human Immunodeficiency Virus Type 1 (HIV-1) is a condition that affects over 60 million people worldwide. Viral infection can be controlled using highly active antiretroviral therapy (HAART) to suppress HIV-1 replication and hinder disease progression, but viremia quickly rebounds following HAART interruption. It is highly likely that the persistence of virus occurs predominantly in latently infected CD4+ T cells, a new strategy to eradicate HIV-1. Previously it has been shown that the viral reservoir is seeded rapidly following the initial infection of rhesus macaques with SIV, even before the establishment of a systemic infection, so destroying this reservoir may be vital to the effective clearance of HIV. We reasoned that long-lived tissue macrophages contribute significantly to the SIV/HIV reservoir, such as those that may be found in adipose tissue. Mediscope 2024;11(2): 68-72

HIV reservoir dynamics in the face of highly active antiretroviral therapy.

Upon discontinuation of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-infected individuals experience a brisk rebound in blood plasma viremia due to the exodus of HIV from various body reservoirs. Assessment of HIV dynamics during HAART and following treatment discontinuation is essential to better understand HIV persistence. Here we will first provide a brief overview of the molecular mechanisms involved in HIV reservoir formation and persistence. After a summary of HAART-mediated HIV decay within peripheral blood, we discuss findings from clinical studies examining the effects of HAART initiation and interruption on HIV reservoir dynamics in major anatomical compartments, including lymph nodes and spleen, gut associated lymphoid tissue, reproductive organs, the central nervous system, and the lungs. Features contributing to these reservoirs as distinct compartments, including anatomical features, the presence of drug transporters, and the effect of co-infection, are also discussed.

Orogastric administration of crushed darunavir tablets for a critically ill patient.

When HIV-positive patients are critically ill and unable to take medications orally, administration of highly active antiretroviral therapy (HAART) becomes challenging. The foremost issue is the lack of parenteral formulations and oral suspensions. Only limited clinical evidence directly addresses the conversion of antiretroviral drugs from the oral to the enteral route. Interruption of HAART is not an acceptable alternative, as this results in HIV viral rebound, immunodeficiency, opportunistic infections, and development of resistance to antiretroviral treatment. Altering the route of administration may affect the plasma concentration of antiretrovirals, which also affects clinical outcomes. For example, as described in one case report, a 28-year-old HIV-positive man with diffuse large B cell–type lymphoma of the duodenum was taking the liquid or powder formulations of lopinavir–ritonavir, abacavir, and lamivudine (at standard adult doses) by oral ingestion, with suppression of the viral load to less than 400 copies/mL. Development of a duodenal obstruction necessitated insertion of a percutaneous jejunal feeding tube (located ≥ 35 cm distal to the ligament of Treitz). HAART was reinitiated via the jejunostomy, leading to HIV viral rebound (to 11 000 copies/mL), undetectable serum concentration of lopinavir, and development of resistance to lamivudine (M184V mutation). Gastric bypass surgery was performed to connect the gastric corpus to the jejunum (20 cm distal from the ligament of Treitz). HAART, including lopinavir–ritonavir (oral liquid), abacavir, and tenofovir, was restarted, and measurement of serum lopinavir concentration 18 weeks later demonstrated adequate absorption of the medication, with HIV viral suppression (to 52 copies/mL). Darunavir is an HIV-1 protease inhibitor recommended for combination HAART regimens for both treatment-naive and treatment-experienced patients. This antiretroviral agent must be administered with ritonavir and food to enhance its pharmacokinetic profile and to ensure adequate antiretroviral activity. The absolute bioavailability of darunavir without ritonavir is only 37%; however, when darunavir is adminstered concurrently with ritonavir, systemic exposure to darunavir increases 14-fold. Limited data suggest adequate absorption of crushed darunavir tablets, both when swallowed and when administered via various enteral tubes. This report describes a case in which crushed darunavir tablets were administered to a critically ill patient through an orogastric feeding tube.

Short Communication: Human Immunodeficiency Virus Rebound in Blood and Seminal Plasma Following Discontinuation of Antiretroviral Therapy

Although there is discordance between human immunodeficiency virus (HIV) blood plasma and seminal plasma viral loads (VL), little is known about the dynamics of VL rebound in these compartments upon discontinuation of highly active antiretroviral therapy (HAART). Therefore, we sought to examine the relationship between blood and semen VL rebound after discontinuation of HAART. Participants in this substudy were men enrolled from two centers of a multicenter, placebo-controlled randomized trial of HIV therapeutic vaccination using ALVAC with or without Remune. With at least 2 years of sustained virologic suppression and following a 20-week vaccination course, subjects underwent structured HAART interruption. Fourteen men provided semen samples. Seven to 12 weeks after HAART interruption, all 14 men had detectable blood VLs whereas 8 of 14 had detectable seminal VLs. There was a significant correlation between blood and seminal VLs (Spearman r=0.58, p=0.03) at the time of semen collection. An earlier time to detectable blood VL after HAART interruption was associated with higher seminal VL (Spearman r=-0.64, p=0.02). These findings support the compartmentalization of HIV and underscore the importance of understanding the genital tract as an HIV reservoir in the quest to minimize HIV transmission.

Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia, so life-long treatment is required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4(+) T cells survived despite viral cytopathic effects, even in the presence of autologous cytolytic T lymphocytes (CTLs) from most patients on HAART. Antigen-specific stimulation of patient CTLs led to efficient killing of infected cells. These results demonstrate that stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials.

Molecular Understanding of HIV-1 Latency

The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs.

Can immunotherapy be useful for a « functional cure » of HIV infection?

Highly active antiretroviral therapy (HAART) alone cannot eliminate HIV from the body and even in patients with undetectable viral load, full recovery of the system is not being obtained, with signs of inappropriate immune activation and immuno-senescence. Therapeutic strategies, complementary to HAART, aim at a cure i.e. control HIV in such a way that it no longer produces harm to the system. Anti-latency drugs, anti-inflammatory agents and/or measures to prevent or eliminate concomitant infections may contribute to a functional cure. Immunotherapy represents another possible strategy, which should reverse deficient T cell generation, aberrant differentiation, exhaustion and ineffective HlV-specific T cell responses. Four major pathways are being attempted: 1. Administration of so called common γ-chain cytokines, including inter-leukin (IL)-2, IL-7, IL-15 or IL-21, which are crucial in T cell generation, differentiation and function. Only IL-2 has been formally evaluated in a phase 3 trial: although it increased CD4 T counts, it failed to improve clinical outcome. 2. Blockade of negative regulator receptor-ligand interaction, including CTLA-4, PD-1, TIM-3 has been shown to improve HlV-specific T cell function in vitro, but seemingly discrepant results have been obtained in the SIV macaque model. PD-1 blockade lowered viral load and improved survival, whereas CTLA-4 blockade increased viral load, probably because of activation. 3. Therapeutic immunization with HIV antigens. Older trials with de-enveloped HIV particles (Remune®) failed to improve clinical outcome in HIV-infected subjects. More recent trials, using ALVAC®, a canarypox vaccine, containing HIV antigens-encoding genes, mitigated viral load rebound after HAART interruption in several trials, but had no effect or even increased rebound in other trials, the latter result being probably linked to inappropriate activation. 4. The most recent tendency is to target dendritic cells with either inactivated autologous virus or virus antigen-encoding RNA. Safety and immunogenicity of this strategy has been well established, but clinical results are equivocal as yet. In any case, this approach is amendable to further refinement, with regard to inclusion of RNA encoded patient-adapted viral sequences and co-stimulatory molecules, as well as improved targeting. In conclusion, several HIV immunotherapy strategies are being attempted, with varying success. The basic challenge remains to find a (combined) strategy, successfully activating effective HlV-specific T cell responses, while reducing inappropriate HIV-promoting activation.

Longitudinal evaluation of occult Hepatitis B infection in HIV-1 infected individuals during highly active antiretroviral treatment interruption and after HAART resumption

The prevalence and clinical significance of overt hepatitis B (OHB) in human immunodeficiency virus (HIV)-infected individuals and the effect of HAART on this cryptic infection remain controversial. We have investigated the potential effect of the interruption and subsequent re-introduction of highly active antiretroviral therapy (HAART) on the frequency and dynamics of OHB in HIV-infected individuals. This pilot study involved 29 HIV-infected individuals who tested positive for HB anti-core antibodies in the absence of surface antigen during a 100-week period (48-week-long interruption of HAART or lamivudine monotherapy plus 52 weeks of follow-up prior to HAART resumption). The frequency and dynamics of OHB were assessed by means of qualitative detection tests and quantification in the plasma. Resistance to HBV was determined by direct sequence analysis of the polymerase gene. Of the 29 HIV-infected individuals enrolled in the study, nine (31%) showed signs of OHB during the 100-week study period: three patients showed intermittent HB virus (HBV)-DNAemia, while six patients were HBV-DNA positive only at 16 weeks following HAART resumption. The HBV-DNA load invariably fell below the sensitivity of the quantitative test (10(3 )copies/mL). The HIV-related immuno-virologic profile and biochemical parameters, including hepatic transaminases, of patients with at least one HBV-DNA positive test result were not significant different from those of individuals who consistently tested negative for HBV-DNA. The only significant parameter was a lower median change (Δ1) in the CD4+/CD8+ ratio (p = 0.038) in occult HBV cases compared to non-occult cases, between the HAART re-introduction time point and baseline. The intermittent nature of HBV-DNAemia poses a diagnostic challenge, but no association was found with transaminase levels at any time.

The Gut Mucosal Viral Reservoir in HIV-Infected Patients Is Not the Major Source of Rebound Plasma Viremia following Interruption of Highly Active Antiretroviral Therapy

Interruption of suppressive highly active antiretroviral therapy (HAART) in HIV-infected patients leads to increased HIV replication and viral rebound in peripheral blood. Effects of therapy interruption on gut-associated lymphoid tissue (GALT) have not been well investigated. We evaluated longitudinal changes in viral replication and emergence of viral variants in the context of T cell homeostasis and gene expression in GALT of three HIV-positive patients who initiated HAART during primary HIV infection but opted to interrupt therapy thereafter. Longitudinal viral sequence analysis revealed that a stable proviral reservoir was established in GALT during primary HIV infection that persisted through early HAART and post-therapy interruption. Proviral variants in GALT and peripheral blood mononuclear cells (PBMCs) displayed low levels of genomic diversity at all times. A rapid increase in viral loads with a modest decline of CD4(+) T cells in peripheral blood was observed, while gut mucosal CD4(+) T cell loss was severe following HAART interruption. This was accompanied by increased mucosal gene expression regulating interferon (IFN)-mediated antiviral responses and immune activation, a profile similar to those found in HAART-naive HIV-infected patients. Sequence analysis of rebound virus suggested that GALT was not the major contributor to the postinterruption plasma viremia nor were GALT HIV reservoirs rapidly replaced by HIV rebound variants. Our data suggest an early establishment and persistence of viral reservoirs in GALT with minimal diversity. Early detection of and therapy for HIV infection may be beneficial in controlling viral evolution and limiting establishment of diverse viral reservoirs in the mucosal compartment.

Beta-2 microglobulin as an immunological marker to assess the progression of human immunodeficiency virus infected patients on highly active antiretroviral therapy

BackgroundAcquired immune deficiency syndrome (AIDS) defines the end stage of Human immunodeficiency viral (HIV) infection before the introduction of highly active antiretroviral therapy (HAART). This study was carried out to assess the serum β-2 microglobulin (B2M) as a marker for progression of HIV infected patients undergoing HAART. MethodsBlood samples were collected from 50 subjects of HIV infected patients residing at semi urban area undergoing treatment at Chellam Hospital, Salem, India. Twenty five age-matched healthy subjects were taken as control group. Serum B2M level was measured by using enzyme immunoassay, absolute CD4 and CD8 counts were carried out by single platform (SP) technology using a flow cytometer. Viral RNA was measured by real time PCR. The serum LDH level and total WBC count were also measured. ResultsOur result showed a statistically high significant increase in B2M in HIV patients on HAART non complaint group whereas absolute CD4, CD8 count, CD4/CD8 ratio and WBC count were decreased significantly when compared to control and HAART complaint group. Statistically a significant negative correlation was observed between B2M and absolute CD4, CD8 count, CD4/CD8 ratio and WBC count. B2M showed a significantly positive correlation with viral RNA and LDH values. ConclusionsThe increase of B2M and reduced absolute CD4, CD8 count, CD4/CD8 ratio and WBC count in HIV patients on HAART non complaint group may have a contributory role in the immune progression of HIV with interruption of HAART. B2M plays an important role in the diagnosis of HIV and might indicate HIV progression.

Effects of highly active antiretroviral therapy on vaccine‐induced humoral immunity in HIV‐infected adults

The acquisition of adequate vaccine-induced humoral immunity is especially important in HIV-infected individuals, who are at increased risk of infections. The aim of the study was to assess the safety of administering a complete vaccination programme to successfully treated HIV-infected adults and to evaluate specific humoral responses and the effect of highly active antiretroviral therapy (HAART) interruption on these responses. A placebo-controlled, double-blind clinical trial was designed and 26 HIV-infected adults enrolled. Study participants were randomized to receive either a complete immunization schedule with commercial vaccines or placebo for 12 months. HAART was then discontinued for 6 months. Specific humoral responses were evaluated at baseline, at month 12 and after HAART interruption and compared between groups. There were neither local nor systemic secondary effects related to vaccination. Specific humoral responses to vaccines were adequate, but a loss of immunoglobulin G titres was observed after HAART interruption in 12 study participants. HAART interruption may cause impairment of previously acquired vaccine-induced immunity in HIV-infected adults.

Influence of repeated cycles of structured therapy interruption on the rate of recovery of CD4+ T cells after highly active antiretroviral therapy resumption

CD4+ T cell recovery dynamics were analysed during the 'on treatment' periods in structured therapy interruption (STI) as well as the long-term immune reconstitution with highly active antiretroviral therapy (HAART) after finishing STI. One hundred and twenty HIV-1-infected patients on successful HAART were randomized to receive for 2 years continuous HAART (n=37) or two different strategies of STI (n=83). After this period, most patients received continuous HAART for 2 years. During the STI period, the rate of recovery of CD4+ T cells decreased progressively from the first to the last resumption of HAART {median change of increase: +232 [interquartile range (IQR): +126, +318], +116 (IQR: +10, +471), +87 (IQR: -54, +252) and -26 (IQR: -352, +211) cells/mm3 after the first, second, third and fourth resumption, respectively}. After the STI period and 2 years of continuous HAART, the median CD4+ count remained significantly lower than at baseline in STI arms, both in the virological arm [559 (IQR: 383, 727) versus 771 (IQR: 625, 913) cells/mm3, P<0.0001] and the immunological arm [619 (IQR: 501, 789) versus 787 (IQR: 657, 954) cells/mm3, P<0.0001], but not in the control arm [886 (IQR: 564, 1122) versus 780 (IQR: 539, 945) cells/mm3, P=0.68]. In a multivariate analysis, the nadir of CD4+ T cells and the baseline value of CD4+ before the STI period independently predicted the level of CD4+ T cells 2 years after resumption of HAART (in both cases, P<0.0001). The drop in CD4+ cell count after a first and a second period of 3 months of interruption of HAART was completely recovered after resuming HAART; conversely, interruptions longer than 6 months were deleterious for the recovery of CD4+. CD4+ cell count did not rebound completely in patients who received 2 years of HAART after 2 years of STIs.

NK-Associated Regulatory Receptors in a Structured HAART Interruption of HIV-1-Positive Individuals

Since highly active antiretroviral therapy (HAART) was introduced a decade ago, it has been shown to be effective in keeping HIV-1 replication under control. Nevertheless, it is also known that HAART has certain limitations, such as its inability to completely inhibit the viral replication that maintains virus reservoirs, its high toxicity when the treatment is maintained for long periods of time, and the appearance of viral resistance to the therapy. These limitations have led to the introduction of structured treatment interruption (STI) of antiretroviral therapy, the principle of which is to reduce the clinical complications of HAART, and hypothetically to boost the cellular immune response of the patient host. The aim of this study was to analyze for the first time the impact of STI on the innate immune system. Specifically, we analyzed NK cells and their regulatory receptors (KIRs, NKG2, NCRs, and ILTs) and the cytokines that might control the NK response. Six months after the initiation of STI, the results revealed in most patients a significant increase in NK cells expressing ILT2 and NKp46 receptors. Slight or no changes were observed in other parameters studied, either during interruption or when HAART was reintroduced. Our data show that the STI strategy, irrespective of whether it improved the patients' clinical evolution, induced functional phenotype changes in NK cell subsets.

Active Tuberculosis Does Not Always Imply the Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients

Infection with HIV is an important risk factor for tuberculosis (TB). One-half million cases of TB attributable to HIV infection occur worldwide each year. Since the advent of highly active antiretroviral therapy (HAART) the morbidity and mortality of HIV-infected patients have declined. However concomitant TB treatment and HAART are hampered by a high pill burden complex drug interactions treatment-related adverse events and paradoxic reactions. Studies that have assessed the effect of HAART in the course of TB and HIV coinfection are few. All these retrospective studies suggest that coinfected patients with a CD4 count less than 100 cells/mm/3 would probably benefit from early initiation of HAART. Unlike other HIV-associated opportunistic infections TB may occur at high CD4 cell counts. The indication for HAART in these particular cases has not been assessed and current antiretroviral (ARV) treatment guidelines are based on expert opinion. We evaluated retrospectively 93 episodes of TB diagnosed in 87 HIV-infected patients from January 2000 to February 2004 at Bichat Hospital in an attempt to assess the clinical aspects and outcome of TB according to the level of immunosuppression at TB diagnosis and to the prescription of HAART in the course of TB treatment. (excerpt)

Association between HIV replication and cholesterol in peripheral blood mononuclear cells in HIV-infected patients interrupting HAART

Cellular cholesterol is essential for HIV replication and may control HIV spread. HIV, in turn, appears to control cholesterol metabolism. To describe the relationships between serum lipids, cellular cholesterol and viral replication during highly active antiretroviral therapy (HAART) interruption. We have correlated virological parameters with the level of circulating lipids in serum and the content of cellular cholesterol in peripheral blood mononuclear cells (PBMCs). The study included 33 patients interrupting HAART with (n = 23) or without (n = 10) atorvastatin treatment. Atorvastatin treatment did not modify PBMC cholesterol levels at week 4 after HAART interruption, although it significantly reduced serum cholesterol (total and LDL, where LDL stands for low density lipoprotein) (P < 0.05). Serum cholesterol or LDL marginally influenced PBMC cholesterol since no significant correlations were found between these parameters either at 0 or 4 weeks after HAART interruption. Analysis of virological data in all patients revealed a negative trend (P = 0.07) between baseline PBMC cholesterol and absolute CD4 T cell counts at baseline but a poor correlation (P = 0.18) with the viral load (VL) at week 4. Separate analysis of control patients showed a correlation between baseline PBMC cholesterol and VL at week 4 (P = 0.01). However, atorvastatin treatment abrogated this correlation by increasing viral replication in individuals with low cellular cholesterol. Our data underscore the potential relevance of PBMC cholesterol in in vivo HIV replication and the complex effects of atorvastatin that seem to be unrelated to PBMC cholesterol.

Comparison of first antiretroviral treatment duration and outcome in HIV, HIV–HBV and HIV–HCV infection

Hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection may differentially influence HIV treatment duration and outcome. This was assessed at The Ottawa Hospital Immunodeficiency Clinic in first-time highly active antiretroviral therapy (HAART) recipients visited between January 2000 and December 2004. Of 968 patients, 526/700 (75%) HIV, 173/230 (75%) HIV-HCV and 30/38 (79%) HIV-HBV-infected patients initiated HAART. Co-infected patients stopped treatment sooner (HBV - 10 months, HCV - 9 months) than HIV mono-infected (17 months) (P<0.001). Injection drug history predicted shorter treatment duration (odds ratio [OR]1.59, P<0.001). Use of non-nucleoside-reverse-transcriptase-inhibitor-containing HAART (OR 0.76, P<0.01) and low-dose ritonavir (<400 mg twice daily)-based HAART (OR 0.83, P = 0.06) predicted longer treatment duration. HCV co-infection did not predict duration of therapy (OR 1.19, P=0.19) once controlled for by these three variables. Poor adherence was a major explanation for eventual treatment interruption in those with HIV-HCV (22% versus 5% in HIV alone; P<0.001) as was substance abuse (7% versus < 1% in HIV; P<0.001). Metabolic complications resulted in HAART interruption in HIV mono-infection (8%) but not with HBV or HCV co-infection (both <1%; P<0.001). Antiretroviral selection is critical to the longevity of initially prescribed regimens, irrespective of viral hepatitis co-infection. Attention to this and strategies targeting substance abuse and adherence in HIV-HCV are predicted to increase the duration of HAART.

Ferritin levels during structured treatment interruption of highly active antiretroviral therapy

The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART. Ferritin levels were retrospectively determined in stored plasma from 138 HAART-naïve, moderately immunosuppressed HIV-infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time-points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption. At baseline, 31% and 16% of the HIV-infected patients included in the study had high (>200 ng/mL) and low (<30 ng/mL) ferritin levels, respectively. Ninety-five per cent of patients with low ferritin levels were female. Ferritin decreased significantly during the interruption phase of HAART (-8.8 ng/mL; P=0.0005) but remained elevated in 62% of the patients with high baseline levels. A low baseline ferritin level was associated with a shorter time (P=0.041) to reach the CD4 cell target for HAART interruption (350 cells/microL), compared with a normal or high baseline ferritin level. Moreover, in a multivariate model, the relative risk (RR) of arriving at this CD4 cell target was significantly higher [RR 1.81; 95% confidence interval (CI) 1.05-3.14] in patients with low baseline ferritin. It is unlikely that inflammation affected ferritin in our patients, as mean levels of C-reactive protein were not elevated in patients with either high or low ferritin levels. Both high and low ferritin levels were highly prevalent in moderately immunosuppressed HIV-positive Thai patients. Structured treatment interruption of HAART resulted in a significant decrease in overall ferritin levels. Furthermore, subjects with low baseline ferritin levels had a faster and greater CD4 response to HAART, suggesting a potential beneficial effect of iron deficiency on immunological recovery after initiation of HAART.

Effects of Active Treatment Discontinuation in Patients With a CD4+ T-Cell Nadir Greater Than 350 Cells/mm3

To evaluate the safety and efficacy of discontinuing highly active antiretroviral therapy (HAART) in HIV-1-positive patients who initiated HAART at a CD4+ T-cell count >350 cells/mm. Eligible patients were identified from the Dutch AIDS Therapy Evaluation, The Netherlands (ATHENA) national observational cohort. Interruption or continuation of HAART was offered to all. Of 71 patients enrolled, 46 (64%) interrupted HAART (STOP group) and 25 (36%) continued HAART (control group). The median CD4+ T-cell nadirs at the start of HAART were 469 (interquartile range [IQR]: 430-720) cells/mm3 and 510 (IQR: 440-637) cells/mm3, respectively. At week 48, the median plasma HIV RNA level in the STOP group had stabilized at approximately pre-HAART values (4.55 log10, IQR: 4.2-4.9 copies/mL), but the CD4+ T-cell count still exceeded the pre-HAART count (563 cells/mm3, IQR: 450-710 cells/mm3). Only 5 patients (11%) had reinitiated HAART after 48 weeks, all for personal reasons. No Centers for Disease Control and Prevention category events or death occurred after interruption. In 6 (13%) of 46 patients, mild symptoms of acute retroviral rebound syndrome (ARVS) were identified. No improvement was observed in mental or physical health scores. In 37% of patients, nonnucleoside reverse transcriptase inhibitor drug concentrations were still detectable 1 week after stopping. Although HAART can safely be interrupted in patients with a high CD4 T-cell nadir, no improvement in quality of life was established. Patients can experience ARVS, the risk for development of resistance after treatment interruption is realistic, and there is a potential hazard of HIV transmission to sexual partners. We would not actively advise stopping treatment in patients who started treatment too early according to current guidelines.

First case of successful allogeneic stem cell transplantation in an HIV-patient who acquired severe Aplastic Anemia

We report on the first successful allogeneic stem cell transplantation (SCT) in an HIV-infected patient with severe aplastic anemia (SAA) per- formed at a tertiary care institution. Highly active antiretroviral therapy (HAART) was administered until transplantation and restarted 34 days later with sustained virological response. The patient did however develop a rapid rise in HIV load during the interruption of HAART associated with an acute febrile illness. Due to the extended period between the onset of SAA until SCT, the posttransplant course was complicated by bacterial infections. Stage two skin GvHD, but no AIDS-defining opportunistic diseases were experienced. Neutrophils recovered to >0.5/nL on day +18 and the CD4 count reached 250/microL on day +71 and >500/microL on day +182. The patient is in good condition with an ECOG score of 0 twelve months after transplantation. This report demonstrates the feasibility of allogeneic stem cell transplantation in the HIV setting.

HIV-associated dementia

The World Health Organization estimates that worldwide there are 40.3 million people infected with HIV (www.who.int/hiv/epi-update2005_en.pdf). Of these, only 2 million live in developed countries and have access to the cocktail of antiretroviral drugs referred to as highly active antiretroviral therapy (HAART). HIV-associated dementia (HAD) along with its less severe forms of minor and asymptomatic neurocognitive impairment is a major complication of HIV disease. Its occurrence in the developing world is the subject of an interesting article by Wong et al.1 in this issue of Neurology . HAD is primarily a feature of advanced HIV disease. HAART has reduced its incidence in half; it now affects approximately 10% of patients with advanced disease. Paradoxically, in developed countries, the prevalence of HAD has increased as an unintended consequence of the very positive effects of HAART on the lifespan of HIV-infected individuals.2 That HAD even occurs in the era of HAART may be due to late commencement or to interruption of HAART or because of insufficient penetration of some HAART regimens through the blood–brain barrier3,4 or other yet-to-be-defined reasons.5 Late or intermittent use of HAART in turn is related to the lack of recognition of cognitive impairment as well as to patient/physician concerns over the potential for HAART toxicity. The recent …