Increase In CD4 Cell Count Research Articles

The role of nevirapine in the antiretroviral therapy

In the presented multicenter study an attempt was made to evaluate the role of nevirapine used in treatment of HIV-seropositive patients in both groups: naive as well as experienced. The therapeutic effect was evaluated while analysing the HIV-RNA level and the increase in CD4 cell count. The reasons for which the new schema with nevirapine was introduced in experienced patients were as well analysed. Among these reasons were mainly side effects of different character. On the basis of the obtained results very good virologic response was reported in both groups, naive and previously treated. Immunologic response in both populations discussed was similar though the initial level of CD4 was two times lower in naive patients in comparison with experienced population.

Thrombotic thrombocytopenic purpura during immune reconstitution

The emergence of newer antiretroviral agents has revolutionized the treatment of patients struggling with multidrug-resistant strains of HIV. As a result, we are witnessing a higher incidence of immune reconstitution inflammatory syndrome, most commonly associated with mycobacterial, cryptococcal, herpetic and other infections, in addition to autoimmune conditions such as photodermatitis, systemic lupus erythematosus [1], Grave's thyroiditis [2] and sarcoid [3]. The pathogenesis of immune reconstitution inflammatory syndrome is unclear, but has been proposed to be a combination of thymic-independent homeostatic peripheral expansion, immune dysregulation between effector and regulatory T cells, increased inflammatory cytokines and dysregulated dendritic cells [4,5]. We present the case of a 48-year-old African-American man, with multiple drug-resistant HIV-1 infection, who was admitted to the hospital with acquired thrombotic thrombocytopenic purpura (TTP) 4 weeks after darunavir/norvir and enfuvirtide was added to tenofovir/emtricitabine. The patient had a past medical history only significant for chronic hepatitis B, with an undetectable viral load. After 4 weeks on the new regimen, his CD4 cell count increased from 94 (10%) to 351 (16.7%) cells/μl and his viral load decreased from more than 100 000 to 151 copies/ml. He presented with a non-productive cough, frontal headache, dark urine, dyspnea on exertion, myalgias and arthralgias from a previously asymptomatic state. Laboratory work-up (baseline in parenthesis) showed a hemoglobin level of 7.4 g/dl (11.2), platelets of 22 × 103/μl (221), lactate dehydrogenase 2450, creatinine 1.8 mg/dl (1.2), and a peripheral smear showed many schistocytes. An assay (Esoterix Inc., Austin, Texas, USA) showed the von Willebrand factor (vWF) cleaving protease to be deficient (< 8%), and the presence of a disintegrin-like and metalloprotease with thrombospondin-type 1 motif-13 (ADAMTS-13) vWF cleaving protease inhibitor (1.2 inhibitor units). No other inciting event was identified after extensive work-up. All his antiretroviral drugs were discontinued except for tenofovir/emtricitabine, whereas plasmapharesis, vincristine and prednisone were initiated. He had a full and uneventful recovery one month later. Subsequently, our patient was successfully restarted on antiretroviral therapy (darunavir/norvir and tenofovir/emtricitabine) without a recurrence of TTP, while experiencing increasing CD4 cell counts and decreasing viral loads. Although TTP has been described in relation to HIV [6], to our knowledge this is the first reported case of acquired TTP in the setting of immune reconstitution. Our patient had a low absolute CD4 cell count and CD4 cell percentage at baseline, followed by a ‘fulminant’ CD4 cell count recovery and viral suppression shortly after starting his new regimen. A Medline search failed to identify any association between TTP and antiretroviral agents, i.e. T-20, darunavir and others. Although a causal mechanism cannot be established from one case, we propose two insults accounting for a major alteration of vWF homeostasis based on previous descriptions of TTP [7]. The first alteration was caused by inflammatory cytokines (IL-6, IL-8, tumour necrosis factor alpha and others) that stimulate the ultralarge, hyperreactive vWF release from endothelial cells. The second insult is immune deregulation mediated by IL-6 and other autoantibodies that inhibit (ADAMTS-13) vWF cleaving protease activity, abrogating the ability of ADAMTS-13 to cleave ultralarge vWF, leading to the accumulation of ultralarge vWF in plasma and on the surface of endothelial cells. Could these two hits combined account for the high tendency for platelet aggregation and thrombosis that patients might be at risk of during the acute phase of immune reconstitution? The second reason we believe this case to be notable is its possible implication in the increase in cardiovascular events after immune reconstitution (unpublished). We believe that further studies should investigate the role of thrombosis in the increased cardiovascular events after acute immune reconstitution.

Review: Immunologic Response to Protease Inhibitor-Based Highly Active Antiretroviral Therapy: A Review

A substantial body of evidence indicates that CD4 cell count is an important independent prognostic indicator for progression of HIV disease. Consequently, in addition to plasma HIV RNA levels, CD4 cell count change is considered to be a key surrogate marker for disease progression in clinical practice and in clinical studies. Given the relationship between changes in CD4 count and disease progression, it is notable that protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) can rapidly increase CD4 cell count early in treatment in both therapy-naïve and -experienced patients, and can sustain clinically relevant levels beyond 24 weeks. A number of trials with a follow-up of more than 3 years allow us to conclude that the gains in CD4 counts are maintained in a durable manner. This review evaluated randomized studies of PI-based and PI-boosted HAART (published between January 1996 and February 2006) to determine the effect of PI-based therapy on CD4 cell count. Only studies that assessed CD4 response in the overall patient population were included. Four mechanisms have been proposed to account for the rapid increase in CD4 cell count that occurs with HAART: CD4 cell redistribution from lymphatic tissues, increased CD4 cell production, reduction of apoptotic CD4 cells and the recovery of hematopoietic activity in bone marrow. Further research is required to clarify the relative importance of these mechanisms and ways in which they might be enhanced.

Impact of Highly Active Antiretroviral Therapy (HAART) on the Natural History of Hepatitis B Virus (HBV) and HIV Coinfection: Relationship between Prolonged Efficacy of HAART and HBV Surface and Early Antigen Seroconversion

Coinfection with hepatitis B virus (HBV) in human immunodeficiency virus (HIV)-infected patients is common. However, little is known about the natural history of chronic hepatitis B in HIV-infected populations, especially the impact of highly active antiretroviral therapy (HAART) on the outcome of HBV early antigen (HBeAg) and HBV surface antigen (HBsAg) status. The characteristics of 92 patients coinfected with HIV and HBV were retrospectively assessed before and after HAART and lamivudine treatment to determine the impact of treatment on chronic hepatitis B and factors associated with HBeAg and/or HBsAg seroconversion. During follow-up, 82 patients received antiretroviral therapy, 79 of whom received HAART. Twenty-eight of the 76 patients who were administered lamivudine therapy developed lamivudine resistance mutations. While receiving antiretroviral therapy, 10 of 59 HBeAg-positive patients developed antibody to HBeAg, 3 of 10 cleared HBsAg, and 2 of 3 developed antibody to HBsAg. Two of 23 HBeAg-negative patients cleared HBsAg and developed antibody to HBsAg. HBeAg and/or HBsAg seroconversion combined with an undetectable HBV DNA level (i.e., an HBV response) correlated with a sustained HIV response (P=.001), shorter duration of antiretroviral therapy (P=.058), and more-severe disease, as evaluated by Centers for Disease Control and Prevention staging (for stage B vs. stage A, P=.029; for stage C vs. stage A, P=.069). For patients with elevated baseline alanine aminotransferase levels, the HBV response correlated significantly with a greater increase in CD4 cell count while receiving HAART. In HIV-HBV-coinfected patients, HBV response correlated with a sustained HIV response to antiretroviral therapy, usually HAART including lamivudine.

Clinical progression of hepatitis C virus–related chronic liver disease in human immunodeficiency virus–infected patients undergoing highly active antiretroviral therapy

Little is known about the natural history of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected subjects under highly active antiretroviral therapy (HAART). The objectives of this study were to obtain information about the mortality, the incidence of hepatic decompensations, and the predictors thereof in this population. In a multicenter cohort study, the time to the first hepatic decompensation and the survival of 1,011 antiretroviral naïve, HIV/HCV-coinfected patients who started HAART and who were followed prospectively were analyzed. After a median (Q1-Q3) follow-up of 5.3 (2.9-7.1) years, 59(5.83%) patients developed a hepatic decompensation and 69 (6.82%) died, 30 (43%) of them because of liver disease. The factors independently associated [HR (95% CI)] with the occurrence of hepatic decompensations were age older than 33 years [2.11 (1.18-3.78)], female sex [2.11 (1.07-4.15)], Centers for Disease Control stage C [2.14 (1.24-3.70)], a diagnosis of cirrhosis at baseline [10.86 (6.02-19.6)], CD4 cell gain lower than 100/mm3 [4.10 (2.18-7.69)] and less than 60% of the follow-up with undetectable HIV viral load [5.23 (2.5-10.93)]. Older age [2.97 (1.18-7.50)], lack of HCV therapy [11.32 (1.44-89.05)], hepatitis D virus coinfection [16.15 (2.45-106.48)], a diagnosis of cirrhosis at recruitment [13.69 (5.55-34.48)], hepatic encephalopathy [62.5 (21.27-200)] and lower CD4 cell gain [3.63 (1.45-9.09)] were associated with mortality due to liver failure. End-stage liver disease is the primary cause of death in HIV/HCV-coinfected patients under HAART. Higher increase of CD4 cell counts, lack of markers of serious liver disease and therapy against HCV are factors associated with better hepatic outcome.

A randomized clinical trial of community-based directly observed therapy as an adherence intervention for HAART among substance users

Adherence interventions for HAART can impact challenging populations, such as active substance users. Community-based modified directly observed therapy (MDOT) is a promising approach that needs to be critically evaluated. This study was a randomized clinical trial. HIV seropositive substance users were randomized to either standard of care (SOC) or MDOT, stratified by HAART experience. All participants were placed on a once-daily regimen and were met by an outreach worker for all 7 days during the first 3 months. We used an intent-to-treat analysis to evaluate differences in viral load suppression [> 2 log drop in plasma viral load (PVL) or PVL < 50] and changes in PVL and CD4 cell count from baseline to 3 months. A total of 87 participants were enrolled (43 in SOC, 44 in MDOT), Using repeated measures logistic regression, MDOT participants were more likely to achieve PVL suppression (odds ratio, 2.16; 95% confidence interval, 1.0-4.7), driven primarily by those HAART experienced (odds ratio, 2.88; 95% confidence interval, 1.2-7.0). A significant treatment effect was also found in CD4 cell count change (P < 0.05). No differences were found by arm in undetectable PVL. This study provides evidence that MDOT is an effective strategy to reduce viral load and increase CD4 cell counts in HAART experienced substance users. MDOT should be included in the spectrum of options to enhance adherence in this population.

Lability of Antiretroviral Drug Resistance Mutations - Correlates with Immunological and Virological Responses

This study assessed the relationship between changes in CD4 T-cell count, HIV Viral Load (VL) level and evolutionary patterns in Antiretroviral (ARV) resistance mutations of circulating HIV in those with persistent viraemia despite treatment. The study examined the dynamics of change in resistance mutations to explore potential predictors of evolution in the circulating virus over a prolonged period. Four longitudinal blood samples from 29 HIV-infected Australian patients at RPAH are analysed for the presence of genotypically resistant HIV virus. The subjects had CD4 cells counts (40-670 cells/mm(3)), VL levels (1.7-5.7 log(10) copies/ml), drug resistance mutations, and had been treated with ARV regimens for varying periods between February 1998 and June 2005 (i.e., 88 months). Parametric and nonparametric tests were used to examine changes in CD4 T-cell counts and VL levels, and in frequencies of mutations at different sample points. Nonparametric LOESS fitting curves were used to analyse changes in CD4 T-cell counts and VL levels. During the study period, changes in mean values of CD4 cell counts and VL levels in patients displaying an evolving genotypic resistance profile differed from those without evidence of an evolving mutational pattern; applied for both Reverse-Transcriptase (RT) and Protease (PR) gene profiles. In patients with Evolution-of-Resistance (EoR) at the RT site, there was a significant decrease in mean CD4 cell count during the first 36 months (-194 cells/mm(3), P=0.0466) but no significant change in the last 52 months or thereafter (-10 cells/mm(3), P=0.8464). Conversely, in patients with EoR at the PR site, there was no significant change in mean CD4 cell count during the first 36 months (-30 cells/mm(3), P=0.6187) but a significant decrease (-155 cells/mm(3), P=0.0348) thereafter. In patients without EoR at the RT site, there was no significant change in mean CD4 count during the first 36 months (-12 cells/mm(3), P=0.8371), however, a significant increase in mean CD4 cell count occurred thereafter (+242 cells/mm(3), P=0.0077). Similarly, in patients without EoR at the PR site there was no significant change in mean CD4 count during the first 36 months (-19 cells/mm(3), P=0.6647) and there was a significant increase in the last 52 months (+145 cells/mm(3), P=0.0348). The only significant decrease in mean value of VL levels occurred in patients without EoR associated with NRTIs thereafter (-1.33 log(10) copies/ml, P=0.0477), while no significant changes in mean value of VL levels in patients with/without EoR associated with any ARV drugs at any other time points (-0.65 to +0.15 log(10) copies/ml, P=0.1855 to 0.7958). Low CD4 cell counts (<250 cells/mm(3)) and high VL levels (>4.50 log(10) copies/ml) in the early stage of HIV infection, a significant decrease in CD4 cell counts during the first 36 months (-50 or more cells/mm(3)), and high frequencies of mutations during the first 36 months of antiretroviral regimen (>3 mutations) emerged as potential predictive factors of EoR associated with NRTI/PRI agents thereafter. Stable VL in the first 36 months correlated with lack of lability of resistance mutations thereafter.

Comparison of the effectiveness of initial combined antiretroviral therapy with nelfinavir or efavirenz at a university-based outpatient service in Brazil

Since there are some concerns about the effectiveness of highly active antiretroviral therapy in developing countries, we compared the initial combination antiretroviral therapy with zidovudine and lamivudine plus either nelfinavir or efavirenz at a university-based outpatient service in Brazil. This was a retrospective comparative cohort study carried out in a tertiary level hospital. A total of 194 patients receiving either nelfinavir or efavirenz were identified through our electronic database search, but only 126 patients met the inclusion criteria. Patients were included if they were older than 18 years old, naive for antiretroviral therapy, and had at least 1 follow-up visit after starting the antiretroviral regimen. Fifty-one of the included patients were receiving a nelfinavir-based regimen and 75 an efavirenz-based regimen as outpatients. Antiretroviral therapy was prescribed to all patients according to current guidelines. By intention-to-treat (missing/switch = failure), after a 12-month period, 65% of the patients in the efavirenz group reached a viral load <400 copies/mL compared to 41% of the patients in the nelfinavir group (P = 0.01). The mean CD4 cell count increase after a 12-month period was also greater in the efavirenz group (195 x 10(6) cells/L) than in the nelfinavir group (119 x 10(6) cells/L; P = 0.002). The efavirenz-based regimen was superior compared to the nelfinavir-based regimen. The low response rate in the nelfinavir group might be partially explained by the difficulty of using a regimen requiring a higher patient compliance (12 vs 3 pills a day) in a developing country.

Predictors of Virological Outcome and Safety in Primary HIV Type 1-Infected Patients Initiating Quadruple Antiretroviral Therapy: QUEST GW PROB3005

Initiation of antiretroviral therapy during primary human immunodeficiency virus (HIV)-1 infection may confer long-term benefit. After initiation of zidovudine, lamivudine, abacavir, and amprenavir therapy in patients in the QUEST cohort, predictors of virological outcome, virological and immunological changes, and adverse events were evaluated over 48 weeks. One hundred forty-eight patients started antiretroviral therapy during primary HIV-1 infection with < or =3 bands on Western Blot (median plasma HIV-1 RNA load, 5.4 log copies/mL; median CD4 cell count, 517 cells/mm(3)). By week 48, 36% of patients had stopped treatment or were lost to follow-up. Among the 115 patients receiving follow-up care at week 48 (102 of whom were receiving antiretroviral therapy), the median viral load decrease was -5.4 log copies/mL (interquartile range [IQR], -6.4 to -3.9 log copies/mL), and the median increase in CD4 cell count was 147 cells/mm(3) (IQR, -1 to 283 cells/mm(3)); 84.2% of patients had a viral load < or =50 copies/mL, and 44.7% of patients had a viral load < or =3 copies/mL. The median cell-associated RNA level decreased from 3.4 log copies/million PBMCs (IQR, 2.9-4.1 log copies/million PBMCs) to 0.8 log copies/million PBMCs (IQR, 0.5-1.4 log copies/million PBMCs), and the median cell-associated DNA level decreased from 2.8 log copies/million PBMCs (IQR, 2.4-3.0 log copies/million PBMCs) to 1.6 log copies/million PBMCs (IQR, 1.2-1.9 log copies/million PBMCs); 33.3% of patients had an undetectable RNA level, and 9.5% of patients had an undetectable cell-associated DNA level. The median CD8(+)/CD38(++) T cell count decreased from 459 cells/mm(3) (IQR, 208-974 cells/mm(3)) to 33 cells/mm(3) (IQR, 19-75 cells/mm(3)). Baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were independent inverse predictors for reaching a viral load < or =3 copies/mL. Eighty-three patients experienced a serious adverse event (median duration of an adverse event, 15 days).Conclusions. Initiation of antiretroviral therapy during primary HIV-1 infection was associated with very significant antiretroviral activity and a decrease in immune activation. Lower baseline CD8(+)/CD38(++) T cell count and cell-associated DNA level were predictive of achieving a viral load < or =3 copies/mL.

Factors influencing tymic function in 55 patients with lymphomas: Candidates to autologous stem cell transplantation (ASCT)

18512 Background: Signal joint T cell receptor excision circles (sjTRECs) have been reported to be a clinical marker to evaluate the tymic reservoir after immunosuppression treatments. Methods: We studied the sjTRECs levels in a mono-institutional series of a cohort of 26 HIV-positive and 29 HIV-negative pts with relapsed or refractory lymphomas, candidates to ASCT, considering important biological and clinical characteristics, virological parameters and immunological settings including age, type of lymphoma, number of first line CT cycles, time from the end of first line chemotherapy to the enrolment (TECT), HIV infection and T subpopulations. Results: The overall study subjects, showed lower sjTRECs levels than healthy donors (p&lt;0.01), but no differences in the sjTRECs content were seen between HIV-negative and HIV-positive pts (536 vs. 401 TRECs/106 PBMCs, respectively) as well as in the T cell naive count. We found a significant correlation between the sjTRECs decay and the increase of age (r=-0.32, p=0.02), CD4 and CD8 naive cell count and the sjTRECs level; on the contrary we did not observe any significant correlation between CT cycles number TECT, lymphoma type in both subgroups. HIV-positive viremic pts showed significant lower level of sjTRECs level than averimic pts. Conclusions: Our analyses suggest that de novo T cell generation is partially maintained in lymphoma pts’ candidates to ASCT and could contribute to restore the immune function after transplantation. Chemotherapeutic treatments seem to induce a similar influence on thymic output despite their intensity and, surprisingly, HIV infection is not a detrimental factor on thymic reservoir at the time of lymphoma relapse, and a good control of HIV replication seems to preserve thymic reservoir. No significant financial relationships to disclose.

CD4 Cell Counts of 800 Cells/mm3 or Greater After 7 Years of Highly Active Antiretroviral Therapy Are Feasible in Most Patients Starting With 350 Cells/mm3 or Greater

CD4 cell count changes in therapy-naive patients were investigated during 7 years of highly active antiretroviral therapy (HAART) in an observational cohort. Three endpoints were studied: (1) time to >or=800 CD4 cells/mm in 5299 therapy-naive patients starting HAART, (2) CD4 cell count changes during 7 years of uninterrupted HAART in a subset of 544 patients, and (3) reaching a plateau in CD4 cell restoration after 5 years of HAART in 366 virologically suppressed patients. Among patients with <50, 50 to 200, 200 to 350, 350 to 500, and >or=500 CD4 cells/mm at baseline, respectively, 20%, 26%, 46%, 73%, and 87% reached >or=800 CD4 cells/mm within 7 years of starting HAART. Periods with HIV RNA levels >500 copies/mL and age >or=50 years were associated with lesser increases in CD4 cell counts between 6 months and 7 years. Having reached >or=800 CD4 cells/mm at 5 years, age >or=50 years, and >or=1 HIV RNA measurement >1000 copies/mL between 5 and 7 years were associated with a plateau in CD4 cell restoration. Restoration to CD4 cell counts >or=800 cells/mm is feasible within 7 years of HAART in most HIV-infected patients starting with >or=350 cells/mm and achieving sufficient suppression of viral replication. Particularly in patients >or=50 years of age, it may be beneficial to start earlier than current guidelines recommend.

Interruption of Antiretroviral Treatment in HIV‐Infected Patients with Preserved Immune Function Is Associated with a Low Rate of Clinical Progression: A Prospective Study by AIDS Clinical Trials Group 5170

We sought to determine the safety of treatment interruption (TI) and to identify parameters that would define patients with human immunodeficiency virus (HIV) for whom TI is safer. AIDS Clinical Trials Group 5170 was a multicenter, 96-week-long, prospective study of HIV-infected patients receiving antiretroviral therapy (ART) who had CD4(+) cell counts >350 cells/mm(3) and who underwent TI. A total of 167 patients were enrolled. The median nadir in CD4(+) cell count was 436 cells/mm(3). The initial decrease (i.e., during the first 8 weeks) in CD4(+) cell count after ART interruption was 20 cells/mm(3)/week; the subsequent decrease was 2.0 cells/mm(3)/week until week 96. Both the CD4(+) cell count before enrollment and the increase in CD4(+) cell count during ART predicted early decrease; later decrease was predicted by the level of interleukin-7 at enrollment. A Centers for Disease Control and Prevention (CDC) diagnosis of a category B or C event was made for 2 and 2 patients, respectively (all had CD4(+) cell counts >350 cells/mm(3)). At week 96, 17 patients had CD4(+) cell counts < or =250 cells/mm(3), and 46 patients had resumed ART; 5 patients died (unrelated to HIV or acquired immunodeficiency syndrome). In a multivariate analysis, a higher nadir in CD4(+) cell count (>400 cells/mm(3)), a lower HIV load (<50 copies/mL) at the time of TI, and an HIV load < or =22,000 copies/mL before ART predicted a longer time to the primary end point (CDC category B or C event, death, CD4(+) cell count < or =250 cells/mm(3), or resumption of ART). Disease progression after TI was low in this cohort. A higher nadir in CD4(+) cell count, a lower HIV load before ART, and an HIV load < or =50 copies/mL at the time of TI predicted a longer time to the primary end point.

The Virologic, Immunologic, and Clinical Effects of Interleukin 2 With Potent Antiretroviral Therapy in Patients With Moderately Advanced Human Immunodeficiency Virus Infection

Interleukin 2 (IL-2) administration increases CD4 counts in persons with higher counts. This study investigated persons with moderately advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy (HAART). Two hundred four patients with CD4 T-cell counts from 50/microL to 350/microL who were treatment naive or had been treated only with reverse transcriptase inhibitors began a specified protease inhibitor HAART regimen. Virologic responders (< or =5000 copies/mL) at 12 weeks were randomized to open-label continuous-infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2), or HAART alone. Thirty were not randomized and 15 enrolled in a substudy, leaving 159 for analysis. Subjects continued HAART alone for 72 weeks (n = 52) or with IV IL-2 (n = 53) or SC IL-2 (n = 54) for 5 days every 8 weeks. The IV IL-2 subjects could switch to SC IL-2 if their CD4 T-cell count increased by 100/microL or by 25%. Patients receiving IV or SC IL-2 had greater increases in CD4 cell counts. At week 84, median increases were 459/microL, 312/microL, and 102/microL. Increases of greater than 50% at week 60 (primary end point) were achieved in 39 patients (81%) and 32 (67%) in the IV and SC IL-2 arms, respectively, compared with 13 (29%) in the HAART arm (P<.001 for both). Treatment with IL-2 did not increase plasma human immunodeficiency virus RNA levels. There were fewer new AIDS-defining events in the IV (P = .006) and SC (P = .03) IL-2 groups than in the HAART group (0, 1, and 7, respectively). Drug-related adverse events were more frequent with IL-2 treatment. Addition of IL-2 to HAART can significantly expand CD4 T-cell counts in moderately advanced human immunodeficiency virus infection, without loss of virologic control.

Pretreatment Factors Associated With 3-Year (144-Week) Virologic and Immunologic Responses to Potent Antiretroviral Therapy

To examine pretreatment factors associated with longer term (144 weeks) responses to antiretroviral therapy (ART). Of 1498 ART-naive subjects randomized to ART regimens, including > or =3 agents, 1083 patients who had plasma HIV RNA (vRNA) levels and CD4 cell counts at baseline and week 144 were analyzed. Primary baseline factors evaluated were CD4 cell count, vRNA level, gender, race, and age, using multivariable Cox, log-binomial, and linear regression models. Shorter time to achieving a vRNA level <50 copies/mL was associated with lower baseline vRNA level (P < 0.001), older age (P = 0.007), and lower baseline CD4 cell count (P = 0.055). After adjusting for race, gender, and baseline CD4 cell count, older age was associated with a vRNA level <50 copies/mL at week 144 (P = 0.018). Greater CD4 count increases from baseline to week 144 (mean = 284 cells/microL) were seen in younger men, blacks, and subjects with higher pretreatment vRNA levels; the effect of pretreatment vRNA level was most apparent in women. Older age was the most important baseline predictor of a vRNA level <50 copies/mL at week 144; lower pretreatment vRNA level and older age were the most important predictors of time to a vRNA level <50 copies/mL. The influence of pretreatment factors on increases in CD4 cell counts differed between men and women.

CD4+ Cell Count 6 Years after Commencement of Highly Active Antiretroviral Therapy in Persons with Sustained Virologic Suppression

Sustained suppression of the human immunodeficiency virus (HIV) type 1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4(+) cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4(+) cell count in patients in clinical practice who maintained sustained viral suppression for up to 6 years. All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for >1 year while receiving HAART and who had sustained suppression of the HIV RNA load at <400 copies/mL. We analyzed annual change in the CD4(+) cell count for up to 6 years after the start of HAART, stratified by baseline CD4(+) cell counts of < or =200, 201-350, >350 cells/microL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis. A total of 655 patients were observed for a median of 46 months (range, 13-72 months). The median change from baseline to most recent CD4(+) cell count was +274 cells/microL, with 92% of patients having an increase in CD4(+) cell count. By 6 years, the median CD4(+) cell count was 493 cells/microL among patients with baseline CD4(+) cell counts < or =200 cells/microL, 508 cells/microL among those with baseline CD4(+) cell counts of 201-350 cells/microL, and 829 cells/microL among those with baseline CD4(+) cell counts >350 cells/microL. In addition to baseline CD4(+) cell count, injection drug use and older age were associated with a lesser CD4(+) cell count response, and duration of therapy was associated with a greater CD4(+) cell count response. Only patients with baseline CD4(+) cell counts >350 cells/microL returned to nearly normal CD4(+) cell counts after 6 years of follow-up. Significant increases were observed in all CD4(+) cell count strata during the first year, but there was a lower plateau CD4(+) cell count at lower baseline CD4(+) cell strata. These data suggest that waiting to start HAART at lower CD4(+) cell counts will result in the CD4(+) cell count not returning to normal levels.

CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV

BackgroundAs part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy.MethodsLymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses.ResultsHuman lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm3; CD4:CD8 ratios 1.55 vs. 0.70, respectively).ConclusionWe postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study.

Adherence in antiretroviral therapy: a review of qualitative studies

Adherence in antiretroviral therapy: a review of qualitative studies

Successful drug treatment of immune reconstitution disease with the leukotriene receptor antagonist, montelukast: a clue to pathogenesis?

Immune reconstitution disease (IRD) is a common clinical syndrome that typically presents as symptoms developing within a few weeks of starting antiretroviral therapy [1]. The pathogenesis is not fully understood, but is thought to relate to changes in the immune response directed against local antigen [2]. Even when there is no obvious specific trigger, the symptoms can be prolonged and severe [3]. Treatment is often with steroids, which carry a degree of risk in an HIV-infected population [4]. A recent report highlighted the potential value of the leukotriene receptor antagonist, montelukast, in IRD [5]. Here we describe its use in a case of urticarial vasculitis associated with antiretroviral therapy. A 59-year-old HIV-infected Caucasian man was started on a nucleoside-sparing regimen of saquinavir and lopinavir with ritonavir boosting 5 months after a voluntary break from treatment. Previously, he had been almost 100% adherent to therapy, and had attained an 800 cells/μl blood CD4 cell count increase from a nadir of 36 cells/μl. At the time of recommencing HAART his blood CD4 cell count, however, had declined to 226 cells/μl and his HIV load had risen to 34 751 viral copies/ml. He was reviewed after 3 weeks of antiretroviral treatment with a one day history of a morbilliform, urticarial rash predominantly affecting his legs, buttocks and arms (Fig. 1). His blood CD4 cell count was unchanged at 236 cells/μl, although his plasma viral load had reduced to 221 copies/ml.Fig. 1: Urticarial rash after 3 weeks of antiretroviral therapy.Blood tests indicated a raised C-reactive protein (CRP) level of 79 mg/l (normal < 5 mg/l), a white cell count of 20.1 × 109/l (normal range 3.0–10.0 × 109/l) and neutrophilia of 14.7 × 109/l (1.5–7.4 × 109/l). Serology for syphilis, rubella, measles and parvovirus B19 demonstrated no active infection. Complement and anti-C1q antibody levels were normal and an autoimmune screen was negative. Symptomatic treatment with antihistamines (cetirizine and ranitidine) was initiated. He was adherent to all of his medication but re-attended 2 weeks later with increasing malaise, worsening rash, fevers, diarrhoea and arthralgia. The serum CRP level was elevated at 199 mg/l, white cell count 17.2 × 109/l and neutrophils 13.9 × 109/l. Renal function was normal. A skin biopsy revealed a perivascular inflammatory cell infiltrate with leukocytoclasia suggestive of a vasculitic process. He continued his antiretroviral drugs and was commenced on 40 mg oral prednisolone with a presumptive diagnosis of IRD-associated urticarial vasculitis. His symptoms resolved and his inflammatory markers returned to normal. Two days after completing a total of one month's reducing steroid course, the rash and arthralgia returned associated with fever and tachycardia. Blood work again showed an acute rise in his white cell count and CRP (to 150 mg/l). He continued his antiretroviral drugs, and therapy with oral montelukast 10 mg daily was initiated. He noted an immediate improvement, and within 5 days his symptoms and signs had settled (including resolution of the increased inflammatory markers). Montelukast was discontinued after 3 months with no untoward effects. Over this time his HIV load became undetectable (< 50 viral copies/ml) and his blood CD4 cell count doubled. Although the diagnosis of IRD is currently clinical (and thus open to some overinterpretation), we believe the time course of this patient's symptoms together with the associated fall in the HIV load is consistent with IRD. He responded rapidly to treatment with steroids and subsequently with montelukast, adding to the evidence base for the use of the latter drug in the management of HIV-related IRD [5]. The pathological mechanism of IRD remains to be determined [6]. In this case of urticarial vasculitis the dramatic effect of montelukast suggests a role for excessive leukotriene activity in its development. Leukotrienes exert broad proinflammatory effects, including leukocyte recruitment to sites of inflammation and the promotion of innate immune responses via the stimulation of cytokines and chemokines [7]. They may also be deficient in advancing HIV infection [8]. We propose that montelukast, acting as a partial agonist, attenuates an over-vigorous leukotriene-driven inflammatory response due to antiretroviral therapy without causing significant immunosuppression itself. Although one cannot yet predict who will respond to drug therapy, or the duration of treatment required, we believe that montelukast may be useful in the treatment of IRD and warrants further study.

HIV and liver disease forum: Conference proceedings

Liver disease has emerged as one of the major causes of morbidity and mortality among patients infected with the human immunodeficiency virus (HIV), particularly in regions where highly active antiretroviral therapy (ART) is widely available. This dramatic change in disease epidemiology is attributable to a complex interaction between etiologic factors that appear to increase the rate of hepatic fibrosis and accelerate progression to end-stage liver disease. Key factors include ART related hepatoxicity, frequent coinfection with hepatitis B and C, and possibly the direct interaction of HIV virus or soluble protein viral products that interact with hepatocytes and other liver resident cell types. Additionally, there is some evidence that gut permeability is altered during active HIV replication, which affects the complex mix of toxins and growth factors present in the portal circulation. It is critical that hepatologists maintain a strong knowledge base to provide the best possible guidance to HIV-infected patients and their healthcare providers. To this end, the second international forum on HIV and Liver Disease was convened in Jackson Hole, WY in September 2008. The first forum, held two years earlier was previously summarized in Hepatology, and has been widely cited by experts in the field.1 However, the fast moving nature of this critical health issue led to development of a second meeting, supported by grants from three institutes of the National Institutes of Health (NIAID, NIDDK, NIAAA) and by unrestricted grants provided by the pharmaceutical industry. As before, the meeting sought to bring together basic and clinical researchers representing multiple disciplines including hepatology, infectious diseases, epidemiology, virology, and drug development as well as governmental experts in health policy, research and research funding. This document provides a summary of key presentations and highlights the current state of knowledge and future directions this field will take.

Disclosure of HIV Status and Sexual Orientation Independently Predicts Increased Absolute CD4 Cell Counts Over Time for Psychiatric Patients

The objective of this study was to replicate the relationship between disclosure of sexual orientation and immune functioning in HIV-positive persons and to extend those findings to a different type of disclosure (HIV status) and a different population (psychiatric outpatients in a publicly funded HIV/AIDS clinic). A sample of psychiatric outpatients (N = 373) from a large, urban HIV clinic was assessed for level of sexual orientation and HIV status disclosure as well as absolute CD4 cell counts over time. Mixed-effects random regression analysis was used to build a predictor model that included biobehavioral covariates. Consistent disclosure of both sexual orientation and HIV status independently predicted increased CD4 cell counts over time controlling for important biobehavioral covariates. The only other significant effects in the model were baseline CD4 cell count and number of days between assessment of disclosure and assessment of CD4 cell count. Relieving potential psychological distress by disclosing sexual orientation and HIV status has a positive impact on CD4 cell counts over time even among outpatients stressed by psychiatric illness and economic disadvantage. Additional research is needed to understand whether and under what conditions disclosure should be part of HIV disease management.