Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early human immunodeficiency virus type 1 infection

The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofold higher in CHI patients (0.122 +/- 0.12/viral load [VL] sample, mean +/- standard deviation) than in PHI patients (0.066 +/- 0.09/VL sample). However, in both groups, viral blip frequency did not increase with longer periods of observation. Also, no difference in viral blip frequency was observed between treatment subgroups, and the occurrence of a blip was not associated with a recent change in CD4(+) T-cell count. Finally, in PHI patients the VL set point was a significant predictor of blip frequency during treatment.     

Granulocyte/monocyte apheresis induces sustained increases in CD4 T cells in HIV-1 infected patients with poor CD4 T cell restoration after suppression of viral replication by HAART

Current antiretroviral regimens (HAART) are generally effective in reducing viral replication to undetectable levels and inducing a raise in CD4 T cells. However, in approximately 5 to 15% of patients suppression of viral replication is not followed by an increase in CD4 T cells. Such patients may be at increased risk for opportunistic infections. Here we report the results from a phase II open label randomised trial on 30 patients classified as poor responders to HAART who were either subjected to eight consecutive cycles of selective monocyte apheresis or maintained under HAART alone. The results show that monocyte apheresis results in increased CD4 T cell counts which are maintained for at least 31 weeks after last apheresis. This effect was observed only on patients with complete suppression of viral replication. Other effects of monocyte apheresis included a strong reduction of TNF-alpha production in patients with high baseline levels of this cytokine and activation of resting T cells during the apheresis cycles. In two patients with high cellular HIV DNA load apheresis was followed by a 98% reduction, suggesting purging of infected cells. There was no evidence of increased viral replication during or after the apheresis cycles. The data show that monocyte apheresis is safe, well tolerated and may be indicated in patients who respond poorly to HAART.     

Durable Suppression of HIV-1 after Virologic Monitoring-Based Antiretroviral Adherence Counseling in Rakai,Uganda

ObjectivesHIV viral load is recommended for monitoring antiretroviral treatment and identifying treatment failure. We assessed the durability of viral suppression after viral load-triggered adherence counseling among patients with HIV viremia 6 months after ART initiation.DesignObservational cohort enrolled in an antiretroviral treatment program in rural Uganda.MethodsParticipants who underwent routine viral load determination every 24 weeks and had at least 48 weeks of follow-up were included in this analysis. Patients with viral loads >400 copies/ml at 24 weeks of treatment were given additional adherence counseling, and all patients were followed to assess the duration of viral suppression and development of virologic failure.Results1,841 participants initiating antiretroviral therapy were enrolled in the Rakai Health Sciences Program between June 2005 and June 2011 and were followed with viral load monitoring every 24 weeks. 148 (8%) of patients did not achieve viral suppression at 24 weeks and were given additional adherence counseling. 85 (60%) of these patients had undetectable viral loads at 48 weeks, with a median duration of viral suppression of 240 weeks (IQR 193-288 weeks). Failure to achieve an undetectable viral load at 48 weeks was associated with age <30 years and 24 week viral load >2,000 copies/ml in multivariate logistic regression analysis.ConclusionsThe majority of patients with persistent viremia who were provided adherence counseling achieved robust viral suppression for a median 4.6 years. Access to virologic monitoring and adherence counseling is a priority in resource-limited settings.     

Immunological and Virological Benefits Resulted from Short-Course Treatment during Primary HIV Infection: A Meta-Analysis

Objectives

To assess the potential immunological and virological effects that result from short-course antiretroviral treatment during primary HIV infection (PHI). And to investigate whether treatment initiation time, treatment duration and follow-up time after treatment interruption would affect these post-treatment immunovirological outcomes.

Methods

We systematically searched PubMed, Cochrane Library (to September 2013) and retrieved conference abstracts for studies regarding effects of early treatment during PHI on CD4 count and viral load (VL). Using the method of calculating weighted mean differences with Stata11.0, we conducted meta-analyses on the effect of early treatment on CD4 count and VL. Then we performed subgroup analyses by follow-up time after treatment interruption, treatment initiation time and treatment duration. Baseline immunovirological characteristics were also analyzed to account for potential bias.

Results

Compared to the untreated arm, treatment during PHI not only increased CD4 count by 85.92 cells/μl but also lowered viral load by 0.30 log copies/ml within one year after treatment interruption. However, the benefits declined gradually, reaching no significance 12-24 months after treatment interruption. Baseline immunovirological characteristics and sensitivity analyses of randomized controlled trials indicated that the benefits mentioned above were underestimated. Extending treatment duration beyond 12 months did not increase efficacy.

Conclusions

Short-course treatment during PHI was associated with immunological and virological benefits which last for at least one year after treatment interruption. The conclusions from our study would help the decision-making in the clinical management of PHI.     

Cumulative viral load and virologic decay patterns after antiretroviral therapy in HIV-infected subjects influence CD4 recovery and AIDS

Background

The impact of viral load (VL) decay and cumulative VL on CD4 recovery and AIDS after highly-active antiretroviral therapy (HAART) is unknown.

Methods and Findings

Three virologic kinetic parameters (first year and overall exponential VL decay constants, and first year VL slope) and cumulative VL during HAART were estimated for 2,278 patients who initiated HAART in the U.S. Military HIV Natural History Study. CD4 and VL trajectories were computed using linear and nonlinear Generalized Estimating Equations models. Multivariate Poisson and linear regression models were used to determine associations of VL parameters with CD4 recovery, adjusted for factors known to correlate with immune recovery. Cumulative VL higher than the sample median was independently associated with an increased risk of AIDS (relative risk 2.38, 95% confidence interval 1.56–3.62, p<0.001). Among patients with VL suppression, first year VL decay and slope were independent predictors of early CD4 recovery (p = 0.001) and overall gain (p<0.05). Despite VL suppression, those with slow decay during the first year of HAART as well as during the entire therapy period (overall), in general, gained less CD4 cells compared to the other subjects (133 vs. 195.4 cells/µL; p = 0.001) even after adjusting for potential confounders.

Conclusions

In a cohort with free access to healthcare, independent of established predictors of AIDS and CD4 recovery during HAART, cumulative VL and virologic decay patterns were associated with AIDS and distinct aspects of CD4 reconstitution.     

Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy.

We measured the longitudinal responses to 95 HLA class I-restricted human immunodeficiency virus (HIV) epitopes and an immunodominant HLA A2-restricted cytomegalovirus (CMV) epitope in eight treatment-naive HIV-infected individuals, using intracellular cytokine staining. Patients were treated with highly active antiretroviral therapy (HAART) for a median of 78 weeks (range, 34 to 121 weeks). Seven of eight patients maintained an undetectable viral load for the duration of therapy. A rapid decline in HIV-specific CD8(+) T-cell response was observed at initiation of therapy. After an undetectable viral load was achieved, a slower decrease in HIV-specific CD8(+) T-cell response was observed that was well described by first-order kinetics. The median half-life for the rate of decay was 38.8 (20.3 to 68.0) weeks when data were expressed as percentage of peripheral CD8(+) T cells. In most cases, data were similar when expressed as the number of responding CD8(+) T cells per microliter of blood. In subjects who responded to more than one HIV epitope, rates of decline in response to the different epitopes were similar and varied by a factor of 2.2 or less. Discontinuation of treatment resulted in a rapid increase in HIV-specific CD8(+) T cells. Responses to CMV increased 1.6- and 2.8-fold within 16 weeks of initiation of HAART in two of three patients with a measurable CMV response. These data suggest that HAART quickly starts to restore CD8(+) T-cell responses to other chronic viral infections and leads to a slow decrease in HIV-specific CD8(+) T-cell response in HIV-infected patients. The slow decrease in the rate of CD8(+) T-cell response and rapid increase in response to recurrent viral replication suggest that the decrease in CD8(+) T-cell response observed represents a normal memory response to withdrawal of antigen.     

Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.     

HIV-1 DNA and RNA kinetics in primary HIV infection

BACKGROUND: HIV-1 reservoir is early established during PHI. It is reduced, but not extinguished by early therapy: DNA containing cells are still detectable after months of successful viremia suppression. To define the best method to measure low level viral replication, we determined the extent of HIV reservoir in 11 acutely infected patients and evaluated how it is renewed even during successful treatment. METHODS: Eleven acutely infected HIV patients were included in the study. Three where not treated with antiretroviral drugs while 8 underwent early aggressive antiretroviral treatment (HAART) which, in 3 cases, was associated to cyclosporin A (CsA) administration. HIV viremia was monitored by commercially available methods while HIV-DNA and cellular RNA quantitation were obtained by in house PCR and RT-PCR respectively, in the gag region. RESULTS: Significant CD4 recover and HIV viremia suppression were reached in a mean period of three to six months in all treated patients. The course of the HIV-DNA and of cellular HIV RNA reduction showed a similar trend. This variation was slower, if compared to plasma viremia and never reached undetectable levels, justifying the rebound of viremia observed at therapy interruption. CONCLUSIONS: These data suggest and confirm that complete abolition of viral replication is not achieved and viral reservoir may be re-expanded even after short term rebound of viremia. Scheduling of possible structured therapy interruption should be designed based on multiple virological parameters and on the individual characteristics of the patients.     

Duration of HIV-1 Viral Suppression on Cessation of Antiretroviral Therapy in Primary Infection Correlates with Time on Therapy

Objective

A minority of HIV-1 positive individuals treated with antiretroviral therapy (ART) in primary HIV-1 infection (PHI) maintain viral suppression on stopping. Whether this is related to ART duration has not been explored.

Design

And Methods: Using SPARTAC trial data from individuals recruited within 6 months of seroconversion, we present an observational analysis investigating whether duration of ART was associated with post-treatment viraemic control. Kaplan-Meier estimates, logistic regression and Cox models were used.

Results

165 participants reached plasma viral loads (VL) <400 copies/ml at the time of stopping therapy (ART stop). After ART stop, 159 experienced confirmed VL ≥400 copies/ml during median (IQR) follow-up of 167 (108,199) weeks.Most participants experienced VL rebound within 12 weeks from ART stop, however, there was a suggestion of a higher probability of remaining <400 copies/ml for those on ART >12 weeks compared to ≤12 weeks (p=0.061). Cumulative probabilities of remaining <400 copies/ml at 12, 52 and 104 weeks after ART stop were 21% (95%CI=13,30), 4% (1,9), and 4% (1,9) for ≤12 weeks ART, and 32% (22,42), 14% (7,22), and 5% (2,11) for >12 weeks.In multivariable regression, ART for >12 weeks was independently associated with a lower probability of being ≥400 copies/ml within 12 weeks of ART stop (OR=0.11 (95%CI=0.03,0.34), p<0.001)). In Cox models of time to VL ≥400 after 12 weeks, we only found an association with female sex (OR=0.2, p=0.001).

Conclusion

Longer ART duration in PHI was associated with a higher probability of viral control after ART stop.

Trial Registration

Controlled-Trials.com 76742797 http://www.controlled-trials.com/ISRCTN76742797.     

Characterisation of AIDS presenters and their response to antiretroviral therapy at legnano general hospital (Italy) during the period 2000-2008

The aim of this study was to characterise the AIDS presenters diagnosed between 2000 and 2008 in Legnano (Italy), and describe their initial response to highly active antiretroviral therapy (HAART) and trends over time. Seventy-six (48.7%) of 156 patients diagnosed as having AIDS in the period 2000-2008 were AIDS presenters. The proportion of AIDS presenters increased from 23.8% in 2000 to 70.6% in 2008 (p = 0.009). The major risk factors were heterosexual transmission and a foreign place of birth, and did not significantly change over time. The median CD4+ cell count at diagnosis was 30 cells/microl and the median level of HIV RNA was 5.38 log copies/ml, with no differences between the transmission risk groups. Fifteen AIDS presenters died of AIDS-defining diseases; the others started HAART (72% with 2 NRTIs + boosted PI), and 40% after a drug resistance test. The median duration of the initial HAART was 107 days. After three months, 34% of the patients had undetectable HIV-RNA levels and the median CD4+ cell count was 140 cells/microl; the corresponding figures after 12, 24 and 48 months were respectively 84%, 82.3% and 94.1%, and 310, 370 and 380 cells/microl. In conclusion, the AIDS presenters were mainly heterosexual men and immigrants. Their proportion increased significantly over time, and a substantial proportion maintained an immunovirological response to HAART.     

Determinants of Highly Active Antiretroviral Therapy Duration in HIV-1-Infected Children and Adolescents in Madrid,Spain, from 1996 to 2012

Objectives

To investigate the duration of sequential HAART regimens and predictors of first-line regimen discontinuation among HIV-1 vertically infected children and adolescents.

Design

Multicentre survey of antiretroviral-naïve patients enrolled in the HIV-Paediatric Cohor,t CoRISpeS-Madrid Cohort, Spain.

Methods

Patients with a follow-up of ≥1 month spent on HAART, with available baseline CD4 count and HIV-viral load (VL) were included. Time spent on sequential HAART regimens was estimated and multivariable regression was used to identify predictors of time to first-line regimen discontinuation.

Results

104 patients were followed for a median 8 years after starting HAART among 1996–2012; baseline %CD4 was 21.5 (12.3–34.0)and viral load was 5.1 (4.6–5.6) log₁₀ copies/mL. Patients received a mean of 1.9 regimens. Median time on first-line HAART (n = 104) was 64.5 months; second HAART (n = 56) 69.8 months; and third HAART (n = 21) 66.5 months. Eleven (11%) patients were lost to follow-up while on first-line HAART and 54% discontinued (cumulative incidence of 16% and 38% by 1 and 3-year, respectively). The main predictor of first-line regimen discontinuation was suboptimal adherence to antiretrovirals (AHR: 2.60; 95% CI: 1.44–4.70).

Conclusions

Adherence to therapy was the main determinant of the duration of the first-line HAART regimen in children. It is important to identify patients at high risk for non-adherence, such as very young children and adolescents, in provide special care and support to those patients.     

Long-Term Hepatitis B Virus (HBV) Response to Lamivudine-Containing Highly Active Antiretroviral Therapy in HIV-HBV Co-Infected Patients in Thailand

BACKGROUND: Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known. METHODOLOGY/PRINCIPAL FINDING: HIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 log(10) IU/mL and 4.47 log(10) copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L. CONCLUSIONS: All HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC.     

Persistant immunodominant anti-gag SLYNTVATL responses in HIV-patients with up to 7 years of HAART

We analyzed Gag-specific CD8+ T-cells in HIV-patients on long-term HAART and in untreated chronically-infected patients by using iTAg MHC class I tetramers (HLA-A*0201) specific for SLYNTVATL. Gag SLYNTVATL-specific CD8+ T-cells were detectable in 18 of 26 treated patients (median 5.2 years of HAART) and in 10 of 14 untreated patients. Median percentage of Gag SLYNTVATL-specific CD8+ T-cells in treated patients was 0.10 (range 0.00-0.70%). Median number of Gag SLYNTVATL-specific CD8+ T-cells per 50,000 CD8+ T-cells was 56.0 cells (range 2.0-344.0 cells) and was not significantly different compared with untreated patients (p = 0.978). Numbers of Gag SLYNTVATL-specific CD8+ T-cells were inversely correlated with the duration of undetectable plasma viremia (p = 0.02, Rho = -0.430). Chronically-infected HIV-patients on HAART (for up to 7.7 years) maintained a stable subpopulation of Gag SLYNTVATL-specific CD8+ T-cells. This finding is relevant for the analysis of treatment-induced immune reconstitution and, possibly, for future therapeutic strategies in HIV-disease.     

Primary HIV infection: molecular approaches in diagnosis and monitoring

OBJECTIVE: The aim of this study was to evaluate, in patients with primary HIV infection (PHI), the modification of HIV molecular parameters (HIV, RNA, and DNA) induced by highly active antiretroviral therapy (HAART) in peripheral blood mononuclear cells (PBMC) and in lymphoid tissue (LNMC). METHODS: Nineteen patients with primary HIV infection, 4 women and 15 men with an average age of 35 years (range 27-62), were included in this study. Ten patients received 4 drugs: zidovudine plus lamivudine plus saquinavir plus ritonavir, 7 patients received 3 drugs: zidovudine plus lamivudine plus saquinavir and 2 patients received a different combination of 3 drugs: zidovudine plus lamivudine plus indinavir. As control group we included 8 patients who had been enrolled in a placebo-controlled trial of zidovudine between 1991 and 1995: four received placebo and 4 were treated with zidovudine alone. Peripheral blood samples and lymphoid tissue obtained by echo-driven fine needle biopsies were drawn to monitor molecular HIV parameters. A quantitative in house PCR method in the HIV gag region was used to monitor viral DNA burden and the NASBA system for viremia. RESULTS: A certain heterogeneity in the baseline values of HIV, DNA, and RNA was observed. Early HAART determined a rapid recovery of the CD4 cell number with normalisation of the CD4/CD8 ratio in most patients. HIV-RNA levels dropped to undetectable levels after a few months of therapy and HIV-DNA was consistently reduced although it never reached undetectable levels. Lymph-node biopsies were well tolerated due to the non-invasive sampling, however an optimisation of the method is needed to improve cell recovery. In the valuable samples the amount of HIV DNA recovered is comparable to that from peripheral blood samples, both at baseline and at follow-up.     

Interruption of antifungal secondary prophylaxis in AIDS-related histoplasmosis

The clinical data of 21 patients, suffering AIDS-related histoplasmosis, who were able to interrupt antifungal secondary prophylaxis, after achieving a partial restoration of the cell mediated immunity by HAART administration, are presented. They were 16 males and five females, whose ages varied between 32 and 54 years (mean = 38.5 years). All of them presented disseminated progressive forms of histoplasmosis, with multiple locations (skin, mucous membranes, liver, spleen, lymph nodes and lungs). The majority of the cases suffered other concomitant diseases (specially tuberculosis and Kaposi sarcoma), 66.6 % of the patients had less than 50 CD4+ cells/microl at the start of treatment and the average viral burden was 278,385 RNA copies/ml. The initial treatment consisted in 400 mg/day of itraconazole, by oral route, in 14 cases and the remaining seven patients were treated with amphotericin B, intravenously, at a daily dose of 0.7 mg/kg of body weight. One patient who did not tolerate amphotericin B and presented a partial response to itraconazole, was treated with posaconazole orally at a daily dose of 800 mg. Fourteen patients received oral itraconazole at a daily dose of 200 mg as a secondary prophylaxis, the remaining three patients were treated with intravenous amphotericin B, 50 mg twice a week. After HAART for an average lapse of 16.7 months (10 to 32 months), five cases showed CD4+ cells counts above 150 cells/microl and the remaining 16 presented more than 200 cells/microl; 18 of them had undetectable viral burden and all cases were asymptomatic. The follow up after secondary prophylaxis discontinuation varied between six months and six years (mean= 33.6 months). Twenty out of 21 patients (95 %) were clinically stable, without any manifestation of relapses, including two patients who abandoned HAART. One patient, who discontinued HAART, contracted a fatal bacterial pneumonia. Even though the limited number of cases, the data presented in this study seem to suggest that it is possible to interrupt antifungal secondary prophylaxis of histoplasmosis, when the patient is clinically asymptomatic and the CD4+ cells counts are above 150 cells/microl.     

Human immunodeficiency virus-type 1 specific cellular immunity in chronic infected patients on prolonged highly active antiretroviral treatment and on structured treatment interruption

We have followed 15 HIV-1 chronically infected patients during prolonged highly active antiretroviral treatment (HAART) and subsequent long term structured treatment interruption (STI). We analyzed Nef, Tat, and p24 specific cellular immunity using IFN-gamma enzyme-linked immunospot assays and T cell proliferation assays. Eight HAART patients showed IFN-gamma responses to at least one antigen, but no positive responses were seen during STI. We observed retained or increased p24 specific IFN-gamma responses in most patients during HAART with viral suppression. These results showed persisting HIV-1 specific cellular immunity during HAART; however, in prolonged STI with viral rebound this immunity declined.     

High Levels of Adherence and Viral Suppression in a Nationally Representative Sample of HIV-Infected Adults on Antiretroviral Therapy for 6, 12 and 18 Months in Rwanda

Background

Generalizable data are needed on the magnitude and determinants of adherence and virological suppression among patients on antiretroviral therapy (ART) in Africa.

Methods

We conducted a cross-sectional survey with chart abstraction, patient interviews and site assessments in a nationally representative sample of adults on ART for 6, 12 and 18 months at 20 sites in Rwanda. Adherence was assessed using 3- and 30-day patient recall. A systematically selected sub-sample had viral load (VL) measurements. Multivariable logistic regression examined predictors of non-perfect (<100%) 30-day adherence and detectable VL (>40 copies/ml).

Results

Overall, 1,417 adults were interviewed and 837 had VL measures. Ninety-four percent and 78% reported perfect adherence for the last 3 and 30 days, respectively. Eighty-three percent had undetectable VL. In adjusted models, characteristics independently associated with higher odds of non-perfect 30-day adherence were: being on ART for 18 months (vs. 6 months); younger age; reporting severe (vs. no or few) side effects in the prior 30 days; having no documentation of CD4 cell count at ART initiation (vs. having a CD4 cell count of <200 cells/µL); alcohol use; and attending sites which initiated ART services in 2003–2004 and 2005 (vs. 2006–2007); sites with ≥600 (vs. <600 patients) on ART; or sites with peer educators. Participation in an association for people living with HIV/AIDS; and receiving care at sites which regularly conduct home-visits were independently associated with lower odds of non-adherence. Higher odds of having a detectable VL were observed among patients at sites with peer educators. Being female; participating in an association for PLWHA; and using a reminder tool were independently associated with lower odds of having detectable VL.

Conclusions

High levels of adherence and viral suppression were observed in the Rwandan national ART program, and associated with potentially modifiable factors.     

Therapeutic dendritic-cell vaccine for chronic HIV-1 infection

We present the results of a preliminary investigation of the efficacy of a therapeutic dendritic cell (DC)-based vaccine for HIV-1. We immunized 18 chronically HIV-1-infected and currently untreated individuals showing stable viral loads for at least 6 months with autologous monocyte-derived DCs loaded with autologous aldrithiol-2-inactivated HIV-1. Plasma viral load levels were decreased by 80% (median) over the first 112 d following immunization. Prolonged suppression of viral load of more than 90% was seen in 8 individuals for at least 1 year. The suppression of viral load was positively correlated with HIV-1-specific interleukin-2 or interferon-gamma-expressing CD4(+) T cells and with HIV-1 gag-specific perforin-expressing CD8(+) effector cells, suggesting that a robust virus-specific CD4(+) T-helper type 1 (T(H)1) response is required for inducing and maintaining virus-specific CD8(+) effectors to contain HIV-1 in vivo. The results suggest that inactivated whole virus-pulsed DC vaccines could be a promising strategy for treating people with chronic HIV-1 infection.     

The amplitudes of viral blips in HIV-1 infected patients treated with antiretroviral therapy are power-law distributed

We previously reported that in patients treated with highly active antiretroviral therapy (HAART) who achieve viral load (VL) suppression, low fluctuations of viral load over the threshold of detection (viral blips) more than 4 weeks apart occur at random, with a frequency that does not change with longer times of observation. The etiology of viral blips is currently unknown, but viral blip frequency inversely correlates with the decay of the latent reservoir, whose stability has been proposed as the major hurdle to HIV eradication. We show here that the distribution of viral blip amplitudes observed in a group of 272 patients successfully treated with highly active antiretroviral therapy appears to be power-law distributed. Such a distribution can be theoretically generated by randomly sampling the arrival of asynchronous and overlapping elementary pulses of viremia, with asymptotic exponential decay of kinetics, thus suggesting that the low fluctuations of viremia observed in patients during HAART treatment is, in part, a discrete phenomenon consistent with random activation of latently infected cells or release of virus and infected cells into the blood compartment from unknown sites of active viral replication.     

T Cell Activation but Not Polyfunctionality after Primary HIV Infection Predicts Control of Viral Load and Length of the Time without Therapy

Objective

Immune changes occurring after primary HIV infection (PHI) have a pivotal relevance. Our objective was to characterize the polyfunctionality of immune response triggered by PHI, and to characterize immune activation and regulatory T cells, correlating such features to disease progression.

Patients and Methods

We followed 11 patients experiencing PHI for 4 years. By polychromatic flow cytometry, we studied every month, for the first 6 months, T lymphocyte polyfunctionality after cell stimulation with peptides derived from HIV-1 gag and nef. Tregs were identified by flow cytometry, and T cell activation studied by CD38 and HLA-DR expression.

Results

An increase of anti-gag and anti-nef CD8+ specific T cells was observed 3 months after PHI; however, truly polyfunctional T cells, also able to produce IL-2, were never found. No gross changes in Tregs were present. T lymphocyte activation was maximal 1 and 2 months after PHI, and significantly decreased in the following period. The level of activation two months after PHI was strictly correlated to the plasma viral load 1 year after infection, and significantly influenced the length of period without therapy. Indeed, 80% of patients with less than the median value of activated CD8+ (15.5%) or CD4+ (0.9%) T cells remained free of therapy for >46 months, while all patients over the median value had to start treatment within 26 months.

Conclusions

T cell activation after PHI, more than T cell polyfunctionality or Tregs, is a predictive marker for the control of viral load and for the time required to start treatment.