Difficult-to-treat HIV in Sweden: a cross-sectional study.

BACKGROUND: Our aim was to examine the prevalence and characteristics of difficult-to-treat HIV in the current Swedish HIV cohort and to compare treatment outcomes between people with difficult and non-difficult-to-treat HIV. METHODS: In this cross-sectional analysis of the Swedish HIV cohort, we identified all people with HIV currently in active care in 2023 from the national register InfCareHIV. We defined five categories of difficult-to-treat HIV: 1) advanced resistance, 2) four-drug regimen, 3) salvage therapy, 4) virologic failure within the past 12 months, and 5) ≥ 2 regimen switches following virologic failure since 2008. People classified as having difficult-to-treat HIV were compared with non-difficult for background characteristics as well as treatment outcomes (viral suppression and self-reported physical and psychological health). RESULTS: Nine percent of the Swedish HIV cohort in 2023 (n = 8531) met at least one criterion for difficult-to-treat HIV. Most of them had ≥ 2 regimen switches (6%), and the other categories of difficult-to-treat HIV were rare (1-2% of the entire cohort). Compared with non-difficult, people with difficult-to-treat HIV were older, had an earlier first year of positive HIV test and lower CD4 counts, and were more often female. The viral suppression rate among people with difficult-to-treat HIV was 84% compared with 95% for non-difficult (p = 0.001). People with difficult-to-treat HIV reported worse physical (but not psychological) health, and this remained statistically significant after adjustment for age, sex, and transmission group. CONCLUSIONS: Although 9% of the HIV cohort in Sweden in 2023 were classified as having difficult-to-treat HIV, a large proportion of these were virally suppressed, and challenges such as advanced resistance and need for salvage therapy are rare in the current Swedish cohort.

Monitoring the progress towards the elimination of hepatitis B and C in Sweden: estimation of core indicators for 2015 and 2018.

INTRODUCTION: To monitor Sweden's progress towards the WHO goal of eliminating viral hepatitis, we estimated the prevalence, notification rate, and liver-related morbidity and mortality for diagnosed hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in 2015 and 2018. METHODS: We identified cases of hepatitis B and C within the National System for Notifiable Diseases and obtained data on treatment and whether the case was deceased or not. We calculated prevalence, notification rates per 100,000, and proportion of newly diagnosed cases of hepatitis with liver disease at the time of diagnosis, and proportion of all deceased cases who died from liver disease. We calculated Poisson 95% confidence intervals (CIs) around the notification rates and Wilson 95% CIs around prevalence and mortality estimates. RESULTS: In 2015 and 2018, the prevalence of diagnosed HBV infections was 0.20% [95% CI: 0.19-0.20] and 0.21% [0.20-0.21]. Notification rates per 100,000 for HBV infections were 13.02 [12.32-13.76] and 7.71 [7.18-8.27]. HBV liver-related morbidity was 2.65% [1.90-3.68] and 2.16% [1.35-3.43]. HBV liver-related mortality was 20.00% [14.81-26.44] and 17.95% [13.20-23.94]. In 2015 and 2018, the prevalence of diagnosed HCV-infections was 0.24% [0.24-0.25] and 0.18% [0.18-0.19]. Notification rates per 100,000 for HCV infections were 15.92 [15.14-16.73] and 13.05 [12.36-13.77]. HCV liver-related morbidity was 8.14% [6.89-9.60] and 3.90% [2.99-5.08]. HCV liver-related mortality was 27.08% [24.54-29.77] and 26.90% [24.12-29.88]. CONCLUSIONS: All indicators decreased or remained stable between 2015 and 2018, indicating progress in the elimination of viral hepatitis, especially for HCV infection.

Transmission of viral hepatitis through blood transfusion in Sweden, 1968 to 2012.

IntroductionViral hepatitis remains a significant threat to transfusion safety, although largely mitigated by donor screening.AimOur objective was to estimate the past and present burden of transfusion transmission of all types of viral hepatitis (A to E) and to find undiagnosed infections with hepatitis C virus (HCV).MethodWe performed a retrospective cohort study using a database of the entire computerised transfusion experience of Sweden from 1968 to 2012 and linking it to a nationwide database of notifiable infections. We then used two independent statistical approaches. Firstly, we tracked recipients of blood from donors with confirmed viral hepatitis. Secondly, we computed a donor-specific risk score, defined as the difference between the observed and the expected number of HCV infections among all previous recipients of all donors, where thresholds were determined using simulation.ResultsAmong 1,146,307 transfused patients, more than 5,000 were infected with HCV. Transfusion transmission only occurred before 1992 when donor screening had been completely implemented. Overall, we found 44 donors and 1,180 recipients likely to be infected with HCV who were still alive but who remained undiagnosed.ConclusionThere is still a substantial number of individuals in Sweden who have probably been infected with HCV through blood transfusion and who are still unaware of their infection. We recommend that a follow-up study should be conducted to validate the method we used by approaching these individuals and offer testing. This would also serve as an opportunity to offer treatment to those who remain infected.

Lyme neuroborreliosis epidemiology in Sweden 2010 to 2014: clinical microbiology laboratories are a better data source than the hospital discharge diagnosis register.

BackgroundIn a study from 2013 that prioritised communicable diseases for surveillance in Sweden, we identified Lyme borreliosis as one of the diseases with highest priority. In 2014, when the present study was designed, there were also plans to make neuroborreliosis notifiable within the European Union.AimWe compared possibilities of surveillance of neuroborreliosis in Sweden through two different sources: the hospital discharge register and reporting from the clinical microbiology laboratories.MethodsWe examined the validity of ICD-10 codes in the hospital discharge register by extracting personal identification numbers for all cases of neuroborreliosis, defined by a positive cerebrospinal fluid-serum anti-Borrelia antibody index, who were diagnosed at the largest clinical microbiology laboratory in Sweden during 2014. We conducted a retrospective observational study with a questionnaire sent to all clinical microbiology laboratories in Sweden requesting information on yearly number of cases, age group and sex for the period 2010 to 2014.ResultsAmong 150 neuroborreliosis cases, 67 (45%) had received the ICD-10 code A69.2 (Lyme borreliosis) in combination with G01.9 (meningitis in bacterial diseases classified elsewhere), the combination that the Swedish National Board of Health and Welfare recommends for neuroborreliosis. All 22 clinical laboratories replied to our questionnaire. Based on laboratory reporting, the annual incidence of neuroborreliosis in Sweden was 6.3 cases per 100,000 in 2014.ConclusionThe hospital discharge register was unsuitable for surveillance of neuroborreliosis, whereas laboratory-based reporting was a feasible alternative. In 2018, the European Commission included Lyme neuroborreliosis on the list of diseases under epidemiological surveillance.

Self-reported infections during international travel and notifiable infections among returning international travellers, Sweden, 2009-2013.

We studied food and water-borne diseases (FWDs), sexually transmitted diseases (STDs), vector-borne diseases (VBDs) and diseases vaccinated against in the Swedish childhood vaccination programme among Swedish international travellers, in order to identify countries associated with a high number of infections. We used the national database for notifiable infections to estimate the number of FWDs (campylobacteriosis, salmonellosis, giardiasis, shigellosis, EHEC, Entamoeba histolytica, yersinosis, hepatitis A, paratyphoid fever, typhoid fever, hepatitis E, listeriosis, cholera), STIs (chlamydia, gonorrhoea and acute hepatitis B), VBDs (dengue fever, malaria, West Nile fever, Japanese encephalitis and yellow fever) and diseases vaccinated against in the Swedish childhood vaccination programme (pertussis, measles, mumps, rubella, diphtheria) acquired abroad 2009-2013. We obtained number and duration of trips to each country from a database that monthly collects travel data from a randomly selected proportion of the Swedish population. We calculated number of infections per country 2009-2013 and incidence/million travel days for the five countries with the highest number of infections. Thailand had the highest number of FWDs (7,697, incidence 191/million travel days), STIs (1,388, incidence 34/million travel days) and VBDs (358, incidence 9/million travel days). France had the highest number of cases of diseases vaccinated against in the Swedish childhood vaccination programme (8, 0.4/million travel days). Swedish travellers contracted most infections in Thailand. Special focus should be placed on giving advice to travellers to this destination.

A nationwide outbreak of listeriosis associated with cold-cuts, Sweden 2013-2014.

In January 2014, the Public Health Agency of Sweden noticed an increase in listeriosis cases. Isolates from 10 cases had identical pulsed field gel electrophoresis (PFGE) profiles, suggesting a common source. We investigated the outbreak to identify the source and stop transmission. We looked for cases in 2013-2014 and also compared cases notified after February 2014 to randomly selected controls. We surveyed food items consumed two weeks prior to symptom onset. Listeria monocytogenes isolates found by food producers were PFGE-typed. Patient and food isolates with the outbreak PFGE profile were whole-genome sequenced and 51 cases with identical PFGE profile were identified; 12/20 cases and 108/186 controls responded to the survey. All cases were exposed to cold-cuts, compared with 72% of controls (p = 0.034). Five isolates of L. monocytogenes with the outbreak PFGE profile were found in cold-cuts from a food producer which stopped production in February 2014, but cases appeared until October 2014. Whole-genome sequencing showed that cold-cut and patient isolates differed by eight single nucleotide polymorphisms. Three patient isolates differed more and were probably not part of the outbreak. Epidemiological and microbiological results indicated cold-cuts as a possible source of the outbreak.

Correction: Communicable Diseases Prioritized According to Their Public Health Relevance, Sweden, 2013.

[This corrects the article DOI: 10.1371/journal.pone.0136353.].

Communicable Diseases Prioritized According to Their Public Health Relevance, Sweden, 2013.

To establish strategic priorities for the Public Health Agency of Sweden we prioritized pathogens according to their public health relevance in Sweden in order to guide resource allocation. We then compared the outcome to ongoing surveillance. We used a modified prioritization method developed at the Robert Koch Institute in Germany. In a Delphi process experts scored pathogens according to ten variables. We ranked the pathogens according to the total score and divided them into four priority groups. We then compared the priority groups to self-reported time spent on surveillance by epidemiologists and ongoing programmes for surveillance through mandatory and/or voluntary notifications and for surveillance of typing results. 106 pathogens were scored. The result of the prioritization process was similar to the outcome of the prioritization in Germany. Common pathogens such as calicivirus and Influenza virus as well as blood-borne pathogens such as human immunodeficiency virus, hepatitis B and C virus, gastro-intestinal infections such as Campylobacter and Salmonella and vector-borne pathogens such as Borrelia were all in the highest priority group. 63% of time spent by epidemiologists on surveillance was spent on pathogens in the highest priority group and all pathogens in the highest priority group, except for Borrelia and varicella-zoster virus, were under surveillance through notifications. Ten pathogens in the highest priority group (Borrelia, calicivirus, Campylobacter, Echinococcus multilocularis, hepatitis C virus, HIV, respiratory syncytial virus, SARS- and MERS coronavirus, tick-borne encephalitis virus and varicella-zoster virus) did not have any surveillance of typing results. We will evaluate the possibilities of surveillance for the pathogens in the highest priority group where we currently do not have any ongoing surveillance and evaluate the need of surveillance for the pathogens from the low priority group where there is ongoing surveillance in order to focus our work on the pathogens with the highest relevance.

Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation.

OBJECTIVE AND DESIGN: Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. METHODS: CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. RESULTS: CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P < 0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P = 0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4 cell count or CNS penetration-efficacy score. CONCLUSION: Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.

An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy.

We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system.

The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial.

The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1ß) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072.

Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies.

HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.

Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers.

OBJECTIVE: Elite controllers are a rare subset of HIV-1-infected individuals who maintain HIV-1 RNA concentrations in plasma below the lower limit of quantification of clinical assays (<20-50 copies/ml) in the absence of antiretroviral therapy. Here, we examine to what extent elite controllers also control infection of the central nervous system (CNS). DESIGN: We analysed paired cerebrospinal fluid (CSF) and plasma samples using a highly sensitive assay for HIV-1 RNA quantification. METHODS: We analysed 28 CSF samples and 27 concurrent plasma samples from 14 elite controllers with the highly sensitive single-copy assay (SCA) that allows for HIV-1 RNA quantification down to less than one copy of HIV-1 RNA per millilitre. RESULTS: Three samples were excluded because of internal standard failure. HIV-1 RNA was detected in only five of 26 CSF samples compared with 14 of 26 plasma samples (P = 0.02), with a median of 0.2 (range, 0.1-6) copies/ml in CSF compared with 0.8 (range, 0.1-189 copies/ml) in plasma (P < 0.0001). CONCLUSION: HIV-1 RNA could not be detected in CSF in most elite controllers using the highly sensitive SCA, and when detected, it was at significantly lower frequencies and concentrations than in plasma. Elite controllers thus control HIV-1 in the CNS very well. Whether the infrequent and small amounts of HIV-1 RNA in the CSF reflect production from a local reservoir or virion exchange between the blood and the CSF is uncertain.

Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: a randomized 48-week study.

BACKGROUND: Residual viraemia is a major obstacle to HIV-1 eradication in subjects receiving HAART. The intensification with raltegravir could impact latent reservoirs and might lead to a reduction of plasma HIV-1 viraemia (viral load [VL]), complementary DNA intermediates and immune activation. METHODS: This was a prospective, open-label, randomized study comprising 69 individuals on suppressive HAART randomly assigned 2:1 to add raltegravir during 48 weeks. RESULTS: Total and integrated HIV-1 DNA, and ultrasensitive VL remained stable despite intensification. There was a significant increase in episomal HIV DNA at weeks 2-4 in the raltegravir group returning to baseline levels at week 48. Median CD4(+) T-cell counts increased 124 and 80 cells/µl in the intensified and control groups after 48 weeks (P=0.005 and P=0.027, respectively), without significant differences between groups. No major changes were observed in activation of CD4(+) T-cells. Conversely, raltegravir intensification significantly reduced activation of CD8(+) T-cells at week 48 (HLA-DR(+)CD38(+), P=0.005), especially in the memory compartment (CD38(+) of CD8(+)CD45RO(+), P<0.0001). Linear mix models also depicted a larger decrease in CD8(+) T-cell activation in the intensification group (P=0.036 and P=0.010, respectively). Raltegravir intensification was not associated to any particular adverse event. CONCLUSIONS: Intensification of HAART with raltegravir during 48 weeks was safe and associated with a significant decrease in CD8(+) T-cell activation, and a transient increase of episomal HIV-1 DNA. However, raltegravir did not significantly contribute to changes in CD4(+) T-cell counts, ultrasensitive VL, and total and integrated HIV-1 DNA. These findings suggest that raltegravir impacts residual HIV-1 replication and support new strategies to impair HIV-1 persistence. ClinicalTrials.gov identifier: NCT00554398.

Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected.

OBJECTIVE: The primary objective was to assess the effect of MVC intensification on latently infected CD4(+) T cells in chronically HIV-1-infected patients receiving antiretroviral therapy. METHODS: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation. RESULTS: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4(+) or CD8(+) counts, although a significant decrease was found in the proportion of HLA-DR(+)/CD38(+) CD4(+) and CD8(+) T-cells. LPS and sCD14 levels increased. CONCLUSIONS: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results. TRIAL REGISTRATION: ClinicalTrials.gov NCT00795444.

Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy.

BACKGROUND: Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation. METHODS: This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4(+) and CD8(+) T-cell surface antigen expression. RESULTS: Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4(+) and CD8(+) T-cell activation. CONCLUSIONS: Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932.

A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response.

BACKGROUND: Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size. METHODS: Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for ≥ 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs). RESULTS: The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. CONCLUSIONS: Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment. CLINICAL TRIALS REGISTRATION: NCT00631449.

Can HIV infection be eradicated through use of potent antiviral agents?

PURPOSE OF REVIEW: This review focuses on recent advances in HIV research and therapy that seek to eradicate persistent HIV in patients on suppressive therapy. RECENT FINDINGS: The source of persistent HIV in patients on suppressive therapy is debated. Recent studies of treatment intensification have produced varied results: no reduction in low-level plasma viremia indicating the source of persistent viremia is long-lived HIV-infected cells that release HIV when activated and increase in episomal HIV DNA indicating active replication persists in some infected individuals on suppressive therapy. In addition, clonal HIV sequences found in plasma from patients on long-term suppressive therapy are rarely found in CD4+ memory T cells. These results indicate that persistent viremia may arise from several different sources. Recent studies emphasize the complexity of HIV latency. Current strategies for HIV eradication focus on compounds that activate viral transcription in memory CD4+ T cells by many routes, including inhibiting histone deacetylation and activating nuclear factor kappa B. Several compounds and combinations of these compounds appear to induce the expression of integrated HIV in different latency models. SUMMARY: The eradication of HIV requires the elimination of persistent HIV during suppressive therapy. Recent studies have focused on the source of persistent viremia, mechanisms of intracellular HIV latency, and reactivation of latent HIV. It remains to be seen whether alternative treatment strategies may be required to eradicate HIV.

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

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

HIV reservoirs, latency, and reactivation: prospects for eradication.

Current antiretroviral therapy effectively suppresses but does not eradicate HIV-1 infection. During therapy patients maintain a persistent low-level viremia requiring lifelong adherence to antiretroviral therapies. This viremia may arise from latently infected reservoirs such as resting memory CD4+ T-cells or sanctuary sites where drug penetration is suboptimal. Understanding the mechanisms of HIV latency will help efforts to eradicate the infection. This review examines the dynamics of persistent viremia, viral reservoirs, the mechanisms behind viral latency, and methods to purge the viral reservoirs. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010.