Antiretroviral Therapy In Individuals Research Articles

Combination anti-HIV antibodies provide sustained virological suppression.

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Cerebrospinal fluid soluble CD30 elevation despite suppressive antiretroviral therapy in individuals living with HIV-1

ObjectivesThe aim of this study was to assess soluble CD30 (sCD30), a protein that colocalises with HIV-1 RNA and DNA in lymphoid cells and tissues, in cerebrospinal fluid (CSF) as a marker of HIV-1 infection in the central nervous system (CNS). MethodsThis was a cross-sectional study using archived samples from two clinical cohorts. Soluble CD30 concentrations were measured in paired CSF and plasma from untreated viraemic individuals (n=52), individuals on suppressive antiretroviral therapy (ART) (n=33), HIV-1 controllers (n=10), participants with CSF HIV-1 ‘escape’ (n=11) and controls without HIV-1 infection (n=16). Nonparametric tests were used to compare levels across groups and evaluate correlations with HIV-1 RNA, CSF neurofilament light chain protein (NFL) and neopterin. ResultsCompared with controls (median 30 ng/mL, interquartile range [IRQ] 23–50), plasma sCD30 levels were elevated in viraemic participants (75 ng/mL, 52–116; P<0.001), but not in those on suppressive ART (38 ng/mL, 32–62). In contrast, CSF sCD30 levels were elevated in ART-suppressed individuals (34 ng/mL, 19–46; P=0.001) and in those with CSF ‘escape’ (33 ng/mL, 27–40; P=0.004) compared with controls (18 ng/mL, 11–23), but not in untreated viraemic individuals. No association was observed between CSF sCD30 and plasma HIV-1 RNA, concurrent or nadir CD4+ T cell count, duration of infection or plasma sCD30. CSF sCD30 correlated with CSF NFL (r=0.34, P=0.001). ConclusionsIn contrast to plasma, sCD30 levels are elevated in the CSF of individuals with HIV-1 infection who are on suppressive ART. Elevated levels of sCD30 in the CSF may be an indicator of persistent CNS HIV-1 infection, although the mechanism underlying this elevation warrants further investigation.

HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer.

While combined antiretroviral therapy (cART) can result in undetectable plasma viral loads, it does not eradicate HIV infection. Furthermore, HIV-infected individuals while on cART remain at an increased risk of developing serious comorbidities, such as cancer, neurological disease, and atherosclerosis, suggesting that during cART, tissue-based HIV may contribute to such pathologies. We obtained DNA and RNA env, nef, and pol sequences using single-genome sequencing from postmortem tissues of three HIV(+) cART-treated (cART(+)) individuals with undetectable viral load and metastatic cancer at death and performed time-scaled Bayesian evolutionary analyses. We used a sensitive in situ hybridization technique to visualize HIV gag-pol mRNA transcripts in cerebellum and lymph node tissues from one patient. Tissue-associated virus evolved at similar rates in cART(+) and cART-naive (cART(-)) patients. Phylogenetic trees were characterized by two distinct features: (i) branching patterns consistent with constant viral evolution and dispersal among tissues and (ii) very recently derived clades containing both DNA and RNA sequences from multiple tissues. Rapid expansion of virus near death corresponded to wide-spread metastasis. HIV RNA(+) cells clustered in cerebellum tissue but were dispersed in lymph node tissue, mirroring the evolutionary patterns observed for that patient. Activated, infiltrating macrophages were associated with HIV RNA. Our data provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread. Combined antiretroviral therapy (cART) reduces plasma HIV to undetectable levels; however, removal of cART results in plasma HIV rebound, thus highlighting its inability to entirely rid the body of infection. Additionally, HIV-infected individuals on cART remain at high risk of serious diseases, which suggests a contribution from residual HIV. In this study, we isolated and sequenced HIV from postmortem tissues from three HIV(+) cART(+) individuals who died with metastatic cancer and had no detectable plasma viral load. Using high-resolution evolutionary analyses, we found that tissue-based HIV continues to replicate, evolve, and migrate among tissues during cART. Furthermore, cancer onset and metastasis coincided with increased HIV expansion, suggesting a linked mechanism. HIV-expressing cells were associated with tissue macrophages, a target of HIV infection. Our results suggest the importance of tissues, and macrophages in particular, as a target for novel anti-HIV therapies.

Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection

BACKGROUND Current guidelines give recommendations for preferred combination antiretroviral therapy (cART). We investigated factors influencing the choice of initial cART in clinical practice and its outcome. METHODS We analyzed treatment-naive adults with human immunodeficiency virus (HIV) infection participating in the Swiss HIV Cohort Study and starting cART from January 1, 2005, through December 31, 2009. The primary end point was the choice of the initial antiretroviral regimen. Secondary end points were virologic suppression, the increase in CD4 cell counts from baseline, and treatment modification within 12 months after starting treatment. RESULTS A total of 1957 patients were analyzed. Tenofovir-emtricitabine (TDF-FTC)-efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)-lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)-efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P&lt;.001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78-4.35), HIV-RNA greater than 100000 copies/mL (1.53; 1.07-2.18), and CD4greater than 350 cells/μL (1.67; 1.04-2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04-3.01), HIV-RNA greater than 100000 copies/mL (1.54; 1.05-2.25), and an opiate substitution program (2.76; 1.09-7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39-6.31) and CD4 cell counts greater than 350 cells/μL (4.50; 2.58-7.86). At 12 months, 1715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89-269) cells/μL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites. CONCLUSIONS Large differences in prescription but not in outcome were observed among study sites. A trend toward individualized cART was noted suggesting that initial cART is significantly influenced by physician's preference and patient characteristics. Our study highlights the need for evidence-based data for determining the best initial regimen for different HIV-infected persons.

An investigation of the possible interaction between the use of Vitamin C and highly active antiretroviral therapy (HAART) adherence and effectiveness in treated HIV+ women

Our goal in this study was to examine how Vitamin C interacts with antiretroviral therapy in individuals with HIV. We specifically evaluated how Vitamin C impacts highly active antiretroviral therapy (HAART) adherence and HAART effectiveness as adjudicated by HIV viral loads and CD4 cell counts. Women served as their own controls, comparing periods of Vitamin C usage with periods of non-usage. An intra-individual, cross-sectional comparative study 'nested' in the WIHS observational cohort study. Women in the Women's Interagency HIV Study (WIHS). Adherence, CD4 count and viral load. Our study population was drawn from 2813 HIV+ participants who contributed 44,588 visits in WIHS from October, 1994 to April, 2009. Among them, there were 1122 Vitamin C users with 4954 total visits where use was reported. In the multivariate model adjusting for age, education, race, income, drug use, Vitamin C use order and depression score, there was a 44% increase in the odds of ≥ 95% HAART adherence among participants during their period of Vitamin C use compared to when they were not using Vitamin C (OR=1.44; 95% CI=1.1-1.9; P-value=0.0179). There was an association with Vitamin C usage and CD4 counts on viral loads. Vitamin C usage appears to be associated with improved adherence. Future Vitamin C studies should target specific HAART drugs, and prospective clinical outcomes.

Effect of baseline CD4 cell counts on the clinical significance of short-term immunologic response to antiretroviral therapy in individuals with virologic suppression.

Achieving virologic suppression is a clear therapeutic goal for patients receiving combination antiretroviral therapy (cART). However, the effects of immunologic responses, whether measured as CD4 count changes from baseline or CD4 counts at follow-up, in patients with virologic suppression, have not been clearly established. Treatment-naive individuals aged > or =16 years, who initiated cART between 1998 and 2005 in participating cohorts of the ART Cohort Collaboration and achieved viral load < or =400 copies per milliliter 6 months after cART initiation, were included. We used Cox models to examine associations of CD4 change from baseline to 6 months, and absolute CD4 counts at 6 months, with subsequent rates of mortality and AIDS. Analyses were stratified by baseline CD4 count. Among 23,679 eligible participants, the median increase in CD4 count at 6 months, and the implications of these increases for subsequent mortality and AIDS, varied with baseline CD4 count. Mortality hazard ratios for increases of 0-50 cells per microliter, compared with >100 cells per microliter, were 1.87 (95% confidence interval: 1.28 to 2.73), 1.60 (1.13 to 2.28), 0.98 (0.58 to 1.65) and 1.24 (0.70 to 2.18) in participants with baseline CD4 cell count <50, 50-199, 200-349 and > or =350 cells per microliter, respectively. In contrast, hazard ratios for mortality or AIDS associated with absolute CD4 cell counts at 6 months were similar across all but the highest baseline CD4 cell count strata. It is not possible to derive thresholds for change in CD4 count that define an adequate immunologic response in individuals receiving cART. Absolute CD4 counts at 6 months are a more useful measure of immunologic response and subsequent prognosis.

Pathogenesis of HIV Disease: Opportunities for New Prevention Interventions

Current efforts to prevent human immunodeficiency virus (HIV) disease, which largely focus on altering human behavior, have had some notable successes yet have failed to halt the spread of the acquired immunodeficiency syndrome pandemic. A greater understanding of the pathogenesis of HIV disease is providing us with the scientific rationale for additional approaches to prevention. Some of the approaches discussed in this article are available now. For example, we have the means to screen for and treat other sexually transmitted diseases that increase vulnerability to HIV, adult male circumcision is readily available in most properly equipped hospitals, and antiretroviral agents that decrease the viral load help prevent transmission from pregnant women to their infants. Other approaches discussed are under investigation. For instance, numerous topical microbicides are in various stages of development, incremental progress is being made toward creation of an HIV vaccine designed to prevent HIV transmission or slow the course of disease in people who become infected, and studies are under way to evaluate the risks and benefits of prophylactic antiretroviral therapy in individuals at high risk for HIV disease.

Use of Hyaluronic Acid for Soft Tissue Augmentation of HIV-Associated Facial Lipodystrophy

Lipodystrophy syndrome is a devastating complication of antiretroviral therapy in individuals with human immunodeficiency virus (HIV). The appearance of the associated facial lipoatrophy can be demoralizing and stigmatizing for the affected individuals to a point at which it may compromise their compliance with antiretroviral medication. We describe the use of hyaluronic acid as an intradermal filler for correction of this disfiguring problem. We treated five patients with grade 2 to 3 facial lipoatrophy. Each patient received approximately 5 to 6 cc in total of hyaluronic acid in the malar area via intradermal injection. There were no adverse events. We found that this technique provided a good cosmetic result with high patient satisfaction. At 6-month follow-up, sustained longevity was observed. We propose the use of hyaluronic acid for HIV-associated facial lipoatrophy as an efficacious and safe, but temporary, option for this problem until a more cost-effective option is available.

Relationship of Emotional Intelligence and Adherence to Combination Antiretroviral Medications by Individuals Living With HIV Disease

Medications are an intentional and purposeful means to the successful management of many chronic diseases. In the treatment of disease caused by HIV, adherence to medication is of particular concern because any level of nonadherence, often a few missed doses, will lead eventually to the development of drug resistance. Many predictors of poor adherence to HIV medications have been identified as significant factors in adherence. Among these is the emotional aspect. The purpose of this study was to examine emotional intelligence (EI) and adherence to combination antiretroviral therapy in individuals who are infected with HIV. EI is defined as the ability to perceive and express emotions, facilitate emotions, understand and reason with emotion, and manage emotions. EI has been correlated with various aspects of success in life. In this study, EI was measured by the Mayer, Salovey, Caruso Emotional Intelligence Test. Adherence to medications was measured by self-report and defined as less than 10% missed doses of medications. Eighty-two participants were recruited from an urban hospital-based HIV clinic. Pearson's r was used to analyze the data for significance, and no correlation was reported. This data set was not large enough to prove significance, statistically, of the research question. However, an unexpected result of this study was that the overall EI scores for this particular population were markedly lower than the test norms. Further study would be warranted and recommended to explore El measurement in people at risk for HIV disease or in those who have the disease to further understand the impact of emotions and EI in this specific population.

Immunological and virological responses to highly active antiretroviral therapy in a non‐clinical trial setting in a developing Caribbean country

Few data exist on the efficacy of antiretroviral therapy in individuals infected with HIV in the Caribbean. We evaluated the virological and immunological responses of HIV-infected adults starting highly active antiretroviral therapy (HAART). This was a prospective observational cohort study. A total of 158 antiretroviral-naive patients who initiated HAART between January 2002 and March 2003, and completed at least 6 months of treatment and follow up, were included in the analysis. The response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. The mean increase in CD4 cell count, the rate of virological success (a viral load of <50 HIV-1 RNA copies/mL) and the rate of immunological success (an increase in CD4 cell count of > or =50 cells/microL over the baseline value) after commencing HAART were measured. In total, 82% of patients (123 of 150) achieved viral loads of <50 copies/mL after 6 months of therapy. Viral success rate after 6 months of HAART was similar irrespective of gender, pre-HAART CD4 cell count and pre-HAART viral load. However, patients older than 40 years were significantly more likely to achieve virological success than those younger than 40 years. At 6 months after starting HAART, 79.5% of patients were estimated to have achieved immunological success and 17.9% had an increase in CD4 cell count of > or =200 cells/microL over the baseline value. The median increase in CD4 cell count for the 156 patients who had CD4 cell counts at baseline and at 6 months of therapy was 122 cells/microL. In this cohort of antiretroviral-naive HIV-infected adults, there was a high rate of virological and immunological success after 6 months of HAART, irrespective of the pre-HAART viral load and CD4 cell count.

New Guidelines for Antiretroviral Therapy in Nonoccupational Postexposure Prophylaxis

In late January, the CDC released guidelines on the use of antiretroviral therapy in individuals possibly exposed to HIV through sexual intercourse,

Use of Hyaluronic Acid for Soft Tissue Augmentation of HIV-Associated Facial Lipodystrophy

BACKGROUND Lipodystrophy syndrome is a devastating complication of antiretroviral therapy in individuals with human immunodeficiency virus (HIV). The appearance of the associated facial lipoatrophy can be demoralizing and stigmatizing for the affected individuals to a point at which it may compromise their compliance with antiretroviral medication. OBJECTIVE We describe the use of hyaluronic acid as an intradermal filler for correction of this disfiguring problem. METHODS We treated five patients with grade 2 to 3 facial lipoatrophy. Each patient received approximately 5 to 6 cc in total of hyaluronic acid in the malar area via intradermal injection. RESULTS There were no adverse events. We found that this technique provided a good cosmetic result with high patient satisfaction. At 6-month follow-up, sustained longevity was observed. CONCLUSIONS We propose the use of hyaluronic acid for HIV-associated facial lipoatrophy as an efficacious and safe, but temporary, option for this problem until a more cost-effective option is available.

Special considerations in the initiation and management of antiretroviral therapy in individuals coinfected with HIV and hepatitis C

Although hepatitis C (HCV) treatment efficacy has improved in recent years, the majority of HIV/HCV-coinfected individuals may not enjoy the full benefits of these treatments and appropriate HIV management is crucial. Evidence is accumulating regarding the impact of HIV/HCV coinfection on the response to, and safety and tolerability of, antiretroviral therapy (ART) in this population. Computerized, English-language literature searches of MEDLINE and PubMed databases (January 1985 to May 2004) for studies of HIV and HCV infection in humans to examine critically (a) the impact of HCV on the HIV virologic and immunologic response to ART; (b) the safety and tolerability of ART in coinfected individuals; and (c) the relationship between immune suppression and immune restoration on hepatic injury. Three key messages emerged regarding the use of ART in HIV/HCV-coinfected individuals: (a) although HCV appeared to have no impact on HIV virologic response, the data are equivocal regarding immunologic response; (b) morbidities associated with HCV infection, such as insulin resistance, diabetes, mitochondrial dysfunction, and liver inflammation, are also associated toxicities of ART, and (c) both immune suppression and restoration can contribute to the onset and acceleration of HCV-related liver disease. The CD4 cell count threshold for initiating ART in HIV/HCV-coinfected patients may be higher because of the impact of immune suppression and restoration on the onset of HCV-associated liver disease and the possibility of a blunted immune response to ART at lower CD4 cell counts. Further, overlapping morbidity between HCV-related mitochondrial and metabolic disease manifestations and ART toxicities warrant careful attention by clinicians.

Viral reservoirs/transient infection in HIV/AIDS: where are we now and where should we go? Summary of the June 13-14, 2002 Think Tank meeting.

Highly active antiretroviral therapy in individuals infected with human immunodeficiency virus (HIV) often lowers serum levels of virus to below current detection limits. However, cessation of therapy results in there appearance of virus replication, indicating that HIV-infected cells persist in such individuals. Identification, and elimination, of such reservoirs of virus-infected cells are crucial for eradicating HIV from infected individuals. More research studies are needed to devise strategies with the potential for eventually curing HIV infections. Specifically, research areas that are of particular importance include (1) identification of reservoirs of resting cells infected by HIV, (2) elucidation of the mechanism of establishment and maintenance of the latent state, (3) understanding the biology and clinical outcome of transient infection, and (4) development of more sensitive methods of detecting and studying HIV infection of cells in vitro and in vivo.

Interleukin-2-associated viral breakthroughs induce HIV-1-specific CD4 T cell responses in patients on fully suppressive highly active antiretroviral therapy.

The combination of intermittent subcutaneous IL-2 and highly active antiretroviral therapy in individuals infected with HIV-1 has been shown to have a beneficial quantitative effect on the CD4 T cell count. We observed IL-2-associated viral load 'blips' inducing HIV-1-specific lymphoproliferative responses at 24 weeks in such individuals. This immunotherapeutic approach, utilizing autologous virus as autovaccination, may be a viable, safer alternative to structured treatment interruption and potentially more efficacious than therapeutic vaccines.

Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1.

Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probably depend on reconstitution of antigen-specific CD4+ lymphocyte responses to important pathogens, including cytomegalovirus (CMV), the leading cause of blindness in AIDS. Several studies have demonstrated an important role for CD4+ lymphocytes in controlling CMV replication in vitro and in clinical studies. It is now possible to quantitate antigen-specific CD4+ lymphocyte responses by flow cytometry. Using this method, we studied CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 with and without a history of active CMV-associated end organ disease (EOD), and in those with quiescent CMV EOD after ganciclovir therapy and HAART. The presence of active CMV-associated EOD strongly correlated with loss of CMV-specific lymphocyte responses (P = 0.0004). In contrast, patients with no history of CMV-associated EOD and most patients with quiescent EOD after HAART demonstrated strong CMV-specific CD4+ lymphocyte responses. These data indicate that the loss of CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 who have active CMV EOD may be restored after ganciclovir therapy and HAART, which provides evidence for functional immune reconstitution to an important pathogen.