Efficacy Of Combination Antiretroviral Therapy Research Articles

Efficacy of combined antiretroviral therapy (cART) in Hepatitis B and C associated hepatocellular carcinoma (HCC): a narrative review

Introduction: HCC is the 3rd leading cancers in the world. Majority of HCC are due to chronic viral hepatitis including HBV, HCV, and HDV. Progression to cirrhosis and HCC in HBV and HCV infection is linked to level of replication and high serum viral DNA load. The use of antiviral agents is an effective strategy of treating HBV- and HCV- associated HCC. Aim: To assess the effectiveness of combined antiretroviral therapy on HBV and HCV-associated HCC Method: A narrative review of literature involving RCT and observational studies was performed. Blinding scores was used to evaluate the quality of the studies. This review was informed by one of the author’s experience with hepatitis virus in Africa. Discussion: The five studies were found to be useful in reducing viral load and improving the pathology of HBV- and HCV- associated cirrhosis, HCC, and decompensated liver disease. The combinations are sofosbuvir plus ledipasvir, declatasvir plus asunaprevir, grazoprevir plus elbasvir with or without ribavirin, ombitasvir, paritaprevir, ritonavir plus ribavirin, sofosbuvir plus ribavirin. However, resistance to either drug or both is a problem that needs to be addressed.

Differential Responsiveness of the Platelet Biomarkers, Systemic CD40 Ligand, CD62P, and Platelet-Derived Growth Factor-BB, to Virally-Suppressive Antiretroviral Therapy.

Systemic biomarkers of inflammation, including cytokines and chemokines, are potentially useful in the management of both HIV infection and non-AIDS-defining disorders. However, relatively little is known about the utility of measurement of circulating biomarkers of platelet activation as a strategy to monitor the efficacy of combination antiretroviral therapy (cART), as well as the persistence of systemic inflammation following virally-suppressive therapy in HIV-infected persons. These issues have been addressed in the current study to which a cohort consisting of 199 HIV-infected participants was recruited, 100 of whom were cART-naïve and the remainder cART-treated and virally-suppressed. Fifteen healthy control participants were included for comparison. The study focused on the effects of cART on the responsiveness of three biomarkers of platelet activation, specifically soluble CD40 ligand (sCD40L), sCD62P (P-selectin), and platelet-derived growth factor-BB (PDGF-BB), measured using multiplex suspension bead array technology. Most prominently sCD40L in particular, as well as sCD62P, were significantly elevated in the cART-naïve group relative to both the cART-treated and healthy control groups. However, levels of PDGF-BB were of comparable magnitude in both the cART-naïve and –treated groups, and significantly higher than those of the control group. Although remaining somewhat higher in the virally-suppressed group relative to healthy control participants, these findings identify sCD40L, in particular, as a potential biomarker of successful cART, while PDGF-BB may be indicative of persistent low-level antigenemia.

Anti-HIV Activity of Standard Combined Antiretroviral Therapy in Primary Cells Is Intensified by CCR5-Targeting Drugs.

The efficacy of combined antiretroviral therapy (cART) against HIV-1 is evidenced by reduction of plasma viremia, disease progression, viral transmission, and mortality. However, major challenges still remain in HIV-1 management, especially the emergence of resistant strains and the persistence of viral reservoirs, apparent after cART treatment interruption. Efforts are ongoing to explore the most effective means to intensify cART and successfully control residual viral replication. We anticipate that the reduction by cART of HIV-1 reservoirs could be further enhanced by combining cART with entry inhibitors and drugs that silence CCR5 expression. CCR5-targeting drugs are attractive option because of their low side effects when combined with other antiretroviral drugs. The concept that their inclusion would be effective has been supported by the reduction in two long terminal repeat unintegrated circular DNA, a marker for new infections, when CCR5-targeting drugs are added to standard antiretroviral treatment. This study is, in part, an extension of our previous study demonstrating greater preservation of human CD4+ T-cells and CD4+/CD8+ cell ratios in HIV-infected CD34+ NSG mice when CCR5-targeting drugs were included with standard cART. In this study, we treated HIV-1-infected cell cultures with cART or cART plus CCR5-targeting drugs (maraviroc and rapamycin). We found that treatment intensification with CCR5-targeting drugs led to a significant reduction of HIV-1 replication in peripheral blood ononuclear cells (PBMCs), as judged by measured viral DNA copies and p24 levels. Our data provide proof of principle for the benefit of adding CCR5-targeting drugs to traditional, standard cART to further lower viremia and subsequently reduce viral reservoirs in clinical settings, while potentially lowering side effects by reducing cART concentrations.

Neuronal-derived extracellular vesicles are enriched in the brain and serum of HIV-1 transgenic rats

ABSTRACT Despite the efficacy of combination antiretroviral therapy (ART) in controlling human immunodeficiency virus (HIV-1) replication, cytotoxic viral proteins such as HIV-1 transactivator of transcription (Tat) persist in tissues such as the brain. Although HIV-1 does not infect neuronal cells, it is susceptible to viral Tat protein-mediated toxicity, leading to neuroinflammation that underlies HIV-associated neurocognitive disorders (HAND). Given the role of extracellular vesicles (EVs) in both cellular homoeostasis and under pathological conditions, we sought to investigate the alterations in the quantity of neuronal-derived EVs in the brain – as defined by the presence of cell adhesion molecule L1 (L1CAM) and to evaluate the presence of L1CAM+ EVs in the peripheral circulation of HIV-1 transgenic (HIV-1 Tg) rats. The primary goal of this study was to investigate the effect of long-term exposure of HIV-1 viral proteins on the release of neuronal EVs in the brain and their transfer in the systemic compartment. Brain and serum EVs were isolated from both wild type and HIV-1 Tg rats using differential ultracentrifugation with further purification using the Optiprep gradient method. The subpopulation of neuronal EVs was further enriched using immunoprecipitation. The current findings demonstrated increased presence of L1CAM+ neuronal-derived EVs both in the brain and serum of HIV-1 Tg rats.

Involvement of Epigenetic Promoter DNA Methylation of miR-124 in the Pathogenesis of HIV-1-Associated Neurocognitive Disorders.

Despite the efficacy of combination antiretroviral therapy (cART) in controlling viremia, the central nervous system (CNS) continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Transactivator of transcription (HIV-1 Tat) protein. Based on the premise that cART does not impact levels of HIV-1 Tat, and since the CNS is inaccessible to the cART regimens, HIV-1-Tat-mediated neuroinflammation has been implicated as an underlying mediator of HIV-1-associated neurocognitive disorders (HAND). The mechanism(s) underlying the pathogenesis of HAND, however, remain less understood. Understanding the epigenetic/molecular mechanism(s) by which viral proteins such as HIV-1 Tat activate microglia is thus of paramount importance. The study published by Periyasamy et al provides new mechanistic insights into the role of HIV-1-Tat-mediated DNA methylation of miR-124 promoter in regulating microglial activation via the MECP2-STAT3 signaling axis. Furthermore, the authors have also reported that exposure of mouse primary microglial cells to HIV-1 Tat notably increased DNA methylation of primary miR-124-1 and primary miR-124-2 promoters (with no change in primary miR-124-3), resulting in turn to downregulated expression of both primary miR-124-1 and primary miR-124-2 as well as mature miR-124 in mouse primary microglial cells. The authors also examined the involvement of MECP2-STAT3 signaling in HIV-1-Tat-mediated microglial activation. Based on these novel findings, it is evident that dysregulation of miR-124 is involved in the pathogenesis of HAND and that restoration of miR-124 could serve as an adjunctive treatment for dampening neuroinflammation associated with HAND.

Evaluating Liver Fibrosis by Transient Elastometry in Patients With HIV-HCV Coinfection and Monoinfection.

Background:Due to the high efficacy of combination antiretroviral therapy (cART), the number of patients living with HIV is increasing. Chronic HCV infection has become a leading cause of non-AIDS related morbidity and mortality in patients with HIV infection.Objectives:The aim of this cross-sectional study was to identify factors associated with liver fibrosis (LF) in patients with HIV monoinfection and HIV-HCV coinfection.Patients and Methods:We analyzed LF by transient elastometry ([TE], Fibroscan) in three groups of patients (HIV, HIV-HCV and HCV) followed at the Infectious Diseases Department of University of Ancona, Italy, between October 2009 and November 2012.Results:In total, 354 adults including 98 HIV, 70 HIV-HCV and 186 HCV patients were studied. HIV-HCV patients had a longer duration of HIV (P < 0.006) and HCV (P < 0.001) infections. Additionally, they were receiving cART therapy for a longer period (P < 0.001); they had higher prevalence of lipodystrophy (P < 0.001) and higher HCV load (P = 0.004). LF was significantly more pronounced in HCV and HIV-HCV compared to HIV patients (P < 0.001). A total of 13.3%, 39.2% and 51.4% of HIV, HCV and HIV-HCV, respectively, showed a LF ≥ F2. Additionally, a severe LF (F = 4) was significantly more frequent among HIV-HCV compared to other groups. A longer exposure to didanosine, stavudine, lopinavir/ritonavir and fosamprenavir resulted in increased LF by univariate analysis (P ranging from < 0.001 to 0.007). By logistic regression analysis, the only variables significantly associated with increased LF were HCV coinfection, older age, and high AST values (P ranging from < 0.001 to 0.036).Conclusions:HCV coinfection, older age and AST were associated with LF in patients with HIV infection.

HIV-1 DNA Levels in Peripheral Blood Mononuclear Cells and Cannabis Use are Associated With Intermittent HIV Shedding in Semen of Men Who Have Sex With Men on Successful Antiretroviral Regimens

Few data exist on the efficacy of combined antiretroviral therapy (cART) in semen of human immunodeficiency virus type 1 (HIV-1) infected men who have sex with men (MSM) with sustained control of HIV replication in blood. HIV-1 infected MSM on successful cART for >6 months were enrolled. HIV-RNA was quantified in seminal plasma (spVL) and in blood plasma (bpVL) from 2 paired samples collected 4 weeks apart. Relationship between spVL and bpVL (measured by an ultrasensitive assay, LOQ 10 copies/mL), total peripheral blood mononuclear cells (PBMC)-associated HIV-DNA, sexually transmitted infections (STIs), and self-reported socio-behavioral characteristics was assessed using GEE logistic regression. In total, 157 patients were included. Median time with bpVL <50 copies/mL was 3.3 years. spVL was detectable in 23/304 samples (prevalence 7.6%). Median spVL was 145 cp/mL (100-1475). spVL was detectable on the first, on the second, and on both samples in 5, 14, and 2 men, respectively. In sum, 33 individuals (21%) had STIs (asymptomatic in 24/33). Residual bpVL was undetectable by ultrasensitive assay in 225/300 samples (75%). After multivariable adjustments, PBMC-associated HIV-DNA (OR 2.6[1.2; 6.0], for HIV-DNA > 2.5 log10 cp/10(6) PBMC, P = .02), and cannabis use during sexual intercourse (OR 2.8[1.2; 6.7], P = .02) were the only factors associated significantly with spVL. We show that HIV-RNA can be detected intermittently in semen of HIV-1 infected MSM despite successful cART. The size of blood HIV-1 reservoir predicted spVL detection. Our results indicated also that the possible effect of cannabis should be taken into account when developing prevention interventions targeted toward HIV-infected MSM on successful cART.

Long-Term Efficacy of First Line Antiretroviral Therapy in Indian HIV-1 Infected Patients: A Longitudinal Cohort Study

BackgroundShort term efficacy of combination antiretroviral therapy (cART) in resource-constrained settings is comparable to that found in western studies. However, long term data are limited. India has the third largest HIV infected population in the world but the long-term outcome of first line therapy according to the national guidelines has not been evaluated yet. Therefore, we conducted a long-term longitudinal analysis of the efficacy of the national first-line therapy in India from an observational cohort of Indian patients in two different clinical settings.Methodology/Principal FindingsA total 323 patients who had been on ART for a median of 23 months and achieved virological suppression <100 copies/ml by their study baseline visit, were included and followed for two years. Blood samples were collected every six months for viral load and CD4 count. Drug resistance genotyping was performed when the viral load was >2000 copies/mL. Adherence and treatment interruptions (>48 h) were assessed via self-report. In the studied patients, the median duration of viral suppression was 44 months; 15.8% of patients showed viral rebound, and 2.8% viral failure. Viral rebound or failure was significantly negatively related to perfect adherence (100% adherence and no treatment interruption >48 hrs). Virological re-suppression in the subsequent visit was observed in three patients without any change in therapy despite the presence of key mutations.Conclusion/SignificanceOur study reports for the first time, a good long-term response to the first line therapy for a median of nearly four years although a less than perfect adherence increases the risk for treatment failure and subsequent drug resistance development. The empirical findings in this study also indicate the overall success of the Indian ART program in two different settings which likely are representative of other clinics that operate under the national guidelines.

Epidemiology of Transmitted Drug Resistance in Chronically HIV-Infected Patients in Germany: The RESINA Study 2001–2009

Objectives: Transmitted HIV drug resistance may impair treatment efficacy of combination antiretroviral therapy (ART). This study describes the epidemiology of transmitted resistance in chronically infected patients. Methods: In a prospective multicenter trial in Nordrhein-Westfalen, Germany, transmitted drug resistance was determined by genotypic resistance testing in patients on initiation of first-line ART. Results: From 2001 to 2009, 2,078 patients were enrolled in the study. 79.9% were male, 81.2% were Caucasians, and a homosexual transmission mode was found in 51.3%. Of these patients, 41.5% were at the stage of AIDS, median CD4 cell count was 230/µl, and median viral load was 64.466 copies/ml. Transmitted drug resistance mutations were seen in 9.2% (95% CI, 7.9–10.4). Resistance in the nucleoside reverse transcriptase inhibitor class was found in 5.8% (4.8–6.8), in the nonnucleoside reverse transcriptase inhibitor class in 2.8% (2.1–3.6), and in the protease inhibitor class in 2.7% (2.0–3.4). After a continuous increase to a level above 10% in the years 2006 and 2007, a decline of drug resistance prevalence followed in 2008 and 2009. Conclusions: Transmitted HIV drug resistance was found in around 10% of chronically infected patients in Germany who started their ART. We showed a moderate decline of the prevalence of mutant virus strains in recent years. Further surveillance of this phenomenon is mandatory.

The Efficacy of Combination Antiretroviral Therapy in HIV Type 1-Infected Patients Treated in Curaçao Compared with Antillean, Surinam, and Dutch HIV Type 1–Infected Patients Treated in The Netherlands

We compared the efficacy of combination antiretroviral therapy (cART) of Antillean HIV-1-infected patients treated on the Caribbean island of Curaçao (CUR-AN) with Antillean (NL-AN), Surinam (NL-SUR), and Dutch (NL-NL) patients treated in The Netherlands. In total 2118 therapy-naive patients who started cART between January 2005 and August 2008 were included in the comparison. The CUR-AN patients initiated cART at a median CD4 cell count of 141 cells/mm(3) and 63% had counts below 200 cells/mm(3). Within 12 months of the start of cART 76% of the CUR-AN patients achieved viral suppression, defined as HIV-1 RNA plasma levels below 80 copies/ml. The percentage achieving viral suppression was higher in patients treated in The Netherlands (NL-AN = 87%, NL-SUR = 93%, and NL-NL = 96%). Lost to follow-up after 30 months of cART was 10% among CUR-AN patients and was higher than observed among patients treated in The Netherlands (NL-AN = 8%, NL-SUR = 3%, and NL-NL = 2%). A similar pattern was found for progression to AIDS and death (10% of CUR-AN vs. 5%, 6%, and 7% of NL-AN, NL-SUR, and NL-NL patients, respectively). Late start of cART and limited viral suppression after the start of cART determine the higher rate of disease progression to AIDS and death among Antillean patients treated in Curaçao. The high percentage of lost to follow-up may result in an underestimation of AIDS and AIDS-related death among HIV-1-infected Antilleans treated in Curaçao.

Therapeutic drug monitoring in highly active antiretroviral therapy

Importance of the field: Despite the efficacy of combination antiretroviral therapy (ART), a large proportion of patients living with HIV/AIDS on ART does not achieve or maintain adequate virological suppression. Therapeutic drug monitoring (TDM) has been utilised to improve treatment outcomes of ART.Areas covered in the review: The potential incorporation of TDM into the clinical HIV management is supported by the existing relationship between drug exposure and efficacy/toxicity, the high inter-patient variability pharmacokinetics, and the accurate, specific and rapid method for drug level determination. The current status of TDM in ART is reviewed in this article with discussions on its feasibility, potential use and limitations.What the reader will gain: Mounting evidence from clinical trials has indicated the potential use of TDM in reducing the rates of treatment failure and adverse effect, avoiding the drug interactions, and special populations, such as children, pregnant women and patients with co-infections. TDM may play an important role even in resource-limited settings, to safeguard expanded use of bioequivalent generic antiretroviral drugs and avoid drug interactions with traditional Chinese medicines.Take home message: TDM is still in the centre of controversy in that several critical issues need to be addressed, such as limited adherence assessment, inappropriate response predictors, insufficient validation of target concentration windows and lack of the quality control of assay. The utility of TDM will remain experimental until more data are obtained from large clinical trials showing the benefit of TDM.

Therapeutic drug monitoring of antiretrovirals for people with HIV

Despite the efficacy of combination antiretroviral therapy (ART) and the improvement in prognosis of those living with HIV/AIDS, a large proportion of individuals on ART does not achieve or maintain adequate virological suppression. Several tools have been proposed to enhance ART outcomes, including therapeutic drug monitoring (TDM) of antiretrovirals (ARVs). The aim of ARV TDM is to identify elevated (potentially toxic) or low (potentially sub-therapeutic) ARV concentrations. ARV TDM may thus optimise efficacy and minimise toxicity of ART. To evaluate whether ARV TDM reduces mortality and morbidity of adult patients on ART. The primary outcome measures that have been assessed include death (all cause); occurrence of HIV-related events (death or AIDS-defining illness) and the proportion of patients achieving and maintaining an undetectable viral load, as defined by the authors. We conducted a comprehensive search including both published and unpublished studies in all languages in MEDLINE, EMBASE and The Cochrane Library, between January 1980 and January 2008. Databases listing conference abstracts and reference lists of articles were searched. Additional data were sought from relevant authors; however, no additional data were provided. Only randomized controlled trials conducted subsequent to the introduction of combination ART were included in this systematic review. Participants could be on either a protease inhibitor (PI)-based regimen or non-nucleoside reverse transcriptase (NNRTI)-based regimen and be either ARV-naive or -experienced. Two reviewers independently assessed and extracted data for analysis. Meta-analysis was conducted where appropriate. Where study outcomes could not be combined, a narrative review was performed. Outcome measures for dichotomous data were reported as a relative risk with 95% confidence intervals. Stratified analyses were conducted by ARV regimen and treatment groups. Heterogeneity between studies was anticipated; therefore, random effects models were chosen to generate pooled effects. Differences in the findings were assessed by the chi square test for heterogeneity (p <0.1) that was quantified by the Higgins I(2) statistic. Identified were 1408 records, and eight trials with a total of 1181 participants were included in the review. Trials were conducted in higher income earning countries between 2002 and 2007. Sample sizes ranged between 40 and 230. The methodological quality of the studies was judged to be generally good, although allocation concealment was reported in only three of the eight studies. A meta-analysis including three studies did not show any significant effect on virological suppression below 500 HIV-RNA copies/mL at one year (RR 1.28; [0.86, 1.92] chi(2) = 11.55 (P = 0.003), I(2) = 83%). Two trials including participants predominantly treated with unboosted PI-based regimens reported a 49% increased likelihood of achieving a HIV-RNA viral load below 500 copies/mL at 52 weeks (RR 1.49 [1.20, 1.83] chi(2) = 0.69 (P = 0.4), I(2) = 0%). Safety outcomes were reported in four studies and were similar between TDM and standard of care. Uptake of expert advice based on TDM results was good in two trials (>70%), but low (<35%) in the remaining three studies that reported uptake of the recommendations. Our review does not support routine use of ARV TDM in ARV-naive or -experienced patients on either boosted PI or NNRTI ART regimens. TDM in treatment-naive participants on a PI-based ART regimen, particularly if unboosted by ritonavir, may improve virological outcomes. Trials were underpowered with small sample sizes, short durations of follow-up and generally poor uptake of TDM recommendations. As these trials were conducted in higher income earning countries, results may not be generalisable to resource-limited countries where the burden of HIV is heaviest.

Efficacy and toxicity of antiretroviral therapy using 4 or more agents: application of a strategy for antiretroviral management in human immunodeficiency virus-infected children.

To characterize the long-term tolerance and virologic efficacy of combination antiretroviral therapy consisting of 4 or more agents in a clinical setting. An observational review of 36 children infected with human immunodeficiency virus 1 (HIV-1) treated with 4 or 5 antiretroviral agents in 2 university hospital clinics between April 1, 1996, and October 31, 2000. Highly active antiretroviral therapy regimens were chosen with regard to the child's past antiretroviral exposure or results of genotypic resistance data. Plasma HIV-1 RNA levels were monitored weekly to monthly after initiation of highly active antiretroviral therapy, and adherence efforts were actively supported and monitored. Number of children with undetectable plasma HIV-1 RNA levels at longest follow-up. Four- or 5-drug highly active antiretroviral therapy reduced plasma HIV-1 RNA levels to less than 50 copies/mL in 32 (89%) of 36 children. After a median of 28.7 months of observation, 28 children (78%) remained at this level of suppression. Adverse reactions were limited to mild neutropenia and mild transient or persistent elevations in alanine aminotransferase levels in 11% of children. Treatment with 4 or 5 antiretroviral agents was well tolerated in HIV-1-infected children and resulted in a high degree of viral suppression, even in children with previous antiretroviral drug experience.

Combination antiretroviral therapy in 100 HIV-1-infected pregnant women.

In recent years, combination antiretroviral therapy has substantially improved the prognosis of human immunodeficiency virus type-1 (HIV-1) infection. However, at present, information regarding the effects of these regimens during pregnancy is limited. Side-effects, vertical transmission rate and neonatal outcome associated with different combination therapies were evaluated retrospectively in a consecutive series of 100 women who attended the II Department of Obstetrics and Gynecology for the management of HIV-1 infection in pregnancy. Antiretroviral treatment was initiated at a median of 16 weeks gestation with a range from pre-pregnancy until 31 weeks gestation. Twentythree women continued their pre-pregnancy therapy during the first trimester of gestation. Protease inhibitors were incorporated in 23 of the final therapeutic regimens. Twentyfive women did not receive zidovudine. Most women (97) delivered by Caesarean section and none breast-fed. Prematurity rate for the entire series was 19%. When women who actively used illicit drugs were excluded, only seven of 69 (10%) women were found to deliver prematurely. The use of protease inhibitors was limited by an elevated frequency of severe gastrointestinal disturbances. The rate of congenital malformations did not appear to differ significantly from that reported in the literature for the general population. Only one of 102 live newborns was found to be HIV-1-infected (1.0%, 95% confidence interval; 0.3-4.6%). The present findings confirm the remarkable efficacy of combination antiretroviral therapy, Caesarean section and refraining from breast-feeding in lowering the rate of vertical HIV-1 transmission. Moreover, they are suggestive that combination antiretroviral therapy may not be related to major neonatal toxicity. The necessity to discontinue the therapy during the first trimester of pregnancy and to systematically incorporate zidovudine into combination regimens is discussed.

Anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency.

The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8(+) T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8(+) T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8(+) T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8(+) cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-gamma production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8(+) CD45RO(+) cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8(+) T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.

Efficacy of combination antiretroviral therapy.

Combination therapy with two nucleosides has been shown to improve clinical outcome compared with zidovudine monotherapy. There is every expectation that more potent antiretroviral combination regimens will increase the clinical benefits. However, this remains to be proven definitely. The increasing number of choices of antiretroviral therapies create new challenges for those studying and those using these therapies.

Inhibition of HIV-1 transmission by interferon and 3′-azido-3′-deoxythymidine during de novo infection of promonocytic cells

HIV-1 infection of promonocytic U937 cells was used to examine induction of IFN-α/β gene expression and to determine the inhibitory effects of IFN-α2 and/or AZT on de novo HIV-1 infection, initiated either by coculture of virus-shedding U9-IIIB cells with uninfected cells or by incubation of U937 cells with virus-containing supernatants. Usually 21–28 days were required to transmit virus to >90% of the cell culture. HIV-1 infection did not stimulate constitutive production of endogenous IFN-α1 /ga2 or IFN-β genes, although induction of IFN RNA was observed following coinfection with the paramyxovirus Sendai. Exogenous rIFN-α2 treatment decreased the intracellular accumulation of viral RNA 5- to 20-fold as determined by Northern blot analysis and the extracellular levels of HIV-1 as measured by p24 ELISA antigen capture. The effect was most dramatic at a time coincident with the rapid increase in virus spread through the cell culture (Days 10–18). During the fourth week of infection, HIV-1 multiplication was able to overcome the IFN-induced block in virus spread. AZT was not effective in limiting virus spread in the cocultivation experiments. When U937 cells were infected with virus-containing supernatants from U9-IIIB cells, IFN and AZT acted in combination to limit the number of infected cells and to inhibit intracellular accumulation of viral RNA. These experiments suggest that subtle differences in the mode of virus transmission in monocytic cells may alter the efficacy of combination antiretroviral therapy.