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PubMed2005

Rates of antiretroviral resistance among HIV-infected patients with and without a history of injection drug use.

BACKGROUND: There exist concerns regarding the potential for elevated rates of antiretroviral resistance among HIV-infected injection drug users (IDUs) prescribed highly active antiretroviral therapy (HAART), however, no population-based study has examined if IDUs have elevated rates of antiretroviral resistance in comparison to non-IDUs. OBJECTIVE: To evaluate the time to the development of antiretroviral resistance among antiretroviral-naive patients with and without a history of injection drug use. METHODS: In British Columbia there is a province-wide HIV/AIDS treatment program that provides antiretrovirals free of charge. We examined all antiretroviral-naive patients initiating HAART between 1 August 1996 and 30 September 2000 and who were followed to 31 March 2002. The main outcome measure was the time to class-specific antiretroviral resistance. Cumulative antiretroviral resistance rates among IDUs and non-IDUs were evaluated using Kaplan-Meier methods and relative hazards were estimated using Cox regression. RESULTS: Overall, 1191 antiretroviral-naive patients initiated HAART during the study period. Resistance mutations were observed in 298 (25%) subjects during the first 30 months of HAART. In comparison with non-IDUs, the risk of protease inhibitor resistance [relative hazard (RH), 0.9; 95% confidence interval (CI), 0.5-1.6] and non-nucleoside reverse transcriptase inhibitor resistance (RH, 1.5; 95% CI, 1.0-2.2) were similar among IDUs, and there were no differences in the rates of resistance to the sub-classes of nucleoside reverse transcriptase inhibitors. CONCLUSIONS: Resistance to all major classes of antiretrovirals were similar among IDUs and non-IDUs after 30 months of follow-up. These findings should help to allay fears that prescribing HAART to IDUs may result in elevated rates of resistance.

Adult↗
PubMed1999

Increased polymerase fidelity of lamivudine-resistant HIV-1 variants does not limit their evolutionary potential.

OBJECTIVE: Anti HIV-1 therapy with nucleoside reverse transcriptase inhibitors can select for drug-resistant reverse transcriptase variants with altered enzyme properties. Some of the mutations, e.g. Met184Val and Met184Ile, result in an increase in polymerase fidelity of the enzyme as measured in biochemical assays; however, the effect of such changes on the fidelity during viral replication is largely unknown. In this study, the codon 184 variants were used to investigate whether the mutation at codon 184 affects the mutation spectrum and mutation rate of the mutant viruses. DESIGN AND METHOD: In vitro selection experiments with either wild-type or lamivudine-resistant viruses (Met184Val and Met184Ile) were performed using a protease inhibitor as the selective drug. In addition, a novel selection approach was developed using a mixture of viruses, instead of individual viruses, during the selection process. RESULTS: Comparison of a total of 108 protease-resistant variants revealed no significant difference in the mutational spectrum of the wild-type and the lamivudine-resistant variants. In addition, the selection experiments with the viral mixtures demonstrated no delay in the kinetics of mutation generation in response to an antiviral drug. CONCLUSION: This study demonstrates that the Met184Val and Met184Ile mutations in the HIV-1 reverse transcriptase enzyme do not significantly affect the evolutionary potential of the corresponding viruses.

Codon↗
PubMed1999

Salvage therapy with regimens containing ritonavir and saquinavir in extensively pretreated HIV-infected patients.

OBJECTIVE: To evaluate the efficacy and toxicity of salvage regimens containing ritonavir and saquinavir in patients failing highly active antiretroviral therapy (HAART), and to correlate outcome with plasma concentrations of protease inhibitors. DESIGN: Prospective, non-randomized interventional study. SUBJECTS AND METHODS: Thirty extensively pretreated HIV-infected patients with virological failure under HAART were treated with ritonavir (400 mg twice daily) and saquinavir (600 mg twice daily) and at least one reverse transcriptase inhibitor. HIV-RNA, CD4 cell counts and plasma concentrations of protease inhibitors were determined, and patients were monitored for toxicity at monthly intervals. RESULTS: Six patients showed complete virological success (HIV-RNA <200 copies/ml at week 12) which was sustained for a median follow-up of 6.3 months. Partial virological response (decrease of HIV-RNA of >1 log10 at week 12) was achieved by a further three patients. Patients with a virological response had significantly higher CD4 cell increases than patients without virological response (mean increase at week 12: 66x10(6) cells/l versus 6x10(6) cells/l; P = 0.01). No clinical events were observed during 6 months of follow-up. Neither the use of a non-nucleoside reverse transcriptase inhibitor (NNRTI) nor the number of newly introduced drugs influenced the virological response. Plasma concentrations of protease inhibitors did not statistically differ between patients with and without success. Toxicity included gastrointestinal disturbances, lipid abnormalities and liver dysfunction. CONCLUSIONS: In extensively pretreated patients, salvage regimens containing ritonavir and saquinavir had only limited and short-term anti-HIV activity and were associated with substantial toxicity. Plasma concentrations of saquinavir were not predictive for virological response.

Adult↗
PubMed2005

[Genotypic resistence in patients infected with HIV and its correlation with therapy].

BACKGROUND AND OBJECTIVE: Our goal was to establish the different therapeutic regimens used in our clinical setting, and to determine the prevalence of genotypic resistances in patients under antiretroviral therapy, analyzing the relationship between the appearance of mutations and treatments along with other HIV related variables. MATERIAL AND METHOD: 191 samples from the same number of patients who were on antiretroviral therapy and virological failure were analyzed. Samples were processed by means of the genotypic technique LiPA in order to study the presence of mutations in the reverse transcriptase (RT) and the protease (P) genes. Prescribed therapeutic regimens and epidemiological variables relevant in HIV infection were also analyzed. RESULTS: Overall resistance prevalence was 72.32%. By LiPA, RT mutations were detected in 71.43% of patients, being M184V, T215Y and L41M the most frequent ones. Moreover, P mutations were detected in 59.38% of cases, being V82A, L90M and I84V the most frequent ones. 61.02% of the patients presented one or more mutations against the reverse transcriptase inhibitors included in their treatment. With regard to protease inhibitors, this fact was documented in 28.81% of cases, and in 23.73% of patients receiving both reverse transcriptase inhibitors and protease inhibitors. CONCLUSIONS: Although the analysis of the mutation patterns by LiPA has known limitations, the prevalence of resistances in our study was different from that reported by other authors, being lower in the P gene and higher in the RT one. Of note, a high proportion of patients showed mutations against the drugs included in their prescribed treatment.

Drug Resistance, Viral↗
PubMed2005

A randomized, prospective study of phenotype susceptibility testing versus standard of care to manage antiretroviral therapy: CCTG 575.

OBJECTIVE: To assess phenotype susceptibility testing (PHENO) with standard of care (SOC) to improve antiretroviral therapy. DESIGN: A prospective, multicenter study of 238 patients taking a stable antiretroviral regimen for > 6 months, with one or two protease inhibitors (PI) and entry HIV RNA > 400 copies/ml. METHOD: Patients were randomized to receive or not receive PHENO results for selecting antiretroviral regimens. Primary outcome was HIV RNA measures. RESULTS: At baseline, median CD4 cell count was 277 x 10 cells/l and HIV RNA was 10 000 copies/ml; 76% had not taken a non-nucleoside reverse transcriptase inhibitor drug (NNRTI). There were significant differences between the groups in selection of baseline nucleoside reverse transcriptase inhibitor (NRTI). At month 6, reduction in HIV RNA was 0.71 and 0.69 log10 copies/ml for PHENO and SOC, respectively; the proportion with < 400 copies/ml (48%) was the same for both groups. No differences were seen at month 12. In a subgroup with resistance to four or more PI, 50% of the PHENO versus 17% of the SOC had HIV RNA < 400 copies/ml at month 6 (P = 0.02). The number of NNRTI and PI, but not NRTI, in the regimen that were active by phenotype at baseline was a strong independent predictor of viral suppression (P < 0.006). Use of alternative NRTI sensitivity cut-offs improved their predictive value. CONCLUSIONS: Although virological outcome was similar in both groups, the potential benefit of PHENO was seen in patients with more resistant virus. Lack of appropriate cut-offs may have partially accounted for the lack of benefit from PHENO and demonstrated the need to identify clinically relevant sensitivity cut-off points.

Adult↗
PubMed2004

Inhibition of HIV-1 reverse transcription: basic principles of drug action and resistance.

Nucleoside and non-nucleoside analog inhibitors of HIV Type 1 reverse transcriptase are currently used in the clinic to treat infection with this retrovirus. Following their intracellular activation, nucleoside analogs act as chain terminators, while non-nucleoside analog reverse transcriptase inhibitors bind to a hydrophobic pocket in close proximity to the active site and inhibit the catalytic step. Compounds that belong to the two different classes of drugs are frequently administered in combination to take advantage of the different mechanisms of drug action. However, the development of drug resistance may occur under conditions of continued, residual viral replication, which is a major cause of treatment failure. This review addresses the interaction between different inhibitors and resistance-conferring mutations in the context of combination therapy with drugs that target the reverse transcriptase enzyme. Focus is placed on biochemical mechanisms and the development of future approaches.

Anti-HIV Agents↗
PubMed2001

Mutations in the non-nucleoside binding-pocket interfere with the multi-nucleoside resistance phenotype.

OBJECTIVES: To investigate the genotypic and phenotypic effects of in vitro resistance selection with lamivudine and/or the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) quinoxaline HBY097 using HIV-1 isolates carrying the multi-nucleoside resistance pattern linked to the Q151M mutation. METHODS: Virus strains were selected in C8166 cells in the presence of increasing concentrations of lamivudine or HBY097. In parallel control experiments, the virus was cultured in C8166 cells in the absence of drugs. The entire reverse transcriptase encoding region was amplified using polymerase chain reaction and was subsequently sequenced. Antiviral activities of drugs were evaluated in C8166 cells. RESULTS: High-level resistant viruses were selected rapidly in the presence of lamivudine and quinoxaline (less than 10 passages). The multi-nucleoside resistance mutations were stable during in vitro resistance selection. Lamivudine elicited the acquisition of the M184I mutation. Phenotypic resistance to all nucleoside-analog reverse transcriptase inhibitors (NRTIs) was increased when M184I was added to the multi-nucleoside resistance background in the absence of NNRTI-resistance mutations. In most cases of HBY097 resistance selection, at least two mutations associated with NNRTI resistance resulted in high-level NNRTI resistance. The NNRTI resistance-related mutations partially reversed the phenotypic resistance to most NRTIs, except to abacavir. The addition of the M184I mutation to the NNRTI-multi-nucleoside resistance set abolished this antagonizing effect for didanosine, zalcitabine and lamivudine, but further potentiated the phenotypic reversal for zidovudine and stavudine. CONCLUSION: Changes in the non-nucleoside binding pocket must affect the conformation of residues at the dNTP binding site, and can result in a partial phenotypic reversal of the multi-nucleoside resistance phenotype.

Anti-HIV Agents↗
PubMed2006

Evolving simplified treatment strategies for HIV infection: the role of a single-class quadruple-nucleoside/nucleotide regimen of trizivir and tenofovir.

Simplified antiretroviral regimens have been developed with the aim of improving treatment adherence and quality of life of HIV-infected patients. The single-class triple-nucleoside reverse transcriptase inhibitor combination has contributed to the improvement of the management of HIV infection, especially in patients with adherence problems and special groups of the patient population. Such a regimen remains an alternative option because of lower virological efficacy compared with the preferred multiclass antiretroviral regimens. However, recently, a nucleoside reverse transcriptase inhibitor abacavir/lamivudine/zidovudine plus tenofovir has been investigated in both antiretroviral-naive patients and in heavily pre-treated patients, as well in the setting of simplification/switching strategies. This experimental combination could be a safe and attractive option that offers the advantages of limited toxicity, few drug interactions and the use of future treatment options with new drugs, especially for patients in later stages of infection.

Adenine↗
PubMed1995

[Chemotherapy and vaccine against HIV infection].

Anti-HIV treatment is the major strategy against HIV infection and AIDS. Nucleoside reverse transcriptase inhibitors have been studied extensively, and some of them have been approved for clinical use. Efficacy of non-nucleoside reverse transcriptase inhibitors and HIV-protease inhibitors are also being confirmed. It became clear, however, that all of these agent, allow emergence of drug-resistant HIV mutants when used as monotherapy. Therefore, combination therapy or alternating therapy using these and other new agents may become the main mode of treatment in the future. Clinical trials for HIV vaccines are now being conducted in U.S.A. and other countries. In many of them, immunological responses were confirmed, although clinical benefit was not known yet. Vaccines which induce cellular immunity against broad spectrum of epitopes are desired to overcome viral mutations. Gene therapy is very attractive, and extensive studies are being conducted in many laboratories including ours. Methodology for early and correct diagnosis of opportunistic infections are now developing especially by using molecular technology. Steady improvement in the clinical management of opportunistic infections is achieved.

AIDS Vaccines↗
PubMed2004

Anti-retroviral therapy with protease inhibitors decreases virulence enzyme expression in vivo by Candida albicans without selection of avirulent fungus strains or decreasing their anti-mycotic susceptibility.

Highly active anti-retroviral therapies (HAART) with human immunodeficiency virus (HIV) protease inhibitors (PIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTI) were compared for their effect on prevalence, aspartyl proteinase (Sap) production and the biotypes and anti-mycotic sequential susceptibility of Candida spp. isolates from the oral cavity in a longitudinal prospective study. HAART-PI, but not HAART-NNRTI strongly inhibited Sap expression in the oral cavity without exerting any consistent effect on the role of Candida spp. isolation or selection of low virulence or anti-mycotic resistant fungus biotype. More importantly, the sequential isolates of Candida albicans from HAART-PI, but not those from suspended HAART-NNRTI, showed an increased Sap production in vitro. While further demonstrating that HIV-PI inhibit Sap expressions, our results do not support the view that the mentioned inhibition could eliminate Candida or its selection of the oral cavity.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Diagnosis and management of body morphology changes and lipid abnormalities associated with HIV Infection and its therapies.

Body-shape changes and lipid abnormalities are common metabolic disorders in HIV-infected persons. It is likely that numerous factors contribute to body-morphology changes, including antiretroviral therapy, HIV infection itself, and immune reconstitution under antiretroviral therapy. A recent large cross-sectional investigation, the Fat Redistribution and Metabolism (FRAM) study, suggests that lipoatrophy is the most common feature of body-shape changes. Recent findings suggest modest benefit in reversing fat wasting by switching to abacavir from stavudine or zidovudine but no benefit from rosiglitazone treatment or switching from protease inhibitor to nonnucleoside reverse transcriptase inhibitor therapy. Human growth hormone treatment reduces fat accumulation, but treatment is expensive and gains in this regard are lost when treatment is stopped. Guidelines for treating lipid abnormalities in the non-HIV-infected population generally apply to HIV-infected persons; however, drug-drug interactions and overlapping toxicities between HIV and lipid therapies must be recognized. Although antiretroviral agents can raise lipid levels, there are data to suggest that in the case of cholesterol, HIV therapy reverses HIV infection-induced reductions of all cholesterol subsets. There are conflicting data regarding whether there is increased cardiovascular morbidity and mortality in the HIV-infected population. On balance, it appears that cardiovascular disease due to HIV-associated lipid disorders currently is a relatively infrequent problem, but once that is increasing in magnitude. This article summarizes a presentation by David A. Wohl, MD, at the February 2004 International AIDS Society-USA course in Atlanta.

Adult↗
PubMed2006

Tenofovir disoproxil fumarate for the treatment of HIV infection.

Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor approved by the FDA for the treatment of HIV infection. It is a potent agent with a long intracellular half-life that allows for once-daily dosing. It has been well tolerated in clinical trials, without evidence of the mitochondrial toxicity that has been associated with long-term treatment of some of the nucleoside analogue reverse transcriptase inhibitors. Because of its demonstrated efficacy and favourable safety profile, tenofovir disoproxil fumarate has quickly become a favoured nucleoside component of antiretroviral regimens for both treatment-naive and -experienced patients.

Adenine↗
PubMed1999

Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine Cohort, France, 1996-1998. Groupe dEpidémiologie Clinique de Sida en Aquitaine (GECSA).

OBJECTIVE: To study hepatic cytolysis in patients treated by highly active antiretroviral therapy (HAART) with protease inhibitor or with two nucleoside reverse transcriptase inhibitors (NRTIs). METHODS: We selected patients of the Aquitaine Cohort who initiated HAART or two NRTIs before 1 January 1998, had alanine amino-transferase (ALT) < or = 200 IU/I at baseline and at least one follow-up measure. Cox model was used to study the association between occurrence of severe hepatic cytolysis (ALT>200 IU/l) and age, gender, HIV transmission group, baseline CD4 and CD8 cell count, history of hepatic cytolysis, antiretroviral drug, baseline liver enzymes (WHO classification level 0: < or = 50 IU/l, level 1: 51 to 100, level 2: 101 to 200), hepatitis B and C co-infection. RESULTS: Sixty-four of 748 (8.5%) patients treated with HAART and 71 of 1249 (5.7%) treated with two NRTIs developed cytolysis. The probability of occurrence was 7.9% after 1 year [95% confidence interval (CI), 5.9-10.4] for patients treated with HAART and 4.8% (95% CI, 3.6-6.4) for patients treated with two NRTIs (log-rank test, P = 0.01). The median time to occurrence was 164 days for HAART-treated patients and 252 days for those treated with two NRTIs. In multivariate analysis, the history of cytolysis [hazard ratio (HR) = 2.3; 95% CI, 1.2-4.4], baseline value of ALT (HR = 2.4; 95% CI, 1.2-4.8 and HR = 3.3; 95% CI, 1.4-7.4 for levels 1 and 2, respectively), hepatitis B (HR = 3.0; 95% CI, 1.4-6.2) and C co-infections (HR = 3.2; 95% CI, 1.7-6.2) remained significantly associated with the occurrence of severe hepatic cytolysis among HAART-treated patients. History of cytolysis, hepatitis B and C were associated with cytolysis in patients treated with two NRTIs (HR = 14.8, 2.6 and 2.7, respectively). CONCLUSION: Hepatic cytolysis is more frequent among patients treated with HAART than with two NRTIs. Hepatitis B and C are the major risk factors after initiation of HAART or treatment with NRTIs. Co-infections with hepatitis B virus or hepatitis C virus may modify the management of HIV-infected patients treated by HAART.

Adolescent↗
PubMed1997

Studies on lymphoid tissue from HIV-infected individuals: implications for the design of therapeutic strategies.

Lymphoid tissue is a major reservoir of human immunodeficiency virus (HIV) infection in vivo. In addition, the lymphoid microenvironment provides a replicative advantage to the virus in that it provides a milieu of activated target cells that allows for efficient virus spread. The process of mobilization and activation of immune competent cells directed against the virus paradoxically contributes to the propagation of virus replication. Disruption of the lymphoid microenvironment during the progression of HIV disease is a poorly understood process, which may be of considerable importance pathogenically. Studies of lymph node biopsy samples taken 8 weeks apart from individuals who did not undergo any change in their therapeutic regimen (i.e., patients who either remained untreated or remained on their ongoing nucleoside analogue reverse transcriptase inhibitor monotherapy regimen) revealed little change in histopathology or viral load over the 8-week period. These results with successive lymph node biopsy samples taken from different sites indicate that an isolated lymph node biopsy accurately reflects the pathologic process associated with HIV infection and that this process diffusely involves the lymphoid system. Treatment with reverse transcriptase inhibitor monotherapy of patients in relatively early stage HIV disease had no detectable impact on the viral load in lymphoid tissue, suggesting the need to investigate more potent antiretroviral regimens during this stage of disease. Among patients with moderately advanced HIV disease, switching to combination therapy from a monotherapy regimen resulted in decreased viral replication in lymph nodes; this effect was associated with decreases in plasma viremia. Despite the fact that measures of viral replication decreased significantly, the net frequency of HIV-infected cells in peripheral blood and lymph nodes remained unchanged. Potent antiretroviral drug combinations may be capable of profound and long-term downregulation of plasma viremia. It will be essential to monitor the status of viral trapping, viral burden, and viral replication within lymphoid tissue during treatment with such drugs to determine accurately their true potential for impact on these key features of HIV pathogenesis.

Anti-HIV Agents↗
PubMed2000

Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity.

OBJECTIVES: This article reviews the clinical manifestations of mitochondrial toxicity associated with the use of nucleoside analog reverse transcriptase inhibitors (NRTIs) and outlines strategies to manage these sequelae. BACKGROUND: NRTIs are the key components of the antiretroviral combinations used in the management of patients infected with HIV. The available NRTIs differ in their convenience of administration, frequency of dosing, resistance profiles, and side-effect profiles. NRTIs act as competitive inhibitors of the RNA/DNA polymerase reverse transcriptase of HIV and cause chain termination in the growing viral DNA chain. Many of the important and treatment-limiting side effects of NRTIs may be related to the effect of these agents on human DNA polymerases, in particular, mitochondrial DNA polymerase gamma. Depletion of mitochondrial DNA during chronic NRTI therapy may lead to cellular respiratory dysfunction and generalized and tissue- and drug-specific toxicities, including myopathy, peripheral neuropathy, and lactic acidosis. Recently, it has been proposed that the fat redistribution syndrome, or lipodystrophy, reported during chronic antiretroviral therapy is a manifestation of the differential impact of at least some NRTIs on peripheral and visceral adipocytes. Management of potential mitochondrial toxicity during NRTI therapy remains a challenge. A range of nutritional supplements, both as treatments and prophylaxes, have been proposed, and some have been investigated in vitro; no in vivo studies have yet been conducted. METHODS: The information in this review was compiled using MEDLINE and AIDSLINE searches of the literature, including conference abstracts. CONCLUSIONS: At present, interruption of NRTI therapy or substitution of the probable causative agent with alternative NRTIs that appear to be better tolerated represents the mainstay of management for mitochondrial toxicity and its clinical manifestations.

Anti-HIV Agents↗
PubMedDate not supplied

Switch to efavirenz in a protease inhibitor-containing regimen.

PURPOSE: This report evaluated the efficacy and safety of switching from a protease inhibitor (PI)-containing HIV treatment regimen to an efavirenz (EFV)-containing regimen. METHOD: We retrospectively analyzed data from 64 patients, with a plasma viral load (VL) less than 50 copies/mL and CD4+ counts >200 cells/mL at baseline, who had been taking a regimen consisting of a PI and two nucleoside reverse transcriptase inhibitors (NRTIs; d4T/3TC [n = 45]; AZT/3TC [n = 19]) for a median of 27.5 months (range, 6-41 months) and who chose to substitute EFV for the PIs in the regimens. Statistical analyses were performed by Wilcoxon test. Fat atrophy was evaluated by physician's assessment and patients' subjective self-estimation with the criteria of well being and body state. RESULTS: 57 patients completed 36 weeks on the EFV regimen; 4 patients changed therapy but continued EFV, 2 moved to another area, and 1 discontinued EFV. During the first weeks of therapy, 56.3% of patients suffered from moderate nervous system symptoms. The plasma VL of 63 patients remained at <50 copies/mL at final analysis. Compared with time of switching to EFV, analysis at 36 weeks showed no statistically significant change from 626+/-283 to 643+/-296 cells/mL in mean absolute CD4+ cells and a statistically significant increase from 26.8+/-9.6% to 28.0+/-9.1% in relative CD4+ cells. There was a statistically significant reduction in relative CD8+CD38+ from 62.2+/-16.3% at time of switching to EFV to 55.1+/-15.0% at week 36. At baseline, 27 patients suffered from lipodystrophy, including fat atrophy and fat accumulation. After 36 weeks, nine patients showed intensified fat atrophy. In contrast, five patients improved their state concerning fat redistribution and 13 patients showed no alterations. CONCLUSION: The switch to a non-PI-containing regimen with EFV offers a good drug alternative for patients with suppressed viral load, problems of adherence, and/or adverse events due to PIs but not for patients suffering from lipoatrophy caused by nucleoside reverse transcriptase inhibitors. The intention of such a switch aims at the avoidance of fatal mutations in HIV.

ADP-ribosyl Cyclase↗
PubMed2000

Rationale for the use of hydroxyurea as an anti-human immunodeficiency virus drug.

Hydroxyurea has been extensively used in medical practice, mainly for treating chronic myelogenous leukemia, sickle cell anemia, and other diseases. In light of its ability to inhibit DNA synthesis and to induce cell cycle arrest through inhibition of ribonucleotide reductase, the effects of hydroxyurea on replication of human immunodeficiency virus type 1 (HIV-1) have been investigated. In vitro hydroxyurea has been shown to block HIV-1 reverse transcription and/or replication in quiescent peripheral blood mononuclear cells (PBMC) and macrophages. Hydroxyurea was also found to be synergistic with the nucleoside reverse transcriptase inhibitor didanosine and to inhibit HIV-1 replication in activated PBMC; this inhibition may be due to a reduction in deoxynucleoside triphosphate pool sizes. Finally, hydroxyurea has been shown to sensitize didanosine-resistant mutants. Hydroxyurea may therefore be useful for limiting the spread of didanosine-resistant HIV-1 variants. The favorable toxicity profile of hydroxyurea and the lack of significant overlapping toxicities with some of the nucleoside reverse transcriptase inhibitors, as well as their distinct mechanisms of action, have provided further rationale for use of these agents in combination therapies.

Anti-HIV Agents↗
PubMedDate not supplied

Efficacy of nevirapine-based HAART in HIV-1-infected, treatment-naive persons with high and low baseline viral loads.

PURPOSE: The objective of this analysis was to assess the efficacy of nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing, protease inhibitor (PI)-sparing, three-drug highly active antiretroviral therapy (HAART) in HIV- 1-infected, treatment-naive patients with high and low baseline viral loads. METHOD: A composite analysis was performed of clinical studies including the NNRTI nevirapine that were presented at international conferences between 1998 and October 2000. In all of the studies, nevirapine was administered in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). For a study to be included in the analysis, more than 25% of participants must have had baseline viral loads >100,000 copies/mL, and more than 25% of participants must have had viral loads <100,000 copies/mL. RESULTS: After 6 months, 139 of 156 (89%) and 82 of 99 (83% ) patients in the low and high baseline viral load groups, respectively, had on-treatment viral loads <200 to 500 copies/mL (depending on assay used). After 12 months, 95 of 124 patients (77%) with lower baseline viral loads and 63 of 76 patients (83%) with high baseline viral loads had on-treatment viral loads below the limit of quantification. CONCLUSION: Baseline viral load does not affect virologic outcome in HIV-1-infected, antiretroviral-naive participants treated with nevirapine-containing, PI-sparing HAART.

Anti-HIV Agents↗