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PubMed2004

Drug transporters relevant to HIV therapy.

Membrane transporters play a key role in the intestinal absorption, tissue distribution, cellular accumulation and renal excretion of anti-HIV drugs. A clear understanding of the individual roles of these transporters is, therefore, essential if we are to attempt to design new drugs and use drug combinations that are more clinically effective. This review attempts to provide an overview of those membrane transporters considered to be relevant to the disposition and effectiveness of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). However, we are still at an early stage in our understanding of these drug transporters and their interactions with anti-HIV drugs. Rapid progress in this area is essential if the therapeutic potential of anti-HIV drugs is to be fully exploited.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Management of antiretroviral therapy.

In a very short period of time, availability of antiretroviral drugs has increased from one drug with very modest activity to 12 approved drugs with remarkable potency, particularly when used in combination. The additional availability of absolutely quantitative assays with a broad dynamic range to measure plasma HIV-1 RNA has dramatically changed the evaluation of these new antivirals and the management of patients infected with the human immunodeficiency virus (HIV). The approved antiretroviral drugs represent three novel classes including nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors as well as protease inhibitors. Clinical trials evaluating different combinations of these drugs have resulted in the generation of some basic guidelines for their appropriate use. These guidelines focus on using these drugs in complex, multidrug regimens with the ultimate goal to keep the viral burden, as measured by plasma viral RNA levels, as low as possible and for as long as possible on a drug regimen that is compatible with long-term tolerance and compliance. To maximize the potential of these new drugs and to avoid significant associated toxicities and drug interactions, the treating physician must be completely aware of the pharmacokinetics and unique antiviral properties of these drugs. This review focuses on these unique properties as well as provides general guidelines for their appropriate use.

Anti-HIV Agents↗
PubMed2001

Comparison of genotyping and phenotyping methods for determining susceptibility of HIV-1 to antiretroviral drugs.

OBJECTIVE(S): To compare antiretroviral resistance susceptibility testing of patient HIV-1 strains using genotype and phenotype methods. DESIGN: Eighteen plasma samples with viral load > 2000 HIV-1 RNA copies/ml were randomly selected for testing by both methods. Disease and treatment data were available for all patients. METHODS: Samples were analysed genotypically using a kit assay (HIV-1 Genotyping Systems, Applied Biosystems), performed by the Clinical Research Laboratory at Macfarlane Burnet Centre for Medical Research. Samples were analysed phenotypically using a rapid phenotypic assay (PhenoSenseTM HIV, ViroLogic), performed by the manufacturer. Results from both methods were interpreted using a defined protocol. Each susceptibility assay was performed and interpreted by individuals unaware of either the clinical data or the results of the other susceptibility assay. Concordance was defined categorically as either the presence of reduced susceptibility (> 2.5-fold change) in the phenotypic assay and resistance associated mutations in the genotypic assay, or the absence of these findings in both assays. RESULTS: Concordance between phenotypic and genotypic susceptibility testing was 81% for nucleoside reverse transcriptase inhibitors, 91% for non-nucleoside reverse transcriptase inhibitors and 90% for protease inhibitors. Complete concordance between phenotype and genotype for all 14 drugs evaluated was observed in three (17%) patient samples. CONCLUSIONS: Phenotypic and genotypic susceptibility appear to provide similar results. However, interpretation of genotypic results can be complicated, and both methods still require clinical validation.

Anti-HIV Agents↗
PubMed2004

Treatment of primary HIV-1 infection with nonnucleoside reverse transcriptase inhibitor-based therapy is effective and well tolerated.

OBJECTIVES: Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection. We investigated the use of a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in this setting. METHODS: Twenty-one antiretroviral-naïve individuals with early HIV-1 disease were treated with a combination of efavirenz and Combivir (GlaxoSmithKline, Uxbridge, Middlesex, UK). They were evaluated for immune and lymphocyte function by standard immunological assays. RESULTS: The median time to an undetectable HIV-1 viral load was 12 weeks (range 4-36 weeks). CD4 and CD16/56 counts increased during treatment and CD8 counts decreased minimally. The main side-effects observed were transient sleep disturbances (five patients). In addition, we observed a decrease in lymphocyte activation as assessed by CD38 surface expression. CONCLUSIONS: This study demonstrates that primary HIV-1 infection can be treated with NNRTI-based HAART.

Adult↗
PubMed2004

Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to nucleoside analog drugs.

HIV reverse transcriptase (RT) is the target of a number of important anti-AIDS drugs. Drugs that inhibit RT are either nucleoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Combinations of various anti-AIDS drugs (highly active anti-retroviral therapies or HAART) can reduce the viral load to non-detectable levels. However, the development of drug resistance leads to the emergence of HIV strains that are resistant to multiple anti-AIDS drugs. The nucleotide analogs that are used as anti-HIV-1 drugs lack the normal 3'-OH and as a consequence act as chain-terminators when incorporated into DNA. One mechanism of nucleoside analog resistance involves ATP-based excision to unblock chain-terminated primers and allow HIV replication to continue. There is an urgent need for new drugs and for new therapies that can overcome the excision mechanism of resistance. Compounds that disrupt the binding of the excision reaction substrate(s) (the blocked primer and/or ATP and/or pyrophosphate), or mimic the dinucleoside tetraphosphate product of the ATP-based excision reaction are potential inhibitors of excision. Detailed understanding of drug resistance mechanisms can reveal novel targets for anti-viral agents.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Age and sex modulate metabolic and cardiovascular risk markers of patients after 1 year of highly active antiretroviral therapy (HAART).

OBJECTIVE: Primary aim: To evaluate the modulating effects of age and sex on changes in plasma lipid levels in the response to highly active antiretroviral therapy (HAART). Secondary aim: To study insulin, leptin, adiponectin, E-selectin and P-selectin levels and their relation to demographics. DESIGN: Comparative, longitudinal, open cohort-study. SETTING: Tertiary care center at a University Hospital. METHODS: Eighty-two consecutive HIV-seropositive patients of either sex were enrolled in the study. Subjects were between 19 and 60 years of age and naive to HAART. Patients were treated with nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitor(s) (PIs) or reverse transcriptase inhibitors (RTIs) only. Subjects were evaluated at baseline and after 3, 6 and 12 months. RESULTS: Total cholesterol levels increased in all patients. The greatest increase was seen in patients of older age treated with PI. Male gender was another risk factor for higher cholesterol but also for higher triglyceride levels. Therapy with protease inhibitors and/or stavudine had a negative influence on plasma triglyceride levels. Selectins, adipokines and insulin were less influenced by HAART. CONCLUSION: Based on the results of this study selection of therapy regimen according to the demographic risk factors sex and age can offer an easy strategy to help to minimize lipid elevations.

Adiponectin↗
PubMed1999

The use of combination antiretroviral therapy in HIV-infected patients.

OBJECTIVE: To review the published clinical trials of combination antiretroviral therapy, current guidelines about the use of combination antiretroviral therapy, information regarding the impact of adherence on treatment effect, and the effects of combination antiretroviral therapy on morbidity and mortality. METHODS: A MEDLINE search (January 1986-March 1998) was performed to identify all relevant articles. Selected articles and abstracts from this time period and references from these selections were included for review. DISCUSSION: Nucleoside analog monotherapy treatment of HIV infection is inferior to treatment with multiple antiretroviral agents. With the availability of new classes of medications (protease inhibitors, nonnucleoside reverse transcriptase inhibitors [NNRTIs], and new nucleoside analogs, combination antiretroviral therapy is now more potent and more complex than ever. The use and effects of protease inhibitors in combination with nucleoside analogs has been well documented. The use of NNRTIs and combination protease inhibitor regimens are not as well documented but may prove to be at least as efficacious as single protease inhibitor-containing regimens. Increases in CD4+ cell counts of >100 cells/mm3 and decreases in HIV RNA (viral load) of >2 log are common with these medications, with antiretroviral naive patients being more likely to have substantial responses to therapy than experienced patients. CONCLUSIONS: Combination antiretroviral therapy in HIV-infected patients is now the standard of care. Combination antiretroviral regimens have been shown to reduce, at least temporarily, the morbidity and mortality associated with HIV infection and AIDS. However, these regimens are quite complex for patients to adhere to successfully. While the true long-term effects of combination antiretroviral therapy are unknown, their current effects on the HIV epidemic are unquestionable.

Anti-HIV Agents↗
PubMedDate not supplied

First-line antiretroviral therapy in Africa--how evidence-base are our recommendations?

According to the World Health Organization guidelines, a non-nucleoside reverse transcriptase inhibitor (NNRTI) along with two nucleoside reverse transcriptase inhibitors (NRTI) is the treatment of choice as first-line antiretroviral therapy. The results of the 2NN and different cohort studies performed in developed countries do not provide sufficient evidence by which to select between nevirapine and efavirenz as the first-line NNRTI for antiretroviral therapy in Africa. The current first-line NNRTI-containing antiretroviral therapy regimens used in Africa are certainly not ideal. Nevirapine interacts with rifampicin and therefore is not indicated in patients with tuberculosis. On the other hand, efavirenz should not be given to pregnant women. NNRTI-containing regimens may be less effective in women who received nevirapine monotherapy at delivery. Stavudine, used in the nucleoside backbone, may lead to lipoatrophy, lactic acidosis and polyneuritis. Zidovudine may cause serious anemia. Mainly because of cost considerations, the generic fixed-drug combination of nevirapine plus two NRTI seems at the moment to be the best choice. It is clear, however, that antiretroviral programs should not rely only on this combination for initial antiretroviral treatment. Most importantly, more HIV clinical trials need to be conducted in Africa, and African cohorts of patients on antiretroviral therapy need to be established in order to develop recommendations that are evidence based.

Africa↗
PubMed2006

Stavudine, lamivudine and nevirapine combination therapy for treatment of HIV infection and AIDS in adults.

BACKGROUND: A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries. OBJECTIVES: To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults. SEARCH STRATEGY: We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status. SELECTION CRITERIA: Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data. MAIN RESULTS: Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ. AUTHORS' CONCLUSIONS: The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Apparent retardation of aging in Drosophila melanogaster by inhibitors of reverse transcriptase.

It is proposed that aging is induced by somatic replication of transposable elements (TEs). Most transposable elements in Drosophila reproduce by reverse transcription. Therefore inhibitors of reverse transcriptase were tested for their ability to retard aging in Drosophila melanogaster. Two inhibitors, phosphonoformic acid (PFA) and dideoxyinosine (ddI), were capable of prolonging life span when administered for the first half of the adult life. PFA was investigated further. It also produced a reduction in the rate of decline of behavior. PFA appeared not to act on an infectious agent in these experiments, nor did it alter the food intake. Analogues unable to inhibit RT had no life span prolonging effect at similar concentrations to that of PFA.

Aging↗
PubMed2005

Intermittent episodes of detectable HIV viremia in patients receiving nonnucleoside reverse-transcriptase inhibitor-based or protease inhibitor-based highly active antiretroviral therapy regimens are equivalent in incidence and prognosis.

BACKGROUND: Intermittent episodes of detectable human immunodeficiency virus (HIV) viremia (hereafter referred to as "blips") are generally not predictive of subsequent virologic failure. Limited data are available for patients treated with nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens. METHODS: A retrospective cohort study evaluated patients receiving highly active antiretroviral therapy who were followed for > or =12 months, achieved an HIV RNA load of <50 copies/mL, and underwent evaluation every 2-3 months. A blip was defined as 1 HIV RNA load measurement of 50-1000 copies/mL that was preceded and followed by another HIV RNA load measurement of <50 copies/mL. The frequency and predictors of blips and virologic failure were studied. RESULTS: There were 244 patients in the NNRTI group and 136 patients in the protease inhibitor (PI) group. Baseline characteristics between the 2 groups were similar. A total of 34% of patients in the NNRTI group and 33% in the PI group experienced viral blips (P=.855), with corresponding incidences of 19.2 and 19.7 blips, respectively, per 100 person-years. Median time to blips was 50.0 months after initiation of therapy in the NNRTI group (95% confidence interval [CI], 44.8-55.3 months) and 43.6 months in the PI group (95% CI, 33.7-53.6 months; P=.632, by the log-rank test). By Cox proportional hazards model analysis, only a history of antiretroviral therapy use (hazard ratio [HR], 2.01; P<.001) and a CD4 cell count of <200 cells/ mu L (HR, 1.70; P=.021) increased the risk for having a blip. During a median follow-up period of 23.5 months, 7.8% of patients in the NNRTI group and 8.1% in the PI group experienced virologic failure (P=.917). Cox proportional hazards model analysis showed that only a baseline CD4 cell count of <200 cells/ mu L predicted virologic failure (HR, 2.74; P=.032). CONCLUSIONS: There is no difference in the frequency or prognostic significance of viral blips between patients receiving NNRTI-based therapy and patients receiving PI-based therapy. Our results suggest that viral blips occur at a similar rate among patients receiving NNRTI-based regimens and patients receiving PI-based regimens and that they are not predictive of virologic failure.

Adult↗
PubMed2004

Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children.

Five heavily pretreated HIV-infected children were put on amprenavir and delavirdine plus two nucleoside inhibitors to reverse transcriptase to boost amprenavir levels and to use the antiretroviral activity of a non-nucleoside reverse transcriptase inhibitor. No data are available about this combination in children. It w;as well tolerated, and the median reduction in viral load was 1.5 log after 18 months. Delavirdine boosted amprenavir trough levels more than 10-fold, and delavirdine trough levels remained i several fold above susceptible HIV strains.

Adolescent↗
PubMed1997

[Antiviral therapy of HIV infection. A practice-based presentation 1997/1998].

New information on the pathogenesis of HIV infection and the possibility of viral quantification have resulted in significant advances in the treatment of this disease. The triple combination of antiviral medications comprising two reverse transcriptase inhibitors and a proteinase inhibitor has brought about an improvement in the quality of life of the patient together with a slowing down of disease progression. For successful patient management, cooperation based on trust and compliance are equally as important as continual observation of the clinical course and monitoring of the viral burden or the T-helper cells.

Antiviral Agents↗
PubMed2005

Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort.

BACKGROUND: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. METHODS: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. RESULTS: Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. CONCLUSION: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Adult↗
PubMed1997

HIV/AIDS management in office practice. Antiretroviral therapy.

Treatment of HIV with nucleoside analog reverse transcriptase inhibitors (RTIs) and protease inhibitors forms the backbone of anti-HIV therapy. Non-nucleoside RTIs, immune modulators, and new entries in existing classes of pharmacologic agents hold promise for the future. Combination therapy with two, three, or more agents has become the standard of care, although additive toxicities often can be dose-limiting. Increases in the understanding of viral dynamics have introduced measures of systemic viral burden into clinical practice, and viral load considered in combination with CD4 lymphocyte numbers guides decisions about initiating and modifying antiviral therapy.

Anti-HIV Agents↗
PubMed2004

[Lactic acidosis in HIV-patients--diagnosis and treatment].

Lactic acidosis is a life-threatening complication of antiretroviral therapy with an incidence of about 1% per year. Its clinical onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. Lactic acidosis is caused by nucleoside analogue reverse transcriptase inhibitors (mainly didanosine, stavudine and zalcitabine), which are relatively strong inhibitors of gamma polymerase, the enzyme responsible for the replication of mitochondrial DNA. Zidovudine is also a mitochondrial toxin, but its toxicity probably reflects several mechanisms unrelated to mtDNA-depletion. When lactic acidosis is diagnosed, nucleoside analogues and other mitochondrial toxins, such as valproic acid and acetylsalicylic acid, must be discontinued immediately. Uridine should be supplemented, a cocktail consisting of vitamins, L-carnitine and coenzyme Q10, may be given.

Acid-Base Equilibrium↗
PubMed2004

Clinical pharmacology of antiretroviral therapy.

Antiretroviral therapy represents by all means a new branch of anti-infective chemotherapy, and in order to describe the mode of action of antiretrovirals, a series of inferences from anti-bacterial chemotherapy were made. The currently available antiretroviral agents can be classified as time-dependent drugs, and therefore the key pharmacokinetic parameter adopted in their clinical-pharmacological assessment is the concentration at the end of the dosing interval (Ctrough). By focusing on this parameter, the application of Therapeutic Drug Monitoring (TDM) allows for the successful individual tailoring of the drug dosage in some clinical circumstances, such as treatment of drug-resistant infections, drug-drug interactions and side effects. While this procedure has now been sufficiently standardized for protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), no clinical applications are yet recognized for nucleoside/nucleotide reverse transcriptase inhibitors (N/NtRTIs) and fusion inhibitors. The main unfavourable peculiarity of HIV infection, such as the need for lifelong treatment, is one of the reasons why increasing attention is being paid to pharmacological aspects of antiretroviral therapy. Issues like treatment potency, maintenance over time of the immunovirological benefit and long-term side effects require intensive pharmacological investigation in order to obtain the information on which basing the most convenient strategy to be adopted for the therapeutical management of this condition.

Anti-HIV Agents↗
PubMed2005

Emerging anti-HIV drugs.

There are now exactly 20 anti-HIV drugs licenced (approved) for clinical use, and > 30 anti-HIV compounds under (pre)clinical development. The licensed anti-HIV drugs fall into five categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir disoproxil fumarate); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz); protease inhibitors (PIs: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir and fosamprenavir); and fusion inhibitors (FIs: enfuvirtide). The compounds that are currently under clinical (Phase I, II or III) or preclinical investigation are either targeted at the same specific viral proteins as the licensed compounds (i.e., reverse transcriptase [NRTIs: PSI-5004, (-)-dOTC, DPC-817, elvucitabine, alovudine, MIV-210, amdoxovir, DOT; NNRTIs: thiocarboxanilide, UC-781, capravirine, dapivirine, etravirine, rilpivirine], protease [PIs: tipranavir, TMC-114]) or other specific viral proteins (i.e., gp120: cyanovirin N; attachment inhibitors: AIs, such as BMS-488043; integrase: L-870,812, PDPV-165; capsid proteins: PA-457, alpha-HCG); or cellular proteins (CD4 downmodulators: CADAs; CXCR4 antagonists: AMD-070, CS-3955; CCR5 antagonists: TAK-220, SCH-D, AK-602, UK-427857). Combination therapy is likely to remain the gold standard for the treatment of AIDS so as to maximise potency, minimise toxicity and diminish the risk for resistance development. Ideally, pill burden should be reduced to once-daily dosing so as to optimise the patient's compliance and reduce the treatment costs.

Animals↗