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PubMed1999

Antiretroviral therapy in 1999 for antiretroviral-naive individuals with HIV infection.

The choice of initial antiretroviral regimen for treating people infected with HIV is crucial to successful long-term control of virus replication. Potent antiretroviral therapy substantially suppresses viral replication as measured by plasma HIV RNA levels to below limits of detection: the current standard of care is usually a combination of at least three drugs and frequently includes a protease inhibitor, or alternatively a non-nucleoside reverse transcriptase inhibitor (nnRTI). Patients who have low CD4+ cell counts (< or = 200 CD4+ cells/mm3) or high plasma HIV RNA levels (> or = 100,000 copies/ml) may not attain maximal suppression of HIV replication when treated with current regimens and may require more aggressive therapy. In contrast, patients with relatively normal CD4+ cell counts and low to non-measurable levels of plasma HIV RNA over prolonged periods (i.e., slow or non-progressors) may not require immediate antiretroviral therapy. These individuals should reconsider treatment when either the CD4+ cell count declines or the HIV RNA level increases. Early and potent antiretroviral therapy should provide more durable virological and clinical benefits for many patients, especially if they receive sufficient counselling and support to aid adherence to the treatment regimen. The optimum time to initiate antiretroviral therapy is not well established, but to maximise the recovery of the immune system and the virological and clinical benefits, initiation of therapy is generally recommended for individuals who have symptoms or those with plasma HIV RNA levels > 5000-10,000 copies/ml, or CD4+ cell counts < 500 cells/mm3. The current choice of initial antiretroviral regimens includes two nucleoside reverse transcriptase inhibitors (nRTI) with a potent, well-tolerated HIV-1 protease inhibitor or nnRTI. Recent short-term activity data (24-week comparative clinical trial data) indicate that regimens combining three nRTI, including abacavir, could also be considered. Other emerging combination regimens for consideration include two HIV-1 protease inhibitors with one or two nRTI, or a combination of drugs from all current categories (e.g., nRTI with a nnRTI and HIV-1 protease inhibitor). The goal of antiretroviral therapy is to maximise suppression of HIV replication and thereby prevent or delay viral resistance, restore immunological function and improve clinical outcome. Since evolution of the virus towards resistance can occur with plasma HIV RNA levels between 50 and 500 copies/ml, current standards for best suppression of HIV replication have shifted to declines in plasma HIV RNA to < 50 copies/ml. In addition, non-adherence to any regimen is associated with the greatest risk for virological failure. Therefore, both the decision to initiate therapy and the choice of initial therapy should be carefully weighted and balanced with the long-term implications of antiretroviral therapy.

Anti-HIV Agents↗

PubMed2000

A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome.

BACKGROUND: Lipodystrophy (LD; peripheral lipoatrophy, central adiposity) hyperlipidaemia and insulin resistance often complicate protease inhibitor-containing antiretroviral therapy. Lipoatrophy and abdominal distension were observed in protease inhibitor-naive nucleoside analogue reverse transcriptase inhibitor (NRTI) recipients with lactic acidaemia and hepatic impairment, which are known NRTI-induced mitochondrial toxicities. DESIGN AND SETTING: Case-control study in a university-based outpatient clinic. PATIENTS AND METHODS: The patients studied included 14 NRTI recipients with lipoatrophy, 32 antiretroviral-naive patients without LD, 28 NRTI recipients without LD, 44 combined NRTI-protease inhibitor recipients without LD, and 102 NRTI-protease inhibitor recipients with LD. Data was obtained on body composition (questionnaire, physical examination, dual-energy x-ray absorptiometry and abdominal computerized tomography), with biochemical, lipid and glycaemic parameters. RESULTS: The NRTI-LD syndrome was characterized by recent onset fatigue and nausea, peripheral lipoatrophy (6 kg loss over 4 months), abdominal distension (ascites +/- hepatomegaly) and elevated lactate (4.6, 1.1, 1.2, 1.4 and 1.7 mmol/l, respectively; P< 0.0001) and liver enzymes. Cases without hepatic involvement also had lower body fat and greater lactate than unaffected controls. Metabolic disturbances and weight improved after cessation. The NRTI-LD syndrome differed from protease inhibitor-related LD syndrome by the presence of recent onset symptoms and weight loss, higher lactate and alanine aminotransferase, and lower albumin, cholesterol, triglycerides, glucose and insulin. In treated controls, current stavudine therapy, protease inhibitor duration, and lactic acidaemia were independently associated with both lipoatrophy and abdominal obesity; total NRTI duration was also associated with lipoatrophy, and lamivudine and protease inhibitor duration with buffalo hump. CONCLUSIONS: A syndrome of lipoatrophy, constitutional illness, lactic acidaemia and hepatic dysfunction can complicate NRTI therapy. Both protease inhibitor and NRTI therapies, particularly if associated with lactic acidaemia, contribute to LD syndrome, but have some distinguishable clinical and metabolic effects.

Acidosis, Lactic↗

PubMed2002

Different degree of immune recovery using antiretroviral regimens with protease inhibitors or non-nucleosides.

BACKGROUND: Protease inhibitors (PI) produce significant immune recovery in most HIV-infected persons, although toxicity and high pill burden often limit this benefit. Combinations including non-nucleoside reverse transcriptase inhibitors (NNRTI) result in similar virological success, but data on immune reconstitution are scarce. METHODS: Baseline plasma viraemia and CD4 cell counts were recorded from 100 patients who began two nucleoside analogue reverse transcriptase inhibitors plus either one PI or one NNRTI in a case-control study [indinavir (82%) and nevirapine (80%), respectively, were most frequently prescribed]. Only patients with baseline CD4 cell counts < 500 x 10(6) cells/l, good treatment adherence and plasma HIV RNA < 50 copies/ml sustained for 1 year were recruited. RESULTS: A rapid CD4 cell gain occurred within 12 weeks on therapy (average 41.8 x 10(6) cells/l per month), irrespective of treatment. In contrast, a trend towards a better CD4 cell gain was noticed between 12 and 48 weeks with a PI (mean CD4 cell increases per month: 15.2 x 10(6) cells/l using PI and 10.4 x 10(6) cells/l using NNRTI). During this period, the difference between therapy with a PI and a NNRTI reached statistical significance for subjects with baseline CD4 counts < 300 x 10(6) cells/l (17.1 x 10(6) and 6.4 x 10(6) cells/l, respectively; P < 0.05). CONCLUSION: A rapid CD4 cell increase occurred shortly after beginning antiretroviral therapy using either PI or NNRTI. Late increases in CD4 cell counts, mostly owing to newly produced cells rather than redistribution, are more pronounced in therapy using a PI, especially in subjects with lower initial CD4 cell counts.

Adult↗

PubMedDate not supplied

Impact of various antiretroviral drugs and their plasma concentrations on plasma lipids in heavily pretreated HIV-infected patients.

OBJECTIVE: To evaluate the frequency and the magnitude of lipid abnormalities (LA) in respect to the nature of the antiretroviral drug and its plasma concentrations. PATIENTS/METHOD: Trough concentrations (C(trough)) of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) were assessed at Weeks 4, 8, 24, 28, and 32. Fasting triglycerides (TG) and total cholesterol (CH) were sampled at Weeks 0, 12, 20, and 32. We analyzed the probability of occurrence of grade 3-4 CH (> 7.8 mmol/L) and TG (> 8.4 mmol/L) during a 24-week period according to the drug taken using a Kaplan-Meier analysis and log rank test. Relation between Week 8 PI or NNRTI C(trough) and Week 12 lipid levels was assessed using the Kendall correlation measure. RESULTS: The PharmAdapt study included 252 patients (mean age 41 years, 83% males); the patients received a PI (73%), an NNRTI (50%), and/or a ritonavir (RTV) booster-containing (46%) regimen. Compared to any other regimen, use of lopinavir (LPV)/RTV or efavirenz (EFV) was associated with a higher risk of grade 3-4 CH. Use of LPV/RTV and RTV booster was associated with a higher risk of grade 3-4 TG. Use of any PI-containing regimen was associated with a higher risk for grade 3-4 CH and TG compared to non PI-based regimens. Kendall correlation coefficients for PI or NNRTI C(trough) and blood lipid levels were close to zero for all drugs and CH or TG, showing the absence of relation between drug concentrations and lipid levels. CONCLUSION: Severity of lipid abnormalities is related to the nature of the antiretroviral drug. There is no short-term relation between PI or NNRTI trough concentrations and blood lipid levels in heavily pretreated patients.

Adult↗

PubMed2006

Effects of highly active antiretroviral therapy and immune recovery on CD8+ T-cell-mediated inhibition of HIV-1 transcription.

SUMMARY: : To date, the relation between the CD8 antiviral factor (CAF) and clinical indicators of disease progression in HIV-1 infection (CD4 T-cell counts and viral load [VL]) is inconclusive. Particularly, the effect of antiretroviral therapy and immune recovery on CAF production remains unclear. Using a transient transfection assay and a reporter gene activated by the HIV-1 long terminal repeat (LTR), we analyzed CAF production in CD8 T cells of HIV-1-positive individuals divided into 3 groups: patients on protease inhibitor (PI)-based therapy, patients on nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy, and patients receiving no therapy. We found that within the untreated group, CAF activity inversely correlated with VL and high CAF was associated with lower VLs over a period of 0.5 to 3 years. Furthermore, patients who were drug-naive demonstrated significantly higher CAF than untreated patients who had previously undergone antiretroviral therapy. CAF activity in treated patients was similar to CAF in drug-naive patients and higher than in off-treatment patients. There seemed to be a trend toward higher CAF in patients on NNRTI-based therapy compared with those on PI-based therapy. These results suggest that immune recovery after highly active antiretroviral therapy (HAART) contributes to the normalization of CAF levels in HIV-1-positive individuals. Furthermore, we have distinguished between CD8 T-cell-mediated suppression of HIV-1 replication and gene transcription.

Anti-HIV Agents↗

PubMed2002

Time trends in primary HIV-1 drug resistance among recently infected persons.

CONTEXT: Transmission of multiclass drug-resistant human immunodeficiency virus type 1 (HIV-1) may increase with wider use of antiretroviral therapy. OBJECTIVE: To determine trends in prevalence of HIV-1 drug resistance among recently infected individuals in a geographic area with a high penetration of antiviral treatment. DESIGN, SETTING, AND PATIENTS: Consecutive case series of 225 patients referred to a San Francisco, Calif, hospital with recent HIV-1 infection from June 1996 through June 2001. MAIN OUTCOME MEASURE: Time trends in the prevalence of genotypic and phenotypic primary drug resistance. RESULTS: Mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) steadily increased from 0% in 1996-1997 to 12 (13.2%) in 2000-2001 (P =.01). There was 1 mutation associated with protease inhibitor resistance in 1996-1997 (2.5%) and there were 7 (7.7%) in 2000-2001 (P =.25). Genotypic resistance to nucleoside reverse transcriptase inhibitors (NRTIs) initially decreased and then returned to prior levels (P =.007 for test of homogeneity). Genotypic resistance to 2 or more classes of drugs increased from 1 (2.5%) to 12 (13.2%) (P =.004), but only 1 infection (1.2%) in the latter period was resistant to all 3 classes of agents (P =.58). Primary phenotypic resistance decreased for NRTIs from 21% to 6.2% (P =.03) and increased for NNRTIs from 0 to 8 (9.9%) (P =.02). Phenotypic resistance increased for protease inhibitors from 2.6% to 6.2% (P =.32). Median time to virologic suppression (<500 copies/mL) during therapy was 12 weeks for patients with genotypic evidence of resistance compared with 5 weeks for patients with drug-sensitive infections (P =.02). CONCLUSIONS: The frequency of primary resistance to NNRTIs is increasing, although resistance to all available classes of antiretroviral therapy remains rare. Genotypic resistance testing in recently infected persons predicts time to viral suppression during therapy.

Adult↗

PubMed2000

Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease.

Therapeutic and prophylactic regimens directed specifically against Mycobacterium avium complex (MAC) are increasingly being used in patients infected with the human immunodeficiency virus (HIV). Several of the drugs used in the management of MAC have been associated with significant drug interactions involving the cytochrome P450 (CYP) enzyme system. This enzyme system is also highly influenced by other drugs used in the management of patients with HIV, particularly the protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and azole antifungals. This article reviews the published concentrations or subtherapeutic concentrations of other drugs have been described. In particular, concurrent use of rifabutin with clarithromycin or fluconazole has resulted in increased concentrations of rifabutin and an accompanying increase in the incidence of rifabutin toxicities, including uveitis and leucopenia. Similar results have been seen when rifabutin is combined with protease inhibitors or delavirdine. The macrolides, clarithromycin and azithromycin, have also been associated with significant drug interactions. Clarithromycin has a higher affinity for CYP than azithromycin and, thus, is more frequently associated with clinically significant drug interactions. Clarithromycin is an inhibitor of CYP and may result in toxic concentrations of other drugs metabolised by this enzyme system. Such interactions have been described with rifabutin and the statin lipid-lowering agents. In addition, nevirapine and efavirenz have been shown to significantly reduce clarithromycin concentrations, whereas the protease inhibitors and delavirdine may increase clarithromycin concentrations. Other drugs used in the management of patients with MAC are not metabolised by CYP and thus have a lower incidence of interactions, although the absorption of ciprofloxacin may be impaired when it is given with products containing multivalent cations, such as didanosine. However, clinicians must remain vigilant for drug interactions when reviewing a patient's medication profile, keeping in mind both interactions that have been described in the literature and those that may be predicted based upon known pharmacokinetic profiles.

Azithromycin↗

PubMed2001

[CBO guidelines 'Antiretroviral therapy in the Netherlands'].

In collaboration with the Dutch Institute for Health Care Improvement (CBO) and on the basis of recent developments, new guidelines have been developed for the diagnosis and treatment of HIV-infected patients. The most important recommendations are: Treatment of adult patients is indicated if HIV load > 30,000 RNA copies/ml, or when CD4+ cell count is < 350 x 10(6) cells/l. Treatment of children is indicated if HIV load > 5,000 copies/ml, even when CD4+ cell count is > 500 x 10(6) cells/l. Optimal antiretroviral treatment consists of a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor, or a combination of two NRTIs and one non-nucleoside reverse transcriptase inhibitor. Patients on antiretroviral treatment should be monitored every 3 months. Undetectable HIV load should be the target of first- or second-line antiretroviral treatment. In order to prevent HIV transmission from mother to child, prescription of antiretroviral drugs after the first three months of pregnancy is indicated in pregnant women with a detectable HIV load. Prophylaxis of opportunistic infections can be discontinued if CD4+ cell count recovers above 200 x 10(6)/l. In case of exposure to HIV due to a needle or other occupational accident or unsafe sexual contact, post-exposure prophylaxis should be offered after careful risk evaluation. Preferably, vaccination to prevent pneumococci infections, influenza, hepatitis A or hepatitis B should be given when CD4+ cell count is > 200 x 10(6)/l.

AIDS-Related Opportunistic Infections↗

PubMed2002

Effects of antiretroviral drug combinations on the differentiation of adipocytes.

OBJECTIVE: Preadipocyte cell lines present a cell model with which to understand the physiopathological mechanisms underlying lipodystrophy syndrome, a common complication observed in patients treated with highly active antiretroviral therapy (HAART) that, in general, is associated with the use of protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI). The aim of this study was to evaluate the effects of NRTI and of PI and NRTI combinations in this cell model. METHODS: The differentiation of 3T3-F442A cells was studied by monitoring the expression of specific genes in the presence of therapeutic concentrations of antiretroviral drugs. Messenger RNA (mRNA) was quantified by two reverse transcription-PCR-based methods. RESULTS: In the presence of 2 microM saquinavir, 30 microM ritonavir or 1 microM zidovudine preadipocytes delayed their differentiation, whereas the use of 10 microM nelfinavir led to cell death. Indinavir (10 microM) promoted lipoprotein lipase expression whereas 1 microM lamivudine or 1 microM stavudine enhanced slightly the expression of the malic enzyme gene. However, the combination of indinavir, lamivudine and stavudine led to a large increase in both lipoprotein lipase and malic enzyme mRNA transcription whereas the combination of indinavir, lamivudine and zidovudine led to a 2.5-fold increase in the expression of the lipogenic malic enzyme gene. Similar potentiating effects of NRTI and PI were observed on the expression of the fatty acid synthase gene. CONCLUSIONS: Our data suggest that, like PI (although to a lesser extent) NRTI interfere with the differentiation process of adipocytes. In addition, we demonstrate that the effects produced by combinations of NRTI and PI are different from those elicited by each drug separately. This point may be particularly relevant in understanding the physiopathological mechanisms underlying the lipodystrophic syndrome.

3T3 Cells↗

PubMed2006

Revisiting monotherapy: heresy or revised orthodoxy?

After the widespread introduction of triple combination antiretroviral therapy in 1996 caused AIDS deaths to plummet, the earlier practice of single-drug treatment--or monotherapy--seemed like an embarrassing phase of medical ignorance. By then, it had become all too apparent that monotherapy promoted the rapid development of drug-resistant virus, often leading to treatment failure. Stories still occasionally surface about an isolated doctor prescribing solo AZT (zidovudine, Retrovir), and many long-time HIV physicians with large practices probably have one or two patients still doing well on two drugs and see no reason to change their regimens. But by and large, hitting hard with two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI) or a non-NRTI (NNRTI) has become dogma, and is now enshrined in all HIV treatment guidelines.

CD4 Lymphocyte Count↗

PubMed2002

Prevalence of HIV-1 polymerase gene mutations in pre-treated patients in Thailand.

To determine the prevalence of drug resistance-conferring mutations in human immunodeficiency virus type 1 (HIV-1), 83 HIV-1 infected Thai patients who had been treated with any antiretroviral drug were studied. HIV-1 RNA was reverse transcribed and amplified by RT-PCR. The direct sequencing of HIV-1 reverse transcriptase (RT) and protease was then performed. Changes in nucleotide and amino acid sequences were determined by comparison with a pNL4-3 reference sequence. Data on mutations associated with resistance to antiretroviral drugs were obtained from literature. The mutations associated with lamivudine resistance (M184V/I) were found most often (in 45.7% of individuals). Zidovudine-resistant mutants: T215Y/F (36%), M41L (28%) and K70R (25.3%) were common; but mutations linked to didanosine (L74V) and multinucleoside-resistant genotypes (Q151M) were rarely recognized (2.4% and 3.6%, respectively). The stavudine-resistant mutant (V75T) and T69 insertions were not found. All subjects who had a significant exposure to antiretroviral drugs and current virological failure in the past carried drug-resistant genotypes. Genotypic resistance to zidovudine, lamivudine, zalcitabine, indinavir and ritonavir appeared in more than one third of the samples, which suggested that the prevalence of the HIV-1 resistance-conferring genotype resisting reverse transcriptase inhibitors and/or protease inhibitors was high in treatment experienced patients.

DNA-Directed RNA Polymerases↗

PubMed2005

Abacavir and lamivudine fixed-dose combination tablet once daily compared with abacavir and lamivudine twice daily in HIV-infected patients over 48 weeks (ESS30008, SEAL).

BACKGROUND: Abacavir (ABC) and lamivudine (3TC) administered twice daily were compared with an ABC + 3TC fixed-dose combination (Epzicom, Kivexa; EPZ) administered once daily, both in combination with a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). METHODS: Two hundred sixty HIV-infected subjects with more than 6 months of ABC and 3TC administered twice daily plus a PI or NNRTI with an HIV-1 RNA level less than 400 copies/mL for more than 3 months and a CD4 count greater than 50 cells/mm were randomized 1:1 to ABC + 3TC administered twice daily or EPZ administered once daily. RESULTS: At baseline, median time on ABC and 3TC administered twice daily was 22 months, and median CD4 count and HIV-1 RNA level were 554 cells/mm and <50 copies/mL, respectively. EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily based on the proportion of nonvirologic failures (confirmed HIV-1 RNA level > or =1265 copies/mL; 90% confidence interval: -3.4 to 6.4; (intent to treat [ITT]: missing [M] = failure [F]). Proportions with an HIV-1 RNA level <50 copies/mL were 81% of those taking EPZ once daily and 82% of those taking ABC + 3TC twice daily at week 48 (ITT: M = F). Virologic failure was rare (2 patients taking the once-daily regimen, 4 patients taking the twice-daily regimen). There was a low incidence of grade 2 through 4 adverse events (AEs) and no drug-related serious AEs or hypersensitivity reactions. CONCLUSIONS: EPZ administered once daily was established as not inferior to ABC + 3TC administered twice daily in a regimen containing an NNRTI or a PI over 48 weeks. A dual-nucleoside backbone of ABC and 3TC administered once or twice daily is effective, durable, and well tolerated.

Adult↗

PubMed2000

An analysis of the catalytic cycle of HIV-1 reverse transcriptase: opportunities for chemotherapeutic intervention based on enzyme inhibition.

This review describes each of the steps in the HIV-1 reverse transcriptase catalytic cycle and evaluates each of these steps as a potential point of inhibition of the enzyme and consequently viral replication. To date, two classes of approved drugs act on the reverse transcriptase. They are: (1) the nucleoside reverse transcriptase inhibitors which either directly inhibit the enzyme or serve as alternative substrates for catalysis (resulting in chain termination) and (2) the non-nucleoside reverse transcriptase inhibitors which bind to an allosteric site and adversely affect the function of the enzyme by slowing the rate of chemical catalysis. In order to provide the best possible analysis of the potential of each of the steps in the catalytic cycle as a site of inhibition, the molecular forces which determine the intrinsic binding affinities and specificity of natural components of the catalytic complex will be described in as much detail as possible.

Animals↗

PubMedDate not supplied

Replacement of protease inhibitors by nevirapine or efavirenz in simplification and rescue interventions: which works better?

The outcome of 162 patients replacing protease inhibitors (PIs) by nonnucleoside reverse transcriptase inhibitors (NNRTIs) was retrospectively assessed. After 48 weeks of follow-up, nevirapine (NVP) and efavirenz (EFV) performed similarly well in simplification interventions in patients with undetectable viremia, while EFV provided significantly better results in rescue interventions after PI failure. Previous suboptimal exposure to nucleoside analogs conditioned lower chances of virologic success using either NVP or EFV. Both drugs were generally well tolerated, although specific toxicities could make one drug more suitable than the other for certain patients.

Adult↗

PubMed2005

The impact of HIV-protease inhibitors on opportunistic parasites.

Opportunistic parasitic infections are an important cause of morbidity and mortality in people infected with HIV. Since the introduction of highly active antiretroviral therapy (HAART), there has been a marked reduction in the occurrence and clinical course of these parasitic infections. Although these changes have been attributed to the restoration of cell-mediated immunity induced by either non-nucleoside reverse transcriptase inhibitors or HIV protease inhibitors, in combination with at least two nucleoside reverse transcriptase inhibitors included in HAART, there is evidence that HIV protease inhibitors have a direct inhibitory effect on the proteases of parasites. The results of studies on opportunistic parasitic infections conducted both before and during the HAART era indicate the need to develop clinical trials on the efficacy of HIV protease inhibitors in controlling parasitic infections in individuals with HIV or other immunocompromised individuals and laboratory investigations on aspartyl proteases of parasites as an important target for the development of new drugs.

AIDS-Related Opportunistic Infections↗

PubMed2006

Variant of hepatitis B virus with primary resistance to adefovir.

The reverse-transcriptase inhibitor lamivudine (Zeffix, GlaxoSmithKline) is often used to treat chronic infection with hepatitis B virus (HBV) until resistance develops. Treatment may then be switched to the reverse-transcriptase inhibitor adefovir (Hepsera, Gilead), which has a lower frequency of resistance. Here, we describe three cases of primary adefovir resistance that were sensitive to tenofovir (Viread, Gilead). All three cases involved a rare HBV variant with a valine at position 233 of the reverse-transcriptase domain instead of isoleucine (rtI233V), as in the wild-type virus. This HBV variant also displayed resistance to adefovir and sensitivity to tenofovir in vitro.

Adenine↗

PubMed2005

Nucleoside analogue-sparing strategy for the treatment of chronic HIV infection: potential interest and clinical experience.

Nucleoside analogue-sparing antiretroviral combinations may be interesting as first-line therapies as they spare a complete class of drugs that will remain fully active for later use and prevent the risk of mitochondrial toxicity related to exposure to nucleoside reverse transcriptase inhibitors (NRTIs). This strategy is also used in patients failing NRTIs with cross-resistance to compounds in this class. Different combinations of antiretroviral drugs are theoretically available. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) associated with protease inhibitor (PI) and boosted double-PI combinations have been studied through small, non-comparative clinical studies and preliminary results suggest that they are efficient and often well-tolerated. However, NNRTIs and PIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions; a good knowledge of the interactions between NNRTIs and PIs, or between PIs, is helpful in assisting physicians in clinical practice in choosing drugs and doses. Access to a therapeutic drug monitoring service to confirm that appropriate drug exposures are achieved is useful when using such regimens. Some negative kinetic interactions may lead to complicated combinations with a high pill burden that reduces their applicability. Gastrointestinal toxicity often remains a limiting factor in the use of boosted double-PI combinations. Non-comparative studies have allowed selection of NRTI-sparing options that now need to be compared with the current standard of care in comparative clinical trials before being considered as valuable options. Other NRTI-sparing therapeutic strategies are emerging: PI monotherapy with lopinavir/ritonavir has been evaluated in a small group of naive patients and appears promising. Drugs belonging to new classes currently under investigation, such as entry inhibitors, might be included early in the antiretroviral treatment of patients as soon as compounds with a convenient route of administration are available, increasing the number of therapeutic combinations without NRTIs.

Anti-HIV Agents↗

PubMed2000

Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons.

OBJECTIVE: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. DESIGN: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 x 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. METHODS: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. RESULTS: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. CONCLUSION: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially.

Adolescent↗