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PubMed2004

Antiviral profile of HIV inhibitors in macrophages: implications for therapy.

Macrophages (M/M) are identified as the second cellular target of HIV and a crucial virus reservoir. M/M are persistently infected cells and not susceptible to the HIV cytophatic effects typical of infected CD4+ T-lymphocytes. HIV replication in M/M is a crucial pathogenetic event during the whole course of the disease. Moreover, the dynamics of HIV-1 replication and cumulative virus production is quite different in M/M and CD4+ T-lymphocytes in the presence or in the absence of antiviral drugs. Thus, for their unique cellular characteristics, the activity of anti-HIV compounds could be different in M/M than in CD4+ T-lymphocytes. Indeed, nucleoside analogues inhibitors of HIV-reverse transcriptase (NRTIs) show potent antiviral activity in macrophages, although the limited penetration of these compounds in sequestered body compartments and the scarce phosphorylation ability of macrophages, suggest that a phosphate group linked to NRTIs may confer a greater anti-HIV activity in such cells. The antiviral activity of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in macrophages is similar to that found in CD4-lymphocytes. Interestingly, protease inhibitors (PIs), acting at post-integrational stages of virus replication, are the only drugs able to interfere with virus production and release from macrophages with established and persistent HIV infection. For these reasons, a careful analysis of the distribution of antiviral drugs, and the assessment of their activity in cells of macrophage lineage, represent key factors in the development of therapeutic strategies aimed to the treatment of the HIV-infected patients.

Anti-HIV Agents↗
PubMed2006

Therapeutic strategies towards HIV-1 infection in macrophages.

It is widely recognized that macrophages (M/M) represent a crucial target of HIV-1 in the body and play a pivotal role in the pathogenic progression of HIV-1 infection. This strongly supports the clinical relevance of therapeutic strategies able to interfere with HIV-1 replication in M/M. In vitro studies showed that nucleoside analogue inhibitors of HIV-1 reverse transcriptase have potent antiviral activity in M/M, although the limited penetration of these compounds in sequestered body compartments and low phosphorylation ability of M/M, suggest that a phosphonate group linked to NRTIs may confer greater anti-HIV-1 activity in M/M. Differently, the antiviral activity of non-nucleoside reverse transcriptase inhibitors in M/M is similar to that found in CD4+ lymphocytes. Interestingly, protease inhibitors, acting at a post-integrational stage of HIV-1 life-cycle are the only drugs active in chronically infected M/M. A careful analysis of the distribution of antiviral drugs, and the assessment of their activity in M/M, represent key factors in the development of therapeutic strategies aimed to the treatment of HIV-1-infected patients. Moreover, testing new and promising antiviral compounds in such cells may provide crucial hints about their efficacy in patients infected by HIV.

Anti-HIV Agents↗
PubMed2003

Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children.

BACKGROUND: Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected adult. SUBJECTS: The objective of this study was to investigate a liquid coformulation of lopinavir/ritonavir, in combination with reverse transcriptase inhibitors, in HIV-infected children. METHODS: One hundred antiretroviral (ARV)-naive and ARV-experienced, nonnucleoside reverse transcriptase inhibitor-naive children between 6 months and 12 years of age participated in this Phase I/II, open label, multicenter trial. Subjects initially received either 230/57.5 mg/m(2) or 300/75 mg/m(2) lopinavir/ritonavir twice daily; ARV-naive subjects also received stavudine and lamivudine, whereas ARV-experienced subjects also received nevirapine and one or two nucleoside reverse transcriptase inhibitors. Lopinavir/ritonavir pharmacokinetics, safety and efficacy were evaluated. RESULTS: All subjects were escalated to the 300/75 mg/m(2) twice daily dose based on results from an interim pharmacokinetic and safety evaluation. The pharmacokinetics of lopinavir did not appear to be dependent on age when dosing was based on body surface area but were decreased on coadministration with nevirapine. Overall 79% of subjects had HIV RNA levels <400 copies/ml at Week 48 (intent-to-treat: missing = failure). Mean increases in absolute and relative (percent) CD4 counts from baseline to Week 48 were observed in both ARV-naive subjects (404 cells/mm(3); 10.3%) and ARV-experienced subjects (284 cells/mm(3); 5.9%). Only one subject prematurely discontinued the study because of a study drug-related adverse event. CONCLUSIONS: The liquid coformulation of lopinavir/ritonavir demonstrated durable antiviral activity and was safe and well-tolerated after 48 weeks of treatment in HIV-infected children.

Administration, Oral↗
PubMed1998

[Diagnosis and treatment of ocular viral infections in AIDS patients].

Ocular complication of AIDS are seen in about 75% of patients. Viral infections are predominant and can involve either external segment in the eye (Herpes type 8 in Kaposi sarcoma, molluscum contagiosum, Herpes simplex and zoster), or the posterior segment of the eye (CMV retinitis). The introduction of a Highly Active Antiretroviral Therapy (HAART) which associates two reverse transcriptase inhibitors and one antiprotease has changed the evolution of AIDS. The decrease of onset of CMV retinitis in AIDS patient is one of the best exemple. For the first time it was possible to stop the maintenance therapy against CMV retinitis in patients that have a sufficient increase in CD4+ cells and they did not present any relapse of CMV retinitis. But an increase of ocular inflammation can be observed with the onset of HAART such as uveitis or cystoid macular edema.

AIDS-Related Opportunistic Infections↗
PubMed2006

Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Adult↗
PubMed1999

Reduction in human immunodeficiency virus patient hospitalizations and nontraumatic mortality after adoption of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) has been recommended for human immunodeficiency virus (HIV)-positive patients with a detectable viral load; it typically consists of two reverse transcriptase inhibitors combined with a protease inhibitor. In 1996, Madigan Army Medical Center began offering HAART to HIV-positive patients with a detectable viral load. We retrospectively reviewed the records of our HIV patients before and after the initiation of HAART to determine the impact of HAART on hospitalizations, mortality, and outpatient pharmacy expenditures. Comparing 1997 with 1994 and 1995, we found a greater than 700% increase in the average expenditure on antiretroviral agents after institution of HAART. At the same time, we found a dramatic reduction in hospitalizations and nontraumatic mortality. Therefore, the increase in expenditures on antiretroviral agents may be offset by a reduction in hospitalizations and mortality.

Adult↗
PubMedDate not supplied

Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society--USA panel.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Journal Article↗
PubMed1997

British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. BHIVA Guidelines Co-ordinating Committee.

Only incomplete data are available to guide decision on anti-HIV treatment. A British HIV Association consensus is that guidance must draw on other evidence besides the randomised trial. Marker studies, work on disease pathogenesis and viral dynamics, and expanding knowledge of resistance patterns mean that the approach to therapy is constantly evolving. There is a need for well-informed dialogue between HIV-infected patient and physician to achieve rational, individualized treatment. However, the following broad principles have a wide consensus amongst HIV-treating physicians in the UK: (1) treatment should be offered before substantial immunodeficiency ensues; (2) initial treatment should include combinations of at least two drugs; (3) switches in therapy should involve substitution or addition of at least two new agents; (4) viral load and CD4 measurements are essential; (5) reduction in viral load to below the detection level of a sensitive assay represents the optimal treatment response and failure to achieve or sustain this control should prompt consideration of therapy modification. This response seems to be achieved most reliably with combinations of two nucleoside analogues plus a third agent (a protease inhibitor, a non-nucleoside reverse-transcriptase inhibitor, or a third nucleoside analogue) or of two protease inhibitors.

Anti-HIV Agents↗
PubMed2006

The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses.

BACKGROUND: Tenofovir disoproxil fumarate, a prodrug of the nucleotide reverse transcriptase inhibitor, tenofovir (9-[9(R)-2-(phosphonomethoxy)propyl]adenine; PMPA), was recently approved for use in the combination therapy of human immunodeficiency virus (HIV)-1 infection. This study was undertaken to understand PMPA distribution to the virus sanctuary sites located in the brain, CSF and choroid plexuses and to clarify its possible role in reducing the neurological problems associated with HIV infection. METHODS: The methods used included an established bilateral carotid artery perfusion of [3H]PMPA and a vascular marker, D-[14C]mannitol, in anaesthetised guinea-pigs followed by scintillation counting, HPLC and capillary depletion analyses. Movement of [3H]PMPA into the brain, cisternal CSF and lateral ventricle choroid plexus was also examined in the absence and presence of additional anti-HIV drugs and a transport inhibitor. Control and test groups were compared by ANOVA or Student's t-test, as appropriate. RESULTS: The distribution of [3H]PMPA in the cerebrum, cerebellum, pituitary gland and cerebral capillary endothelial cells was not significantly different to that measured for D-[14C]mannitol. However, [3H]PMPA accumulation was significantly higher than that of D-[14C]mannitol in the choroid plexus and CSF. Further experiments revealed no cross-competition for transport of [3H]PMPA by probenecid, a non-specific inhibitor of organic anion transport, or the nucleoside reverse transcriptase inhibitors into any of the CNS regions studied. The octanol-saline partition coefficient measurement for [3H]PMPA was 0.0134 +/- 0.00003, which is higher that the 0.002 +/- 0.0004 measured for D-[14C]mannitol in an earlier study. CONCLUSION: There is negligible transport of [3H]PMPA across the blood-brain barrier, but it can cross the blood-CSF barrier. This is a reflection of the differing physiological and functional characteristics of the blood-CNS interfaces. Self- and cross-inhibition studies did not suggest the involvement of a transport system in the CNS distribution of this drug. However, the ability of PMPA to accumulate in the choroid plexus tissue, but not the cerebral capillary endothelial cells, and the hydrophilic nature of PMPA, does point to the possibility of a transporter at the level of the choroid plexus. PMPA that has crossed the choroid plexus and is in the CSF could treat HIV-infected perivascular and meningeal macrophages, but it is unlikely to reach the infected microglia of deep brain sites.

Journal Article↗
PubMed2004

Effect of a combination of clevudine and emtricitabine with adenovirus-mediated delivery of gamma interferon in the woodchuck model of hepatitis B virus infection.

Our aim was to evaluate the antiviral effect of a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and clevudine (L-FMAU), with the addition of an adenovirus-driven delivery of recombinant gamma interferon (IFN-gamma) in the woodchuck model of hepatitis B virus infection. Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-gamma (Ad-IFN) at weeks 4 and 8. In the control group, two animals received Ad-IFN alone, two received adenovirus vector expressing the green fluorescent protein reporter gene, and one remained untreated. In less than 2 weeks, all woodchucks that received L-FMAU plus FTC showed a rapid and marked inhibition of viral replication, with a 4-log(10) drop in serum WHV DNA. In two animals, viremia remained suppressed for several months after the end of treatment. Similarly, a dramatic decrease in intrahepatic replicative intermediates of viral DNA was observed in the L-FMAU/FTC-treated groups. The additional administration of Ad-IFN led to increased inflammation in the liver but did not enhance the antiviral effect of the L-FMAU/FTC combination. In conclusion, therapies combining L-FMAU and FTC in WHV-infected woodchucks resulted in a potent and sustained antihepadnaviral effect both in the liver and in the blood circulation. However, no extra benefit of adding IFN-gamma gene transduction to the L-FMAU/FTC combination could be detected.

Adenoviridae↗
PubMed2003

Prevalence of genotypic and phenotypic HIV-1 drug-resistant strains among patients who have rebound in viral load while receiving antiretroviral therapy in the UNAIDS-Drug Access Initiative in Abidjan, Côte d'Ivoire.

OBJECTIVE: To determine the prevalence of genotypic and phenotypic antiretroviral (ARV) drug-resistant HIV-1 strains among patients with viral load rebound while receiving ARV therapy in Abidjan, Côte d'Ivoire. METHODS: Between August 1998 and April 2000, we selected all patients (n = 241) who had received ARV drug therapy for at least 6 months in the UNAIDS-Drug Access Initiative (DAI), in Abidjan. We analyzed for genotypic and phenotypic drug resistance among 97 (40%) of the 241 patients who had a rebound in plasma viral load, defined as an initial decrease of > 0.5 log10 copies/ml followed by a subsequent increase of > 0.25 log10 copies/ml. RESULTS: Of the viruses isolated from the 97 patients, 86 (88.7%) had usable sequences and 68 (79%) of the 86 patients had genotypic resistance to at least one reverse transcriptase inhibitor (RTI) or protease inhibitor (PI). Resistant mutations were found for zidovudine in 50 (78%) of 64 patients who had received the drug, 11 (68.7%) of 16 patients on lamivudine, for nevirapine in two (2%), for indinavir in one (1%), and for ritonavir in one (1%). Phenotypic resistance to at least one nucleoside RTI was seen in 45 (56%) of the 80 patients tested, to non-nucleoside RTIs in eight (10%), and to PIs in one (1.3%). Multivariate regression analysis showed factors associated with resistance to be initial treatment with dual therapy (P = 0.04) compared with highly active antiretroviral therapy, and maximal initial viral load response (P = 0.006). CONCLUSION: Our results demonstrate a high prevalence of ARV drug resistance associated with dual ARV therapy. These results indicate the limited role for dual ARV therapy.

Adult↗
PubMed2006

Depletion of mitochondrial DNA copies/cell in peripheral blood mononuclear cells in HIV-1-infected treatment-naïve patients.

OBJECTIVES: Mitochondrial toxicity is believed to be the main reason for adverse effects related to nucleoside reverse transcriptase inhibitors (NRTIs). The aim of the present study was to compare mitochondrial toxicity in NRTI-treated HIV-positive patients, HIV-positive treatment-naïve patients and HIV-negative controls by comparing mitochondrial DNA (mtDNA) copies/cell in peripheral blood mononuclear cells (PBMCs) and lactate/pyruvate (L/P) ratios in the different groups. METHODS: We enrolled 60 participants in the study: 31 patients on combined antiretroviral therapy (CART), 14 HIV-positive treatment-naive patients and 15 HIV-negative controls. mtDNA (copies/cell) in peripheral blood was analysed using quantitative real-time polymerase chain reaction (PCR). Standard curves and serial dilutions of plasmid-cloned mitochondrion and retinoblastoma (RB1) PCR products with known concentrations were generated to estimate the mtDNA and nuclear DNA (nDNA) copy numbers in each sample. The L/P ratio was enzymatically and spectrophotometrically analysed in samples from individuals in a fasted, non-exercise state. Results The median mtDNA copy number was 63 copies/cell (interquartile range 33-94) in HIV-positive patients and 153 (132-283) in HIV-negative controls (P<0.001). No significant difference was seen between the HIV-positive NRTI-exposed patients and the HIV-positive treatment-naive patients. Current use of didanosine was negatively correlated with depletion of mtDNA (r=-0.36, P=0.046). HIV-positive patients also had a higher L/P ratio compared with HIV-negative controls (P=0.004). CONCLUSIONS: The number of mtDNA copies/cell in PBMCs was depleted in HIV-positive treatment-naive patients as well as in HIV-positive NRTI-exposed patients. HIV-positive patients also had a higher L/P ratio compared with HIV-negative controls, which supports this conclusion. The study suggests that neither mtDNA in PBMCs nor L/P ratio is a good marker of NRTI-associated mitochondrial toxicity.

Adult↗
PubMed2004

Drug resistance in non-subtype B HIV-1.

Treatment of HIV-1 with antiretroviral therapy may select mutations in the pol gene associated with resistance to reverse transcriptase inhibitors and protease inhibitors. To provide durable clinical benefit, emergence of drug resistance is countered by prescription of alternative drug regimens. Data on sequential treatments that are effective after virologic failure and the selection of drug resistance is largely confined to HIV-1 subtype B, the clade that has circulated in North America and Europe. However, HIV-1 subtype B currently accounts for only 12% of the estimated 40 million HIV infected individuals worldwide. The global HIV-1 epidemic includes infection with nine identified HIV-1 group M subtypes (A-K), as well as distinct sub-subtypes and numerous chimerical or recombinant forms. Increasing access to treatment of HIV-1 in the developing world and increasing non-subtype B infection through travel and migration pose new questions about the susceptibility and response of these diverse HIV-1 viruses to antiretroviral drugs. Here we review HIV diversity and the published literature on drug resistance, comparing the known resistance mutations in individuals infected with subtype B to the growing experience in the treatment of non-subtype B HIV-1 worldwide.

Anti-HIV Agents↗
PubMed2000

Contrasting patterns of response to lamivudine monotherapy in chronic hepatitis B patients.

In this paper we describe a cohort of patients treated with lamivudine, a reverse transcriptase inhibitor with a strong virus-suppressive effect on the hepatitis B virus. Eighty-nine patients were included in the intention-to-treat analysis. Evaluation with the Kaplan-Meier method was based on response to therapy of HBV DNA levels as well as normalization of transaminases. Subgroup evaluation based on the per protocol data was performed on two groups within this cohort based on the HBV DNA level at the end of therapy. During a 52-week treatment period, the chance of being HBV DNA negative at one point in time, as measured by the Digene Hybrid Capture assay (HCS) (limit of detection 1.5 x 10(6) geq/ml), the quantitative PCR assay (Q PCR) (limit of detection 1000 geq/ml), or the chance of normalization of transaminases at one point in time is 78%, 57% and 66%, respectively. Nineteen out of 73 patients who had continuing active viral replication after at least 24 weeks of lamivudine therapy were evaluated for the emergence of mutations resistant to lamivudine. In 3 out of 19 patients a mutation in the highly conservative YMDD region of the polymerase gene was detected. Baseline viral load in this group was significantly higher compared to the other 54 patients who were treated for 24 weeks or longer. Thirty-one out of 73 patients (46%) became negative by Q PCR. HBV DNA level at start of treatment was significantly lower compared to the 42 patients who remained HBV DNA positive. Eleven consecutive patients within this group who became negative by qualitative PCR (limit of detection 400 geq/ml) were evaluated to obtain characteristics for lamivudine withdrawal. Ten out of 11 patients became HBeAg negative with anti-HBe in 6. HBeAg in the liver biopsy was negative in 10 out of 11 patients; 9 out of 10 obtained biopsies were positive for HBV DNA, indicating low-level viral replication. In two patients in whom lamivudine was withdrawn, rebound of virus occurred. Further research is needed to obtain better insight into the variability in response. This might lead to a tailor-made individualized treatment regimen.

Adolescent↗
PubMed2004

Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1.

BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.

Adult↗
PubMed2002

The relationship between ritonavir plasma trough concentration and virological and immunological response in HIV-infected children.

BACKGROUND: We studied a number of factors, including ritonavir plasma levels, and their capability of predicting response to therapy with ritonavir (RTV). METHODS: Eleven HIV-positive children, nucleoside reverse transcriptase inhibitor (NRTI)-experienced, protease inhibitor (PI) naive, receiving RTV in combination with two NRTIs were enrolled in the study. Demographic parameters were: median age (range) 10 (2-13) years, weight 26 (10-38) kg, body surface area (BSA) 0.93 (0.47-1.21) m(2). Baseline values of CD4, percent CD4 and viral load were 137 (2-1390) cells/microL, 9.5 (0.4-32.4)%, and 5.15 (4.30-6.18) log10 copies/mL, respectively. The dose of RTV was 318 (266-409) mg/m(2) twice daily. Peak (3.5 h after administration) and trough (predose) plasma concentrations of RTV were determined on one occasion at steady-state after a morning dose. Virological response to treatment was quantified as the difference between the baseline value of viral load and the value observed at 6 months of therapy (Delta(6)). RESULTS: The relationship between Delta(6) and demographic parameters (age, weight, BSA, and baseline CD4, percent CD4, and viral load) and plasma concentrations of RTV was studied by linear regression. Median (range) Delta(6) was 0.88 (0.77-2.62) log10 copies/mL. Peak and trough of RTV were 14.9 (3.2-31.4) and 5.0 (0.1-15.6) mg/L, respectively. Trough concentration of RTV was the best predictor of Delta(6), although the relationship between these two variables was not statistically significant (r = 0.56, P = 0.075). CONCLUSION: Our observation of a trend for a greater decrease in viral load in patients with higher trough concentration of RTV warrants further pharmacodynamic studies of PI in paediatric patients.

Area Under Curve↗
PubMed2004

Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study.

BACKGROUND: Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected patient. OBJECTIVE: To analyse virological response to lopinavir/ritonavir therapy in previously protease inhibitor (PI)-experienced HIV-1-infected children. MATERIALS AND METHODS: Sixty-seven HIV-1-children on lopinavir/ritonavir were studied in a multicentre prospective cohort observational study. The outcome variables were undetectable viral load (uVL; VL < or =400 copies/mL) and virological failure after uVL with a rebound of VL >400 copies/mL. VL and genotype of HIV-1-isolates were measured using standard assays. RESULTS: 83.5% of children had a 1 log10 VL decrease including 65.6% who reached uVL. Children with >2 changes of antiretroviral therapy (ART) or >5 drugs needed a median time of 3-4 months higher than children with < or =2 changes of ART or < or =5 drugs previous to lopinavir/ritonavir, to reach those values, and the relative proportions (RP) were 2.2 (P =0.038) and 1.9 (P=0.050), respectively. Children with CD4+>15% (P=0.122), VL < or =30,000 (P < 0.001) copies/mL, and age >12 years (P=0.096) achieved an earlier control of VL during the follow-up. The children with virological failure or rebound of VL had higher baseline VL and lower CD4+ T-lymphocytes/mm3 and had taken a greater number of drugs previous to lopinavir/ritonavir. HIV-children with a new nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI) or PI plus non-nucleoside reverse transcriptase inhibitors (NNRTI) in the current regimen had a better virological response than children without these new drugs. Also, children with <6 protease mutations had an RP of 2.31 of achieving uVL. CONCLUSIONS: Highly active antiretroviral therapy (HAART) including lopinavir/ritonavir induces beneficial effects in terms of virological outcome responses, and it is an effective option for salvage therapy in PI-experienced HIV-1-infected children.

Acquired Immunodeficiency Syndrome↗
PubMed1990

X-ray analysis of 2',3'-lyxoanhydrothymidine, a conformationally restricted inhibitor of retroviral reverse transcriptases.

2',3'-Lyxoanhydrothymidine (LAT), a conformationally restricted inhibitor of retroviral reverse transcriptases, has been studied by X-ray analysis. The unit cell contains two crystallographically independent molecules A and B. Their sugar moieties have an identical structure: an 04'-endo pucker of the furanose cycle and a trans conformation about the exocyclic C4'-C5' bond. The conformations of A and B molecules differ with respect to the N-glycosidic bond: chi A(04 'Cl' N1C2) = -121.9 degrees which is typical of a common anti conformation whereas chi B (04'Cl'N1C2) = 121.2 degrees corresponds to a rare high-syn conformation. All the conformation properties of LAT molecules stem from the presence of an epoxide cycle in their molecules.

Antiviral Agents↗