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MedGenMed : Medscape General Medicine Oct 2007To study the effectiveness and tolerance of an antiretroviral therapy (ART) regimen composed of the antiretroviral agents (ARVs) stavudine (d4T) plus didanosine (ddI)... (Clinical Trial)
Clinical Trial
OBJECTIVE
To study the effectiveness and tolerance of an antiretroviral therapy (ART) regimen composed of the antiretroviral agents (ARVs) stavudine (d4T) plus didanosine (ddI) plus efavirenz (EFV) in patients with advanced HIV infection in Senegal.
DESIGN AND METHODS
This was an open-label, single-arm, 18-month trial in treatment-naive patients. The primary virologic end point was the percentage of patients with plasma HIV RNA < 500 copies/mL at months 6 (M6), 12 (M12) and 18 (M18). The primary analysis was done as intent-to-treat.
RESULTS
The staging of HIV disease, performed using the definitions of the US Centers for Disease Control and Prevention (CDC), was CDC stage B or C for all 40 recruited patients. At baseline, the mean CD4+ cell count was 133 +/- 92/mcL (+/- standard deviation [SD]; range 1-346), and 23% of patients had CD4+ cell counts below 50/mcL. The mean baseline plasma HIV RNA level was 5.5 +/- 0.4 log(10) copies/mL (+/- SD; range 4.6-5.9). The proportion of patients with plasma HIV-1 RNA below 500 copies/mL fell during the study from 73% (95% CI [56; 85]) at M6 to 56% (95% CI [41; 73]) at M12 and 43% (95% CI [27; 59]) at M18. Plasma HIV-RNA was below 50 copies/mL in 50% of study subjects (95% CI [31; 66]) at M6, 43% (95% CI [27; 59]) at M12, and 33% (95% CI [19; 49]) at M18. The mean increase in the CD4+ cell count was 105 +/- 125/mcL (n = 38) at M3 and 186 +/- 122/mcL (n = 21) at M18. Eight patients died, including 6 because of infectious complications. The last viral load (VL) value before death was < 500 copies/mL in all these patients except 1 nonadherent patient. Fifteen patients (37.5%) had peripheral neuropathy that was severe enough in 5 patients (12.5%) to require ddI and d4T discontinuation.
CONCLUSION
Virologic efficacy combination therapy with d4T, ddI, and EFV was measured by the percentage of patients with plasma HIV RNA values below 500 copies/mL and 50 copies/mL; for both parameters, virologic efficacy decreased during the study period. This is explained by the high mortality rate (20%) and treatment modifications due to adverse events (13%). These data strengthen the recently revised World Health Organization (WHO) guidelines advocating initiation of highly active antiretroviral therapy (HAART) before profound CD4 lymphocyte depletion occurs and avoiding HAART regimens containing d4T and ddI because of treatment-limiting side effects.
Topics: Administration, Oral; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Developing Countries; Didanosine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; Humans; Male; Maximum Tolerated Dose; Patient Compliance; RNA, Viral; Risk Assessment; Senegal; Severity of Illness Index; Stavudine; Survival Rate; Treatment Outcome; Viral Load
PubMed: 18311357
DOI: No ID Found -
BMC Pregnancy and Childbirth Feb 2016Universal multi drug antiretroviral treatment in pregnancy is a global priority in our bid to eliminate paediatric HIV infections although few studies have documented...
BACKGROUND
Universal multi drug antiretroviral treatment in pregnancy is a global priority in our bid to eliminate paediatric HIV infections although few studies have documented the impact of antiretroviral coverage on overall pregnancy outcomes.
METHODS
We conducted a maternity audit at a large regional hospital in South Africa during July-December 2011 and January-June 2014 with an aim to determine an association between pregnancy outcomes and the ARV treatment guidelines implemented during those specific periods. During 2011, women received either Zidovudine/sd Nevirapine or Stavudine/Lamivudine/Nevirapine if CD4+ count was < 350 cells/ml. During 2014, all HIV positive pregnant women were eligible for a fixed dose combination (FDC) of triple ARVs (Tenofovir/Emtracitabine/Efavirenz).
RESULTS
In 2011, 622 (35.9%) of 1732 HIV positive pregnant women received triple antiretrovirals (D4T/3TC/NVP) and in 2014, 2104 (94.8%) of 2219 HIV positive pregnant women received the fixed dose combination (TDF/FTC/EFV). We observed a reduction in the proportion of unregistered pregnancies, caesarean delivery rate, still birth rate, very low birth weight rate, and very premature delivery rate in 2014. In a bivariate analysis of all 9,847 deliveries, unregistered pregnancies (2.2%) and HIV infection (37.8%) remained significant risk factors for SB(OR 6.36 and 1.43 respectively), PTD(OR 4.23 and 1.26 respectively),LBW (OR 4.07 and 1.26 respectively) and SGA(OR 2.17 and 1.151 respectively). In a multivariable analysis of HIV positive women only, having received AZT/NVP or D4T/3TC/NVP or EFV/TDF/FTC as opposed to not receiving any ARV was significantly associated with reduced odds of a SB (OR 0.08, 0.21 and 0.18 respectively), PTD (OR 0.52, 0.68 and 0.56 respectively) and LBW(0.37, 0.61 and 0.52 respectively).
CONCLUSION
An improvement in birth outcomes is likely associated with the increased coverage of triple antiretroviral treatment for pregnant women. And untreated HIV infected women and women who do not seek antenatal care should be considered most at risk for poor birth outcomes.
Topics: Adolescent; Adult; Anti-Retroviral Agents; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Prenatal Care; South Africa; Stavudine; Young Adult; Zidovudine
PubMed: 26867536
DOI: 10.1186/s12884-016-0821-3 -
Current Pharmaceutical Design 2013Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile... (Review)
Review
Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.
Topics: Anti-HIV Agents; Cell Line; Drug Discovery; Epoxy Compounds; HIV-1; Humans; Magnetic Resonance Spectroscopy; Nucleosides; Stavudine
PubMed: 23092278
DOI: 10.2174/1381612811319100011 -
HIV Medicine Sep 2007The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and... (Comparative Study)
Comparative Study
OBJECTIVES
The aim of the study was to describe the prevalence of and risk factors for HIV-associated sensory neuropathy (HIV-SN) in 2006 [the era of stavudine, didanosine and zalcitabine (dNRTI)-sparing highly active antiretroviral therapy (HAART)] and to compare our findings with data obtained in the same clinic in 1993 (pre-HAART) and 2001 (frequent use of dNRTI-containing HAART).
METHODS
This was a cross-sectional comparative study using convenience sampling. HIV-positive adults attending a tertiary referral clinic over a 2-week period were screened for HIV-SN using the AIDS Clinical Trials Group screening tool. HIV-SN was defined as present if the patient had both neuropathic symptoms and abnormal signs. Demographic, clinical, laboratory and treatment data were considered as possible risk factors for HIV-SN, and results were compared with data obtained in the same clinic in 1993 and 2001.
RESULTS
One hundred patients were screened. The prevalence of HIV-SN was 42%, which was unchanged since 2001 (44%) despite a significant reduction in the use of dNRTIs. HIV-SN remained much more common than in 1993 (42% vs 13%; P<0.0001). The only independent associations with HIV-SN in 2006 were increasing patient age and a history of exposure to either stavudine or indinavir. This compares with 1993 when neuropathy was increased in those with Mycobacterium avium complex infection, and 2001 when patient age and use of stavudine and didanosine were the independent associations with HIV-SN in this clinic.
CONCLUSIONS
HIV-SN remained common among ambulatory patients in 2006 (42% prevalence) despite a significant reduction in the use of dNRTIs. In addition to patient age and stavudine exposure, indinavir use may be a risk factor for HIV-SN.
Topics: Adolescent; Adult; Aged; Antiretroviral Therapy, Highly Active; Australia; Cross-Sectional Studies; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Polyneuropathies; Prevalence; Reverse Transcriptase Inhibitors; Risk Factors; Stavudine
PubMed: 17661844
DOI: 10.1111/j.1468-1293.2007.00478.x -
HIV Medicine Jan 2001To assess the short-term and long-term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor-naive... (Clinical Trial)
Clinical Trial
OBJECTIVE
To assess the short-term and long-term effect of a combination of saquinavir, ritonavir and stavudine in moderately to severely immunosuppressed protease inhibitor-naive patients.
DESIGN
Prospective open-label multicentre study.
PATIENTS AND METHODS
A total of 64 protease inhibitor-naive and stavudine-naive HIV-infected patients with a CD4 count of < 250 cells/microL and > 10 000 HIV-1 RNA copies/mL received saquinavir hard-gelatin capsules, ritonavir and stavudine. Full (drop in viraemia of > 2 log10 and/or < 500 copies/mL) and partial responders (drop to between 500 and 5000 viraemia copies/mL) at week 9 (end of phase I) entered the second phase (additional 12-month period).
RESULTS
Fifty-six patients completed phase I, 45 (70%) full responders and nine (14%) partial responders by intent-to-treat analysis. Thirty-nine patients completed phase II, 33 (52%) full responders and two (3%) partial responders. Six patients had < 50 HIV-1 RNA copies/mL at week 9, and 20 (31%) patients at month 12 of phase II. Mean CD4 cell counts increased significantly in the 56 patients from 89 to 184 cells/microL after 9 weeks and from 100 to 292 cells/microL in the 39 patients treated for another 12 months. Higher baseline viraemia and lower baseline CD4 cell counts were not associated with an unfavourable virological response at week 9 and month 12 of phase II. HIV DNA in peripheral blood monocytes decreased substantially (- 1.5 log10) but was detectable in all except one patient at the end of phase II.
CONCLUSION
In protease- and stavudine-naive HIV-infected patients with moderate to severe immunosuppression, saquinavir in combination with ritonavir and stavudine caused a substantial long-term decrease in plasma viral load in approximately half the participants and a substantial increase in CD4 cell counts.
Topics: Adolescent; Adult; Aged; Cohort Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunocompromised Host; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Switzerland; Treatment Outcome; Viral Load
PubMed: 11737374
DOI: 10.1046/j.1468-1293.2001.00047.x -
PloS One 2013Lipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART). Both are assumed to be antiretroviral adverse drug reactions. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART). Both are assumed to be antiretroviral adverse drug reactions.
METHODS
We conducted a systematic review to determine whether fat loss or gain was more common in HIV-infected patients on ART than in uninfected controls; was associated with specific antiretrovirals; and would reverse after switching antiretrovirals.
RESULTS
Twenty-seven studies met our inclusion criteria. One cohort study reported more lipoatrophy, less subcutaneous fat gain, but no difference in central fat gain in HIV-infected patients on ART than in controls. Randomised controlled trials (RCTs) showed more limb fat loss (or less fat gain) with the following regimens: stavudine (versus other nucleoside reverse transcriptase inhibitors (NRTIs)); efavirenz (versus protease inhibitors (PIs)); and NRTI-containing (versus NRTI-sparing). RCTs showed increased subcutaneous fat after switching to NRTI-sparing regimens or from stavudine/zidovudine to abacavir/tenofovir. There were no significant between-group differences in trunk and/or visceral fat gain in RCTs of various regimens, but results from efavirenz versus PI regimens were inconsistent. There was no significant between-group differences in central fat gain in RCTs switched to NRTI-sparing regimens, or from PI-containing regimens.
CONCLUSIONS
There is clear evidence of a causal relationship between NRTIs (especially thymidine analogues) and lipoatrophy, with concomitant PIs possibly having an ameliorating effect or efavirenz causing additive toxicity. By contrast, central fat gain appears to be a consequence of treating HIV infection, because it is not different from controls, is not linked to any antiretroviral class, and doesn't improve on switching.
Topics: Absorptiometry, Photon; Adiposity; Antiretroviral Therapy, Highly Active; Drug-Related Side Effects and Adverse Reactions; HIV Protease Inhibitors; Humans; Intra-Abdominal Fat; Lipodystrophy; Reverse Transcriptase Inhibitors; Subcutaneous Fat; Tomography, X-Ray Computed; Torso
PubMed: 23723990
DOI: 10.1371/journal.pone.0063623 -
Molecules (Basel, Switzerland) Oct 2020Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither a cure nor a vaccine is available. However, the highly active antiretroviral...
Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither a cure nor a vaccine is available. However, the highly active antiretroviral therapy (HAART) has improved the life expectancy for patients with acquired immunodeficiency syndrome (AIDS). Nucleoside reverse transcriptase inhibitors (NRTIs) are in almost all HAART and target reverse transcriptase (RT), an essential enzyme for the virus. Even though NRTIs are highly effective, they have limitations caused by RT resistance. The main mechanisms of RT resistance to NRTIs are discrimination and excision. Understanding the molecular mechanisms for discrimination and excision are essential to develop more potent and selective NRTIs. Using protein X-ray crystallography, we determined the first crystal structure of RT in its post-catalytic state in complex with emtricitabine, (-)FTC or stavudine (d4T). Our structural studies provide the framework for understanding how RT discriminates between NRTIs and natural nucleotides, and for understanding the requirement of (-)FTC to undergo a conformation change for successful incorporation by RT. The crystal structure of RT in post-catalytic complex with d4T provides a "snapshot" for considering the possible mechanism of how RT develops resistance for d4T via excision. The findings reported herein will contribute to the development of next generation NRTIs.
Topics: Anti-HIV Agents; Catalysis; Crystallography, X-Ray; Drug Resistance, Viral; Emtricitabine; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Models, Molecular; Nucleotides; Reverse Transcriptase Inhibitors; Stavudine
PubMed: 33096918
DOI: 10.3390/molecules25204868 -
AIDS Research and Therapy Oct 2019During the initial scale up of ART in sub-Saharan Africa, prescribed regimens included drugs with high potential for toxicity (particularly stavudine). More recently a...
BACKGROUND
During the initial scale up of ART in sub-Saharan Africa, prescribed regimens included drugs with high potential for toxicity (particularly stavudine). More recently a growing number of patients requires second line treatment due to treatment failure, especially following the expansion of viral load testing. We aim to determine the reasons and risk factors for modification of first line ART across the years.
METHODS
We included patients started on standard first line ART (2NRTI + 1 NNRTI) between 2005 and 2016 at the Infectious Diseases Institute, Kampala, Uganda. We described the reasons for treatment modification categorized in (1) toxicity (2) treatment failure (3) other reason (new TB treatment, new pregnancy). We used Cox proportional hazard to identify factors associated with treatment modification due to toxicity.
RESULTS
We included 14,261 patients; 9114 (63.9%), were female, the median age was 34 years (IQR: 29-40), 60.8% were in WHO stage 3 and 4. The median BMI and CD4 count were 21.9 (IQR: 19.6-24.8) and 188 cell/µL (IQR: 65-353) respectively; 27.5% were started on stavudine, 46% on zidovudine, and 26.5% on a tenofovir containing regimens. We observed 6248 ART modifications in 4868/14,261 patients (34.1%); 1615 were due to toxicity, 1077 to treatment failure, 1330 to contraindications, and 1860 patients following WHO recommendation of phasing out stavudine and substituting with another NRTI. Modification for drug toxicity declined rapidly after the phase out of stavudine (2008), while switches to second line regimes increased after the implementation of viral load monitoring (2015). Patients with normal BMI compared to underweight, (HR: 0.79, CI 0.69-0.91), with CD4 counts 200-350 cells/µL compared to < 200 cells/µL (HR: 0.81- CI 0.71-0.93), and started on zidovudine (HR: 0.51 CI 0.44-0.59) and tenofovir (HR: 0.16, CI 0.14-0.22) compared to stavudine were less likely to have ART modification due to toxicity. Older patients (HR: 1.14 per 5-year increase CI 1.11-1.18), those in WHO stage 3 and 4 (HR: 1.19, CI 1.06-1.34) were more likely to have ART modification due to toxicity.
CONCLUSIONS
Toxicity as reason for drugs substitution decreased over time mirroring the phase out of stavudine, while viral load expansion identified more patients in need of second line treatment.
Topics: Adult; Anti-HIV Agents; Contraindications, Drug; Drug Substitution; Female; HIV Infections; Humans; Male; Retrospective Studies; Risk Factors; Stavudine; Treatment Failure; Uganda; Viral Load
PubMed: 31597561
DOI: 10.1186/s12981-019-0246-y -
European Review For Medical and... Feb 2020The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
OBJECTIVE
The current study was designed to investigate the effects of some nucleoside reverse transcriptase inhibitors (NRTIs) on HSV-1 infection.
MATERIALS AND METHODS
Initially, the SwissTargetPrediction server was used to predict the interactions between HSV-1 thymidine kinase and acyclovir, stavudine, zidovudine, didanosine, and entecavir. The effect of each component on Vero cell viability was assessed by the MTT assay. After treatment, the cell supernatants were collected, and HSV-1 replication was analyzed by quantitative real-time PCR.
RESULTS
The qPCR results revealed that viral titers were reduced 41, 40, 19, 44, and 31-fold in the presence of acyclovir, zidovudine, stavudine, didanosine, and entecavir, respectively.
CONCLUSIONS
Our findings indicate that NRTIs significantly reduce HSV-1 replication in cell culture.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Dose-Response Relationship, Drug; Herpesvirus 1, Human; Reverse Transcriptase Inhibitors; Vero Cells; Virus Replication
PubMed: 32096195
DOI: 10.26355/eurrev_202002_20204 -
Journal of the International AIDS... Sep 2011East Africa has experienced a rapid expansion in access to antiretroviral therapy (ART) for HIV-infected patients. Regionally representative socio-demographic,...
BACKGROUND
East Africa has experienced a rapid expansion in access to antiretroviral therapy (ART) for HIV-infected patients. Regionally representative socio-demographic, laboratory and clinical characteristics of patients accessing ART over time and across sites have not been well described.
METHODS
We conducted a cross-sectional analysis of characteristics of HIV-infected adults initiating ART between 2002 and 2009 in Kenya, Uganda and Tanzania and in the International Epidemiologic Databases to Evaluate AIDS Consortium. Characteristics associated with advanced disease (defined as either a CD4 cell count level of less than 50 cells/mm3 or a WHO Stage 4 condition) at the time of ART initiation and use of stavudine (D4T) or nevirapine (NVP) were identified using a log-link Poisson model with robust standard errors.
RESULTS
Among 48,658 patients (69% from Kenya, 22% from Uganda and 9% from Tanzania) accessing ART at 30 clinic sites, the median age at the time of ART initiation was 37 years (IQR: 31-43) and 65% were women. Pre-therapy CD4 counts rose from 87 cells/mm3 (IQR: 26-161) in 2002-03 to 154 cells/mm3 (IQR: 71-233) in 2008-09 (p<0.001). Accessing ART at advanced disease peaked at 35% in 2005-06 and fell to 27% in 2008-09. D4T use in the initial regimen fell from a peak of 88% in 2004-05 to 59% in 2008-09, and a greater extent of decline was observed in Uganda than in Kenya and Tanzania. Self-pay for ART peaked at 18% in 2003, but fell to less than 1% by 2005. In multivariable analyses, accessing ART at advanced immunosuppression was associated with male sex, women without a history of treatment for prevention of mother to child transmission (both as compared with women with such a history) and younger age after adjusting for year of ART initiation and country of residence. Receipt of D4T in the initial regimen was associated with female sex, earlier year of ART initiation, higher WHO stage, and lower CD4 levels at ART initiation and the absence of co-prevalent tuberculosis.
CONCLUSIONS
Public health ART services in east Africa have improved over time, but the fraction of patients accessing ART with advanced immunosuppression is still high, men consistently access ART with more advanced disease, and D4T continues to be common in most settings. Strategies to facilitate access to ART, overcome barriers among men and reduce D4T use are needed.
Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cross-Sectional Studies; Drug Utilization; Female; HIV Infections; Humans; Immune Tolerance; Kenya; Male; Middle Aged; Nevirapine; Sex Factors; Stavudine; Tanzania; Uganda
PubMed: 21955541
DOI: 10.1186/1758-2652-14-46