Showing papers on "Zidovudine published in 2006"
TL;DR: The combination of tenofovir DF and emtricitabineplus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efvirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs.
Abstract: background Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere. methods We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir–emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine–lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study. results Through week 48, significantly more patients in the tenofovir–emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine–lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P = 0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir– emtricitabine group vs. 70 percent in the zidovudine–lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P = 0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P = 0.002). More patients in the zidovudine–lamivudine group than in the tenofovir–emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P = 0.02). In none of the patients did the K65R mutation develop. conclusions Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials. gov number, NCT00112047.)
882 citations
TL;DR: Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine -triph phosphate concentrations and CYP3A5 expression was associated with fasterIndinavir oral clearance.
Abstract: Objective: The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes. Study Design: Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV RNA. Results: Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log 10 changes in HIV RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA] 7 /[TA] 7 genotypes. No relationships were identified with BCRP. Discussion: Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.
160 citations
TL;DR: K65R and TAMs exhibit bidirectional phenotypic antagonism, which likely explains the negative association of these mutations in genotype databases, the rare emergence of K65R with antiretroviral therapies that contain AZT, and its more frequent emergence with combinations that exclude AZT.
Abstract: The K65R mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is selected in vitro by many D-nucleoside analog RT inhibitors (NRTI) but has been rarely detected in treated patients. In recent clinical trials, the K65R mutation has emerged frequently in patients experiencing virologic failure on antiretroviral combinations that do not include 3'-azidothymidine (AZT). The reason for this change is uncertain. To gain insight, we examined trends in the frequency of K65R in a large genotype database, the association of K65R with thymidine analog mutations (TAMs) and other NRTI mutations, and the viral susceptibility profile of HIV-1 with K65R alone and in combination with TAMs. Among >60,000 clinical samples submitted for genotype analysis that contained one or more NRTI resistance mutations, the frequency of K65R increased from 0.4% in 1998 to 3.6% in 2003. Among samples with K65R, a strong negative association was evident with the TAMs M41L, D67N, L210W, T215Y/F, and K219Q/E (P 50-fold to <2.5-fold in both backgrounds. In addition, TAMs antagonized the phenotypic effect of K65R, reducing resistance to tenofovir, abacavir, 2',3'-dideoxycytidine, dideoxyinosine, and stavudine. In conclusion, K65R and TAMs exhibit bidirectional phenotypic antagonism. This antagonism likely explains the negative association of these mutations in genotype databases, the rare emergence of K65R with antiretroviral therapies that contain AZT, and its more frequent emergence with combinations that exclude AZT.
133 citations
Journal Article•
TL;DR: In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often.
Abstract: Objectives: To evaluate virologic response up to 48 weeks, and emergence of HIV-1 resistance mutations at 24 weeks, in therapy-naive adults initiating zidovudine/lamivudine/tenofovir DF.Design: A cohort within the DART trial.Methods: Plasma HIV-1 RNA was assayed in 300 adults with baseline CD4 cell count 1000 copies/ml at 24 weeks were sequenced in the pol region.Results: Median baseline CD4 cell count was 101 cells/mu l and HIV-1 RNA 279910copies/ml (mean, 5.4 log(10)). At 48 weeks, 61% (165/272) had HIV-1 RNA 1000 copies/ml (6 and 17% > 10000 copies/ml), and mean CD4 cell count increases were 103 and 127 cells/mu l, respectively. Higher baseline CD4 cell count was the most important predictor of virological suppression at 48 weeks, with little effect of baseline viral load. Eighteen of 20 genotypes from week 24 samples with HIV-1 RNA > 1000 copies/ml showed key resistance mutations in reverse transcriptase. Fourteen had M184V [10 with one to four additional nucleoside analogue mutations (NAMs)]; one had three NAMs only; and the remaining three had K65R. One participant with M184V had major non-nucleoside reverse transcriptase inhibitor-associated mutations, despite no disclosed treatment with this class.Conclusion: Zidovudine/lamivudine/tenofovir has good virological efficacy in advanced HIV disease. In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often. (c) 2006 Lippincott Williams & Wilkins.
129 citations
TL;DR: Despite increasing access to lower cost generic HAART in India, even less expensive and more tolerable first-line regimens and cost-effective treatment monitoring tools need to be introduced to achieve better treatment outcomes and access in resource-constrained settings.
Abstract: The objective was to describe reasons for modification and discontinuation of antiretroviral regimens in association with adverse events (AEs) treatment failure and cost among patients in southern India. Secular trends of patients initiating highly active antiretroviral therapy (HAART) between January 1996 and October 2004 at a tertiary HIV referral center in India were analyzed using a previously validated natural history database. All previously antiretroviral therapy-naive patients who initiated HAART (N = 1443) and had at least 1 follow-up visit were evaluated. The median CD4 count at the time of initiating HAART was 108 cells/mL The most common first-line regimens were stavudine (d4T) plus lamivudine (3TC) plus nevirapine (NVP) (63%) zidovudine (AZT) plus 3TC plus NVP (19%) d4T plus 3TC plus efavirenz (EFV) (9%) and AZT plus 3TC plus EFV (4%). Twenty percent of patients modified their first-line regimen. The most common reason for modifying therapy was the development of an AE (64%) followed by cost (19%) and treatment failure (14%) with median times to modify therapy being 40 151 and 406 days respectively. Common AEs were itching and/or skin rash (66%) hepatotoxicity (27%) and anemia (23%). Nine percent of patients discontinued therapy entirely after a median duration of 124 days primarily because of cost (64%). The most common reason for modifying therapy was the occurrence of AEs whereas cost was the most common reason for discontinuing therapy. Despite increasing access to lower cost generic HAART in India even less expensive and more tolerable first-line regimens and cost-effective treatment monitoring tools need to be introduced to achieve better treatment outcomes and access in resource-constrained settings. (authors)
109 citations
TL;DR: Failure to detect clinical improvement may have been due irreversible nerve damage in patients with a long clinical history and future studies should target patients presenting earlier and reflect a lack of activity of these nucleoside analogues against HTLV-I RT in vivo.
Abstract: No therapies have been proven to persistently improve the outcome of HTLV-I-associated myelopathy. Clinical benefit has been reported with zidovudine and with lamivudine in observational studies. We therefore conducted a randomised, double blind, placebo controlled study of six months combination therapy with these nucleoside analogues in sixteen patients. Primary outcomes were change in HTLV-I proviral load in PBMCs and clinical measures. Secondary endpoints were changes in T-cell subsets and markers of activation and proliferation. Six patients discontinued zidovudine. No significant changes in pain, bladder function, disability score, gait, proviral load or markers of T-cell activation or proliferation were seen between the two arms. Active therapy was associated with an unexplained decrease in CD8 and non-T lymphocyte counts. Failure to detect clinical improvement may have been due irreversible nerve damage in these patients with a long clinical history and future studies should target patients presenting earlier. The lack of virological effect but may reflect a lack of activity of these nucleoside analogues against HTLV-I RT in vivo, inadequate intracellular concentrations of the active moiety or the contribution of new cell infection to maintaining proviral load at this stage of infection may be relatively small masking the effects of RT inhibition.
107 citations
TL;DR: It is shown that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication and the view that Gag-Pol multimerization is an important step in viral assembly is supported.
Abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation
103 citations
TL;DR: In the setting of maternal zidvudine and infant zidovudine plus single- dose nevirapine, infant HIV infection rates were similar whether women received single-dose nevirabine or placebo, and this strategy avoids the potential for maternal nevirAPine resistance.
Abstract: Single-dose nevirapine given to women and infants reduces mother-to-child HIV transmission but nevirapine resistance develops in a large percentage of women. The objective was to determine whether the maternal nevirapine dose could be eliminated in the setting of zidovudine prophylaxis. A 2 x 2 factorial randomized clinical trial with a double-blinded peripartum factor designed to assess the equivalence of maternal single-dose nevirapine versus placebo with respect to HIV transmission. A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana resulting in 694 live first-born infants. HAART was available for women with AIDS. All women received a background of zidovudine from 34 weeks gestation through delivery and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor. Main outcome measures: The primary endpoint was infant HIV infection by the 1-month visit. Of the 694 infants in this equivalence study 15 (4.3%) of 345 in the maternal nevirapine arm were HIV infected by 1 month versus 13 (3.7%) of 349 in the maternal placebo arm (95% confidence interval for difference _2.4% to 3.8%) meeting pre-determined equivalence criteria. Nevirapine resistance at 1 month postpartum was detected in 45% of a random sample of women who received nevirapine. In the setting of maternal zidovudine and infant zidovudine plus singledose nevirapine infant HIV infection rates were similar whether women received single-dose nevirapine or placebo. This strategy avoids the potential for maternal nevirapine resistance. (authors)
102 citations
TL;DR: HIV infection increases the oxidative stress process, while antiretroviral combination therapy increased protein oxidation as well as the level of oxidative stress already present in HIV infection.
Abstract: The study assessed the effect of some highly active antiretroviral therapies (HAART), used in the management of HIV/AIDS in Cameroon, on oxidative stress markers such as malondialdehyde (as TBARs), albumin, protein carbonyl content and protein sulfhydryls groups. 85 HIV positive patients (34.8 ± 9.3 years) were on three different highly active antiretroviral therapies (HAART patients). 65 HIV positive patients (32.2 ± 10.9 years) on no treatment (Pre-HAART patients), and 90 non-HIV infected patients (32.6 ± 9.3 years), were the control groups. Plasma TBARs as well as carbonyl levels were significantly higher in HIV patients on HAART compared to pre-HAART patients or non-HIV infected controls. On the other hand, the protein sulfhydryl group content was not different for patients on HAART compared to pre-HAART patients, but both were significantly lower than non-HIV infected controls (P < 0.0001, 0.001). The combination treatment Therapy I [stavudin (80 mg) + Lamivudin (600 mg) + Nevirapin + (400 mg) zidovudin (600 mg)] brought about a significant (p < 0.05) reduction in the plasma concentration of protein sulfhydrl groups as well as TBARs compared to Therapy II [stavudin (80 mg) + Lamivudin (300 mg) + nevirapin (400 mg)] or with combination Therapy III of [zidovudine (600 mg) + lamivudin(300 mg) with efavirenz (600 mg)] (P < 0.05). The content of the antioxidant, Vitamin C was lower in the plasma of patients on Therapy I compared to those on Therapy II (P < 0.01) and Therapy III (P < 0.001). HIV infection therefore increases the oxidative stress process, while antiretroviral combination therapy increased protein oxidation as well as the level of oxidative stress already present in HIV infection.
100 citations
TL;DR: Worsening HIV disease parameters are associated with neutropenia in HIV-infected women and treatment with HAART, without zidovudine in the regimen, protects against development of neutropania, whereas HAART use and higher CD4 cell counts areassociated with resolution of neutopenia.
Abstract: Background: Neutropenia is well described in individuals infected with human immunodeficiency virus (HIV) and occurs in approximately 10% to 50% of cases. Neither the effect of highly active antiretroviral therapy (HAART) on neutrophil counts nor the significance of neutropenia in terms of survival has previously been evaluated. Methods: The prevalence of neutropenia among 1729 HIV-infected women, followed up as part of the Women's Interagency HIV Study, was evaluated. The CD4 lymphocyte counts, HIV-1 RNA levels, and complete blood cell counts, including absolute neutrophil counts, were obtained at 6-month intervals. Results: Neutropenia was common among HIV-infected women; at baseline, 44% had neutrophil counts less than 2000/μL, whereas 7% had counts less than 1000/μL. During 7.5 years of follow-up, neutrophil counts less than 2000/μL occurred on at least 1 occasion in 79%, whereas absolute neutrophil counts less than 1000/μL were documented in 31%. Worsening HIV disease parameters, such as lower CD4 cell counts ( P P P P =.007). We found that HAART, without zidovudine, was associated with protection against development of neutropenia. On multivariate analysis, neutropenia was not found to be associated with decreased survival among HIV-infected women. Conclusions: Worsening HIV disease parameters are associated with neutropenia in HIV-infected women. Treatment with HAART, without zidovudine in the regimen, protects against development of neutropenia, whereas HAART use and higher CD4 cell counts are associated with resolution of neutropenia. Neutropenia is not associated with decreased survival in HIV-infected women.
95 citations
01 Jan 2006
TL;DR: Significant advances in HIV/AIDS treatment regimens have fundamentally altered the natural history of the disease and sharply reduced HIV-related morbidity and mortality in countries where such treatments are accessible and prompted numerous developing countries to introduce antiretroviral therapy through the public sector.
Abstract: Enormous advances in HIV/AIDS treatment regimens have fundamentally altered the natural history of the disease and sharply reduced HIV-related morbidity and mortality in countries where such treatments are accessible. The advent of antiretroviral drugs in the late 1980s began a revolution in the management of HIV which can be seen as analogous to the use of penicillin for treating bacterial infections in the 1940s. The most notable advance on the treatment front is the use of combination antiretroviral therapy which is far more effective than monotherapy (zidovudine or AZT) the standard of care when the first edition of this volume was published. Recent declines in the price of combination antiretroviral therapy in developing countries from US$15000 per year to less than US$150 in some countries have prompted numerous developing countries to introduce antiretroviral therapy through the public sector. These declines also pose difficult questions regarding the optimal allocation of limited resources for HIV/AIDS as well as the potential impact on already strained health care infrastructures. (excerpt)
TL;DR: To describe the maternal tolerability of nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland and to determine risk factors for development of significant hepatotoxicity.
Abstract: Objectives
To describe the maternal tolerability of nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland and to determine risk factors for development of significant hepatotoxicity.
Methods
A retrospective study was carried out of all women prescribed nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland (October 2000 to February 2003). Toxicities experienced were graded according to the Division of AIDS toxicity guidelines for adults. Statistical analysis was performed to determine whether there were differences between those that did and those that did not experience significant hepatotoxicity.
Results
A total of 123 women initiated nevirapine as part of combination antiretroviral therapy in the study period. Eight women developed significant hepatotoxicity, including two women who died from fulminant hepatitis. Women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts (P=0.01).
Conclusions
In this cohort, women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts, lending additional weight to the need for caution in using nevirapine as part of combination antiretroviral therapy in women not requiring antiretroviral therapy for their own health.
TL;DR: Emtricitabine (FTC) is a new nucleoside agent that has activity against both human immunodeficiency virus (HIV) and hepatitis B virus and it is very similar to lamivudine (3TC) with respect to its activity, convenience, and safety and resistance profile.
Abstract: Emtricitabine (FTC) is a new nucleoside agent that has activity against both human immunodeficiency virus (HIV) and hepatitis B virus. It is very similar to lamivudine (3TC) with respect to its activity, convenience, and safety and resistance profile. Indeed, with the exception of the longer intracellular half-life of triphosphate FTC, there is little to distinguish between the 2 drugs. Clinical trials comparing FTC with 3TC as part of a triple-drug regimen have demonstrated their equivalence, whereas a study comparing activity of FTC with that of stavudine demonstrated FTC's superiority. In clinical practice, the choice of 3TC versus FTC will most likely be made in the context of drugs coformulated with them. Although FTC is not formally approved for use in patients coinfected with HIV and hepatitis B virus, it is often a preferred choice for such patients when combined with tenofovir, which also has anti-hepatitis B virus activity. Recent treatment guidelines for the treatment of HIV infection by both the International AIDS Society-USA and US Department of Health and Human Services have placed FTC in combination with tenofovir, didanosine, or zidovudine in the preferred category of nucleoside backbone regimens for patients receiving antiretroviral therapy.
TL;DR: There appears to be no net NRTI resistance benefit for TAMs and K65R to develop together in patients taking AZT and TFV disoproxil fumarate, where the TAM pathway alone provides the greatest resistance for both drugs.
Abstract: The HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TFV), abacavir, didanosine and stavudine can select for K65R, whereas zidovudine (AZT) and stavudine can select for thymidin...
TL;DR: This study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs.
Abstract: We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naive patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L+L210W+T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N+K70R+K219Q+T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs.
TL;DR: A comparison of HIV-1 and HIV-2 RT shows that there are numerous differences in the putative ATP binding sites that could explain why HIV- 1 RT binds ATP more effectively, and suggests thatAIDS-1 RT has a better nascent ATP binding site than HIV- 2 RT, making it easier for HIV-3 RT to develop a more effective ATP bindingsite by mutation.
Abstract: The human immunodeficiency virus type 1 (HIV-1) develops resistance to all available drugs, including the nucleoside analog reverse transcriptase inhibitors (NRTIs) such as AZT. ATP-mediated excision underlies the most common form of HIV-1 resistance to AZT. However, clinical data suggest that when HIV-2 is challenged with AZT, it usually accumulates resistance mutations that cause AZT resistance by reduced incorporation of AZTTP rather than selective excision of AZTMP. We compared the properties of HIV-1 and HIV-2 reverse transcriptase (RT) in vitro. Although both RTs have similar levels of polymerase activity, HIV-1 RT more readily incorporates, and is more susceptible to, inhibition by AZTTP than is HIV-2 RT. Differences in the region around the polymerase active site could explain why HIV-2 RT incorporates AZTTP less efficiently than HIV-1 RT. HIV-1 RT is markedly more efficient at carrying out the excision reaction with ATP as the pyrophosphate donor than is HIV-2 RT. This suggests that HIV-1 RT has a better nascent ATP binding site than HIV-2 RT, making it easier for HIV-1 RT to develop a more effective ATP binding site by mutation. A comparison of HIV-1 and HIV-2 RT shows that there are numerous differences in the putative ATP binding sites that could explain why HIV-1 RT binds ATP more effectively. HIV-1 RT incorporates AZTTP more efficiently than does HIV-2 RT. However, HIV-1 RT is more efficient at ATP-mediated excision of AZTMP than is HIV-2 RT. Mutations in HIV-1 RT conferring AZT resistance tend to increase the efficiency of the ATP-mediated excision pathway, while mutations in HIV-2 RT conferring AZT resistance tend to increase the level of AZTTP exclusion from the polymerase active site. Thus, each RT usually chooses the pathway best suited to extend the properties of the respective wild-type enzymes.
TL;DR: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy, particularly in populations at risk of iron deficiency.
Abstract: Objective: Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. Design: Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. Methods: Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddl) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. Results: Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddl plus d4T. Among ddl/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddl/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (Cl) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddl/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. Conclusions: Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.
TL;DR: In this paper, isolated rat liver mitochondria were incubated with labeled thymidine or AZT, and the rate and extent of phosphorylation were determined by HPLC analysis of acid-soluble extracts of the incubated mitochondria.
TL;DR: Data pertaining to some of the most common antiretrovirals (ARTs) are reviewed and information regarding nephrotoxicity of the medications frequently used to combat opportunistic infections is included.
TL;DR: These results are in line with current World Health Organisation guidelines suggesting equivalence of choice between single-dose NVP and short-course ZDV, and confirm the greater efficacy of ZDv+3TC than with any single antiretroviral drug.
Abstract: There are positive reports about the ability of antiretroviral agents to prevent mother-to-child transmission (MTCT) of HIV. The authors undertook a pooled analysis of African breast-feeding mothers from clinical trials of various antiretroviral regimens to directly compare their efficacy in lowering the prevalence of MTCT 6 weeks postpartum. A total of 3465 live-born singleton infants participating in 6 randomized clinical trials made up the study population. There were 2 West African zidovudine (ZDV)/placebo trials; 2 regimens of ZDV + lamivudine (3TC) and placebo (pre-/intra-/ postpartum and intra-/postpartum); nevirapine (NVP) and ZDV + 3TKC; NVP and ultra-short ZDV; and a vitamin A trial as a placebo arm. Peripartum HIV infection was diagnosed from a positive RNA or DNA polymerase chain reaction test before 2 months of age. In multivariable logistic regression analysis using placebo for comparison and adjusting for numerous factors (maternal CD4 cell count, breast feeding, low birth weight, geographic area), the lowest rates of MTCT 6 weeks postpartum were observed with ZDV + 3TC pre-/intra-/postpartum with an adjusted odds ratio (AOR) of 0.23. Next most effective, in declining order, were ZDV + 3TC intra-/postpartum (AOR, 0.49); antenatal ZDV short (AOR, 0.55); and NVP (AOR, 0.60). Compared with NVP, only the longest regimen of ZDV + 3TC was significantly more effective (AOR, 0.39). The risk of MTCT was not influenced by cesarean delivery or gender on univariate analysis. In multivariable analysis, the 6-week rate of MTCT was significantly associated with the maternal CD4 cell count. These findings are consistent with current World Health Organization guidelines that consider single-dose NVP and short-course ZDV to be equivalent regimens. Also evident from this study is that the regimen of ZDV + 3TC is more effective than any single antiretroviral agent.
TL;DR: Hepatotoxicity is the commonest adverse effect noted followed by elevated serum amylase and zidovudine induced anemia, and Hepatot toxicity is seen at higher viral load as compared to other adverse effects.
Abstract: The aim of this prospective study was to determine the adverse effects of antiretroviral therapy in HIV-1 infected children and factors associated with adverse effects. The study was performed in a pediatric and perinatal HIV clinic in a tertiary general hospital. Forty-three HIV positive children from the age group of 5 months to 14 years were started on antiretroviral therapy ART. Thirteen patients (30%) had adverse effects related to the ART. Seven patients (16%) had hepatotoxicity, 5 patients (12%) had raised serum amylase without symptomatic pancreatitis, 5 patients (12%) had zidovudine AZT induced anemia, 4 patients (9%) had Nevirapine NVP induced rash, 1 patient (2%) had Didanosine ddI induced pain in abdomen, 1 patient (2%) had Stavudine d4T induced angioedema, and 1 patient (2%) had hepatic steatosis. Five patients (71%) with hepatotoxicity responded to dose adjustment of ART whereas in 2 patients (29%), the elevated liver enzymes resolved on its own. Two patients (40%) with AZT induced anemia required omission of AZT and remaining 3 patients (60%) responded to dosage adjustment. ddI induced abdominal pain, d4T induced angioedema and hepatic steatosis resolved on omitting the respective antiretroviral drug. NVP induced rash and raised serum amylase subsided without any intervention. Hepatotoxicity was seen at higher viral load (Mean = 118608 copies/ml) whereas elevated serum amylase was seen at lower viral load (mean = 37631 copies/ml), which was statistically significant (p < 0.0001). NVP induced rash was seen in early weeks of therapy, serum amylase abnormalities were seen at a mean interval of 0.9 years after starting therapy, hepatotoxicity was seen at a mean interval of 1.7 years and AZT induced anemia was seen at a mean interval of 2.0 years after starting therapy. Adverse effects with antiretroviral drugs in HIV-infected children are quite common. Hepatotoxicity is the commonest adverse effect noted followed by elevated serum amylase and zidovudine induced anemia. Hepatotoxicity is seen at higher viral load as compared to other adverse effects. Most of the adverse effects are reversible on dosage modification or omitting the offending drug.
TL;DR: A simple, fast, isocratic, reversed-phase high performance liquid chromatographic method for simultaneous determination of plasma zidovudine and nevirapine with UV detection at 260 nm that spans the blood concentration range of clinical interest was applied to a pharmacokinetic study in HIV-infected patients who were receiving antiretroviral treatment.
TL;DR: Concern has been raised, however, that these exposures may lead to persistent mitochondrial dysfunction or later cancers, underscoring the need for long-term surveillance of antiretroviral-exposed, HIV-uninfected infants.
Abstract: The expanded use of multiple antiretroviral drugs during pregnancy has led to a reduction in the occurrence of perinatal transmission of HIV to 250 cells/μL at treatment initiation and among pregnant women on long-term didanosine and stavudine. These drugs should be avoided in such situations if alternatives are available. Efavirenz has been associated with birth defects in monkeys, and several cases of neural tube defects have been reported in humans after first trimester exposure, so treatment with this drug should be avoided during the first trimester. Protease inhibitors have been associated with an increased risk of maternal glucose intolerance, pre-eclampsia and preterm birth in some, but not all, studies. Pregnancies exposed to antiretroviral therapy should be registered with the Antiretroviral Pregnancy Registry as early in pregnancy as possible in order to provide data on the risk of birth defects after exposure. The pharmacokinetics of nucleoside and non-nucleoside reverse transcriptase inhibitors are not significantly changed in pregnancy, so standard dosing may be used. However, concentrations of several protease inhibitors are lower in pregnancy, so ritonavir-boosting or increased doses are required. Of great theoretical concern is the impact of resistance mutations that develop following single-dose nevirapine therapy on the response to later therapy among women and their infected infants. The use of dual nucleoside therapy for 3–7 days after single-dose nevirapine in the mother reduces but does not eliminate the risk of nevirapine resistance; alternative regimens for prevention of resistance are under study, as are the subsequent responses of the mother and her infant to therapy. Short courses of prophylactic zidovudine and nevirapine have been well tolerated in neonates. Concern has been raised, however, that these exposures may lead to persistent mitochondrial dysfunction or later cancers, underscoring the need for long-term surveillance of antiretroviral-exposed, HIV-uninfected infants.
TL;DR: The purpose of this work is to characterize the nature of AZT inhibition of thymidine phosphorylation in isolated rat heart and rat liver mitochondria, and find AZT was found to be a competitive inhibitor of theosphorylation ofThymidine to TMP, catalyzed by Thymidine kinase 2.
TL;DR: A nucleoside backbone of zidovudine/lamivudine or any tenofovir-based backbone was associated with significantly poorer increases in CD4 cell count compared to a nucleosid backbone of stavudine/.
Abstract: BACKGROUND: It is unknown if the CD4 cell count response differs according to antiretroviral drugs used in combination antiretroviral therapy (cART) in patients with maximal virological suppression [viral load (VL) < 50 copies/ml]. OBJECTIVES: To compare the change in CD4 cell count over consecutive measurements with VL < 50 copies/ml at both time-points according to nucleoside backbones and other antiretrovirals used. METHODS: Generalized linear models, accounting for multiple measurements within patients, were used to compare CD4 cell count changes after adjustment for antiretrovirals, time from starting cART, age, CD4 at first VL < 50 copies/ml, prior antiretroviral treatment, and change in CD4 cell count since starting cART. RESULTS: We studied 28418 instances of VL < 50 copies/ml in 4041 patients. The mean annual change in CD4 cell count was +45.5/microl [95% confidence interval (CI) +39.4 to +51.6/microl). Comparing two drug nucleoside backbones, there was a lower annual change in CD4 cell count for zidovudine/lamivudine (n = 13038; -15.4/microl; P = 0.012) and for those on tenofovir (n = 1809; -27.3/microl; P = 0.029) compared to lamivudine/stavudine (n = 7339). Compared to the boosted-protease inhibitor regimen (n = 5915), use of an abacavir-based triple-nucleoside regimen was associated with a lower annual change in CD4 cell count (n = 2504 pairs; -26.1/microl; P = 0.011). CONCLUSIONS: A nucleoside backbone of zidovudine/lamivudine or any tenofovir-based backbone was associated with significantly poorer increases in CD4 cell count compared to a nucleoside backbone of stavudine/lamivudine, as was an abacavir-based triple nucleoside regimen compared to a boosted protease inhibitor regimen. Long-term studies are needed to determine whether the differences in immunological response seen here translate into differences in the risk of clinical disease
TL;DR: The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis, and the nucleoside analogue backbone in a HAART regimen may influence this association.
Abstract: Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection or = F3). PI-based HAART versus no use of HAART (AOR = 0.4, 95% CI = 0.2-0.7, P = 0.001) was negatively associated with fibrosis progression rate > or = 0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed > or = F3, compared with 65 (37%) patients without HAART (P = 0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed > or = F3 (P = 0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.
TL;DR: The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing.
Abstract: The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing. Although administration of oral zidovudine during labor may not provide equivalent serum drug exposure as with continuous intravenous infusion, the clinical relevance of the difference is unknown. Nevirapine is well absorbed during labor, and sufficient drug for prophylaxis against perinatal transmission crosses the placenta if an oral dose is administered to the mother at least 1 hour before delivery. Placental transfer of reverse transcriptase inhibitors is good, whereas preliminary data suggest that protease inhibitors do not cross the placenta well. The use of antiretrovirals during pregnancy is becoming increasingly common, although their safety, toxicity, and teratogencity in pregnancy have not been well described. Normal growth and development have a profound impact on the pharmacokinetics of antiretrovirals in newborns and infants. Washout elimination of transplacentally acquired drug is slow. The pattern of increase in drug clearance over time will depend on the specific elimination pathway for the agent. Dosing regimens must take into account developmental changes in clearance and appropriate scaling for size. Adherence to antiretroviral regimens is a critical factor in determining the success of prophylactic and therapeutic regimens and is made difficult by the inability of infants to swallow pills and capsules.
TL;DR: A novel series of nonnucleoside inhibitors of HIV-1, exemplified byVRX-329747 and VRX-413638, which inhibit both NNRTI- and N RTI-resistant HIV- 1 isolates with the potential to augment current therapies are reported.
Abstract: Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.
TL;DR: In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity, and added effects in combination with other NRTIs, tenofovir, nevirapine, or saquinavir.
Abstract: SPD754 (AVX754) is a deoxycytidine analogue nucleotide reverse transcriptase inhibitor (NRTI) in clinical development. These studies characterized the in vitro activity of SPD754 against NRTI-resistant human immunodeficiency virus type 1 (HIV-1) and non-clade B HIV-1 isolates, its activity in combination with other antiretrovirals, and its potential myelotoxicity and mitochondrial toxicity. SPD754 was tested against 50 clinical HIV-1 isolates (5 wild-type isolates and 45 NRTI-resistant isolates) in MT-4 cells using the Antivirogram assay. SPD754 susceptibility was reduced 1.2- to 2.2-fold against isolates resistant to zidovudine (M41L, T215Y/F, plus a median of three additional nucleoside analogue mutations [NAMs]) and/or lamivudine (M184V) and was reduced 1.3- to 2.8-fold against isolates resistant to abacavir (L74V, Y115F, and M184V plus one other NAM) or stavudine (V75T/M, M41L, T215F/Y, and four other NAMs). Insertions at amino acid position 69 and Q151M mutations (with or without M184V) reduced SPD754 susceptibility 5.2-fold and 14- to 16-fold, respectively (these changes gave values comparable to or less than the corresponding values for zidovudine, lamivudine, abacavir, and didanosine). SPD754 showed similar activity against isolates of group M HIV-1 clades, including A/G, B, C, D, A(E), D/F, F, and H. SPD754 showed additive effects in combination with other NRTIs, tenofovir, nevirapine, or saquinavir. SPD754 had no significant effects on cell viability or mitochondrial DNA in HepG2 or MT-4 cells during 28-day exposure at concentrations up to 200 μM. SPD754 showed a low potential for myelotoxicity against human bone marrow. In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity.
Journal Article•
TL;DR: This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M1841/V, and more discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M18 41/V in COLATE.
Abstract: Background: Lamivudine (3TC) therapy can cause the emergence of M184I/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M184I/V in patients receiving combination antiretroviral therapy (cART). Methods: HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log(10) average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and >= 1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M184I/V. Results: The overall 48-week log(10) HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC (n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC (n=66; P=0.51). No difference was seen in the magnitude of the CD4(+) T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients (P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M184I/V (P<0.0001). Conclusion: This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M184I/V. Evolutionary distances from baseline were larger in viruses that did not contain M184I/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M184I/V in COLATE.