When should antiretroviral therapy for HIV be started?
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
Brian G Gazzard
Publications and source records attributed to Brian G Gazzard.
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↗
The management of meningeal lymphoma in patients with HIV in the era of HAART: intrathecal depot cytarabine is effective and safe.
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Adult↗
Use of tenofovir disoproxil fumarate and emtricitabine combination in HIV-infected patients.
With the continuing spread of HIV infection, particularly in developing countries, cost-effective treatment for its management is a high priority. Truvada (Gilead Sciences) is a single combination pill of the nucleotide reverse transcriptase inhibitors tenofovir disoproxil fumarate and emtricitabine, which is used once daily. It is anticipated to be a clinically potent combination that is free of short-term irritating toxicity. The drug has recently been licensed but there are currently little clinical efficacy data regarding its use. The limited published data have indicated that emtricitabine and lamivudine have equivalent potency, and randomised controlled trials have produced evidence of the efficacy of lamivudine combined with tenofovir disoproxil fumarate in a regimen containing either the non-nucleoside reverse transcriptase inhibitor efavirenz or a protease inhibitor lopinavir/ritonavir. In these trials, long-term durability data are available for < or = 96 weeks.
Adenine↗
Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine- and zidovudine-containing regimens.
OBJECTIVES: Despite evidence for the role of adipokines such as adiponectin in the metabolic toxicities of protease inhibitor (PI)-treated patients, little is known about their role in nucleoside reverse transcriptase inhibitor (NRTI)-induced lipoatrophy (LA). We analyzed the relations between mitochondrial toxicity, adipokine expression, and clinical LA in peripheral blood mononuclear cells (PBMCs) and adipose samples from individuals treated with stavudine (d4T) or zidovudine (ZDV) in comparison to patients undergoing highly active antiretroviral therapy (HAART) as well as HIV-negative individuals. METHODS: In this cross-sectional analysis, we studied 18 PI-naive HIV-infected patients with LA treated with d4T (d4T+LA+ [n = 12]) or zidovudine (ZDV+LA+ [n = 6]) in comparison to HAART-treated patients with (HAART+LA+ [n = 8]) and without (HAART+LA- [n = 8]) LA as well as HIV-negative controls (n = 12). Adipose samples were assessed for protein and/or messenger RNA (mRNA) levels of adiponectin, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, and sterol regulatory element-binding protein (SREBP) 1a/c in all groups, whereas adipose and PBMC samples from the d4T+LA+, ZDV+LA+, and HIV-negative subgroups were assessed for mitochondrial DNA (mtDNA) depletion and cytochrome c-oxidase (COX) II/COX IV ratios. RESULTS: There was no change in mtDNA levels in adipose or PBMC samples in NRTI-treated patients with LA, although patients treated with d4T had reduced COX II/COX IV ratios in adipose and PBMC samples. Adipose tissue adiponectin mRNA and plasma levels were reduced in the d4T- and ZDV-treated patients regardless of the use of PIs. Tissue SREBP1c mRNA levels were also significantly reduced in both NRTI groups when compared with the HIV-negative controls. Significant reductions in SREBP1c levels were also evident with the HAART+LA+ group when compared with HAART+LA- controls. CONCLUSIONS: Patients with LA on d4T-based regimens show evidence of mitochondrial respiratory chain dysfunction, whereas the d4T- and ZDV-based regimens also demonstrated reduced SREBP1c and adiponectin levels, findings that have previously been shown with PIs.
Adiponectin↗
Switch from inhibitory to activating NKG2 receptor expression in HIV-1 infection: lack of reversion with highly active antiretroviral therapy.
BACKGROUND: HIV-1 infection is characterized by increase in inhibitory receptors and loss of activating receptors on natural killer (NK) cells, resulting in loss of cell activity. Exceptionally, for an inhibitory receptor, the proportion of NK cells bearing CD94-NKG2A decreases during HIV-1 infection. It is not understood whether HIV-1 itself or other concomitant infections drive these changes. OBJECTIVES: To investigate the relationship between HIV-1 viraemia and changes in C-type lectin-like receptor expression in NK cells and to investigate the effect of highly active antiretroviral therapy (HAART) on these changes. METHODS: Three cohorts of patients were studied: (1) before, during and after treatment interruption in aviraemic and viraemic patients receiving HAART (n = 15); (2) HIV-1-positive treatment-naive individuals (n = 13); and (3) HIV-1-positive individuals receiving successful HAART for a minimum of 1 year without interruption (n = 11). Flow cytometry was used to study the expression of NKG2A before and after treatment interruption and to define expanded populations of NK cells in untreated and treated HIV-1-positive individuals. Assays were performed in vitro to assess the cytotoxicity of the expanded populations. RESULTS: Increases in plasma HIV-1 RNA during treatment interruption in aviraemic HAART-treated individuals did not influence the proportion of NK cells carrying the complex CD94-NKG2A. Loss of NKG2A NK cells corresponded to the dramatic expansion of a distinct population of cells expressing a functional activating CD94-NKG2C receptor with skewed expression of killer cell immunoglobulin-like receptor family and natural cytotoxicity receptors. CONCLUSION: Changes in the NK cell repertoire during HIV-1 infection were not a result of HIV-1 viraemia alone but resembled those associated with concomitant infections.
Antibodies, Viral↗
Transmission of hepatitis C virus among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin.
OBJECTIVE: To evaluate treatment outcome of acute hepatitis C virus (HCV) in HIV-positive individuals. DESIGN: Open-label, prospective study conducted in London, January 1997-December 2003. METHODS: Patients in whom acute HCV infection had been diagnosed had sequential HCV RNA levels measured at 0, 4, 12, 24, 32, and 48 weeks. If HCV RNA positive at 12 weeks, patients were offered pegylated interferon alpha-2b 1.5 microg/kg/wk and ribavirin 800-1200 mg/d for 24 weeks. Patients with increasing HCV RNA titers were offered treatment earlier. RESULTS: Fifty male homosexuals with a mean age 37 years were identified: 44 from abnormal liver function test results, 4 from sexual contact with an HCV-positive partner, and 2 at HIV seroconversion. Overall, 12 individuals became HCV RNA negative spontaneously. This was significantly associated with high baseline median CD4(+) count (P = 0.029), CD4(+) count >500 cells/mm(3) (P = 0.017), and lower HCV RNA titers (P = 0.017). Only 27 patients accepted treatment, 16 (59%) of whom reached sustained virologic response. This was associated with higher peak mean alanine aminotransferase (P < 0.001) and higher baseline CD4% (P = 0.041). CONCLUSIONS: Sustained virologic response rates in HIV-positive patients treated for acute HCV infection are lower than in HIV-negative subjects. Because a high percentage of individuals seroconvert spontaneously, treatment should be delayed until after 12 weeks.
Acute Disease↗
Rising rates of HIV infection.
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AIDS Vaccines↗
Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection.
BACKGROUND: CXCR4-using virus is associated with higher viral load and accelerated human immunodeficiency virus (HIV) disease progression. Additionally, CCR5 antagonists may not reduce the HIV-1 RNA load when mixed/dual-tropic or CXCR4-using virus is present. The determination of coreceptor tropism may be required before CCR5 or CXCR4 antagonists are initiated, unless reliable predictive markers of coreceptor use are established. METHODS: Samples from treatment-naive and -experienced HIV-1-positive individuals with date-matched CD4 and CD8 cell counts and HIV-1 RNA, clade, and pol sequences were assessed for coreceptor usage, by use of the ViroLogic PhenoSense assay. RESULTS: Coreceptor use determination was successful in 563 of 861 samples. Non-clade B virus was present in 18.6% of samples. CXCR4 or mixed/dual-tropic CCR5/CXCR4 virus was present in 112 of samples (19.9%). Only 4 samples (0.7%) showed exclusive CXCR4 use. In a multivariate model, higher CD4 cell count, lower viral load, and higher natural killer cell counts were significantly associated with CCR5 usage. No associations with treatment experience, clade, or pol gene mutations were observed. CONCLUSION: The prevalence of CCR5-tropic HIV-1 phenotype declines with decreasing CD4 cell count and increasing viral load. Mixed/dual tropic virus is found in all CD4 cell count and viral load strata. Coreceptor usage is not influenced by viral clade.
Adult↗
Clinical characteristics of IRIS syndrome in patients with HIV and tuberculosis.
BACKGROUND: Some patients with HIV/tuberculosis (TB) coinfection who are on anti-TB treatment and highly active antiretroviral therapy (HAART) will develop an exacerbation of symptoms, signs or radiological manifestations of TB that are not due to relapse or recurrence of their TB. The aetiology of these immune reconstitution inflammatory syndrome (IRIS) reactions is unknown but it is presumed that they occur, at least in part, as a consequence of HAART-related reconstitution of immunity. METHODS: Patients who were diagnosed with their first episode of definitive or presumed TB between January 2001 and July 2003 were identified from the Chelsea and Westminster TB/HIV database. The patients were classified into those who developed IRIS and those who did not using a set definition of the syndrome. Demographic, clinical and laboratory data relating to both HIV and TB were compared between the two groups. RESULTS: A total of 55 cases of TB were identified, of which 45 cases were confirmed on culture or gene probe and 10 were presumed cases. Fourteen cases (25.5%) developed IRIS with a median (range) duration of 2.53 (0.53-14.97) months. The median baseline CD4 [interquartile range (IQR)] for the IRIS group was significantly lower at 80 (33-117) cells/mm3 (P = 0.05) than the non-IRIS group at 139 (77-284) cells/mm3. A significantly greater proportion of patients in the IRIS group [11/14 (78.60%), P = 0.011] had baseline CD4 < 100cells/mm3 compared with the non-IRIS group [16/41 (39.0%)]. There was no significant difference between the two groups when comparing the log10 baseline viral load (VL). Eight (57.0%) patients in the IRIS group had disseminated TB at baseline compared with seven (17.0%) in the non-IRIS group (P = 0.006). In those who had a detectable VL at baseline, the median fold change (IQR) in CD4 from baseline to 3 months was significantly higher in the IRIS group patients, 1.5 (0.6-5.6), compared with 0.7 (-0.2 to 1.0) for those in the non-IRIS group (P = 0.046). CONCLUSIONS: Patients who develop IRIS are more likely to present with disseminated TB, have a CD4 count < 100 cells/mm3 and have a prompt rise in CD4 count in the initial 3 months of HAART.
Adult↗
The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine.
BACKGROUND: In vitro phenotypic resistance studies suggest that the presence of the M184V mutation leads to a reduction in HIV-1 susceptibility to didanosine (ddl). The relevance of this to clinical outcomes remains unclear. In this study, we compared the virological response of ddl- and non-ddl-containing regimens in the presence or absence of the M184V mutation. METHODS: Data from an observational cohort study of all HIV-1 patients who had phenotypic resistance testing following the emergence of virological failure to an existing highly active antiretroviral therapy (HAART) regimen were analysed. A total of 586 patients entered the study and were followed-up over 48 weeks; 281 (48%) were switched to ddl-containing HAART, of whom 105 had the M184V mutation at baseline. Virological efficacy of combination therapy was studied by reference to average area under the curve of viral load (VL) response and the proportion of patients attaining an undetectable VL (<400 copies/ml). Baseline characteristics and univariate analysis of changes in VL were compared using the Wilcoxon rank sum test. Multivariate analyses were performed using the Van Elteren test. Additional variables included the number of baseline nucleoside reverse transcriptase inhibitor mutations and the number of active antiretroviral drugs given to each group as compared by 'real phenotype' resistance test results. RESULTS: Amongst patients on ddl-containing HAART, median fold changes in phenotypic susceptibility to ddl were greater in patients with the M184V mutation (fold changes of 2.2 vs 1.2, P<0.001). Nonetheless, the median change in VL and percentage of patients attaining an undetectable VL were similar in those taking ddl, irrespective of whether the M184V mutation was present at baseline. In the group of patients with the M184V mutation at baseline, the virological outcome was significantly better in those treated with ddl-containing HAART than in those on HAART without ddl (P<0.05). CONCLUSIONS: While the M184V did increase the fold resistance of HIV to ddl, these changes appeared to be lower than the clinically relevant threshold for phenotypic resistance for this drug.
Anti-HIV Agents↗
Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel.
CONTEXT: Substantial changes in the field of human immunodeficiency virus (HIV) treatment have occurred in the last 2 years, prompting revision of the guidelines for antiretroviral management of adults with established HIV infection. OBJECTIVE: To update recommendations for physicians who provide HIV care regarding when to start antiretroviral therapy, what drugs to start with, when to change drug regimens, and what drug regimens to switch to after therapy fails. DATA SOURCES: Evidence was identified and reviewed by a 16-member noncompensated panel of physicians with expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care. The panel was designed to have broad US and international representation for areas with adequate access to antiretroviral management. STUDY SELECTION: Evidence considered included published basic science, clinical research, and epidemiological data (identified by experts in the field or extracted through MEDLINE searches using terms relevant to antiretroviral therapy) and abstracts from HIV-oriented scientific conferences between July 2002 and May 2004. DATA EXTRACTION: Data were reviewed to identify any information that might change previous guidelines. Based on panel discussion, guidelines were drafted by a writing committee and discussed by the panel until consensus was reached. DATA SYNTHESIS: Four antiretroviral drugs recently have been made available and have broadened the options for initial and subsequent regimens. New data allow more definitive recommendations for specific drugs or regimens to include or avoid, particularly with regard to initial therapy. Recommendations are rated according to 7 evidence categories, ranging from I (data from prospective randomized clinical trials) to VII (expert opinion of the panel). CONCLUSION: Further insights into the roles of drug toxic effects, drug resistance, and pharmacological interactions have resulted in additional guidance for strategic approaches to antiretroviral management.
Adult↗
Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen.
OBJECTIVE: To determine the pharmacokinetics of saquinavir hard-gel capsules/ritonavir/atazanavir co-administered once daily at 1600/100/300 mg in HIV-infected individuals. METHODS: Eighteen patients receiving saquinavir/ritonavir switched to 1600/100 mg once daily a minimum of 3 days before the study. On study day 1, levels of saquinavir and ritonavir were determined over 24 h. Atazanavir (300 mg once daily) was then added to the regimen. On day 11, a pharmacokinetic analysis was performed. Atazanavir was discontinued on day 32. Drug concentrations were measured by high-pressure liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir and ritonavir pharmacokinetic parameters, with and without atazanavir. A safety analysis was performed at screening, days 1, 11, 32 and follow-up. RESULTS: After the addition of atazanavir, statistically significant increases in saquinavir trough plasma concentration (Ctrough GMR, 95% CI 2.12, 1.72-3.50), maximum plasma concentration (Cmax 1.42, 1.24-1.94), area under the plasma concentration-time curve from 0-24 h (AUC0-24 1.60, 1.35-2.43) and ritonavir Cmax (1.58, 1.32-2.08), AUC0-24 (1.41, 1.22-1.74) were observed. The pharmacokinetics of atazanavir compared with those obtained in patients receiving atazanavir/ritonavir without saquinavir. Four patients developed scleral icterus and two jaundice. Total and unconjugated bilirubin increased approximately fivefold during atazanavir therapy. CONCLUSION: The addition of atazanavir to saquinavir/ritonavir increased saquinavir Ctrough, Cmax and AUC0-24 by 112, 42 and 60%. Ritonavir Cmax and AUCo-24 increased by 34 and 41%. The regimen was well tolerated, with no significant change in laboratory parameters, except for the occurrence of hyperbilirubinemia.
Adult↗
Does atazanavir cause lipodystrophy?
Atazanavir is a once-a-day non-pepsidic inhibitor of HIV protease which is licensed for use in the UK and the USA. One of its major advantages is that it does not produce lipid abnormalities in patients who receive it. This feature has been widely interpreted as implying that in the future there will be no abnormalities associated with fat redistribution when the drug is administered. This article explores that view.
Antiretroviral Therapy, Highly Active↗
An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance.
UNLABELLED: The development of resistance to any of the currently licensed non-nucleoside reverse transcriptase inhibitors (NNRTI) invariably leads to cross-resistance to the drugs in that class. New NNRTI, that have the promise of being active even when such 'signature' mutations are present, are in development. Such novel therapies could be effective after current NNRTI failure as there would probably be no cross-resistance. We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1. TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial. METHODS: Sixteen individuals receiving an NNRTI-containing antiretroviral regimen (efavirenz or nevirapine) with an HIV-1 RNA viral load of > 2000 copies/ml and phenotypic resistance to NNRTI, received TMC 125 for 7 days, as a substitute for their current NNRTI in their failing therapy. Full pharmacokinetic profiles were investigated. FINDINGS: The primary end point--viral load decay rate per day--was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of > 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6. INTERPRETATION: TMC 125, a next generation NNRTI, is well tolerated and demonstrates significant and rapid antiviral activity in patients with high levels of phenotypic NNRTI resistance to current NNRTI.
Adult↗
Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection.
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Adult↗
Interleukin-2-associated viral breakthroughs induce HIV-1-specific CD4 T cell responses in patients on fully suppressive highly active antiretroviral therapy.
The combination of intermittent subcutaneous IL-2 and highly active antiretroviral therapy in individuals infected with HIV-1 has been shown to have a beneficial quantitative effect on the CD4 T cell count. We observed IL-2-associated viral load 'blips' inducing HIV-1-specific lymphoproliferative responses at 24 weeks in such individuals. This immunotherapeutic approach, utilizing autologous virus as autovaccination, may be a viable, safer alternative to structured treatment interruption and potentially more efficacious than therapeutic vaccines.
Antiretroviral Therapy, Highly Active↗
The efficacy of lopinavir in individuals experiencing protease inhibitor failure.
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Adult↗