Should we be initiating antiretroviral therapy earlier? An argument in favour.
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Anti-Retroviral Agents↗
Biomedical subjects
Robin Wood
Publications and source records attributed to Robin Wood.
Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1.
BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.
Adult↗
A 42-week open-label study to assess the pharmacokinetics, antiretroviral activity, and safety of amprenavir or amprenavir plus ritonavir in combination with abacavir and lamivudine for treatment of HIV-infected patients.
The pharmacokinetics, antiviral activity, and safety of an amprenavir-ritonavir (APV-RTV) 600/100 mg b.i.d. regimen and an APV-RTV 1200/200 mg q.d. regimen were studied in a human immunodeficiency virus (HIV)-infected population. The geometric least-square mean ratio (90% confidence interval) of steady-state trough concentrations, compared with that of the amprenavir 1200 mg b.i.d. regimen, was 6.08 (4.94-7.49) for the twice-daily APV-RTV regimen, and it was 4.19 (2.90-6.08) for the daily APV-RTV regimen. The regimens were well tolerated, which supports APV-RTV as an option for twice-daily or daily therapy for HIV.
Adolescent↗
SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir /ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients.
OBJECTIVE: To compare the magnitude and durability of the antiviral response to fosamprenavir (FPV) plus ritonavir (RTV) once-daily (FPV/r QD) with nelfinavir twice-daily (NFV BID), each administered with abacavir and lamivudine twice-daily. METHODS: An international, phase III, randomized, open-label study in antiretroviral therapy-naive, HIV-infected adults. RESULTS: Patients with advanced HIV disease received FPV/r QD (n = 322) or NFV BID (n = 327). At week 48, 69% of patients in the FPV/r QD group and 68% in the NFV BID group had plasma HIV-1 RNA (vRNA) < 400 copies/ml, whereas 55% of patients in the FPV/r QD group and 53% in the NFV BID group had vRNA < 50 copies/ml (intent to treat, rebound/discontinuation = failure). More patients in the NFV BID group (17%) experienced virological failure than in the FPV/r QD group (7%). Efficacy of FPV/r QD was maintained in patients with CD4+ cell counts < 50 x 10 cells/l or vRNA >/= 100 000 copies/ml at entry. At week 48, median CD4+ cell counts were increased to 203 x 10 cells/l (FPV/r QD group) and 207 x 10 cells/l (NFV BID group). Both regimens were generally well tolerated. Diarrhea was more common on NFV BID than on FPV/r QD (16 versus 9%; P = 0.008). Fasting lipid profile results were generally favorable in both treatment arms. FPV/r QD maintained plasma amprenavir (APV) trough concentrations above the mean phenotypic drug-susceptibility (IC50) for wild-type virus for APV. CONCLUSION: As a first choice protease inhibitor with a low daily pill burden, FPV/r QD was well tolerated and provided potent, durable antiviral suppression.
Adolescent↗
Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.
The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.
Adult↗
Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines.
OBJECTIVES: To assess the utility of the 2003 revised World Health Organization (WHO) criteria [initiating highly active antiretroviral therapy (HAART) in stage IV, in stage III plus CD4 cell count < 350 x 10(6) cells/l, or in stage I or II plus CD4 cell count < 200 x 10 cells/l] relative to other scenarios of HAART initiation. METHODS: Progression to AIDS and death in 292 patients taking HAART and 974 not taking HAART in a South African institution in 1992-2001, stratifying patients by baseline CD4 cell count and WHO stage. RESULTS: HAART was associated with decreased AIDS [adjusted rate ratio [ARR], 0.16; 95% confidence interval (CI), 0.08-0.31) and death (ARR, 0.10; 95% CI, 0.06-0.18). Benefit of HAART was significant across all WHO stages plus CD4 cell counts. The greatest number of deaths averted was in stages IV [74.0/100 patient-years (PY); 95% CI, 50.2-84.5) and III (32.8/100 PY; 95% CI, 22.4-40.9). AIDS cases averted in stage III (22.0/100 PY; 95% CI, 6.1-26.9) were higher than in stage I and II with CD4 cell count < 200 x 10(6) cells/l (8.9/100 PY 95% CI, 5.6-13.3). Treatment initiation for symptomatic disease resulted in greater benefits than using any CD4 cell thresholds. Application of WHO criteria increased the treatment-eligible proportion from 44.5% to 56.7% (P < 0.05) but did not prevent more death (P > 0.05) than treating symptomatic disease. CONCLUSION: Implementation of the revised WHO guidelines in sub-Saharan Africa may result in a significantly increased number of individuals eligible for treatment but would not be as effective a strategy for preventing death as treating symptomatic disease.
Acquired Immunodeficiency Syndrome↗
Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects.
OBJECTIVE: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. METHODS: : HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add NVP and/or HU to the triple NRTI backbone of zidovudine plus lamivudine plus abacavir. Primary endpoint was treatment failure, defined as having plasma HIV RNA levels > 50 copies/ml after week 24, or discontinuation of randomized treatment. Follow-up was 72 weeks. RESULTS: For the 229 subjects, median plasma HIV-1 RNA was 4.61 log10 copies/ml and median CD4 cell count was 269 x 10 cells/l. NVP users reached plasma HIV-1 RNA < 50 copies/ml more rapidly than subjects using no NVP (log-rank test; P = 0.011). In the as-treated analysis, 21.6% of subjects using NVP versus 48.8% using no NVP reached the primary endpoint (P = 0.013). In the intent-to-treat analysis, 83.3% of subjects using HU versus 73.0% using no HU experienced treatment failure (P = 0.060), while no difference was observed in the as-treated analysis (34.5 versus 36.7%). Differences in the intent-to-treat analysis were accounted for by toxicity: 52.6% of subjects using HU experienced toxicity leading to discontinuation of randomized treatment versus 28.7% of subjects using no HU. CONCLUSION: The use of NVP in addition to a triple NRTI regimen improved both short- and long-term antiretroviral efficacy. The use of HU significantly contributed to treatment failure because of toxicity.
Adult↗
Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients.
This study compared the plasma amprenavir pharmacokinetics of the human immunodeficiency virus (HIV) protease inhibitors amprenavir (Agenerase) 1,200 mg twice daily (BID) and the amprenavir prodrug GW433908, a formulation that substantially reduces the number of tablets per dose compared with amprenavir, at doses of 1,395 mg and 1,860 mg BID, in combination with abacavir 300 mg BID and lamivudine 150 mg BID in patients with HIV infection. Overall, 78 patients received study treatment. Compared with amprenavir 1,200 mg BID, both GW433908 1,395 mg BID and GW433908 1,860 mg BID delivered equivalent steady-state (ss) values for area under the plasma amprenavir concentration-time curve (AUC) at the end of a dosing interval (tau), lower maximum plasma amprenavir concentrations (30% lower), and higher plasma amprenavir concentrations at the end of a dosing interval (28% higher for GW433908 1,395 mg BID and 46% higher for GW433908 1,860 mg BID). Time-variant plasma amprenavir pharmacokinetics were observed with reductions in plasma amprenavir exposure over the first 4 weeks of dosing; the decrease in plasma amprenavir AUC(tau,ss) versus the AUC from 0 h to infinity was 27% for GW43308 1,395 mg, 45% for GW433908 1,860 mg, and 23% for amprenavir 1,200 mg. All three regimens reduced plasma HIV-1 RNA ( approximately 2 log(10) copies/ml) and increased CD4(+) cell counts ( approximately 100 cells/mm(3)) over the initial 28 days. Adverse event profiles were consistent with those previously reported for amprenavir. Although not statistically tested, the GW433908 groups appeared to have fewer gastrointestinal symptoms. In conclusion, the protease inhibitor GW433908 delivered comparable plasma amprenavir concentrations to those delivered by amprenavir 1,200 mg BID. GW433908, in combination with abacavir and lamivudine, demonstrated potent antiviral activity and was generally well tolerated over a 4-week period.
Adolescent↗
Adherence is not a barrier to successful antiretroviral therapy in South Africa.
OBJECTIVE: To determine adherence of an indigent African HIV-infected cohort initiating antiretroviral therapy (ART); to identify predictors of incomplete adherence (< 95%) and virologic failure (> 400 HIV RNA copies/ml). DESIGN: Prospective monitoring of adherence in a poor HIV-positive cohort, attending a public sector hospital and receiving ART through phase III studies. METHODS: Adherence to ART was determined over 48 weeks by counting tablet-returns. Logistic regression models including age, WHO HIV stage, home language, socio-economic status, complexity and type of regimen were fitted to determine predictors of incomplete adherence and virologic failure at 48 weeks. RESULTS: 289 patients were recruited between January 1996 and May 2001. Median (mean) adherence of the cohort was 93.5% (87.2%). Three times daily dosing [risk ratio (RR), 3.07; 95% confidence interval (CI), 1.40-6.74], speaking English (RR, 0.41; 95% CI, 0.21-0.80) and age (RR, 0.97; 95% CI, 0.94-0.99) were independent predictors of incomplete adherence. Socio-economic status, sex and HIV stage did not predict adherence. Independent predictors of virologic failure included baseline viral load (RR, 2.57; 95% CI, 1.57-4.22) and three times daily dosing (RR, 2.64; 95% CI, 1.23-5.66), incomplete adherence (RR, 1.92; 95% CI, 1.10-3.57), age (RR, 0.96; 95% CI, 0.92-0.99) and dual nucleoside therapy (RR, 2.69; 95% CI, 1.17-6.15). CONCLUSION: The proportion of individuals achieving viral suppression matched results from the developing world. Speaking the same language as site staff and simplified dosing frequency were beneficial. Socio-economic status had no impact on adherence and should not be used as a limitation to ART access.
Adult↗
Usefulness of total lymphocyte count in monitoring highly active antiretroviral therapy in resource-limited settings.
OBJECTIVE: To assess the usefulness of total lymphocyte count (TLC) for monitoring HIV-infected patients receiving highly active antiretroviral therapy. DESIGN Observational cohort study. METHODS: Correlation between difference (Delta) from baseline at week 4, 8, 12 and 48 in TLC, CD4 cell count and viral load was determined in patients initiating HAART in phase III clinical trials between 1995 and 2001 at the HIV Clinical Research Unit, Somerset Hospital, Cape Town. RESULTS: The study included 266 patients. At weeks 4, 8, 12 and 48, median increase in TLC was 30, 52, 139 and 219 cells x 10 /l, median increase in CD4 cell count was 8, 48, 88, and 145 cells x 10 /l, and median decrease in viral load was -1.6, -2.2, -2.5 and -2.7 log copies/ml, respectively. The correlation between all pairs of DeltaTLC and DeltaCD4 cell counts was significant (r, 0.61; P < 0.0001), but between DeltaTLC and Delta viral load it was not (r, -0.014; P= 0.73). However, the correlation between median viral load reduction and median increase in both DeltaCD4 cell count (r, -0.96; P< 0.0001) and DeltaTLC (r, -0.89; P< 0.0001) was significant. The slope of DeltaCD4 cell count was [52.493 + 0.14(DeltaTLC)]. Sensitivity and specificity of an increase or decrease from baseline in TLC for similar trend in CD4 cell count during follow-up were 83.4% and 87.3% respectively. CONCLUSION: TLC correlated well with changes in CD4 cell count and at a group level with viral load changes. TLC may have a role in inexpensive monitoring of the immunological response to highly active antiretroviral therapy in a resource-constrained setting.
Adult↗
Antiretroviral therapy in a community clinic--early lessons from a pilot project.
OBJECTIVES: To report on operational and clinical problems encountered during the first 6 months of a community-based antiretroviral therapy (ART) programme. METHODS: ART was implemented in a primary care setting utilising an easily replicable service-delivery model based on a medical officer and nurse. Therapeutic counsellors, themselves HIV-infected, provided counselling and adherence support. Drug and monitoring costs were charitably funded and provincial health authorities supplied the medical infrastructure. The HIV Research Unit, University of Cape Town, supplied training and additional clinical support. Local HIV primary care clinics provided patient referrals. Standardised ART regimens were used with strict entry criteria (AIDS or CD4 count < 200 cells/microliter). RESULTS: Demand for the service was high. Referred patients had advanced disease (AIDS 57%, median CD4 count 96/microliter) and high pre-treatment mortality (83/100 person-years). Mycobacterial disease was a major contributor to this mortality (40%). Scheduled clinic visit hours were six times higher during recruitment than maintenance. Attributable costs were: drugs 61%, staff 27%, viral load and CD4 cell counts 10% and safety monitoring 2%. Viral load after 16 weeks of therapy was < 400 copies/ml in the first 16 patients. CONCLUSIONS: ART can be successfully implemented within a primary care setting. Drug purchases and staff salaries drive programme costing. The service model is capable of managing 250-300 patients on chronic ART, but staffing needs to be increased during recruitment. Attention must be given to the diagnosis of tuberculosis during screening and early ART. Incorporating therapeutic counsellors into the programme increased community involvement and utilised a valuable and previously untapped resource.
Acquired Immunodeficiency Syndrome↗
Do we need a national antiretroviral treatment register?
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Acquired Immunodeficiency Syndrome↗
Time-dependent changes in HIV nucleoside analogue phosphorylation and the effect of hydroxyurea.
BACKGROUND: Nucleoside analogues are activated to their triphosphates, which compete with endogenous deoxynucleoside triphosphate (dNTP) pools to inhibit HIV reverse transcriptase. Hydroxyurea has been administered with nucleoside analogues to modulate intracellular dNTP pools and thus the ratio of drug triphosphate:endogenous triphosphate. OBJECTIVES: To examine changes in drug activation over time and investigate the effects of hydroxyurea on intracellular phosphorylation of antiretroviral nucleoside analogues. PATIENTS: A total of 229 HIV-infected individuals receiving abacavir, lamivudine and zidovudine were randomly assigned to receive or not nevirapine and hydroxyurea. Twenty-four patients were recruited to an observational substudy measuring intracellular drug triphosphate and dNTP concentrations at 0, 2, 6, 12, 24 and 48 weeks. METHODS: Drugs were extracted from isolated peripheral blood mononuclear cells before analysis of endogenous dNTP and drug triphosphates by primer extension assays. RESULTS: Twenty-two out of 24 patients were followed to completion of the substudy. Hydroxyurea had no demonstrable effect on endogenous dNTP or drug triphosphate levels at any timepoint. However, the ratio of zidovudine triphosphate to endogenous deoxythymidine triphosphate was significantly increased with hydroxyurea. A significant decrease in lamivudine triphosphate (3TCTP) and the 3TCTP:endogenous deoxycytidine triphosphate ratio was seen over 48 weeks. In five patients who failed therapy in the first 24 weeks, significantly reduced 3TCTP was seen. CONCLUSION: Hydroxyurea does not affect measurable pools of endogenous nucleosides in vivo. Decreased lamivudine phosphorylation over time may provide a novel pharmacological explanation for the mechanism of resistance to this drug.
Adult↗
Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study.
BACKGROUND: Studies of the effect of highly active antiretroviral therapy (HAART) on the risk of HIV-1-associated tuberculosis have had variable results. We set out to determine the effect of HAART on the risk of tuberculosis in South Africa. METHODS: We compared the risk of tuberculosis in 264 patients who received HAART in phase III clinical trials and a prospective cohort of 770 non-HAART patients who were attending Somerset Hospital adult HIV clinic, University of Cape Town, between 1992 and 2001. Poisson regression models were fitted to determine risk of tuberculosis; patients were stratified by CD4 count, WHO clinical stage, and socioeconomic status. FINDINGS: HAART was associated with a lower incidence of tuberculosis (2.4 vs 9.7 cases per 100 patient-years, adjusted rate ratio 0.19 [95% CI 0.9-0 38]; p<0.0001). This finding was apparent across all strata of socioeconomic status, baseline WHO stage, and CD4 count, except in patients with CD4 counts of more than 350 cells/microL. The number of tuberculosis cases averted by HAART was greatest in patients with WHO stage 3 or 4 (18.8 averted cases per 100 patient-years, adjusted rate ratio 0. 22 [0.09-0.41]; p=0.03) and in those with CD4 counts of less than 200 cells/microL (14.2 averted cases per 100 patient-years, adjusted rate ratio 0.18 [0.07-0.47]; p,0.0001). INTERPRETATION: HAART reduced the incidence of HIV-1-associated tuberculosis by more than 80% (95% CI 62-91) in an area endemic with tuberculosis and HIV-1. The protective effect of HAART was greatest in symptomatic patients and those with advanced immune suppression.
AIDS-Related Opportunistic Infections↗
Antiretroviral therapy in South Africa--can we do it?
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Anti-HIV Agents↗
Exploring the costs of a limited public sector antiretroviral treatment programme in South Africa.
BACKGROUND: The role of antiretroviral treatment for adults in the pubic sector in South Africa is debated with little consideration of programme choices that could impact on the cost-effectiveness of the intervention. This study seeks to explore the impact of these programme choices at an individual level, as well as explore the total cost of a rationed national public sector antiretroviral treatment programme. METHODS: Eight scenarios were modelled of limited national treatment programmes over the next 5 years, reflecting different programme design choices. The individual cost-effectiveness of these scenarios were compared. The total costs of the most cost-effective scenario were calculated, and the potential for savings in other areas of health care utilisation was explored. RESULTS: The direct programme costs per life-year saved varied between scenarios from R5,923 to R11,829. All the costs of the most cost-effective scenario could potentially be offset depending on assumptions of health care access and utilisation. The total programme costs for the most cost-effective scenario in 2007 with 107,000 people on treatment are around R409 million. CONCLUSION: Specific policy choices could almost double the number of people who could benefit from an investment in a limited national antiretroviral treatment programme. Such a programme is affordable within current resource constraints. The consideration of antiretroviral treatment calls for a unique public health approach to the rationing of health services in the public sector.
Adult↗