Low-dose growth hormone for 40 weeks induces HIV-1-specific T cell responses in patients on effective combination anti-retroviral therapy.

Recombinant human growth hormone (rhGH) administered to combination anti-retroviral therapy (cART)-treated human immunodeficiency virus-1 (HIV-1)-infected individuals has been found to reverse thymic involution, increase total and naive CD4 T cell counts and reduce the expression of activation and apoptosis markers. To date, such studies have used high, pharmacological doses of rhGH. In this substudy, samples from treated HIV-1(+) subjects, randomized to receive either a physiological dose (0·7 mg) of rhGH (n = 21) or placebo (n = 15) daily for 40 weeks, were assessed. Peptide-based enzyme-linked immunospot (ELISPOT) assays were used to enumerate HIV-1-specific interferon (IFN)-γ-producing T cells at baseline and week 40. Individuals who received rhGH demonstrated increased responses to HIV-1 Gag overlapping 20mer and Gag 9mer peptide pools at week 40 compared to baseline, whereas subjects who received placebo showed no functional changes. Subjects with the most robust responses in the ELISPOT assays had improved thymic function following rhGH administration, as determined using CD4(+) T cell receptor rearrangement excision circle (TREC ) and thymic density data from the original study. T cells from these robust responders were characterized further phenotypically, and showed decreased expression of activation and apoptosis markers at week 40 compared to baseline. Furthermore, CD4 and CD8 T cell populations were found to be shifted towards an effector and central memory phenotype, respectively. Here we report that administration of low-dose rhGH over 40 weeks with effective cART resulted in greater improvement of T lymphocyte function than observed with cART alone, and provide further evidence that such an approach could also reduce levels of immune activation.

Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients.

OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.

Switching from twice-daily abacavir and lamivudine to the once-daily fixed-dose combination tablet of abacavir and lamivudine improves patient adherence and satisfaction with therapy.

BACKGROUND: Patients prefer fewer pills and once-daily (qd) dosing without food restrictions. We assessed the impact on adherence [by Medication Event Monitoring System (MEMS) cap monitoring] of switching from abacavir (ABC) and lamivudine (3TC) twice daily (bid) to ABC/3TC fixed-dose formulation (FDC, Kivexa) qd to achieve a qd regimen. METHODS: A randomized, open-label, 8-week study comparing adherence, efficacy and safety of immediate vs. delayed switching from ABC/3TC to FDC qd. RESULTS: Ninety-four patients were dosed. Significantly improved adherence was observed at week 4 with qd ABC/3TC across all three adherence variables: taking compliance 99.2% (90.7-100%) vs. 96.6% (60.0-100%) (P=0.017); dosing compliance 97.1% (64.3-100%) vs. 91.9% (33.3-100%) (P=0.016); and timing compliance 95.5% (53.8-100%) vs. 86.3% (4.3-100%) (P=0.006). Treatment satisfaction increased significantly at week 4 with ABC/3TC qd [92% (82-99%) vs. 85% (75-93%) (P=0.004)]. Two patients were withdrawn from the study because of intolerance to ABC/3TC. CONCLUSIONS: Switching from ABC and 3TC bid to ABC/3TC FDC qd significantly improved adherence by MEMS cap monitoring at week 4 and improved patient satisfaction with therapy. The results remain to be confirmed over a longer follow-up. Use of qd regimens supports adherence and improves treatment satisfaction relative to bid regimens.

Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy.

BACKGROUND: Therapy with a HIV protease inhibitor is associated with elevations in cholesterol and triglycerides. HMG-CoA reductase inhibitors ('statins') are the established therapy for persons with primary hypercholesterolaemia. Because of drug interactions, pravastatin may represent the preferred choice in those taking HIV protease inhibitors. DESIGN: A randomized, open-label comparative 24 week trial of dietary advice alone or with pravastatin in 31 male patients established on protease inhibitor-based regimens for greater than 12 weeks with viral load < 500 copies/ml and cholesterol > 6.5 mmol/l. RESULTS: There were no significant clinical or laboratory events and no patient discontinuation secondary to adverse effects. Viral rebound did not occur. Relative to baseline, total cholesterol at week 24 fell significantly in the pravastatin (1.2 mmol/l; 17.3%) (P < 0.05) but not in the dietary advice (0.3 mmol/l; 4%) group. The difference between the two groups approached significance at week 24 (P = 0.051). This fall was accounted for entirely by a reduction in low density lipoprotein [calculated change 1.24 mmol/l (19%) and 0.07 mmol (5.5%) in pravastatin and dietary advice groups, respectively] as high density lipoprotein rose non-significantly by 0.6 mmol/l in both groups. Weight, basal metabolic rate, fasting glucose and triglycerides did not change significantly in either group. CONCLUSIONS: Dietary advice plus pravastatin significantly reduced total cholesterol in HIV-positive individuals taking protease inhibitors, without significant adverse effects. The inclusion of pravastatin substantially increases the magnitude of the change, which is comparable with changes achieved in endogenous hyperlipidaemia.

Finding a role for zalcitabine in the HAART era.

Zalcitabine (ddC) is a nucleoside analogue reverse transcriptase inhibitor with demonstrated clinical benefit in combination use. More widespread use of zalcitabine has been limited by a number of factors including peripheral neuropathy and three times daily dosing. However, screening for the risk factors for peripheral neuropathy may enable a reduction in the incidence of neuropathy to below 10%. Additionally, new data on the use of zalcitabine twice daily suggest, based on the long intracellular half-life of the active triphosphate, that this is feasible. Additionally, while limited data exist for zalcitabine in true HAART combinations, data from small trials suggest a similar proportion of responders to standard HAART regimens.

The role of didanosine in the management of HIV-1 infection.

Large-scale clinical end point studies comparing antiretroviral therapy with zidovudine alone, didanosine alone, and zidovudine combined with didanosine indicate that both didanosine alone and zidovudine/didanosine provide a better clinical outcome than zidovudine alone in patients with human immunodeficiency virus (HIV) infection. The superiority of combination didanosine/zidovudine therapy over zidovudine monotherapy was most significant in treatment-naive patients, but benefit was also seen in patients who had previously received zidovudine and also in all stages of disease. Activity marker data from other studies suggest that double or triple combination therapies that include didanosine and nucleoside analogues other than zidovudine, non-nucleoside reverse transcriptase inhibitors or protease inhibitors result in powerful suppression of viral replication that will provide additional clinical benefits. Apart from mostly mild gastrointestinal disturbances, didanosine alone and in various combination therapies has been generally well tolerated. Thus, didanosine represents a potent, versatile nucleoside analogue with potential benefits in both current and future antiretroviral regimens for HIV infection.

The role of stavudine in the management of adults with HIV infection.

Combinations of two nucleoside analogue reverse transcriptase inhibitors plus a third agent represent the current standard for antiretroviral therapy. Stavudine is a nucleoside analogue that demonstrates in vitro activity against human immunodeficiency virus type 1 (HIV-1) and HIV-2 within an acceptable therapeutic index in a range of T lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a number of other antiretrovirals including protease inhibitors in two and three way combinations and is active against zidovudine-resistant virus. It exhibits excellent oral bioavailability, with CSF penetration. In clinical use, stavudine exhibits antiretroviral activity as a monotherapy similar to zidovudine, and is of proven clinical benefit in zidovudine-pretreated patients. In combination with didanosine and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Comparative trials in zidovudine-experienced patients suggest a similar frequency of adverse events to that observed with zidovudine. Peripheral neuropathy is the most common dose-limiting toxicity with haematological and hepatic function disturbance being infrequent. Reasons for stavudine failure are not established, with no consistent genotypic pattern being associated with changes in stavudine sensitivity in vitro or in vivo. The role of stavudine is as a component of triple therapy regimens both in initial therapy and in patients with prior zidovudine experience.

Safety and activity of zalcitabine and zidovudine combination in HIV-positive people with CD4 cell counts < or = 300 cells/mm3. The Roche M50002 Study Group.

We carried out an open-label, single-arm, multicentre 1-year study of the safety and activity of therapy with a zalcitabine-zidovudine combination in 561 patients with CD4 cell counts < or = 300 cells/mm3 who were either established on zidovudine or had not previously received antiretroviral therapy. Additionally, we assessed the impact of baseline characteristics on clinical outcome during therapy. The study used specialist HIV-care centres in Argentina, Belgium, Brazil, Hungary, Italy, Luxembourg, Mexico, Peru, Spain and Venezuela. Participants were regularly assessed for adverse experiences, changes in laboratory values and clinical progression. A total of 561 patients entered the study, with 353 completing 12 months of follow-up. The 492 zidovudine-experienced patients had a mean duration of previous therapy of 18.5 months. No unexpected adverse events were reported. Peripheral neuropathy was observed in 12.7% of patients and was more common in participants with CD4 cell counts < or = 100 cells/mm3 at baseline. Clinical disease progression was significantly associated with lower baseline CD4 cell counts, a history of previous AIDS-defining events and a baseline haemoglobin < 11 g/dl. The median CD4 cell count at baseline was 141.5 cells/mm3, rising to 174 cells/mm3 after 12 weeks and to 148 cells/mm3 at 12 months. In conclusion, zalcitabine-zidovudine combination therapy was found to be well tolerated in this patient population, although patients with CD4 cell counts < or = 100 cells/mm3 were found to require more intensive monitoring for toxicities and disease events. The changes in the CD4 cell count seen in this study and in others provide evidence of the therapeutic activity of this combination.

Zidovudine monotherapy versus zidovudine plus zalcitabine combination therapy in HIV-positive persons with CD4 cell counts 300-500 cells/mm3: a double-blind controlled trial. The M50003 Study Group Coordinating and Writing Committee.

OBJECTIVE: To assess the safety and clinical and immunological activity of zalcitabine/zidovudine combination therapy compared with zidovudine monotherapy in persons with no or limited antiretroviral experience and CD4 counts of 300-500 cells/mm3. DESIGN AND SETTING: A double-blind controlled multi-centre study conducted in specialist human immunodeficiency virus (HIV) care centres in Spain, Portugal and Australia. Participants were randomized at study entry to zidovudine (200 mg three times daily) plus zalcitabine (0.75 mg three times daily) or matched placebo. The primary end point was the proportion of patients with CD4 above baseline value at 24 months. The secondary end points were time to AIDS/death, quality of life (by MOS-30) and safety. RESULTS: The study was terminated prematurely following the results of the Delta and ACTG 175 studies. Two-hundred and fifty-six patients entered the protocol of whom all but 15 were treatment naive. One hundred and twenty-seven patients commenced zidovudine and 129 commenced a combination of zidovudine/zalcitabine. The median duration of follow-up was 634 days with a median time on blinded therapy of 500 days. Using the last available CD4 count data, 32.4% randomized to zidovudine and 65.1% randomized to zidovudine/zalcitabine remained above baseline at study close (P < 0.001). No significant differences were observed in the time taken for CD4 count to return to baseline. Over 104 weeks, median CD4 counts rose in the combination group from 399 to 509 cells/mm3 whereas those randomized to zidovudine fell from 410 to 374 cells/mm3. Only 12 AIDS events and two deaths (both accidental) occurred during the study with no differences between groups. No differences in quality of life were observed. Adverse events were the cause of treatment discontinuation in 8.6% of patients with no differences between treatment arms. A further 8.2% of patients were lost to follow-up. At least one adverse event (all severities, all relationships) was experienced by 80.3% of patients randomized to zidovudine and 79.8% of patients on combination. Peripheral neuropathy (all grades) was reported in 10.1% of patients randomized to the combination and 3. 1% in the zidovudine arm (P = 0.026). Oral ulcers were reported in 7.8% and 4.7% of combination and zidovudine monotherapy arms, respectively. Neutropenia was more common in the zidovudine group (22%) than the combination group (14%). CONCLUSIONS: Combination of zidovudine/zalcitabine as initial therapy maintains CD4 count above commencement levels in a significantly greater proportion of patients than zidovudine monotherapy. In persons with CD4 counts > or = 300 cells/mm3 inclusion of zalcitabine with zidovudine does not increase the incidence of adverse events or adversely affect quality of life.

Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences.

High rates of viral replication throughout HIV infection, and the frequency of mutation occurring during each replication cycle due to the inaccuracy of reverse transcriptase, drive the potential for drug-resistant viral variants to appear under the selective pressure of antiretroviral therapy. Loss of antiviral effect with a variety of antiretroviral agents has been reported to coincide with the appearance of viral mutants with reduced drug sensitivity. Additionally, the presence of both phenotypic and genotypic zidovudine resistance is associated with an increased risk of clinical disease progression and death, independent of a change of therapy to didanosine. The patterns of resistance to and cross-resistance between antiretroviral agents are increasingly well characterised, and represent an important consideration when deciding how to combine and/or sequence antiretrovirals to achieve optimal antiviral effects. Given the limited number of antiretrovirals currently available or in advanced development, it is important not to potentially limit future therapeutic options by using, early in the treatment sequence, therapies which may select for cross-resistant viral variants and hence potentially reduce the additional therapeutic response when treatment is changed to another member of that drug class.

Antiretroviral therapy for HIV infection. A knowledge-based approach to drug selection and use.

In the absence of evidence that eradication of HIV from an infected individual is feasible, the established goal of antiretroviral therapy is to reduce viral load to as low as possible for as long as possible. Achieving this with the currently available antiretroviral agents involves appropriate selection of components of combination regimens to obtain an optimal antiviral response. In addition, consideration of a plan for a salvage or second-line regimen is required if initial therapy fails to achieve an optimal response or should loss of virological control occur despite effective initial therapy. Such a planned approach, based on consideration of the likely modes of therapeutic failure (viral resistance, cellular resistance, toxicity) could be called rational sequencing. Choice of therapy should never involve compromise in terms of activity. However, the choice of drug should also be guided by tolerability profiles and considerations of coverage of the widest range of infected cells, compartmental penetration, pharmacokinetic interactions and, importantly, the ability of an agent or combination to limit future therapeutic options through selection of cross-resistant virus. Available clinical end-point data clearly indicate that combination therapy is superior to monotherapy, with clinical and surrogate marker data supporting the use of triple drug (or double protease inhibitor) combinations over double nucleoside analogue combinations. Thus, 3-drug therapy should represent current standard practice in a nontrials setting. Treatment should be considered as early as practical, and may be best guided by measurement of viral load, with a range of other markers having potential utility in individualising treatment decisions. Therapeutic failure may be defined clinically, immunologically or, ideally, virologically, and should prompt substitution of at least 2, and preferably all, components of the treatment regimen. Drug intolerance may also be best managed by rational substitution.

Efficacy of a nelfinavir- and nevirapine-containing salvage regimen.

PURPOSE: In this study, our purpose was to assess the efficacy of nelfinavir- and nevirapine-containing salvage regimens in nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients virologically failing a protease inhibitor (PI)-based combination. METHOD: A retrospective case note review of all patients virologically failing their PI-based combination who were switched to a regimen containing both nelfinavir (1 g t.d.s.) and nevirapine (200 mg b.d.). CD4 cell counts and viral loads were monitored. Genotypic analysis was performed using RT-PCR sequencing. RESULTS: Nineteen patients commenced a salvage regimen containing nelfinavir and nevirapine. Five patients also changed at least one nucleoside reverse transcriptase inhibitor (NRTI), although in one case this represented recycling. Thirty-eight percent (6/16) of patients achieved a viral load below the level of detection (BLD; <200 copies/mL; complete responders [CR]), 3 achieved <20 copies/mL. Five patients achieved > or =1 log drop (partial responders [PR]) that was not sustained over follow-up, and five failed to respond to therapy (nonresponders [NR]). CRs tended to have wild-type NNRTI and PI sequences relative to PRs and NRs. CONCLUSION: In heavily pretreated patients, a nelfinavir-and nevirapine-containing salvage regimen resulted in a virological response in 38% of patients that was sustained in 31% over 63 weeks.

Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management.

Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multi-factorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a sub-optimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetyl-L-carnitine) and nerve growth factors such as recombinant human nerve growth factor.

A risk-benefit assessment of HIV protease inhibitors.

The use of triple regimens, often called highly active antiretroviral therapy (HAART), generally involving 2 nucleoside analogues and an HIV protease inhibitor, have been endorsed as the standard of care for persons with HIV initiating therapy by a number of sets of international guidelines. The widespread availability of protease inhibitor-containing regimens has been associated with a dramatic drop in the incidence of new AIDS events and mortality throughout the developed world. Use of HAART regimens, particularly in treatment-naïve individuals, is also associated with dramatic reductions in HIV RNA load, rises in CD4+ cell numbers and improvements in some aspects of immune function. However, protease inhibitor therapy is associated with a range of adverse effects, which varies between agents, and regimens frequently involve inconvenient administration schedules and disruption to patient's lives. Thus, the undoubted benefits of antiretroviral therapy come at some cost in terms of both physical and psychological morbidity to the recipient. In assessing an individual for therapy, consideration of the risk of disease events and the benefit of therapy in reducing or preventing these events must be weighed against the potential of therapy to cause morbidity. Using these criteria, we suggest that an individual with a 3 year risk of disease progression of less than 10% (based on CD4+ cell count and HIV RNA load) is more likely to a experience a morbidity if treated with HAART than if left untreated and monitored. For individuals with higher risks of HIV progression the risk versus benefit of initiating therapy may, in many cases, still be in favour of no therapy and continued observation. This will vary depending on the individuals risks (such as family and past medical history) and on the choice of agents in the regimen, some regimens having greater risks than others.

Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir: results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus.

The safety, antiretroviral activity, and pharmacokinetic profile of nelfinavir, a potent and specific inhibitor of human immunodeficiency virus (HIV) protease, were assessed in a small open-label phase I/II dose-ranging study in protease inhibitor-naive HIV-positive men. A total of 22 patients with baseline plasma HIV RNA > or = 20,000 copies/mL and CD4+ counts between 200 and 500 cells/mm3 were enrolled in the study. Of the 22 patients, 20 were evaluated for activity; 10 patients assigned to 771 mg/day base equivalent (300 mg three times daily) and 10 patients assigned to 1,026 mg/day base equivalent (600 mg twice daily) given monotherapy. A capsule formulation of nelfinavir was used. The initial study period was 28 days; patients showing a virologic response of 1 log10 reduction were eligible for enrollment in an extension phase and addition of nucleoside analogues. A maximally tolerated dose of nelfinavir was not established. A dose-response relationship was observed for four (40%) patients in the 771-mg group and six (60%) patients in the 1,026-mg group experiencing a reduction from baseline in plasma HIV RNA of at lest 1 log during the 28-day study. Of these patients, five sustained the reduction in plasma HIV RNA beyond day 28 (2 patients receiving 771 mg/day and 3 patients receiving 1,026 mg/day). Median increases from baseline in CD4+ counts at day 28 were 216 cell/mm3 and 86 cell/mm3 in the 771-mg and 1,026-mg groups, respectively. After oral administration, median nelfinavir plasma concentrations on day 28 reached a maximum at 1 hour (2,966 ng/mL) in the 771-mg group and at 3 hours (3,157 ng/mL) in the 1,026-mg group. Data for 22 patients were included in the safety analysis; 12 patients (55%) reported at least one grade 2 or worse (moderate, severe, or very severe) adverse event. The most common grade 2 or worse adverse event was diarrhea, reported by two patients (20%) receiving 771 mg/day and seven patients (70%) receiving 1,026 mg/day; followed by nausea, flatulence, asthenia, and headache (each reported in 1 patient [10%] in the 771-mg group) and dizziness (reported in 1 patient [10%] receiving 1,026 mg/day). In the small subgroup (n = 6) who continued taking nelfinavir for longer periods (between 8 and 15 months), virologic responses were sustained in the majority of patients with good tolerability. Nelfinavir is an active HIV-protease inhibitor with favorable pharmacokinetics, good tolerability, and sustained antiviral effects. Results of this early phase I/II dose-ranging study provided data for the safety and antiretroviral activity of nelfinavir and led to the selection of higher doses for phase II/III trials to further optimize virologic and immunologic responses.