Therapy In Treatment-Experienced Patients Research Articles

Optimizing Antiretroviral Therapy in Treatment-Experienced Patients Living with HIV: A Critical Review of Switch and Simplification Strategies. An Opinion of the HIV Practice and Research Network of the American College of Clinical Pharmacy.

Simplifying or switching antiretroviral therapy (ART) in treatment-experienced people living with HIV (PLWH) may improve adherence, tolerability, toxicities, and/or drug–drug interactions. The purpose of this review is to critically evaluate the literature for efficacy and safety associated with switching or simplifying ART in treatment-experienced PLWH. A systematic literature search using MEDLINE was performed from January 1, 2010 to April 30, 2018. References within articles of interest, the Department of Health and Human Services guidelines, and conference abstracts were also reviewed. Switch/simplification strategies were categorized as those supported by high-level clinical evidence and those with emerging data. Rates of virologic suppression were noninferior for several switch/simplification strategies when compared to baseline ART. Potential for reducing adverse events was also seen. Additional evidence for some strategies, including most 2-drug regimens, is needed before they can be recommended.

Clinical Outcomes Associated With Once-Daily Ritonavir-Boosted Darunavir Plus Tenofovir/Emtricitabine in HIV-Infected Patients Harboring at Minimum a M184V/I Resistance Mutation.

Limited data exist on the use of a boosted protease inhibitor plus <2 active nucleoside/nucleotide reverse transcriptase inhibitors without use of additional classes of antiretroviral (ARV) therapy in treatment-experienced patients with background resistance. To evaluate clinical outcomes in HIV-infected patients harboring single- or multiclass resistant virus and receiving once-daily tenofovir/emtricitabine (TDF/FTC) plus darunavir/ritonavir (DRV/r) administered for >24 weeks. This was a single-center chart review of HIV-infected patients receiving daily TDF/FTC plus DRV/r and identified with resistant virus (including, but not limited to, an M184V/I). The primary outcome was HIV viral load (VL) <200 copies/mL (cp/mL) at last measurement. Additional end points included virological rebound (VR), resuppression, or failure (VF); VL <40 cp/mL at last measurement; and development of additional mutations. Of 171 eligible patients, 32 were included in the study and received DRV 800 mg/r 100 mg daily with fixed-combination TDF/FTC. All patients had a baseline M184V/I mutation, with 10 (31%) having resistance to TDF; 27 (84%) achieved a VL <200 cp/mL, and 25(78%) had a VL <200 cp/mL at the last reading; 22 (69%) achieved a VL <40 cp/mL. VF occurred in 6/32 (19%) patients and VR in 1/32 (3%) patients. Conclusion and Relevance: Although providing a regimen containing ≤2 active drugs, the use of once-daily DRV/r plus TDF/FTC in treatment-experienced patients with single-/multiclass resistant virus resulted in virological suppression in more than three-fourths of patients. These retrospective data suggest that despite the presence of an M184V/I, this combination may be an option in patients seeking a once-daily ARV therapy to improve adherence.

Eficacia de dolutegravir en pacientes experimentados: estudios SAILING y VIKING

Dolutegravir is an HIV integrase inhibitor with a high genetic barrier to resistance and is active against raltegravir- and/or elvitegravir-resistant strains. The clinical development of dolutegravir for HIV infection rescue therapy is based on 3 clinical trials. In the SAILING trial, dolutegravir (5 mg once daily) in combination with 2 other antiretroviral agents was well tolerated and showed greater virological effect than raltegravir (400 mg twice daily) in the treatment of integrase inhibitor-naïve adults with virological failure infected with HIV strains with at least two-class drug resistance. The VIKING studies were designed to evaluate the efficacy of dolutegravir as rescue therapy in treatment-experienced patients infected with HIV strains with resistance mutations to raltegravir and/or elvitegravir. VIKING-1-2 was a dose-ranging phase IIb trial. VIKING-3 was a phase III trial in which dolutegravir (50 mg twice daily) formed part of an optimized regimen and proved safe and effective in this difficult-to-treat group of patients. Dolutegravir is the integrase inhibitor of choice for rescue therapy in multiresistant HIV infection, both in integrase inhibitor-naïve patients and in those previously treated with raltegravir or elvitegravir.

Adefovir plus Entecavir Therapy in Chronic Hepatitis B Patients with Treatment Failure to Lamivudine-Entecavir Sequential Therapy: Outcome at 2 Years

The efficacy of adefovir add-on therapy in treatmentexperienced patients with chronic hepatitis B (CHB) is debatable. This study aimed to evaluate the efficacy of adefovir add-on therapy in CHB patients with antiviral resistance to lamivudine/entecavir sequential therapy. CHB patients who exhibited documented resistance to lamivudine and switched to entecavir 1.0 mg monotherapy were evaluated and 19 of them showed active viral replication (HBV DNA levels ≥ 10⁵ copies/mL) or a history of treatment failure to lamivudine/ entecavir sequential therapy. Adefovir 10 mg/day has been added to these 19 patients and the virologic parameters were monitored every three months for 96 weeks. A primary responder was defined as patient who had a decline in serum HBV DNA ≥ 1 log10 copies/mL after 12 weeks of therapy, compared with the pretreatment value. In 19 CHB patients, 10(52.6%) patients were HBeAg positive, 7 (36.8%) had cirrhosis. The mean duration of previous entecavir therapy was 84.4 ± 22.5 weeks. The mean HBV DNA levels and ALT at baseline were 6.17 ± 0.96 log10 copies/mL, 53 ± 35 IU/L. The reduction of serum HBV DNA levels from baseline was 2.27 ± 1.34, 2.77 ± 1.41, and 3.09 ± 1.37 log10 copies/mL, at 24, 48 and 96 weeks, respectively. The rate of undetectable serum HBV DNA was 10.5% (2/19), 26.3% (5/19), and 31.5% (6/19) and ALT levels were normalized in 5 (55.6%), 6(66.7%), and 6(66.7%) of 9 patients with elevated ALT at baseline. Initial HBV DNA level was the only independent factor that was inversely associated with serum HBV DNA negativity at 96 weeks. Among 7 primary non-responders, 6 patients achieved serum HBV-DNA level < 4 log10 copies/mL at 96 weeks. Until 96 weeks, viral breakthrough was not detected in 19 patients. The adefovir add-on therapy may be helpful, even if not sufficient enough, for CHB patients with antiviral resistance to lamivudine/entecavir sequential therapy.

Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies

Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of simeprevir and peginterferon-α-2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection. In CONCERTO-2, prior non-responders to IFN-based therapy (N = 106) received simeprevir (TMC435) 100 mg QD with PR for 12 (SMV12, n = 53) or 24 weeks (SMV24, n = 53) followed by response-guided therapy (RGT) with PR for 12/36 (SMV12) or 0/24 (SMV24) weeks. In CONCERTO-3, relapsers after IFN-based therapy (N = 49) received simeprevir 100 mg QD with PR for 12 weeks followed by RGT with PR for 12/36 weeks. Primary endpoints were the rates of sustained virologic response 12 weeks after treatment end (SVR12). SVR12 rates were 52.8% (SMV12) and 35.8% (SMV24) for prior non-responders, and 95.9% for prior relapsers (SMV12; p ≤ 0.0001 vs null hypothesis, respectively). Most prior non-responders (SMV12: 81.1%; SMV24: 73.6%) and prior relapsers (95.9%) met RGT criteria and completed PR to Week 24. Of these, 60.5%, 48.7%, and 95.7%, respectively, achieved SVR12. Viral breakthrough occurred in 13.2 % (SMV12) and 11.3% (SMV24) of prior non-responders; no viral breakthrough occurred in prior relapsers. Viral relapse occurred in 38.6% (SMV12) and 51.1% (SMV24) of prior non-responders and 8.2% of prior relapsers. Simeprevir with PR was generally well tolerated in both studies. Re-treatment with 12 weeks of simeprevir QD with PR provided high SVR in treatment-experienced patients with chronic HCV genotype 1 infection, and allowed most patients to complete treatment in 24 weeks.

Risk factors predictive of anemia development during telaprevir plus peginterferon/ribavirin therapy in treatment-experienced patients

Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management. This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin <10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia. Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin <13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (>45 years), lower BMI (≤25 mg/m(2)) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment. These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring.

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure

Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

Switching virally suppressed, treatment-experienced patients to a raltegravir-containing regimen does not alter levels of HIV-1 DNA.

BackgroundCurrent HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group.Methods14 ART experienced individuals with a suppressed viral load (<50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at ≥2 timepoints up to 48±6 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays.ResultsThere was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95% CI: −11.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/106 PBMCs at baseline and the other had 34 copies/106 PBMCs at week 51.ConclusionsThe switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravir treatment initiation.

Sitagliptin/Metformin Fixed-Dose Combination

Sitagliptin/metformin is a single-tablet, fixed-dose combination of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide antihyperglycaemic metformin that achieves greater improvements in glycaemic control than either component alone in patients with type 2 diabetes mellitus. Recommended dosages of sitagliptin plus metformin, either as the fixed-dose tablet or a combination of the individual agents, significantly reduced glycosylated haemoglobin (HbA(1c)) levels in two well designed clinical trials in treatment-naive patients with type 2 diabetes. The improvements in glycaemic control seen with sitagliptin plus metformin therapy after 18 or 24 weeks were greater than those observed with the individual components alone and/or placebo, and sustained over treatment durations of up to 2 years. As add-on therapy in treatment-experienced patients with inadequate glycaemic control, the HbA(1c)-lowering efficacy of sitagliptin plus metformin was noninferior to that of glimepiride plus metformin in a 30-week, double-blind trial. Sitagliptin plus metformin and glipizide plus metformin lowered HbA(1c) levels by generally similar magnitudes, with the noninferiority of sitagliptin plus metformin to glipizide plus metformin being established in one 52-week study. As part of triple combination therapy, also in treatment-experienced patients with inadequate glycaemic control, sitagliptin added to ongoing glimepiride with or without metformin or ongoing insulin with or without metformin significantly improved glycaemic control over 24 weeks. Sitagliptin plus metformin, as the fixed-dose tablet or a combination of the individual agents, was generally well tolerated in patients with type 2 diabetes, and was associated with a low risk of hypoglycaemia.

Pharmacokinetic Interactions between Etravirine and Non-Antiretroviral Drugs

Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.

Clinical Management of Treatment-Experienced, HIV/AIDS Patients in the Combination Antiretroviral Therapy Era

Despite the success of combination antiretroviral therapy (ART) in improving clinical outcomes, treatment failure remains a significant challenge, particularly for highly treatment-experienced patients. This review evaluates current issues in the management of HIV-infected, treatment-experienced patients. It may provide guidance in selecting active, tolerable drug combinations that promote a reasonable quality of life, full adherence and a durable treatment response. Current treatment guidelines and clinical trial data were reviewed to identify reasons for treatment failure and to summarize therapy options for treatment-experienced and highly treatment-experienced patients. Current treatment options include nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and inhibitors of viral fusion, entry and integration. The use of NRTIs may be limited by resistance and short- and long-term toxicities. Resistance has restricted the NNRTI class with cross-resistance preventing their sequential use. Etravirine, a next-generation NNRTI, however, demonstrates effective virological suppression in patients with baseline NNRTI resistance. Boosted PIs are key components of ART for treatment-experienced patients. The newer boosted PIs tipranavir and darunavir have demonstrated impressive activity in patients with resistance to NRTIs, NNRTIs and PIs, as well as in less treatment-experienced patients for darunavir. The fusion inhibitor enfuvirtide has demonstrated efficacy in heavily treatment-experienced patients, although injection-site reactions can be problematical. The recently approved integrase inhibitor raltegravir has also shown impressive potency and tolerability in highly treatment-experienced patients. Finally, the entry inhibitor maraviroc has also been approved recently, although its use is somewhat limited by the need for HIV tropism testing. The availability of potent next-generation PIs, NNRTIs, integrase and entry-inhibitors may offer improved therapy for treatment-experienced patients, including those with multiresistant virus. These new drugs may reduce HIV immunological and clinical progression and in doing so may also reduce treatment costs.

A Double‐Blind, Placebo‐Controlled Trial of Maraviroc in Treatment‐Experienced Patients Infected with Non‐R5 HIV‐1

Maraviroc, a CCR5 antagonist, is active against R5 but not X4 or dual- or mixed-tropic strains of human immunodeficiency virus type 1 (HIV-1). A phase 2b study was conducted to determine the safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced patients infected with dual- or mixed-tropic HIV-1. Treatment-experienced patients with an HIV-1 RNA level 5000 copies/mL who had received 3 classes of drugs and/or were infected with virus resistant to 2 drug classes and were infected with non-R5 HIV-1 were randomized to receive optimized background therapy plus maraviroc (once or twice daily) or placebo. The primary end point was change in HIV-1 RNA level from baseline to 24 weeks. Among 167 patients infected with dual- or mixed-tropic HIV-1, baseline mean HIV-1 RNA levels were >5 log(10) copies/mL and median CD4(+) cell counts were <50 cells/microL. From baseline to 24 weeks, patients who received placebo demonstrated a mean decrease in HIV-1 RNA levels of 0.97 log(10) copies/mL, compared with mean decreases of 0.91 and 1.20 log(10) copies/mL for those who received maraviroc once (P =.83) or twice (P +.38) daily, respectively. Mean increases in CD4(+) cell counts from baseline were 36 cells/microL for patients who received placebo, 60 cells/microL among patients who received maraviroc once daily, and 62 cells/microL among patients who received maraviroc twice daily. The incidences of serious adverse events were similar among groups. In this exploratory study involving extensively treatment-experienced patients with advanced, non-R5 HIV-1 infection, neither superiority nor noninferiority was statistically demonstrated for either maraviroc dosage compared with placebo at 24 weeks of treatment. Clinicaltrials.gov identifier NCT00098748 .

Boosted darunavir as a new therapeutic option for treatment-naive HIV-infected patients

HIV infection is one of the major global public health problem. Currently, among the specialists, an estimated 33 million people are infected with HIV worldwide. At present, six main classes of antiretroviral drugs exist, and almost all of them are used in antiretroviral therapy regimen in treatment-experienced as well as treatment-naive patients. Protein inhibitors are selective inhibitors of the cleavage of HIV-encoded gag-pol polyproteins. Darunavir, previously known as TMC-114, is a new, second-generation PI. Darunavir has high potency, genetic barrier and very good clinical and metabolic tolerance. In twice-daily dose darunavir is used as a rescue therapy in treatment-experienced patients. However, after ARTEMIS study, it was recently approved in first-line antiretroviral therapy for treatment-naïve HIV-infected patients.

Raltegravir: Its use in the Treatment of HIV Infection

Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of HIV infection. Administered orally in doses of 400 mg twice daily, it is well-tolerated and has minimal drug-drug interactions with coadministered antiretrovirals and other agents. In clinical trials including treatment-experienced and treatment-naïve HIV-infected adults, raltegravir in combination with other antiretroviral agents has demonstrated a rapid and potent virologic effect and a generally benign safety profile. Like other antiretrovirals, raltegravir should ideally be given with two additional agents to which the patient's virus is susceptible based on results of resistance testing. In this context, raltegravir offers a safe and effective option as a component of combination therapy in treatment-experienced patients who are infected with HIV-1 strains showing evidence of resistance to other antiretroviral agents. Pending the availability of longer-term efficacy and safety data, raltegravir cannot currently be recommended as part of first-line therapy for treatment-naïve patients.

Update on the Development of HIV Entry Inhibitors

HIV fusion and entry are two steps in the viral lifecycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular co-receptors used by the virus for entering cells, and on the various steps of such processes that are subject to interactions with small molecules. Intense research has led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds, grouped into three main classes (attachment inhibitors, co-receptor binding inhibitors and fusion inhibitors), which may be developed as novel antiretrovirals. Thus, several inhibitors of the gp120–CD4 interaction have been discovered (e.g., zintevir and BMS-378806). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors have also been described recently, including those which interact with both the CXCR4 co-receptor (e.g., AMD3100, AMD3465, ALX40-4C, T22, T134 and T140) and CCR5 co-receptor antagonists (TAK-779, TAK-220, E913, AK-602 and NSC 651016 in clinical trials). Recently, a third family of antivirals started to be used clinically (in addition to reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, thus offering the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently being investigated in controlled clinical trials, and a number of them are bioavailable as oral formulations. In 2007, the US FDA approved maraviroc as an anti-HIV agent. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin. Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. Furthermore, in October 2007, the FDA announced the approval of raltegravir for the treatment of HIV-1 infection as part of combination antiretroviral therapy in treatment-experienced patients with evidence of HIV-1 replication despite optimized background antiretroviral therapy. At present, raltegravir is the only drug in the integrase inhibitor class approved for clinical use. With the approval of raltegravir, oral agents targeting all three constitutive viral enzymes, reverse transcriptase, protease and integrase, are now represented in FDA-approved therapies.

Virologic and Immunologic Impact and Durability of Enfuvirtide-Based Antiretroviral Therapy in HIV-Infected Treatment-Experienced Patients in a Clinical Setting

Objective: To evaluate the effectiveness and safety of enfuvirtide–based therapy in treatment–experienced patients in a clinical setting. Method: Retrospective study of treatment–experienced patients receiving enfuvirtide-based therapy for a minimum of 2 months. Endpoints included virologic suppression, virologic rebound, immunologic response, and adverse events. Results: Sixty-four patients were eligible for inclusion in the analysis. Median baseline viral load and CD4+ count were 4.7 log10 copies/mL (interquartile range [IQR], 4.0–5.2) and 150 cells/mm3 (IQR, 60–250), respectively. At month 12, viral load declined by a median of 2.53 log10 copies/mL (IQR, 0.97–3.12). The unadjusted median time to virologic suppression was 7.7 months (95% CI 4.1–10.4 months). Baseline viral load and number of protease inhibitors in the current regimen were significantly associated with virologic suppression following multivariate analysis (hazard ratio [HR] 0.45, 95% CI 0.31–0.63,p<.0001, and HR 0.51, 95% CI 0.27–0.94, p = .03, respectively). Among the 42 patients who attained sustained virologic suppression, 10 experienced virologic rebound during a median follow–up of 13.3 months (IQR, 7.0–19.1). Injection site reactions were reported in 33 (52%) patients, resulting in treatment discontinuation in nine patients. Conclusion: Enfuvirtide-based therapy provides durable antiretroviral activity for treatment–experienced patients in a clinical setting.

A cohort study of enfuvirtide immunological and virological efficacy in clinical practice

The aim of the study was to evaluate, under routine circumstances, the immunological and virological efficacy of antiretroviral regimens containing enfuvirtide in multi-class experienced HIV-1 infected patients. This retrospective monocentric study analyzed the clinical, immunological, and virological data of 18 HIV-1 infected patients who started enfuvirtide and completed at least 3 months of therapy. Following 3 months of enfuvirtide therapy, 11 (61%) patients had HIV-1 RNA below 400 copies/ml, among whom 8 (44%) patients below 50 copies/ml. In the ten patients still receiving enfuvirtide after 12 months, the median increase in CD4 cell count was 159 cells/microl (range, -25 to +301) and the mean decrease in HIV-1 RNA was 2.5 +/- 1.4 log(10) copies/ml; in six of these patients, viral load remained below 50 copies/ml. Five patients discontinued enfuvirtide for virological failure but none as a consequence of adverse event. Mutations located within the 36-45 amino acid domain of HR1 region of gp41 and associated to enfuvirtide resistance were found in all seven patients with persistent viral replication. In addition, a new mutation, A50V, emerged in one patient with late viral rebound. Its disappearance after treatment discontinuation suggests that it could play a role in resistance to enfuvirtide. In conclusion, enfuvirtide may be a good therapeutic option as rescue therapy in treatment-experienced patients. However, the mutations conferring resistance to enfuvirtide develop rapidly when viral load is not controlled confirming that enfuvirtide should be prescribed in association with an active background regimen.

Cost-Effectiveness of Enfuvirtide in HIV Therapy for Treatment-Experienced Patients in the United States

Enfuvirtide (ENF) is the first of a new class of antiretrovirals (ARVs) known as the HIV fusion inhibitors. Two phase III studies of ENF, TORO 1 and TORO 2, demonstrated that ENF given in combination with optimized background (OB) therapy significantly improved virological response, increased the time to virological failure, and increased CD4-cell count compared with OB alone among highly treatment-experienced patients. The present study investigated the long-term clinical outcomes, costs, and cost-effectiveness of ENF. Outcomes, costs, and cost-effectiveness were estimated using a Markov model. Viral suppression and immune reconstitution were determined from the outcomes of the clinical trials. Time to immunological failure, time to AIDS-defining event (ADE), and time to death were estimated based on published mathematical models of disease progression. Costs were based on published estimates of the use and costs of ARVs, cost of managing ADEs, and cost of laboratory and other outpatient services. Cost-effectiveness was calculated as the incremental cost per year of life gained, adjusted for quality of life. The combined effects of an increase in CD4 count and delayed time to virological and immunological failure with ENF + OB were predicted to produce a mean life expectancy of 7.4 years from initiation of therapy, which was 1.8 years (1.5 quality-adjusted lifeyears [QALYs]) greater than the life expectancy associated with OB alone. The incremental cost-effectiveness of ENF + OB was estimated to be Dollars 24,604 per QALY. ENF is projected to increase time to immunological failure, delay onset of new AIDS-defining events, and increase life expectancy by more than 1.5 years among treatment-experienced HIV-infected patients. The cost-effectiveness of ENF is comparable to many existing treatment and prevention management strategies for HIV.

Tenofovir disoproxil fumarate.

To review the pharmacology, virology, pharmacokinetics, efficacy, safety, resistance profile, and clinical use of tenofovir disoproxil fumarate. A MEDLINE search was performed (1966-August 2002) using the following terms: tenofovir, tenofovir disoproxil fumarate, PMPA (9-(R)-[2-(phosphonomethoxy)propyl]adenine), and Viread. Abstracts from HIV-related meetings were reviewed. DATA EXTRACTION AND STUDY SELECTION: Publications and meeting abstracts regarding tenofovir were reviewed. The most recent and pertinent items were included. Tenofovir disoproxil fumarate is a nucleotide prodrug that is diphosphorylated to its active moiety, tenofovir diphosphate. In this form, tenofovir acts as a reverse transcriptase inhibitor to inhibit HIV-1 replication. In clinical trials, tenofovir was effective at suppressing HIV-1 RNA and boosting CD4+ cell counts. Tenofovir has a long intracellular half-life, which permits once-daily dosing. Since tenofovir does not interact with the cytochrome P450 pathway, it exhibits minimal drug interactions, with the exception of didanosine. Compared with other reverse transcriptase inhibitors, tenofovir may have advantages in terms of toxicity and medication adherence profiles. Ongoing studies are also analyzing tenofovir's activity against hepatitis B virus. Tenofovir has been shown to be active against HIV-1 in combination with other antiretrovirals. The drug's benefit as a single-agent intensifier of highly active antiretroviral therapy in treatment-experienced patients has been established, and preliminary data for treatment-naïve patients are encouraging.