ritonavir and abacavir

Abacavir is part of WHO-recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation.. A total of 230 HIV-infected African children were included, with median (range) age of 2.1 (0.1-12.8) years and weight of 9.8 (2.5-30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed-effects modelling.. Abacavir pharmacokinetics was best described by a two-compartment model with first-order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co-treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin-based antituberculosis treatment and super-boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir-based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation.. In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super-boosted lopinavir gave significantly reduced abacavir concentrations.

Topics: Anti-HIV Agents; Child; Child, Preschool; Dideoxynucleosides; HIV Infections; Humans; Infant, Newborn; Lopinavir; Malnutrition; Ritonavir

Abacavir is one of the recommended nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infections among children and adolescents. However, there are concerns that the antiviral efficacy of abacavir might be low when compared to other NRTIs especially among children. There are also concerns that abacavir use may lead to serious adverse events such as hypersensitivity reactions and has potential predisposition to developing cardiovascular diseases. We searched four electronic databases, four conference proceedings and two clinical trial registries in August 2014, without language restrictions. Experimental and observational studies with control groups that examined the efficacy and safety of abacavir-containing regimens in comparison with other NRTIs as first-line treatment for HIV-infected children and adolescents aged between one month and eighteen years were eligible. Two authors independently screened search results, extracted data and assessed the risk of bias of included studies using a pre-specified, standardised data extraction form and validated risk of bias tools. We also assessed the quality of evidence per outcome with the GRADE tool.. We included two randomised controlled trials (RCTs) and two analytical cohort studies with a total of 10,595 participants. Among the RCTs we detected no difference in virologic suppression after a mean duration of 48 weeks between abacavir- and stavudine-containing regimens (2 trials; n = 326: RR 1.28; 95 % CI 0.67-2.42) with significant heterogeneity (P = 0.02; I(2) = 81 %). We also found no significant differences between the two groups for adverse events and death. After five years of follow-up, virologic suppression improved with abacavir (1 trial; n = 69: RR 1.96; 95 % CI 1.11-3.44). For cohort studies, we detected that the virologic suppression activity of abacavir was less effective than stavudine in both the lopinavir/ritonavir (1 study, n = 2165: RR 0.79, 95 % CI 0.67-0.92) and efavirenz sub-groups (1 study, n = 3204: RR 0.79, 95 % CI 0.67-0.92) respectively. The quality of evidence from RCTs was moderate for virologic suppression but low for death and adverse events, while that of cohort studies was low for all three these outcomes.. Available evidence showed little or no difference between abacavir-containing regimen and other NRTIs regarding efficacy and safety when given to children and adolescents as a first-line antiretroviral therapy.

Topics: Adolescent; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Lopinavir; Male; Ritonavir; Stavudine

HIV infection is a serious but treatable disease, yet current treatment is limited by development of resistance and high rates of adverse drug reactions. Antiretroviral therapy is especially suitable for pharmacogenomic investigation as both drug exposure and treatment response can be reliably measured. Increasing knowledge about genes implicated in pharmacokinetics, mode of action, efficacy, and toxicity of drugs has already provided relevant results for clinical practice, for example: The strong association of the abacavir hypersensitivity reaction with HLA-B*5701 permits testing patients for the allele, and if present avoiding the drug and therefore preventing the reaction. Persons with the allele CYP2B6*6 present higher efavirenz "area under the curve" and have increased risk of neuropsychological toxicity. Additional gene variants are being discovered that influence the action of antiretroviral drugs. And, moreover, it is expected that larger-scale comprehensive genome approaches will profoundly improve the landscape of knowledge of HIV therapy in the future. The present article shows some recent patents related to the treatment of viral infections.

Topics: Alkynes; Anti-Retroviral Agents; Aryl Hydrocarbon Hydroxylases; Atazanavir Sulfate; Benzoxazines; Central Nervous System Diseases; Cyclopropanes; Cytochrome P-450 CYP2B6; Dideoxynucleosides; Drug Hypersensitivity; Drug Resistance, Viral; Dyslipidemias; Genetic Predisposition to Disease; Genetic Testing; Glucuronosyltransferase; HLA Antigens; Humans; Hyperbilirubinemia; Nevirapine; Oligopeptides; Oxidoreductases, N-Demethylating; Patents as Topic; Patient Selection; Pharmacogenetics; Pyridines; Ritonavir

Although the reduction in HIV-1-related deaths with highly active antiretroviral therapy (HAART) is similar in adults and children, the extent of the changes in two important surrogate markers HIV-1 RNA levels and CD4+ T cell counts, differs widely. In most paediatric studies virological response rates to HAART are inferior to those in adults. This review provides an overview of the paediatric clinical studies using HAART and seeks to improve the understanding of factors that may contribute to success or failure of HAART in children. An overview of all current articles on paediatric clinical trials using HAART is provided. 23 papers were available. HIV-1 RNA loads and CD4+ T cell counts were used as primary outcome measures. Virological response rates were highly variable, both among the different antiretroviral drugs but also among different studies using the same medication. Four studies in which dosages of the administrated protease inhibitor (PI) were adjusted after pharmacokinetic evaluation had superior virological response rates compared with those in which fixed dosages were used. Immunological response rates were more uniform than virological responses. In almost all studies increases of CD4+ T cell counts are reported independent of the extent of the virological response. Side-effects of HAART were generally mild, transient, and of gastrointestinal origin. Significant percentages of patients with serum lipid abnormalities were reported in three paediatric studies. However, signs of clinical lipodystrophy were not observed. The inferior virological response rates, which have been reported in HIV-1 infected children treated with HAART form a reflection of the challenges that are encountered in the treatment of these children. Difficulties with adherence and with the pharmacokinetics of PIs in children require an intensive, child-adjusted approach. A practical approach to therapy in institutions without tertiary care facilities may be induction therapy with a lopinavir containing regimen (lacking a need for therapeutic drug monitoring), to reduce high viral load levels followed by an easily tolerated maintenance regimen, for example containing abacavir or nevirapine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Child; Clinical Trials as Topic; Cyclopropanes; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; HIV Infections; HIV-1; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Ritonavir; Saquinavir; Stavudine; Zalcitabine; Zidovudine

Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates.. The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration.. Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation.. The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Infant, Newborn; Lamivudine; Lopinavir; Ritonavir

Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.. Prospective, multicenter, randomized open-label, 2 arm, phase-3 trial comparing the 48-week virological response of two different regimens: abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive with CD4+ counts < 200/mm3 and a viral load (VL)<500,000 copies/mL. The primary Endpoint was the proportion of patients with undetectable viremia (VL<50 copies/mL) after 48 weeks. The planned sample size for this trial was 350 patients.. In 3 years, 53 patients were screened and 46 enrolled: 22 randomized to raltegravir and 24 to darunavir/r; 7 patients were excluded, 4 because of a VL >500,000 copies/mL and 3 for HLAB5701 positivity. The snapshot analysis at 48 weeks showed a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r. Time to starting treatment was 34.5 days in raltegravir and 53 days in darunavir/r. At the as treated analysis, the median CD4 counts at 48 weeks was 297 cells/μL in raltegravir and 239 cells/μL in darunavir/r. No difference in total cholesterol, while triglycerides were higher in the darunavir/r arm. No statistical analyses were performed due to the low number of patients enrolled.. Late presenter patients are frequent but very difficult to enroll in clinical trials, especially in western countries. These regimens and the conditions of many patients could not allow the test and treat strategy. The rate of virologic success was higher than 65% in both arms with a median CD4 cell count >200/μL at week 48.. EUDRACT number: 2011-005973-21.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Delayed Diagnosis; Dideoxynucleosides; Female; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Raltegravir Potassium; Ritonavir

Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression.. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm.. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively.. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy.. NCT02159599.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Medication Therapy Management; Middle Aged; Ritonavir; RNA, Viral; Tenofovir; Viral Load

Tenofovir disoproxil fumarate (TDF) causes kidney toxicity in some patients. We carried out genomewide analyses to identify associations with plasma tenofovir clearance and change in creatinine clearance (CrCl) during the first 6 months after initiating therapy among patients randomized to TDF/emtricitabine-containing regimens in AIDS Clinical Trials Group protocol A5202.. Pharmacokinetic analyses involved 501 patients randomized to the tenofovir arm. CrCl analyses involved 1096 patients, including 548 controls randomized to abacavir-containing regimens. All had been randomized to also receive atazanavir/ritonavir or efavirenz. Multivariable linear regression and generalized least squares models were used to test for associations between polymorphisms and tenofovir clearance and CrCl change, with Bonferroni correction. Planned subanalyses considered candidate genes and polymorphisms.. Median CrCl at baseline was 116 ml/min (interquartile range 99.8-135.5). The median change in CrCl after 6 months was -0.5 ml/min (-10.7 to +10.8) and 2.2 (interquartile range -9.9 to +13.2) in tenofovir and abacavir arms, respectively. In genomewide analyses SLC17A1 rs12662869 was found to be associated with an increase in tenofovir clearance (P=7.1×10). In candidate gene analysis for tenofovir clearance, most polymorphisms evaluated were in ABCC4. In the ABCC4 region, the lowest P-value was for CLDN10 rs12866697 (P=1.4×10). Among African Americans, SLC22A2 rs3127573 was associated with a greater 6-month CrCl increase in the tenofovir arm after correcting for multiple comparisons (P=3.3×10).. Among patients randomized to receive TDF/emtricitabine in A5202, there were no significant genomewide associations with change in CrCl. This study did not replicate polymorphisms previously implicated in tenofovir-associated renal injury.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Creatinine; Cyclopropanes; Dideoxynucleosides; Female; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Ritonavir; Tenofovir

WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study.. As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance.. From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3.0 (1.3-4.3) in the NtRTI group and 3.0 (1.0-4.3) in the raltegravir group. The median sGSS in the NtRTI group was 1.0 (0.5-1.8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2.18, 95%CI 1.07-4.47; p=0·03) and week 48 (2.49, 1.09-5.69; p=0.03), baseline plasma viral load greater than 100,000 copies per mL (3.43, 1.70-6.94; p=0.0006), baseline gGSS >4.25 (4.73, 1.94-11.6; p=0.0007), and being Hispanic (3.13, 1.21-8.13; p=0.02) or African (3.49, 1.68-7.28; p=0.0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2.47, 95% CI 1.02-5.99; p=0.05), baseline log10 viral load (1.83, 1.12-2.97; p=0.02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3.18, 1.12-9.02; p=0.03).. Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable.. University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Ritonavir; South Australia; Tenofovir; Treatment Outcome; Viral Load; Young Adult

The aim of the study was to investigate the effect of a simplified regimen, in terms of reducing pill burden, dietary requirements and possible adverse effects, on patients' adherence, treatment satisfaction and quality of life (QoL).. Antiretroviral-naïve patients who achieved a viral load < 50 HIV-1 RNA copies/ml after induction therapy with twice-daily (bid) lopinavir/ritonavir (LPV/r) and fixed-dose zidovudine (ZDV)/lamivudine (3TC) (CBV) were randomly assigned to continue CBV/LPV/r or switch to fixed-dose ZDV/3TC/abacavir (TZV). Patients completed standardized questionnaires on adherence, treatment satisfaction and QoL at randomization (between weeks 12 and 24) and at weeks 48, 72 and 96.. Patients on CBV/LPV/r were more likely to have skipped medicines in the last week (P = 0.035) and during the preceding weekend (P = 0.027) than patients on TZV. Patients on CBV/LPV/r were significantly less satisfied with the convenience of their treatment (P = 0.004) and tended to be less satisfied with the side effects of their treatment (P = 0.091) and continuation of their present treatment (P = 0.056) than patients on TZV. Patients on CBV/LPV/r reported significantly lower levels of role functioning (P = 0.013) than patients on TZV.. In this randomized controlled trial, simplification of therapy to fixed-dose TZV among patients with suppressed HIV RNA was perceived to be more convenient, and resulted in improved adherence and better role functioning, than continuing treatment with CBV/LPV/r.

Topics: Adult; Antiretroviral Therapy, Highly Active; Belgium; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Medication Adherence; Middle Aged; Netherlands; Odds Ratio; Patient Satisfaction; Quality of Life; Ritonavir; Zidovudine

Twice-daily darunavir/ritonavir is indicated in treatment-experienced children (≥3 years). This study assessed once-daily administration in treatment-naïve adolescents.. Phase 2, 48-week, open-label, single-arm study evaluating pharmacokinetics, safety and efficacy of once-daily darunavir/ritonavir 800/100 mg in treatment-naïve, HIV-1-infected adolescents (≥12 to <18 years, ≥40 kg) with zidovudine/lamivudine or abacavir/lamivudine.. Twelve patients (67% female; median 14.4 years) were enrolled. After 24 and 48 weeks, respectively, 11 of 12 (92%) and 10 of 12 (83%) patients achieved viral load <50 copies/mL (intent-to-treat time-to-loss of virologic response); all had ≥1 log10 drop in viral load versus baseline. Median CD4 cell count increased by 175 and 221 cells/mm (intent-to-treat-noncompleter = failure) after 24 and 48 weeks, respectively. Eighty-three percent of patients were adherent to darunavir/ritonavir. One patient was never suppressed and 1 patient rebounded. No patients developed darunavir resistance-associated mutations or lost phenotypic susceptibility to any commercially available protease inhibitor or any background nucleoside reverse transcriptase inhibitor. Eleven patients (92%) reported ≥1 adverse event (AE), considered in 2 patients to be at least possibly related to darunavir (gastrointestinal-related events and dizziness). Four patients had ≥1 serious AE. Three patients reported ≥1 grade 3/4 AE; no serious or grade 3/4 AEs were considered darunavir related. No patients discontinued because of AEs.. Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1-infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Topics: Adolescent; Anemia; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Medication Adherence; Nausea; Neutropenia; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Time Factors; Viral Load; Vomiting; Zidovudine

To compare the efficacy and safety of fixed-dose abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) with ritonavir-boosted atazanavir (ATV/r) in treatment-naïve Japanese patients with HIV-1 infection.. A 96-week multicenter, randomized, open-label, parallel group pilot study was conducted. The endpoints were times to virologic failure, safety event and regimen modification.. 109 patients were enrolled and randomly allocated (54 patients received ABC/3TC and 55 patients received TDF/FTC). All randomized subjects were analyzed. The time to virologic failure was not significantly different between the two arms by 96 weeks (HR, 2.09; 95% CI, 0.72-6.13; p=0.178). Both regimens showed favorable viral efficacy, as in the intention-to-treat population, 72.2% (ABC/3TC) and 78.2% (TDF/FTC) of the patients had an HIV-1 viral load <50 copies/mL at 96 weeks. The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms (adverse event: HR 0.66; 95% CI, 0.25-1.75, p=0.407) (regimen modification: HR 1.03; 95% CI, 0.33-3.19, p=0.964). Both regimens were also well-tolerated, as only 11.1% (ABC/3TC) and 10.9% (TDF/FTC) of the patients discontinued the allocated regimen by 96 weeks. Clinically suspected abacavir-associated hypersensitivity reactions occurred in only one (1.9%) patient in the ABC/3TC arm.. Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC, this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients, such as the Japanese population.

Topics: Adenine; Adult; Anti-HIV Agents; Antiviral Agents; Asian People; Atazanavir Sulfate; Deoxycytidine; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Oligopeptides; Organophosphonates; Pilot Projects; Pyridines; Ritonavir; Tenofovir; Treatment Outcome

Topics: Adult; Alkynes; Anti-Retroviral Agents; Benzoxazines; Breast Feeding; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Drug Eruptions; Drug Substitution; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Lopinavir; Nevirapine; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Ritonavir; Uganda; World Health Organization

Discontinuation of thymidine nucleoside reverse transcriptase inhibitors (tNRTIs) is the only proven strategy for improving lipoatrophy. It is unclear whether switching to NRTI-sparing or to non-thymidine NRTI-containing therapy has differential effects on body fat recovery.. This was a 96 week, open-label, randomized study in suppressed patients with moderate/severe lipoatrophy and no prior virological failure while receiving a protease inhibitor and who had their triple NRTI regimen (zidovudine/lamivudine/abacavir) switched to lopinavir/ritonavir plus abacavir/lamivudine for a 1 month run-in period and then randomized to lopinavir/ritonavir plus abacavir/lamivudine versus lopinavir/ritonavir monotherapy. The KRETA trial is registered with ClinicalTrials.gov (number NCT00865007).. Of 95 patients included, 88 were randomized to lopinavir/ritonavir plus abacavir/lamivudine (n = 44) or lopinavir/ritonavir monotherapy (n = 44). Median (IQR) baseline limb fat was 2.5 (1.6-3.7) kg in the lopinavir/ritonavir plus abacavir/lamivudine group and 2.5 (2.0-5.4) kg in the lopinavir/ritonavir monotherapy group. Six patients in the triple therapy group and 13 in the monotherapy group had discontinued study drugs by week 96. Although there were limb fat gains in each group at weeks 48/96 (+324/+358 g in lopinavir/ritonavir plus abacavir/lamivudine, P = 0.09/0.07, versus +215/+416 g in the lopinavir/ritonavir monotherapy group, P = 0.28/0.16), differences between groups were not significant [difference +109 g (95% CI -442, +660)/-57 g (95% CI -740, +625)].. In lipoatrophic patients treated with zidovudine/lamivudine/abacavir, switching to lopinavir/ritonavir monotherapy had no additional benefit in limb fat recovery relative to switching to lopinavir/ritonavir with abacavir/lamivudine. These data suggest that non-thymidine nucleosides such as abacavir/lamivudine are not an obstacle to limb fat recovery.

Topics: Absorptiometry, Photon; Adipose Tissue; Adult; Antiretroviral Therapy, Highly Active; Atrophy; Body Composition; Chemistry, Pharmaceutical; Dideoxynucleosides; Female; HIV Infections; HIV Protease Inhibitors; Humans; Intention to Treat Analysis; Lamivudine; Lipids; Lipodystrophy; Lopinavir; Male; Middle Aged; Reverse Transcriptase Inhibitors; Ritonavir; Treatment Failure

Improvements in neurocognitive (NC) function have been associated with commencing antiretroviral therapy in HIV-infected subjects. However, the dynamics of such improvements are poorly understood.. We assessed changes in NC function via a validated computerized battery (CogState™, Melbourne, Victoria, Australia) at baseline and after 24 and 48 weeks in a subset of therapy-naïve neuro-asymptomatic HIV-infected subjects, randomized to commence three different antiretroviral regimens.. Of 28 subjects enrolled in the study, nine, eight and 11 were randomly allocated to commence tenofovir/emtricitabine with efavirenz (arm 1), atazanavir/ritonavir (arm 2) and zidovudine/abacavir (arm 3), respectively. Overall improvements in NC function were observed at week 24 and function continued to improve at week 48 (changes in z-score for overall cognitive global score of 0.16 and 0.18 at weeks 24 and 48, respectively). Within the NC speed domains, generally greater improvements were observed in arms 2 and 3, compared with arm 1 (changes in z-score for composite speed scores at weeks 24/48 of 0.16/0.16, -0.29/-0.24 and -0.15/-0.31 in arms 1, 2 and 3, respectively; P = 0.04 for change at week 48 in arm 3 versus arm 1). Finally, improvements in executive function occurred later (only observed at week 48) and were driven by improvements in arm 3 (z-score changes of 0.23, 0.06 and -0.78 in arms 1, 2 and 3, respectively; P = 0.02 for change in arm 3 versus arm 1).. Improvements in NC function continue over the first year after initiating antiretroviral therapy in neuro-asymptomatic HIV-infected subjects.

Topics: Adenine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cognition; Cognition Disorders; Cyclopropanes; Deoxycytidine; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; HIV Infections; Humans; Male; Oligopeptides; Organophosphonates; Pyridines; Ritonavir; Tenofovir; Zidovudine

Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily.. HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs.. A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir.. There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Topics: Adult; Anti-HIV Agents; Area Under Curve; Cross-Over Studies; Darunavir; Deoxyguanine Nucleotides; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

The side-effects of anti-retroviral drugs are different between Japanese and Caucasian patients. Severe central nerve system (CNS) side-effects to efavirenz and low rate of hypersensitivity against abacavir characterize the Japanese.. The objective of this study was to select a once daily regimen for further non-inferior study comparing the virological efficacy and safety of the first line once daily antiretroviral treatment regimens in the current HIV/AIDS guideline.. The study design was a randomized, open label, multicenter, selection study. One arm was treated with efavirenz and the other with ritonavir-boosted atazanavir. A fixed-dose lamivudine plus abacavir were used in both arms. The primary endpoint was virologic success (viral load less than 50 copies/mL) rate at 48 weeks. Patients were followed-up to 96 weeks with safety as the secondary endpoint. Clinicaltrials.Gov (NCT00280969) and the University hospital Medical Information Network (UMIN000000243).. A total of 71 participants were enrolled. Virologic success rates in both arms were similar at week 48 [efavirenz arm 28/36 (77.8%); atazanavir arm 27/35 (77.1%)], but were decreased at week 96 to 55.6% in the efavirenz arm and 68.8% in the atazanavir arm (p=0.33). At the 96-week follow-up, 52.8% of the EFV arm and 34.3% of the ATV/r arm reached total cholesterol more than 220 mg/dL and required treatment. None of the patients developed cardiovascular complications in this study by week 96.. There was no significant difference in the efficacy of efavirenz and ritonavir-boosted atazanavir combined with lamivudine plus abacavir at 48 weeks. The evaluation of safety was extended to 96 weeks, which also showed no significant difference in both arms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Alanine Transaminase; Alkynes; Anti-Retroviral Agents; Atazanavir Sulfate; Benzoxazines; Bilirubin; Cholesterol; Cyclopropanes; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Japan; Lamivudine; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome

Treatment simplification strategies involving induction with a ritonavir (RTV)-boosted (/r) protease inhibitor regimen followed by simplification (without RTV) are appealing because they may offer sustained virologic suppression while minimizing potential long-term adverse effects associated with RTV.. This open-label, randomized, noninferiority study enrolled 515 antiretroviral therapy-naive patients to receive abacavir/lamivudine plus atazanavir/RTV (ATV/r) followed by randomization at week 36 (N = 419) to maintain or discontinue RTV for an additional 48 weeks. Eligibility for randomization required confirmed HIV RNA level below 50 copies/ml and no virologic failure. Protocol-defined virologic failure after week 36 was confirmed rebound of HIV RNA level at least 400 copies/ml. The primary endpoint was the proportion of patients with HIV RNA level below 50 copies/ml at week 84 (time to loss of virologic response). This study is registered with ClinicalTrials.gov number NCT00440947.. At week 84, noninferiority of ATV to ATV/r (95% confidence interval around the treatment difference -1.75 to 12.48%) was demonstrated with 181 of 210 (86%) patients in the ATV group and 169 of 209 (81%) in the ATV/r group maintaining HIV RNA level below 50 copies/ml. During the randomized phase (weeks 36-84), 10 versus 14% of patients in the ATV and ATV/r arms, respectively, experienced a drug-related grades 2-4 adverse event with hyperbilirubinemia being the most frequently reported (4 versus 10%). The overall rate of protocol-defined virologic failure was 2%; no patient had virus that developed a major protease inhibitor mutation.. ATV in combination with abacavir/lamivudine is a potent and well tolerated regimen in patients who have achieved initial suppression on an induction regimen and represents a viable treatment simplification strategy.

Topics: Adult; Aged; Anti-HIV Agents; Atazanavir Sulfate; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome; Viral Load; Young Adult

Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC(0-4)), the maximum concentration of the drug (C(max)), and the residual concentration of the drug at the end of the dosing interval (C(trough)) for plasma and the AUC(0-4) and C(trough) for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC(0-4) was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C(trough) values for women.

Topics: Adenine; Adult; Anti-HIV Agents; Area Under Curve; Cross-Sectional Studies; Dideoxynucleosides; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Longitudinal Studies; Lopinavir; Male; Middle Aged; Organophosphonates; Pilot Projects; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Treatment Outcome

The long-term efficacy of once-daily (qd) fosamprenavir (FPV) 1400 mg boosted by ritonavir 100 mg (FPV/r100) has not been evaluated previously. A 96-week open-label, randomized, multicenter study compared the efficacy/safety of FPV/r100 with FPV 1400 mg boosted by ritonavir 200 mg qd (FPV/r200), plus abacavir/lamivudine 600 mg/300 mg qd, in antiretroviral-naive, HIV-infected patients with viral load (VL)> or =1000 copies/ml. Primary endpoints were proportion of patients achieving VL <400 copies/ml or discontinuing for drug-related reasons. In the intent-to-treat:exposed (ITT-E) population, missing = failure (M = F), and observed approaches were used to assess between-arm differences in VL responses by Cochran-Mantel-Haenszel test and CD4(+) count by Wilcoxon rank-sum test. One hundred and fifteen (115) patients enrolled, with 58 on FPV/r100 (median VL 4.7 log(10) copies/ml; CD4(+) count 259 cells/mm(3)) and 57 on FPV/r200 (median VL 4.9 log(10) copies/ml; CD4(+) count 179 cells/mm(3)). Fewer FPV/r100-treated patients discontinued treatment prematurely (12 vs. 24) and experienced virologic failure (5 vs. 8, none developing major protease inhibitor resistance mutations). At week 96, more FPV/r100-treated patients had VL <400 copies/ml [ITT-E,M = F: 78% (45/58) vs. 53% (30/57), p = 0.006; observed: 98% (45/46) vs. 94% (30/32)] and VL<50 copies/ml [ITT-E,M = F: 66% (38/58) vs. 53% (30/57); observed: 83% (38/46) vs. 94% (30/32)]. The FPV/r100 and FPV/r200 arms were similar at week 96 regarding median change from baseline in CD4(+) count (+265 vs. +260 cells/mm(3)) and total cholesterol (+33 vs. +35 mg/dl), and in total-cholesterol:HDL-cholesterol ratio (4.0 vs. 4.1) and type/frequency of treatment-related grade 2-4 adverse events, although FPV/r100 was associated with a lower elevation in triglycerides (+27 vs. +48 mg/dl). In conclusion, through 96 weeks, FPV/r100 was more effective and prompted less elevation in triglycerides than FPV/r200.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; Furans; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Organophosphates; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients.. Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks.. At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups.. Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cardiovascular Diseases; CD4 Lymphocyte Count; Deoxycytidine; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Lamivudine; Lopinavir; Male; Organophosphonates; Pyrimidinones; Ritonavir; RNA, Viral; Tenofovir; Treatment Outcome

Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals.. HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI).. Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml.. No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.

Topics: Adult; Area Under Curve; Atazanavir Sulfate; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir

Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients.. This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943.. At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir.. Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

Topics: Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Organophosphates; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

Highly active antiretroviral therapy containing three nucleoside reverse transcriptase inhibitors has been somewhat successful, but the clinical efficacy is unclear.. Randomized, controlled, open-label trial of 180 antiretroviral drug-naive HIV-infected patients allocated to a regimen of abacavir, stavudine and didanosine (A/S/D, n = 60), ritonavir and saquinavir (R/S 400/400 mg twice daily; n = 60) or nelfinavir and nevirapine (N/N 1250/200 mg twice daily; n = 60); the latter two in combination with lamivudine and zidovudine. The primary endpoint was HIV plasma RNA < or = 20 copies/ml after 48 weeks.. At baseline, the median CD4 cell count was 161 x 106 cells/l (range, 0-920) and the HIV RNA was 5.0 log10 copies/ml (range, 2.7-6.7). At 48 weeks, 43% in the A/S/D arm had a HIV RNA < or = 20 copies/ml, compared with 69% in the N/N arm (P < 0.01) and 62% in the R/S arm (P < 0.05). In a multivariate analysis, the A/S/D arm had an odds ratio of obtaining a viral load of < or = 20 copies/ml at week 48 of 0.25 [95% confidence interval (CI) 0.10-0.59] versus N/N and 0.53 (95% CI, 0.33-0.83) versus R/S. The A/S/D arm had a particularly poor outcome in patients with higher viral load and AIDS at baseline: 63% had to discontinue A/S/D (any drug). Side effects were more frequent in the A/S/D arm and included neuropathy 27%, suspicion of hypersensitivity 12%, and increase in lactate accompanied by systemic symptoms 8%.. The A/S/D regimen had a low efficacy and a high frequency of adverse events and cannot be recommended.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; Humans; Lactates; Male; Middle Aged; Nelfinavir; Nervous System Diseases; Nevirapine; Ritonavir; RNA, Viral; Saquinavir; Stavudine; Treatment Outcome

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Enfuvirtide; Female; Furans; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Peptide Fragments; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides; Treatment Outcome; Viral Load

This article discusses the design of an ongoing open-label, randomized trial comparing three strategies of initial and subsequent HIV therapy in terms of long-term immunological and virological effect. The three treatment arms are (1) didanosine (ddI) plus stavudine (d4T) plus efavirenz (EFV) followed by zidovudine (ZDV) plus lamivudine (3TC) plus abacavir (ABC) plus nelfinavir (NFV); (2) ddI plus d4T plus NFV followed by ZDV plus 3TC plus ABC plus EFV; (3) ddI plus d4T plus EFV plus NFV followed by ZDV plus 3TC plus ABC plus saquinavir plus ritonavir. The primary objective is to determine whether it is best to start with a protease inhibitor (PI)-containing regimen, a non-nucleoside analogue reverse transcriptase inhibitor (NNRTI)-containing regimen, or with a regimen containing both a PI and an NNRTI. The aim is to recruit over 1000 patients followed for at least 3 years. The entry criteria are broad with no restriction on stage of disease, CD4 count, or HIV viral load. The criteria for therapeutic failure determining change of treatment are not defined and are left to the clinicians, but randomization is stratified by country and by the current criteria used for changing treatment. We describe the rationale behind various aspects of the design and discuss the complexities involved in undertaking such a large trial in HIV-infected patients from 180 clinical sites in 17 countries. Control Clin Trials 2001;22:160-175

Topics: Adult; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nelfinavir; Patient Selection; Randomized Controlled Trials as Topic; Research Design; Ritonavir; Sample Size; Saquinavir; Stavudine; Zidovudine

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

Topics: Adult; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Nelfinavir; Nevirapine; Phenotype; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Salvage Therapy; Saquinavir

Immune reconstitution inflammatory syndrome (IRIS) represents paradoxical immune-mediated inflammation in response to an infecting pathogen, occurring after initiation of antiretroviral therapy (ART), concomitantly with immune system recovery. It has also been described in Kaposi's sarcoma (KS). We report a case of a 9-year-old Guinean girl, who developed Kaposi's sarcoma, following introduction of ART. KS associated with immune reconstitution inflammatory syndrome is rare, especially in children, but with the increased use of ART is becoming more prevalent.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Dideoxynucleosides; Drug Therapy, Combination; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Lopinavir; Ritonavir; Sarcoma, Kaposi

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Topics: Anti-HIV Agents; Antitubercular Agents; Biological Availability; Child; Child, Preschool; Dideoxynucleosides; Drug Combinations; Drug Interactions; HIV Infections; Humans; Lopinavir; Prospective Studies; Rifampin; Ritonavir; Tuberculosis, Pulmonary

Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Oxazines; Pandemics; Piperazines; Pneumonia, Viral; Pyridones; Ritonavir; SARS-CoV-2; Tenofovir; Transgender Persons

Protective antibody responses to human immunodeficiency virus (HIV)-1 infection evolve only in a fraction of infected individuals by developing broadly neutralizing antibodies (bnAbs) and/or effector functions such as antibody-dependent cellular cytotoxicity (ADCC). HIV-1 chronically infected adults and children on combination antiretroviral therapy (cART) showed a reduction in ADCC activity and improvement in HIV-1 specific neutralizing antibody (nAb) responses. Early initiation of cART in infected adults is found to be beneficial in reducing the viral load and delaying disease progression. Herein, we longitudinally evaluated the effect of cART on HIV-1 specific plasma ADCC and nAb responses in a cohort of 20 perinatally HIV-1 subtype-C infected infants and children ≤2 years of age, pre-cART and up to 1 year post-cART initiation. Significant reductions in HIV-1 specific plasma ADCC responses to subtype-C and subtype-B viruses and improvement in HIV-1 neutralization were observed in HIV-1 infected children 1 year post-cART initiation. A positive correlation between reduction in viral load and the loss of ADCC response was observed. This study provides information aiding the understanding of the effects of early initiation of cART on antibody effector functions and viral neutralization in HIV-1 infected children, which needs to be further evaluated in large cohorts of HIV-1 infected children on cART to plan future intervention strategies.

Topics: Anti-HIV Agents; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; Antiretroviral Therapy, Highly Active; Child, Preschool; Cohort Studies; Dideoxynucleosides; Drug Combinations; HIV Antibodies; HIV Infections; HIV-1; Humans; Infant; Lamivudine; Lopinavir; Ritonavir; Viral Load; Zidovudine

Growth Hormone (GH) deficiency is frequent in HIV-infected patients treated with antiretroviral therapy. We treated GH3 cells with antiretrovirals (nevirapine, ritonavir or abacavir sulfate; 100 pM-1 mM range), after transfection with human growth hormone releasing hormone (GHRH) receptor cDNA. Cells viability, intracellular cAMP, phosphorylation of CREB and calcium increase, GH production and secretion were evaluated both in basal condition and after GHRH, using MTT, bioluminescence resonance energy transfer, western blotting and ELISA. Antiretroviral treatment did not affect GHRH 50% effective dose (EC

Topics: Anti-Retroviral Agents; Calcium; Cell Line; Cell Survival; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Dideoxynucleosides; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Nevirapine; Phosphorylation; Ritonavir; Somatotrophs; Transfection

Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure. The effect of the protease inhibitor, lopinavir, alone or in combination with the protease inhibitor, abacavir, and the integrase inhibitor, raltegravir (LAR), with and without morphine co-exposure was also explored. Exposure with emtricitabine alone or ERA in HIV-infected astrocytes caused a significant decrease in viral replication and attenuated HIV-induced inflammatory molecules, while co-exposure with morphine negated the inhibitory effects of ERA, leading to increased viral replication and inflammatory molecules. Exposure with emtricitabine alone or in combination with morphine caused a significant disruption of mitochondrial membrane integrity. Genetic analysis revealed a significant increase in the expression of p62/SQSTM1 which correlated with an increase in the histone-modifying enzyme, ESCO2, after exposure with ERA alone or in combination with morphine. Furthermore, several histone-modifying enzymes such as CIITA, PRMT8, and HDAC10 were also increased with LAR exposure alone or in combination with morphine. Accumulation of p62/SQSTM1 is indicative of dysfunctional lysosomal fusion. Together with the loss of mitochondrial integrity and epigenetic changes, these effects may lead to enhanced viral titer and inflammatory molecules contributing to the neuropathology associated with HIV.

Topics: Acetyltransferases; Anti-HIV Agents; Astrocytes; Atazanavir Sulfate; Chromosomal Proteins, Non-Histone; Dideoxynucleosides; Drug Combinations; Emtricitabine; Gene Expression Regulation; Histone Deacetylases; HIV-1; Host-Pathogen Interactions; Humans; Lopinavir; Lysosomes; Membrane Proteins; Mitochondria; Morphine; Narcotics; Nuclear Proteins; Primary Cell Culture; Protein-Arginine N-Methyltransferases; Raltegravir Potassium; Ritonavir; Sequestosome-1 Protein; Signal Transduction; Trans-Activators; Virus Replication

There are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low-resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa.. The Pediatric Enhanced Surveillance Study enrolled HIV-infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub-distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date.. Of 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight-for-age z-score (WAZ) was -1.7 (interquartile range (IQR):-3.1 to -0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty-four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub-distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds.. We found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.

Topics: Adult; Alkynes; Ambulatory Care Facilities; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cohort Studies; Cyclopropanes; Dideoxynucleosides; Female; Health Resources; HIV Infections; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Medication Adherence; Ritonavir; South Africa; Viral Load

The current World Health Organization guideline for first line antiretroviral therapy (ART) in HIV-infected children recommends the use of abacavir and lamivudine as nucleoside backbones and no longer includes stavudine. We compared treatment outcomes with abacavir (ABC) versus stavudine (d4T) in a cohort of HIV-1 infected children 6 and 12 months after antiretroviral therapy was initiated.. This was a retrospective case-cohort study, using programmatic data from children enrolled in the Paediatric Wellness Programme at the Perinatal HIV Research Unit in Soweto, South Africa between 2005 and 2013. Children on abacavir/stavudine who had initiated ART at age <3 years with a regimen including lamivudine and lopinavir/ritonavir and had at least one 6 or 12 month viral load result were eligible. All ABC cases identified were matched for age at ART initiation and gender to eligible d4T controls (1:2). Outcomes analysed at 6 and 12 months post ART initiation included virological failure, mortality, immunological failure and anthropometry. Chi-square tests compared categorical measures while Kruskal-Wallis compared continuous measures.. We identified 57 eligible ABC cases and selected 114 matched d4T controls. Overall, 57% were females and 89% started treatment at age <1year. The median age at ART initiation was 3.11 (IQR: 1.98-6.05) months. There was no difference in the proportion of children virologically suppressed between the groups at 6 (ABC 54.5% vs. d4T 67.0%, p = 0.125) and 12 (ABC 66.7% vs. d4T 71.6%, p = 0.53) months post ART-initiation. The proportion of children with adherence levels >90% for ABC and d4T were similar too (95% in ABC vs. 86% in d4T, p = 0.10). The proportion of children who died over 12 months was 3.5% in the ABC and 7.9% in the d4T group (p = 0.27). Similarly, the anthropometric measures were comparable.. It is reassuring that in the short term, in this group of patients, the treatment outcomes were similar.

Topics: Child, Preschool; Dideoxynucleosides; Drug Combinations; Female; HIV; HIV Infections; Humans; Infant; Lamivudine; Lopinavir; Male; Retrospective Studies; Ritonavir; South Africa; Stavudine; Treatment Outcome; Viral Load

HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.. An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).. There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.. The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV-1; Lamivudine; Lopinavir; Nelfinavir; Oxazines; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine

Treatment of HIV has reduced HIV/AIDS-related mortality. Sustaining >90% virologic suppression in sub-Saharan Africa requires decentralized care and prevention services to rural communities. In Zimbabwe, the number of people receiving antiretroviral treatment (ART) has increased rapidly. However, access to treatment monitoring tools such as viral load and drug resistance testing is limited. We assessed virologic treatment outcomes among ART recipients in Nyamutora, a rural community receiving bimonthly ART and prevention services. We enrolled all ART recipients (143) at 6-monthly visits in the Nyamutora community in 2014 and 2015. Whole blood samples were collected in K-EDTA tubes, transported to Harare for CD4 counts and viral load testing, and genotype was obtained in participants with viral loads >1,000 copies/ml. Ages ranged from 2 to 75 years (median 43 years) with a median 42 months on ART at follow-up. Eight of 143 (6%) had viral loads >1,000 copies/ml at one of the 3 visits, 7 on first-line nevirapine (NVP)-based ART and 1 on second-line LPV/r-based ART. Seven participants had sequence data available, and five had drug resistance mutations, K65R, T69N, K101E, K103N, Y181C/I, M184V, and G190A. Virologic failure (p = .001) and drug resistance mutations (p = .01) on first-line NVP-based ART were associated with younger age by univariate exact logistic regression. The participants had high viral suppression (94%) despite less than optimal (NVP based) ART regimens without laboratory monitoring. Virologic failure and drug resistance were higher among children and adolescents. Effective ART delivery to the community achieved high rates of virologic suppression and minimal drug resistance.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Child; Child, Preschool; Community Health Centers; Cross-Sectional Studies; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Female; HIV-1; Humans; Lopinavir; Male; Middle Aged; Nevirapine; Ritonavir; Rural Population; Treatment Failure; Viral Load; Young Adult; Zimbabwe

There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.. We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.. We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.. While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Child; Child, Preschool; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Follow-Up Studies; HIV; HIV Infections; Humans; Infant; Kaplan-Meier Estimate; Lopinavir; Outcome Assessment, Health Care; Proportional Hazards Models; Ritonavir; South Africa; Stavudine; Withholding Treatment; Zidovudine

The aim of the study was to evaluate in human immunodeficiency virus (HIV)-infected patients estimated glomerular filtration rate (eGFR) trajectories during treatment with different protease inhibitors (PIs) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus tenofovir (TDF) or abacavir (ABC) and lamivudine or emtricitabine (xTC).Retrospective study of patients followed at a single clinical center; all patients who started TDF or ABC for the first time with a NNRTI or lopinavir/r (LPV/r) or atazanavir/r (ATV/r) or darunavir/r (DRV/r), for whom at least 1 eGFR value before the start and during the studied treatment was known, were included in this analysis. eGFR was calculated by means of the CKD-EPI formula. Univariate and multivariate mixed linear model (MLM) was applied to estimate eGFR slope with the considered antiretroviral treatment.In the 1658 patients treated with TDF/xTC (aged 43 [37-48] years, with an eGFR of 105 [96; 113] mL/min/1.73 m, 80% males, 92% Caucasians, 10% coinfected with HCV, 4% with diabetes, 11% with hypertension, 38% naive for antiretroviral therapy (ART), 37% with HIV-RNA <50 copies/mL) the median follow-up was 2.5 (1.2-4.6) years. Their adjusted eGFR slopes (95% CI) were -1.26 (-1.58; -0.95), -0.43 (-1.20; +0.33), -0.86 (-1.28; -0.44), and -0.20 (-0.42; +0.02) mL/min/1.73 m per year in patients treated with ATV/r, DRV/r, LPV/r, and NNRTI, respectively. Patients receiving ATV/r or LPV/r had a greater adjusted decline in eGFR compared with those receiving NNRTIs (difference -1.06 [-1.44; -0.69] mL/min/1.73 m per year, P <0.001; and -0.66 [-1.13; -0.20] mL/min/1.73 m per year, P = 0.005, respectively); adjusted eGFR slopes were similar in patients receiving DRV/r and in those receiving NNRTIs. Patients receiving ATV/r had a greater adjusted eGFR decline than those treated with DRV/r (difference -0.83 [-1.65; -0.02] mL/min/1.73 m per year; P = 0.04), but not than those receiving LPV/r; no significant difference was observed in adjusted eGFR slopes between patients receiving DRV/r and those receiving LPV/r. In the 286 patients treated with ABC and lamivudine, eGFR slopes were similar, independent of the PI.In patients receiving TDF/xTC, eGFR trajectories were small for all regimens and declined less in patients receiving DRV/r or NNRTIs than in those treated with ATV/r or LPV/r.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Comorbidity; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Female; Glomerular Filtration Rate; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Retrospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Tenofovir; Viral Load

Data on pediatric treatment outcomes and drug resistance while on second-line antiretroviral therapy (ART) are needed to guide HIV care in resource-limited countries.. HIV-infected children <18 years who were switched or switching to second-line ART after first-line failure were enrolled from 8 sites in Indonesia, Thailand, and Vietnam. Genotyping was performed at virologic failure (VF; HIV-RNA >1000 copies/mL). Cox proportional hazards regression was used to evaluate factors predicting VF.. Of 277 children, 41% were female. At second-line switch, age was 7.5 (5.3-10.3) years, CD4 count was 300 (146-562) cells per cubic millimeter, and percentage was 13 (7-20%); HIV-RNA was 5.0 (4.4-5.5) log10 copies per milliliter. Second-line regimens contained lamivudine (90%), tenofovir (43%), zidovudine or abacavir (30%), lopinavir (LPV/r; 91%), and atazanavir (ATV; 7%). After 3.3 (1.8-5.3) years on second-line ART, CD4 was 763 (556-1060) cells per cubic millimeter and 26% (20-31%). VF occurred in 73 (27%), with an incidence of 7.25 per 100 person-years (95% confidence interval [CI]: 5.77 to 9.12). Resistance mutations in 50 of 73 children with available genotyping at first VF included M184V (56%), ≥1 thymidine analogue mutation (TAM; 40%), ≥4 TAMs (10%), Q151M (4%), any major LPV mutation (8%), ≥6 LPV mutations (2%), and any major ATV mutation (4%). Associations with VF included age >11 years (hazard ratio [HR] 4.06; 95% CI: 2.15 to 7.66) and HIV-RNA >5.0 log10 copies per milliliter (HR 2.42; 95% CI: 1.27 to 4.59) at switch and were seen more commonly in children from Vietnam (HR 2.79; 95% CI: 1.55 to 5.02).. One-fourth of children developed VF while on second-line ART. However, few developed major mutations to protease inhibitors.

Topics: Adolescent; Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Dideoxynucleosides; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Indonesia; Lamivudine; Male; Prospective Studies; Ritonavir; Thailand; Treatment Outcome; Vietnam; Viral Load; Zidovudine

A myristoylated abacavir (ABC) prodrug was synthesized to extend drug half-life and bioavailability.. Myristoylated ABC (MABC) was made by esterifying myristic acid to the drug's 5-hydroxy-cyclopentene group. Chemical composition, antiretroviral activity, cell uptake and retention and cellular trafficking of free MABC and poloxamer nanoformulations of MABC were assessed by proton nuclear magnetic resonance and tested in human monocyte-derived macrophages. Pharmacokinetics of ABC and nanoformulated MABC were evaluated after intramuscular injection into mice.. MABC antiretroviral activity in monocyte-derived macrophages was comparable to native drug. Encasement of MABC into poloxamer nanoparticles extended drug bioavailability for 2 weeks.. MABC synthesis and encasement in polymeric nanoformulations improved intracellular drug accumulation and demonstrate translational potential as part of a long-acting antiretroviral regimen.

Topics: Animals; Anti-HIV Agents; Cell Line; Delayed-Action Preparations; Dideoxynucleosides; Drug Liberation; Half-Life; HIV Infections; HIV-1; Humans; Hydrophobic and Hydrophilic Interactions; Injections, Intramuscular; Macrophages; Male; Mice; Nanoparticles; Particle Size; Poloxamer; Prodrugs; Ritonavir

Tenofovir disoproxil fumarate (TDF)-associated renal dysfunction may abate when TDF is replaced with abacavir (ABC). The extent to which the third drug atazanavir contributes to renal dysfunction is unclear.. A retrospective analysis was conducted on adults who had plasma viral load (pVL)<200 copies/mL for≥six months while receiving TDF/lamivudine (3TC) - or TDF/emtricitabine (FTC)-based antiretroviral therapy (ART), then switched to ABC/3TC while retaining the third drug in the ART regimen. CD4, pVL, creatinine, estimated glomerular filtration rate (eGFR), serum phosphorus, urine albumin to creatinine ratio and serum lipids were compared between pre-switch baseline and 3, 6 and 12 months after the switch to ABC.. A total of 286 patients switched from TDF to ABC between 2004 and 2014: 232 (81%) male, median age 48 years (interquartile range (IQR) 42, 56). The third drug was atazanavir (± ritonavir) in 141 (49%) cases. The pVL was<50 copies/mL in 93 to 96% at all time points. Median serum creatinine was 93 µmol/L (IQR 80-111) at baseline and decreased to 88 µmol/L (IQR 78-98) at 12 months after the switch to ABC. Median eGFR increased from 74 (IQR 60-88) mL/min at baseline to 80 mL/min (IQR 69-89) at 12 months. Results were not significantly different between patients on atazanavir versus those on another third drug.. Viral suppression was maintained among patients who switched from TDF/3TC or TDF/FTC to ABC/3TC. Serum creatinine and eGFR improved up to 12 months after switching to ABC/3TC, irrespective of whether or not patients were also receiving atazanavir±ritonavir.

Topics: Adenine; Adult; Anti-HIV Agents; Atazanavir Sulfate; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Kidney; Lamivudine; Male; Middle Aged; Retrospective Studies; Ritonavir; Tenofovir; Viral Load

Incidence of brain infections in Human Immunodeficiency Virus (HIV) positive patients is reduced after the availability of current high active antiretroviral therapy (HAART). Herpes Simplex Virus type 2 (HSV-2) is an infrequent cause of encephalitis in HIV patients despite it is frequently involved in sexual transmitted infections. Here, we report a case of HSV-2 encephalitis occurring in a patient without full suppression of HIV replication within the brain. A 38 year-old HIV infected man was admitted to our department because of recurrent generalized seizure and fever during the previous 24 hours. Eight months before our observation the patient was switched from a protease inhibitor based regimen to a rilpivirine-based regimen without any evidence of HIV-RNA replication in the plasma. When the patient was admitted in our hospital, he was febrile and moderately confused, no deficit of cranial nerves was reported, motility was conserved, but he was unable to walk. Laboratory examinations performed at admission demonstrated an increase of cerebrospinal fluid (CSF) protein and cells with lymphocyte prevalence, and normal CSF glucose. HSV-2-DNA and HIV-RNA were present within CSF at admission. Nuclear Magnetic Resonance imaging of the brain revealed lesions of the medial part of both temporal lobes including hippocampus without any sign of bleeding. A 21-day course of acyclovir therapy was administered with consistent improvement of clinical findings and disappearance of HSV-2-DNA within CSF. After the episode, HAART was switched to a regimen with high CSF penetrability containing abacavir, lamivudine, darunavir and ritonavir. Twelve months after HSV-2 encephalitis neurologic evaluation was normal, but symptoms of depression were reported, HIV-RNA remained undetectable both in the plasma and CSF, and CD4+ lymphocytes were above 500/μL. No opportunistic infection was reported. Patients switched to regimen well tolerated such those containing rilpivirine, that have poor drug concentration within CSF could be considered at risk for opportunistic infection of the brain. Further larger investigation needs to confirm this finding.

Topics: Acyclovir; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Darunavir; Dideoxynucleosides; Drug Substitution; Encephalitis, Herpes Simplex; Herpesvirus 2, Human; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Rilpivirine; Ritonavir; Virus Replication

Topics: Alopecia; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; CD8-Positive T-Lymphocytes; Clone Cells; Dideoxynucleosides; Drug Therapy, Combination; Humans; Immunophenotyping; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Remission Induction; Ritonavir

Topics: Anti-HIV Agents; Atazanavir Sulfate; Dideoxynucleosides; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Lamivudine; Oligopeptides; Pyridines; Ritonavir

The treatment of HIV disease has led to a new division of management costs by shifting most of the necessary resources from inpatient treatment to outpatient management. Among the initiatives aimed at rationalising the resources available, we compared efficacy, tolerability and pharmacoeconomic impact of different regimes of antiretroviral therapy (ART). The survey covered the first 50 patients, clinically stable and with good viro-immunological response, who switched in June 2012 from an ART based on the triple combination of tenofovir (TDF), emtricitabine (FTC) and a protease inhibitor boosted with ritonavir (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), to a treatment based on abacavir (ABC), lamivudine (3TC) and a PI/r or NNRTI. Of the 50 patients who operated the switch, 39 replaced a PI with nevirapine (NVP), for which the largest group of patients was treated with ABC + 3TC + NVP. On 31 May 2015, all patients completed the observation period of 96 weeks, with a mean observation period of 132 weeks and clinical-laboratory checks every four months. Laboratory analysis revealed an optimal maintenance of viral suppression and absolute and relative number of CD4 + lymphocytes and improving trend of creatinine, proteinuria, serum phosphate and bone alkaline phosphatase. There was a variable effect on lipids, with a drop in triglycerides associated with a modest increase in total cholesterol. Much of the HIV-positive population reporting to our hospitals (>50%) comprises individuals who have for years been in stable viraemic suppression, making a satisfactory immune recovery while in good overall clinical condition. This type of patient was the target of the present survey. At the end of 96 weeks of observation the new regimes were well tolerated and did not lead to viro-immunological or clinical deterioration. Pharmacoeconomic analysis showed better containment of the overall costs. No patient needed to be hospitalised during the observation period.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Male; Middle Aged; Ritonavir; Surveys and Questionnaires; Tenofovir; Treatment Outcome

Regimens sparing RATE (ritonavir, abacavir, tenofovir, efavirienz) agents might have better long-term safety. We conducted a feasibility exercise to assess the potential for a randomised trial evaluating RATE-sparing regimens.. Observational.. We first calculated RATE-sparing options available to an average patient receiving RATE agents. We reviewed treatment history and all resistance assays from patients attending the St. Vincent's Hospital (Sydney) clinic and receiving ≥2 RATE agents (n = 120). A viable RATE-sparing regimen with 2 or 3 fully-active agents was constructed from the following six 'safer' agents: rilpivirine or etravirine; atazanavir; raltegravir; maraviroc; and lamivudine. Activity for each drug was predicted as 1 (full-activity), 0.5 or 0 (no activity) using the Stanford mutation database. The utility of maraviroc was calculated assuming both maraviroc activity and inactivity where unknown. The analysis was restricted to regimens for which supporting evidence was identified in the literature or conference proceedings. Finally, we calculated the proportion of patients in the nationally representative Australian HIV Observational Database (AHOD) cohort receiving ≥2 RATE agents (n = 1473) to measure the potential population-level uptake of RATE-sparing agents.. Assuming full maraviroc activity, 117(97.5%) and 107(89.2%) individuals had at least one option with 2 or 3 active RATE-sparing agents, respectively. Assuming no maraviroc activity this decreased to 113(94.2%) and 104(86.7%), respectively. In AHOD, 837(56.8%) patients were receiving ≥2 RATE agents.. Feasible treatment switch options sparing RATE agents exist for the majority of patients. Understanding the pros and cons of switching stable patients onto new RATE-sparing regimens requires evidence derived from randomised controlled trials.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Clinical Trials as Topic; Cyclohexanes; Cyclopropanes; Dideoxynucleosides; Feasibility Studies; Female; Humans; Male; Maraviroc; Middle Aged; Organophosphonates; Ritonavir; Tenofovir; Triazoles

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

Topics: Anti-Retroviral Agents; Atazanavir Sulfate; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Uric Acid; Urinary Calculi; Urolithiasis

Topics: Abscess; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Axilla; Clarithromycin; Darunavir; Dideoxynucleosides; Enfuvirtide; Ethambutol; HIV Envelope Protein gp41; HIV-1; Humans; Immune Reconstitution Inflammatory Syndrome; Isoniazid; Lamivudine; Lymph Node Excision; Lymphadenitis; Male; Mycobacterium avium-intracellulare Infection; Peptide Fragments; Pyrazinamide; Rifampin; Ritonavir; Streptomycin; Sulfonamides

We present a case of relapsing cryptococcal meningitis unresponsive to standard therapy. Voriconazole induction, including the utilization of voriconazole therapeutic drug monitoring in both serum and CSF, with transition to voriconazole plus interferon-gamma (IFN-gamma) was successfully used in a patient receiving antiretroviral therapy with abacavir/lamivudine and lopinavir/ritonavir. Initial voriconazole levels at standard doses of 4 mg/kg twice daily intravenously were low when co-administered with lopinavir/ritonavir but increased to recommended therapeutic levels with an increase of the voriconazole dose to 7 mg/kg twice daily. This case highlights the utility of voriconazole therapeutic drug monitoring when prescribed concurrently with a ritonavir boosted protease inhibitor and the potential role of combination therapy with IFN-G for refractory cryptococcal meningitis.

Topics: Anti-HIV Agents; Antifungal Agents; Cerebrospinal Fluid; Dideoxynucleosides; Drug Monitoring; HIV Infections; Humans; Interferon-gamma; Lamivudine; Male; Meningitis, Cryptococcal; Pyrimidines; Ritonavir; Serum; Triazoles; Voriconazole; Young Adult

The role of exposure to specific antiretroviral drugs on risk of myocardial infarction in human immunodeficiency virus (HIV)-infected patients is debated in the literature.. To assess whether we confirmed the association between exposure to abacavir and risk of myocardial infarction (MI) and to estimate the impact of exposure to other nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-NRTIs on risk of MI, we conducted a case-control study nested within the French Hospital Database on HIV. Cases (n = 289) were patients who, between January 2000 and December 2006, had a prospectively recorded first definite or probable MI. Up to 5 controls (n = 884), matched for age, sex, and clinical center, were selected at random with replacement among patients with no history of MI already enrolled in the database when MI was diagnosed in the corresponding case. Conditional logistic regression models were used to adjust for potential confounders.. Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample (odds ratios [ORs], 2.01; 95% confidence interval [CI], 1.11-3.64) but not in the subset of matched cases and controls (81%) who did not use cocaine or intravenous drugs (1.27; 0.64-2.49). Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir (OR, 1.53; 95% CI, 1.21-1.94 per year) and lopinavir with ritonavir (1.33; 1.09-1.61 per year). Exposure to all non-NRTIs was not associated with risk of MI.. The risk of MI was increased by cumulative exposure to all the studied PIs except saquinavir and particularly to amprenavir/fosamprenavir with or without ritonavir and lopinavir with ritonavir, whereas the association with abacavir cannot be considered causal.

Topics: Adult; Anti-HIV Agents; Carbamates; Case-Control Studies; Cohort Studies; Confidence Intervals; Dideoxynucleosides; Female; France; Furans; HIV Infections; Hospitals, Isolation; Humans; Logistic Models; Male; Middle Aged; Myocardial Infarction; Odds Ratio; Organophosphates; Regression Analysis; Risk; Ritonavir; Sulfonamides

Topics: Adenine; Adult; Alkynes; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis D, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Lopinavir; Male; Nephrolithiasis; Oligopeptides; Organophosphonates; Pyridines; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Stavudine; Tenofovir

The aim of the study was to determine the factors that may contribute to decreases in bone mineral density (BMD) in patients with AIDS.. This was a prospective, non-randomized study. Dual X-ray absorptiometry (DXA) was used to determine the BMD of the lumbar spine, femoral neck and distal radius in treatment-naïve HIV-infected male patients with AIDS before and after 1 year of treatment with zidovudine (ZDV)/lamivudine (3TC) plus abacavir (ABC) or lopinavir/ritonavir (LPV/r).. Basal DXA was performed in 50 patients with CD4 counts <200 cells/microL and/or any AIDS-defining condition. Thirty-two patients completed 1 year with full adherence (17 on ABC and 15 on LPV/r) and a second DXA was then performed. At baseline, 19% had osteopenia at the lumbar spine and 19% at the femoral neck. Low body weight was related to low BMD. After 48 weeks, BMD loss was significant at the three locations. The percentage of BMD loss at the femoral neck tended to be greater in the lopinavir group (5.3 vs. 3.2%, P=0.058). The differences became significant at the lumbar spine (5.7 vs. 2.7%, P=0.044). In the multivariate analysis, the treatment with LPV/r remained associated with bone loss at the lumbar spine.. Osteopenia is frequent in treatment-naïve HIV-infected men with AIDS. Bone loss is higher with LPV/r-based regimens compared with triple nucleoside reverse transcriptase inhibitors.

Topics: Absorptiometry, Photon; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Bone Density; Case-Control Studies; Dideoxynucleosides; Femur Neck; HIV Infections; Humans; Lamivudine; Lopinavir; Lumbar Vertebrae; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; Zidovudine

The effects of HIV infection, highly active antiretroviral therapy (HAART), and specific antiretroviral agents on lipoproteins in women are not well described.. In a cross-sectional substudy of the Women's Interagency HIV Study with 623 HIV-negative and 1556 HIV-positive women (636 untreated, 419 on non-protease inhibitor [PI] HAART, and 501 on PI-containing HAART), we performed multivariate analyses of associations among fasting lipoprotein levels, HIV infection, and HAART.. Untreated HIV-positive women had lower high-density lipoprotein cholesterol (HDL-C) and higher triglycerides (TGs) but not lower low-density lipoprotein cholesterol (LDL-C) than HIV-negative women and were the most likely to have unfavorable HDL-C by National Cholesterol Education Program (NCEP) guidelines. PI HAART users had higher LDL-C than untreated HIV-infected women (107 vs. 100 mg/dL, P = 0.0006) and were the most likely to have unfavorable LDL-C and TGs by NCEP guidelines. HIV-negative women and non-PI HAART users had similar HDL-C levels (55 and 53 mg/dL, respectively), which were higher than those in untreated HIV-infected women and PI HAART users (42 and 49 mg/dL, respectively; P < 0.001 for all). Lamivudine, didanosine, nevirapine, and efavirenz were independently associated with higher HDL-C (P < 0.001 for all). Ritonavir, indinavir/ritonavir, and nelfinavir were associated with higher LDL-C (P < 0.01 for all). Stavudine, abacavir, and all ritonavir-containing regimens were associated with higher TGs (P < 0.05 for all), and tenofovir was associated with lower TGs (P = 0.009).. A dyslipidemic pattern was associated with HIV infection itself, was more severe in users of PI-containing HAART, but was not present in women taking non-PI HAART.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Black People; Cholesterol; Cross-Sectional Studies; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Fasting; Female; Hispanic or Latino; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1; Humans; Indinavir; Lamivudine; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Multivariate Analysis; Nelfinavir; Nevirapine; Organophosphonates; Ritonavir; Stavudine; Tenofovir; Triglycerides; United States; White People

HPV infections have become a major problem in immunocompromised patients, particularly in HIV-positive subjects. HPV lesions are observed more frequently in the ano-genital area and rarely in different body areas, such as the skin and oral cavity. However, in HIV-positive subjects there is an increased risk of oral condylomas. We describe the case of an HIV-positive Nigerian young woman, who came to our notice due to the appearance of small labial and mouth mucous membrane lesions, related to HPV infection, as shown by a biopsy. These lesions were not evident in the genital area. After two years in which the patient no longer received therapy, there was a progressive reduction in CD4 count, associated with the development of the oral condylomas. Hence the patient began a new HAART combination, but after seven months, although a slight improvement emerged in the CD4 count with the disappearance of HIV-RNA, there has been no regression of oral condylomas.

Topics: Adenine; Adult; Alphapapillomavirus; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Dideoxynucleosides; Emtricitabine; Female; HIV Infections; Humans; Italy; Lamivudine; Lopinavir; Mouth Mucosa; Nigeria; Organophosphonates; Papillomavirus Infections; Pyrimidinones; Ritonavir; Sex Work; Stomatitis; Tenofovir; Treatment Refusal; Zidovudine

A 38-year-old Caucasian woman with uncontrolled human immunodeficiency virus (HIV) infection was treated with highly active antiretroviral therapy (HAART) consisting of zidovudine, lamivudine, and nevirapine. Because her therapeutic response was inadequate, the HAART regimen was changed to abacavir, lamivudine, and lopinavir-ritonavir. Three months after this therapy was started, the patient developed progressive and notable hair loss. Her hair became fair and thin, and her appearance deteriorated considerably. Hair loss due to HAART was diagnosed. Lopinavir-ritonavir was stopped, and efavirenz was substituted; abacavir and lamivudine were continued. After 4 weeks, her hair growth substantially improved, as evidenced by rapid growth of new hair. Her general condition also improved. No relapse was observed with the new HAART regimen, and the patient's hair loss completely reversed in 8 weeks. Alopecia is a possible adverse event in HIV-infected patients treated with protease inhibitors, particularly indinavir. Our patient's severe and generalized alopecia was temporally related to the initiation and discontinuation of lopinavir-ritonavir. On the basis of the Naranjo adverse drug reaction probability scale, the adverse reaction was considered probable. Although generalized hair loss due to lopinavir-ritonavir is rare, clinicians should be aware of this potential adverse reaction of this widely used drug. If alopecia is severe or particularly distressing to the patient, the offending drug should be discontinued, and therapy with another HIV drug should be started.

Topics: Adult; Alkynes; Alopecia; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Combinations; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Lopinavir; Probability; Pyrimidinones; Ritonavir

Cryptococcus neoformans is an opportunistic pathogen that can manifest in immunocompromised patients with acquired immune deficiency syndrome. Prevention of cryptococcosis and other opportunistic diseases is an objective in the management of human immunodeficiency virus (HIV)-infected patients. The goal of highly active antiretroviral therapy (HAART) is to reduce the viral loads and enhance CD4 counts in HIV-infected patients. These 2 mechanisms keep HIV-infected patients healthier and enhance their immune systems, thus reducing and often preventing opportunistic infections such as ocular cryptococcal infections. Discontinuation of HAART can lead to ocular opportunistic infections such as cryptococcal choroiditis.. Presented here is a case of a patient who was treated successfully with HAART of stavudine (D4T), abacavir (Ziagen), ritonavir (Norvir), and saquinavir (Invirase). His last CD4 count before HAART was discontinued was 131 cells/mm(3), and viral load was less than 50 copies/mL. He discontinued his HAART regimen for 2 years and presented to the emergency room with complaints of a severe headache with neck pain, lightheadedness, nausea, disorientation, and unsteady gait. Lumbar puncture results showed cryptococcal infection, and the patient was admitted for the treatment of cryptococcal meningitis with amphotericin B and 5-flucytosine. Cryptococcal choroiditis was diagnosed after treatment of the meningitis. After resolution, his resultant visual acuities were 10/350 in the right eye and 10/600 in the left eye. He is on a maintenance dose of antifungal therapy and has been reinitiated on HAART of abacavir/zidovudine/lamivudine (Trizivir) and lopinavir/ritonavir (Kaletra).. This case exemplifies the importance of HAART in the prevention of opportunistic infections, cryptococcal meningitis/choroiditis in particular. Eye care professionals can play a role in encouraging patients to comply with their HAART regimens.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Choroiditis; Cryptococcus neoformans; Dideoxynucleosides; Eye Infections, Fungal; Follow-Up Studies; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Ritonavir; Saquinavir; Stavudine

Chronic viral hepatitis is common among persons with HIV-1 infection, because of shared modes of transmission, and coinfection results in accelerated liver damage, compared with persons with chronic viral hepatitis alone. The use of highly active antiretroviral therapy (HAART) has led to a significant decrease in the morbidity and mortality associated with HIV-1 infection. A number of the medications that are commonly used in HAART regimens are metabolized by the hepatic CYP enzymes, which raises the possibility of significant interactions between antiretroviral medications and hepatic impairment induced by chronic viral hepatitis. Although the data are still very scant, the pharmacokinetics of several antiretroviral medications have been shown to be significantly altered in the presence of liver disease. In the present report, we review the available data and consider potential options, such as dose adjustment and therapeutic drug monitoring, for the administration of antiretroviral therapy to patients with significant hepatic impairment.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Therapy, Combination; Hepatitis; HIV Infections; Humans; Indinavir; Liver Function Tests; Lopinavir; Nelfinavir; Nevirapine; Oxazines; Protease Inhibitors; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Zidovudine

Little is known about the long term risk of development of HIV-1 drug resistance for patients starting antiretroviral therapy (ART) with three or four drug regimens in routine clinical practice.. We analysed a large cohort study of patients seen in one of six large HIV clinics in and around London, UK. The focus of this analysis was on patients who started ART with two nucleosides plus either a single protease inhibitor (PI), a PI with ritonavir, abacavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI).. 4306 patients were followed; 1436 (33%) started with a single PI, 279 (6%) with a PI plus ritonavir, 156 (4%) with triple nucleosides and 2435 (57%) with an NNRTI. The overall cumulative risk of viral load failure was 38% by 6 years. Risk of > or =1 major IAS-USA mutation was 27% by 6 years; risk of mutations from at least two of the three main drug classes was 20% over the same period. These are lower limit estimates as test results were not available for many with viral load failure. Risk of PI mutations being detected in people who started ART with regimens containing a PI with ritonavir was significantly lower than the risk of NNRTI mutations being detected in those starting with NNRTI-containing regimens (relative hazard 0.3195% CI 0.15-0.61; p = 0.0008).. In routine practice, rates of viral load failure and of resistance detection in patients who started ART with three or four drugs are appreciable.

Topics: Adult; Anti-Retroviral Agents; Cohort Studies; Dideoxynucleosides; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Mutation; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Time Factors; Viral Load

To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy.. A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response.. The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002).. A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.

Topics: Adult; Antiretroviral Therapy, Highly Active; Antiviral Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Failure

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

Topics: Aged; Carbamates; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; Humans; Lopinavir; Male; Patient Compliance; Pyrimidinones; Ritonavir; Stavudine; Sulfonamides; Viral Load

Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline.. Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV.. A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72.. Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9).. IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.

Topics: Adult; Antiretroviral Therapy, Highly Active; Dideoxynucleosides; Disease Reservoirs; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Semen; Stavudine; Viral Load; Zidovudine

The effect on humoral immune responses of highly active antiretroviral therapy (HAART) commenced during primary or chronic human immunodeficiency virus type 1 (HIV-1) infection was investigated. HAART inhibited the development of anti-gp120 antibodies when initiated during primary infection and could sometimes reduce antibody titers in patients treated within 2 years of HIV-1 infection. Conversely, antibody responses in patients infected for several years were less sensitive to HAART. Administering HAART during primary infection usually did not substantially affect the development of weak neutralizing antibody responses against autologous virus. However, 2 patients treated very early after infection did not develop neutralizing responses. In contrast, 3 of 4 patients intermittently adherent to therapy developed autologous neutralizing antibodies of unusually high titer, largely coincident with brief viremic periods. The induction of strong neutralizing antibody responses during primary HIV-1 infection might require the suppression of virus replication by HAART, to allow for the recovery of immune competency, followed by exposure to native envelope glycoproteins.

Topics: Anti-HIV Agents; Carbamates; Dideoxynucleosides; Furans; HIV Antibodies; HIV Core Protein p24; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lamivudine; Neutralization Tests; Ritonavir; Sulfonamides; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Anti-HIV Agents; Carbamates; Coronary Disease; Dideoxynucleosides; Drug Therapy, Combination; Furans; Hepatitis B; HIV Protease Inhibitors; Humans; Hyperlipoproteinemias; Male; Middle Aged; Pancreatitis; Risk Factors; Ritonavir; Sulfonamides

To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs.. Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study.. Participants with > or = 10 000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers.. The elimination rate constants for HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens.. With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

Topics: Adult; Anti-HIV Agents; Data Interpretation, Statistical; Dideoxynucleosides; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Virus Replication; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Carbamates; Dideoxynucleosides; Drug Therapy, Combination; Furans; HIV Protease Inhibitors; Humans; Indinavir; Nelfinavir; Ritonavir; Saquinavir; Sulfonamides; Viral Load

To augment the limited antiviral treatments available for children, new therapies to treat children are being investigated. On recommendation from Federal guidelines, many treatment regimens approved for adults are being prescribed for children, but these have little information available about dosing and long-term effects. Ritonavir in different combinations and dose levels has shown good short-term results, and it is believed that the long-term outcomes will mirror the adult outcomes. The Pediatric AIDS Clinical Trials Group study 338 indicated that the three- drug combinations used had a similar impact on viral load when compared to the adult studies. An additional study of Ritonavir, given as a salvage therapy to children with high viral loads, illustrates that pediatric trials should use the experiences learned from adult trials to formulate beneficial regimens. Descriptions of studies for children utilizing Nelfinavir, Saquinavir, and abacavir describe the triple drug combinations that were most successful, the side effects that were experienced, and the need for liquid formulations of the drugs for easier administration. Critical issues that need to be addressed are: adherence to treatment, modifications of side effects, toxicity, and appropriate dosing. A summary of current Federal guidelines for treating children and adolescents with HIV is included.

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Child; Child, Preschool; Clinical Trials as Topic; Dideoxynucleosides; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Nelfinavir; Practice Guidelines as Topic; Ritonavir; Saquinavir; Viral Load