pyrimidinones and Viremia

Simplification of triple antiretroviral therapy to lopinavir/ritonavir (LPV/r) monotherapy in patients with well-controlled viremia for prolonged periods (more than 6 months) without prior failure with a protease inhibitor has been proposed as a strategy that could reduce the toxicity and costs of antiretroviral therapy in the long term while also preserving other therapeutic options. The results of several studies are currently available, some of which had a large number of patients and follow-up of up to 4 years. These studies indicate that this strategy is safe and efficacious, thus allowing its clinical use when indicated. This strategy may be especially useful in reducing the costs of treatment in countries with scarce economic resources. The role of LPV/r monotherapy in the prevention and management of lipodystrophy and in improving the selection of patients with an optimal risk-benefit ratio remains to be defined.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Cost Control; Developing Countries; Drug Combinations; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-Associated Lipodystrophy Syndrome; Humans; Lopinavir; Multicenter Studies as Topic; Pilot Projects; Prospective Studies; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Treatment Outcome; Viral Load; Viremia; Virus Replication

Treatment with lopinavir/ritonavir (LPV/r) monotherapy has been shown to be an effective alternative, especially in the maintenance of patients previously treated with combination therapy and prolonged virological suppression. LPV/r monotherapy is associated with a greater number of low-level viremia episodes than combination therapy, without resistance mutations being detected in the majority of patients. The incidence of the development of major resistance mutations in the OK pilot and OK04 studies was very low: 0.51 per 100 patients-year, and was mainly related to mutations in positions 46, 54 and 82, which have not compromised other therapeutic options. The contribution of low-level resistance mutations to loss of virological control seems small, and no different from that observed in combination therapy. However, this phenomenon should be studied in larger, long-term trials.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Multiple, Viral; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Incidence; Lopinavir; Mutation, Missense; Pilot Projects; Point Mutation; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Viremia

To reduce lipid abnormalities and other side-effects associated with antiretroviral regimens containing lopinavir-ritonavir, patients might want to switch one or more components of their regimen. We compared substitution of raltegravir for lopinavir-ritonavir with continuation of lopinavir-ritonavir in HIV-infected patients with stable viral suppression on lopinavir-ritonavir-based combination therapy.. The SWITCHMRK 1 and 2 studies were multicentre, double-blind, double-dummy, phase 3, randomised controlled trials. HIV-infected patients aged 18 years or older were eligible if they had documented viral RNA (vRNA) concentration below the limit of assay quantification for at least 3 months while on a lopinavir-ritonavir-based regimen. 707 eligible patients were randomly allocated by interactive voice response system in a 1:1 ratio to switch from lopinavir-ritonavir to raltegravir (400 mg twice daily; n=353) or to remain on lopinavir-ritonavir (two 200 mg/50 mg tablets twice daily; n=354), while continuing background therapy consisting of at least two nucleoside or nucleotide reverse transcriptase inhibitors. Primary endpoints were the mean percentage change in serum lipid concentrations from baseline to week 12; the proportion of patients with vRNA concentration less than 50 copies per mL at week 24 (with all treated patients who did not complete the study counted as failures) with a prespecified non-inferiority margin of -12% for each study; and the frequency of adverse events up to 24 weeks. Analyses were done according to protocol. These trials are registered with ClinicalTrials.gov, numbers NCT00443703 and NCT00443729.. 702 patients received at least one dose of study drug and were included in the efficacy and safety analyses for the combined trials (raltegravir, n=350; lopinavir-ritonavir, n=352). Percentage changes in lipid concentrations from baseline to week 12 were significantly greater (p<0.0001) in the raltegravir group than in the lopinavir-ritonavir group in each study, yielding combined results for total cholesterol -12.6%vs 1.0%, non-HDL cholesterol -15.0%vs 2.6%, and triglycerides -42.2%vs 6.2%. At week 24, 293 (84.4%, 95% CI 80.2-88.1) of 347 patients in the raltegravir group had vRNA concentration less than 50 copies per mL compared with 319 (90.6%, 87.1-93.5) of 352 patients in the lopinavir-ritonavir group (treatment difference -6.2%, -11.2 to -1.3). Clinical and laboratory adverse events occurred at similar frequencies in the treatment groups. There were no serious drug-related adverse events or deaths. The only drug-related clinical adverse event of moderate to severe intensity reported in 1% or more of either treatment group was diarrhoea, which occurred in ten patients in the lopinavir-ritonavir group (3%) and no patients in the raltegravir group. The studies were terminated at week 24 because of lower than expected virological efficacy in the raltegravir group compared with the lopinavir-ritonavir group.. Although switching to raltegravir was associated with greater reductions in serum lipid concentrations than was continuation of lopinavir-ritonavir, efficacy results did not establish non-inferiority of raltegravir to lopinavir-ritonavir.. Merck.

Topics: Adult; Anti-HIV Agents; Cholesterol, LDL; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Treatment Outcome; Viremia

Protease inhibitor (PI)-based therapy is recommended for infants infected with human immunodeficiency virus (HIV) who were exposed to nevirapine for prevention of mother-to-child HIV transmission. However, there are limitations of continuing PI-based therapy indefinitely and reuse of nevirapine has many advantages.. To test whether nevirapine-exposed infants who initially achieve viral suppression with PI-based therapy can maintain viral suppression when switched to nevirapine-based therapy.. Randomized trial conducted between April 2005 and May 2009 at a hospital in Johannesburg, South Africa, among 195 children who achieved viral suppression less than 400 copies/mL for 3 or more months from a cohort of 323 nevirapine-exposed children who initiated PI-based therapy before 24 months of age.. Control group children continued to receive ritonavir-boosted lopinavir, stavudine, and lamivudine (n = 99). Switch group children substituted nevirapine for ritonavir-boosted lopinavir (n = 96).. Children were followed up for 52 weeks after randomization. Plasma HIV-1 RNA of greater than 50 copies/mL was the primary end point. Confirmed viremia greater than 1000 copies/mL was used as a criterion to consider regimen changes for children in either group (safety end point).. Plasma viremia greater than 50 copies/mL occurred less frequently in the switch group (Kaplan-Meier probability, 0.438; 95% CI, 0.334-0.537) than in the control group (0.576; 95% CI, 0.470-0.668) (P = .02). Confirmed viremia greater than 1000 copies/mL occurred more frequently in the switch group (0.201; 95% CI, 0.125-0.289) than in the control group (0.022; 95% CI, 0.004-0.069) (P < .001). CD4 cell response was better in the switch group (median CD4 percentage at 52 weeks, 34.7) vs the control group (CD4 percentage, 31.3) (P = .004). Older age (relative hazard [RH], 1.71; 95% CI, 1.08-2.72) was associated with viremia greater than 50 copies/mL in the control group. Inadequate adherence (RH, 4.14; 95% CI, 1.18-14.57) and drug resistance (RH, 4.04; 95% CI, 1.40-11.65) before treatment were associated with confirmed viremia greater than 1000 copies/mL in the switch group.. Among HIV-infected children previously exposed to nevirapine, switching to nevirapine-based therapy after achieving viral suppression with a ritonavir-boosted lopinavir regimen resulted in lower rates of viremia greater than 50 copies/mL than maintaining the primary ritonavir-boosted lopinavir regimen.. clinicaltrials.gov Identifier: NCT00117728.

Topics: Anti-HIV Agents; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infectious Disease Transmission, Vertical; Lamivudine; Lopinavir; Male; Maternal Exposure; Nevirapine; Protease Inhibitors; Pyrimidinones; RNA, Viral; Stavudine; Treatment Outcome; Viremia

To identify potential causes and clinical implications of transient increases in plasma viral load (hereafter, "blips").. M99-056 and M02-418 were prospective, randomized trials evaluating the safety and efficacy of lopinavir/ritonavir (LPV/r) capsules administered twice per day or once per day to subjects infected with human immunodeficiency virus-1 (HIV-1). Plasma viral load was measured every 4 weeks (from baseline through week 24, excluding week 12 and week 20 in M02-418), every 8 weeks (from week 24 through week 48), and every 12 weeks (from week 48 through week 96). Blips were defined by 1 plasma viral load measurement of between 50-1000 copies/mL, immediately preceded and immediately followed by a measurement of <50 copies/mL. A medication event monitoring system was used to record the date and time subjects administered a dose of LPV/r.. Of 228 subject enrolled, event monitor data were available for 223 (98%) subjects (92 of whom received twice-daily LPV/r therapy, and 131 of whom received once-daily therapy). Viral load blips (median plasma viral load, 82 copies/mL [range, 51-858 copies/mL]) were identified in 60 (27%) of the subjects (21 in the LPV/r twice-daily group and 39 in the LPV/r once-daily group). Neither the baseline plasma viral load nor the CD4(+) T cell count were associated with blips. During the week prior to a blip, the mean number of days that the subject administered the prescribed number of doses was lower than the number during a matched period for the same subject during which a blip did not occur (5.55 vs. 6.22 days; P = .007). Blips were not associated with virologic failure or the development of drug resistance.. Blips were associated with decreased adherence, but not with virologic failure or development of drug resistance in these studies of LPV/r.. Clinicaltrials.gov identifier: NCT00043966 .

Topics: Adult; Aged; Drug Administration Schedule; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Pyrimidinones; Ritonavir; RNA, Viral; Treatment Refusal; Viral Load; Viremia

To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz.. HIV-infected antiretroviral-naive patients with viral load > or =30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed.. A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) (P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen (P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L1001/V108l in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively.. A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz.

Topics: Adenine; Adult; Aged; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Didanosine; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Mutation; Organophosphonates; Oxazines; Pyrimidinones; RNA, Viral; Tenofovir; Time Factors; Treatment Failure; Viremia

We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months. At baseline, the median level of plasma viraemia was 4.61 log10 copies/ml (range 3-6.48) and the median CD4 cell count was 219 cells/mm3 (range 1-836). During a median follow-up of 272 days (range 92-635), we observed an increase in the number of CD4 cells (P=0.02) and a dramatic decrease in plasma viraemia levels (P=0.0001), which became undetectable in 122 patients (54.5%). The closely related predictive factors were baseline plasma viraemia levels and the number of mutations known to reduce susceptibility to LPV/RTV. Thirty-one patients (13.8%) discontinued LPV/RTV during the follow-up, and one AIDS event and three deaths were recorded. Of the 134 patients (59.8%) who underwent a baseline genotype resistance test, 22 (16.4%) had > or = 6 mutations known to reduce LPV/RTV susceptibility; plasma viraemia became undetectable in 76 patients (56.7%), only five of whom harboured > or = 6 mutations at baseline (P=0.0001). The independent predictive factors related to virological success were plasma viraemia levels and the number of mutations reducing susceptibility to LPV/RTV at baseline; each additional log10 copies/ml of HIV RNA reduced the probability of virological success by 34.0% and each extra mutation by 14.5%.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Multiple, Viral; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Mutation; Proportional Hazards Models; Pyrimidinones; Ritonavir; Salvage Therapy; Viremia

We report the case of a patient with non-Hodgkin's lymphoma who, during chemotherapy according to the r-CHOP schedule (rituximab-cyclophosphamide-doxorubicin-vincristine and prednisone), showed a hepatic flare with jaundice. Given the patient's state of asymptomatic carrier of HBsAg, we began a treatment of telbivudine (600 mg/die), resulting in a regression of hepatitis flare and negativization of HBV viraemia.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Cyclophosphamide; Cytomegalovirus; Cytomegalovirus Infections; Doxorubicin; Hepatitis B virus; Hepatitis B, Chronic; Humans; Hyperbilirubinemia; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nucleosides; Prednisone; Pyrimidinones; Rituximab; Telbivudine; Thymidine; Vincristine; Viremia; Virus Activation

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Infections; Humans; Lopinavir; Pyrimidinones; Ritonavir; Treatment Outcome; Viral Load; Viremia

Hyperexpression of the programmed death 1 (PD-1) molecule is a hallmark of exhausted T-cells, having a negative impact on T-cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)-positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment-induced viremia reduction and HBeAg seroconversion with respect to PD-1 levels and T-cell reactivity. PD-1 expression was assessed by (1) flow cytometry and (2) quantitative real-time polymerase chain reaction; hepatitis B virus (HBV)-specific CD8+ T-cells were quantitated by pentamer staining; T-cell reactivity to HBV antigens was determined by interferon gamma (IFNgamma) and interleukin 10 (IL-10) enzyme-linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia levels. On therapy, PD-1 decreased significantly on total CD8+ T-cells, HBV-specific CD8+ T-cells, and CD3+/CD8- T-cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD-1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD-1 decrease with a 50% reduction in the frequency of PD-1+/CD8+ T-cells, which was not observed in patients remaining HBeAg-positive. The decrease in PD-1 expression was associated with increased frequencies of IFNgamma-producing T-cells and decreased frequencies of IL-10 producing T-cells. At baseline, PD-1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD-1 expression and HBcAg-specific effector phenotypes.. These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunotherapeutic interventions are needed for restoration of T-cell functions.

Topics: Adult; Alanine Transaminase; Antigens, CD; Antiviral Agents; Apoptosis Regulatory Proteins; Biopsy; CD8-Positive T-Lymphocytes; DNA, Viral; Female; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferon-gamma; Interleukin-10; Lamivudine; Liver; Longitudinal Studies; Male; Middle Aged; Nucleosides; Programmed Cell Death 1 Receptor; Pyrimidinones; Telbivudine; Thymidine; Treatment Outcome; Viral Load; Viremia

The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression.. This was a single-armed single-centre pilot trial.. Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated.. All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4-23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed.. LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up.

Topics: Adult; Aged; Antiretroviral Therapy, Highly Active; Brazil; CD4 Lymphocyte Count; Cytochrome P-450 CYP3A; Drug Administration Schedule; Female; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Pilot Projects; Polymorphism, Genetic; Pyrimidinones; Ritonavir; RNA, Viral; Viral Load; Viremia

Topics: Adenine; Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Deoxycytidine; Emtricitabine; Enfuvirtide; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; Lopinavir; Male; Organophosphonates; Peptide Fragments; Pyrimidinones; Ritonavir; Tenofovir; Viral Load; Viremia

To determine whether the level of persistent HIV-1 viremia is affected by simplifying standard antiretroviral therapy to lopinavir/ritonavir (LPV/r) alone.. Measurement of HIV-1 RNA levels < 50 copies/ml in longitudinal plasma samples from 41 of 42 subjects enrolled in the 'Only Kaletra' study that compared maintenance therapy with LPV/r alone to standard of care (SOC) with two nucleoside reverse transcriptase inhibitors (NRTI) and LPV/r.. Plasma samples for each subject from study screening to week 48 were tested using a modified Roche Amplicor HIV-1 RNA assay with a quantification limit of 3 copies/ml.. Median plasma HIV-1 RNA values at baseline and weeks 4, 8, 12, 24 and 48 were not significantly different between the LPV/r alone and the SOC arms, being 5.1 versus 3.0 (P = 0.29), 4.5 versus 2.9 (P = 0.44), 3.3 versus 2.9 (P = 0.99), 1.9 versus 1.0 (P = 0.68), 3.7 versus 3.6 (P = 0.49), and 2.8 versus 1.6 copies/ml (P = 0.78), respectively. In the 17 of 21 subjects who maintained virus suppression < 50 copies/ml on LPV/r alone, median HIV-1 RNA values did not increase significantly from baseline at any time point after discontinuing NRTI, in comparison to the three subjects with virologic failure whose median HIV-1 RNA levels began to rise at week 8.. The level of persistent viremia did not increase after stopping NRTI therapy among subjects who maintained virus suppression < 50 copies/ml on LPV/r alone through 48 weeks. This supports further studies of induction-simplification therapy for treatment of HIV-1 infection including the identification of factors predicting success or failure of simplified therapy.

Topics: Drug Resistance, Viral; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Longitudinal Studies; Lopinavir; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; RNA, Viral; Treatment Failure; Viral Load; Viremia

We compared immunovirological outcomes and toxicities of HAART regimens including LPV/r and IDV/r in antiretroviral naïve HIV-1 patients. We retrospectively selected 55 patients starting LPV/r and 52 starting IDV/r as first-line HAART. Immunovirological and metabolic parameters were recorded at baseline and every 3 months as were side effects, AIDS-defining events and deaths. Demographic characteristics and NRTIs included in the regimens were comparable. Both groups reached undetectable HIV-RNA plasma viremia from third month and maintained during follow-up. However, patients receiving IDV/r had a lower probability to obtain virological success (RH: 0.46). Patients receiving IDV/r patients showed a greater increase of total cholesterol (P = 0.01). Three patients on LPV/r and 21 on IDV/r discontinued the drug for toxicity, leading to a 8.40 higher risk of discontinuation in the latter group. In our clinical setting IDV/r showed to be less effective and more toxic than LPV/RTV as first-line HAART.

Topics: Adult; Antiretroviral Therapy, Highly Active; Cholesterol; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir; RNA, Viral; Viremia

There is limited knowledge about how to treat and interpret results from genotypic resistance assays in HIV-2 infection. Here, genetic variation in HIV-2 pol gene was studied in 20 of 23 known HIV-2 cases in Sweden. Five patients with signs of virological treatment failure were longitudinally studied. Clinical, virological and immunological data were collected and the protease (PR) and first half of the reverse transcriptase (RT) was amplified and directly sequenced from plasma samples. Moderate to extensive genetic evolution was observed in four of the five patients who failed treatment. Some mutations occurred at positions known to confer resistance in HIV-1, but many occurred at other positions in PR and RT. All patients had been treated with zidovudine alone or in combination with other antiretroviral drugs, but none displayed a mutation at position 215, which is the primary zidovudine resistance site in HIV-1. Instead, a E219D mutation evolved in virus from two patients and a Q151M mutation evolved in two other patients. A M184V mutation indicative of lamivudine resistance was detected in three patients. The virus of one patient who had been treated with ritonavir, nelfinavir, and lopinavir successively acquired nine unusual mutations in the protease gene, most of which are not considered primary or secondary resistance mutations in HIV-1. Our data indicate that the evolutionary pathways that lead to antiretroviral resistance in HIV-2 and HIV-1 exhibit both similarities and differences. Genotypic HIV-2 resistance assays cannot be interpreted using algorithms developed for HIV-1, instead new algorithms specific for HIV-2 have to be developed.

Topics: Adolescent; Adult; Africa, Western; Amino Acid Sequence; Amino Acid Substitution; Anti-HIV Agents; Codon; Drug Resistance, Multiple, Viral; Evolution, Molecular; Female; Genes, pol; Genetic Variation; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nelfinavir; Prospective Studies; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sequence Alignment; Sequence Homology, Amino Acid; Sweden; Treatment Failure; Viremia; Zidovudine

Genotypic correlates of reduced phenotypic susceptibility to amprenavir (APV) and lopinavir (LPV) were examined in 271 HIV isolates from 207 protease inhibitor (PI)-experienced subjects. All samples were from LPV-naive subjects; two were from APV-experienced subjects. Using a fold resistance (FR) of <2.5, 179 (66%) were APV susceptible. Using FRs of <2.5 and <10, 107 (39%) and 194 (72%), respectively, were LPV susceptible. The I84V mutation was the strongest APV resistance marker in PI-experienced subjects in both univariate and multivariate analyses, with an increased relative incidence (RI) of 6.9 with >2.5 FR. Mutations L10I (RI, 1.7), M46I (RI, 2.3), and L90M (RI, 1.9, but 65% linked with the I84V) were associated with decreased APV susceptibility in the univariate analysis (p < 0.001). Mutations L10I, G48V, I54T, I54V, and V82A were significantly associated with decreased LPV susceptibility (p < 0.001 for each) and had increased RIs of 2.2, 4.4, 13, 4.6, and 3.2, respectively. Decreased susceptibility to LPV (FR, >or=10) was significantly associated with prior exposure to the following PIs: ritonavir (RTV) (p < 0.001), saquinavir (SQV) (p < 0.001), nelfinavir (NFV) (p = 0.008), and indinavir (IDV) (p = 0.028). Decreased APV susceptibility (FR, >or=2.5) was significantly associated with prior exposure to RTV (p = 0.009), NFV (p = 0.003), and IDV (p = 0.021) but not with prior SQV (p = 0.103). These results suggest that APV and LPV have different cross-resistance mutation patterns that may help determine choice of PI therapy after therapy failure.

Topics: Carbamates; Cross-Sectional Studies; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Microbial Sensitivity Tests; Mutation; Phenotype; Pyrimidinones; Retrospective Studies; RNA, Viral; Sulfonamides; Viremia