Protease Inhibitor-based Antiretroviral Regimens Research Articles

Predictors of virologic outcome among people living with HIV who continue a protease inhibitor-based antiretroviral regimen following virologic failure with no or limited resistance

BackgroundTreatment management after repeated failure of antiretroviral therapy (ART) is difficult due to resistance and adherence challenges. For people who have failed non-nucleoside reverse transcriptase inhibitor-(NNRTI-) and protease inhibitor-(PI-) based regimens with no or limited resistance, remaining on PI-based ART is an option. Using data from an ART strategy trial (A5288) in low/middle-income countries which included this option, we explored whether predictors can be identified distinguishing those who experienced further virologic failure from those who achieved and maintained virologic suppression.MethodsA5288 enrolled people with confirmed HIV-1 RNA ≥ 1000 copies/mL after ≥ 24 weeks of PI-based ART and prior failure on NNRTI-based ART. This analysis focused on the 278 participants with no resistance to the PI being taken and no or limited nucleoside reverse transcriptase inhibitor (NRTI) resistance, who continued their PI with flexibility to change NRTIs. Proportional hazards models were used to evaluate predictors of virologic failure during follow-up (VF: confirmed HIV-1 RNA ≥ 1000 copies/mL at ≥ 24 weeks of follow-up).Results56% of participants were female. At study entry, median age was 40 years, time on ART 7.8 years, CD4 count 169 cells/mm3, HIV-1 RNA 20,444 copies/mL; and 37% had NRTI resistance. The estimated proportion experiencing VF increased from 39% at week 24 to 60% at week 96. In multivariable analysis, significant predictors at study entry of VF were higher HIV-1 RNA (adjusted hazard ratio: 2.20 for ≥ 10,000 versus < 10,000 copies/mL), lower age (1.96 for < 30 versus ≥ 30 years), NRTI resistance (1.74 for present versus absent), lower CD4 count (1.73 for < 200 versus ≥ 200 cells/mm3), and shorter ART duration (1.62 for < 10 versus ≥ 10 years). There was a strong trend in proportion with VF at week 96 with the number of these five risk factors that a participant had, varying from 8% for zero, to 31%, 40%, 73%, and 100% for one, two, three, and four/five. Only 13% of participants developed new NRTI or PI resistance mutations.ConclusionA simple count of five predictors might have value for identifying risk of continued VF. Novel antiretroviral and adherence support interventions are needed to improve virologic outcomes for higher risk individuals.

A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan

Introduction: Second-line antiretroviral therapy (ART) regimens are used when patients develop treatment failure from first-line drug regimens. The present study is aimed to compare treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in human immunodeficiency virus (HIV) patients, switched to various second-line ART regimens and to assess adverse drug reactions (ADRs). Materials and Methods: A longitudinal observational study was conducted at ART center, SMS Hospital, Jaipur, after approval from Institutional Research Review Board. One hundred HIV positive patients, resistant to first line ART, switched to either of the 2 s line ART regimens were followed for 1 year for early treatment outcomes and any ADRs. Results: Out of 97 patients enrolled 65 patients received Tenofovir and 32 patients received Zidovudine (ZDV) along with lamivudine and Atazanavir/ritonavir. There was significant increment in CD4 count from the baseline value (202.51–438.52 cells/mm3) after 12 months of therapy. On comparison, CD4 cell rise was not significantly different between the two groups. However, Plasma viral load suppression was achieved insignificantly more number of patients in ZDV group than in tenofovir group: 31 (96.9%) versus 57 (87.7%), respectively. Opportunistic infections (OI) were seen in 21.5% and 28.1% patients respectively at the time of switching of second-line ART. Out of 59 ADRs reported, nausea, vomiting, diarrhea, hyperbilirubinemia, dyslipidemia, and anemia were most common. Conclusion: Nonadherence, drug resistance, and treatment failure are the major challenges in controlling HIV disease. Our study shows that both the second-line regimens were comparable in improvement in CD4 count and viral load suppression with 1 year success rate of 90.7%.

A comparative study on early treatment outcome and adverse drug reaction profile of two protease inhibitor-based antiretroviral regimens in human immunodeficiency virus patients at a tertiary care teaching hospital, Rajasthan

Introduction: Second-line antiretroviral therapy (ART) regimens are used when patients develop treatment failure from first-line drug regimens. The present study is aimed to compare treatment outcome in terms of clinical, virological, and immunological effectiveness over 1 year of follow-up in human immunodeficiency virus (HIV) patients, switched to various second-line ART regimens and to assess adverse drug reactions (ADRs). Materials and Methods: A longitudinal observational study was conducted at ART center, SMS Hospital, Jaipur, after approval from Institutional Research Review Board. One hundred HIV positive patients, resistant to first line ART, switched to either of the 2 s line ART regimens were followed for 1 year for early treatment outcomes and any ADRs. Results: Out of 97 patients enrolled 65 patients received Tenofovir and 32 patients received Zidovudine (ZDV) along with lamivudine and Atazanavir/ritonavir. There was significant increment in CD4 count from the baseline value (202.51–438.52 cells/mm3) after 12 months of therapy. On comparison, CD4 cell rise was not significantly different between the two groups. However, Plasma viral load suppression was achieved insignificantly more number of patients in ZDV group than in tenofovir group: 31 (96.9%) versus 57 (87.7%), respectively. Opportunistic infections (OI) were seen in 21.5% and 28.1% patients respectively at the time of switching of second-line ART. Out of 59 ADRs reported, nausea, vomiting, diarrhea, hyperbilirubinemia, dyslipidemia, and anemia were most common. Conclusion: Nonadherence, drug resistance, and treatment failure are the major challenges in controlling HIV disease. Our study shows that both the second-line regimens were comparable in improvement in CD4 count and viral load suppression with 1 year success rate of 90.7%.

The effect of protease inhibitor-based dual antiretroviral regimens on CD4/CD8 ratio during the first year of therapy in ART-naïve patients with HIV-infection.

To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio >1 at 48weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients >50years old, with baseline CD4 counts ≤200cells/μL, viral load >100000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P=0.729) or in the proportion of patients with CD4/CD8 ratio >1 (17.9% vs. 19.3%, P=0.678) 48weeks after ART initiation. Subgroup analysis showed no further differences. The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.

In utero exposure to protease inhibitor-based antiretroviral regimens delays growth and developmental milestones in mice

Antiretroviral therapy (ART) in pregnancy has dramatically reduced HIV vertical transmission rates. Consequently, there is a growing number of children that are HIV exposed uninfected (CHEUs). Studies suggest that CHEUs exposed in utero to ART may experience developmental delays compared to their peers. We investigated the effects of in utero ART exposure on perinatal neurodevelopment in mice, through assessment of developmental milestones. Developmental milestone tests (parallel to reflex testing in human infants) are reflective of brain maturity and useful in predicting later behavioral outcomes. We hypothesized that ART in pregnancy alters the in utero environment and thereby alters developmental milestone outcomes in pups. Throughout pregnancy, dams were treated with boosted-atazanavir combined with either abacavir/lamivudine (ATV/r/ABC/3TC), or tenofovir/emtricitabine (ATV/r/TDF/FTC), or water as control. Pups were assessed daily for general somatic growth and on a battery of tests for primitive reflexes including surface-righting, negative-geotaxis, cliff-aversion, rooting, ear-twitch, auditory-reflex, forelimb-grasp, air-righting, behaviors in the neonatal open field, and olfactory test. In utero exposure to either ART regimen delayed somatic growth in offspring and evoked significant delays in the development of negative geotaxis, cliff-aversion, and ear-twitch reflexes. Exposure to ATV/r/ABC/3TC was also associated with olfactory deficits in male and forelimb grasp deficits in female pups. To explore whether delays persisted into adulthood we assessed performance in the open field test. We observed no significant differences between treatment arm for males. In females, ATV/r/TDF/FTC exposure was associated with lower total distance travelled and less ambulatory time in the centre, while ATV/r/ABC/3TC exposure was associated with higher resting times compared to controls. In utero PI-based ART exposure delays the appearance of primitive reflexes that involve vestibular and sensory-motor pathways in a mouse model. Our findings suggest that ART could be disrupting the normal progress/maturation of the underlying neurocircuits and encourage further investigation for underlying mechanisms.

Progesterone supplementation for HIV-positive pregnant women on protease inhibitor-based antiretroviral regimens (the ProSPAR study): a study protocol for a pilot randomized controlled trial.

BackgroundIn Canada, the majority of HIV-positive pregnant women receive combination antiretroviral therapy that includes a ritonavir-boosted protease inhibitor to prevent mother-to-child HIV transmission. However, protease inhibitor-based combination antiretroviral therapy has been associated with increased rates of preterm, low birth weight, and small for gestational age births. Our previous experimental findings demonstrate that protease inhibitor use during pregnancy is associated with decreased progesterone levels that correlate with fetal growth, and that progesterone supplementation can improve protease inhibitor-induced fetal growth restriction. We hypothesize that HIV-positive pregnant women who receive protease inhibitor-based combination therapy may also benefit from progesterone supplementation during pregnancy.Methods/designIn order to test this hypothesis, we have designed an open-label, multi-centre, randomized controlled (parallel group) pilot trial. The initial goal of this trial is to test feasibility and acceptability of our intervention. Forty HIV-positive pregnant women who are either on, or intending to start or switch to a boosted protease inhibitor-based combination antiretroviral regimen will be enrolled from six sites across Ontario, Canada. Twenty-five women will be randomized to self-administer natural progesterone (Prometrium, 200 mg) vaginally every night starting between gestational week 16 and 24 until week 36, and 15 women will be randomized to no intervention. While the participants and treating physicians will not be blinded, the laboratory personnel performing the biochemical and morphological evaluations will be blinded to ensure unbiased evaluation. The primary outcome of the pilot study is the feasibility of enrolment as measured by the recruitment rate and patient-reported reasons to decline participation. Secondary outcomes in participants include safety, acceptability, and adherence to progesterone supplementation.DiscussionGiven the safety of intravaginal progesterone and its current use in the general obstetrical population to prevent recurrent preterm delivery, this pilot study will provide data to determine the feasibility of a larger randomized controlled trial to assess the impact of this intervention on improving neonatal health in the context of HIV-positive pregnancies.Trial registrationClinicalTrials.gov, NCT02400021

The Impact of Protease Inhibitor-Based Antiretroviral Regimens On Renal Transplant Outcomes in HIV-Infected Recipients.

Background: Protease inhibitors (PI) pose a challenge post-transplant due to significant drug interactions with calcineurin inhibitors (CNI), leading to altered CNI dosing and the potential for increased CNI exposure. This has prompted many clinicians to convert patients to newer, non-CNI interacting antiretroviral (ARV) agents prior to transplant. The purpose of this study was to examine the impact of PI-based regimens on graft outcomes in HIV-infected renal transplant recipients. Methods: Retrospective study of renal allograft recipients transplanted between 2003-2013 with ≥6 months of follow-up. Maintenance IS included CNI/MMF ± steroids. Results: During this period, 45 renal transplants were performed in HIV-infected individuals.Table: No Caption available.There was no difference in mean tacrolimus trough levels at days 30, 60, 90, and 180 post-transplant. Rejection-free survival at 6 and 12 months was 63.5% and 59.3% in the PI group and 50.5% and 37.9% in the non-PI group, respectively. The cumulative incidence of acute rejection was lower in the PI group (p=0.08). There was no difference between groups in the degree of IF/TA in available biopsies (p=0.687). Patients who received a PI-based regimen had significantly reduced graft failure rates, independent of the induction regimen (HR=0.24, p=0.023).Figure: No Caption available.Conclusions: In HIV-infected renal transplant recipients, PI-based ARV regimens are associated with a lower rate of rejection and better graft survival. Our data suggests that converting patients to non-PI regimens is not warranted.

The vulnerability of men to virologic failure during antiretroviral therapy in a public routine clinic in Burkina Faso

IntroductionGender differences in antiretroviral therapy (ART) outcomes are critical in sub-Saharan Africa. We assessed the association between gender and virologic failure among adult patients treated in a public routine clinic (one of the largest in West Africa) in Burkina Faso.MethodsWe performed a case-control study between July and October 2012 among patients who had received ART at the Bobo Dioulasso Day Care Unit. Patients were eligible if they were 15 years or older, positive for HIV-1 or HIV-1+2, and on first-line ART for at least six months. Cases were all patients with two consecutive HIV loads >1000 copies/mL (Biocentric Generic or Abbott Real Time assays), or one HIV load >1000 copies/mL associated with immunologic or clinical failure criteria. Controls were all patients who only had HIV loads <300 copies/mL. The association between gender and virologic failure was assessed using a multivariate logistic regression, adjusted on age, level of education, baseline CD4+ T cell count, first and current antiretroviral regimens and time on ART.ResultsOf 2303 patients (74.2% women; median age: 40 years; median time on ART: 34 months), 172 had virologic failure and 2131 had virologic success. Among the former, 130 (75.6%) had confirmed virologic failure, 38 (22.1%) had viro-immunologic failure, and four (2.3%) had viro-clinical failure. The proportion of men was significantly higher among the cases than among the controls (37.2% vs. 24.9%; p<0.001). Compared to controls, cases were also younger, more immunodeficient at ART initiation, less likely to receive a protease inhibitor-based antiretroviral regimen and had spent a longer period of time on ART. After adjustment, male gender remained strongly associated with virologic failure (odds ratio 2.52, 95% CI: 1.77–3.60; p<0.001).ConclusionsMen on ART appeared more vulnerable to virologic failure than women. Additional studies are needed to confirm the poorer prognosis of men in this setting and to determine the causes for their vulnerability in order to optimize HIV care. From now on, efforts should be made to support the adherence of men to ART in the African setting.

High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting

BackgroundLimited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens.MethodsA retrospective chart review was conducted at 8 Thai sites of children who switched to PI –based regimens due to failure of NNRTI –based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks.ResultsData from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10 copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10 copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002).ConclusionSecond-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed.

Immune Reconstitution in Severely Immunosuppressed Antiretroviral-Naive HIV Type 1-Infected Patients Using a Nonnucleoside Reverse Transcriptase Inhibitor-Based or a Boosted Protease Inhibitor-Based Antiretroviral Regimen: Three-Year Results (The Advanz Trial): A Randomized, Controlled Trial

Late diagnosis of HIV-1 infection is quite frequent in Western countries. Very few randomized clinical trials to determine the best antiretroviral treatment in patients with advanced HIV-1 infection have been performed. To compare immune reconstitution in two groups of very immunosuppressed (less than 100 CD4(+) cells/microl), antiretroviral-naive HIV-1-infected adults, 65 patients were randomly assigned in a 1:1 ratio to receive zidovudine + lamivudine + efavirenz (group A, 34 patients) or zidovudine + lamivudine + ritonavir-boosted indinavir (group B, 31 patients). The median (interquartile range) CD4(+) cell increase after 12 and 36 months was +199 (101, 258) and +299 (170, 464) cells/microl in the efavirenz arm and +136 (57, 235) and +228 (119, 465) cells/microl in the ritonavir-boosted indinavir arm (p > 0.05 for all time points). The proportion (95% confidence interval) of patients achieving HIV-1 RNA levels under 50 copies/ml was significantly greater in the efavirenz arm at 3 years by the intention-to-treat analysis [59% (41%, 75%) vs. 23% (10%, 41%)], whereas no differences were found in the on-treatment analysis. Immune activation (CD8(+)CD38(+) and CD8(+)CD38DR(+) T cells) was significantly lower for the efavirenz arm from month 6 to month 24. Adverse events were more frequent in the ritonavir-boosted indinavir arm. Almost all cases of disease progression and death were observed in the first year of treatment, with no significant differences between the two arms (p = 0.79 by the log-rank test). At 1 and 3 years, the immune reconstitution induced by an efavirenz-based regimen in very immunosuppressed patients was at least as potent as that induced by a ritonavir-boosted protease inhibitor-based antiretroviral regimen.

Protease Inhibitor–Based Antiretroviral Prophylaxis during Pregnancy and the Development of Drug Resistance

The aim of this study was to determine the development of drug resistance among pregnant women receiving a protease inhibitor-based antiretroviral prophylaxis for the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). HIV-infected pregnant women without maternal indication for antiretroviral therapy were enrolled prospectively. Genotypic resistance testing was performed prior to initiation of antiretroviral prophylaxis and was repeated 4-8 weeks after cessation of antiretroviral therapy at the time of delivery. Forty pregnant women with HIV infection (Centers for Disease Control and Prevention stage A1 or A2) were included. All women received an antiretroviral regimen including either fixed-dose lopinavir/ritonavir (n = 33) or ritonavir-boosted saquinavir (n = 7) and a backbone consisting of 2 nucleoside reverse-transcriptase inhibitors. The mean duration of antiretroviral treatment was 8.4 weeks (range, 5-22 weeks). Primary resistance mutations were found in 2 patients (nonnucleoside reverse-transcriptase inhibitor resistance, K103N; protease inhibitor resistance, G48V). Postpartum genotypic resistance revealed no new relevant resistance mutations. In our study no clinically significant resistance mutations developed in pregnant women receiving a short-term protease inhibitor-based antiretroviral regimen for prophylaxis of mother-to-child transmission of HIV. Future therapeutic options are therefore preserved.

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV.

Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults

Thymidine-based nucleoside analogue reverse transcriptase inhibitors and some protease inhibitors of HIV are associated with lipoatrophy, relative central fat accumulation and insulin resistance. The latter associations have not been well evaluated prospectively in adults commencing antiretroviral therapy. We studied the effects of protease inhibitor-based antiretroviral regimens on body composition, insulin sensitivity and adipocytokine levels. 48-week substudy of a randomized, open-label, three-arm trial. Hospital and community HIV clinics. 140 HIV-infected adults naive to antiretroviral therapy. Tipranavir/ritonavir [500/200 mg twice a day (TPV/r200)] or [500/100 mg twice a day (TPV/r100)] or lopinavir/ritonavir [400/100 mg twice a day (LPV/r)], each with tenofovir + lamivudine. Body composition [dual-energy x-ray absorptiometry for limb fat; L4, abdominal computed tomography for visceral adipose tissue (VAT)]; and fasting metabolic parameters. The primary analysis was change in limb fat mass in each TPV/r group vs. LPV/r. Limb fat increased in all three groups: LPV/r (1.17 kg) versus TPV/r200 (0.83 kg; P = 0.16) and TPV/r100 (0.41 kg; P = 0.07). VAT decreased in all groups: LPV/r (-3 cm) vs. TPV/r200 (-9 cm; P = 0.04) and TPV/r100 (-6 cm; P = 0.40). No significant change in insulin sensitivity was observed, including by oral glucose tolerance testing. The increase in leptin levels was significantly correlated with the increase in limb fat mass (r = 0.67; P < 0.0001). Despite increased limb fat, adiponectin levels increased, but significantly more with TPV/r200 (+6010 ng/ml; P < 0.0001) or TPV/r100 (+4497 ng/ml; P = 0.002) when compared with LPV/r (+1360 ng/ml). Unlike many other antiretroviral regimens, TPV/r or LPV/r with tenofovir-lamivudine increased subcutaneous fat without evidence for increasing visceral fat or insulin resistance over 48 weeks.

Darunavir Inhibitory Quotient Predicts the 48-Week Virological Response to Darunavir-Based Salvage Therapy in Human Immunodeficiency Virus-Infected Protease Inhibitor-Experienced Patients

The aim of this study was to evaluate the relationship between the virological response to darunavir-based salvage antiretroviral therapy and the darunavir genotypic and virtual inhibitory quotients (gIQ and vIQ, respectively). Thirty-seven HIV-infected patients failing protease inhibitor-based antiretroviral regimens who started salvage therapy containing darunavir-ritonavir were prospectively studied. The primary outcome of the study was a viral load (VL) of <50 copies/ml at week 48. The trough concentrations of darunavir in plasma, the number of darunavir resistance mutations, the change in the 50% inhibitory concentration (IC(50)) of darunavir in the virtual phenotype, and the darunavir gIQ and vIQ were correlated with the virological outcome in regression analyses adjusted by the number of active drugs in the background regimen. The VL was <50 copies/ml in 56.8% of patients at week 48. Changes in the VL were not significantly associated with the darunavir concentration (P = 0.304), the number of darunavir resistance mutations (P = 0.695), or the change in the IC(50) (P = 0.750). However, patients with darunavir vIQs of >or=1.5 had a 12-fold greater chance of achieving a >or=1 log(10) reduction in the VL (odds ratio [OR], 12.7; 95% confidence interval [95% CI], 1.9 to 81.6; P = 0.007), and a 5-fold greater chance of achieving a VL of <50 copies/ml (OR, 5.4; 95% CI, 1.2 to 24.5; P = 0.028), at week 48 than patients with darunavir vIQs of <1.5. The positive and negative predictive values of this darunavir vIQ cutoff for achieving a VL of <50 copies/ml at week 48 were 70% and 69%, respectively. The darunavir vIQ predicts virological response to darunavir-based salvage therapy better than the darunavir trough concentration or resistance mutations alone. We suggest targeting a darunavir vIQ of 1.5 for achieving long-term viral suppression.

Evaluation of the consistency of refills for antiretroviral medications in two hospitals in the state of Rio de Janeiro, Brazil

We conducted a retrospective cohort study using pharmacy records to assess the frequency of delay in picking up antiretroviral (ARV) medication refills from the pharmacy and to identify determinants of delay among HIV-infected patients at two Brazilian hospitals. We selected patients who were on ARV therapy before January 2001 at Nova Iguaçu Hospital (NIPRH) (N = 265) and Evandro Chagas (N=424) Clinical Research Institute. We abstracted medical records and pharmacy data using standardised forms and analysed potential associations between delay in refilling medications and patients’ demographic characteristics, type of ARV drug regimen and evolution of HIV disease. Sixty-nine patients (26%) had delays in medication refills >1 month at least once in 2001 at NIPRH compared with 140 (33%) patients at IPEC (p=0.052). No factor was found to be associated with having a delay in medication refill >1 month at NIPRH. At IPEC, delays in medication refill >1 month were associated with a median CD4+ T cell count <200/mm3 versus >500/mm3 (adjusted odds ratio (AOR) = 3.8; 95% confidence interval (CI) =1.6–8.9) and with dual protease inhibitor-based ARV regimens versus other regimens (AOR = 4.3; 95% CI = 1.9–9.4). In conclusion, rates of delay in medication refills were similar to rates of adherence to ARV therapy found in other studies in Brazil, suggesting that delay in medication refills could be used as a surrogate for adherence. Analysing ARV medication refills can complement self-reported information on adherence.

Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir

To determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development. Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy. The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >/= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level. The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%. The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity. Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g, efficacy and non-hepatic toxicity) should guide individual treatment decisions.

Steady-State Pharmacokinetics of a Double-Boosting Regimen of Saquinavir Soft Gel plus Lopinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Infected Adults

Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Resolution Of Diabetes After Initiation Of Antiretroviral Therapy In Two Human Immunodeficiency Virus-Infected Patients

To describe two cases of human immunodeficiency virus (HIV)-infected patients who had diabetes mellitus, which resolved after initiation of antiretroviral therapy. We present the clinical and laboratory findings and describe the clinical course of these two patients. A 48-year-old HIV-infected black woman presented with multiple infections and hyperglycemia. After her acute infections were treated and she was feeling well, she continued to have diabetes that necessitated insulin therapy. Administration of a protease inhibitor-based antiretroviral regimen resolved her diabetes and eliminated the need for insulin or oral therapy. Our second patient, a 37-year-old HIV-infected black man, presented with polyuria and polydipsia and a hemoglobin A1c value of 11%. He received antiretroviral therapy, and his diabetes resolved after a period of 2 1/2 months. Protease inhibitor-based antiretroviral therapy is associated with diabetes mellitus in up to 6% of HIV-infected patients. Although most HIV-infected patients in whom diabetes develops have this disorder after initiation of protease inhibitor therapy, the current two cases illustrate patients in whom diabetes resolved after use of antiretroviral therapy. This finding supports the presence of other mechanisms that affect glucose metabolism in patients infected with HIV and suggests that control of HIV infection may have a role in controlling diabetes.