PI-based Highly Active Antiretroviral Therapy Research Articles

Cumulative effects of hypertriglyceridemia in HIV-infected patients switching from NNRTIs to PI-based antiretroviral therapy.

The objective of this study was to investigate changes in serum lipids among HIV-infected patients switching from non-nucleoside-reverse transcriptase inhibitors (NNRTI) to protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), and to determine if changes of lipid profiles impacted the monocyte subsets recovery. Fifty-seven subjects who switched from NNRTIs to PI-based HAART (NNRTIs to PI group) and fifty-five subjects who initially started with PI-based HAART (initial PI group) were recruited. According to their baseline triglyceride (TG) levels, the NNRTIs to PI and initial PI groups were further divided into non-hypertriglyceridemia and hypertriglyceridemia subgroups, respectively. The effects of PI-based HAART on lipid profiles and monocyte subsets were analyzed. At 48 weeks, the TG changes in the NNRTIs to PI group was higher than that of the initial PI group. The increases of serum TG levels in the initial PI non-hypertriglyceridemia group was greater than that of the NNRTIs to PI non-hypertriglyceridemia group. For the hypertriglyceridemia group at baseline, significant increment in TG levels were observed in the NNRTIs to PI hypertriglyceridemia group. The percentages of circulating CD14highCD16+ and CD14lowCD16+ subsets were elevated in the two groups. At 48 weeks, the proportion of CD14highCD16+ monocytes declined gradually, and the proportion of CD14lowCD16+ monocytes decreased independently of the TG level. For non-hypertriglyceridemia individuals at baseline, PI-based regimens increased the TG level in the initial PI group. For the NNRTIs to PI hypertriglyceridemia group, PI-based regimens reinforced HAART-related hypertriglyceridemia.

The prevalence and risk factors for dyslipidaemia in human immunodeficiency virus-infected children on highly active antiretroviral therapy in Kano, Nigeria

Prolonged administration of Highly Active Anti Retroviral Therapy (HAART) is associated with metabolic side effects, especially dyslipidaemia, with potential increase in the risk of development of cardiovascular disease as the affected children mature into adulthood. This study determined the prevalence and risk factors for dyslipidaemia among HIV infected children aged 2-15 years. The study was a comparative study conducted on children aged 2- 15 years attending the Paediatric Infectious Disease Clinic of the Aminu Kano Teaching Hospital, Kano. Study subjects that fulfilled the inclusion criteria were recrutited using systematic sampling technique. Serum lipid profile parameters were measured on blood samples from eighty HIV-infected children on HAART and eighty HIV-infected HAART naive children as patients and controls respectively. Data was analysed using the SPSS software for Windows version16.0. P-values of <0.05 were considered as statistically significant. The overall prevalence of dyslipidaemia in HIVinfected children on HAART was 62.5% (95% CI: 51.8% - 73.1%), while 52.5% (95% CI: 41.5% - 63.4%) of the HIV- infected HAART naive children also had dyslipidaemia. The risk factors associated with hypercholesterolaemia were: age at commencement of HAART less than 2 years (P<0.048; Adjusted Odds Ratio,OR, of 0.38, 95% CI:0.13-1.08) and PI- based HAART regimen (P<0.001; OR=0.18, 95% CI: 0.07-0.49), while age group greater than 5 years (P<0.02; OR=2.78 (95% CI:0.76-10.23), duration of HIV diagnosis greater than one year (P<0.02 fisher’s exact) and duration of treatment on HAART for more than one year (P<0.04; OR=2.32, 95% CI:0.14-38.99) were the risk factors associated with hypertriglyceridaemia among the HIV infected children on HAART. However, on multivariate analysis, PI-based HAART regimen was the only independent predictor of hypercholesterolaemia in the HAART treated children (OR=0.18, 95% CI: 0.07-0.49). Duration of diagnosis greater than 1 year was associated with hypercholesterolaemia in HAART naïve HIV-infected children (P=0.05). The most common dyslipidaemia in HIV-infected children on HAART was hypertriglyceridaemia followed by hypercholesterolaemia while low HDL-cholesterol was the commonest lipid abnormality in the HIV-infected HAART naive children.

Higher rates of rejection in HIV-infected kidney transplant recipients on ritonavir-boosted protease inhibitors: 3-year follow-up study.

Rejection rates in HIV-infected kidney transplant (KTx) recipients are higher than HIV-negative recipients. Immunosuppression and highly active antiretroviral therapy (HAART) protocols vary with potentially significant drug-drug interactions, likely influencing outcomes. This is an IRB-approved, single-center, retrospective study of adult HIV-infected KTx patients between 5/2009 and 12/2014 with 3-year follow-up, excluding antibody-depleting induction. A total of 42 patients were included; median age was 52years, 81% male, 50% African American, 29% Hispanic, 17% Caucasian. The most common renal failure etiology was hypertensive nephrosclerosis (50%) with 5.8 median years of pre-transplant dialysis. All patients received IL-2 receptor antagonist, were maintained on tacrolimus (76%) or cyclosporine (17%), and 40% received ritonavir-boosted PI-based HAART (rtv+) regimen. Patient and graft survival at 3years were 93% and 90%. At 1-, 2-, and 3-year time points, median serum creatinine was 1.49, 1.35, and 1.67; treated biopsy-proven rejection was 38%, 38%, and 40.5%; and 92% of episodes were acute rejection. At these time points, rejection rates were significantly higher with boosted PI HAART regimens compared to other HAART regimens, 59% vs 24% (P=0.029), 59% vs 24% (P=0.029), and 68% vs 24% (P=0.01). Despite higher rejection rates, HIV-infected KTx recipients have reasonable outcomes. Given significantly higher rejection rates using rtv+ regimens, alternative HAART regimens should be considered prior to transplantation.

Brief Report: Antimalarial Benefit of HIV Antiretroviral Therapy in Areas of Low to Moderate Malaria Transmission Intensity.

We previously used mathematical modeling to predict reduced malaria incidence in children with protease inhibitor (PI)-, compared with nonnucleoside reverse transcriptase inhibitor-, based highly active antiretroviral therapy (HAART), in moderate to high malaria transmission areas. These effects were accounted for, in part, by pharmacokinetic (PK) interactions between PIs and artemether-lumefantrine (AL). Because of potentially reduced malaria transmission reservoirs in HIV-infected children due to PI/AL PK interactions impacting non-HIV-infected children, we estimate the antimalarial benefit of PI-based HAART in all children, and in HIV-infected children only residing in low to moderate malaria transmission areas. A dynamic model of malaria transmission was developed to evaluate the PK interaction of PI-based HAART with the antimalarial, AL for preventing malaria. To evaluate the benefit of HIV PI-based HAART on malaria incidence, a malaria transmission model with varying degrees of HIV newborn prevalence was developed using recent pediatric clinical trial data in Lilongwe, Malawi. Comparing situations of low to high HIV newborn prevalence, and low to moderate malaria transmission intensities, our model predicts the combination of PI-based HAART with AL-treated malaria prevents 0.04-24.8 and 0.05-34.5 annual incidences of malaria overall per 1000 children, and saves 0.003-1.66 and 0.003-2.30 disability-adjusted life years per 1000 children, respectively. When incorporating seasonality, 0.01-7.3 and 0.01-5.9 annual incidences of malaria overall per 1000 children, and 0.0-0.5 and 0.001-0.41 disability-adjusted life years per 100 children, are prevented, respectively. In low to moderate malaria transmission intensity areas, PI-based HAART may reduce malaria events in children when AL is used.

Higher Rates of Rejection in HIV-infected Kidney Transplant Recipients on Ritonavir-Boosted Protease Inhibitors-Three-Year Follow Up

Background One-year rejection rates in HIV-infected kidney transplant recipients range from 15-40%, compared to overall rejection rates of 10% in HIV-negative patients. Protocols for immunosuppression and highly active antiretroviral therapy (HAART) vary substantially and there is potential for significant drug-drug interactions, specifically between ritonavir-boosted protease inhibitors (rtv+ PI) and calcineurin inhibitors. Methods This is an IRB-approved, single center, retrospective study of adult HIV-infected patients who underwent a kidney transplantation between 5/2009 to 12/2014 with a three-year follow up for each patient. Results Forty-two patients were identified with a median age of 52 (47, 57) years. Of these, 81% were male and 50% were African American, 29% were Hispanic, and 17% were Caucasian. The most common cause of renal failure was hypertensive nephrosclerosis (50%) followed by HIV-associated nephropathy (14%), and the median duration of pre-transplant dialysis was 5.8 (2.8, 8.7) years. All patients were induced with IL-2 receptor antagonist (IL-2 RA): 83% with basiliximab and 17% with daclizumab induction. Calcineurin inhibitor therapy included tacrolimus (76%), cyclosporine (17%), or transitions between these two (7%). 40% of patients received a rtv+ PI-based HAART regimen. At 30 days, patient and graft survival were 100%. Patient and graft survival were consistent at 93% and 90%, respectively, at years one, two, and three. Overall treated biopsy-proven rejection rates at one, two, and three years were 38%, 38%, and 41%, respectively, and 92% of these episodes were acute rejection. At one, two, and three years, rejection rates were significantly higher for recipients on rtv+PI compared to those on other HAART regimens as 59% vs 24% (p=0.029), 59% vs 24% (p=0.029), and 68% vs 24% (p=0.01), respectively. Conclusion HIV-infected kidney transplant recipients maintain excellent outcomes despite higher rates of acute rejection relative to HIV negative recipients. Given the significantly higher rates of rejection at one, two, and three years in the rtv + PI group, alternative HAART regimens should be considered prior to transplant when possible.

Aerobic Fitness and Moderate to Vigorous Physical Activity in Children and Adolescents Living with HIV.

To examine aerobic fitness, total moderate to vigorous physical activity (MVPA) and also patterns in terms of MVPA between children and adolescents with human immunodeficiency virus (HIV) and controls, and to determine whether differences, if any, are associated with HIV, sex and highly active antiretroviral therapy (HAART). A cross-sectional analysis was carried out with 130 children and adolescents, aged between 8 and 15 years, divided into two groups (HIV group= 65 patients, control group= 65 healthy participants). Total MVPA was measured by accelerometers and 5 and 10-min bouts were estimated. The peak oxygen uptake (peak VO2) was measured by breath-by-breath respiratory exchange in an incremental cycle ergometer test. HIV-positive participants had lower peak VO2 (39.2 ± 6.8 vs. 44.5 ± 9.1 ml.kg-1min-1), lower bouts of MVPA of 5-min (19.7 ± 16.6 vs. 26.6 ± 23.5) and 10-min (3.6 ± 3.9 vs. 5.8 ± 7.2), but similar total MVPA (49.5 ± 28.9 vs. 49.1 ± 30.6 min.day-1). HIV infection in untreated, nonprotease inhibitors (PI)- based HAART and PI-based HAART patients was associated with lower 8.5 (95%CI= 12.5-4.6), 7.1 (95%CI= 10.6-3.6) and 4.5 (95%CI= 7.0-2.0) ml.kg-1min-1 of peak VO2. Children and adolescents with HIV demonstrated lower aerobic fitness compared with the controls and the absence of HAART may increase peak VO2 impairment. Lower bouts of MVPA were also observed in HIV group despite the similar values of total MVPA of controls.

Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy

BackgroundHuman herpesvirus 8 (HHV-8) replication increases the risk of Kaposi sarcoma (KS). Highly-active antiretroviral therapy (HAART) reduces the incidence of KS, and regimens that contain protease inhibitors (PIs) may be particularly effective. ObjectiveTo determine whether PI-based HAART regimens may more effectively inhibit HHV-8 shedding compared to regimens without PIs. Study designProspective, observational study of 142 HIV-1 and HHV-8 co-infected men conducted in Seattle, Washington. Quantitative HHV-8 PCR testing was performed on daily swabs of the oropharynx, the primary site of HHV-8 replication. Associations between antiretroviral regimen and detection of HHV-8 DNA in swabs were evaluated using generalized estimating equations. ResultsHHV-8 DNA was detected in 3016 (26%) of 11,608 specimens collected. PI-based HAART was associated with a statistically significantly lower frequency of detection (RR 0.2; 95% CI 0.1–0.5) compared to ART-naïve persons, whereas HAART without a PI was not (RR 0.7; 95% CI 0.4–1.3). Compared to ART-naïve persons, there was also a trend toward lower quantities of HHV-8 detected during treatment with HAART regimens that contained a PI. These associations between PIs and measures of HHV-8 shedding could not be attributed to use of nelfinavir, which inhibits HHV-8 replication in vitro, and were independent of CD4 count and HIV plasma viral load (VL). ConclusionsHAART regimens that contain PIs appear to decrease HHV-8 shedding compared to NNRTIs. Further study of PI-based HAART is warranted to determine the optimal regimens for prevention and treatment of KS.

Protease Inhibitor Vs. Non-Protease Inhibitor Based Antiretroviral Therapy In HIV-Infected Patients With Hodgkin and Non-Hodgkin Lymphoma Receiving Chemotherapy

▪HIV-infected individuals are at an increased risk of developing AIDS-defining cancers like high-grade B-cell non-Hodgkin lymphoma (NHL). Hodgkin lymphoma (HL), although not an AIDS-defining cancer, also occurs at increased frequency in HIV-infected patients. One of the main challenges that face clinicians is the high likelihood of Highly Active Antiretroviral Therapy (HAART) and chemotherapy drug-drug interactions. Antiretroviral agents that inhibit the metabolism of chemotherapy drugs may result in increasing the risk of adverse effects, which in turn could lead to life-threatening toxicities and treatment delays. On the other hand, antiretroviral agents that induce the metabolism of chemotherapy drugs may reduce their efficacy, and hence compromise treatment outcomes. Therefore, the choice of appropriate HAART regimen is essential when treating HIV-associated lymphomas.The aim of our study was to compare toxicities, response rates and survival outcomes in patients with HIV-associated lymphoma treated with chemotherapy according to whether patients received protease inhibitor (PI) or non-PI based HAART.This was a retrospective study, which included HIV-infected patients who were on HAART and treated with chemotherapy for NHL or HL from January 1st 2003 to December 31st2010 at a single institution. Patients were identified from the Haematology and Immunology departmental databases. All patients had biopsy proven lymphoma and were HIV positive at lymphoma diagnosis. We compared differences in adverse effects between patients on PI and non-PI based HAART. Univariate and multivariate logistic regression analyses were used to test for factors associated with grade 3-4 toxicities. Differences in response rates and overall survival (OS) between patients on PI vs. those on non-PI based HAART were also investigated.A total of 53 patients were included, n=37 with NHL and n=16 with HL. Of the 53 patients, 47% and 53% were on PI and non-PI based HAART, respectively. Median baseline CD4 cell count value for all 53 patients was 273 (range 14-970) cells/μL. Baseline HIV viral load (VL) was undetectable (<50 copies/mL) in 15 (28%) of 53 patients. By multivariate analysis, the use of PI-based cART was significantly associated with increased odds ratio (OR) of developing grade 3-4 neurotoxicity (OR= 11.42, 95% CI 1.7-76.49, p-value=0.012) and grade 3-4 infections (OR=14.08, 95% CI 2.13-93.07, p-value=0.006). By univariate analysis, the use of PI-based cART was significantly associated with decreased OR of completion of stage appropriate chemotherapy (OR=0.23, 95% CI 1.1-19.07, p-value=0.023). The complete remission (CR) or unconfirmed complete remission (CRu) rate at the end of treatment for 51 evaluable patients was 86%. The OS rate for all 53 patients was 77%, with a median OS of 53 (range, 3-121) months. There were no statistically significant differences in response rates or OS between patients receiving PI-based HAART and those receiving non-PI based HAART.This study demonstrated that PI-based HAART was significantly associated with more treatment related toxicities compared to non-PI based HAART in patients undergoing chemotherapy for HIV-associated lymphoma. However, there were no significant differences in survival outcomes or response rates between the two groups. If appropriate, non-PI based HAART should be considered during chemotherapy for HIV-associated lymphoma in order to minimize treatment-related toxicities. Disclosures:No relevant conflicts of interest to declare.

Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor–Based HAART During Pregnancy

(See the editorial commentary by Kourtis, on pages 493–4.) Background. Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. Methods. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm3 were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. Results. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26–3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. Conclusions. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.

Increased Risk of Preterm Delivery Among HIV-Infected Women Randomized to Protease Versus Nucleoside Reverse Transcriptase Inhibitor-Based HAART During Pregnancy

Protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) use in pregnancy has been associated with preterm deliveries in some observational studies. HIV-infected, HAART-naive pregnant women with CD4+ counts ≥200 cells/mm(3) were randomized between 26 and 34 weeks gestation to lopinavir/ritonavir/zidovudine/lamivudine (PI group) or abacavir/zidovudine/lamivudine (NRTI group) in a clinical trial to prevent mother-to-child HIV transmission. Risk factors for preterm delivery (<37 weeks) and differences by randomization arm were evaluated for live infants by logistic regression. Preterm delivery rates were higher among 267 women in the PI group than 263 women in the NRTI group (21.4% vs 11.8%, P = .003). PI-based HAART was the most significant risk factor for preterm delivery [odds ratio = 2.03, 95% confidence interval 1.26-3.27, P = .004]. Mean change in maternal body mass index (BMI) 1 month after HAART initiation was lower in the PI group (P < .001); however, this was not significantly associated with preterm delivery. Neither infant hospitalizations nor mortality through 6 months of life differed by maternal regimen. PI-based HAART was associated with increased preterm delivery but not increased infant hospitalizations or mortality in a clinical trial setting. The association between PI use and lower increase in BMI in late pregnancy warrants further study.

Cost-Efficacy Analysis of the MONET Trial Using UK Antiretroviral Drug Prices

In virologically suppressed patients, switching to darunavir/ritonavir (DRV/r) monotherapy maintains HIV RNA suppression, and could also lower treatment costs. The purpose of this analysis was to calculate the potential cost savings from the use of DRV/r monotherapy in the UK. In the MONET trial, 256 patients with HIV RNA < 50 copies/mL on current highly active antiretroviral therapy (HAART) for over 24 weeks (non-nucleoside reverse-transcriptase inhibitor [NNRTI] based [43%] or protease inhibitor [PI] based [57%]), switched to DRV/r 800/100 mg once daily, either as monotherapy (n = 127) or with two NRTIs (n = 129). The UK costs per patient with HIV RNA < 50 copies/mL at week 48 (responders) were calculated using a 'switch included' analysis to account for additional antiretrovirals taken after initial treatment failure. By this analysis, efficacy was 93.5% versus 95.1% in the DRV/r monotherapy and triple therapy arms, respectively. British National Formulary 2009 values were used. Before the trial, the mean annual cost of antiretrovirals was £6906 for patients receiving NNRTI-based HAART, and £8348 for patients receiving PI-based HAART. During the MONET trial, the mean annual per-patient cost of antiretrovirals was £8642 in the triple therapy arm, of which 55% was from NRTIs and 45% from PIs. The mean per-patient cost in the monotherapy arm was £4126, a saving of 52% versus triple therapy. The mean cost per responder was £9085 in the triple therapy arm versus £4413 in the DRV/r monotherapy arm. Based on the MONET results, the lower cost of DRV/r monotherapy versus triple therapy in the UK would allow more patients to be treated for fixed budgets, while maintaining HIV RNA suppression at < 50 copies/mL. If all patients meeting the inclusion criteria of the MONET trial in the UK were switched to DRV/r monotherapy, there is the potential to save up to £60 million in antiretroviral drug costs from the UK NHS budget.

Previous Antiretroviral Therapy for Prevention of Mother-to-Child Transmission of HIV Does not Hamper the Initial Response to PI-Based Multitherapy During Subsequent Pregnancy

Few data are available on the possible long-term negative effects of a short exposure to antiretroviral therapy (ART) for prevention of mother-to-child transmission (PMTCT). To determine whether ART for PMTCT, discontinued after delivery, affects the virological response to highly active antiretroviral therapy (HAART) administered during subsequent pregnancies. All current pregnancies of HIV-1-infected women enrolled in the French Perinatal Cohort (ANRS CO-01 EPF) between 2005 and 2009 and not receiving ART at the time of conception were eligible. We studied the association between history of exposure to ART during a previous pregnancy and detectable viral load (VL) under multitherapy at current delivery (VL ≥ 50 copies/mL). Among 1116 eligible women, 869 were ART naive and 247 had received PMTCT during a previous pregnancy. Previous ART was protease inhibitor (PI)-based HAART in 48%, non-PI-based HAART in 4%, nucleoside reverse transcriptase inhibitor bitherapy in 19% and zidovudine monotherapy in 29% of the women. At current pregnancy, women with or without prior exposure to ART had similar CD4 cell counts and VL before ART initiation. PI-based HAART was initiated in 90% of the women. VL was undetectable (<50 copies/mL) at delivery in 65% of previously ART-naive women, 72% of women previously exposed to HAART, 62% previously exposed to bitherapy, and 67% previously exposed to monotherapy for prophylaxis (P = 0.42). Detectable VL was not associated with previous exposure in multivariate analysis (adjusted OR for previous versus no previous exposure to ART: 0.92; 0.95% confidence interval: 0.59 to 1.44). Efficacy of PI-based combinations is not decreased in women previously exposed to various regimens of antiretroviral PMTCT.

Predicting Direct Costs of HIV Care During the First Year of Darunavir-Based Highly Active Antiretroviral Therapy Using CD4 Cell Counts

Given the association between CD4 cell counts and HIV-related morbidity/mortality, new antiretroviral therapies could potentially lower the direct costs of HIV care by raising CD4 cell counts. To predict the effects of the ritonavir-boosted, HIV protease inhibitor (PI) darunavir on the direct costs of care, while accounting for CD4 cell counts, during the first year of therapy in highly treatment-experienced, HIV-infected adults in different healthcare settings. The mean annual per-patient cost of darunavir/ritonavir (DRV/r) and control PI-based highly active antiretroviral therapy (HAART) was calculated from the proportional use of antiretroviral agents in the DRV/r and control PI arms of the pooled POWER 1 and 2 trials, applying drug-acquisition costs for five healthcare settings. Non-antiretroviral-related costs by CD4 cell count, derived from non-interventional studies in the same settings, were applied to the POWER data (proportion of patients with CD4 cell counts in different strata at week 48) to estimate mean annual non-antiretroviral-related costs per patient in patients receiving DRV/r or control PI-based HAART during year 1. Across all settings, the mean annual per-patient cost of DRV/r-based treatment was 2-19% higher than that of control PI-based therapy during the first year of therapy. By raising CD4 cell counts, however, DRV/r-based regimens were predicted to lower mean annual non-antiretroviral-related costs by 16-38% compared with control PI-based therapy. When combined, the total annual per-patient cost of HIV care during the first year of therapy was estimated to be 7% lower in the DRV/r compared with the control PI arm using US data, 8% lower using Swedish data, budget neutral using UK and Belgian data and 5% higher using Italian data. Darunavir-based HAART may lower non-antiretroviral-related costs compared with control PI-based therapy in highly treatment-experienced, HIV-infected patients during the first year of therapy by improving patients' CD4 cell counts. These costs could partly/fully offset the increased acquisition cost of DRV/r in this patient population over the same period.

Costs to Achieve Undetectable HIV RNA with Darunavir-Containing Highly Active Antiretroviral Therapy in Highly Pretreated Patients

Very few studies have evaluated the cost of highly active antiretroviral therapy (HAART) per successful treatment in HIV-infected patients. To evaluate the cost of achieving undetectable plasma HIV-RNA levels in highly treatment-experienced, HIV-1-infected adults receiving darunavir/ritonavir (DRV/r 600 mg/100 mg twice a day) or control protease inhibitor (PI)-based HAART. The mean annual per-patient cost of DRV/r and control PI-based HAART was determined from the proportional use of antiretroviral agents in the DRV/r and control PI arms of the pooled POWER 1 and 2 trials, applying drug acquisition costs for 13 healthcare settings. The mean annual cost per patient of achieving undetectable plasma HIV-RNA levels (<50 copies/mL) was calculated by dividing the cost of each treatment by the proportion of patients with undetectable plasma HIV-RNA levels after 48 weeks in the DRV/r (45%) and control PI (10%) arms of the POWER trials. Whereas absolute costs of treatment were 1-19% higher with DRV/r versus control PI-based HAART depending on the healthcare setting, the mean annual per-patient cost of achieving undetectable plasma HIV-RNA levels was 73-78% lower. These cost savings were maintained in the sensitivity analyses, adjusting for control PI and enfuvirtide use, and the number of active drugs in the background regimen. The incremental annual cost per additional patient achieving undetectable plasma HIV-RNA levels with DRV/r versus control PI-based HAART in POWER 1 and 2 (£4148) compared favourably with that determined for enfuvirtide (£137, 740; TORO trials) and tipranavir/ritonavir (£32,176; RESIST) versus control therapy. DRV/r-based HAART provided consistent reductions in the cost of achieving undetectable plasma HIV-RNA levels compared with control PI-based therapy in highly treatment-experienced patients across various healthcare settings. The incremental cost per additional patient achieving undetectable plasma HIV-RNA levels with DRV/r versus control PI-based HAART was also lower than that calculated for other treatment options in this population. These results suggest that DRV/r is an economically viable option for highly treatment-experienced patients.

Factors associated with HIV RNA levels in pregnant women on non-suppressive highly active antiretroviral therapy at conception

Little is known about pregnancy patterns and levels of HIV RNA in HIV-infected women conceiving on highly active antiretroviral therapy (HAART) with non-suppressed viral load (VL), nor about their therapeutic management. Linear mixed models were fitted to study changes in VL and potential associated factors including HAART type or duration and immune status among 127 women receiving HAART at conception with detectable VL enrolled in the prospective European Collaborative Study. Median duration of HAART at conception was 10 months. A total of 78 (61%) women conceived while on protease inhibitor (PI)-based HAART. Overall, 72 (57%) women remained on the same HAART regimen throughout pregnancy, 24 (19%) switched regimens and 31 (24%) interrupted HAART during early pregnancy. The intention-to-treat model indicated constant VL up to 10 gestational weeks; thereafter, levels decreased significantly, by 0.06 log(10) copies/ml weekly until delivery. At baseline, immune status was significantly associated with HIV RNA levels. Excluding those with treatment interruption, there was no significant difference in VL slope between women who did and did not modify their HAART regimens (P=0.14); women conceiving on non-nucleoside reverse transcriptase inhibitor-based HAART had consistently lower VL throughout pregnancy than those on PI-based HAART (P=0.02). Most (64/103, 62%) women had detectable VL within 4 weeks of delivery (median 2.40 log(10) copies/ml). The overall mother-to-child transmission rate was 1.72% (95% confidence interval 0.21-6.1). Practices regarding management of women conceiving on HAART with detectable VL vary in Western Europe. The existence of this group of pregnant women highlights the need for improved monitoring of and support for treated women before they become pregnant, as well as during pregnancy.

Impact of PI and NNRTI HAART‐based therapy on oral lesions of Brazilian HIV‐infected patients

The incidence of oral lesions related to human immunodeficiency virus (HIV) infection have been investigated after treatment with highly active antiretroviral therapy (HAART) including protease inhibitors (PI) but no data are available on the effect of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy on incidence of acquired immunodeficiency syndrome (AIDS) oral manifestations or impact of HAART on oral manifestations of HIV infection in Brazil. The aim of this study was to describe the effects of anti-HIV therapy on the incidence of oral lesions during 17 years of AIDS epidemics in a Brazilian population. From 1989 to 2006, we collected data from 1595 consecutive HIV patients at the Special Care Dentistry Center, São Paulo, Brazil. We compared the effect of PI- and NNRTI-based antiretroviral therapy (ARVT) on the annual incidence of Kaposi sarcoma (KS), oral candidiasis (OC) and hairy leukoplakia (HL). The chi-squared test was used to test the association between oral lesions and therapeutic regimen (P < 0.05). None of patients on ARVT presented with KS. Patients who used (nucleoside reverse transcriptase inhibitors) NRTI + PI were 0.9 times as likely to present with HL as those who used NRTI + NNRTI. This finding, however, was not statistically significant (P = 0.5). The relative risk for OC was 0.8 in patients with PI-based HAART. The increased risk among those on PIs was statistically significant (P = 0.004). The superiority of NNRTI regimens in decreasing OC incidence is consistent with current therapeutic guidelines which recommend NNRTI-based therapy as the treatment of choice for initial ARVT.

Long-Term Evaluation of Glucose Homeostasis in a Cohort of HAART-Treated HIV-Infected Children

Few and mainly cross-sectional studies of glucose homeostasis are available in HIV-infected children treated with highly active antiretroviral therapy (HAART). The aim of the present study was to describe a 4-year course of glucose homeostasis in a cohort of HAART-treated children and adolescents, using glucose and insulin levels during an oral glucose tolerance test (OGTT) as outcome measures. In addition, we investigated possible risk factors, both related and unrelated to antiretroviral therapy, associated with insulin resistance. We assessed glucose metabolism yearly for 4 consecutive years in 37 HIV-infected children receiving a protease inhibitor (PI)-based HAART regimen containing lamivudine/stavudine plus indinavir or ritonavir or nelfinavir or a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen containing lamivudine/tenofovir/efavirenz. Generalized estimating equations were used to evaluate the relationship between the loge-transformed area under the serum concentration-time curve (AUC) of insulin during OGTT and antiretroviral therapy, controlling for time, sex, baseline age, puberty, body mass index and CD4+ T cells percentage. Ritonavir-unboosted PI-based HAART regimens were administered to most children at baseline; however, their use decreased during follow-up in favour of an NNRTI-based regimen. The nelfinavir/lamivudine/stavudine (regression coefficient=-0.69, p<0.05) and efavirenz/lamivudine/tenofovir (regression coefficient=-0.93, p<0.05) regimens, but not the ritonavir/lamivudine/stavudine regimen, were negatively associated with loge-transformed insulin AUC compared with indinavir/lamivudine/stavudine. Puberty was positively associated with loge-transformed insulin AUC. This 4-year prospective study of HAART-treated HIV-infected children shows that: (i) the nelfinavir/lamivudine/stavudine and the efavirenz/lamivudine/tenofovir regimens but not the ritonavir/lamivudine/stavudine regimen were associated with higher insulin sensivity, i.e. lower insulin AUC, compared with indinavir/lamivudine/stavudine; (ii) the treatment switched substantially in favour of NNRTI from the third year on and this change was associated with an improvement in insulin sensitivity compared with the previous HAART-based regimens; and (iii) puberty is a primary determinant of insulin sensitivity.

British HIV Association and Children's HIV Association guidelines for the management of HIV infection in pregnant women 2008

Top of page Abstract Introduction 1.0 Summary of recommendations 2.0 Scenarios: interventions to reduce mother-to child transmission of HIV 3.0 Background: UK prevalence of HIV in pregnancy and risk of transmission 4.0 Antenatal HIV testing 5.0 Preconception and fertility management in men and women infected with HIV 6.0 Sexual health of HIV-positive pregnant women 7.0 Psychosocial issues 8.0 Viral load and resistance 9.0 Management of HIV-related complications in pregnancy 10.0 Antiretroviral therapy in pregnancy: efficacy 11.0 Antiretroviral therapy in pregnancy: toxicity 12.0 Antiretroviral therapy and pregnancy: pharmacokinetics 13.0 Obstetric management of pregnancy and delivery 14.0 Pregnancy in women with HIV-2 infection 15.0 HIV and hepatitis B and C coinfections 16.0 Management of infants born to HIV-infected mothers 17.0 Infant feeding and HIV transmission during breastfeeding References Appendix

Analyses of HIV-1 Drug-Resistance Profiles Among Infected Adolescents Experiencing Delayed Antiretroviral Treatment Switch After Initial Nonsuppressive Highly Active Antiretroviral Therapy

Treatment failure and drug resistance create obstacles to long-term management of HIV-1 infection. Nearly 60% of infected persons fail their first highly active antiretroviral therapy (HAART) regimen, partially because of nonadherence, requiring a switch to a second regimen to prevent drug resistance. Among HIV-infected youth, a group with rising infection rates, treatment switch is often delayed; virologic and immunologic consequences of this delay are unknown. We conducted a retrospective, longitudinal study of drug resistance outcomes of initial HAART in U.S. youth enrolled between 1999-2001 in a multicenter, observational study and experiencing delayed switch in their first nonsuppressive treatment regimen for up to 3 years. HIV-1 genotyping was performed on plasma samples collected longitudinally, and changes in drug resistance mutations, CD4+ T cell numbers and viral replication capacity were assessed. Forty-four percent (n = 18) of youth in the parent study experiencing virologic nonsuppression were maintained on their initial HAART regimen for a median of 144 weeks. Drug resistance was detected in 61% (11/18) of subjects during the study. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (8/10) drug resistance mutations than those on protease-inhibitor (PI) regimens (2/7) (p = 0.058). Subjects developing NNRTI-resistance (NNRTI-R), showed a trend toward lower CD4+ T cell gains (median: -6 cells/mm(3) per year) than those without detectable NNRTI-R (median: +149 cells/mm(3) per year) (p = 0.16). HIV-1-infected youth maintained on initial nonsuppressive NNRTI-based HAART regimens are more likely to develop drug-resistant viremia than with PI-based HAART. This finding may have implications for initial treatment regimens and transmission risk in HIV-infected youth, a group with rising infection rates.

Increased Resilience to the Development of Drug Resistance with Modern Boosted Protease Inhibitor–Based Highly Active Antiretroviral Therapy

We explore the temporal and regimen-specific changes of HIV-1 drug resistance in a large cohort of antiretroviral-naive individuals starting highly active antiretroviral therapy (HAART). Individuals (n = 2350) initiating first HAART between August 1996 and November 2004 were followed until November 2005 (median follow-up, 4.8 years; n = 6066 tests). A logistic regression model was used to predict the probability of the emergence of resistance, adjusting for baseline predictors. The cohort included 991 individuals initiating nonboosted protease inhibitor (PI)-based regimens, 475 initiating ritonavir-boosted PI-based regimens, and 884 initiating nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens. There was no difference in the development of resistance between nonboosted PI-based regimens (reference group) and NNRTI-based HAART regimens (odds ratio [OR], 1.09 [95% confidence interval {CI}, 0.84-1.42]), but there were greatly reduced odds for boosted PI-based regimens (OR, 0.42 [95% CI, 0.28-0.62]). Individuals initiating HAART more recently (2002-2004) were at a reduced risk of resistance, compared with those who started HAART between 1996 and 1998 (OR, 0.43 [95% CI, 0.30-0.61]). Individuals initiating first HAART with a boosted PI-based regimen had a 2.4-fold lower OR for developing HIV drug resistance than did those starting nonboosted PI-based or NNRTI-based HAART, at all adherence levels. The data demonstrate marked temporal improvement in the likelihood of the development of drug resistance for those initiating more recent HAART regimens.