Switching to Dolutegravir/Lamivudine Two-Drug Regimen: Durability and Virologic Outcomes by Age, Sex, and Race in Routine US Clinical Care.

Purpose: Two-drug regimens (2DR) may address drug-drug interactions and toxicity concerns. Dolutegravir/lamivudine (DTG/3TC) 2DR was approved in the US for both treatment-naïve and treatment-experienced individuals with a viral load <50 copies/mL. This study describes real-world DTG/3TC 2DR treatment outcomes among treatment-experienced individuals, stratified by age, sex, and race. Methods: From the OPERA® cohort, people with HIV with a viral load <50 copies/mL who switched from a commonly used three-drug regimen to DTG/3TC 2DR as per the label between April 8, 2019 and April 30, 2021 were included. Incidence rates (Poisson regression) for loss of virologic control (first viral load ≥50 copies/mL), confirmed virologic failure (2 viral loads ≥200 copies/mL or discontinuation after 1 viral load ≥200 copies/mL), and DTG/3TC 2DR discontinuation were estimated overall and stratified by age, sex, and race. Results: The 787 individuals included were followed for a median of 13.6 months (IQR: 8.2, 22.3). Confirmed virologic failure occurred in ≤5 individuals. Loss of virologic control occurred at a rate of 14.0 per 100 person-years (95% CI: 11.7, 16.8). DTG/3TC 2DR discontinuation occurred at a rate of 17.5 per 100 person-years (95% CI: 15.0, 20.3); 4% discontinued for treatment-related reasons (viremia, adverse diagnosis, side effect, lab abnormality). For all outcomes, incidence rates were comparable across strata of age, sex, and race. Conclusion: This descriptive study demonstrates that DTG/3TC 2DR is an effective and well-tolerated treatment option for people with HIV with a viral load <50 copies/mL at switch, regardless of their age, sex, or race.

Heavily treatment-experienced people living with HIV in the OPERA® cohort: population characteristics and clinical outcomes.

BACKGROUND: Multi-class resistance, intolerance, and drug-drug interactions can result in unique antiretroviral (ART) combinations for heavily treatment-experienced (HTE) people living with HIV (PLWH). We aimed to compare clinical outcomes between HTE and non-HTE PLWH. METHODS: Eligible ART-experienced PLWH in care in the OPERA® Cohort were identified in a cross-sectional manner on December 31, 2016 and observed from the date of initiation of the ART regimen taken on December 31, 2016 until loss to follow up, death, study end (December 31, 2018), or becoming HTE (non-HTE group only). In the absence of resistance data, HTE was defined based on the ART regimens used (i.e., exposed to ≥ 3 core agent classes or regimen suggestive of HTE). Time to virologic undetectability, failure, and immunologic preservation were assessed using Kaplan-Meier methods; cumulative probabilities were compared between the two groups. Regimen changes, incident morbidities, and death were described. RESULTS: A total of 24,183 PLWH (2277 HTE PLWH, 21,906 non-HTE) were followed for a median of 28 months (IQR 21, 38). Viremic HTE PLWH (viral load [VL] ≥ 50 copies/mL) were less likely to achieve undetectability (VL < 50 copies/mL; 24-month cumulative probability: 80% [95% Confidence Interval 77-82]) than their non-HTE counterparts (85% [84-86]). No difference was observed in the probability of maintaining VLs < 200 copies/mL over the first 48 months after achieving suppression (< 50 copies/mL). HTE PLWH were less likely than non-HTE PLWH to maintain CD4 cell counts ≥ 200 cells/µL (24-month cumulative probability: 95% HTE [91-93]; 97% non-HTE [97-97]), and more likely to change regimens (45% HTE; 41% non-HTE). Incident non-AIDS defining event (ADE) morbidities were common in both populations, though more likely among HTE PLWH (45%) than non-HTE PLWH (35%). Incident ADE morbidities and deaths were uncommon among HTE (ADEs 5%; deaths 2%) and non-HTE (ADEs 2%; deaths 1%) PLWH. CONCLUSIONS: HTE PLWH were at greater risk of unfavorable treatment outcomes than non-HTE PLWH, suggesting additional therapeutic options are needed for this vulnerable population.

Diet in a global cohort of adults with HIV at low-to-moderate traditional cardiovascular disease risk.

OBJECTIVE: To characterize diet quality across a global cohort of people with HIV (PWH). DESIGN: Cross-sectional analysis. METHODS: Leveraging REPRIEVE data from baseline across five Global Burden of Disease (GBD) regions, we analyzed participant responses to the Rapid Eating Assessment for Participants questionnaire. An overall diet quality score and scores for specific diet components were generated. Higher scores indicate better diet quality. RESULTS: Among 7736 participants (median age 50 years, 30% women, median BMI 25.8 kg/m 2 ) overall diet quality score (max score 30) was optimal in 13% of participants and good, suboptimal or poor in 45%, 38%, and 4% of participants, respectively; saturated fat score (max score 18) was good, suboptimal, or poor in 38%, 40%, or 7% of participants, respectively. Diet quality scores differed across GBD region with the highest scores reported in the South Asia region [median 23 (21-25)] and lowest in the sub-Saharan Africa region [median 15 (12-18)]; 61% of participants in the South Asia region reported optimal diet quality compared with only 6% in the sub-Saharan Africa region. Higher atherosclerotic cardiovascular risk scores were seen with worsening diet quality. CONCLUSION: Among PWH eligible for primary CVD prevention, diet quality was suboptimal or poor for almost half of participants, and there were substantial variations in diet quality reported by GBD region. TRIAL REGISTRATION: NCT02344290.

Placental pathology and fetal demise at 35 weeks of gestation in a woman with SARS-CoV-2 infection: A case report.

The consequences of SARS-CoV-2 infection in pregnancy have not been well defined. However, there have been a number of reports of poor maternal and fetal outcomes worldwide. This report presents a case of stillbirth with associated placental pathology during week 35 in an otherwise healthy pregnant woman with SARS-CoV-2 infection. Placental findings in this case showed patchy acute chorionitis and diffuse infarction/villous necrosis of the placental parenchyma resulting in extensive vascular malperfusion. Fetal autopsy was most significant for placental findings and no congenital malformations were discovered. The findings in this case are consistent with reports in the literature of pathological placental changes associated with COVID-19. This case of fetal demise in a woman with confirmed SARS-CoV-2 infection without any other medical or obstetric disorders and no alternate cause suggests that fetal death can be an outcome of COVID-19 during pregnancy. This outcome was supported by the histopathological findings in the placenta. Continued research is imperative to confirm the findings in this case and multiple similar cases. Additionally, increased screening and collection of COVID-19 data specific to pregnant women and their fetuses and infants is needed to increase knowledge, support research efforts, and create guidelines for clinical practice that will prevent potential negative outcomes and loss of life.

Two-drug antiretroviral regimens: an assessment of virologic response and durability among treatment-experienced persons living with HIV in the OPERA® Observational Database.

INTRODUCTION: Two-drug regimens (2-DR) have the potential to be a viable solution to the challenges of treatment complexity, cost, adverse effects and contraindications. We sought to describe the real-world use and effectiveness of 2-DR among persons living with HIV (PLHIV) in the United States. METHODS: We analysed data for 10,190 treatment-experienced patients from the OPERA® Observational Database initiating a new 2-DR or three-drug regimen (3-DR) between 1 January 2010 and 30 June 2016. Multivariate Cox Proportional Hazards models were used to estimate the association among 2-DR or 3-DR initiation and virologic suppression (viral load (VL) <50 copies/mL), virologic failure (2 VLs > 200 copies/mL or 1 VL > 200 copies/mL + discontinuation) or regimen discontinuation. RESULTS: Patients initiating a 2-DR (n = 1337, 13%) were older, and more likely to have a lower CD4 count, a history of AIDS and comorbid conditions than patients initiating a 3-DR. There was no difference between groups in time to virologic suppression (aHR: 1.00 (95% CI: 0.88, 1.13)) among viraemic patients (baseline VL ≥ 50 copies/mL, n = 4180), or time to virologic failure (aHR: 1.15 (95% CI: 0.90, 1.48)) among virologically stable patients (baseline VL < 50 copies/mL, n = 6010). However, time to discontinuation was shorter following 2-DR than 3-DR initiation (aHR: 1.51 (95% CI: 1.41, 1.61)). CONCLUSIONS: In this large cohort of treatment-experienced patients, 2-DR prescriptions were common and more frequent among patients with significant comorbidity. Virologic response was similar, but duration of use was shorter with a 2-DR than a 3-DR, suggesting that 2-DRs may be a virologically effective treatment strategy for treatment-experienced PLHIV with existing comorbidities.

Virologic Effectiveness of Abacavir/Lamivudine with Darunavir/Ritonavir Versus Other Protease Inhibitors in Treatment-Experienced HIV-Infected Patients in Clinical Practice.

BACKGROUND AND OBJECTIVES: The standard of care for HIV treatment is a three-drug regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor (PI) or an integrase strand transfer inhibitor. Darunavir boosted with ritonavir (DRV/r) is the only preferred PI in the US Department of Health and Human Services (DHHS) HIV treatment guidelines for antiretroviral-naïve patients, recommended in combination with tenofovir/emtricitabine for antiretroviral-naïve patients. For treatment-experienced and certain antiretroviral-naïve patients, abacavir and lamivudine (ABC/3TC) in combination with DRV/r is considered an effective and tolerable alternative, despite limited research on the effectiveness of this particular combination. This study evaluated virologic outcomes in treatment-experienced patients taking ABC/3TC + DRV/r compared to treatment-experienced patients taking ABC/3TC with any other PI. METHODS: Treatment-experienced HIV-infected patients initiating their first regimen containing ABC/3TC in combination with any PI in the year 2005 or later were selected from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA®) cohort, a prospective observational cohort reflecting routine medical care. Viral load measurements taken during follow-up were compared between patients taking ABC/3TC + DRV/r and ABC/3TC with a PI other than DRV/r. Logistic regression models were fit to assess the association between regimen exposure and viral load suppression. RESULTS: A total of 151 patients initiating ABC/3TC + DRV/r and 525 patients initiating ABC/3TC + a non-darunavir PI were included. Patients in both treatment groups had comparable clinical indicators (viral load, CD4) at baseline. A regimen of ABC/3TC + DRV/r was more likely to be prescribed in the later years of the study period, leading to a shorter median follow-up in the DRV/r treatment group (as-treated analysis: 14 vs. 17 months, p = 0.04; intent-to-treat analysis: 33 vs. 68 months, p < 0.001). Multivariable logistic regression models accounting for year of regimen initiation, among other factors, indicated no statistically significant differences in achieving an undetectable viral load for patients taking DRV/r with ABC/3TC compared with other PIs, both in the as-treated (odds ratio [95 % confidence interval]: 0.84 [0.53-1.34]) and intent-to-treat analyses (0.82 [0.48-1.40]). Patients in both treatment groups also showed similar reductions in viral load (median darunavir vs. non-darunavir: -23.0 vs. -23.0 copies/mL; p = 0.72) and gains in CD4 T cell counts (median darunavir vs. non-darunavir: 106 vs. 108 cells/mm3; p = 0.59] while being treated with the regimen of interest. CONCLUSIONS: Patients receiving ABC/3TC + DRV/r appear to experience similar treatment benefit to patients taking ABC/3TC with other PIs in terms of achieving suppression, as well as absolute reductions in viral load and CD4 lymphocyte gains.

Injectable poly-L-lactic acid for human immunodeficiency virus-associated facial lipoatrophy: cumulative year 2 interim analysis of an open-label study (FACES).

BACKGROUND: Studies of injectable poly-L-lactic acid (PLLA) in human immunodeficiency virus (HIV)-associated facial lipoatrophy have predominantly included male Caucasians. OBJECTIVE: To report cumulative year 2 interim study results examining the safety and efficacy of injectable PLLA in subjects with HIV categorized according to Fitzpatrick skin type and sex. MATERIALS AND METHODS: This is an ongoing open-label, multicenter, 5-year study of 290 treated subjects. After correction with injectable PLLA, subjects are being followed annually. Primary end points include incidence and severity of treatment-emergent adverse events (TEAEs). Secondary end points include mean change from baseline of James scale severity grade and treatment satisfaction. RESULTS: At 2 years, TEAE incidences were: potentially related to study product (n = 53,18.3%) or injection procedure (n = 71, 24.5%), injection-site nodules (n = 24, 8.3%) and papules (n = 25, 8.6%). No hypertrophic scars, keloids, or product-related serious TEAEs were reported. Mean improvement in James scale grade for all groups was 1.4 (p < .001), and 89.4% of subjects and 95.5% of physicians rated treatment satisfaction as very good or excellent. CONCLUSION: At 2 years, injectable PLLA is a safe and effective long-term treatment for HIV-associated facial lipoatrophy regardless of Fitzpatrick skin type; confirmation of these results will be needed at the completion of this 5-year study.

Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the brain, caused by reactivation of the polyomavirus JC (JCV). PML has classically been described in individuals with profound cellular immunosuppression such as patients with AIDS, haematological malignancies, organ transplant recipients or those treated with immunosuppressive or immunomodulatory medications for autoimmune diseases. METHODS AND CASE REPORTS: The authors describe five HIV seronegative patients with minimal or occult immunosuppression who developed PML including two patients with alcoholic cirrhosis, one with untreated dermatomyositis and two with idiopathic CD4(+) T cell lymphocytopenia. The authors performed a review of the literature to find similar cases. RESULTS: The authors found an additional 33 cases in the literature. Of a total of 38 cases, seven (18.4%) had hepatic cirrhosis, five (13.2%) had renal failure, including one with concomitant hepatic cirrhosis, two (5.2%) were pregnant women, two (5.2%) had concomitant dementia, one (2.6%) had dermatomyositis, and 22 (57.9%) had no specific underlying diagnosis. Among these 22, five (22.7%) had low CD4(+) T cell counts (0.080-0.294x10(9)/l) and were diagnosed as having idiopathic CD4(+) lymphocytopenia, and one had a borderline CD4(+) T cell count of 0.308x10(9)/l. The outcome was fatal in 27/38 (71.1%) cases within 1.5-120 months (median 8 months) from onset of symptoms, and 3/4 cases who harboured JCV-specific T cells in their peripheral blood had inactive disease with stable neurological deficits after 6-26 months of follow-up. DISCUSSION: These results indicate that PML can occur in patients with minimal or occult immunosuppression, and one can revisit the generally accepted notion that profound cellular immunosuppression is a prerequisite for the development of PML.

Seven-year follow-up on lopinavir/ ritonavir monotherapy.

Previous studies of lopinavir/ritonavir (LPV/r) monotherapy have shown that over 70% of patients achieved HIV RNA levels <500 copies/mL over a follow-up period of 48 to 96 weeks, but the long-term durability is undetermined. Herein, the authors report 2 patients that started LPV/r monotherapy after virologic failure on an NNRTIbased regimen and have been successfully treated for greater than 7 years. Both patients demonstrated long-term control of viral replication over the course of treatment, although the first patient had 3 viral load blips and the second had 1 blip under 400 copies/mL. Both patients had increases in CD4+ lymphocyte counts. The first patient from 96 cells/microL to 378 cells/microL and the second patient from 71 cells/microL to 411 cells/microL. To the authors knowledge, these 2 cases represent the longest experience with LPV/r monotherapy and provide some measure of reassurance about the durability of LPV/r for control of HIV replication.

Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatment-experienced patients (BI Study 1182.51).

BACKGROUND: Given the limited treatment options for patients with high-level resistance, antiretroviral (ARV) regimens based on concomitant use of 2 ritonavir (RTV)-boosted protease inhibitors (PIs) were considered a therapeutic option. METHODS: Boehringer Ingelheim (BI) study 1182.51 examined the pharmacokinetic profile, safety, and efficacy of RTV-boosted tipranavir (TPV/r), alone and in combination with comparator PIs (CPIs) in 315 triple-class-experienced, HIV-infected patients. RESULTS: Two weeks after single PI therapy, the addition of TPV/r reduced plasma trough levels 52%, 80%, and 56% for lopinavir (LPV), saquinavir (SQV), and amprenavir (APV) recipients, respectively. After 2 weeks, a TPV/r-only regimen reduced HIV viral load (VL) by a median of 1.06 log(10) copies/mL. VL reductions at 2 weeks between single-boosted CPIs were difficult to compare, because the numbers of patients maintaining their previous failing PI after randomization were different. At week 4, patients initiating treatment with TPV-containing regimens sustained VL reduction (median decrease of 1.27 log(10) copies/mL). Patients adding TPV to regimens at week 2 achieved median reductions from a baseline of 1.19 log(10), 0.96 log(10), and 1.12 log(10) copies/mL at week 4 in dual-boosted LPV, SQV, and APV groups, respectively. At 24 weeks, VL reductions (median: -0.24 to -0.47 log(10) copies/mL) were comparable between treatment groups. CONCLUSIONS: The efficacy of a dual PI regimen depended on the presence of TPV, with additional recycled CPIs having limited activity, even in drug-resistant patient populations with plasma trough concentrations regarded as likely to be adequate in this study. No clear guidelines exist about ARV plasma trough concentrations in treatment-experienced patients, however.

Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients.

BACKGROUND: Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed. METHODS: TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a >or= 1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm. RESULTS: For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/mul; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved >or= 1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P

Efficacy and safety of three doses of tipranavir boosted with ritonavir in treatment-experienced HIV type-1 infected patients.

The efficacy, safety, and pharmacokinetics of three doses of tipranavir/ritonavir (TPV/r) in highly treatment-experienced human immunodeficiency virus (HIV)-1-infected patients with protease inhibitor (PI)-resistant isolates were evaluated. A 24-week multicenter, double-blind, randomized, dose-finding trial was conducted. All patients were three-drug class experienced and had taken at least two PI-based regimens. All had at least one primary PI mutation and had plasma HIV-RNA > 1000 copies/ml. Patients remained on their background non-PI antiretroviral medications for the first 14 days. After this 14-day period of functional TPV/r monotherapy, the background antiretroviral medications were optimized based on treatment history and the screening genotype. A total of 216 patients were randomized. All groups [TPV/r 500 mg/100 mg (n = 73), 500 mg/200 mg (n = 72), and 750 mg/200 mg (n = 71) twice daily] achieved an approximate 1 log10 reduction in the median HIV-RNA at week 2. A significant reduction was sustained through 24 weeks in the TPV/r 500 mg/200 mg and 750 mg/200 mg groups. The 500 mg/200 mg dose achieved optimal median TPV trough concentrations and lower interpatient variability. The most frequently reported adverse events (AEs) were diarrhea, nausea, vomiting, fatigue, and headache. The TPV/r 750 mg/200 mg group had the highest rate of grade 3 or 4 laboratory abnormalities and study discontinuations due to AEs. All doses of TPV/r tested in this study were associated with HIV-1 viral load reductions through 24 weeks. The 500 mg/200 mg dose achieved the best efficacy, safety, and pharmacokinetic profile in this highly treatment-experienced population and was selected for the pivotal phase 3 studies.

A pilot study of switch to lopinavir/ritonavir (LPV/r) monotherapy from nonnucleoside reverse transcriptase inhibitor-based therapy.

PURPOSE: This study evaluated the safety and efficacy of switching HIV-infected patients with stable viral suppression on nonnucleoside reverse transcriptase inhibitor/nucleoside reverse transcriptase inhibitor (NNRTI/NRTI) therapy to lopinavir/ritonavir (LPV/r) monotherapy. METHOD: Eligible patients discontinued NNRTI and started LPV/r. Two weeks later NRTIs were stopped and LPV/r monotherapy was continued. Patients were seen every 4 weeks throughout the 48-week study. RESULTS: Twelve of 18 (66%) participants met the primary endpoint with HIV RNA <75 copies/mL at week 48. Thirteen (72%) participants completed 48 weeks of LPV/r monotherapy, and 12 of 13 (92%) participants on treatment at week 48 had HIV RNA <75 copies/mL. Ten (55%) of 18 patients maintained HIV RNA <75 copies/mL at all time points. Two patients were withdrawn with virologic failure but demonstrated no evidence of virologic resistance. Three (17%) patients withdrew due to diarrhea, 2 with hyperglycemia at baseline developed diabetes mellitus, 7 (54%) required addition of or increase in lipid-lowering agents, but none had grade 3 or 4 hyperlipidemia. CONCLUSION: Results from this pilot study suggest that LPV/r monotherapy may be an option for management of HIV infection. Larger, randomized trials are warranted to evaluate the safety, efficacy, and patient population who might benefit from LPV/r monotherapy.

Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial.

BACKGROUND: Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS: Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS: Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS: TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

The safety and tolerability of Z-100 in patients infected with HIV-1.

Z-100 is an extract of the Mycobacterium tuberculosis strain Aoyama B, which contains various polysaccharides. Aoyama B has previously been shown to induce a T helper 1-type cytokine response in various murine oncological models and has also demonstrated inhibitory activity against HIV-1 in vitro. This multicentre study primarily determined the safety of Z-100 in early HIV-1-infected patients who were treatment naive; were treatment experienced, but had elected to discontinue highly active antiretroviral therapy (HAART) 8 weeks or longer before the study; or were stable on their first or second HAART regimen for at least 12 weeks before the study. Thirty-two individuals participated in this study and self-injected either placebo, 20 microg or 40 microg Z-100 twice a week for 8 weeks. Z-100 was well tolerated and the safety profiles of the Z-100 treatment groups were not meaningfully different compared with the placebo group. Plasma levels of HIV-1 RNA were not statistically significantly different in any treatment group at the end of the treatment period. There were no statistically significant differences among the treatment groups in the change from baseline to week 8 for any of the biological endpoints including plasma levels of HIV-1 RNA; CD4+ and CD8+ T-cell counts; levels of macrophage inflammatory protein 1; soluble tumour necrosis factor receptor 1; C-reactive protein; interleukin-6; and granulocyte colony stimulating factor. Consequently, this trial demonstrates the safety of Z-100 in HIV-1 infected patients without evidence of any activity at the doses administered.

Treating morphologic and metabolic complications in HIV-infected patients on antiretroviral therapy. A consensus statement of an advisory committee of the International Association of Physicians in AIDS Care.

OBJECTIVE: Clinicians are increasingly challenged by presentation of morphologic and metabolic complications in HIV-infected patients. These complications are associated with HIV infection and/or combination antiretroviral therapy. This Consensus Statement is intended to offer guidance to clinicians actively involved in HIV/AIDS care. PARTICIPANTS: Seven clinicians with expertise in HIV medicine were invited by the International Association of Physicians in AIDS Care (IAPAC) to serve on an ad hoc Advisory Committee. CONSENSUS PROCESS: IAPAC convened the Advisory Committee to develop a draft Consensus Statement. Each clinician was tasked with drafting a specific section of the Consensus Statement corresponding with his or her expertise around a morphologic and/or metabolic complication. Scientific and clinical research, and other data in published literature and abstracts from scientific conferences were considered by strength of evidence. This document represents the consensus agreement of the Advisory Committee.

Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial.

BACKGROUND: Resistance to antiretroviral agents remains a leading cause of treatment failure for patients infected with HIV-1. OBJECTIVE: To describe the efficacy and safety of tenofovir disoproxil fumarate (tenofovir DF) compared with placebo in patients with detectable viral replication despite current antiretroviral therapy. DESIGN: Randomized, double-blind, placebo-controlled study through 24 weeks. After 24 weeks, all patients received open-label tenofovir DF for the remainder of the 48-week study. SETTING: 75 North American, European, and Australian HIV clinics. PATIENTS: 552 HIV-1-infected adults who were receiving antiretroviral therapy and had stable HIV-1 RNA levels ranging from 400 to 10,000 copies/mL. MEASUREMENTS: Change in HIV-1 RNA level (time-weighted average from baseline through week 24); proportion of patients with grade 3 or 4 laboratory abnormalities and adverse events; and genotypic HIV-1 resistance testing in a separate substudy at baseline, week 24, and week 48. RESULTS: A statistically significant decrease in HIV-1 RNA level through week 24 (the primary end point) was observed in the tenofovir DF group versus the placebo group (-0.61 log10 copies/mL vs. -0.03 log10 copies/mL, respectively [P < 0.001]; difference, -0.58 log10 copies/mL [95% CI, -0.68 to -0.49 log10 copies/mL]). In a virologic substudy, 94% of 253 patients had plasma isolates expressing reverse transcriptase mutations associated with nucleoside resistance mutations at baseline. Through week 24, the incidence of clinical adverse events was similar between patients receiving placebo and those receiving tenofovir DF (14% vs. 13%). No evidence of tenofovir DF-related toxicity was seen through week 48. CONCLUSION: In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo.

Efficacy and safety of twice-daily versus three-times daily saquinavir soft gelatin capsules as part of triple combination therapy for HIV-1 infection.

OBJECTIVE: The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. METHODS: This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1,600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1,200 mg twice-daily and nelfinavir 1,250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48. RESULTS: At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B-arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C-arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (+/- 12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). CONCLUSIONS: A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.