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Background Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. Methods We enrolled 420 females aged ≥9 years (range, 9–65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. Results Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1–4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2–4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3–2.6) and of genital warts was 1.0/100PY (95% CI, 0.3–2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02–0.03), 1.5 (95% CI, 1.1–2.0), and 1.2 (95% CI, 0.2–3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). Conclusions Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH. [ABSTRACT FROM AUTHOR]

Background. Highly effective hepatitis C virus (HCV) therapies have spurred a scale-up of treatment to populations at greater risk of reinfection after sustained virologic response (SVR). Reinfection may be higher in HIV-HCV coinfection, but prior studies have considered small selected populations. We assessed risk factors for reinfection after SVR in a representative cohort of Canadian coinfected patients in clinical care. Methods. All patients achieving SVR after HCV treatment were followed with HCV RNA measurements every 6 months in a prospective cohort study. We used Bayesian Cox regression to estimate reinfection rates according to patient reported injection drug use (IDU) and sexual activity among men who have sex with men (MSM). Results. Of 497 patients treated for HCV, 257 achieved SVR and had at least 1 subsequent RNA measurement. During 589 person-years of follow-up (PYFU) after SVR, 18 (7%) became HCV RNA positive. The adjusted reinfection rate (per 1000 PYFU) in the first year after SVR was highest in those who reported high-frequency IDU (58; 95% credible interval [CrI], 18-134) followed by MSM reporting high-risk sexual activity (26; 95% CrI, 6-66) and low-frequency IDU (22; 95% CrI, 4-68). The rate in low-risk MSM (16; 95% CrI, 4-38) was similar to that in reference patients (10; 95% CrI, 4-20). Reinfection rates did not diminish with time. Conclusions. HCV reinfection rates varied according to risk. Measures are needed to reduce risk behaviors and increase monitoring in high-risk IDU and MSM if HCV elimination targets are to be realized. [ABSTRACT FROM AUTHOR]

Background: Atazanavir/ritonavir and darunavir/ritonavir are common protease inhibitor-based regimens for treating patients with HIV. Studies comparing these drugs in clinical practice are lacking.Methods: We conducted a retrospective cohort study of antiretroviral naïve participants in the Canadian Observational Cohort (CANOC) collaboration initiating atazanavir/ritonavir- or darunavir/ritonavir-based treatment. We used separate Fine and Gray competing risk regression models to compare times to regimen failure (composite of virologic failure or discontinuation for any reason). Additional endpoints included virologic failure, discontinuation due to virologic failure, discontinuation for other reasons, and virologic suppression.Results: We studied 222 patients treated with darunavir/ritonavir and 1791 patients treated with atazanavir/ritonavir. Following multivariable adjustment, there was no difference between darunavir/ritonavir and atazanavir-ritonavir in the risk of regimen failure (adjusted hazard ratio 0.76, 95% CI 0.56 to 1.03) Darunavir/ritonavir-treated patients were at lower risk of virologic failure relative to atazanavir/ritonavir treated patients (aHR 0.50, 95% CI 0.28 to 0.91), findings driven largely by high rates of virologic failure among atazanavir/ritonavir-treated patients in the province of British Columbia. Of 108 discontinuations due to virologic failure, all occurred in patients starting atazanavir/ritonavir. There was no difference between regimens in time to discontinuation for reasons other than virologic failure (aHR 0.93; 95% CI 0.65 to 1.33) or virologic suppression (aHR 0.99, 95% CI 0.82 to 1.21).Conclusions: The risk of regimen failure was similar between patients treated with darunavir/ritonavir and atazanavir/ritonavir. Although darunavir/ritonavir was associated with a lower risk of virologic failure relative to atazanavir/ritonavir, this difference varied substantially by Canadian province and likely reflects regional variation in prescribing practices and patient characteristics. [ABSTRACT FROM AUTHOR]

Purpose: The 144-week results of the open-label, multicenter Atazanavir/Ritonavir Induction with Epzicom Study (ARIES) were stratified by gender to compare treatment responses. Methods: A total of 369 HIV-infected, antiretroviral-naïve subjects receiving once-daily abacavir/ lamivudine + atazanavir/ritonavir (ATV/r) whose HIV-1 RNA was <50 copies/mL by week 30 were randomized 1:1 at week 36 to maintain or discontinue ritonavir for 108 subsequent weeks. Between- and within-treatment gender-related efficacy and safety differences were analyzed. Results: Subjects were 85% male; 64% white; and had a mean age of 39 years, baseline median HIV-1 RNA of 114,815 copies/mL, and median CD4+ cell count of 198 cells/mm3. Gender (ATV [n=189]: 29 females/160 males; ATV/r [n=180]: 25 females/155 males) and most other demographics were similar between groups; more females than males were black (65% vs 25%) and fewer females had baseline HIV-1 RNA ?100,000 copies/mL (41% vs 58%). At week 144, no significant differences between genders were observed in proportion maintaining HIV-1 RNA <50 copies/mL (ATV, 79% vs 77%; ATV/r, 60% vs 75%) or <400 copies/mL (ATV, 83% vs 84%; ATV/r, 68% vs 82%) (intent-to-treat-exposed: time to loss of virologic response analysis); median CD4+ change from baseline (ATV, +365 vs +300 cells/mm3; ATV/r, +344 vs +301 cells/ mm3); proportion with treatment-related grade 2-4 adverse events (baseline to week 144: ATV, 41% vs 31%; ATV/r, 36% vs 43%; weeks 36 to 144: ATV, 14% vs 13%; ATV/r, 24% vs 23%); or proportion developing fasting lipid changes. Female and male virologic failure rates (ATV, 0 vs 5; ATV/r, 2 vs 4) and proportions completing the study were similar during the extension phase. Primary withdrawal reasons were loss to follow-up and pregnancy for females and loss to follow-up and other for males. Conclusion: Over 144 weeks, no significant gender differences were observed in efficacy, safety, or fasting lipid changes with abacavir/lamivudine +ATV or abacavir/lamivudine +ATV/r. [ABSTRACT FROM AUTHOR]

Objectives: Despite substantial improvements in HIV outcomes with combination antiretroviral therapy (cART), morbidity and mortality remain above population norms. The gut mucosal immune system is not completely restored by cART, and the resultant microbial translocation may contribute to chronic inflammation, inadequate CD4 T-cell recovery, and increased rates of serious non-AIDS events. Since the microbial environment surrounding a CD4 T cell may influence its development and function, we hypothesize that probiotics provided during cART might reduce inflammation and improve gut immune health in HIV-positive treatment-naïve individuals (PROOV IT I) and individuals with suboptimal CD4 recovery on cART (PROOV IT II). Methods:These prospective, double-blinded, randomized, placebo-controlled, multicenter pilot studies will assess the impact of the probiotic Visbiome at 900 billion bacteria daily. Forty HIV positive cART-naïve men will be randomized in the PROOV IT I study, coincident with antiretroviral initiation, and be followed for 24 weeks. In PROOV IT II, 36 men on cART, but with a CD4 T-cell count below 350 cells/mm3will be followed for 48 weeks. The primary outcome for both studies is the comparison of blood CD8 T-cell immune activation. Secondary analyses will include comparison of blood inflammatory biomarkers, microbial translocation, blood and gut immunology and HIV levels, the bacterial community composition, diet, intestinal permeability, and the safety, adherence and tolerability of the study product. Discussion: These studies will evaluate the ability of probiotics as a safe and tolerable therapeutic intervention to reduce systemic immune activation and to accelerate gut immune restoration in people living with HIV. [ABSTRACT FROM PUBLISHER]

Background: It has been reported that pregnant women receiving protease inhibitor (PI)-based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level.Methods: We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)-infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism.Results: HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20α-HSD; median, 2.5 arbitrary units [AU]; interquartile range [IQR], 1.00-4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66-1.26 AU;P= .002). Prolactin, a key regulator of 20α-HSD, was lower (P= .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART-induced decreases in progesterone levels.Conclusions: Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women. [ABSTRACT FROM AUTHOR]

Background. Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. Methods. Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. Results. Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/ 530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%). Conclusions. DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection-individuals for whom real-world data are urgently needed. [ABSTRACT FROM AUTHOR]

Background: Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-toplatelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC). Methods: Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC.Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent. Results: A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%). Conclusions: Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV- coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used. [ABSTRACT FROM AUTHOR]

Introduction: The MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naïve people with HIV infection. Objective: We planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions. Methods: Participants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS). Results: Prior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (r = 0.21, p = 0.02) with a 21 pmol/L reduction in B12 per 100 cells/µL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (r = 0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants. Conclusion: Micronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects. Trial Registration: ClinicalTrials.gov NCT00798772 [ABSTRACT FROM AUTHOR]

The article discusses a study on the efficacy of dolutegravir plus Abacavir-Lamivudine in treating human immunodeficiency virus type 1 (HIV-1) infection. The study involved adult participants who had not received therapy for HIV-1 infection. The authors conclude that dolutegravir plus Abacavir-Lamivudine is more safe and effective through 48 weeks than the regimen with efavirenz-tenofovir disoproxil fumarate-emtricitabine.

Background. The Canadian Women's HIV Study (CWHS) enrolled human immunodeficiency virus (HIV)–positive and high-risk HIV-negative women in a longitudinal cohort. This analysis considered the effects of HIV and highly active antiretroviral therapy (HAART) on HPV persistence and cervical squamous intraepithelial lesions (SILs).Methods. Longitudinal cytopathologic and HPV DNA results were analyzed using multistate models. States of cervical SIL were defined as absent, present, and treatment; HPV states were defined as negative or positive. Demographic variables and markers of sexual activity were considered predictors. Results were calculated on the basis of transition probabilities and reported as hazard ratios (HRs).Results. The CWHS followed 750 HIV-positive and 323 HIV-negative women during 1993–2002. A total of 467 and 456 women were included in the longitudinal cervical cytopathologic and HPV DNA analyses, respectively. HIV-positive women had increased prevalence (46.6% vs 28.7%; P < .0001), increased acquisition (HR, 2.3; P = .03), and decreased clearance (HR, 0.4; P < .001) of oncogenic HPV as compared to HIV-negative women. Oncogenic HPV infection predicted progression of cervical dysplasia from normal to abnormal SIL (HR, 2.8; P = .002). Among HIV-positive participants, HAART increased the likelihood of regression (from present to absent) of cervical SIL (HR, 3.3; P = .02) and increased the clearance of oncogenic HPV types other than HPV-16 or HPV-18 (HR, 2.2; P = .01).Conclusions. This analysis demonstrated beneficial effects of HAART on cervical SIL in HIV-positive women. [ABSTRACT FROM AUTHOR]

Background: Although some studies show higher antiretroviral concentrations in women compared to men, data are limited. We conducted a cross-sectional study of HIV-positive women to determine if protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin and Cmax values were significantly different than historical general population (predominantly male) averages and to evaluate correlates of higher concentrations. Methods: HIV-positive women with virologic suppression (viral load < 50copies/mL) on their first antiretroviral regimen were enrolled. Timed blood samples for Cmin and Cmax were drawn weekly for 3 weeks. The ratio of each individual's median Cmin and Cmax to the published population mean values for their PI or NNRTI was calculated and assessed using Wilcoxon sign-rank. Intra- and inter-patient variability of antiretroviral drug levels was assessed using coefficient of variation and intra-class correlation. Linear regression was used to identify correlates of the square root-transformed Cmin and Cmax ratios. Results: Data from 82 women were analyzed. Their median age was 41 years (IQR=36-48) and duration of antiretrovirals was 20 months (IQR=9-45). Median antiretroviral Cmin and Cmax ratios were 1.21 (IQR=0.72-1.89, p=0.003) (highest ratios for nevirapine and lopinavir) and 0.82 (IQR=0.59-1.14, p=0.004), respectively. Nevirapine and efavirenz showed the least and unboosted atazanavir showed the most intra- and inter-patient variability. Higher CD4+ count correlated with higher Cmin. No significant correlates for Cmax were found. Conclusions: Compared to historical control data, Cmin in the women enrolled was significantly higher whereas Cmax was significantly lower. Antiretroviral Cmin ratios were highly variable within and between participants. There were no clinically relevant correlates of drug concentrations. [ABSTRACT FROM AUTHOR]

Background: Participation bias is a well-known phenomenon in epidemiologic research, where individuals consenting to research studies differ from individuals who are not able or willing to participate. These dissimilarities may limit the generalizability of results of research studies. Quantification of the participation bias is essential for the interpretation of research findings. Methods: The Ontario HIV Treatment Network Cohort Study (OCS) is an ongoing open cohort study of HIV positive individuals receiving care at one of 11 sites in Ontario. OCS participants from 4 sites were compared to nonparticipants (those who declined or were not approached) at those sites with regard to gender, age, HIV risk factor, CD4 count and viral load (VL). Generalized logit regression models were used to identify predictors of declining to participate or not being approached to participate. Results: Compared to participants (P) in the OCS, individuals who declined to participate (D) and those who were not approached (NA) were slightly younger (D:45, NA:44 vs P:46), less likely to be male (D: 71%, NA:75% vs P:88%), less likely to be Caucasian (D:41%, NA:57% vs P:72%) and less likely to be Canadian-born (D: 39%, NA: 52% vs P: 69%). Patients who were not approached to participate were less likely to have VL < 50 copies/mL than other patients (D: 75%, NA: 62%, P: 74%) and had lower CD4 counts than OCS participants (D: 450 cells/mm³, NA: 420 cells/mm³, P: 480 cells/mm³). Conclusions: Significant demographic and clinical differences were found between OCS participants and non-participants. Extrapolation of research findings to other populations should be undertaken cautiously. [ABSTRACT FROM AUTHOR]

Lipohypertrophy in HIV-infected patients is associated with metabolic abnormalities. Raltegravir (RAL) is not known to induce fat changes or severe metabolic perturbations. HIV-infected women with central adiposity and HIV-1 RNA less than 50 copies per milliliter on non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-based antiretroviral therapy (ART) continued their nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open label RAL immediately or after 24 weeks. The primary end point was 24-week between-group change in computed tomography (CT)-quantified visceral adipose tissue (AT) volume. Fasting lipids, glucose, C-reactive protein (CRP), anthropometric measurements, and patient-reported quality of life assessments were also measured. Thirty-six subjects provided 80% power to detect a 10% between-group difference in visceral AT over 24 weeks. Thirty-seven of 39 enrolled subjects completed week 24. At entry, subjects were 75% black or Hispanic, and on 62% PI-based and 38% NNRTI-based regimens. The median age was 43 years, CD4 count 558 cells per microliter, and body mass index (BMI) 32 kg/m2. After 24 weeks, no statistically significant changes in visceral or subcutaneous AT, anthropometrics, BMI, glucose, or CRP were observed. In subjects receiving RAL, significant improvements in total and LDL cholesterol ( p=0.04), self-reported belly size ( p=0.02) and composite body size ( p=0.02) were observed. Body size changes correlated well with percent visceral AT change. No RAL-related adverse events occurred. Compared to continued PI or NNRTI, switch to RAL was associated with statistically significant 24-week improvements in total and LDL cholesterol but not AT volumes. Additional insights into AT and metabolic changes in women on RAL will be provided by 48-week follow-up of the immediate-switch arm. [ABSTRACT FROM AUTHOR]

Purpose: To determine the impact of baseline viral load (VL) and CD4+ cell count, race/ethnicity, and gender on response in a post hoc analysis of the Gemini study.Methods: In this 48-week study, treatment-naïve, HIV-infected participants received as initial therapy twice-daily saquinavir/ritonavir (SQV/r) 1000/100 mg (n=167) or lopinavir/ritonavir (LPV/r) 400/100 mg (n=170), each with emtricitabine 200 mg/tenofovir 300 mg daily. The proportion of participants achieving HIV RNA<50 copies/mL (primary endpoint) and median change from baseline in CD4+ cell count were compared by baseline VL (>100,000 vs ≤100,000 copies/ mL) and CD4+ cell count (&nvgt;100 vs ≤100 cells/µL). The impact of baseline and demographic variables on virologic response was assessed by logistic regression analysis.Results: Responses were similar between arms (SQV/r vs LPV/r) with or without stratification. In a pooled analysis of SQV/r and LPV/r arms, CD4+ cell count &nvgt;100 cells/µL (odds ratio [OR], 1.628;P = .0416), non-Thai/non-Black versus Black race (OR, 1.518;P = .0023), and non-Thai/non-Black versus Thai (OR, 0.467;P = .0046) were significant predictors of virologic response.Conclusions: Treatment groups had similar efficacy. Baseline CD4+ cell count and race/ethnicity were independent predictors of virologic response, whereas baseline VL and gender were not. [ABSTRACT FROM AUTHOR]

Background: More severe influenza disease and poor vaccine immunogenicity in HIV-infected patients necessitate improved immunization strategies to maximize vaccine efficacy. Methods: A phase III, randomized trial was conducted at 4 Cana-dian sites. Two dosing strategies (standard dose vs standard dose plus booster on day 21) were assessed in HIV patients aged 20 to 59 years during the H1N12009 pandemic. A single antigen, inactivated split adjuvanted (AS03A) influenza vaccine (Arepanrix) was utilized. Serum hemagglutination inhibition (HAI) titres were assessed at days 21 and 42 and at month 6. Results: 150 participants received at least one injection. Baseline parameters were similar between groups: 83% male, 85% on HAART, median CD4 = 519 cells/mm3, 84% with HIV RNA < 50 copies/mL. At day 21, seroprotection (HAI &nvge;1:40) was achieved in 80% (95% CI, 70-89) of participants. Seroconversion occurred in 74% (63-85). Seroprotection and seroconversion were further improved in those randomized to booster dosing: day 42, 94% (85-98) versus 73% (60-83) (P < .01) and 86% (75-93) versus 66% (5-77) (P = .01). Seroprotec-tion was retained in 40% (28-54) of recipients at month 6 with trends toward greater retention of immunity in booster recipients. Conclusion: High-level immunogenicity was achieved with a single dose of this adjuvanted vaccine. Immunogenicity was further improved with booster dosing. Use of this adjuvanted vaccine and booster represent an important approach to increasing immunogenicity in this vaccine hypo-responsive population. [ABSTRACT FROM AUTHOR]

Objective: To determine the impact of thiazolidinediones (TZD) on changes in limb fat mass in HIV-infected individuals, particularly in those not receiving a thymidine analogue.Methods: Individual patient data from placebo-controlled, randomized trials of rosiglitazone (n = 5) or pioglitazone (n = 1) were combined. Generalized estimating equation (GEE) models were used to estimate the treatment effect on changes in limb fat mass.Results: In the combined dataset of 427 patients, the baseline median age was 45 years, 86% were male, 80% were Caucasian, 63% were receiving stavudine (d4T) or zidovudine (AZT), 66% were on protease inhibitors, and median body mass index was 23 kg/m2. In a univariate GEE model, TZD was associated with an increase in limb fat mass (coeff = 0.14 kg vs placebo,P = .04). In a multivariable GEE model, patients receiving pioglitazone had significantly higher limb fat mass gains (coeff = 0.35 kg,P δ .01) compared to patients receiving placebo, while patients on rosiglitazone did not (coeff = 0.05 kg,P = .48). Interactions between thymidine analogue use and rosiglitazone and pioglitazone were not significant.Conclusions: In this meta-analysis, pioglitazone therapy was more effective than placebo to increase limb fat mass whereas rosiglitazone was not significantly better than placebo. The effectiveness of these drugs did not vary according to whether the patients were receiving thymidine analogues. [ABSTRACT FROM AUTHOR]

Background: Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression. Methods/Design: The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4 + T-cell count = 350 cells/mm3 or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log10 HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms. Discussion: Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications. Trial Registration: Current Controlled Trials ISRCTN66756285 ClinicalTrials.gov NCT00860977 [ABSTRACT FROM AUTHOR]

The article describes a randomized controlled trial designed by the Canadian HIV Trials Network to know if a 12-week structured treatment interruption (STI) before switching to a salvage antiretrovirals versus immediate switching (IS) in patients with virologic failure could lead to a sustained virologic benefit. The authors note that success was achieved by 64% in the IS arm and 51% in the STI arm. They also mention the lack of differences in median CD4 cell counts or HIV RNA levels at week 60.

Lopinavir is a protease inhibitor (PI) for the treatment of HIV infection that was specifically designed to overcome the shortcomings of earlier agents in this class. It is the only PI coformulated with ritonavir, whose pharmacological boosting effect results in a highly potent, well-tolerated, clinically effective antiretroviral agent with a high genetic barrier to resistance. Lopinavir/ritonavir is a recommended first-line option for antiretroviral-naive patients initiating PI-based therapy, and has an equally important role in the management of treatment-experienced individuals. Its favorable pharmacological and clinical characteristics have recently prompted investigators to explore its potential novel applications in HIV monotherapy and double-boosted regimens. [ABSTRACT FROM AUTHOR]

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 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 ≥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, ritonavirboosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection. [ABSTRACT FROM AUTHOR]

Lipodystrophy severity among 77 people living with HIV/AIDS (PHA) with body fat redistribution was not related to antiretroviral adherence including doses missed during the previous month, categorical rating of maximal adherence, and the PMAQ7 adherence behavior scale. Two thirds of the sample reported submaximal adherence, 19% missing more than two doses, but adherence behavior ratings reflected good overall adherence. Overall symptom burden, convenience of regimen schedule and remembering to organize and take antiretroviral doses, but not regimen adaptation or treatment support, were associated with adherence. Remembering was most strongly related to adherence indicators, retaining statistical significance in adjusted multivariate regression analyses. [ABSTRACT FROM AUTHOR]

Initial studies have shown impaired access to antiretrovirals and slower adoption of new therapies by women. It is unclear if similar treatment delays still occur, especially in those with a publicly funded health care system in Ontario, Canada. The objectives of this study were (1) to evaluate longitudinal patterns of antiretroviral use in patients with HIV in Ontario and (2) to determine if gender differences exist in access to and uptake of antiretroviral drugs over time. A retrospective medical chart review was undertaken. One hundred four HIV-positive patients were recruited from nine hospital-based HIV outpatient clinics throughout Ontario. From time of study enrollment in 1999–2001 to the first clinic visit (8.1 ± 3.2 years; range, 2.3–16.8 years), CD4+ T-cell counts, date of and agents used in initial antiretroviral regimen, and first HAART regimen were evaluated by gender. Kaplan-Meier plots were used to evaluate time to drug initiation from known HIV diagnosis. Serial cross sections of numbers and types of antiretroviral drugs prescribed in March, June, September, and December 1988 to 2001 were also compared as was number of regimens used. There were few differences between men and women in antiretroviral use; both initiated therapy within 2.2 ± 2.3 years of HIV diagnosis at an average CD4 counts of 300.3 ± 150.1 cells per microliter. Antiretroviral treatment regimens changed over time, with limited variation by gender. In the period immediately surrounding the first highly active antiretroviral therapy (HAART) recommendations by the U.S. Department of Health and Human Services in July 1997, significantly more antiretroviral drugs were prescribed for men than women. Antiretroviral prescribing in patients attending hospital- based HIV outpatient programs in Ontario is consistent with antiretroviral treatment guidelines over time, without substantial differences in antiretroviral access and use by gender. [ABSTRACT FROM AUTHOR]

The relationship between 12-month CD4+ cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with a human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4+ cell count responses were divided into 5 categories, ranging from decrease or no change (29% of patients) to a ⩾100-cell/mm³ increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4+ cell count response. A 25-cell/mm³ increase in CD4+ cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P< .0001). [ABSTRACT FROM AUTHOR]

The goal of this study was to describe and compare the prevalence, predictors and patterns of marijuana use, specifically medicinal marijuana use among patients with HIV in Ontario, Canada. Any marijuana use in the year prior to interview and self-defined medicinal use were evaluated. A cross-sectional multicenter survey and retrospective chart review were conducted between 1999 and 2001 to evaluate overall drug utilization in HIV, including marijuana use. HIV-positive adults were identified through the HIV Ontario Observational Database (HOOD), 104 consenting patients were interviewed. Forty-three percent of patients reported any marijuana use, while 29% reported medicinal use. Reasons for use were similar by gender although a significantly higher number of women used marijuana for pain management. Overall, the most commonly reported reason for medicinal marijuana use was appetite stimulation/weight gain. Whereas male gender and history of intravenous drug use were predictive of any marijuana use, only household income less than $20,000 CDN was associated with medicinal marijuana use. Age, gender, HIV clinical status, antiretroviral use, and history of intravenous drug use were not significant predictors of medicinal marijuana use. Despite the frequency of medicinal use, minimal changes in the pattern of marijuana use upon HIV diagnosis were reported with 80% of current medicinal users also indicating recreational consumption. Although a large proportion of patients report medicinal marijuana use, overlap between medical and recreational consumption is substantial. The role of poverty in patient choice of medicinal marijuana despite access to care and the large proportion of women using marijuana for pain constitute areas for further study. [ABSTRACT FROM AUTHOR]

Increasing rates of HIV infection in women worldwide, especially among those of childbearing age, reinforce the importance of understanding the management of HIV in pregnancy. Over the past decade, significant advances have been made in the prevention of vertical HIV transmission, including the use of single and combination antiretroviral therapy, elective caesarean section as the preferred mode of delivery and the elimination of breast feeding. Multiple clinical trials assessing antiretroviral therapy in pregnancy have been carried out worldwide. The first pivotal clinical trial, the AIDS Clinical Trials Group (ACTG) 076 study, was conducted in 1994 using a three-part zidovudine regimen. Despite the success of this regimen at decreasing rates of vertical transmission, it is not affordable in many developing countries. Consequently, many international clinical trials have concentrated on short-course antiretroviral regimens including zidovudine alone, zidovudine and lamivudine, and nevirapine alone. In the developed world, the management of nonpregnant HIV-infected individuals has also undergone significant advances and has implications for the management of HIV in pregnancy. A number of countries have participated in the development of guidelines for the management of HIV in pregnancy, which recommend that HIV-infected pregnant women should be offered combination antiretroviral therapy based on viral load and CD4+ cell count cut-offs used for individuals who are not pregnant, preferably with the inclusion of zidovudine. However, to maximise the benefits to their offspring, therapy is recommended at lower viral load thresholds than for nonpregnant adults. For antiretroviral-naive women, therapy is deferred until the second trimester because of the potential and uncertain risk of teratogenesis and the low risk of transmission during this period. Research has also found that maternal factors including viral load, immune status, chorioamnionitis, prematurely ruptured membranes and, to a lesser extent, intravenous drug use and smoking are associated with increased vertical transmission. These represent potentially modifiable risk factors that should be addressed before and throughout pregnancy. Despite the benefits of antiretroviral therapy to reduce HIV vertical transmission, its use can be complicated by known and unknown risks of toxicity to the mother, fetus or both as well as carrying the risk of developing drug-resistant virus. The latter can potentially compromise future treatment options for both the mother and child. Other important challenges include the use of antiretroviral drugs during pregnancy when the mother does not meet criteria for them for her own health, and balancing the relative risks and benefits of elective caesarean section at various degrees of viral load suppression. Clinicians managing HIV in pregnancy need to keep up to date with all the literature to provide optimal care, including counselling to allow mothers to balance the risks and benefits while deciding on treatment for both themselves and their children. [ABSTRACT FROM AUTHOR]

Presents information on a study regarding the therapeutic use of topical alitretinoin gel in the treatment of patients with AIDS-related cutaneous Kaposi's sarcoma. Methodology; Results; Discussion on the results.

Presents a study which determined whether administration of N-acetylcysteine could decrease the incidence of hypersensitivity reactions to trimethoprim-sulfamethoxazole when used for primary pneumocystis carinii pneumonia prophylaxis in patients with HIV infection. Methods used on the study; Analysis; Results and discussion.

Background There are limited data on the real-world effectiveness of direct-acting antiviral (DAA) treatment in patients coinfected with hepatitis C virus (HCV) and HIV—a population with complex challenges including ongoing substance use, cirrhosis, and other comorbidities. We assessed how patient characteristics and the appropriateness of HCV regimen selection according to guidelines affect treatment outcomes in coinfected patients. Methods We included all patients who initiated DAA treatment between November 2013 and July 2017 in the Canadian Co-Infection Cohort. Sustained virologic response (SVR) was defined as an undetectable HCV RNA measured between 10 and 18 weeks post-treatment. We defined treatment failure as virologic failure, relapse, or death without achieving SVR. Bayesian logistic regression was used to estimate the posterior odds ratios (ORs) associated with patient demographic, clinical, and treatment-related risk factors for treatment failure. Results Two hundred ninety-five patients initiated DAAs; 31% were treatment-experienced, 29% cirrhotic, and 80% HCV genotype 1. Overall, 92% achieved SVR (263 of 286, 9 unknown), with the highest rates in females (97%) and lowest in cirrhotics (88%) and high-frequency injection drug users (89%). Many patients (38%) were prescribed regimens that were outside current clinical guidelines. This did not appreciably increase the risk of treatment failure—particularly in patients with genotype 1 (prior odds ratio [OR], 1.5; 95% credible interval [CrI], 0.38–6.0; posterior OR, 1.0; 95% CrI, 0.40–2.5). Conclusions DAAs were more effective than anticipated in a diverse, real-world coinfected cohort, despite the use of off-label, less efficacious regimens. High-frequency injection drug use and cirrhosis were associated with an increased risk of failure. [ABSTRACT FROM AUTHOR]

The article discusses the study "Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis" by C.M. Denkinger and colleagues and published in a 2014 issue of the periodical "European Respiratory Journal". Topics discussed include detection of extrapulmonary tuberculosis (TB), and recommendation by the World Health Organization to use Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) as the preferred test for diagnosis of TB meningitis.

Background: Lopinavir is a newly developed inhibitor of human immunodeficiency virus (HIV) protease that, when formulated with ritonavir, yields mean trough plasma lopinavir concentrations that are at least 75 times as high as that needed to inhibit replication of wild-type HIV by 50 percent. Methods: We conducted a double-blind trial in which 653 HIV-infected adults who had not received antiretroviral therapy for more than 14 days were randomly assigned to receive either lopinavir–ritonavir (400 mg of lopinavir plus 100 mg of ritonavir twice daily) with nelfinavir placebo or nelfinavir (750 mg three times daily) with lopinavir–ritonavir placebo. All patients also received open-label stavudine and lamivudine. The primary efficacy end points were the presence of fewer than 400 HIV RNA copies per milliliter of plasma at week 24 and the time to the loss of virologic response through week 48. Results: At week 48, greater proportions of patients treated with lopinavir–ritonavir than of patients treated with nelfinavir had fewer than 400 copies of HIV RNA per milliliter (75 percent vs. 63 percent, P<0.001) and fewer than 50 copies per milliliter (67 percent vs. 52 percent, P<0.001). The time to the loss of virologic response was greater in the lopinavir–ritonavir group than in the nelfinavir group (hazard ratio, 2.0; 95 percent confidence interval, 1.5 to 2.7; P<0.001). The estimated proportion of patients with a persistent virologic response through week 48 was 84 percent for patients receiving lopinavir–ritonavir and 66 percent for those receiving nelfinavir. Both regimens were well tolerated, with the rate of discontinuation related to the study drugs at 3.4 percent among patients receiving lopinavir–ritonavir and 3.7 percent among patients receiving nelfinavir. Among patients with more than 400 copies of HIV RNA per milliliter at some point from week 24 through week 48, resistance mutations in HIV protease were demonstrated in viral isolates from 25 of 76 nelfinavir-treated patients (33 percent) and none of 37 patients treated with lopinavir–ritonavir (P<0.001). Conclusions: For the initial treatment of HIV-infected adults, a combination regimen that includes lopinavir–ritonavir is well tolerated and has antiviral activity superior to that of a nelfinavir-containing regimen. (N Engl J Med 2002;346:2039-46.) [ABSTRACT FROM AUTHOR]

Comments on the potential use of alitretinoin in the treatment of AIDS-related cutaneous Kaposi's sarcoma (KS). Problems on the traditional treatment of KS; Mechanism of action of alitretinoin; Results of clinical trials on the therapeutic potential of alitretinoin.

Background: Severe food insecurity (FI) is common among individuals living with HIV-hepatitis C virus (HCV) co-infection. We hypothesize that the injection of opioids is partly responsible for the association between injection drug use and severe FI. Therefore, this analysis examines whether methadone maintenance treatment for opioid dependence is associated with a lower risk of severe FI.Methods: We used biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). Methadone treatment (exposure) was self-reported and severe FI (outcome) was measured using the Household Food Security Survey Module. To quantify the association between methadone treatment and severe FI, we estimated an average treatment effect on the treated (marginal risk difference [RD]) using propensity score matching.Results: Among participants, 25% experienced severe FI in the six months preceding the first time-point in the analytical sample and 5% concurrently reported receiving methadone treatment. Injection of opioids in the six months preceding the treatment and outcome measurements was much higher among those who received methadone treatment (39% vs. 12%). Among the treated participants, 97% had injected opioids in their lifetimes. After propensity score matching, the average risk of experiencing severe FI is 12.3 percentage-points lower among those receiving methadone treatment, compared to those who are not receiving treatment (marginal RD = -0.123, 95% CI = -0.230, -0.015).Conclusions: After adjustment for socioeconomic, sociodemographic, behavioural, and clinical confounders, methadone treatment is associated with a lower risk of severe FI. This finding suggests that methadone treatment may mitigate severe FI in this vulnerable subset of the HIV-positive population. [ABSTRACT FROM AUTHOR]

Objective To evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24 months. Design Between November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5 mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 12, 18, and 24 months. Adverse events were recorded throughout. Results Of 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38 years (IQR 32–45, range 15–66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had a suppressed HIV viral load (VL < 40 c/ml) at baseline, with a median CD4 count of 510 cells/mm 3 (376–695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74–3.05 fold higher peak antibody response compared to those without ( p from 0.006 to <0.0001). Conclusions This study is the first to examine the qHPV vaccine in HIV-positive women out to 24 months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination. Clinical trial registration: http://www.isrctn.com/ISRCTN33674451 [ABSTRACT FROM AUTHOR]

Summary Background Treatment options for HIV-1 infected individuals who have received extensive previous antiretroviral therapy are limited. We compared efficacy and safety of the novel non-peptidic protease inhibitor tipranavir co-administered with ritonavir plus an optimised background regimen with that of an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI-ritonavir) in such patients. Methods We did a combined analysis of 48-week data from two ongoing, randomised, open-label, multinational, phase III, RESIST studies. HIV-1-infected adults with 3 months or longer previous triple antiretroviral class experience, two or more previous protease inhibitor regimens, HIV-1 RNA 1000 copies per mL or greater, and genotypically demonstrated primary resistance to protease inhibitor, were eligible. Primary endpoints were proportion of treatment responders (with reduction in viral load of 1 log10 copies per mL or greater below baseline without treatment change) at 48 weeks and time to treatment failure through 48 weeks (intention-to-treat analysis). The RESIST studies are registered with ClinicalTrials.gov, numbers NCT00054717 (RESIST-1) and NCT00144170 (RESIST-2). Findings 3324 patients were screened; 746 received tipranavir-ritonavir and 737 CPI-ritonavir. 486 (65·1%) patients on tipranavir-ritonavir and 192 (26·1%) on CPI-ritonavir remained on assigned treatment until week 48. At week 48, more patients achieved and maintained treatment response in the tipranavir-ritonavir group than in the CPI-ritonavir group (251 [33·6%] vs 113 [15·3%]; p<0·0001). Median time to treatment failure was significantly longer in the tipranavir-ritonavir group than in the CPI-ritonavir group (113 days vs 0 days; p<0·0001). Gastrointestinal system disorders and raised transaminase, cholesterol, and triglycerides were more frequent in the tipranavir-ritonavir group than in the CPI-ritonavir group. Interpretation Compared with CPI-ritonavir, tipranavir-ritonavir with an optimised background regimen provides better virological and immunological responses over 48 weeks in patients who have received extensive previous antiretroviral treatment. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to the article "Treatment of antiretroviral-drug-resistant HIV-1 infection," by S. G. Deeks.

Background: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. Methods: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. Results: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. Conclusions: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection. N Engl J Med 2003;348:2175-85. [ABSTRACT FROM AUTHOR]

Background: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. Methods: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. Results: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P = 0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). Conclusions: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better. (N Engl J Med 1996;335:377-83.) [ABSTRACT FROM AUTHOR]