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.

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 >= 1 log(10)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 4.7log(10)copies/ml, median CD4 cell count was 106 cells/mu l; 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 > 1.0 loglocopies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P <= 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18-39% of TMCI 14/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59-75 versus 12cells/mu l (TMC114/r versus CPI: P <= 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups.Conclusions: TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks. (c) 2007 Lippincott Williams & Wilkins.

The profession of medicine has developed codes of ethical conduct for thousands of years. From the Hippocratic Oath of ancient Greece onward to modern times, a universal and central element of such codes has expressed the imperative that a physician shall “Do no harm.”

To the Editor: The profession of medicine has developed codes of ethical conduct over thousands of years. A central element of such codes is expressed in the imperative to “do no harm.” Disclosures with regard to the treatment of detainees by licensed medical personnel in the “war on terror” in Iraq, Afghanistan, and Guantanamo Bay, Cuba, have revealed undeniable breaches of medical ethics among U.S. military health care personnel involved at these — and perhaps other — sites.1 The International Red Cross has charged that some of the physical and emotional tactics used constitute cruel and unusual punishment. The Geneva . . .

Objective To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response. Design A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States. Participants A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor. Interventions Randomization was to antiretroviral therapy guided by PRT or SOC. Main outcome measures The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of ‘active’ (less than fourfold resistance) antiretroviral agents used (secondary). Results At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed;P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml;P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more ‘active’ antiretroviral agents than in the SOC arm (P = 0.003). Conclusion Antiretroviral treatment guided prospectively by PRT led to the increased use of ‘active’ antiretroviral agents and was associated with a significantly better virological response.

The development of decreased viral susceptibility to one or more of the antiretroviral agents used in the combination treatment of HIV-1-infected patients frequently causes failure to achieve or maintain complete suppression of the virus. A decrease in antiretroviral drug susceptibility may develop during the course of therapy through the accumulation of resistance-associated mutations. Alternatively, an individual may become infected with a virus that already harbours mutations conferring decreased susceptibility to nucleoside reverse transcriptase inhibitors (NRTI), non- nucleoside reverse transcriptase inhibitors (NNRTI), or protease inhibitors (PI). Therapeutic options for such newly infected patients may be limited as a consequence. Although transmission of virus with decreased susceptibility to each of the three classes of drugs has been demonstrated, only limited and mainly retrospective data on the frequency of drug resistance in newly infected patients is available [1–12]. Two prospective studies analysed the results of 81 and 57 patients, respectively [13,14]. We report here the detailed results of a prospective study performed on 230 antiretroviral-naive HIV-1-infected patients from the USA. Both the genetic sequence and the phenotypic drug susceptibility profiles of the patient HIV-1 isolates were studied. The eligibility criteria for a subject to be enrolled in the study were as follows: laboratory evidence of acute primary HIV-1 infection (detectable HIV-1 RNA in plasma using sensitive polymerase chain reaction or branched DNA assays together with negative or indeterminate HIV antibody test) or seropositivity for HIV-1 infection (enzyme-linked immunosorbent assay and Western blot positive) first documented within the past three years (i.e. not known to be seropositive for more than 3 years) and no previous antiretroviral therapy of any kind, (including NRTI, NNRTI, PI, and therapeutic HIV vaccines). Patients were enrolled in the study solely with the aim of determining the prevalence of resistance in therapy-naive patients. All eligible patients who gave their informed consent to participate in the study were enrolled until the targeted number of subjects was reached. Plasma samples were obtained from 230 antiretroviral-naive HIV-1-infected individuals between August 1998 and January 1999. The samples originated from nine clinical centres across six states in the USA. The samples were shipped to the laboratory on dry ice and stored at −70°C until analysis. Phenotypic drug susceptibility testing was performed using a recombinant virus assay (Antivirogram®) [15–17]. The results of this analysis are expressed as the fold-increase in mean IC50 (μM) of a particular drug when tested with patient-derived recombinant virus isolates, relative to the mean IC50 (μM) of the same drug obtained when tested with a reference wild-type virus (IIIB/LAI). Drug susceptibility values generated by the phenotypic assay were classified into one of three drug susceptibility categories: sensitive (S), intermediately resistant (I) and resistant (R), i.e. with a substantial decrease in susceptibility, representing fold-changes in the IC50 values of 4 or less, between 4 and 10, and over 10, respectively, compared with the IC50 value for the reference wild-type virus. Genotypic analysis was performed by automated, population-based, full-sequence analysis (Applied Biosystems Inc., ABI, Foster City, CA, USA). Sequencing results are reported as amino acid changes at positions in protease and reverse transcriptase (RT) compared with the wild-type (HXB2) reference sequence. The sequencing methodology allows the detection of the simultaneous presence of different nucleotides at any position of the region sequenced. The level of sensitivity of detecting such mixtures is of the order of 10–20% for the minority population. Whenever such a mixture of sequences was observed in a sample, the clinical isolate was classified as being mutant. Phenotypic drug susceptibility testing and genotypic analyses were performed on 192 and 199 patient samples, respectively. The ages of the patients enrolled varied between 21 and 64 years (median age 34). Ninety per cent were men. The racial distribution was 64% Caucasian, 23% black, 9% Hispanic, and 4% other. The mode of HIV-1 transmission was homosexual, heterosexual, bisexual, transfusion, drug use or other in the following proportions: 74, 15, 4, 3, 3 and 1%, respectively. Eleven per cent of the patient cohort had a viral load of less than 1000 copies HIV-1 RNA/ml, 21% had a viral load of between 1000 and 10 000 copies/ml and 68% had a viral load greater than 10 000 copies/ml. The distribution of patients across the participating states was: California 31%, Florida 25%, Georgia 22%, Massachusetts 12%, Minnesota 7%, and Pennsylvania 3%. Table 1 shows the frequencies of drug resistance-associated mutations [18–22] found in the RT and protease genes of HIV-1 isolated from this antiretroviral drug-naive patient cohort. The list includes primary as well as so-called 'secondary' mutations [18–22]. The percentage of subjects with virus exhibiting decreased phenotypic susceptibility and the percentage of subjects having virus with mutations associated with decreased susceptibility are represented for each drug in Fig. 1. Overall, 35 and 6% of 192 patients tested had virus with a moderate or substantial decrease in phenotypic susceptibility to one or more antiretroviral drugs, respectively. Patients showed decreased phenotypic susceptibility to one, two or to all three classes of antiretroviral agents in 23.4, 10.4 and 1% of cases, respectively, for intermediately resistant virus, and in 4.7, 1 and 0% of cases for resistant virus. Genotypically, 14 and 16% of 199 patients tested had virus with one or more mutations associated with a decrease in susceptibility to NRTI and NNRTI, respectively. For PI, the figure was 54% if mutations at position 77 are included, and 33% if not. Primary mutations in protease were present in six patients (3%) and secondary mutations in 53% (including mutations at position 77 of protease) and 32% of patients (excluding mutations at position 77 of protease). Of the six patients harbouring primary mutations in protease, four also harboured secondary mutations. The primary mutations in protease were found predominantly in the recently infected group, but a greater sample size would be needed to confirm these preliminary observations. All cases of 41L, 215Y, 184V and 103N mutations of RT were found in the recently infected group. The mode of transmission of the virus, sex of the patient, race or city of origin had no effect on the prevalence of resistance in this patient group. It should be emphasized that the primary objective of this virological study was to characterize the drug susceptibility profile of HIV-1 in such patients. The clinical implications of these findings will need to be addressed in further studies.Fig. 1.: Prevalence of (a) phenotypic drug susceptibility and of (b) mutations associated or possibly associated with drug resistance in therapy-naive patients. Abac, Abacavir; Adef, adefovir; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; DLV, delavirdine; EFV, efavirenz; IDV, indinavir; NLV, nelfinavir; NVP, nevirapine; RTV, ritonavir; SQV, saquinavir; 3TC, lamivudine; ZDV, zidovudine.Table 1: Frequency of mutations found in reverse transcriptase and protease at positions in which changes are known to be or may be associated with drug resistance. Mutation K103N in RT, which can develop rapidly during NNRTI monotherapy [23], was detected in three individuals. A total of 2.6 and 3.6% of the study subjects had virus with a greater than 10-fold reduction in phenotypic susceptibility to nevirapine and delavirdine, respectively, and 15.6 and 17.7% had virus with an intermediate decrease in phenotypic susceptibility (Fig. 1). The significance of the size of these 'intermediate' groups should be considered in the light of recent data suggesting that the clinically significant level of resistance to NNRTI may be greater than 10-fold [24]. Patients who have virus with moderate decreases in phenotypic susceptibility to NNRTI may still respond to therapy regimens that include this class of drugs [25]. In the case of the PI mutations, 'primary' mutations at positions 46, 50, 82, 84 and 90 were detected, but not those at positions 30 and 48. These 'primary' mutations occur at low frequencies, whereas 'secondary' mutations such as those at positions 10, 36, 71 and 77 were each found to occur at greater than 10% frequency in this patient group. Similar distributions in the frequencies of these classes of mutations in protease have been observed in previous studies evaluating HIV-1 mutational patterns in therapy-naive patients [7,9,14]. Some studies reported not finding any 'primary' mutations and only a number of 'secondary' mutations in therapy-naive patients [4,13]. Secondary mutations have often been considered as natural polymorphisms, alone contributing little or nothing to drug resistance [4,26]. The high frequency of 'secondary' mutations in protease observed in the viral isolates in our study does not translate into a high incidence of decreased phenotypic susceptibility in those isolates. However, some of these secondary mutations are possibly involved in the development of cross-resistance among almost all PI. It seems that even though a number of primary mutations are necessary for the development of resistance to a single PI, co-resistance to several PI may have a different genetic basis [27]. The administration of PI to patients whose virus already harbors such 'secondary' mutations and the subsequent acquisition of 'primary' mutations may lead to the development of broad PI co-resistant virus. The transmission of such 'secondary' mutations may, therefore, compromise future therapy success in that initial therapy with PI may be successful despite the presence of secondary mutations [13], but once 'primary' mutations appear at first therapy failure in this mutational background, broad PI cross-resistance may rapidly develop.#OIn conclusion, we present a substantial HIV-1 susceptibility data set from therapy-naive individuals. This study confirms the substantial presence of pre-existing drug resistance, presumably caused by transmission. Continued surveys of this nature will be important to gain insight into the significance of the transmission of HIV-1 drug-resistant strains. Werner Verbiesta Stephen Brownb Calvin Cohenc Marcus Conantd Keith Henrye Susan Huntf Michael Sensiong Alan Steinh Richard Strykeri Melanie Thompsonj Patricia Schela Remi Van Den Broeckk Stuart Bloorl Timothy Alcornm Margriet Van Houttea Brendan Larderl Kurt Hertogsa

OBJECTIVE:To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN:Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS:Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS:Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS:Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months.

Background: Kaposi's sarcoma (KS) is the most frequent malignancy in patients with HIV. Given the promise that retinoids show in the treatment of various hyperproliferative skin disorders and in vitro evidence of inhibition of proliferation of KS cells, a randomized, controlled clinical trial was conducted. Methods and Results: A 12-week, multicenter, randomized, double-blind, vehiclecontrolled safety and efficacy evaluation of topical alitretinoin 0.1% gel applied to cutaneous KS lesions was conducted in HIV-infected patients. The primary efficacy endpoint was the patient's response rate, as determined by evaluating six index lesions representative of the patient's overall KS cutaneous disease using AIDS Clinical Trials Group (ACTG) response criteria applied to topical therapy. Of 268 patients entered in the blinded treatment phase of the study (alitretinoin group, n = 134; vehicle group, n = 134), 47 patients (35%) treated with alitretinoin 0.1% gel had a positive response, compared with 24 patients (18%) treated with vehicle gel. Of 184 patients receiving open-label alitretinoin treatment following the blinded phase of the trial, 90 patients (49%) met criteria for a positive response. This superior efficacy of alitretinoin gel over vehicle gel was maintained when the data were adjusted or analyzed for age, race, Karnofsky scores, baseline CD4+ lymphocyte counts, number of raised lesions at baseline, and aggregate area of index lesions. Alitretinoin 0.1% gel was superior to vehicle gel regardless of the number of concurrent antiretroviral therapies. Most adverse events were mild to moderate in severity, limited to the application site, and reversible on reduction in frequency or suspension of application. Relatively few patients (7%) discontinued alitretinoin therapy because of to related adverse events. Conclusions: The results show that alitretinoin gel application is safe and generally well tolerated, and they indicate the superiority of alitretinoin 0.1% gel over vehicle gel in the treatment of cutaneous AIDS-related KS lesions.

ABSTRACT Combination therapy with protease (PR) and reverse transcriptase (RT) inhibitors can efficiently suppress human immunodeficiency virus (HIV) replication, but the emergence of drug-resistant variants correlates strongly with therapeutic failure. Here we describe a new method for high-throughput analysis of clinical samples that permits the simultaneous detection of HIV type 1 (HIV-1) phenotypic resistance to both RT and PR inhibitors by means of recombinant virus assay technology. HIV-1 RNA is extracted from plasma samples, and a 2.2-kb fragment containing the entire HIV-1 PR- and RT-coding sequence is amplified by nested reverse transcription-PCR. The pool of PR-RT-coding sequences is then cotransfected into CD4 + T lymphocytes (MT4) with the pGEMT3ΔPRT plasmid from which most of the PR (codons 10 to 99) and RT (codons 1 to 482) sequences are deleted. Homologous recombination leads to the generation of chimeric viruses containing PR- and RT-coding sequences derived from HIV-1 RNA in plasma. The susceptibilities of the chimeric viruses to all currently available RT and/or PR inhibitors is determined by an MT4 cell–3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based cell viability assay in an automated system that allows high sample throughput. The profile of resistance to all RT and PR inhibitors is displayed graphically in a single PR-RT-Antivirogram. This assay system facilitates the rapid large-scale phenotypic resistance determinations for all RT and PR inhibitors in one standardized assay.

BACKGROUND AND OBJECTIVES:Education and counseling constitute a substantial portion of management of patients with genital herpes. Innovative methods for education about genital herpes are needed.GOAL:To test the ability of an interactive, computer-based program to educate patients about genital herpes.STUDY DESIGN:Persons seeking care at five urban offices were asked to participate. A knowledge test about genital herpes was administered before and after participation. Participants' satisfaction was assessed with a questionnaire.RESULTS:Four hundred thirty-five participants enrolled, and 428 completed the herpes knowledge test. Of six questions evaluated, a statistically significant increase in the proportion of correct answers was noted on five of six questions. Fifty-one percent of participants answered all the questions correctly after the program, compared with 39% before the program. Satisfaction with the program was very high.CONCLUSIONS:Innovative, computer-based programs can provide education and assist in the management of chronic sexually transmitted infections.

A phase I/II dose-ranging open-label 28-day monotherapy study of the safety, pharmacokinetics, and antiviral activity of nelfinavir mesylate (Viracept), an inhibitor of human immunodeficiency virus (HIV)-1 protease, was done in 65 HIV-l-infected subjects, After 28 days, 54 responding subjects entered an open-label extension that allowed for the addition of nucleoside inhibitors of reverse transcriptase and dose escalation to maintain durability. The drug was well-tolerated and demonstrated robust antiviral activity, with demonstrable superiority of the 750 mg and 1000 mg three times daily regimens. Thirty subjects who continued to receive therapy at 12 months attained a persistent 1.6 log(10) reduction in HIV RNA, accompanied by a mean increase in CD4 cells of 180-200/mm(3). Studies of viral genotype and phenotype after virus rebound revealed that the initial active site mutation allowing for nelfinavir resistance is mediated by a unique amino acid substitution in the HIV-1 protease D30N, which does not confer in vitro phenotypic cross-resistance to the currently available protease inhibitors.

Background: A recent study done in Baltimore showed HSV-2 seroprevalence of 81% among 64 HIV-positive homosexual or bisexual men. Objective: Our purpose was to examine HSV-2 as a risk factor for acquiring HIV infection, as well as to explore the possibility that acyclovir, an agent that inhibits the replication or infectivity in herpesviruses, might have a survival benefit to patients with HIV infection. Methods: Studies were undertaken among HIV-positive patients to see if concomitant treatments including acyclovir offered a survival benefit. Results: A Multicenter AIDS Cohort Study held at four university-affiliated clinics and two landmark analyses demonstrated that acyclovir offered a significant survival advantage for HIV-positive patients. Another study had less conclusive results. Conclusion: Enough evidence of a survival benefit in HIV-positive patients on long-term acyclovir therapy warrants consideration of long-term prophylactic therapy with suppressive doses of acyclovir as routine intervention for HIV-positive patients.

Sustained-release morphine (SRM) was studied in patients with acquired immune deficiency syndrome (AIDS)-related chronic pain. Outpatients and inpatients with AIDS-related pain were studied for 3-18 days in an open-label prospective survey. Patients were stratified according to prior opioid analgesic use for the purposes of initiating and titrating SRM, which was administered at a 12-hr interval. Immediate-release morphine (IRM) was offered every 2 hr as needed for supplemental analgesia at one-quarter to one-third of the 12-hourly SRM dose. Pain intensity (PI), quality of life (QL), acceptability of therapy (AT), side effects, safety, and morphine usage were evaluated. Of 44 patients enrolled, 40 (91%) were evaluable for intent-to-treat analysis, and 24 (55%) completed the study. PI decreased by 50% (from severe to mild-moderate) in the intent-to-treat patients and by 65% (from severe to mild) in the completed patients. QL was fair to good in 80% and poor in 20% of both groups. AT was good to excellent in 78% of the intent-to-treat and in 96% of the completed patients. Of 61 adverse events reported, 61% required intervention, and 92% were resolved. Total morphine dose remained stable while IRM dosage and frequency of use significantly decreased with escalation of the SRM dose. A significant reduction in PI was achievable with SRM in a variety of painful conditions experienced by AIDS patients, with limited or manageable side effects in most. This study supports the usefulness of opioid analgesia for severe pain in AIDS.