Marshall J. Glesby

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

CONTEXT Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adults with HIV infection. OBJECTIVES To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. DATA SOURCES AND STUDY SELECTION A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. DATA EXTRACTION AND SYNTHESIS New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. CONCLUSIONS Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count < or = 500/microL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count > 500/microL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.

Guidelines for the Evaluation and Management of Dyslipidemia in Human Immunodeficiency Virus (HIV)-Infected Adults Receiving Antiretroviral Therapy: Recommendations of the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group

Michael P. Dube, James H. Stein, Judith A. Aberg, Carl J. Fichtenbaum, John G. Gerber, Karen T. Tashima, W. Keith Henry, Judith S. Currier, Dennis Sprecher, and Marshall J. Glesby, for the Adult AIDS Clinical Trials Group Cardiovascular Subcommittee Indiana University, Indianapolis; University of Wisconsin, Madison; Washington University, St. Louis, Missouri; University of Cincinnati and Cleveland Clinic, Ohio; University of Colorado, Denver; Brown University, Providence, Rhode Island; University of Minnesota, St. Paul; University of California at Los Angeles; and Cornell University, New York, New York

Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection

AMD3100 is a CXCR4 receptor inhibitor with anti–HIV-1 activity in vitro. We tested the safety, pharmacokinetics, and antiviral effect of AMD3100 administered for 10 days by continuous intravenous infusion in an open-label dose escalation study from 2.5 to 160 μg/kg/h. Forty HIV-infected patients with an HIV RNA level >5000 copies/mL on stable antiretroviral (ARV) regimens or off therapy were enrolled. Syncytium-inducing (SI) phenotype in an MT-2 cell assay was required in higher dose cohorts. Most subjects were black (55%), male (98%), and off ARV therapy. HIV phenotype was SI (30%), non–SI (45%), or not tested (25%). One patient (5 μg/kg/h) had serious and possibly drug-related thrombocytopenia. Two patients (40 and 160 μg/kg/h) had unexpected, although not serious, premature ventricular contractions. Most patients in the 80- and 160-μg/kg/h cohorts had paresthesias. Steady-state blood concentration and area under the concentration-time curve were dose proportional across all dose levels; the median terminal elimination half-life was 8.6 hours (range: 8.1–11.1 hours). Leukocytosis was observed in all patients, with an estimated maximum effect of 3.4 times baseline (95% confidence interval: 2.9–3.9). Only 1 patient, the patient whose virus was confirmed to use purely CXCR4 and who also received the highest dose (160 μg/kg/h), had a significant 0.9-log10 copies/mL HIV RNA drop at day 11. Overall, however, the average change in viral load across all patients was +0.03 log10 HIV RNA. Given these results, AMD3100 is not being further developed for ARV therapy, but development continues for stem cell mobilization.

Survivor Treatment Selection Bias in Observational Studies: Examples from the AIDS Literature

Although the randomized, clinical trial is the gold standard for evaluating the effectiveness of treatment regimens for chronic diseases, observational treatment studies are useful and perhaps necessary. For many reasons, including ethical and economic considerations, clinical trials are not always feasible. For example, in diseases with a long natural history, such as human immunodeficiency virus (HIV) infection [1, 2], the long-term effectiveness of treatment is of obvious interest. However, a clinical trial will not provide data on long-term effectiveness if it is stopped early because one treatment shows greater short-term effectiveness in an interim analysis. Furthermore, the results of a prolonged clinical trial of one drug are difficult to interpret when new and potentially superior drugs become available to participants during the trial. Because of these difficulties, investigators have resorted to observational studies to evaluate therapies for chronic diseases. Although observational studies may complement clinical trials, they are prone to methodologic problems that create bias. In treatment studies, bias results from any systematic error in design, conduct, or analysis that yields a mistaken estimate of treatment effect [3]. Unlike clinical trials, in which patients are randomly assigned to treatment, observational studies allow patients and their physicians to select treatments. This can create an important bias; differences between patients who do and do not select a treatment exist and must be considered. For example, everything else being equal, sicker patients may elect to begin receiving treatment sooner than would patients who feel well [4]. Biases can also originate from the misanalysis of observational data rather than from the data themselves. One analytic bias has persistently appeared in many recently reported analyses of observational studies of therapy for HIV infection [5-19]. Longer survival may increase a patients chance to use treatment in an observational study. Patients who die sooner have less time to select treatment and thus, by default, are more likely to remain untreated. If this is not considered in the data analysis, the estimate of the treatment effect will be biased. This bias, which we have termed survivor treatment selection bias, is the focus of our paper. Survivor Treatment Selection Bias Correlation of longer patient survival with use of the treatment in question is often interpreted as evidence that the treatment prolongs survival. However, even an ineffective treatment will correlate with longer survival in observational studies, because longer survival causes treatment use. That is, longer survival increases the likelihood of treatment selection because patients who live longer have more time and more opportunities to gain access to or decide to begin treatment. This survivor treatment selection bias, unless considered appropriately, can lead to the incorrect inference that an ineffective drug improves survival. Consider the following extreme example of a hypothetical observational cohort of patients with the acquired immunodeficiency syndrome (AIDS), none of whom are using antiretroviral therapy at the start of the study. After 1 year of observation, a hypothetical new antiretroviral drug called placebovir becomes available; placebovir provides no survival benefit yet is widely believed to work. All patients who are alive at 1 year begin receiving treatment with placebovir, and all patients who have died by 1 year are untreated by default. If we compare survival in treated and untreated patients, the use of placebovir will obviously correlate strongly with longer survival: All of the patients surviving for more than 1 year and none of the patients dying within 1 year use placebovir. Attributing this improved survival of treated patients to placebovir, however, is obviously erroneous and is an illustration of survivor treatment selection bias. The next example more realistically simulates the survivor treatment selection bias that occurs in most observational studies. In a cohort study of 1000 patients with AIDS, a new treatment becomes available after the first month of observation. The treatment, placebovir, again provides no survival benefit. Overall, 50 of the 1000 patients (5%) die each month regardless of placebovir use, so that all patients are dead by 20 months of observation. Beginning after the first month, 10% of patients per month who are alive and not yet receiving treatment initiate treatment with placebovir. Thus, at the end of the second month of observation, 100 patients will have died. The first 50 died during the first month and were untreated, and, of the subsequent 50 patients who died, 5 (10%) had begun treatment and 45 were untreated. As time passes, more patients who are still living will be using treatment because, as they survive longer, more of them gain access to the drug. Eventually 561 of the patients (56%) will use placebovir. Of the 50 patients who died at 20 months, 43 used placebovir. A Kaplan-Meier analysis [20] of crude survival in those who did or did not gain access to treatment in this hypothetical example shows greater survival for the group that used placebovir (Figure 1). The median survival is 13 months in the treated patients and 5.5 months in the untreated group. With even a very few study participants (< 100), the P values for differences in survival curves shown in Figure 1 are low (P < 0.001). Direct comparisons of these Kaplan-Meier survival rates makes an ineffective drug appear to improve survival, because of survivor treatment selection bias. Figure 1. Hypothetical example of survivor treatment selection bias. dashed line The problem of survivor treatment selection bias has been previously recognized in the medical and statistical literature. Similar length biases have been discussed in the context of disease screening [21] and analysis of prevalent cohorts [22]. Several letters have been published in recent years commenting on the presence of this bias in observational studies of zidovudine use [23-27]. Nonetheless, as shown by its continuing occurrence in recent publications, investigators and reviewers still do not recognize this problem [5, 7-1012, 13, 15-19] or do not address it thoroughly [6, 11, 14]. Several of these publications, which are biased toward overestimating treatment effects, are cited as showing the effectiveness of zidovudine for HIV infection. However, because clinical trials have proven the effectiveness [28, 29] (albeit time-limited [30, 31]) of zidovudine, one could argue that it may not be important if some biased analyses from observational studies have overestimated the treatment effect of zidovudine. Indeed, two studies [6, 11] that were perceived by critics to have been misanalyzed with respect to survivor treatment selection bias [23-26] were subsequently reanalyzed using methods that appropriately address this bias [32, 33]. The investigators observed treatment effects of zidovudine that were similar to those from their original analyses. We contend, however, that survivor treatment selection bias is more than an academic issue and can lead to erroneous conclusions. To support this contention, we describe two studies that we believe reached debatable conclusions because of biased analyses. We focus on these particular studies only to illustrate the potential for misleading conclusions when survivor treatment selection bias is not considered. In the first study [10], the investigators compared survival after the onset of AIDS between male and female patients with AIDS whose cases were reported to a city public health department between 1981 and 1990. Using the Kaplan-Meier method, the investigators concluded that the median survival times of men and women who received antiretroviral therapy were similar, but that men who were untreated survived significantly longer than women who were untreated [median survival time, 14.6 months compared with 6.4 months]. They postulated that factors such as less access to care, older age, competing health risks, and diagnosis later in the course of HIV infection might account for the decreased survival of untreated women relative to that of untreated men. We believe, however, that the survival difference could have been caused by a stronger effect of survivor treatment selection bias in women, given that zidovudine was not available in the initial years of the AIDS epidemic and that the epidemic affected women later than men in the United States. Of the many reasons why a given person with AIDS in this study might have died without having taken zidovudine, two important reasons are central to our argument: 1) The person may have died before 1987, the year in which zidovudine became available, or 2) the person may have received a diagnosis of AIDS after 1987 but may have died relatively soon thereafter, having had little opportunity to initiate zidovudine treatment. In this study, only 25% of the female patients with AIDS but almost 50% of the male patients with AIDS had received a diagnosis before 1987. Thus, many of the untreated women may have lacked treatment because they died relatively soon (after 1987), whereas more of the untreated men may have lived longer but remained untreated only because zidovudine was not yet on the market. In the second study [19], the investigators analyzed data from a cohort of HIV-infected men and concluded that receiving both antiretroviral therapy and prophylaxis for Pneumocystis carinii pneumonia was significantly associated with longer survival time, but antiretroviral therapy alone was not. This finding is not consistent with those of other reports [34-36], and the data analysis was done so that survivor treatment selection bias is a legitimate concern. Routine use of prophylaxis for P. carinii pneumonia began chronologically after antiretroviral therapy, and this prophylaxis is generally initiated at a la

Coronary Artery Disease and Human Immunodeficiency Virus Infection

Recent reports of myocardial infarctions in young persons infected with human immunodeficiency virus (HIV) who are receiving protease inhibitor therapy have raised concerns about premature coronary artery disease in this population. Endothelial dysfunction, hypercoagulability, hypertriglyceridemia, and abnormal coronary artery pathology were in fact associated with HIV infection prior to the availability of protease inhibitor therapy. Newly recognized risk factors, such as insulin resistance, hypercholesterolemia, and fat redistribution syndrome, may exacerbate underlying atherosclerotic risk for patients receiving protease inhibitors. Data on the incidence of myocardial infarction among these patients are largely limited to case reports but are of concern. Pending the availability of further data, it is prudent to monitor these patients for hyperlipidemia and consider interventions to modify cardiac risk factors.

Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women.

BACKGROUND Whether the natural history of human papillomavirus (HPV) infection is affected by bacterial vaginosis (BV) or Trichomonas vaginalis (TV) infection has not been adequately investigated in prospective studies. METHODS Human immunodeficiency virus 1 (HIV-1)-infected (n=1763) and high-risk HIV-1-uninfected (n=493) women were assessed semiannually for BV (by Nugents criteria), TV infection (by wet mount), type-specific HPV (by polymerase chain reaction with MY09/MY11/HMB01 HPV primers), and squamous intraepithelial lesions (SIL) (by cytological examination). Sexual history was obtained from patient report at each visit. Risk factors for prevalent and incident HPV infection and SIL were evaluated by use of multivariate models. RESULTS BV was associated with both prevalent and incident HPV infection but not with duration of HPV infection or incidence of SIL. TV infection was associated with incident HPV infection and with decreased duration and lower prevalence of HPV infection. TV infection had no association with development of SIL. Effects of BV and TV infection were similar in HIV-1-infected and high-risk HIV-1-uninfected women. HIV-1 infection and low CD4(+) lymphocyte count were strongly associated with HPV infection and development of SIL. CONCLUSIONS BV and TV infection may increase the risk of acquisition (or reactivation) of HPV infection, as is consistent with hypotheses that the local cervicovaginal milieu plays a role in susceptibility to HPV infection. The finding that BV did not affect persistence of HPV infection and that TV infection may shorten the duration of HPV infection helps explain the lack of effect that BV and TV infection have on development of SIL.

Current Concepts in the Diagnosis and Management of Metabolic Complications of HIV Infection and Its Therapy

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection.

HIV-associated lipodystrophy often includes excess accumulation of visceral fat. Recombinant human growth hormone (rhGH) is a potential treatment for the excess visceral fat. Prospective, open-label trials of 24 weeks of rhGH 6 mg/d and 24 weeks of 4 mg every other day were conducted with an intervening washout period of 12 weeks. Thirty HIV-positive participants (26 men and 4 women) with visceral adiposity were enrolled. The main outcome measure was change in visceral adipose tissue (VAT) on whole-body magnetic resonance imaging scan. Changes in whole-body subcutaneous adipose tissue and skeletal muscle, glucose metabolism, serum lipids, and quality of life were also assessed. Despite stable body weight, VAT decreased in evaluable subjects an average of 42% with rhGH 6 mg/d (n = 24; p <.001) and 15% with 4 mg every other day (n = 10; p <.01) after 12 weeks, with trends toward further decreases after an additional 12 weeks at each dose. Subcutaneous adipose tissue also decreased, but proportionately less and not significantly on the lower dose. Skeletal muscle increased. Body composition rebounded to or near baseline after the washout period. Effects on lipids were inconsistent. Total cholesterol levels fell on the higher dose only, whereas high-density lipoprotein cholesterol levels increased on the lower dose only, and there was no effect on triglyceride levels. Joint pain was the most common adverse event, and was reflected in subjective quality of life measurements as an increase in bodily pain. Insulin sensitivity fell, and 4 participants developed diabetes. Other adverse events included cancer of unknown relationship to treatment in 3 participants. Levels of distress decreased after 24 weeks on the higher dose. In conclusion, rhGH effectively reduces the excess visceral adipose tissue often associated with HIV fat redistribution/lipodystrophy. However, frequent adverse effects warrant controlled studies and careful patient monitoring, especially regarding glucose tolerance.

Osteonecrosis in Patients Infected with Human Immunodeficiency Virus: A Case-Control Study

To evaluate risk factors for osteonecrosis in human immunodeficiency virus (HIV)-infected patients, demographic and clinical characteristics of case patients (n=17) and control patients (n=34) matched on initial clinic visit date, length of follow-up, and baseline CD4 cell count were compared. Case patients were more likely to have received corticosteroids (47.1% vs. 8.8%; matched odds ratio [OR], 13.1; 95% confidence interval [CI], 1.6-106), to have had an increase in CD4 cell count from nadir >0.050 x 10(9) cells/L (64.7% vs. 35.3%; OR, 4.9; 95% CI, 1.0-24), and to have had Pneumocystis carinii pneumonia (52.9% vs. 11.8%; OR, 7.6; 95% CI, 1.6-36). Use of protease inhibitors and history of other opportunistic infections did not significantly differ. In multivariate analysis, use of corticosteroids remained significantly associated with osteonecrosis, independently of HIV disease stage and protease inhibitor therapy. Corticosteroid use is an important risk factor for osteonecrosis, but its pathogenesis is likely multifactorial.

Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States

Background:Vitamin D deficiency is of increasing concern in HIV-infected persons because of its reported association with a number of negative health outcomes that are common in HIV. We undertook this study to determine the prevalence and predictors of vitamin D deficiency among a nationally representative cohort of middle-aged, ethnically diverse, HIV-infected and HIV-uninfected women enrolled in the Womens Interagency HIV Study (WIHS). Methods:Vitamin D testing was performed by Quest Diagnostics on frozen sera using the liquid chromatography/mass spectroscopy method. Vitamin D deficiency was defined as 25(OH)D ≤20 ng/mL. Comparisons of continuous and categorical characteristics among HIV-infected and HIV-uninfected women were made by Wilcoxon tests and Pearson χ2 tests, respectively. Results:One thousand seven hundred seventy-eight women (1268 HIV positive) were studied. Sixty-three percent had vitamin D deficiency (60% HIV positive vs. 72% HIV negative; P < 0.001). Multivariable predictors of vitamin D deficiency were being African American (adjusted odds ratio 3.02), Hispanic (adjusted odds ratio 1.40), body mass index (adjusted odds ratio 1.43), age (adjusted odds ratio 0.84), HIV positive (adjusted odds ratio 0.76), glomerular filtration rate <90·mL−1·min−1 (adjusted odds ratio 0.94), and WIHS sites Los Angeles (adjusted odds ratio 0.66) and Chicago (adjusted odds ratio 0.63). In the HIV-positive women, multivariate predictors were undetectable HIV RNA (adjusted odds ratio 0.69), CD4 50-200 cells per cubic millimeter (adjusted odds ratio 1.60), CD4 <50 cells per cubic millimeter (adjusted odds ratio 1.94), and recent protease inhibitor use (adjusted odds ratio 0.67). Conclusions:In this study of more than 1700 women in the United States, most women with or without HIV infection had low vitamin D levels and African American women had the highest rates of vitamin D deficiency. An understanding of the role that vitamin D deficiency plays in non-AIDS-related morbidities is planned for investigation in WIHS.