Abstract: HIV-associated neurocognitive disorder (HAND) is the result of neural damage caused by HIV replication and immune activation Potent antiretroviral therapy has reduced the prevalence of severe HAND but not mild to moderate HAND Brief symptom questionnaires, screening tests, and neuropsychological tests can be used with relative ease in the clinic to identify cognitive and neurologic deficits and to track patient status Increasing data on pharmacokinetics of antiretrovirals in cerebrospinal fluid (CSF) have permitted formulation of central nervous system (CNS) penetration-effectiveness (CPE) rankings for single drugs and combinations Available data indicate that regimens with higher CPE scores are associated with lower HIV RNA levels in CSF and improvement in neurocognitive functioning This article summarizes a presentation by Scott Letendre, MD, at the IAS-USA live continuing medical education course held in San Francisco in May 2011

Abstract: When to start antiretroviral therapy in patients with tuberculosis (TB) was addressed in the SAPIT (Starting Antiretroviral Therapy in Three Points in Tuberculosis Therapy) trial (Abstract 36a). In this 3-arm study, 645 South African adults with a CD4+ count lower than 500 cells/µL and a positive acid-fast bacillus (AFB) smear for TB underwent randomization to start antiretroviral therapy at TB treatment initiation or after the intensive phase of TB therapy but before TB treatment completion (the “integrated” groups), or after TB treatment completion (the “sequential” group). The antiretroviral regimen was daily didanosine, lamivudine, and efavirenz. The Data and Safety Monitoring Board (DSMB) halted the trial when the mortality of patients in the 2 integrated antiretroviral therapy and TB treatment groups was 56% lower than those in the sequential group. These data support current World Health Organization (WHO) guidelines that patients with TB who meet criteria for antiretroviral therapy should not wait until completion of TB therapy to start antiretroviral therapy. Although mortality in patients with CD4+ counts between 200 cells/µL and 500 cells/µL was lower in patients in the integrated treatment groups, the study was not powered to determine the benefit of antiretroviral therapy in persons with a CD4+ count between 350 cells/µL and 500 cells/µL, for whom guidelines currently recommend completion of TB therapy before starting antiretroviral therapy. An important remaining question is the optimal timing of antiretroviral therapy during TB therapy, for which the ongoing 2 integrated treatment groups of the SAPIT trial, the CAMELIA (Cambodian Early Versus Late Introduction of Antiretrovirals) study and the AIDS Clinical Trials Group (ACTG) A5221 study, will inform the field. Which antiretroviral therapy to start in patients with TB was addressed in Swaminathan and colleagues’ Chennai, India– based TB treatment study (Abstract 35). In this study, 127 HIV-seropositive adults with TB underwent randomization to 1 of 2 once-daily antiretroviral regimens after completing a 2-month TB treatment induction phase: nevirapine, didanosine, and lamivudine or efavirenz, didanosine, and lamivudine. The DSMB also recommended stopping this study early when virologic suppression rates were 28% higher in the efavirenz- than in the nevirapine-containing regimen. The oncedaily dosing of nevirapine and its interaction with rifampin likely resulted in lower levels of nevirapine and worse virologic outcome. Thus, when using a once-daily antiretroviral regimen in patients with

Abstract: The ultimate goal of hepatitis C virus (HCV) treatment is the eradication of the virus. Ongoing research continues to add to knowledge of the HCV life cycle, revealing new potential viral and host targets for the development of therapy. Understanding of HCV was initially hampered by the inability to achieve viral replication in cell culture. Advances such as the HCV replicon and complete cell culture systems, however, have permitted rapid growth in knowledge and accelerated testing of candidate antiviral agents. Among potential targets are viral entry factors, including scavenger receptor type B1 (SR-B1) and CD81, as well as neutralizing antibodies against the viral glycoproteins. Popular targets related to translation and replication are the NS3/4A protease (inhibited by telaprevir and boceprevir) and the NS5B polymerase, as well as the NS2/3 autoprotease, the NS3 helicase, and nonenzymatic targets such as NS4B and NS5A proteins. Host targets are also available, including microRNAs and cyclophilins. This article summarizes a presentation by Charles M. Rice, PhD, at the IAS-USA live continuing medical education course, Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes, held in New York City in April 2011.

Abstract: Developing and testing safer conception methods that reduce HIV transmission to HIV-seronegative partners in serodiscordant couples and reduce superinfection in HIV-seroconcordant couples is a crucial but often unaddressed component of HIV prevention programs. Most research has focused on developed-world settings, where "high-technology" assisted reproduction techniques are used for HIV-serodiscordant couples in which the male is HIV-infected. There is a dearth of research on safer conception methods for HIV-seropositive women and "low-technology" harm-reduction strategies for HIV-affected couples, including vaginal insemination for HIV-seropositive women and natural conception methods for HIV-seroconcordant and -serodiscordant couples. This review summarizes international studies of safer conception interventions for HIV-affected couples, with a focus on feasibility in public-sector health settings where assisted reproductive technology is not readily available. Given that such low-technology options are feasible in most settings, well-designed, prospective interventions offering low-technology safer conception methods need to be developed and tested.

Abstract: Detection of acute HIV infection is important to public health because this stage is one of high infectiousness and appears to account for a disproportionate amount of HIV transmission. Newer technologies in HIV testing, including third-generation enzyme immunoassays (EIAs) that detect anti-HIV IgM and IgG antibodies, fourth-generation combination EIAs that detect both anti-HIV antibodies and HIV p24 antigen, and nucleic acid-based testing for HIV RNA, have markedly reduced the interval between infection and detection of infection. Rapid diagnostic tests including assays for IgG and IgM anti-HIV antibodies have high sensitivity and specificity. The availability and wide use of these newer technologies have motivated review of recommended HIV testing algorithms. Individuals' knowledge of their HIV serostatus contributes to reducing transmission risk behaviors. Thus, widespread testing, facilitated by newer technology, allows more individuals to know their serostatus and is the first step in any successful effort to curb the incidence of HIV infection. This article summarizes a lecture by Demetre Daskalakis, MD, at the New York City IAS-USA continuing medical education program held in November 2009 and re-presented in December 2010.

Abstract: The 19th Conference on Retroviruses and Opportunistic Infections (CROI) highlighted new information and provided in-depth discussion on advances in antiretroviral therapy (ART). Data regarding investigational drugs, including integrase strand transfer inhibitors (InSTIs) and zinc-finger nucleases disrupting CC chemokine receptor 5 (CCR5), were presented. Treatment trials in treatment-naive and treatment-experienced patients added to the knowledge base of which antiretroviral agents to initiate and when. Data from trials and observational cohorts suggested that, for patients on successful ART in resource-rich settings, mortality from non-HIV-related diseases may surpass that from HIV-related diseases, and overall lifespan may be nearing that of people without HIV infection. In resource-limited settings (RLS), prevention of mother-to-child transmission (PMTCT) and ART scale-up remained priorities. New data on antiretroviral resistance in RLS and on the implications of low-frequency mutations were presented.

Abstract: Vitamin D is important for cell growth, immunity, and metabolism. Deficiency has classically been associated with rickets and decreased bone density and more recently with increased risk and severity of autoimmune diseases, cancers, myocardial infarction, diabetes, and infectious diseases. How vitamin D can affect these diverse conditions is the subject of much research. The active form of vitamin D (vitamin D3) has been implicated recently in an intracellular process known as autophagy. In addition to its role in maintaining cellular homeostasis during conditions of stress, autophagy plays an important role in the control of many intracellular microorganisms including Mycobacterium tuberculosis. Recent work has identified that HIV-1 reduces autophagy during permissive infection and that agents that induce autophagy, including vitamin D3, can inhibit HIV-1 replication. These findings help provide a biological explanation for the increased risk of more rapid disease progression observed in HIV-infected persons with low levels of vitamin D or with genetic variants within the vitamin D receptor that alter binding to vitamin D. Controlled trials are needed to determine the potential for therapeutic benefit of vitamin D supplementation in HIV disease. This article summarizes a presentation by Stephen A. Spector, MD, at the IAS-USA continuing medical education program held in Chicago in April 2010.

Abstract: Alcohol use is common among persons with HIV infection and is associated with worse HIV treatment outcomes. Patients with hazardous levels of use are less likely to be receiving antiretroviral therapy, to be adherent to therapy, and to achieve virologic suppression. Screening, intervention, and referral to care for alcohol use disorder is an integral part of clinical care for individuals with HIV infection. Brief screening procedures can identify level of risk and determine whether patients require brief alcohol intervention or should be considered for behavioral therapy and pharmacologic treatment. Identification of concurrent mental health disorders is an important aspect of treating alcohol use disorders in HIV infection and other clinical settings. This article summarizes a presentation by Geetanjali Chander, MD, MPH, at the 14th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in Tampa, Florida, in June 2011. The Clinical Conference is sponsored by the IAS-USA under the Health Resources and Services Administration (HRSA) contract number HHSH250200900010C.

Abstract: HIV preexposure prophylaxis (PrEP) has demonstrated efficacy in 4 studies: 1) the CAPRISA 004 trial of pericoital administration of 1% tenofovir gel showed moderate (39%) efficacy in reducing risk of HIV acquisition in young women; 2) the iPrEx trial of daily oral emtricitabine/tenofovir had moderate (44%) efficacy in reducing risk of HIV acquisition among high-risk men who have sex with men (MSM); 3) the Partners PrEP Study in African HIV-serodiscordant couples, in which the HIV-seronegative partner received daily oral tenofovir or emtricitabine/tenofovir, showed high efficacy (62% and 73%, respectively); and 4) the TDF2 trial in young heterosexual men and women in Botswana demonstrated 62% efficacy of daily oral emtricitabine/tenofovir Greater adherence to PrEP is associated with greater efficacy Resistance to tenofovir and emtricitabine have been rare and were primarily observed during PrEP initiation in those with acute HIV infection PrEP has been found to be safe and well tolerated The FEM-PrEP trial of oral emtricitabine/tenofovir and the VOICE trials of daily 1% tenofovir gel and oral tenofovir (both studies conducted in African women) did not show protective benefit, for reasons that currently remain unknown The Bangkok Tenofovir Study of oral tenofovir in injection drug users, and the emtricitabine/tenofovir study arm of the VOICE trial, are ongoing Establishing PrEP programs will be a great challenge and a great opportunity This article summarizes a presentation by Connie L Celum, MD, MPH, at the IAS-USA live continuing education course held in Chicago in June 2011, and includes updates on PrEP trial results reported since July 2011

Abstract: Identification and treatment of advanced hepatitis C virus (HCV) infection is often challenging. Accurate fibrosis staging can be performed only by liver biopsy. For patients with advanced fibrosis (Metavir score, F3 or F4), progression to decompensated liver disease occurs at a rate of approximately 5% per year and progression to hepatocellular carcinoma occurs at a rate of 1% to 2% per year. Liver decompensation primarily results from altered hepatic blood flow caused by liver scarring and is characterized by ascites and its complications (hepatorenal syndrome, hepatic hydrothorax, and spontaneous bacterial peritonitis), hepatic encephalopathy, bleeding varices, and coagulopathy. Patients with advanced fibrosis need to be regularly monitored for evidence of decompensated disease, and complications need to be aggressively managed. This article summarizes a presentation by Kenneth E. Sherman, MD, at the IAS-USA live continuing medical education course, Management of Hepatitis C Virus in the New Era, held in New York City in April 2011.

Abstract: Providing antiretroviral therapy for the HIV-infected population is a complex and challenging task. Treatment is often complicated by the shifting demographic of HIV-infected patients that now includes a large aging population in which patients often have multiple comorbidities. HIV clinicans are challenged with choosing the optimal combination of antiretrovirals based on potency, tolerability, bioavailability, and ease of administration. The issue of bioavailability is of paramount importance for those patients who can't swallow tablets, are unable to take anything by mouth before a procedure, or who need medication through a nasogastric tube or percutaneous endoscopic gastrostomy tube. A thorough search of several drug databases, a literature search of MEDLINE through Ovid, and a review of full prescribing information for each currently available antiretroviral drug, was performed to obtain insight into the bioavailability of antiretrovirals. Implications for the findings are discussed as they relate to adherence, resistance, alternative methods of administration, and the sometimes conflicting information on bioavailability that exists for various antiretroviral agents.

Abstract: Thirty years after the first AIDS cases were reported in the United States, the HIV epidemic continues to be heavily concentrated among men who have sex with men (MSM) in the United States. MSM are heavily impacted throughout most of the world and are the predominant risk group throughout the Americas and Western Europe; heterosexuals are the predominant risk group in sub-Saharan Africa; and injection drug users predominate throughout Eastern Europe and Southeast Asia. In the United States, blacks and Latinos continue to be disproportionately affected, despite overall advances in HIV testing and care. The 2011 Conference on Retroviruses and Opportunistic Infections focused on populations heavily impacted throughout the world: adolescents, women, MSM, and serodiscordant couples. Several presentations focused on the unique relationship between herpes simplex virus type 2 (HSV-2) and HIV-1; although many opportunistic infections increase HIV acquisition risk, HSV-2 is likely the only one whose effective prevention or treatment could substantially influence HIV infection rates, because of the high prevalence and persistence of HSV-2. The 2011 conference also celebrated the substantial advances made in the use of antiretroviral drugs for prevention of HIV acquisition (eg, oral preexposure prophylaxis, topical microbicides) and transmission (eg, antiretroviral therapy). Further progress is also being made in evaluating other prevention strategies and their rollout, including male condoms, male circumcision, and HIV testing and linkage to care.

Abstract: Presentations at the 2011 Conference on Retroviruses and Opportunistic Infections reflected the resurging interest in antibody responses against HIV given the encouraging results of the Thai vaccine trial. A plenary talk and an entire symposium were devoted to HIV-specific antibody responses describing newly isolated, potent neutralizing monoclonal antibodies. These antibodies undergo extensive somatic mutation to achieve their remarkable neutralizing properties. Inducing these types of antibodies by vaccination, however, still represents a challenge. New data were presented suggesting that neutralizing antibodies, but not binding antibodies, can provide protection against infection in the nonhuman primate (NHP) model. Several interesting discoveries were also reported showing that cellular immune responses recognizing HLA-C and HLA class II molecules might also be important in control of viral replication. Finally, new vaccine studies in the NHP model showed that electroporated DNA, along with the adjuvant interleukin 12 may be an efficacious vaccine regimen.

Abstract: Among the most frequently asked questions by callers to the National Perinatal HIV Hotline are those on the use of hormonal contraception in women receiving antiretroviral therapy. Estradiol levels are reduced by ritonavir-boosted protease inhibitors (PIs), nelfinavir, and nevirapine and increased by non-ritonavir-boosted PIs (except nelfinavir), efavirenz, and etravirine. Oral contraceptives do not affect antiretroviral drug levels, and several options are available for hormonal contraception that can compensate for or avoid the effects of antiretroviral drugs on estrogen levels. Other common questions on the hotline involve interpretation and management issues that arise from indeterminate Western blot test results early and late in pregnancy and from positive rapid test results during labor. Many questions focus on appropriate selection of antiretroviral drugs in pregnancy and the need to change regimens to reduce risk of birth defects in the child. This articlesummarizes a presentation by Jess Fogler Waldura, MD, at the 13th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in August 2010 in Washington, DC.

Abstract: 1 Dr Pape is professor of medicine at the Weill Medical College of Cornell University in New York, New York, and director of Les Centres GHESKIO in Port-au-Prince, Haiti. Dr Fitzgerald, assistant article editor, is associate professor of medicine at the Weill Medical College of Cornell University. The 2007 estimated prevalence of adult HIV infection in the Caribbean region was 1.1%. Prevalence rates in the large Caribbean countries ranged from 1.1% in the Dominican Republic to 3% in the Bahamas, with the highest rates in men who have sex with men, female sex workers, tuberculosis (TB) patients, crack-cocaine users, children living on the streets, and prisoners. HIV disease is the leading cause of death among Caribbean people aged 25 years to 44 years. There are an estimated 20,000 new infections per year, representing 2 new infections for every patient starting antiretroviral therapy. The CIPRA HT001 trial, which assessed 2006 World Health Organization guidelines for antiretroviral therapy initiation, showed substantial reduction of mortality and new-onset tuberculosis with treatment starting at CD4+ cell counts between 200/μL and 350/μL versus initiating at counts below 200/μL. However, in practice, CD4+ cell count at the start of treatment remains well below 200/μL in the majority of locales. Successes in the battle against HIV disease in the Caribbean include reduction in prevalence and mother-to-child transmission rates in some locales, increased use of antiretroviral therapy, increased use of condoms by female sex workers, and vastly improved safety of donated blood units. Much work remains to be done. This article summarizes a presentation by Jean William Pape, MD, at the International AIDS Society–USA continuing medical education program held in New York City, just weeks before the devastating earthquake in Haiti on January 12, 2010. The original presentation is available as a Webcast at www.iasusa.org. Perspective HIV Disease in the Caribbean

Abstract: The Infectious Diseases Society of America Annual Meeting serves as a time of expert review of the year's most important innovations. Important new information on HIV infection incidence was discussed. The remarkable efficacy of "treatment as prevention" in the HIV Prevention Trials Network (HPTN) 052 study and the proper place of oral preexposure prophylaxis were among the important prevention topics. Key engagement-in-care research indicates that only 19% of HIV-infected persons in the United States have a plasma HIV RNA level below the limits of assay detection. Among antiretroviral topics, the role of the newly approved nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine was discussed. Primary care topics for the HIV-infected population included treatment of triglyceride level elevations and bone health. The newly published data on the proper timing of antiretroviral therapy initiation after starting tuberculosis treatment were highlighted. Finally, exciting advances in the treatment of hepatitis C virus (HCV) infection necessitate that practitioners understand the complexities of treating HIV/HCV coinfections.

Abstract: The Conference on Retroviruses and Opportunistic Infections (CROI) provides an annual international forum for basic scientists and clinical and global health researchers to present and become current on the most recent advances in the field of HIV and AIDS research. The 18th conference contained a number of strong basic science sessions. HIV-1 infection of the cell is opposed by cellular factors that attack the viral replication cycle at various points. However, the virus has evolved defenses against these innate cellular antiviral proteins. CROI continues to be a strong forum for presentation of the most recent developments in this area of research. In addition, there were numerous presentations on cellular factors that regulate virus-host cell interplay as well as on research that is providing detailed insight into the mechanism of action of integrase inhibitors. Some presentations focused on approaches to studying and intervening with viral latency, particularly in primary cell models. Research on the use of zinc-finger nucleases to knock out CC chemokine receptor R5 expression in CD34+ stem cells also received a lot of interest. The hope is that these strategies will provide new therapeutic approaches to generate resistance to HIV-1 infection.

Abstract: HIV-associated neurocognitive disorders (HAND) remain a substantial problem in the era of combination antiretroviral therapy. Neither the Mini Mental State Exam nor the HIV Dementia Scale is sufficiently sensitive for HAND. The Montreal Cognitive Assessment shows promise, but current data suggest that adding an additional test will be needed to improve sensitivity for the clinical setting. Patient reporting of symptoms is insensitive as most cases of HAND are asymptomatic. Examination of cerebrospinal fluid (CSF) is sometimes warranted in select patients to evaluate for CSF HIV RNA detectability. CSF escape of virus, when CSF HIV RNA is detectable but plasma HIV RNA is not, appears to be a relatively uncommon event in the clinical setting where the level of detectability for typical clinical assays is around 50 copies/mL. In cases of CSF escape, cognitive improvement has been linked to changes in antiretroviral regimens that are aimed at either overcoming antiretroviral resistance or improving central nervous system (CNS) penetration-effectiveness. Currently, for most patients with HAND in the absence of unusual features, there are insufficient data for a recommendation to routinely intensify therapy with a neurointensive antiretroviral regimen; however, there is considerable uncertainty given emerging data and variability in approach among experts in the field. This article summarizes a case-based presentation by Victor G. Valcour, MD, at the 14th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in Tampa, Florida, in June 2011. The Clinical Conference is sponsored by the IAS-USA under the Health Resources and Services Administration (HRSA) contract number HHSH250200900010C.

Abstract: Poor retention in HIV disease care is a common, modifiable risk factor associated with poor outcomes, including higher rates of antiretroviral therapy failure, increased HIV transmission risk behaviors, and worse survival. Predictors of poor retention include younger age, female sex, racial or ethnic minority status, low socioeconomic status, no usual source of health care, less advanced HIV disease, fewer non-HIV-related comorbidities, and greater unmet psychosocial needs. Thus far, there have been few published randomized trials of interventions to improve retention. The fact that most clinics are understaffed and underresourced in a flat funding environment raises serious questions about the translation, dissemination, and sustainability of interventions found to be successful in the research setting. Efforts to improve retention in care should incorporate informational, motivational, and behavioral skills components. Practical steps can be taken by clinics to improve retention. This article summarizes a lecture by Thomas P. Giordano, MD, MPH, at the 13th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in Washington, DC, in August 2010.

Abstract: Cardiovascular disease (CVD) is the leading cause of non-HIV-related death in HIV-infected persons. The risk of CVD in HIV-infected persons appears to reflect the contribution of a number of factors, including non-HIV-related (traditional) cardiovascular risk factors, chronic inflammation associated with HIV infection, and metabolic adverse effects of antiretroviral therapy. Traditional CVD risk factors, however, are the major determinants of risk in HIV-infected patients and this population carries a high burden of such factors. HIV infection may also be an independent risk factor for CVD, but there is not yet sufficient evidence to consider HIV infection itself a coronary heart disease risk equivalent (eg, in the same manner as diabetes) or to change calculation of risk in the HIV-infected population. In the absence of specific randomized trials in the HIV-infected population, HIV-infected persons should be treated for cardiovascular risk factors according to current national guidelines for reducing risk, including those for aspirin use and for treatment of dyslipidemia, hypertension, and metabolic syndrome. This article summarizes a presentation by Wendy S. Post, MD, at the 14th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in Tampa, Florida, in June 2011. Dr Kerunne Ketlogetswe provided additional editing. The Clinical Conference is sponsored by the IAS-USA under the Health Resources and Services Administration (HRSA) contract number HHSH250200900010C.