搜索结果：Current opinion in HIV and AIDS

Introduction A panel of experts met in Paris on 18 April to present research and practice protocols, and to discuss topics of current interest related to the treatment of HIV/hepatitis C virus (HCV) co-infection. The information presented focussed on the following main aspects: The magnitude of the problem of HIV/HCV co-infection The differences and similarities between HIV and HCV disease paradigms, thereby allowing extrapolation of the lessons learned in HIV on the care of patients with HCV or HIV/HCV co-infections Strategies for managing HIV in HCV-co-infected patients using antiretroviral drugs Current standards for HCV treatment and ongoing management Strategies for treating HCV in HIV-co-infected patients using pegylated interferon (peg-IFN) plus ribavirin, and the management of possible adverse effects Special challenges in HIV/HCV co-infection, including non-responders to IFN/ribavirin, patients with cirrhosis, extrahepatic manifestations, and hepatitis B virus co-infection. The bulk of the meeting was devoted to a discussion of the specifics of HIV/HCV co-infection treatment, answering the questions: why? how? who? when? After presentations and discussions, a consensus of opinion regarding general treatment strategy was formulated. Hepatitis C virus treatment in co-infected patients: why? AIDS-related morbidity and mortality in HIV-infected patients continue to decrease as a result of effective antiretroviral therapy and prophylaxis for traditional opportunistic infections [1]. HIV-infected patients now have hope for a prolonged AIDS-free survival. Concurrently, however, the morbidity and mortality from co-morbid HCV infection within this population is on the increase. The magnitude of the co-infection problem becomes clear when its prevalence and impact on morbidity and mortality are considered [2–9]. Prevalence of hepatitis C virus–HIV co-infection In the United States, it is estimated that 30% of the 800 000 HIV-infected living individuals are co-infected with HCV [10,11]. Similar rates (33%) have been estimated for western Europe, although the number of HIV-infected individuals is less well defined [12]. However, the magnitude of the problem is alarming in countries such as Spain, where at least half of the 130 000 HIV-infected patients are estimated to be HIV/HCV co-infected [12]. In fact, among some sub-groups of HIV-infected patients, such as injection drug users, the prevalence of co-infection is as high as 70–90% [11–13]. Hepatitis C virus and clinical progression of HIV disease The Swiss Cohort Study demonstrated that HCV accelerates the progression of HIV disease [14]. This prospective study of patients starting highly active antiretroviral therapy (HAART) found that HCV was independently associated with an increased risk of progression to AIDS and death. This finding was not related to a lower usage or much poorer tolerance of antiretroviral drugs among individuals with hepatitis C, which is in agreement with findings from other European groups [15]. Therefore, hepatitis C might be considered to be a co-factor for HIV disease progression. On the other hand, the Johns Hopkins Cohort Study found that co-infected patients who had a baseline CD4 cell count of between 50 and 200 cells/mm3 progressed to death more quickly than their HIV-mono-infected counterparts [16]. This observation probably highlighted the fact that HCV-positive patients, most of whom were intravenous drug addicts, had significantly less exposure to HAART, with a delay in treatment until CD4 cell counts dropped below 50 cells/mm3. In contrast with this potential deleterious effect of hepatitis C on HIV disease progression, recent reports [17,18] have pointed out that the hepatitis G virus, an agent closely related to HCV, seem to exert a protective effect on the course of HIV disease. As treatment of HCV with IFN is equally effective against hepatitis G, its clearance might negatively influence HIV infection. Hepatitis C virus and response to highly active antiretroviral therapy The Swiss Cohort Study also demonstrated that HCV may impair immune reconstitution after effective HAART [14]. HCV-positive individuals were less likely to achieve a CD4 cell increase of at least 50 cells/mm3 at one year after the start of HAART compared with HCV-negative individuals. This observation has not, however, been confirmed by others [19], and warrants further studies. HIV and acceleration of hepatitis C virus liver disease HIV accelerates HCV-related liver disease [20–25]. Progression that typically takes up to 30 years or longer in HCV-mono-infected individuals has been shown to take less than half that time in co-infected individuals. An early study by Martin et al. [26] identified the development of cirrhosis within 3 years after HCV diagnosis in three co-infected patients. In 1993, Eyster et al. [27] found that liver failure was accelerated by HIV in HCV-infected haemophiliac individuals. The following year, Telfer et al. [28] published a retrospective study, which found that the median time from first exposure to HCV to clinical demise was only 16.5 years in co-infected haemophiliac individuals. In a large study of HCV-mono-infected and HIV/HCV co-infected individuals, Sánchez-Quijano et al. [29] found that within 15 years of initial HCV infection, 25% of those who were co-infected with HIV developed cirrhosis compared with only 6.5% of those without HIV infection. Similar data were obtained by Soto et al. [30], who followed a large group of HCV-mono-infected and co-infected patients. In the first 10 years, 14.9% of co-infected patients developed cirrhosis compared with only 2.6% of HCV-mono-infected patients. Overall, cirrhotic HIV-infected patients with HCV do very poorly. In a study conducted by Di Martino and colleagues [31], HIV/HCV-co-infected patients with cirrhosis were more likely to decompensate and die than patients who were HIV negative. Interestingly, HCV treatment with IFN plus ribavirin appeared to be protective in most instances, with protection extending to those with HIV. This suggests retrospectively that although HCV treatment is less effective in cirrhotic patients from an antiviral perspective, it may delay decompensation [32]. Hepatocellular carcinoma in co-infected patients Hepatocellular carcinoma (HCC) appears to occur at a younger age and after a shorter duration of HCV infection in co-infected individuals. This was the finding in a case–control study in which seven co-infected individuals with HCC were analysed [33]. The mean age at HCC diagnosis was 42 years in the co-infected group compared with 69 years in the control group. The estimated mean length of HCV infection before HCC diagnosis was 18 years in the co-infected group, compared with 28 years in the control group. End-stage liver disease mortality in co-infected patients A number of studies have demonstrated the association of HIV co-infection with an increased risk of morbidity and mortality caused by end-stage liver disease (ESLD) (Table 1) [2–9]. Iribarren et al. [34] reviewed the causes of death among a population of 1600 co-infected patients in a Spanish hospital over a 21 month period. Of the 44 total deaths, liver disease was responsible for up to 25%. Recent studies from Italy [3] and Spain [2,4] have compared the percentage of total in-hospital deaths caused by ESLD before 1995 with in-hospital deaths occurring within a time period after 1995. Although the total number of in-hospital deaths declined from the first time period to the later, the percentage of deaths caused by ESLD increased from 13 to 35% in the Italian study, and from 5 to 45% in the Spanish studies.Table 1: Mortality caused by end-stage liver disease among HIV-infected individuals. Similar results were seen in a US study [6]. In 1991, 11% of deaths in the studied HIV population were caused by ESLD. By 1998, ESLD was the leading cause of death, causing 50% of deaths (Table 1). Of those patients who died in 1998 of ESLD, 90% were HCV positive. In France, Cacoub et al. [8] documented a fivefold increase in deaths caused by liver disease in the time period before 1995 compared with after 1997, despite an overall declining death rate among co-infected individuals (Table 1). In 1997, Darby et al. [35] published a cohort study demonstrating the impact of co-infection among young men with haemophilia. HIV-infected patients, regardless of the severity of haemophilia, were found to be approximately sevenfold more likely to die of liver disease. Lesens et al. [36] also demonstrated a sevenfold increased risk of death in a 1999 prospective study of 147 HCV-positive haemophiliac individuals. Interestingly, co-infected patients with genotype 1 may have a more rapid progression of liver disease than individuals carrying other HCV genotypes [37]. Immune status influences hepatitis C virus liver disease Rockstroh et al. [38] looked at the association between immune function and the development of HCV liver disease. The study concluded either that immunosuppression accelerates the progression of liver disease or that once liver failure begins, deterioration with respect to AIDS also begins, progressing to death more rapidly. The finding of a greater severity of HCV liver disease as the immunodeficiency progresses has been confirmed by others [39]. Accordingly, the 1999 US Public Health Service/Infectious Diseases Society of America guidelines recognized HCV co-infection as an important opportunistic pathogen among HIV-infected patients [36,40]. Impact of highly active antiretroviral therapy on hepatitis C virus liver disease The impact of HAART on the progression of HCV liver disease is controversial. One possibility is that antiretroviral therapy could increase hepatic necroinflammatory activity and thereby accelerate the progression of HCV-related liver disease. Vento et al. [41] reported an increased mean Knodell score (from 8 to 13) in patients after starting HAART. Conversely, other studies have suggested that the use of HIV protease inhibitors (PI) may be associated with an improvement in liver histology with respect to those without PI [42,43]. This benefit may probably equally be seen with other potent antiretroviral regimens without PI. Prospective studies involving paired liver biopsies are needed to address the impact of HAART and immune reconstitution on HCV-related liver disease. Hepatotoxicity of highly active antiretroviral therapy in co-infected patients The association of chronic HCV with hepatotoxicity during HAART is well established [44,45]. Hepatitis C is an independent risk factor for hepatotoxicity with HAART (Table 2) [46–52]. Overall, significant liver enzyme elevations are seen in approximately 15% of individuals receiving antiretroviral drugs. Severe hepatotoxicity, however, leading to drug discontinuation, occurs in less than 10% of cases. Two mechanisms have been involved (Table 3), the first of which represents a hypersensitivity reaction, often affecting the skin and other organs, and occurring a few days to weeks after beginning antiretroviral therapy. A second mechanism with delayed onset (typically appearing several months after beginning therapy) is limited to the liver, and represents an intrinsic toxic effect of the drugs in use, and therefore is dose related [52]. Drugs such as nevirapine can produce liver toxicity by both mechanisms; whereas abacavir tends to involve just the first mechanism, often in the context of a multiorganic reaction. Drugs such as stavudine may cause liver toxicity through a cumulative effect.Table 2: Major studies assessing the risk of severe hepatic damage after beginning antiretroviral therapy. Table 3: Mechanisms of liver toxicity using antiretroviral drugs [32]. More rarely, in HCV chronic carriers experiencing a dramatic CD4 cell increase after beginning antiretroviral therapy, increases in transaminases can reflect an immune reconstitution syndrome [53], resembling what has been described in individuals with latent cytomegalovirus or mycobacterial infections. Further research is needed to determine the mechanism by which HCV infection or HCV-related liver disease increases the risk of HAART-associated liver injury. Hepatitis C virus-RNA dynamics in HIV infection and impact of highly active antiretroviral therapy Overall, serum HCV-RNA titres are 1.5 to twofold higher in HIV/HCV co-infected individuals with respect to individuals with single HCV infections [54–56], probably reflecting an impairment in the control of HCV replication in the setting of immunodeficiency. Whether this increase in HCV viral burden contributes to explaining the greater liver injury noticed in HIV/HCV co-infected patients is unknown, although there is no clear correlation between the extent of liver fibrosis and the level of HCV RNA. In individuals who begin potent antiretroviral therapy, serum HCV-RNA levels tend to increase during the first 3 months [57–59], decreasing slowly thereafter, first returning to baseline levels and even decreasing much later [60] (Fig. 1). Antiretroviral therapy may thus indirectly benefit the prognosis of HCV-related liver disease, reducing HCV replication on the long term. However, the relationship of HCV load and the progression of liver disease is uncertain.Fig. 1.: Dynamics of serum hepatitis C virus RNA in HIV infection and impact of antiretroviral treatment.Hepatitis C virus treatment in co-infected patients: how? The primary goal of HCV treatment is to achieve a sustained virological response that permits fibrosis regression, the disappearance of extrahepatic manifestations, and a reduction of the risk of transmission [61]. Moreover, in patients without sustained virological response, the progression of fibrosis could be ameliorated through suppressive maintenance therapy [32,62]. Until recently, IFN plus ribavirin combination therapy was the standard of care for the treatment of HCV infection [11,61]. Peg-IFN plus ribavirin combination therapy is, however, currently the preferred option, as it allows one to achieve the highest virological response rates to date: 41–42% for genotype 1 and 76–80% for genotypes 2 and 3 (Table 4) [63,64]. In addition to inducing virological response, peg-IFN/ribavirin also allows fibrosis regression in viral sustained responders [64,65]. In non-responders, in whom the first goal is not achieved, viral eradication, the second goal, slows fibrosis progression, and the prevention of clinical outcomes (ESLD, HCC, and death) [32] might be attained with maintenance therapy using peg-IFN monotherapy.Table 4: Sustained virological response to pegylated interferons in HIV-negative individuals with chronic hepatitis C. Factors associated with sustained virological response The achievement of sustained response depends on host and viral factors. Poynard et al. [65] identified five independent predictors of sustained response to IFN/ribavirin. Genotype 2 or 3 is the most important predictor. The remaining four predictors were: low viral load (< 3.5 million copies/ml), no or just portal fibrosis, female sex, and age below 40 years. Subsequent analyses demonstrated that female sex as a predictor was an issue of body mass index rather than sex. Ribavirin doses particularly need to be adequate to weight if optimal response rates are to be achieved [64]. For instance, when using adequate ribavirin doses, up to 48% of individuals with genotype 1 and up to 88% of those with genotypes 2/3 reached sustained response using peg-IFN plus ribavirin [64]. Additional predictive factors of response related to HIV include CD4 cell counts greater than 500 cells/mm3, plasma HIV-RNA levels below 10 000 copies/ml, and no alcohol consumption [23,66]. Treatment considerations related to CD4 cell counts Co-infected patients with CD4 cell counts greater than 500 cells/mm3 should be treated for HCV eradication. In individuals with CD4 cell counts of less than 500/mm3, treatment is less effective [66], but may be considered in order to reduce the risk of hepatotoxicity of antiretroviral drugs and the higher risk of progression to liver failure among patients with lower CD4 cell counts [38,39]. Overall, current HCV treatment in HIV/HCV co-infected patients can normalize alanine aminotransferase (ALT) levels and clean HCV RNA by 50%, decrease the progression of fibrosis by 60%, and decrease the risk of dying by 16% [20–25,42,43]. Weight-based dosing Dosing on the basis of the patient's body weight seems to be the key to optimized success with minimal side-effects using peg-IFN/ribavirin: peg-IFN alfa-2b (1.5 μg/kg per week) or peg-IFN alfa-2a (180 μg per week) plus ribavirin (> 10.6 mg/kg per day) represents the most effective HCV treatment option [63,64,67]. This is especially important when considering the weight variation among population groups. For example, Americans weigh an average of 10 kg more than Europeans. Weight-based dosing not only ensures that patients receive enough drug, it also ensures that they do not receive too much drug, thereby reducing the risk of adverse events that may result if a standard dose is given to a low-weight patient. An adequate ribavirin dose, particularly at the beginning of treatment, is linked to an increased likelihood of sustained virological response. In a recent multicentre trial [68], greater ribavirin use at week 4 of treatment was associated with a greater response rate at week 24. Considering these findings, an adequate dose of ribavirin, particularly at the start of therapy, should not be modified without first trying other strategies to increase tolerance, such as the use of epoetin alfa [69]. Concern about ribavirin use in co-infected patients There has been concern about the use of ribavirin in HIV/HCV co-infected patients because of dose-dependent anaemia and drug–drug interactions [23,70]. Ribavirin-induced anaemia may be more significant in co-infected patients [21,22]. This risk, however, should not preclude treatment, because it can quite often be successfully managed with erythropoietin [69] or by ribavirin dose reduction. Prospective studies examining the efficacy of this approach are ongoing. Concerns regarding interactions between ribavirin and antiretroviral drugs are more complex. Ribavirin, a guanosine nucleoside analogue, is known to inhibit the intracellular phosphorylation of zidovudine, stavudine and zalcitabine in vitro. There is concern that this may cause anti-HIV antagonism in vivo. However, to date, clinical data have not supported these in-vitro observations [70,71]. In addition, ribavirin enhances the phosphorylation of didanosine (Fig. 2), which may be of benefit in increasing the anti-HIV effect [72]. However, recent case reports have led to concern about the possible increased risk of pancreatitis and mitochondrial toxicity in patients taking ribavirin and didanosine [73–76]. Therefore, patients receiving ribavirin in combination with nucleoside analogues such as zidovudine or didanosine should be observed closely, and in some cases, consideration may be given to modyfing HAART to avoid the combination of these drugs. Another aspect that is still unclear regards the potential compromise in the effect of ribavirin on HCV as a result of the concomitant use of zidovudine or stavudine, because all these compounds share the same phosphorylation pathways. Prospective studies are underway to evaluate the clinical and pharmacological interactions of HAART and peg-IFN/ribavirin therapy.Fig. 2.: Metabolic pathways leading to the potentiation of didanosine by ribavirin. Ribavirin inhibits inosine monophosphate (IMP) dehydrogenase. This leads to an increase of the IMP pool, which acts as a phosphate donor for the conversion of didanosine (ddI) into dideoxy-IMP (ddIMP). This compound is then metabolized into the triphosphorylated metabolites dideoxy-adenosine monophosphate (ddAMP), dideoxy-adenosine 5'-diphosphate (ddADP) and dideoxy-adenosine triphosphate (ddATP). The increased concentrations of ddATP inhibits both HIV reverse transcriptase and mitochondrial DNA polymerase γ.Warning on the risk of lactic acidosis acidosis is of the of associated with mitochondrial toxicity of mitochondrial toxicity may not be and include and lactic analogues not only in the of more but in their potential for causing disease there is no of mitochondrial toxicity of lactic acidosis with the use of ribavirin without other nucleoside A 1995 study observed patients over 5 years with anti-HIV and found a rate of lactic acidosis of per A more recent study found per among patients observed over 18 with nucleoside only patients taking stavudine and didanosine were the increased to per The and has reports of of lactic acidosis associated with nucleoside Of were associated with a single nucleoside and with [69]. Overall, stavudine and didanosine were the most associated with lactic and of the cases, A mortality rate of among these reported to the US and the severity of the Ribavirin is a potent of inosine monophosphate (IMP) which leads to levels of the active of a key involved in mitochondrial toxicity (Fig. of the of ribavirin as a for has not been as the development of ribavirin that of lactic acidosis with ribavirin have been described in individuals with HCV of lactic acidosis or mitochondrial toxicity associated with ribavirin have been identified up to however, in HIV/HCV-co-infected individuals of had data reported that the specifics of what drugs the patients were were on a fact that suggests the possibility that was the One was not receiving nucleoside and that was with and was to continue with of the were also on stavudine, and of the were on abacavir is a analogue, it is involved in the same as didanosine (Fig. it could with ribavirin. However, current data that abacavir has a very low potential for mitochondrial toxicity treating HIV/HCV co-infected patients need to be of the potential risk of lactic acidosis associated with the concomitant use of ribavirin and nucleoside Although this has been seen only in combination with the risk may also in combination with other nucleoside into these the use of ribavirin with particularly with clinical and should of serum and levels in HIV/HCV co-infected patients to didanosine and ribavirin. in co-infected patients Until 2 years IFN was the only drug for the treatment of chronic hepatitis C. Overall, response rates to IFN observed in co-infected patients were to those observed in HIV-negative patients (Table However, response rates were significantly lower among HIV/HCV co-infected patients with low CD4 cell counts In combination therapy the standard of care for the treatment of chronic hepatitis C [61]. on the and efficacy of combination therapy in co-infected individuals is (Table and Table co-infected patients treated with standard were followed by et al. at 18 months had a sustained virological response. et al. noticed a sustained response rate of taking in 18 HIV/HCV to a course of IFN studies and others were a of to determine with adequate CD4 HCV could be in a co-infected patient. in a prospective study, et al. followed co-infected patients who were non-responders to IFN at 3 After months on combination therapy, one achieved and HCV-RNA Treatment response to interferon in HIV/hepatitis C virus co-infected patients. Table Treatment response to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients. Table to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients who or to after a course of interferon data that patients receiving achieve a higher sustained response rate than patients receiving IFN/ribavirin, especially in those with HCV genotype 1 In an ongoing study from the Hepatitis HCV-RNA after weeks of therapy in 35% of patients receiving IFN plus ribavirin compared with only of those receiving standard IFN three plus ribavirin. This the that exposure to rather than three is more effective for viral eradication. findings that an with IFN are by an ongoing large Spanish trial In patients who after a course of IFN with an overall rate of response of one (Table in co-infected patients The first of the and efficacy of combination therapy with peg-IFN plus ribavirin in individuals has shown that the overall rate of response was The trial is conducted in Spain, and individuals have The rate of for these patients should be at the of the The study is a prospective multicentre trial currently in date, patients have been to receive either IFN 3 three a week plus ribavirin 800 or peg-IFN 1.5 μg/kg per week plus ribavirin 800 for to weeks after the onset of treatment, the HIV viral load has in both treatment groups. CD4 cell total and counts all declined after the onset of HCV treatment, with no between the groups. of severe adverse events have been in the peg-IFN/ribavirin group, in the group, and one before events and for drug The of in 13 in the peg-IFN/ribavirin group and in the group. Of these cases, were by the as a result of and a not to start the trial studies with peg-IFN/ribavirin in co-infected patients are ongoing. The trial to include and an study include patients. The first results of these studies are to be in of therapy The duration of therapy should be to the patient's virological response at weeks of treatment and the number of predictors of response HCV RNA is by polymerase treatment should be and other strategies is and the has than four predictors of response, treatment should continue the has four or more treatment may be at Moreover, results from a recent trial suggested that the of HCV RNA after weeks on peg-IFN plus ribavirin is highly predictive of a of further sustained response. Therefore, treatment might be at this early drug exposure and This observation is of in patients, most of whom are other drugs. Further studies are needed to this of anaemia with erythropoietin The of ribavirin is levels below in to 35% of patients receiving therapy Although this is managed by ribavirin dose reduction or discontinuation, erythropoietin therapy has to be an effective treatment In addition, the ribavirin dose is more likely to in patients with anaemia treated with what is known about the of adequate and

Introduction While the incidence of cryptococccal meningitis in the developed world has declined with widespread, early antiretroviral therapy (ART), cryptococcal disease remains a major opportunistic infection and leading cause of mortality in patients infected with HIV in much of the developing world. Most HIV-related cases are caused by Cryptococcus neoformans var. grubii (serotype A), while var. neoformans (serotype D) is responsible for a proportion, especially in Europe, and there are a small number of Cryptococcus gatti infections (formerly C. neoformans serotypes B and C) [1,2]. The last includes a small number of cases in HIV-infected individuals forming part of an unprecedented outbreak of C. gattii infections, predominantly in apparently immunocompetent patients, on Vancouver Island, Canada [3,4]. C. neoformans is distributed worldwide. An ubiquitous environmental saphrophyte, it is found in soil contaminated with pigeon droppings and has also been isolated from the heartwood of several tree species in South America [5] and India [6], and from the homes of African HIV-seropositive patients [7,8]. Exposure may be common [9], although the exact circumstances are usually unclear. Inhalation of small, thinly encapsulated yeasts, or basidiospores [10], may lead to an initial pulmonary infection, which, depending on host immune response and the number and virulence of the organisms, is cleared, contained within granulomata as a latent infection or disseminates. The minority in whom disease disseminates typically have defects in T cell function, through malignancy, immunosuppressive medication, autoimmune disease or sarcoidosis [11,12] or HIV infection, indicating the role of T cell-mediated immunity in host defence. In HIV-seropositive patients, most episodes of cryptococcal meningitis probably represent reactivation of latent infection, which may have been acquired many years earlier. There is compelling evidence for latent infection in a rat model [13] and humans [14]. Dromer and colleagues [15] typed C. neoformans isolates from HIV-seropositive patients diagnosed with cryptococcosis in France, some of whom were from Africa but had lived in France for a median of over 9 years. There was a significant clustering of isolates from African compared with European patients, suggesting that the patients had acquired their isolates long before the development of clinical disease. A proportion of HIV-related cases, however, may result from dissemination of new or primary infection [16], as has been observed in the recent outbreak of C. gattii infection in British Columbia [17]. HIV-associated cryptococcal meningitis usually presents as a subacute meningo-encephalitis in profoundly immunosuppressed patients (CD4 cell counts < 100 cells/μl), with malaise, headache, fever and, later, visual disturbance and altered mental status. Signs, if present, may include meningism, papilloedema, cranial nerve palsies [particularly sixth nerve palsies reflective of raised pressure in cerebrospinal fluid (CSF)] and reduced conscious level. The diagnosis is usually straightforward. The high organism load in this setting means the sensitivity of India ink staining of CSF is high. Those who have a negative result with India ink can be diagnosed by highly sensitive and specific cryptococcal antigen testing of CSF, or serum if CSF cannot be obtained [18]. Lumbar puncture often reveals markedly elevated opening pressures, an important complicating factor, with only modestly elevated or normal white cell counts (usually lymphocytes), elevated protein and low or normal glucose. High organism burden at baseline (indicated by quantitative CSF culture or CSF antigen titre) and abnormal mental status are the most important predictors of death [19,20], while high opening pressures and a poor inflammatory response in the CSF have also been associated with poor outcome [19,21,22]. Autopsy series reveal the lack of a protective granulomatous response in HIV-seropositive patients with cryptococcal meningitis. There is extensive involvement of brain parenchyma in addition to meningitis and higher organism burdens (which are predominantly extracellular) compared with the infection in HIV-seronegative individuals [23–25]. The remainder of this review will focus on the current epidemiology and management of HIV-associated cryptococcal meningitis, with some emphasis on the developing world where the burden of disease is highest. In addition to antifungal therapy, the important complications of elevated CSF pressure and immune reconstitution inflammatory syndrome (IRIS) and future approaches to prevention and therapy are discussed. Epidemiology Increasing numbers of cases of cryptococcal meningitis were reported in young adults in the former Zaire throughout the 1960s, possibly representing the first signs of the evolving HIV epidemic [26,27]. The late 1970s and early 1980s saw a sharp increase in the numbers of cases both in Kinshasa [28,29] and in Zairian immigrants to Europe [30–32], many of whom had, in retrospect, features suggestive of AIDS [33]. As the HIV epidemic expanded in the 1980s, C. neoformans emerged as an important opportunistic infection in the United States, Europe and Australia, occurring in 5–10% of all AIDS patients [34–38]. Rates of infection declined through the 1990s, initially with the widespread and frequent use of azoles to treat candidiasis [38,39], and subsequently with the introduction of HAART [40,41]. The annual incidence in AIDS patients in Atlanta fell from 66 per 1000 in 1992 to 7 per 1000 in 2000 [41]. HIV-related cryptococcal meningitis is now a problem in the West in patients who present with late-stage HIV infection, typically those with limited access to healthcare [40,41]. However, it remains a major opportunistic infection in the developing world in areas of high HIV seroprevalence [42,43]. C. neoformans is the leading cause of meningitis in central and southern Africa, accounting for 26.5% of cases in a series from Malawi [44], 31% in a series from the Central African Republic [45] and 45% from Zimbabwe [46]. In these areas, it is one of the main causes of mortality in cohorts of HIV-infected individuals, responsible for 13–44% of all deaths [47–49]. For comparison, 5–13% of deaths were attributed to tuberculosis in these studies. In Thailand, cryptococcosis accounts for up to 20% of AIDS-defining illnesses [43,50] and it is reported as a major opportunistic infection in India [51] and Brazil [52]. There are interesting geographical variations in incidence that presumably relate to differential rates of exposure. For example, cryptococcal disease appears to be more common in southern and east Africa than in west Africa [53], and in north and northeast Thailand compared with southern Thailand [43]. Even with current optimal treatment, the 10-week mortality of HIV-associated cryptococcal meningitis is high, ranging from 10 to 25% in developed countries, with no evidence of any decrease in recent years [54]. Of note, mortality is higher in less selected series [55] compared with clinical trails in which very sick patients are excluded [21]. In unselected series from resource-poor settings, acute mortality is up to 43% even with amphotericin B therapy [56]. In Zambia, median survival with low-dose fluconazole monotherapy was 19 days [57], barely better than that in the absence of antifungal therapy [57–59]. In South Africa, in a recent unselected prospective series [60], overall 10-week mortality was 37% despite initial treatment with amphotericin B for most patients and access to ART (Fig. 1).Fig. 1: Prospective observational study of survival of 54 patients with HIV-associated cryptococcal meningitis treated according local protocol (49 with amphotericin B 1 mg/kg daily, 5 with fluconazole) in Cape Town South Africa. Patients not already taking antiretroviral therapy at the time of presentation were started on therapy from 4 weeks after antifungal therapy. (From data in Bicanic et al. [60].)However, this last study also confirmed that, once over the acute cryptococcal infection and established on ART, the long-term outlook is good, as in the developed country setting, with a levelling of the survival curve. Therefore, in the setting of expanding access to ART across the developing world, the urgent challenge is to improve acute management and thereby increase the proportion of patients surviving the critical initial months. Antifungal therapy Current antifungal treatment guidelines (Table 1; [61,62]) are based in large part on the results of a large, randomized trial published a decade ago [21]. Initial therapy was with amphotericin B (0.7 mg/kg daily) with or without flucytosine (100 mg/kg daily) for 2 weeks, followed by an 8-week consolidation phase with either fluconazole (400 mg daily) or itraconazole (400 mg daily). The rationale was to gain control of infection with initial more rapidly active amphotericin B-based therapy but switch to well-tolerated azoles for consolidation treatment to minimize the dose-dependent toxicity of amphotericin B. The mortality was the lowest of any published trial, at 9.4% in the first 10 weeks. The addition of flucytosine was associated with a trend towards a higher proportion of patients with sterile CSF at 2 weeks and reduced relapse. Fluconazole was superior to itraconazole for consolidation treatment [21]. That the combination of amphotericin B plus flucytosine is more rapidly fungicidal than amphotericin B alone has been demonstrated in a subsequent study in Thailand using serial quantitative cultures to assess the rate of clearance of cryptococcal colony-forming units from the CSF or early fungicidal activity. The clearance of cryptococci from CSF was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone, amphotericin B plus fluconazole (at 400 mg daily ) or a combination of all three (Fig. 2[20]).Table 1: Antifungal treatment recommendations for HIV-associated cryptococcal meningitisa.Fig. 2: Fall in Cryptococcus neoformans colony-forming units (CFU) in cerebrospinal fluid (CSF) over time by treatment group. The decrease in log CFU/ml CSF per day was calculated for each patient using the slope of the linear regression of log CFU against time. For each treatment group, early fungicidal activity (EFA) is shown as the mean (±SD) rate of fall in log CFU. EFA was significantly greater for amphotericin B (AmB) plus flucytosine compared with AmB alone (P < 0.001), AmB plus fluconazole (P = 0.02), or triple therapy with AmB, flucytosine and fluconazole (P = 0.02). (Adapted from Brouwer et al. [20], with permission).Both these studies also demonstrated that, with appropriate monitoring, conventional amphotericin B is reasonably well tolerated, with drug discontinuations in 3% of patients in the first 2 weeks in the Mycoses Study Group trial [21]. Saline and fluid loading equivalent to 1 litre normal saline daily should be given unless contraindicated, to minimize nephrotoxicity [63], and electrolytes replaced as required. Anaemia, secondary to suppression of erythropoietin transcription [64], is also a predictable side effect of amphotericin B [65–67]. This may be more clinically significant in populations with lower baseline haemoglobin levels, and where transfusion, when occasionally needed, is difficult. Flucytosine, at the historically low daily dose of 100 mg/kg, was also well tolerated without real-time drug level monitoring in either trial. A substudy of the Thai trial comparing oral and intravenous flucytosine at the same daily dosage of 100 mg/kg has provided some insight into this observation. In contrast to earlier studies in other patient populations, oral bioavailability of flucytosine in these patients at a late stage of HIV infection was only around 50%, resulting in relatively low serum concentration, of an order not usually associated with toxicity. Nevertheless, despite the lower serum levels, patients on oral formulation had the same rate of clearance of infection as those on intravenous formulation [68], consistent with evidence for the dose-independent activity of flucytosine [69–71]. The data suggest that even 100 mg/kg daily, if given intravenously, may be in excess of that required for maximal additional fungicidal activity. If renal impairment does develop, liposomal amphotericin B, at 3 mg/kg daily, provides a less nephrotoxic and equally effective alternative. A small study suggested liposomal amphotericin B, at 4 mg/kg daily, was more active than conventional amphotericin B [72], but a larger study found no difference in the proportion of patients with sterile CSF at 2 weeks in patients receiving daily liposomal amphotericn B at 3 or 6 mg/kg compared with conventional amphotericin B at 0.7 mg/kg daily [73]. Unfortunately, in many resource-poor settings, amphotericin B is not available or cannot be used safely because of lack of monitoring, and fluconazole, widely available, through a free access programme or in generic form, is the only treatment option. Outcomes with initial fluconazole monotherapy at 200–400 mg daily have not been good, either in early US-based studies [19,74], including a small randomized study in which 400 mg daily was clinically inferior to amphotericin B plus flucytosine [74], or in more recent series from Africa [57,75,76]. Although the earlier randomized study comparing amphotericin B with fluconazole found no significant difference in clinical outcomes, time to sterilization was very long for fluconazole (median 64 days), and outcomes for both drugs were poor [19]. Furthermore, the dosages used for both drugs were lower than currently recommended, making interpretation difficult. The 10-week mortality of approximately 50% with initial fluconazole monotherapy reported by Schaars and colleagues [75] in South Africa represents a minimum estimate in this setting given the retrospective nature of the study with incomplete out-patient follow up. Recent work from Cape Town has demonstrated that 400 mg fluconazole daily is essentially fungistatic over the first 2 weeks of treatment [60]. The resulting prolonged period with a high viable organism load may predispose to the development of fluconazole resistance. Such resistance is a significant problem when initial therapy is with fluconazole [77]. A further concern is that prolonged active infection could also increase the risk of immune reconstitution reactions (see below) following introduction of ART, although data on this point are studies suggest a with fluconazole There is a linear with fluconazole at up to 2 daily and up to mg daily have in small numbers of patients In addition there is a of a in of the time to sterilization of with a median time to CSF sterilization of 64 days with 200–400 mg daily a mean time of days with 400 mg daily [74], and and days with mg this and given the results of treatment at lower a study of fluconazole therapy is currently in In the in where amphotericin B cannot be used safely and fluconazole is the only the suggest a dose of at mg daily (Table The combination of fluconazole plus flucytosine is or in although not in a study in A clinical study in suggested with addition of flucytosine to fluconazole, although the dose of fluconazole was low mg daily) and in a small series from the United States, the combination of flucytosine and fluconazole at 400 mg daily in a relatively median time to sterilization of CSF of although side with the combination frequent to the fungicidal activity and toxicity of this combination with higher of fluconazole are in where intravenous amphotericin B-based therapy is not While not as at conventional as amphotericin B for initial therapy, fluconazole is highly effective and as therapy Increasing evidence of this secondary is if there has been a significant and immune reconstitution with ART (CD4 cell for 6 cerebrospinal fluid opening pressure raised pressure is a major problem in cryptococcal meningitis, with over of patients pressures and a pressures in an of the last Study Group CSF pressure was associated with more cranial nerve and raised CSF pressure usually as headache, papilloedema, and of impairment and level of The leading to pressure are Although a inflammatory response is not a of HIV-associated cryptococcal meningitis, it is a role in some factor, a of has been in the CSF of patients with cryptococcal disease although no of this and CSF opening pressure has been the primary is to be of CSF at the because of the of and [23–25]. This be consistent with the of raised pressure with higher CSF antigen and higher rates of India ink and it usually remains as there is no pressure the and the CSF over the of the In of have been recommendations are based on small series and Current guidelines suggest daily for all patients with elevated baseline opening pressures with the of CSF to pressures by 50%, pressure has been normal for several days The of CSF that is to at a puncture is but is probably If or of the should be to initial puncture or if raised CSF pressure on therapy in order to cases of and In the cases in which a should be to control pressure and the is CSF can be with a less is long the in CSF but it may be that a significant proportion of patients will to relatively with a the of high of fluid daily) to a pressure are relatively to and have a low risk of complications with monitoring and and who are with their use The use of and for raised CSF pressure is not by available evidence A randomized trial of was early and were associated with higher mortality in patients with elevated CSF pressures in a large, although study meningitis immune reconstitution syndrome As has been with other opportunistic infections of ART can lead to of immune to viable or or in can lead to a clinical with the of cryptococcal disease or of treated has been reported in of patients with cryptococcal meningitis following of ART and may be In the the median time to of after ART was days however, cases have been reported after many include and with the of meningitis of have been by a higher CSF white cell and also higher opening pressures for cryptococcal include higher cryptococcal antigen at or widely disease and ART within 1 of antifungal therapy The diagnosis of cryptococcal is one of the following this ART and clinical presentation evidence of immune in cell of or resistance to fluconazole, a clinical features new or CSF white cell or consistent with an cell-mediated immune response negative cryptococcal cultures The role of is less in when cryptococcal cultures are but it is that immune reconstitution also to the presentation and of some patients who are culture [77]. The of cryptococcal has for the of The increase in the risk of cryptococcal with earlier of ART has to be against the risk of other HIV-related complications if of ART is of ART may be earlier in developing where rates of death to of ART are high currently most ART from 4 weeks into antifungal therapy, although it is earlier ART may be if a rapidly fungicidal is used for initial antifungal therapy. of cryptococcal is further If clinical despite appropriate antifungal therapy and management of any raised CSF which have been used in can be and The for primary antifungal is as access to ART the immune reconstitution with in the absence of ART, or in those who to to treatment, a for primary with fluconazole in those with cell counts < 100 in areas with a high incidence of cryptococcal disease Such a was in Thailand to widespread of ART and is in east Africa. In areas of high in of the significant proportion of patients now after ART [60], a can also be for with serum antigen to ART in order to and treat infection before it is by immune However, studies are needed, and a is not and is not used in areas of lower incidence for the high mortality of HIV-related cryptococcal disease include the of current antifungal therapy, access to some drugs in many areas the problem of raised CSF pressure and the lack of data on optimal of As are to some of these access to antifungal fluconazole is widely available through a free access programme and in generic In although generic amphotericin B is also available, the is and may be significant in very In has been an in some areas, including the United to the reduced for amphotericin B for other infections in the developed world. is a and that is not widely available either in Africa or where the burden of cryptococcal disease is high. one the drug to In where are not flucytosine can be obtained on a patient from If currently comparing fluconazole with flucytosine as a drug to with amphotericin B that flucytosine remains the drug of is to access to The rate of clearance of infection, or early fungicidal from serial quantitative cultures of CSF provides a means by which the activity of new drugs or for antifungal therapy can be in small numbers of this for testing in phase to be selected on a more Such clearance studies are to 1 mg/kg amphotericin B daily is associated with a significant increase in fungicidal activity compared with 0.7 mg/kg daily, and to flucytosine and fluconazole as a drug to with amphotericin B. studies are also with new azoles with activity against C. as although with and antiretroviral are a model data and into the central for and are shown in Of note, have limited activity because which are not important in the cryptococcal cell 2: on activity of and in the of current antifungal and over further drug there is in A against the of neoformans has phase studies and a against protein and reported to be when given with amphotericin B in candidiasis also has activity against C. in cryptococcal meningitis are An is use of There is evidence that is important for clearance of cryptococcal infection in HIV-infected patients A trial that therapy was and well tolerated, with no on HIV load or cell There was also a trend towards outcomes, with of negative cultures at 2 weeks compared with or of those receiving The trend in of was already after 2 weeks of treatment, and studies have shown that in the CSF at day 3 and is by day suggesting that of which be more to may be studies to cryptococcal for development and to the in the of as those with HIV infection

Table of contents 1.0 Introduction 2.0 Methodology 2.1 Basing recommendations on evidence 2.2 Implications for research 2.3 Use of surrogate marker data 2.4 Issues concerning design and analysis of clinical trials 2.4.1 Trial designs 2.4.2 Viral load outcome measures 2.4.3 Noninferiority 2.4.4 Cross-study comparisons and presentation of data 2.5 Adverse event reporting 3.0 When to start 3.1 Primary HIV infection 3.2 Established HIV infection 3.3 Patients with a CD4 count >350 cells/μL 3.4 Comorbidities 4.0 What to start with 4.1 Which HAART regimen is best? 4.2 Recommendations 4.3 Two NRTIs plus an NNRTI 4.3.1 Efavirenz (preferred regimen) 4.3.2 Nevirapine 4.4 Two NRTIs plus a boosted PI 4.4.1 Boosted lopinavir 4.4.2 Boosted fosamprenavir 4.4.3 Boosted saquinavir 4.4.4 Boosted or unboosted atazanavir 4.4.5 Boosted darunavir (unlicensed for naïve patients) 4.5 Three NRTIs 4.6 Choice of two NRTIs 4.7 Coformulated two NRTIs 4.7.1 Tenofovir/emtricitabine (Truvada) 4.7.2 Abacavir/lamivudine (Kivexa) 4.7.3 Zidovudine/lamivudine (Combivir) 4.8 Other two-NRTI combinations 4.9 Conclusions 5.0 Virological failure: after first-line treatment 5.1 Viral load blips 5.2 Sustained viral load rebound 5.3 Changing therapy 5.4 Virological failure with no resistance 5.5 First-line virological failure with PI mutations 5.6 Virological failure with NNRTI mutations 5.7 Virological failure with NRTI mutations alone 6.0 Subsequent virological failure 6.1 The patient with therapy options 6.2 The patient with few or no therapy options: continue, interrupt or change therapy? 6.2.1 Continuing the failing regimen 6.3 Treatment interruption 6.4 Change 7.0 New drugs 7.1 Etravirine (TMC-125) 7.1.1 Pharmacokinetics 7.1.2 Resistance 7.1.3 Efficacy, safety and tolerability 7.2 Maraviroc 7.2.1 Pharmacokinetics 7.2.2 Resistance 7.2.3 Efficacy, safety and tolerability 7.3 Integrase inhibitors 7.3.1 Raltegravir in treatment-experienced patients 7.3.2 Resistance 7.3.3 Raltegravir in treatment-naïve patients 8.0 Treating patients with chronic hepatitis B or C 8.1 Hepatitis B 8.1.1 When to treat 8.1.2 What to treat with 8.2 Hepatitis C 8.2.1 When to treat 8.2.2 What to treat with 8.2.3 Avoiding antiretroviral hepatotoxicity 8.2.4 Recommendations 9.0 Guidelines for the management of metabolic complications in HIV infection 9.1 Lipid abnormalities 9.1.1 Evaluation of risk 9.1.2 Which calculator to use 9.1.3 Treatment of lipid disorders 9.1.4 Switching ART 9.1.5 Lipid-lowering treatments 9.1.6 Which agents to use 9.2 Insulin resistance and diabetes 9.2.1 Recommendations for assessment and monitoring of insulin resistance 9.2.2 Treatment 9.3 Prevention and management of lipodystrophy 9.3.1 Assessment of lipodystrophy 9.4 Management of lipoatrophy 9.4.1 Surgical intervention 9.5 Lipohypertrophy 9.5.1 Prevention 9.5.2 Pharmacological intervention 9.5.3 Surgical therapy 9.6 Lactic acidosis and hyperlactataemia 10.0 Recommendations for resistance testing 10.1 Treatment-naïve patients 10.2 Treatment-experienced patients 10.3 Key principles in the interpretation of antiretroviral resistance in treatment-experienced patients 10.3.1 General recommendations 11.0 Adherence 11.1 Assessing adherence 11.2 Interventions to support adherence 11.3 Costs 12.0 Pharmacology 12.1 Drug interactions 12.2 Therapeutic drug monitoring (TDM) 12.3 Stopping therapy 12.4 Pharmacogenetics 13.0 HIV testing 14.0 Cost-effectiveness 15.0 Conflict of interest 16.0 References 17.0 Appendix The 2008 BHIVA Guidelines have been updated to incorporate all the new relevant information (including presentations at the 15th Conference on Retroviruses and Opportunistic Infections 2008) since the last iteration. The guidelines follow the methodology outlined below and all the peer-reviewed publications and important, potentially treatment-changing abstracts from the last 2 years have been reviewed. The translation of data into clinical practice is often difficult even with the best possible evidence (i.e. two randomized controlled trials) because of trial design, inclusion criteria and precise surrogate marker endpoints (see Appendix). The recommendations based upon expert opinion have the least good evidence but perhaps provide an important reason for writing the guidelines to produce a consensual opinion about current practice. It must, however, be appreciated that such opinion is often wrong and should not stifle research to challenge it. Similarly, although the Writing Group seeks to provide guidelines to optimize treatment, such care needs to be individualized and we have not constructed a document that we would wish to see used as a ‘standard’ for litigation. The Writing Group used an evidence-based medicine approach to produce these guidelines. In reality, if only the most reliable form of clinical evidence were taken into account (i.e. results of one or more randomized controlled trials with clinical endpoints), it would be impossible to formulate these guidelines. Many important aspects of clinical practice remain to be formally evaluated and very few trials with clinical endpoints are ongoing or planned. Many trials have been performed in order to obtain licensing approval for a drug. In many cases, they are the only source of evidence for comparing two drug regimens. However, the designs are not ideally suited to addressing questions concerning clinical use. The most significant drawbacks of such trials are their short duration and the lack of follow-up data on patients who switch therapy. In most cases, the only available data on long-term outcomes are from routine clinical cohorts. While such cohorts are representative of routine clinical populations, the lack of randomization to different regimens means that comparisons between the outcomes of different regimens are highly susceptible to bias [1,2]. Expert opinion forms an important part of all consensus guidelines; however, this is the least valuable and robust form of evidence. Unless guidelines are interpreted and applied cautiously and sensibly, valuable research initiatives that might improve standards of care will be stifled. It would be wrong to suggest that certain controlled clinical trials would be unethical if they did not conform to the guidelines, especially when these guidelines are based mainly upon expert opinion rather than more reliable evidence [3]. CD4 cell counts and plasma viral load are used as markers of the effect of antiretroviral therapy (ART). Reduction in viral load leads to a rise in peripheral blood CD4 cell count, with greater rises being seen in those with greater and more sustained viral suppression [4]. Changes in these markers in response to therapy are strongly associated with clinical response [5–9]. CD4 cell counts measured in people on ART have been associated with a risk of AIDS-defining diseases no higher than that expected in untreated individuals with similar CD4 cell counts [10–13]. The CD4 cell count is a better indicator of the immediate risk of AIDS-defining diseases than the viral load in those on ART [14,15]. However, it should be remembered that CD4 cell count and viral load responses do not precisely reflect the expected clinical outcome and are not perfect surrogates of the clinical response [9,16,17]. This is because the drugs have other effects with clinical consequences besides those reflected in viral load and CD4 cell count changes. Even so, for patients with a given CD4 cell count and viral load, the risk of AIDS disease appears to be similar, regardless of the specific antiretroviral drugs being used [18]. The relatively short length of trials designed to obtain drug approval means that, at the time of licensing, little is known about the long-term consequences of a drug. As stated above, most antiretroviral drug trials are performed by pharmaceutical companies as part of their efforts to obtain licensing approval and the designs are often not ideally suited to deriving information on using the drugs in clinical practice. Besides the short duration of follow-up, their key limitation is the lack of data on outcomes in people who change from the original randomized regimen and a description of what those new regimens are. The results are, therefore, only clearly interpretable as long as a very high proportion of participants remain on the original, allocated regimens. Clinical questions about which drugs to start with, or switch to, require longer term trials that continue following patients despite changes to the original treatment. Such changes in regimen are common in real-life practice and so, from a clinical perspective, it makes little sense to ignore what happens to patients after a specific regimen has been discontinued. The use of a given drug can affect outcomes long after it has been stopped. For example, it may select for virus resistant to drugs not yet encountered or cause toxicities that overlap with those caused by other drugs. However, interpretation of such longer term trials is not straightforward, and account must be taken of which drugs were used subsequent to the original regimen in each arm. The Writing Group generally favours entry into well-constructed trials for patients whose clinical circumstances are complex, with a number of specific instances being mentioned in these guidelines. NAM maintains a list of trials currently recruiting in the UK at http://www.aidsmap.com, and treatment units should work to ensure arrangements are in place to enable eligible patients to enter trials at centres within or indeed outside their clinical networks. In most efficacy trials, treatments are compared in terms of viral load as defined by plasma HIV RNA. Depending on the target population, the primary outcome measure may be defined to include the achievement of viral suppression below a certain limit (usually 50 HIV-1 RNA copies/mL) at a pre-specified time (e.g. 24 or 48 weeks after randomizations), time to viral rebound or time-weighted average change from baseline. To avoid selection bias, all enrolled patients must be included in an analysis comparing the treatments, and all in the group to which they were randomized, even if no longer taking the treatment they were allocated (the intent-to-treat principle). The inability to assess outcomes for some patients, leading to missing data, for example as a result of patient dropout before completion of the trial, is a potential source of bias. The frequency of and reasons for missing outcomes may be affected by many factors, including the efficacy of treatments, toxicity and the length of follow-up. Interpretation of the results of the trial is particularly problematic if a substantial number of patients drop out for reasons related to the outcome whether by design, as in many pharmaceutical industry trials where patients are withdrawn when they change their randomized treatment, or otherwise. This problem can be addressed at three levels: in the design, conduct and analysis stages of the trial. Changes in treatment during the trial must be anticipated and it is necessary to continue collecting data on all patients, even if they have switched from the original regimen, thus avoiding missing data by design and/or poor implementation. While several analytical methods have been published for handling missing outcome in clinical trials, all make assumptions that cannot be completely verified. Whichever method is used for handling missing outcomes at the analysis stage must be pre-specified in the protocol or the statistical analysis plan. When the outcome is the proportion of people with viral load below 50 copies/mL at a given time-point, the approach widely adopted is to assign an outcome of failure to achieve a value below 50 copies/mL to all patients with missing outcome (and those who have switched from the randomized treatment, regardless of whether they remain under follow-up). This is known as the missing equals failure (MEF) approach [14–21]. This approach to missing outcome is used in trials for drug licensing because it considers anyone who has to stop the drug of interest as having failed and thus prevents any tendency for drugs used by a patient after the drug of interest has failed to influence the trial results. Such an approach implicitly equates failure of a regimen as a consequence of inadequate potency and/or viral drug resistance not only with the inability to tolerate a regimen compared with other possible approaches because of pill burden, inconvenience and/or adverse effects but also with assessments being missing for other reasons, including randomly missing visits, even though the implications of these various outcomes are likely to be substantially different. This approach is often labelled conservative compared with other possible approaches because it gives a minimum proportion of patients with viral load below 50 copies/mL for any given treatment group over all possible approaches. However, the primary purpose of an endpoint is to compare treatment arms and the reasons for missing outcomes may well differ between treatments. In this context, this approach is not conservative in any general sense and its indiscriminate use without consideration of its inherent limitations involves a degree of risk of bias that could be greater than simply ignoring missing values. For these reasons, trials that are conducted for purposes of licensing a particular drug, and which treat stopping of the drug as treatment failure and ignore outcomes occurring after the drug has stopped, do not always provide the type of information that is most useful for clinical practice. In the past, trials have generally considered whether the viral load is below 50 copies/mL or not at a given time-point (e.g. 48 weeks). In recent years, the tendency has been to consider whether virological failure (or ‘loss of virological response’, usually defined as two consecutive values above 50 copies/mL) has occurred by a certain time-point, rather than whether the viral load at the time-point is below 50 copies/mL or not, as described above. In the (common) case where missing viral load values and switches in therapy are treated the same as values above 50 copies/mL, this approach uses a ‘time to loss of virological response’ (TLOVR) algorithm [20]. The two approaches will give similar but not identical results; for example, patients can fulfil the definition of loss of virological response before 48 weeks but then have a viral load value below 50 copies/mL at 48 weeks itself, without any change in regimen. Randomization in a trial ensures balance in prognosis between the treatment arms at baseline. Inability to assess outcomes for some patients can disturb this balance and create bias in the comparison between the treatment arms. In order to avoid risk of such bias, analysis by intent to treat includes outcomes for all randomized patients. So-called ‘on-treatment’ analyses consider outcomes only in those still receiving the original allocated treatment. Here, the difference between assessing the proportion with viral load below 50 copies/mL at a given time-point and assessing the proportion with viral load above 50 copies/mL by a given time-point becomes greater. In the context of an assessment of the proportion of people with viral load below 50 copies/mL at a given time-point, on-treatment analysis makes little sense because therapy has been switched in patients who experience viral load rebound during a trial, so the only patients who remain on the regimen are those with viral load below 50 copies/mL. Hence, all regimens that lead to a viral load below 50 copies/mL in at least one person should lead to a value of 100%, unless there are patients who have viral load above 50 copies/mL at the time-point but are yet to have their regimen switched. In contrast, an assessment of whether the viral load was above 50 copies/mL by a given time-point (i.e. time to virological failure or loss of virological response), which censors observation on patients once they have switched from the original randomized regimen, may be more revealing, but is still subject to potential bias. In contrast to superiority trials where the primary objective is to demonstrate that a new treatment regimen, or strategy, is more efficacious than a well-established treatment, the aim of a noninferiority trial is to show that there is no important loss of efficacy if the new treatment is used instead of the established reference. This is particularly relevant in evaluating simplification strategies where the new treatment strategy is better than the reference treatment in aspects other than efficacy, for example toxicity, tolerability or cost. A critical aspect of noninferiority trials is the judgement of what degree of possible loss of efficacy will be tolerated – the noninferiority margin (sometimes referred to as the delta). The choice of the noninferiority margin depends on what is considered to be a clinically unimportant difference in efficacy taking into account other potential advantages of the new treatment. To demonstrate noninferiority, large numbers of patients are usually required because of the need to exclude the possibility that there is even moderate loss of efficacy with the new treatment. The trial protocol must pre-specify the noninferiority margin (e.g. the proportion with viral load below 50 copies/mL at 48 weeks, in people receiving the new treatment, is not smaller than the same proportion in the reference treatment by more than 5%). As an illustration of the interpretation of the results of noninferiority trials, we shall consider the case where the primary efficacy outcome is the proportion of participants with viral load below 50 copies/mL at 48 weeks. Conclusions on the noninferiority of a new treatment are then based on the lower confidence bound, which is the lower limit of the one-sided 95% (or sometimes 97.5%) confidence interval for the difference (new – standard) between the outcome for the new treatment and the outcome for the standard treatment. Noninferiority is indicated when this lower confidence bound for the difference between the two treatments excludes loss of efficacy greater than the pre-specified noninferiority margin. So, for example, if the proportion with viral load <50 copies/mL with the standard treatment is 85% and the corresponding proportion with the new treatment is 87%, then the observed difference in proportions (new – standard) is 2%. If the lower confidence bound of this difference is −8%, this can be interpreted as meaning that (within the appropriate level of confidence) the new treatment is at most 8% inferior to the standard treatment. If (and only if) our pre-specified noninferiority margin is 8% or above then this means we would conclude that the new treatment is noninferior to the standard. If the proportions were instead 85% for the standard treatment and 79% for the new treatment, with a difference of −6% and lower confidence bound of −11%, then noninferiority of the new treatment could again be concluded if the pre-specified noninferiority margin was 11% or higher regardless of whether the observed difference of −6% was significantly different from zero; i.e. even if the proportion of participants receiving the new treatment with viral load <50 copies/mL was significantly lower than the corresponding proportion for the standard treatment. If, however, the pre-specified non-inferiority margin was less than 11% (e.g. 5%) and we obtained the same outcome data, then noninferiority would not be established even if the difference between the two treatments was not This the of a choice of a noninferiority margin. have to from to which The smaller the noninferiority the the for the new treatment but the the It should be that that the response to the new treatment is not significantly inferior to that of the standard treatment in a is not evidence for It is also important to that a very high standard of trial conduct (e.g. of entry to allocated regimens and loss to is more critical in noninferiority than in superiority Such from the protocol would to bias the difference between the two treatments and thus the of Two questions we superiority or of a new treatment from the results of a trial designed to its noninferiority to the standard What about noninferiority of the new treatment on the of the results of a trial designed to demonstrate its The to the is Conclusions of superiority (or are not on the one-sided confidence interval as for noninferiority, but on the standard 95% confidence If the proportion of patients with viral load <50 copies/mL with the standard treatment is 85% and the corresponding proportion with the new treatment is then the observed difference in proportions (new – standard) is If the 95% confidence interval for this difference is with the lower bound greater than then this can be interpreted as the superiority of the new treatment at the level to the standard treatment in a regardless of the value of the pre-specified noninferiority margin. If the proportions are instead 85% for the standard treatment and for the new treatment, with a difference of and a 95% confidence interval of to then this can be interpreted as a of of the new treatment that the noninferiority margin is or If instead the noninferiority margin is is not the highly significant lower efficacy of the new treatment, because an 8% difference has been defined a as a clinically unimportant This again the of a noninferiority margin the clinically loss of efficacy with the new treatment. in to the any about noninferiority from the results of a superiority trial would not be because the noninferiority margin cannot be with of or data from the trial. It is to compare results of drug combinations in different Such comparisons are, however, difficult to because of in entry criteria with to viral load and CD4 cell methods of analysis (e.g. intent to treat of adherence and of viral load Many of ART have been only after drug It is that any adverse as as possible so that these are A by the and in the UK for reporting adverse to the treatment of HIV The for with antiretroviral drugs in primary HIV infection is as of specific responses that would be and which are associated with long-term in untreated Reduction in associated with high and CD4 during Reduction in the risk of of have results of therapy with effects on viral load and CD4 However, in order to make a the results of a randomized are The is and results are anticipated in In the treatment in primary infection a should only be considered in those any AIDS-defining a CD4 cell count cells/μL (i.e. for or data show that of patients with HIV infection in the UK remain when have a CD4 cell count below cells/μL In data from two BHIVA have that of patients have CD4 cell counts less than cells/μL when therapy is It has been clearly that therapy with a CD4 cell count below cells/μL is associated with a substantially greater risk of disease and and this risk for a significant after treatment is the Writing Group that should be to start treatment before the CD4 cell count has to less than that adherence to ART is critical to treatment and may be on the of the for treatment, the advantages and of treatment should ideally at an for example when the CD4 count below from UK that, even in patients whose HIV infection is relatively highly antiretroviral therapy has often not been the CD4 cell count has below cells/μL (the minimum CD4 count for in the of these The reasons for this are likely to include the that patients and may to start the sometimes of to treatment As a means of with patients, Table gives an of the risk of disease over the following if HAART is or This the that the in risk is in those patients with a high risk (i.e. those who are and who have a CD4 cell count and high viral It is important to out that these data do not that may be in part by of HAART and disease It may also be that patients who are at a high risk of for example over are likely to more from treatment from the the from that there is a of risk of and disease associated with lower CD4 cell counts and no specific at which risk has that untreated HIV infection is associated with greater of and that have not been to be including those to In those individuals the who were treatment-naïve or who not been on therapy for the the risk of a new of disease or a event in the treatment was 7.0 compared with in the virological suppression However, this also means that of therapy were required to one if treatment was before the CD4 count below As a result of these factors, our is that the of therapy should be in all patients with a CD4 count of cells/μL on at least one consecutive in the of any reason for CD4 have that CD4 may have a value of the CD4 cell count, although the data are This may of antiretroviral treatment in some patients with CD4 counts cells/μL but high CD4 but also may support a to start therapy in patients with CD4 counts >350 cells/μL but with CD4 where is indicated some have indicated risk of disease in patients with CD4 As above, at CD4 counts >350 have that there might be to This is by data from the of patients not on therapy at entry to the of the about of therapy have been because of the of less and better tolerated antiretroviral and options after virological For the of patients, the risk of therapy the CD4 count is cells/μL is likely to be but in a at particularly high risk of clinical that may be by this is not the For all these reasons, in a number of patients, treatment may be or considered before the C

BACKGROUND: HIV/AIDS-related stigma and discrimination are significant determinants of HIV transmission in the Caribbean island nation of Trinidad and Tobago (T&T), where the adult HIV/AIDS prevalence is 2.5%. T&T is a spiritually-aware society and over 104 religious groups are represented. This religious diversity creates a complex social environment for the transmission of a sexually transmitted infection like HIV/AIDS. Religious leaders are esteemed in T&T's society and may use their position and frequent interactions with the public to promote HIV/AIDS awareness, fight stigma and discrimination, and exercise compassion for people living with HIV/AIDS (PWHA). Some religious groups have initiated HIV/AIDS education programs within their membership, but previous studies suggest that HIV/AIDS remains a stigmatized infection in many religious organizations. The present study investigates how the perception of HIV/AIDS as a sexually transmitted infection impacts religious representatives' incentives to respond to HIV/AIDS in their congregations and communities. In correlation, the study explores how the experiences of PWHA in religious gatherings impact healing and coping with HIV/AIDS. METHODS: Between November 2002 and April 2003, in-depth interviews were conducted with 11 religious representatives from 10 Christian, Hindu and Muslim denominations. The majority of respondents were leaders of religious services, while two were active congregation members. Religious groups were selected based upon the methods of Brathwaite. Briefly, 26 religious groups with the largest followings according to 2000 census data were identified in Trinidad and Tobago. From this original list, 10 religious groups in Northwest Trinidad were selected to comprise a representative sample of the island's main denominations. In-depth interviews with PWHA were conducted during the same study period, 2002-2003. Four individuals were selected from a care and support group located in Port of Spain based upon their perceived willingness to discuss religious affiliation and describe how living with a terminal infection has affected their spiritual lives. The interviewer, a United States Fulbright Scholar, explained the nature and purpose of the study to all participants. Relevant ethical procedures associated with the collection of interview data were adopted: interviews were conducted in a non-coercive manner and confidentiality was assured. All participants provided verbal consent, and agreed to be interviewed without financial or other incentive. Ethics approval was granted on behalf of the Caribbean Conference of Churches Ethics Committee. Interview questions followed a guideline, and employed an open-ended format to facilitate discussion. All interviews were recorded and transcribed by the interviewer. RESULTS: Religious representatives' opinions were grouped into the following categories: rationale for the spread of HIV/AIDS, abstinence, condom use, sexuality and homosexuality, compassion, experiences with PWHA, recommendations and current approach to addressing HIV/AIDS in congregations. Religious representatives expressed a measure of acceptance of HIV/AIDS and overwhelmingly upheld compassion for PWHA. Some statements, however, suggested that HIV/AIDS stigma pervades Trinidad's religious organizations. For many representatives, HIV/AIDS was associated with a promiscuous lifestyle and/or homosexuality. Representatives had varying levels of interaction with PWHA, but personal experiences were positively associated with current involvement in HIV/AIDS initiatives. All 4 PWHA interviewed identified themselves as belonging to Christian denominations. Three out of the 4 PWHA described discriminatory experiences with pastors or congregation members during gatherings for religious services. Nonetheless, PWHA expressed an important role for faith and religion in coping with HIV. CONCLUSION: Religious groups in Trinidad are being challenged to promote a clear and consistent response to the HIV/AIDS epidemic; a response that may reflect personal experiences and respect religious doctrine in the context of sex and sexuality. The study suggests that (1) religious leaders could improve their role in the fight against HIV/AIDS with education and sensitization-specifically aimed at dismantling the myths about HIV transmission, and the stereotyping of susceptible sub-populations, and (2) a consultative dialogue between PWHAs and religious leaders is pivotal to a successful faith-based HIV intervention in Trinidad.

OBJECTIVE: To provide clinical recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease with currently (mid 1996) available drugs. When to start therapy, what to start with, when to change, and what to change to were addressed. PARTICIPANTS: A 13-member panel representing international expertise in antiretroviral research and HIV patient care was selected by the international AIDS Society-USA. EVIDENCE: Available clinical and basic science data, including phase 3 controlled trials, clinical endpoint data, virologic and immunologic endpoint data, interim analyses, studies of HIV pathophysiology, and expert opinions of panel members were considered. Recommendations were limited to drugs available in mid 1996. PROCESS: For each question posed, 1 or more member(s) reviewed and presented available data. Recommendations were determined by group consensus (January 1996); revisions as warranted by new data were incorporated by group consensus (February-May 1996). CONCLUSIONS: Recent data on HIV pathogenesis, methods to determine plasma HIV RNA, clinical trial data, and availability of new drugs point to the need for new approaches to treatment. Therapy is recommended based on CD4+ cell count, plasma HIV RNA level, or clinical status. Preferred initial drug regimens include nucleoside combinations; at present protease inhibitors are probably best reserved for patients at higher progression risk. For treatment failure or drug intolerance, subsequent regimen considerations include reasons for changing therapy, available drug options, disease stage, underlying conditions, and concomitant medication(s). Therapy for primary (acute) infection, high-risk exposures to HIV, and maternal-to-fetal transmission are also addressed. Therapeutic approaches need to be updated as new data continue to emerge.

IMPORTANCE: Approximately 1.1 million persons in the United States are currently living with HIV, and more than 700 000 persons have died of AIDS since the first cases were reported in 1981. There were approximately 38 300 new diagnoses of HIV infection in 2017. The estimated prevalence of HIV infection among persons 13 years and older in the United States is 0.4%, and data from the Centers for Disease Control and Prevention show a significant increase in HIV diagnoses starting at age 15 years. An estimated 8700 women living with HIV give birth each year in the United States. HIV can be transmitted from mother to child during pregnancy, labor, delivery, and breastfeeding. The incidence of perinatal HIV infection in the United States peaked in 1992 and has declined significantly following the implementation of routine prenatal HIV screening and the use of effective therapies and precautions to prevent mother-to-child transmission. OBJECTIVE: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on screening for HIV infection in adolescents, adults, and pregnant women. EVIDENCE REVIEW: The USPSTF reviewed the evidence on the benefits and harms of screening for HIV infection in nonpregnant adolescents and adults, the yield of screening for HIV infection at different intervals, the effects of initiating antiretroviral therapy (ART) at a higher vs lower CD4 cell count, and the longer-term harms associated with currently recommended ART regimens. The USPSTF also reviewed the evidence on the benefits (specifically, reduced risk of mother-to-child transmission of HIV infection) and harms of screening for HIV infection in pregnant persons, the yield of repeat screening for HIV at different intervals during pregnancy, the effectiveness of currently recommended ART regimens for reducing mother-to-child transmission of HIV infection, and the harms of ART during pregnancy to the mother and infant. FINDINGS: The USPSTF found convincing evidence that currently recommended HIV tests are highly accurate in diagnosing HIV infection. The USPSTF found convincing evidence that identification and early treatment of HIV infection is of substantial benefit in reducing the risk of AIDS-related events or death. The USPSTF found convincing evidence that the use of ART is of substantial benefit in decreasing the risk of HIV transmission to uninfected sex partners. The USPSTF also found convincing evidence that identification and treatment of pregnant women living with HIV infection is of substantial benefit in reducing the rate of mother-to-child transmission. The USPSTF found adequate evidence that ART is associated with some harms, including neuropsychiatric, renal, and hepatic harms, and an increased risk of preterm birth in pregnant women. The USPSTF concludes with high certainty that the net benefit of screening for HIV infection in adolescents, adults, and pregnant women is substantial. CONCLUSIONS AND RECOMMENDATION: The USPSTF recommends screening for HIV infection in adolescents and adults aged 15 to 65 years. Younger adolescents and older adults who are at increased risk of infection should also be screened. (A recommendation) The USPSTF recommends screening for HIV infection in all pregnant persons, including those who present in labor or at delivery whose HIV status is unknown. (A recommendation).

BACKGROUND: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. METHODS: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. FINDINGS: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990-2010 time period, with the greatest annualised rate of decline occurring in the 0-9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10-24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10-24 years were also in the top ten in the 25-49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50-74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. INTERPRETATION: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and development investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. FUNDING: Bill & Melinda Gates Foundation.

As policy-makers search for ways to reduce poverty and income inequality, and to achieve sustainable income growth, they are being encouraged to focus on an emerging challenge to health, well-being and development: non-communicable diseases (NCDs). After all, 63% of all deaths worldwide currently stem from NCDs – chiefly cardiovascular diseases, cancers, chronic respiratory diseases and diabetes. These deaths are distributed widely among the world’s population – from highincome to low-income countries and from young to old (about one-quarter of all NCD deaths occur below the age of 60, amounting to approximately 9 million deaths per year). NCDs have a large impact, undercutting productivity and boosting healthcare outlays. Moreover, the number of people affected by NCDs is expected to rise substantially in the coming decades, reflecting an ageing and increasing global population. With this in mind, the United Nations is holding its first High-Level Meeting on NCDs on 19-20 September 2011 – this is only the second time that a high-level UN meeting is being dedicated to a health topic (the first time being on HIV/ AIDS in 2001). Over the years, much work has been done estimating the human toll of NCDs, but work on estimating the economic toll is far less advanced. In this report, the World Economic Forum and the Harvard School of Public Health try to inform and stimulate further debate by developing new estimates of the global economic burden of NCDs in 2010, and projecting the size of the burden through 2030. Three distinct approaches are used to compute the economic burden: (1) the standard cost of illness method; (2) macroeconomic simulation and (3) the value of a statistical life. This report includes not only the four major NCDs (the focus of the UN meeting), but also mental illness, which is a major contributor to the burden of disease worldwide. This evaluation takes place in the context of enormous global health spending, serious concerns about already strained public finances and worries about lacklustre economic growth. The report also tries to capture the thinking of the business community about the impact of NCDs on their enterprises. Five key messages emerge: • First, NCDs already pose a substantial economic burden and this burden will evolve into a staggering one over the next two decades. For example, with respect to cardiovascular disease, chronic respiratory disease, cancer, diabetes and mental health, the macroeconomic simulations suggest a cumulative output loss of US$ 47 trillion over the next two decades. This loss represents 75% of global GDP in 2010 (US$ 63 trillion). It also represents enough money to eradicate two dollar-a-day poverty among the 2.5 billion people in that state for more than half a century. • Second, although high-income countries currently bear the biggest economic burden of NCDs, the developing world, especially middle-income countries, is expected to assume an ever larger share as their economies and populations grow. • Third, cardiovascular disease and mental health conditions are the dominant contributors to the global economic burden of NCDs. • Fourth, NCDs are front and centre on business leaders’ radar. The World Economic Forum’s annual Executive Opinion Survey (EOS), which feeds into its Global Competitiveness Report, shows that about half of all business leaders surveyed worry that at least one NCD will hurt their company’s bottom line in the next five years, with similarly high levels of concern in low-, middle- and high-income countries – especially in countries where the quality of healthcare or access to healthcare is perceived to be poor. These NCD-driven concerns are markedly higher than those reported for the communicable diseases of HIV/AIDS, malaria and tuberculosis. • Fifth, the good news is that there appear to be numerous options available to prevent and control NCDs. For example, the WHO has identified a set of interventions they call “Best Buys”. There is also considerable scope for the design and implementation of programmes aimed at behaviour change among youth and adolescents, and more costeffective models of care – models that reduce the care-taking burden that falls on untrained family members. Further research on the benefits of such interventions in relation to their costs is much needed. It is our hope that this report informs the resource allocation decisions of the world’s economic leaders – top government officials, including finance ministers and their economic advisors – who control large amounts of spending at the national level and have the power to react to the formidable economic threat posed by NCDs.

BACKGROUND: Clinical practice is not always evidence-based and, therefore, may not optimise patient outcomes. Opinion leaders disseminating and implementing 'best evidence' is one method that holds promise as a strategy to bridge evidence-practice gaps. OBJECTIVES: To assess the effectiveness of the use of local opinion leaders in improving professional practice and patient outcomes. SEARCH STRATEGY: We searched Cochrane EPOC Group Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, HMIC, Science Citation Index, Social Science Citation Index, ISI Conference Proceedings and World Cat Dissertations up to 5 May 2009. In addition, we searched reference lists of included articles. SELECTION CRITERIA: Studies eligible for inclusion were randomised controlled trials investigating the effectiveness of using opinion leaders to disseminate evidence-based practice and reporting objective measures of professional performance and/or health outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each study and assessed its risk of bias. For each trial, we calculated the median risk difference (RD) for compliance with desired practice, adjusting for baseline where data were available. We reported the median adjusted RD for each of the main comparisons. MAIN RESULTS: We included 18 studies involving more than 296 hospitals and 318 PCPs. Fifteen studies (18 comparisons) contributed to the calculations of the median adjusted RD for the main comparisons. The effects of interventions varied across the 63 outcomes from 15% decrease in compliance to 72% increase in compliance with desired practice. The median adjusted RD for the main comparisons were: i) Opinion leaders compared to no intervention, +0.09; ii) Opinion leaders alone compared to a single intervention, +0.14; iii) Opinion leaders with one or more additional intervention(s) compared to the one or more additional intervention(s), +0.10; iv) Opinion leaders as part of multiple interventions compared to no intervention, +0.10. Overall, across all 18 studies the median adjusted RD was +0.12 representing a 12% absolute increase in compliance in the intervention group. AUTHORS' CONCLUSIONS: Opinion leaders alone or in combination with other interventions may successfully promote evidence-based practice, but effectiveness varies both within and between studies. These results are based on heterogeneous studies differing in terms of type of intervention, setting, and outcomes measured. In most of the studies the role of the opinion leader was not clearly described, and it is therefore not possible to say what the best way is to optimise the effectiveness of opinion leaders.

BACKGROUND: The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. METHODS: In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. RESULTS: In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. CONCLUSIONS: This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

INTRODUCTION: Across the globe, children born with perinatal HIV infection (PHIV) are reaching adolescence and young adulthood in large numbers. The majority of research has focused on biomedical outcomes yet there is increasing awareness that long-term survivors with PHIV are at high risk for mental health problems, given genetic, biomedical, familial and environmental risk. This article presents a review of the literature on the mental health functioning of perinatally HIV-infected (PHIV+) adolescents, corresponding risk and protective factors, treatment modalities and critical needs for future interventions and research. METHODS: An extensive review of online databases was conducted. Articles including: (1) PHIV+ youth; (2) age 10 and older; (3) mental health outcomes; and (4) mental health treatment were reviewed. Of 93 articles identified, 38 met inclusion criteria, the vast majority from the United States and Europe. RESULTS: These studies suggest that PHIV+ youth experience emotional and behavioural problems, including psychiatric disorders, at higher than expected rates, often exceeding those of the general population and other high-risk groups. Yet, the specific role of HIV per se remains unclear, as uninfected youth with HIV exposure or those living in HIV-affected households displayed similar prevalence rates in some studies, higher rates in others and lower rates in still others. Although studies are limited with mixed findings, this review indicates that child-health status, cognitive function, parental health and mental health, stressful life events and neighbourhood disorder have been associated with worse mental health outcomes, while parent-child involvement and communication, and peer, parent and teacher social support have been associated with better function. Few evidence-based interventions exist; CHAMP+, a mental health programme for PHIV+ youth, shows promise across cultures. CONCLUSIONS: This review highlights research limitations that preclude both conclusions and full understanding of aetiology. Conversely, these limitations present opportunities for future research. Many PHIV+ youth experience adequate mental health despite vulnerabilities. However, the focus of research to date highlights the identification of risks rather than positive attributes, which could inform preventive interventions. Development and evaluation of mental health interventions and preventions are urgently needed to optimize mental health, particularly for PHIV+ youth growing up in low-and-middle income countries.

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

BACKGROUND: Stigma across HIV/AIDS, mental illness, and physical disability can be co-occurring and may interact with other forms of stigma related to social identities like race, gender, and sexuality. Stigma is especially problematic for people living with these conditions because it can create barriers to accessing necessary social and structural supports, which can intensify their experiences with stigma. This review aims to contribute to the knowledge on stigma by advancing a cross-analysis of HIV/AIDS, mental illness, and physical disability stigma, and exploring whether and how intersectionality frameworks have been used in the systematic reviews of stigma. METHODS: A search of the literature was conducted to identify systematic reviews which investigated stigma for HIV/AIDS, mental illness and/or physical disability. The electronic databases MEDLINE, CINAHL, EMBASE, COCHRANE, and PsycINFO were searched for reviews published between 2005 and 2017. Data were extracted from eligible reviews on: type of systematic review and number of primary studies included in the review, study design study population(s), type(s) of stigma addressed, and destigmatizing interventions used. A keyword search was also done using the terms "intersectionality", "intersectional", and "intersection"; related definitions and descriptions were extracted. Matrices were used to compare the characteristics of reviews and their application of intersectional approaches across the three health conditions. RESULTS: Ninety-eight reviews met the inclusion criteria. The majority (99%) of reviews examined only one of the health conditions. Just three reviews focused on physical disability. Most reviews (94%) reported a predominance of behavioural rather than structural interventions targeting stigma in the primary studies. Only 17% of reviews used the concept and/or approach of intersectionality; all but one of these reviews examined HIV/AIDS. CONCLUSIONS: The lack of systematic reviews comparing stigma across mental illness, HIV/AIDS, and physical disability indicates the need for more cross-comparative analyses among these conditions. The integration of intersectional approaches would deepen interrogations of co-occurring social identities and stigma.

OBJECTIVE: To assess the costs and health effects of a range of interventions for preventing the spread of HIV and for treating people with HIV/AIDS in the context of the millennium development goal for combating HIV/AIDS. DESIGN: Cost effectiveness analysis based on an epidemiological model. SETTING: Analyses undertaken for two regions classified using the WHO epidemiological grouping-Afr-E, countries in sub-Saharan Africa with very high adult and high child mortality, and Sear-D, countries in South East Asia with high adult and high child mortality. DATA SOURCES: Biological and behavioural parameters from clinical and observational studies and population based surveys. Intervention effects and resource inputs based on published reports, expert opinion, and the WHO-CHOICE database. MAIN OUTCOME MEASURES: Costs per disability adjusted life year (DALY) averted in 2000 international dollars (Int dollars). RESULTS: In both regions interventions focused on mass media, education and treatment of sexually transmitted infections for female sex workers, and treatment of sexually transmitted infections in the general population cost < Int150 dollars per DALY averted. Voluntary counselling and testing costs < Int350 dollars per DALY averted in both regions, while prevention of mother to child transmission costs < Int50 dollars per DALY averted in Afr-E but around Int850 dollars per DALY in Sear-D. School based education strategies and various antiretroviral treatment strategies cost between Int500 dollars and Int5000 dollars per DALY averted. CONCLUSIONS: Reducing HIV transmission could be done most efficiently through mass media campaigns, interventions for sex workers and treatment of sexually transmitted infections where resources are most scarce. However, prevention of mother to child transmission, voluntary counselling and testing, and school based education would yield further health gains at higher budget levels and would be regarded as cost effective or highly cost effective based on standard international benchmarks. Antiretroviral therapy is at least as cost effective in improving population health as some of these interventions.

An 8-person subcommittee of the National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group evaluated available data on the treatment of cryptococcal disease. Opinion regarding optimal treatment was based on personal experience and information in the literature. The relative strength of each recommendation was graded according to the type and degree of evidence available to support the recommendation, in keeping with previously published guidelines by the Infectious Diseases Society of America (IDSA). The panel conferred in person (on 2 occasions), by conference call, and through written reviews of each draft of the manuscript. The choice of treatment for disease caused by Cryptococcus neoformans depends on both the anatomic sites of involvement and the host's immune status. For immunocompetent hosts with isolated pulmonary disease, careful observation may be warranted; in the case of symptomatic infection, indicated treatment is fluconazole, 200-400 mg/day for 36 months. For those individuals with non-CNS-isolated cryptococcemia, a positive serum cryptococcal antigen titer >1:8, or urinary tract or cutaneous disease, recommended treatment is oral azole therapy (fluconazole) for 36 months. In each case, careful assessment of the CNS is required to rule out occult meningitis. For those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/day for 6-12 months) is an acceptable alternative. For patients with more severe disease, treatment with amphotericin B (0.5-1 mg/kg/d) may be necessary for 6-10 weeks. For otherwise healthy hosts with CNS disease, standard therapy consists of amphotericin B, 0.7-1 mg/kg/d, plus flucytosine, 100 mg/kg/d, for 6-10 weeks. An alternative to this regimen is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 2 weeks, followed by fluconazole (400 mg/day) for a minimum of 10 weeks. Fluconazole "consolidation" therapy may be continued for as along as 6-12 months, depending on the clinical status of the patient. HIV-negative, immunocompromised hosts should be treated in the same fashion as those with CNS disease, regardless of the site of involvement. Cryptococcal disease that develops in patients with HIV infection always warrants therapy. For those patients with HIV who present with isolated pulmonary or urinary tract disease, fluconazole at 200-400 mg/d is indicated. Although the ultimate impact from highly active antiretroviral therapy (HAART) is currently unclear, it is recommended that all HIV-infected individuals continue maintenance therapy for life. Among those individuals who are unable to tolerate fluconazole, itraconazole (200-400 mg/d) is an acceptable alternative. For patients with more severe disease, a combination of fluconazole (400 mg/d) plus flucytosine (100-150 mg/d) may be used for 10 weeks, followed by fluconazole maintenance therapy. Among patients with HIV infection and cryptococcal meningitis, induction therapy with amphotericin B (0.7-1 mg/kg/d) plus flucytosine (100 mg/kg/d for 2 weeks) followed by fluconazole (400 mg/d) for a minimum of 10 weeks is the treatment of choice. After 10 weeks of therapy, the fluconazole dosage may be reduced to 200 mg/d, depending on the patient's clinical status. Fluconazole should be continued for life. An alternative regimen for AIDS-associated cryptococcal meningitis is amphotericin B (0.7-1 mg/kg/d) plus 5-flucytosine (100 mg/kg/d) for 6-10 weeks, followed by fluconazole maintenance therapy. Induction therapy beginning with an azole alone is generally discouraged. Lipid formulations of amphotericin B can be substituted for amphotericin B for patients whose renal function is impaired. Fluconazole (400-800 mg/d) plus flucytosine (100-150 mg/kg/d) for 6 weeks is an alternative to the use of amphotericin B, although toxicity with this regimen is high. In all cases of cryptococcal meningitis, careful attention to the management of intracranial pressure is imperative to assure optimal c

BACKGROUND: Adherence to prescribed regimens is required to derive maximal benefit from many highly active antiretroviral therapy (HAART) regimens in people living with HIV/AIDS. OBJECTIVES: To conduct a systematic review of the research literature on the effectiveness of patient support and education to improve adherence to HAART. SEARCH STRATEGY: A systematic search of electronic databases was performed from January 1996 to May 2005. SELECTION CRITERIA: Randomized controlled trials examining the effectiveness of patient support and education to improve adherence to HAART were considered for inclusion. Only those studies that measured adherence at a minimum of six weeks were included. DATA COLLECTION AND ANALYSIS: Study selection, quality assessments and data abstraction were performed independently by two reviewers. MAIN RESULTS: Nineteen studies involving a total of 2,159 participants met criteria for inclusion. It was not possible to conduct a meta-analysis due to study heterogeneity with respect to populations, interventions, comparison groups, outcomes, and length of follow-up. Sample sizes ranged from 22 to 367. The populations studied ranged from general HIV-positive populations to studies focusing exclusively on children, women, Latinos, or adults with a history of alcohol dependence, to studies focusing almost exclusively on men. Study interventions included cognitive behavioral therapy, motivational interviewing, medication management strategies, and interventions indirectly targeting adherence, such as programs directed to reduce risky sexual behaviours. Ten studies demonstrated a beneficial effect of the intervention on adherence. We found that interventions targeting practical medication management skills, those administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. We also found that interventions targeting marginalized populations such as women, Latinos, or patients with a past history of alcoholism were not successful at improving adherence. We were unable to determine whether effective adherence interventions were associated with improved virological or immunological outcomes. Most studies had several methodological shortcomings leaving them vulnerable to potential biases. AUTHORS' CONCLUSIONS: We found evidence to support the effectiveness of patient support and education interventions intended to improve adherence to antiretroviral therapy. Interventions targeting practical medication management skills, those interventions administered to individuals vs groups, and those interventions delivered over 12 weeks or more were associated with improved adherence outcomes. There is a need for standardization and increased methodological rigour in the conduct of adherence trials.

Treatment decision-making is complex and involves many factors. A systematic decision-making and optimization technology capable of handling variations and uncertainties of patient characteristics and physician's subjectivity is currently unavailable. We recently developed a novel general-purpose fuzzy discrete event systems theory for optimal decision-making. We now apply it to develop an innovative system for medical treatment, specifically for the first round of highly active antiretroviral therapy of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients involving three historically widely used regimens. The objective is to develop such a system whose regimen choice for any given patient will exactly match expert AIDS physician's selection to produce the (anticipated) optimal treatment outcome. Our regimen selection system consists of a treatment objectives classifier, fuzzy finite state machine models for treatment regimens, and a genetic-algorithm-based optimizer. The optimizer enables the system to either emulate an individual doctor's decision-making or generate a regimen that simultaneously satisfies diverse treatment preferences of multiple physicians to the maximum extent. We used the optimizer to automatically learn the values of 26 parameters of the models. The learning was based on the consensus of AIDS specialists A and B on this project, whose exact agreement was only 35%. The performance of the resulting models was first assessed. We then carried out a retrospective study of the entire system using all the qualifying patients treated in our institution's AIDS Clinical Center in 2001. A total of 35 patients were treated by 13 specialists using the regimens (four and eight patients were treated by specialists A and B, respectively). We compared the actually prescribed regimens with those selected by the system using the same available information. The overall exact agreement was 82.9% (29 out of 35), with the exact agreement with specialists A and B both at 100%. The exact agreement for the remaining 11 physicians not involved in the system training was 73.9% (17 out of 23), an impressive result given the fact that expert opinion can be quite divergent for treatment decisions of such complexity. Our specialists also carefully examined the six mismatched cases and deemed that the system actually chose a more appropriate regimen for four of them. In the other two cases, either would be reasonable choices. Our approach has the capabilities of generalizing, learning, and representing knowledge even in the face of weak consensus, and being readily upgradeable to new medical knowledge. These are practically important features to medical applications in general, and HIV/AIDS treatment in particular, as national HIV/AIDS treatment guidelines are modified several times per year.

While several clinical studies have shown that HIV-1 infection is associated with increased permeability of the intestinal tract, there is very little understanding of the mechanisms underlying HIV-induced impairment of mucosal barriers. Here we demonstrate that exposure to HIV-1 can directly breach the integrity of mucosal epithelial barrier, allowing translocation of virus and bacteria. Purified primary epithelial cells (EC) isolated from female genital tract and T84 intestinal cell line were grown to form polarized, confluent monolayers and exposed to HIV-1. HIV-1 X4 and R5 tropic laboratory strains and clinical isolates were seen to reduce transepithelial resistance (TER), a measure of monolayer integrity, by 30-60% following exposure for 24 hours, without affecting viability of cells. The decrease in TER correlated with disruption of tight junction proteins (claudin 1, 2, 4, occludin and ZO-1) and increased permeability. Treatment of ECs with HIV envelope protein gp120, but not HIV tat, also resulted in impairment of barrier function. Neutralization of gp120 significantly abrogated the effect of HIV. No changes to the barrier function were observed when ECs were exposed to Env defective mutant of HIV. Significant upregulation of inflammatory cytokines, including TNF-alpha, were seen in both intestinal and genital epithelial cells following exposure to HIV-1. Neutralization of TNF-alpha reversed the reduction in TERs. The disruption in barrier functions was associated with viral and bacterial translocation across the epithelial monolayers. Collectively, our data shows that mucosal epithelial cells respond directly to envelope glycoprotein of HIV-1 by upregulating inflammatory cytokines that lead to impairment of barrier functions. The increased permeability could be responsible for small but significant crossing of mucosal epithelium by virus and bacteria present in the lumen of mucosa. This mechanism could be particularly relevant to mucosal transmission of HIV-1 as well as immune activation seen in HIV-1 infected individuals.

UNLABELLED: Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT01365065.