CCR5 Δ32/wt genotype and demographic, epidemiological, clinical and immunological factors associated with mortality in the cART era.Investigation of the interplay between the Δ32 allele detection were analyzed.Longitudinal data from 507 HIV-infected patients following the CCR5 Δ32/wt genotype prior to the antiretroviral treatment (cART) initiation (n = 507) and on the therapy (n = 422) was also performed.Cumulative 15 years mortality was calculated using Kaplan-Meyer methodology. Hazard ratios were estimated using univariate Cox models. Basing on Akakie information criteria and statistical significance multivariate Cox model was constructed and effect plots presenting adjusted hazard ratio time-dependency were drawn. Analysis of the association of all-cause mortality and CCR5 genotype, gender, history of cART, AIDS diagnosis and also CD4 lymphocyte nadir, zenith, the latest CD4 count and stable levels >500 cells/µl. For multivariate analysis the following predictors were selected: CCR5 genotype , gender , introduction of combined antiretroviral treatment  CD4 count of 500 cells/µl for six months or more , the latest CD4 count  and history of AIDS . Among untreated individuals the Δ32/wt genotype was associated with notably better survival (p = 0.026), while among cART treated individuals the Δ32 mutation did not correlate significantly with higher survival rates (p = 0.23).A mortality rate of 2.66 (CI 2.57–3.19) per 100 person-years was observed. Univariate analysis factors modifying the risk of death included the Δ32 CCR5 allele is associated with a reduction of the risk of all-cause mortality in HIV (+) patients alongside clinical and immunologic predictors such as AIDS, history of cART, lymphocyte CD4 cell count and gender.The  Δ32) in the reading frame of the CCR5 gene associated with reduced susceptibility to infection and delayed disease progression Δ32/Δ32 homozygotes remain resistant to infection with CCR5 tropic variants of HIV, while among heterozygous Δ32/wild-type (wt) subjects beneficial, AIDS protective effects, have been noted in the early years of infection Infection with the human immunodeficiency virus type 1 (HIV-1) requires attachment to one of the principal chemokine coreceptors, namely CCR5 and CXCR4 for effective entry into CD4+ T-cells CCR5 Δ32 mutation on the long-term mortality of patients living with HIV. Characteristically in Europe, as well as in Poland, most HIV cases are diagnosed late necessitating immediate initiation of combined antiretroviral treatment In the era of combined antiretroviral treatment (cART) and expected long term survival an array of interplaying factors influence mortality among people living with HIV. Lymphocyte CD4 metrics, early introduction of antiretroviral treatment and preservation of immunological function are the key contributors to the risk of mortality in this group For the study longitudinal data of 507 patients followed-up from January 1996 to June 2010 at the Department of Infectious Diseases and Hepatology, Pomeranian Medical University, Szczecin, Poland and Out Patients' Clinic for Acquired Immunodeficiency, Regional Hospital, Szczecin, Poland were analyzed. The study protocol was approved by the bioethical committee of Pomeranian Medical University, Szczecin, Poland . Written informed consent was obtained from all subjects participating in the study. Time zero was defined as a date of positive screening HIV test if later confirmed by Western-blot, immunoblotting or positive serum HIV-RNA or a confirmation test itself. The following data were collected: age, gender, date of HIV diagnosis, route of transmission, hepatitis C co-infection, clinical category at diagnosis according to CDC case definition st of June 2010 for the patients remaining under care (termination of data collection). When it was impossible to determine the exact date of death (6 cases) the median date between the last recorded visit and information on death was assumed as the death date.Study endpoint was defined as all-cause mortality excluding cases with documented accidental death. Determination of the reason of death was based on the following data: autopsy report (42 cases), medical record of in-hospital treatment with cause of death defined by the treating physician (32 cases), other medical report or letter (19 cases); in four cases the cause of death remained undetermined. Validation of the underlying cause of death was performed by an independent clinician not involved in the patient care with discrepancies in the data thoroughly discussed. AIDS related death was assumed if the criteria (either presumptive or definitive) outlined by the CDC case definition were met with at least one AIDS defining condition observed at the time of death. End of observation date was defined as either death date, last recorded date of visit (cases lost to follow-up) or 1CCR5 Δ32/wt genotyping a previously described methodology was used For genomic DNA extraction from whole blood samples QIAamp DNA Blood Mini Kit  was used with re-suspended DNA stored at 4°C for further analyses. If whole blood samples were unavailable frozen serum samples were used with extraction performed using Sherlock AX kits . For the CCR5 genotype, transmission route, hepatitis C co-infection, HIV infection stage at diagnosis, history of antiretroviral treatment, baseline viral load (log HIV-RNA copies/ml), baseline CD4 count (cells/µl), nadir CD4 count (cells/µl), zenith CD4 count (cells/µl), time with CD4 count >500 cells/µl, the most recent CD4 count (cells/µl) and history of AIDS. Moreover, for every parameter Kaplan-Meyer cumulative mortality was calculated and plotted with statistical significance testing using log-rank test. To select the most informative parameters for the multivariate model Akaike information criteria (AIC) were used to assess the fit of the each model (lower AIC indicates better fit) Statistical analyses for nominal variables were performed with chi-square test using EPI6 Statcalc software , for continuous variables, the Mann–Whitney U-test was used . Cox models for survival were used to assess the effect of analyzed parameter on the risk of death. For all analyzed parameters unadjusted (univariate) Cox models were used to calculate the hazard ratio (HR) and included CCR5 Δ32 genotype frequency was 14.0% with Δ32 allele frequency of 7.0%. No Δ32/Δ32 homozygotes were observed in the group. All patients were of Caucasian ethnicity with predominance of men , median baseline age of 30 years, 50.0% infected by injection drug use, median (inter quartile range - IQR) baseline CD4 count of 229 (634-518) cells/µl and median (IQR) viral load of 74000 (14222–315000) HIV-RNA copies/ml  patients the opies/ml . Mean  and overall number of deaths . Similar CCR5 Δ32/wt genotype frequency was observed among patients with AIDS related deaths (7.6%) while in the group with non-AIDS related death the frequency of the CCR5 Δ32/wt genotype was lower . Other differences with borderline significance in the CCR5 Δ32/wt genotype distribution included transmission route  related transmissions, respectively, p = 0.07), female vs. male gender  and initiation of antiretroviral treatment . Majority of women with the Δ32 allele were infected sexually , while among men predominated IDU  over sexual transmissions  while heterosexual in 7 cases (12.3%) (p = 0.17). No significant difference between the groups with and without the Δ32 allele in the overall number of AIDS diagnoses was observed  but the AIDS-free time was slightly longer among HIV positive patients with the CCR5 Δ32/wt genotype (median (IQR) of 75(19-134) vs. 48 (10-109) months, p = 0.14), despite similar age at diagnosis (median (IQR) for the CCR5 Δ32/wt of 29 (25-35) vs. 30 (25-38) years of age for CCR5 wt/wt, p = 0.62) and observation time (85 (41-148) for the CCR5 Δ32/wt vs. 82 (33-19) months for CCR5 wt/wt, p = 0.23).Notable differences in the frequency of the CCR5 wt/Δ32 genotype was noted, in majority of these patients (n = 5) AIDS-defining conditions were observed at the time of death while two deaths were non-AIDS related. There were no significant differences for the reasons of death between the groups with and without the CCR5 Δ32 allele.In the group there were 97 deaths observed, 55 (56.7%) being AIDS-related and 42 (43.3%) non-AIDS related. All-cause mortality of 2.66 (95%CI 2.57–3.19) per 100 person-years with AIDS-related mortality of 1.51 (95% CI 1.44–1.90) and non-AIDS related of 1.15 (95% CI 1.09–1.50) per 100 person-years was noted. The most common causes of AIDS related deaths were pneumonia, malignancy and tuberculosis while drug overdose, endocarditis and hepatic events were leading causes of non-AIDS related deaths  and 2. ICCR5 genotype, male gender, symptomatic HIV infection at diagnosis, antiretroviral treatment history and AIDS diagnosis (iagnosis . The anaiagnosis  as well iagnosis  and for iagnosis . It mustiagnosis . No statCCR5 genotype (HR for wt/wt homozygotes 2.53 (95%CI 1.16–5.53), p = 0.02), gender , p = 0.023), introduction of antiretroviral treatment (HR 4.85 (95%CI 3.0–7.89) if untreated or treated for less than one month, p<0.0001, CD4 count of 500 cells/µl for six months (HR 4.16 (95%CI 1.95–8.88) if the parameter was not achieved, p = 0.028), the latest CD4 count (HR 5.44 (95%CI 3.39–8.74) for <100 cells/µl, p<0.0001) and the history of AIDS (HR 1.69 (95%CI 1.03–2.79) for patients with this diagnosis), p = 0.039 , starting from the HIV diagnosis and censored at the time of the cART initiation, loss to follow-up or death , however among cART treated individuals the Δ32 mutation did not correlate significantly with higher survival rates (p = 0.23).To assess the influence of the or death . The secor death . Among uCCR5 Δ32 allele on long term survival among HIV-1 infected patients in the era of cART. An array of factors influencing survival were analyzed in this study including demographics as well as clinical and immunological parameters. The frequency of the CCR5 Δ32/wt heterozygotes in this study was 14.0% and is consistent to the previous reports for Caucasian populations, while use of archived samples allowed to avoid the bias related to the survival benefit of the mutation in HIV infected patients who may have died Δ32 allele for every gender, depending on the type of exposure.This study investigates the combined effect of selected parameters and the Δ32 allele and delayed progression to AIDS has previously been reported including a suggestion that this deletion is the strongest protective factor for both viral and immununologic control of the HIV-associated disease and improved survival outside the HLA system Δ32 allele. In the meta-analysis by Ioannidis et al., the relative hazard for both AIDS and death was notably lower among the CCR5 Δ32/wt heterozygotes if compared to the individuals homozygous for the wild-type variant CCR5 Δ32/wt genotype was also found by Brumme et al. An association between the CCR5 Δ32 variant was significantly higher at the time of HIV diagnosis, however for the entire follow-up period the number of AIDS cases was not notably different between the groups with and without this allele. This could be related to the fact that the cohort used for this analysis consisted of a large number of late diagnosed individuals, in 372 (73.4%) cases infection was diagnosed in either the symptomatic stage or with baseline CD4 count<350 cells/µl, which is characteristic for HIV infections diagnosed in Poland Δ32 allele among antiretroviral naive patients is probably related to a higher number of patients asymptomatic at baseline who would not require cART. Other differences of borderline statistical significance for the CCR5 Δ32 allele frequency include a lower frequency among women, confirming the finding by Philpott et al., of a more extensive protective effect of the CCR5 Δ32/wt heterozygous genotype in women In our study the number of AIDS-free individuals with the Δ32 allele, found also to be a statistically significant protective influence on mortality, as it has been reported that in individuals bearing this variant time of progression to AIDS after initiation of cART as well as time from AIDS diagnosis to death is increased Δ32 allele was associated with decreased mortality risk observed for as long as 15 years of follow-up. This association remained significant after adjustment for other factors strongly influencing mortality: gender, nadir and zenith CD4 count, time with CD4 >500 cells/µl, most recent CD4 levels and AIDS diagnosis.In the univariate analysis of all the factors significantly modifying all-cause mortality the strongest protective effect was observed for cART as well as CD4 metrics, namely nadir, zenith lymphocyte CD4, time with CD4 count above 500 cells/µl and AIDS-free observation. Effects of these parameters were extensively studied before and remain well documented CCR5 Δ32/wt genotype was associated with better survival in untreated individuals only, which is probably associated to the slower development of the symptomatic disease as suggested by Brumme et al., CCR5 Δ32/wt genotype with 23 on cART for 5 years and 6 for more than 10 years). No significant effect of the Δ32 allele, survival and AIDS free survival was also found by Laurichesse et al. CCR5 Δ32/wt genotype and time to virological failure in the study of 436 individuals observed for the median follow-up of 22 months CCR5 Δ32/wt genotype on virologic treatment efficacy Δ32 allele among antiretroviral treated patients observed in our study might be associated not only to the size of the group, but also differences in the time from the infection to treatment initiation, which is related to late diagnosis of HIV and high prevalence of AIDS at the time of diagnosis. However, it must be noted that the Δ32 allele has been associated with the decrease in the likelihood of viral suppression failures, defined as HIV-RNA ≥200 copies/ml at 16–28 weeks of therapy, accelerated viral suppression to <200 HIV-RNA copies/ml, as well as significantly better virologic response to antiretrovirals both at 6 and 12 months following treatment initiation CCR5 Δ32/wt heterozygous patients was noted It must be noted, that the CCR5 Δ32/wt genotype was observed over 36 months of follow-up with stable HR of 2.5–2.6 noted up to 96 months, the end of observation period. This suggests that in the cART era the protective effect of this variant on survival is not lost over time as was observed for the Δ32 allele and AIDS diagnosis. Hazard ratio effect plots for gender and diagnosis of AIDS proved time-dependent, with female gender associated with significant protection up to 108 month of observation while for AIDS two periods associated with favorable prognosis in AIDS free patients were noted, namely from months 36 to 54 and 108 to 180 months. The reason for this time dependent relationship remains to be elucidated.In adjusted multivariate analyses both AIDS diagnosis and antiretroviral treatment remained significant predictors of mortality. Moreover, it was confirmed that of all the CD4 metrics studied, the latest CD4 count is the strongest predictor of mortality, as has been suggested before CCR5 Δ32 deletion on long term survival among HIV (+) patients in the cART era remain sparse, especially with implementation of Cox regression models adjusted for clinical variables significantly contributing to the mortality risk.Studies analyzing the impact of the A potential limitation of the study was use of interval censoring for six cases when the exact date was unknown, with the death date fixed as the median date between the last observation time and information that the patients actually died. Another limitation is related to the lack of possibility to observe the patients from the time of seroconversion, however in the setting of the late testing and referral of majority of cases with symptomatic immunodeficiency such a study was not feasible. Another limitation is related to the lack of information on adherence, therefore the results could not be controlled for this factor.CCR5 Δ32 on long term survival in conjunction with well established factors influencing mortality provides an insight into the interplay between genetic and virus/host-related factors. Such an effect is of the greatest importance in the late-tested populations, such as the one in Poland, allowing for the longer period of delay from infection to disease detection and treatment initiation, whereas it is of the lesser importance in the cART treated individuals. Testing for the CCR5 Δ32 mutation in clinical practice might be useful for elucidation of the reason for delayed progression of HIV infection, however it should probably not influence decision on antiretroviral treatment initiation or modification.Host genetics strongly interacts with HIV leading to the modification of the course of infection. Our finding of the beneficial effect of the


Two integrases inhibitors, raltegravir and elvitegravir, have now been approved by regulatory agencies for use in the treatment of HIV-infected patients; and the approval of a third such drug, dolutegravir, is expected during 2013 on the basis of several phase 3 clinical trials. The advent of this new class of antiretroviral (ARV) medications represents a major advance in the management of HIV infection, and each of these three drugs can be expected to continue to be an important component of ARV combination regimens. The recent approval by the Food and Drug Administration (FDA) of Elvitegravir (EVG) as an anti-HIV integrase strand transfer inhibitor (INSTI) is good news for patients who will want to take a potent once-daily single tablet antiretroviral regimen (STR). INSTIs target the HIV enzyme integrase through a selective effect on strand transfer. This is a result of both the binding of the inhibitor to the specific complex between integrase and viral DNA, resulting in displacement of the reactive 3′ end of the viral DNA and chelation of the two essential magnesium ions present in the integrase active site . In geneAt the same time, it must be recognized that one other INSTI is currently available for treatment and that other members of this family of compounds are now in late stage clinical development and may be approved for therapy in the near future. The drug that has already been approved is raltegravir (RAL), and it has the advantage of being extremely potent as well as safe and very well tolerated over more than five years of clinical experience . MoreoveIt is worth noting that RAL was approved by regulatory agencies as a twice daily drug on the basis of the Startmrk clinical trial. However, attempts were made to demonstrate that RAL might be used on a once-daily basis if dosed at 800mg once-daily (qd) as opposed to the twice-daily (bid) dosing schedule of 400 mg that is recommended . AlthougRecent clinical findings suggest that a new second generation INSTI termed dolutegravir (DTG) is also superior to EFV over 48 weeks of therapy, when both drugs are used in combination with a fixed dose of once-daily NRTIs, abacavir/lamivudine or TDF/FTC, respectively . However10 c/ml) than in the Stribild® studies (4.75 and 4.88 log10 c/ml) and the DTG studies (4.52 and 4.67 log10 c/ml) [Of note, comparison of the different phase 3 studies of the three INSTIs is difficult. For example, median baseline plasma viral load was significantly higher in the Startmrk 5.1 log c/ml tha10 c/ml) ,15. This10 c/ml) ,15. FurtTable Thus, we are privileged to have multiple options in regard to the use of various INSTIs for therapy of HIV-infected individuals. EVG is the newest INSTI to be approved, and the promise of DTG for the future therapy of HIV disease is exciting. Resistance against both RAL and EVG have been reported on the basis of both clinical failures (fewer with RAL than EVG) and tissue culture drug selection studies, and it is clear from this work that the most frequent mutations in the HIV integrase gene that confer resistance against RAL also confer resistance against EVG, making it highly improbable that these two molecules might be used to salvage one another in the event of drug resistance . Indeed,Each of RAL, EVG, and DTG will continue to be important components of combination anti-HIV therapy over many years. Although there are more long-term efficacy and safety data now available on RAL than on the other two drugs, the use of the other options in first-line therapy is also compelling. Due to its more favorable resistance profile, DTG will probably be the only member of the INSTI family of drugs that will be useful in both first-line therapy as well as in subsequent HIV INSTI-based treatment.Drs Raffi and Wainberg have received research funding and/or consultancy honoraria from Gilead Sciences, Merck Inc., ViiV Healthcare and Bristol-Myers Squibb Inc.Both FR and MAW conceived of the idea for this Viewpoint, and both authors contributed to its writing. Both authors read and approved the final manuscript.


Classic Kaposi's sarcoma (CKS) is a subtype that traditionally occurs in elderly HIV-negative males of Mediterranean origin. Patients with CKS characteristically present with skin lesions in the distal extremities. Involvement of the viscera is uncommon but may occur in the late stages of the disease. Patients with extensive KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS, especially Paclitaxel, have activity against CKS after failure of prior therapy. We report a patient treated with weekly Paclitaxel, as initial chemotherapy, for CKS presenting with multiple visceral involvement and having a contraindication for Bleomycin. The patient had quasi-complete response after three months of chemotherapy suggesting that weekly Paclitaxel might be effective as a first-line therapy for classical type KS with visceral involvement.  Classic Kaposi's sarcoma (CKS) is an angioproliferative disorder that is thought to develop from endothelial cells, myofibroblasts, and monocyte-macrophages. Widespread, or rapidly progressive CKS, is an indication for systemic chemotherapy. Although no cytotoxic chemotherapeutic agents have been approved for treatment of CKS, a number of drugs indicated for AIDS-associated KS have activity against CKS. These include Bleomycin, Vinblastine, Etoposide, Pegylated liposomal Doxorubicin, Gemcitabine, and Paclitaxel –5. We reA 80-year-old male was admitted to Hassan II University Hospital in 2010 for treatment of long-standing Kaposi's sarcoma. Disease had presented 2 years earlier with the appearance of a few papules on his legs with gradual extension. Physical examination showed multiple violaceous to dark red patches and plaques of varying sizes on his face, trunk, and limbs with acral predominance . SimilarClassic Kaposi's sarcoma is primarily a cutaneous disease of the lower extremities affecting predominantly elderly men of Mediterranean origin. This form is associated with an altered immune system and malignant diseases without HIV infection . Clinica2 every 3 wks) or Docetaxel (60 mg/m2 every 3 wks) [Patients with extensive or recurrent KS can be treated with systemic chemotherapy. A number of drugs approved for treatment of AIDS-associated KS have activity against CKS after failure of prior therapy. These include Vinblastine, Bleomycin, Doxorubicin, and Etoposide alone or in combination –4. Pacliy 3 wks) . For allRecently, Brambilla et al. have evaluated the clinical efficacy and tolerability of Paclitaxel (100 mg weekly) in 17 patients with advanced aggressive and refractory CKS. The response to the therapy was evaluated after 12 weeks. Partial and/or complete response was achieved in 14 of 17 patients. The treatment was generally well tolerated. Mean time to recurrence was 4.5 months from the end of the therapy . This stIn the case reported above, treatment was administered with low-dose Paclitaxel to minimize toxicity in an elderly patient with comorbidities and aggressive form of classic Kaposi's sarcoma. A major response and good tolerability were observed, suggesting that weekly Paclitaxel might be effective as first-line chemotherapy in treating classical type KS with visceral involvement.The experience reported here would suggest that weekly low-dose Paclitaxel is effective as first-line chemotherapy in treating classical KS in life-threatening localizations. The low toxicity of this regimen is well tolerated, especially in elderly patients with comorbidities.


In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS).Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year.Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients , those with a high education level  or a high CD4 count  were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens  whereas CD4 count increase after one year of treatment was similar in both groups.Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations. After 1996, the use of combined antiretroviral therapy (ART) transformed HIV infection from a progressive, fatal disease to a treatable chronic condition and dramatically reduced its related morbidity and mortality In 2001, the Swiss Federal Office of Public Health stopped issuing recommendations Even though comprehensive treatment recommendations are now widely available, choosing an initial antiretroviral combination often remains a challenging task. In the industrialized world, the availability of more than twenty different antiretroviral drugs has led to highly personalized ART prescriptions, according to patient characteristics and wishes, co-morbidities and resistance testing. This contrasts to the public health approach to ART, as shown by Keiser et al., who compared initial ART regimens prescribed in South Africa and the SHCS CD4 cell count, viral load and socio-demographic characteristics such as age and ethnicity have been shown to be associated with the type of ART prescribed and the probability of being treated with an ART in violation of current guidelines The main goal of official treatment guidelines is to improve the choice of ART. A publication from a small US cohort showed that patients receiving ART according to the IAS recommendations had clear virological and immunological benefits The aims of this study were to (1) describe first-line ART regimens in the SHCS from 1998 to 2007 and compare them with the corresponding IAS-USA recommendations, (2) describe the socio-demographic and clinical characteristics of the HIV-infected sub-population that did not receive regimens consistent with the IAS-USA recommendations, and (3) compare the efficacy of regimens prescribed according to these recommendations with those in violation with them.Local ethical committees of all seven participating study sites , Ethikkommission des Kantons St. Gallen, Kantonale Ethikkommission Zürich, Comitato etico cantonale del Ticino, Commission d'éthique de la recherche clinique de la faculté de biologie et de medicine de l'université de Lausanne, Comité d'éthique du départment de médicine des hôpitaux universitaires de Genève) have approved the study and written consent has been obtained from all participants.www.shcs.ch) is a prospective cohort study with the ongoing enrolment of HIV-positive adults in seven outpatient clinics and their affiliated hospitals and private practice physicians in Switzerland. It is estimated to cover about 45% of the cumulative number of HIV infections declared to the Swiss public health authorities and 69% of all patients living with AIDS in Switzerland Set up in 1988, the Swiss HIV Cohort Study  who started ART between 01.08.1998 and 31.12.2007, 4189 were included in the analysis. Of the 115 patients that were excluded, 8 received unspecified ART and the remaining 107 patients were women who started treatment because of pregnancy while having a CD4 count above 200 cells/µl. Unlike patients with severe immune deficiency, many of these women started treatment because of the pregnancy and stopped it after having given birth. These women could therefore not be compared with the other patients.Initial ART regimens were compared with the newest IAS recommendations available at treatment start date. Updated recommendations were taken into account from the first day of the month following the publication. ART regimens were classified by two experienced physicians as follows: 1) recommended regimen; 2) alternative regimen; 3) active but not yet recommended regimen; 4) drug combination suggesting primary resistance ; 5) prescription within a study protocol; 6) violation of recommendations. Any regimen consisting of one or two active drugs only were considered as violations of the recommendations. In 1998, only PI-based regimens were recommended. In 2000, NNRTI-based regimens were added to the recommended treatments list and triple-NRTI regimens were only accepted as first-line treatments in the 2002 recommendations. We encountered several difficulties in the classification process. There were inconsistencies between the presentations of the different recommendations from one year to the other. For instance, the recommendations elaborated in 2000 did not mention any alternative treatments, and the ones released in 2002 did not specify which combinations of NRTI were to be used or avoided. Importantly, new drugs and combinations are approved all year long but are only included in the subsequent guidelines. To avoid classifying such new, active and safe regimens as violations of recommendations, we created a separate category for them (category 3: active but not yet recommended regimen).All statistical analyses were performed using Stata 10 . Baseline characteristics of patients receiving violation treatments were compared to all other patients (categories 1–5). Crude associations between baseline characteristics and initial regimen type were evaluated using chi-square tests. Predictors of receiving a violation regimen were then assessed in a multivariable logistic regression analysis. Explanatory variables included sex, age category at treatment start , region of origin , risk group according to mode of HIV acquisition (Men who have Sex with Men (MSM), heterosexual, Injection Drug Users (IDU) or other), source of follow-up (SHCS center or other), CD4 count at treatment initiation , hepatitis B antigenemia at baseline (defined as having had at least once a positive HBsAg), chronic hepatitis C virus (HCV) infection (defined as positive HCV serology and HCV RNA), plasma HIV load at baseline , education level (low or high education) and start of ART more than three months before being included in the SHCS.The proportion of patients achieving undetectable viral load after 12 months of ART , as well as the CD4 increase during this period, were compared between patients receiving violation ART and the others, using multivariable logistic and linear regression analyses respectively. An undetectable viral load was defined as being less than 400 copies/ml. In a sensitivity analysis, a threshold of 50 copies/ml was used. Time to switching of ART was evaluated using a Cox proportional hazards model.Multiple imputation was used to impute missing values at baseline. Imputations were based on logistic and linear regression models with six dependent variables  and six independent variables . Analyses were run on each of 25 datasets and results were combined with Rubin's rules. In a sensitivity analysis we also compared these results with a complete case analysis.Baseline socio-demographic and clinical characteristics of the 4,189 HIV-infected patients who started ART between August 1998 and December 2007 are listed in The classification of initial ART regimens according to the IAS-USA recommendations in force at time of ART start is listed in online supporting information: Table S1). This was also true for patients older than 40 years, compared to those under 30. Patients originating from Sub-Saharan Africa were less likely to achieve an undetectable viral load compared to those from Western Europe, as were IDU's compared to MSM. Finally, participants starting ART more than 3 months before enrolment in the SHCS or with a CD4 count above 350 cells/µl were least likely to have an undetectable viral load after one year.Patients who initiated ART in the SHCS between 1998 and 2007 had a median CD4 count increase of 165 cells/µl (IQR 76-273) within one year, and 85% of them had a viral load below 400 copies/ml one year after treatment start. Patients given violation regimens were less likely to achieve an undetectable viral load  one year after treatment start Table 4.online supporting information: Table S2).Immunological recovery one year after ART start was similar in both treatment groups Table 4.Within the first year of treatment, 34% of patients on violation regimens were switched to a second regimen, as compared to 25% in the other groups. The corresponding adjusted hazard ratio in the Cox regression model was 1.66 .When the threshold of HIV viral load was set at 50 copies/ml instead of 400, the difference in the proportion of patients having a favourable outcome at one year between the two treatment groups was not statistically significant. With this second definition, participants with initial treatment in violation of the recommendations were 25% less likely to reach an undetectable viral load compared to those on recommended regimens, after adjustment for all co-factors . When analyzed separately, patients on dual-NRTI regimen were also less likely to reach an undetectable viral load (<400copies/mL) after 1 year than patients on recommended regimens .Since 1998 and the first version of the IAS-USA recommendations, more than four thousand treatment-naïve HIV-infected patients started ART in the SHCS until the end of 2007, being prescribed one of more than two hundred different regimens. The majority of these participants received initial treatment according to IAS-USA recommendations in force at the time ART was started, as well as according to IAS-USA recommendations on antiretroviral drug resistance testing if primary antiretroviral resistance was shown The baseline characteristics of the patients receiving violation combinations were of special interest, since it was suspected that these regimens might lead to a higher proportion of viral failures. In our study, these patients were more often female and highly educated. Even though it is unknown why these sub-populations were more likely to receive initial ART in violation of recommendations, physicians should be aware of these associations in order to avoid the prescription of these inferior regimens.. Highly educated patients may also have been more active in the negotiations regarding the choice of the initial treatment regimen with the physician, favouring sometimes regimens known to be of low virological efficacy. In their small study of self-reported initial treatment in a US-cohort of HIV infected women, Cocohoba et al. reported a significant association between the prescription of violation regimens in patients with a higher CD4 count and lower viral load at baseline In the SHCS, patients treated according to the IAS-USA recommendations between 1998 and 2007 were significantly more likely to achieve an undetectable viral load (<400 cp/mL) after one year, compared with those on a violation regimen. Importantly, patients on violation regimens were more likely to change their treatment to a different regimen during the first six months of ART. As a consequence, changes from a violation regimen to a recommended one might have had a positive impact on clinical outcomes in this sub-group of patients. This might have decreased the difference in virological outcome between patients on violation ART and those on recommended regimens. When the definition of an undetectable viral load was restricted to less than 50 copies/ml, the association between treatment group and virological outcome was not statistically significant. Even though this second definition is widely used in the clinical settings, it may not be appropriate in this context, as some patients might experience single episodes of low-level viremia, so-called blips, which often do not have any clinical consequences. Notably, IDU's and patients from Sub-Saharan Africa were less likely to have an undetectable viral load one year after treatment start compared to the other risk groups, even though they were not prescribed violation regimens more often. These associations have both been described in previous studies and might be explained by lower treatment adherence, as described in the SHCS by Glass et al. Another relevant finding of this study relates to the important role of the SHCS in the daily clinical management of HIV infected patients in Switzerland. Participants who started ART more than 3 months before being included in the SHCS were more often prescribed regimens in violation with the recommendations and were less likely to have an undetectable viral load after one year. Although this seems to support the management of HIV infected patients by physicians experienced in the field of HIV medicine, this finding could also be explained by differences in access to care or other socio-economic factors.Finally, immunological response to ART in patients on violation regimens showed a less favorable trend compared to CD4 recovery in patients on recommended initial ART, although the difference was not statistically significant in the multivariable model. As expected, younger patients and those with a low CD4 count at baseline had a better immunologic recovery than the others.There are several limitations to this study. First, it has to be noted that our classification of the different initial ART regimens in the SHCS was based on expert judgement and not on pre-specified objective criteria. Second, detailed description of antiretroviral combinations is not available in every set of recommendations thus allowing for a wider range of treatments accepted in the different treatment categories depending on the year of release. Third, our statistical analyses rely on observational data, which leads to different types of bias. For example, data on patient history is only collected twice a year, and is therefore subject to recall bias. CD4 counts and viral load values were not always obtained exactly 12 months after ART initiation, the ones measured closest to this time period had to be used. Finally, the logistic regression models cannot be adjusted for every single existing confounder, which means that residual confounding has to be taken into account when interpreting the results. Finally, given the large amount of ART-related issues discussed in the IAS-USA treatment recommendations, we could not consider all determinants of ART prescription for our analyses. As a consequence, even though possible adverse events and pill count, for instance, should be considered when choosing the appropriate initial ART regimen, we decided to limit our analyses to the description of individual predictors for receiving violation regimens and the evaluation of the virological and immunological response to the different ART regimens.In summary, our results show that in the SHCS, 5% of patients received initial regimens in violation with the IAS-USA recommendations. These patients were less likely to achieve viral load suppression after one year. Our results suggest that, in the context of constant increase in the number of therapeutic options and knowledge on specific drug-related side-effects and interactions, the release of updated treatment recommendations as well as the promotion of their use are important to guarantee the best possible care of HIV infected patients.Table S1Univariable and multivariable regression models estimating the proportion of patients having an undetectable viral load (<400 copies/mL) one year after ART start.(DOCX)Click here for additional data file.Table S2Univariable and multivariable regression models estimating the average change in CD4 cell count one year after initial ART start.(DOCX)Click here for additional data file.


Once-daily darunavir/ritonavir 800/100 mg is licensed for first-line treatment and data are available in treatment-experienced patients with no resistance-associated mutations to darunavir. We designed an investigator study to evaluate the switch to once-daily darunavir/ritonavir 800/100 mg in treatment-experienced patients with suppressed HIV-1 replication on a twice-daily ritonavir-boosted protease-inhibitor (bid PI/r) containing regimen, i.e. in a setting where genotypic resistance test cannot be performed.In this open-label, noncomparative, multicenter study, patients on a bid PI/r-containing triple combination, with suppressed viral replication, were switched to once-daily darunavir/r 800/100 mg containing triple combination. The primary endpoint was the proportion of patients with plasma HIV-RNA< 50 cp/ml 24 weeks after the switch. Detailed darunavir pharmacokinetic evaluation was performed at Week 4 (W4) and measurement of HIV-RNA in seminal plasma at baseline and W48 in a subset of patients.85 patients were enrolled. All had HIV-RNA<50 cp/ml at screening with a median of 478 CD4/mm3 (range 40-1559) and pre-exposure to a median of 2 PI (1-5). 61 patients were currently on lopinavir/r, 18 on fosamprenavir/r, 4 on saquinavir/r and 2 on indinavir/r. At baseline, 15/16 patients had a seminal HIV-RNA< 100 cp/ml and 125 cp/ml for the remaining one. By intent-to-treat analysis (missing=failure), 78/85 patients  maintained an HIV-RNA<50 cp/ml at W24. 7 patients experienced protocol-defined treatment failure between baseline and W24: 2 had confirmed viral rebound (88 and 70 cp/ml), 1 discontinued study treatment at W4 for adverse event, 3 withdrew their consent and 1 was lost to follow-up. By on-treatment analysis, 78/80 patients  maintained an HIV-RNA<50 cp/ml at W24. At W4, the median area under the darunavir plasma concentration-time curve measured in 11 patients was 61 380 ng.h/ml (IQR 25-75% 42 094-97 313), darunavir median trough concentration 1340 ng/ml (907-1830) and darunavir half-life was 12.2 h (8.3-13.7). Tolerability of once-daily darunavir/r 800/100 mg was excellent.In PI/r-experienced patients with suppressed viral replication on a bid PI/r-containing regimen, switching to once-daily darunavir/r 800/100 mg containing regimen was able to maintain suppression of viral replication and was safe in this setting where genotypic resistance test could not be performed.


Nevirapine belongs to the group of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and is commonly administered in first-line treatment of HIV infection.Systematic review and meta-analysis was undertaken to compare effectiveness of nevirapine-based regimens with other antiretroviral schedules used as an initial treatment of HIV-infected antiretroviral-naive subjects.® V 5.2 software.Electronic databases  were searched up to 28 December 2012 for randomized controlled trials (RCTs) published as a full text and regarding nevirapine-based regimens used as a initial treatment for HIV infection. Meta-analysis was performed with RevManTwelve RCTs were included in the systematic review and all of them were suitable for meta-analysis. Results of the meta-analysis have shown that nevirapine, efavirenz, and ritonavir-boosted protease inhibitor, added to the background regimens, were equally effective in terms of reaching undetectable plasma HIV RNA level as well as risk of disease progression or death. Compared with ritonavir-boosted protease inhibitor-based regimens, nevirapine-based regimens statistically significantly increased the risk of discontinuation of assigned treatment .Despite limited RCTs data available for particular comparisons, our results suggest that nevirapine-based regimens may be considered for first-line treatment of HIV-infected adults, due to their comparable efficacy to the other currently recommended initial antiretroviral therapies. Although the efficacy of antiretroviral therapy in HIV-positive patients is indisputable, the variability of antiretroviral regimens used in clinical practice raises the question of the most effective treatment schedules. A combination of three or more drugs, known as highly active antiretroviral therapy (HAART), is now typically used. HAART is effective at lowering viral load and increasing CD4+ T cell levels . AccordiThis report was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines  and meth® V 5.2 software.The search and selection of the trials were performed independently by two reviewers . All disagreements were resolved by discussion with a third author (A.M.) to obtain consensus. Full texts of articles were reviewed according to the predefined inclusion or exclusion criteria. Data extracted by the first reviewer (P.K.) were verified by the second reviewer (J.K.). Extracted information included: study design, participant characteristics, interventions, duration of treatment, and clinical outcomes. To assess the methodological quality of included trials, the Jadad scale was used  Table 2Table 2. The electronic search yielded 783 items after duplicates were removed. The selection of titles and abstracts resulted in 60 potentially relevant full-text articles, of which 49 references were excluded due to the reasons presented in Twelve randomized controlled trials published in English as peer-reviewed articles were included. These included studies were grouped in the following way. Firstly, background regimen, common in compared groups, was identified. Active drugs added to the common background regimen were considered as comparators. Two different regimens adequate for comparisons with nevirapine were identified: 1 NNRTI or bPI (ritonavir-boosted protease inhibitor), all the above added to specified background regimens. We did not take into consideration regimens containing unboosted PI and triple NRTIs regimens as they are no longer used in clinical practice.A predefined inclusion criterion for studies was the absence of any prior treatment with antiretroviral therapy. Finally, trials recruiting patients with limited previous exposure to antiretroviral therapy were included . Data ofPlasma viral load (pVL) is a globally accepted endpoint used to measure the efficacy of antiretroviral drugs . AvailabThe characteristics of studies included in this report are presented in All studies ,18,19,20Of seven studies  in the target population of treatment-naive adult HIV-infected patients. These results are supported by clinical guidelines that recommend the above regimens as initial therapeutic options for HIV infection. Our results are also consistent with previous meta-analyses, showing that nevirapine and efavirenz in combination with 2 NRTIs given to antiretroviral-naive HIV-infected patients have similar efficacy . It shouThe main limitation of the conducted meta-analysis was the number of trials available for particular comparisons and heterogeneity of the included studies regarding background regimens, baseline characteristics of randomized patients , lengths of follow-up periods, and differences in the analyzed endpoint definitions. Some of the included studies recruited patients with previous limited exposure to antiretroviral therapy, for example single exposure to nevirapine for the prevention of mother-to-child transmission of HIV. Nevirapine, as well as other NNRTIs, has a low genetic barrier. The OCTANE study showed that resistance to nevirapine occurred in 14% of women with previous exposure to a single-dose of nevirapine, leading to decreased efficacy of subsequent nevirapine-based treatments in comparison to NNRTI-naive women ,25. HoweMoreover, in some studies the exact data on the particular, clinically relevant outcomes were unavailable within the papers, or they were not intended to be evaluated at all. Therefore, only some of the identified studies could be included in a quantitative analysis, and only some of the presented results were suitable for meta-analysis, especially in the case of efficacy evaluation see .Another limitation of the performed meta-analysis is the absence of subgroup analysis according to background regimens, due to the limited number of trials adequate for inclusion in separate comparisons. Bartlett et al.  comparedWe did not perform subgroup analysis according to nevirapine dosage. Most of the included studies analyzed nevirapine given according to product characteristic -200 mg twice a day. Three trials used nevirapine given as one daily dose of 400 mg ,20,24. NIt could be suggested that a network meta-analysis to support the results obtained in direct analyses should be performed. However, a mixed treatment comparison (MTC), a special case of network meta-analysis combining direct evidence and indirect evidence for particular pairwise comparisons, has several limitations. First, the mixed treatment approach is not a substitute for a large, well-designed randomized controlled trial examining relative clinical efficacy and safety. The validity of the adjusted indirect comparisons (as with MTC) depends on the internal validity and homogeneity of the included trials ,34,35. TAccording to the practice guidelines antiretroviral therapy in HIV-infected patients should maximally and durably suppress plasma HIV viral load and also reduce HIV-associated morbidity and prolong the duration and quality of survival . In our Results from other observational studies do not give a clear answer on the issue of the higher efficacy of nevirapine or efavirenz in the analyzed population. The above-mentioned study conducted in Senegalese patients , as wellThe overall toxicity profiles of nevirapine and other regimens were comparable. However, a higher risk of treatment discontinuation due to adverse events in comparison to ritonavir-boosted protease inhibitor (bPI) was found. Due to limited data it was also not possible to compare particular adverse events between analyzed regimens. Regarding the safety profile of nevirapine, hepatotoxicity and skin reactions, especially rashes, are a special concern. In a large prospective controlled trial that included nevirapine as a part of the antiretroviral regimen, a high frequency of hepatotoxicity was observed . Data frResults of previous meta-analyses comparing nevirapine and efavirenz in combination with other antiretroviral agents showed differences between both drugs in terms of toxicity ,30. SiegIn summary, our data demonstrate the comparable efficacy of nevirapine-based therapy versus other regimens recommended as initial therapy for HIV-infected patients (PI-based and efavirenz-based treatments). Concerning safety, special groups of patients can achieve significant clinical benefits from nevirapine-based regimens. However, when nevirapine treatment is initiated the risk of hepatotoxicity and rashes should be taken into account. Despite the potential limitations of the performed meta-analysis our results provide important guidance for choosing first-line nevirapine-based treatment for HIV-infected patients.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


There are limited data on paediatric HIV care and treatment programmes in low-resource settings.A standardized survey was completed by International epidemiologic Databases to Evaluate AIDS paediatric cohort sites in the regions of Asia-Pacific (AP), Central Africa (CA), East Africa (EA), Southern Africa (SA) and West Africa (WA) to understand operational resource availability and paediatric management practices. Data were collected through January 2010 using a secure, web-based software program (REDCap).N=10; CA, N=4; EA, N=29; SA, N=10; WA, N=10). Most were in urban settings  and received funding from governments , PEPFAR , and/or the Global Fund . The majority were combined adult–paediatric clinics . Prevention of mother-to-child transmission was integrated at 35 (56%) sites; 89% (N=56) had access to DNA PCR for infant diagnosis. African (N=40/53) but not Asian sites recommended exclusive breastfeeding up until 4–6 months. Regular laboratory monitoring included CD4 , and viral load . Although 42 (67%) sites had the ability to conduct acid-fast bacilli (AFB) smears, 23 (37%) sites could conduct AFB cultures and 18 (29%) sites could conduct tuberculosis drug susceptibility testing. Loss to follow-up was defined as >3 months of lost contact for 25 (40%) sites, >6 months for 27 sites (43%) and >12 months for 6 sites (10%). Telephone calls  and outreach worker home visits to trace children lost to follow-up  were common.A total of 64,552 children were under care at 63 clinics (AP, In general, there was a high level of patient and laboratory monitoring within this multiregional paediatric cohort consortium that will facilitate detailed observational research studies. Practices will continue to be monitored as the WHO/UNAIDS Treatment 2.0 framework is implemented. UNAIDS estimates that 3.4 million children under the age of 15 years are currently living with HIV infection; 91% of these children reside in sub-Saharan Africa . Highly To date, data are limited with regards to the structure and outcomes of paediatric HIV care and treatment programmes in resource-constrained settings. Understanding the availability of clinical management resources as well as the application of prevention, diagnosis and treatment standards is necessary to provide a context for observational cohort studies. In turn, such studies are necessary to optimize programme development, and to improve patient access and outcomes. While information about local or national programmes may be available, the indicators used are not necessarily comparable between countries or across regions –7. Largewww.iedea.org) is a global network that includes paediatric cohorts located in Asia; the Caribbean and South America; and Central, East, Southern, and West Africa [The International epidemiologic Databases to Evaluate AIDS , general cancer diagnostics and management (N=44), paediatric-specific information (N=61) and paediatric cancer diagnostics and management (N=38). Multi-lingual versions of the site assessment tool were implemented using the REDCap (Research Electronic Data Capture) system, a secure, web-based application designed to support data capture for research studies (project-redcap.org). REDCap was developed at the Vanderbilt Institute for Clinical and Translational Research. It provides an interface for validated data entry, audit trails for tracking data manipulation and automated import and export procedures to common statistical packages [Regional investigators developed and standardized a site assessment tool that included questions regarding site resources, clinical practices and access to drugs and laboratory monitoring for adult, paediatric and combined adult–paediatric clinical settings. Sites that had either paediatric-only or combined paediatric–adult programmes were asked to respond to 253 questions regarding general programme resources and clinical management  interventions, HIV diagnostic testing, access to and use of antiretroviral drugs, management of tuberculosis (TB), prophylaxis for Pneumocystis jiroveci pneumonia, malaria management, and follow-up and transfer practices. Categories were selected based on clinical and programmatic relevance. Site-level responses were evaluated for inconsistencies and sent to the IeDEA regional paediatric representatives to coordinate an additional quality control check, as needed. The corrected individual data summaries were combined to produce a regional-level data summary report.Ten data categories were selected N=51, 81%), research grants , the US PEPFAR programme , the Global Fund  and patient fees . None of the sites required patients to pay for first-line ART; two sites in West Africa required partial payment for second-line ART.Data were collected from all 63 sites contributing data on 64,762 children exposed to and/or living with HIV to the IeDEA cohort for regional and multiregional analyses. This included 10 clinics/sites in Asia, 4 in Central Africa, 29 in East Africa, 10 in Southern Africa and 10 in West Africa . The majThe median upper age limit of children attending the clinic ranged from 14 years at participating sites in East Africa to 18 years in Asia and Southern Africa. The median number of half-day clinic sessions per week dedicated to children ranged from one in East Africa to 10 in Southern African sites; paediatric care provided during mixed adult–paediatric clinics is not reflected in this response. Direct food assistance was uncommon in Asia (30%) but available for malnourished children in almost all East African sites (93%). Across the regions, half of the sites had support groups for children, and most offered disclosure counselling for caregivers (81%) and children (71%).After a missed clinic visit, sites utilized phone calls (83%), home visits by clinic staff (21%) and home visits by outreach workers (71%) to track patients and reschedule appointments, when feasible. Loss to follow-up was defined as >3 months of lost contact for 25 (40%) sites, >6 months for 27 sites (43%) and >12 months for 6 sites (10%). The reasons reported by sites for patient loss included non-disclosure to family or neighbours (19%), death (35%) and lack of financial resources within the family to sustain regular care (44%).Outside of East Africa, PMTCT programmes were less commonly embedded into clinical care. Maternal antiretroviral regimens varied among sites and ranged from single-dose nevirapine at delivery to triple-drug ART. Infant care after delivery most commonly included post-natal antiretrovirals (79%), early infant diagnostic testing (79%) and co-trimoxazole prophylaxis until infection status was confirmed (81%). Sites reported their most commonly recommended infant feeding approaches, with 63% preferring exclusive breastfeeding through to 4–6 months of age, and 21% preferring formula/replacement feeding at the time of the survey.PCP prophylaxis was not discontinued in children on therapy at some sites within the African regions , while all Asian sites stopped co-trimoxazole after immunologic improvement on ART. With regards to malaria, most (70%) African sites reported that they used blood smears for diagnosis. Available diagnostic testing for paediatric TB included skin testing (33%), chest x-ray (89%), acid-fast bacilli smear (67%) and culture (37%), as well as gastric washing (35%) and induced sputum (21%) on-site. Most reported that TB treatment was available (79%), with children at 60% of these sites being offered directly observed therapy. Almost all sites reported that isoniazid (92%), rifampicin (92%) and pyrazinamide (89%) were standard drugs in first-line induction therapy for TB in children, while 44% included ethambutol and 13% included streptomycin as additional options. Although 71% of sites reported using efavirenz in the initial ART regimens in children older than three years of age during TB treatment, 79% used efavirenz or nevirapine.Sites reported having better access to stavudine-based (68% with easy access) than to zidovudine-based (25% with easy access) antiretroviral fixed-dose combinations for children. Atazanavir was not available or not used in children in 98% of African sites and 50% of Asian sites. There was no single dominant method to assess paediatric treatment adherence, with 40% of sites monitoring pill counts and 24% relying on RNA viral load testing. Multiple interventions to support adherence were utilized beyond counselling, including having a pharmacist on the core clinical team (73%), routine reviews of medication pick-up (67%) and pill boxes or blister packs (48%).HIV DNA PCR, CD4 and RNA PCR testing were widely available across the regions, with reduced access to plasma HIV-1 RNA viral load in Central and West Africa . CD4 wasThe World Health Organization (WHO) and UNAIDS’ “Treatment 2.0” is a global framework whose objective is to achieve universal access for adults and children living with HIV infection through simplified treatment with optimized drug regimens, point-of-care diagnostics and decentralized service delivery . Given tPaediatric IeDEA is a multicentre, international collaboration of paediatric HIV treatment programmes in Asia and Africa that forms an operational research network to describe paediatric HIV care and treatment programmes, treatment outcomes and their determinants. Characterizing intra- and inter-country differences in current paediatric HIV care and treatment management programmes can help to guide the development of clinical practice guidelines, improve understanding of local resource availability and inform policy and programmes by examining various models of care, clinical outcomes and operational issues over time. However, ongoing changes inherent to progressive regional ART scale-up and international prevention and treatment guidelines make cross-regional comparisons over time even more challenging. In addition, the sites participating in this survey were predominantly in urban settings and the survey characterizes resources reflecting the highest levels of HIV care and treatment for children in these countries. Although they may not necessarily be representative of the local HIV programmes, many are national referral centres that provide advice and direction for paediatric HIV care throughout the different regions.Although clinical resources and access to paediatric antiretroviral formulations were generally high, there was some variation between the regions. African and Asian sites notably differed with regards to infant feeding recommendations. International guidelines promote the use of exclusive breastfeeding due to higher levels of morbidity and mortality in non-breastfed infants ,16, but To assess the long-term outcomes of ART in perinatally infected children as they age into adolescence, national paediatric HIV programmes in resource-constrained settings will need to expand their focus beyond diagnosis and early monitoring to a chronic disease model. More complex laboratory monitoring and targeted sub-cohort studies of toxicities and disease complications will also be needed to understand the impact of HIV and its treatment on adolescents and perinatally infected adults. Multiregional platforms like IeDEA have the capacity to facilitate this more advanced research agenda, promote data harmonization and guide national programmes and inform global policy.


Though the advantages of routine virological monitoring for patients on anti-retroviral therapy have been established, cost and complexity limit its full implementation. Monitoring is important for diagnosing virological failure early on, before the development of drug resistance mutations, and to trigger early adherence interventions. Simple and cost-effective viral load tests that facilitate simplification and decentralization of testing and strategies, such as the use of dried blood spots and pooled sample testing, which further aid simplification, are becoming available. In addition, replacing immunological monitoring with virological monitoring in non-viremic patients in a phased manner will reduce the costs associated with dual immuno-virological monitoring. Going forward, the simplification of testing paired with price reducing strategies that will allow for healthy competition between multiple manufacturers will enable the implementation of viral load testing in resource-poor settings. It is important that future HIV and AIDS treatment guidelines provide clear recommendations for routine virological monitoring and that governments and donors fund the implementation of accurate and operationally proven testing platforms in a comprehensive manner. The benefits of virological monitoring for patients on anti-retroviral therapy (ART) are well established and include the ability to diagnose adherence problems and treatment failure, and optimize therapy to support reduced transmission –3. HowevEvidence of the benefit of viral load monitoring at the population level is mixed. Trials evaluating the short-term benefit of virological monitoring against clinical endpoints, which are considered delayed outcomes, have concluded no major benefit over-and-above clinico-immunological monitoring –7. HowevRecognizing these multiple benefits, the latest World Health Organization (WHO) guidelines for ART in resource-limited settings, issued in 2010, recommend that all countries begin to phase-in viral load monitoring. This viewpoint article provides an overview of current implementation barriers to viral load testing in resource-limited settings and provides some practical recommendations for increasing capacity for routine virological monitoring in low- and middle-income countries.Effective treatment should suppress viral replication. A measurable viral load is, therefore, a very accurate measure of unsuccessful treatment. The WHO defines virological failure as a viral load above 5000 copies/ml and recommends that virological monitoring be performed biannually . FrequenIn the absence of virological monitoring, immunological monitoring by CD4 count change is recommended. WHO guidelines define immunological failure as a CD4 count falling to or below the baseline value, or a 50% fall from the on-treatment peak or persistent CD4 values below 100 cells/µl . Howeverpersistent virological failure [Unsuccessful treatment, leading to virological failure, may be due to a number of reasons, including drug interactions, malabsorption and poor adherence –21. Whil failure , the fir failure –23. Earl failure , and the failure .Once non-adherence has been ruled out, persistent viremia indicates treatment failure and the need for an appropriate treatment switch. According to WHO guidelines, a persistent viral load above 5000 copies/ml confirms treatment failure , althougImportantly, the poor accuracy and positive predictive value of clinico-immunological monitoring compared to virological monitoring for predicting treatment failure means that, without viral load testing, patients are either diagnosed very late or misdiagnosed completely, with the result that patients can be kept on a failing regimen or switched unnecessarily. Furthermore, when clinico-immunological criteria are used to diagnose treatment failure, extensive drug resistance occurs, limiting the use of future treatment options ,29. ViroThe superiority of virological monitoring over clinico-immunological monitoring for diagnosing virological failure has multiple benefits beyond the initiation of adherence interventions and the appropriate switching of treatment regimens. Reducing the risk of virological failure through targeted adherence counselling and support prevents the development of drug resistance mutations, leading to the preserved use of affordable, fixed-dose, first-line drugs ,31. The To scale up treatment to the millions of people in need, ART delivery needs to be made as simple as possible, in line with the public health approach to HIV treatment and care promoted by the WHO. The management of treatment failure is one area where simplification is becoming increasingly urgent. Detection of treatment failure using standard immunological definitions is poorly implemented in resource-limited settings. Only 1.6% of patients receiving treatment as part of HIV programmes supported by Médecins Sans Frontières (MSF) in 19 countries have been switched to second-line therapy, suggesting very poor levels of detection . CalculaHaving a test that clearly confirms virological suppression may also allow for less frequent clinical follow-up and further task shifting. Simplification of treatment monitoring using an annual clinical visit with review of the viral load could significantly reduce the number of clinical contacts required, having both a cost-saving effect and reducing the burden on patients and healthcare workers alike.An overview of current and pipeline tests for viral load has been provided elsewhere .Viral load assays have traditionally been based on the amplification of nucleic acid using molecular techniques, such as real-time polymerase chain reaction (PCR). However, contamination with foreign nucleic acid or amplicon (PCR products) can cause false positive results, and great care must be taken to avoid cross-contamination of samples ,39. MoreAs an alternative, a non-molecular test, such as the ExaVir Load Assay , may be used. This method relies on the detection of reverse transcriptase as a surrogate marker for HIV RNA using an ELISA-type technique routinely used even at district laboratory level . A majorViral load may also be measured by quantifying the concentration of p24 antigen. This non-molecular test is cheaper and simpler than a test for HIV RNA . While tMSF has set up a molecular laboratory at the district level in Thyolo, Malawi, to offer viral load testing using the NucliSENS EasyQ HIV-1 v2.0 assay . The NASBA-based technique was chosen due to the fact that the test has been validated on dried blood spots (DBS) ,46, whicThese findings are not unique to MSF and the two main implementation barriers to be overcome for facilitating access to viral load testing in resource-limited settings are cost and complexity . The devThere is a pipeline of devices that, if shown to be technically validated, cost-effective and field appropriate, will greatly enhance our ability to implement viral load testing in a decentralized approach, at point of service. The first products are predicted to be available from 2013. These include greatly simplified laboratory-based tests that can be used at district level, or in mini-laboratories set up alongside public health clinics, and automated, all-in-one, point-of-care tests that can be used at the clinic level by clinicians or even lay workers. A review of the pipeline has recently been published and will not be considered further here .A number of operational challenges will have to be overcome during the implementation of these new devices, including the cost-effectiveness compared to centralized laboratory-based testing; the ability to meet through-put requirements; the effect on health service outcomes, such as staff work-load at the clinics, and number of transcription errors; and the effect on patient outcomes . In addition, staff should be adequately trained to acquire the appropriate sample and operate the instruments correctly, and strict quality control should be mandatory, even at decentralized facilities –49.Options for roll-out of routine viral load may be considered in three tiers: (1) a centralized high through-put approach utilizing traditional platforms paired with DBS as a sample transport method; (2) simple, automated devices at district laboratory level; and (3) true point-of-care devices at individual clinic level. The choice will depend on the individual programme setting, cohort size, and whether the epidemic is generalized or concentrated. Where a decentralized approach to ART provision is implemented, careful consideration needs to be given to through-put requirements, feasibility of ensuring quality control and the cost-effectiveness of a true point-of-care test. These should be balanced against the need for an effective specimen collection and result delivery system in a centralized approach.Experience of moving CD4 testing for ART initiation from a centralized laboratory to a point-of-care approach provides some insights about potential challenges for implementation of point-of-care viral load testing. Task shifting for performance of the test has proven feasible, with improved patient retention prior to ART initiation ,51. HoweThe benefits of providing routine viral load monitoring in resource-limited settings were recognized a decade ago , but, wiThe sensitivity of molecular viral load testing is dependent on the volume of sample, and 1ml of plasma is usually recommended to achieve a sensitivity down to 50 viral copies/ml. The disadvantages of using plasma as a sample type are that whole venous blood must be drawn by a health professional and plasma must be separated from the whole blood within six hours of blood draw . This isThere are two potential disadvantages to DBS. First, the small sample volume (50 to 100µl) results in poor sensitivity at lower viral loads below 3000 viral copies/ml ,45, makiPooled sample testing is a strategy to reduce the number of samples run by combining five to ten samples together –62. If tPooled viral load testing can reduce the number of individual tests required by up to 60%, without compromising on accuracy. Cost savings are significant, with one study from Mexico quoting a saving of up to $14,308 by a 30% reduction in individual testing  and a stA recent costing study assessing the cost-effectiveness of viral load compared to CD4 testing determined that the cost-effectiveness of viral load testing was sensitive to the frequency of testing, with annual viral loads being more cost-effective than the currently recommended six-monthly viral load testing . CurrentClinical trials conducted so far have only assessed the added value of viral load monitoring, rather than evaluating the potential to use viral load testing to replace CD4 as a patient-monitoring strategy –7. FuturEven with the many potential opportunities for simplifying the provision and reducing the cost of viral load testing, roll out at national level may still need to be phased in. Scale up of a triggered viral load testing approach using a clear algorithm to identify patients with CD4 reductions of 30% or more, specific clinical signs and those with poor adherence may be one approach. The MSF programme in Zimbabwe, recognizing a severe under-detection of treatment failure in their setting, implemented such an algorithm and saw a substantial increase in the number of viral load tests requested and subsequent detection of cases eligible for second-line ART. Alternative approaches, where routine viral load testing may not yet be feasible, may include the introduction of viral load testing to assess early adherence, continuing subsequent monitoring with CD4; as a tool to detect virological failure prior to switching to a less toxic first-line regimen; to confirm treatment failure before switching to second-line ART; or to monitor ARV-treated pregnant women before birth and during breast-feeding to confirm viral suppression. Introducing viral load in such a phased manner may allow for the logistical and technical laboratory capacity to be firmly established before scaling up the service to support routine virological monitoring for all.Routine virological monitoring for HIV-positive patients on ART is important for early detection of virological failure, preventing the development of drug-resistant mutations, identifying patients in need of intensive adherence support and accurately diagnosing treatment failure. Through these clinically advantageous outcomes, the use of first-line drugs may be preserved and transmission of viral strains that are both drug sensitive and drug resistant may be limited.Use of viral load testing may facilitate task shifting and reduce the number of clinical visits required for the patient. A once yearly viral load test could be the only treatment efficacy monitoring test required, which, if undetectable, allows for a simplified follow-up of patients on ART through community-based models, in line with the current priorities of the WHO .Despite clear benefits, virological monitoring, especially on a routine basis, is the exception in resource-limited settings. It is therefore important for both national and international guidelines to clearly recommend routine virological monitoring for all patients on ART as the standard of care and for donors and governments to fund the implementation of accurate and operationally proven testing platforms in a comprehensive manner. Importantly, operational research will be required to investigate which tests work better at different levels of the healthcare system and in different settings.The implementation of point-of-care viral load testing will need to be accompanied by operational research to determine which system, or combination of systems, work best in which contexts. Further simplification of laboratory-based tests, so that they can be performed at district level, will allow for the decentralization of testing currently performed at national level and should thus be prioritized.Ultimately, the price of viral load testing will have to be reduced to benefit the majority of patients in need. There are currently only four main suppliers of single-manufacturer viral load testing platforms, and just one of those has a majority stake in Africa . These f


To assess the effects of TCHM on patients with HIV infection and AIDS, we reviewed eleven randomized placebo-controlled trials involving 998 patients. Due to the limited number of RCTs for included trials and the small sample size of each study, we are not able to draw firm conclusions concerning TCHM therapy in treating patients with HIV infection and AIDS. However, some high-quality clinical studies do exist. Studies of diarrhea and oral candidiasis, which are challenging symptoms of AIDS, were demonstrated to have positive effects. Study of peripheral leukocytes, which are a side effect of antiretroviral drugs, suggested that an integrated treatment approach may be of benefit. The overall methodological quality of the trials was adequate; however, randomization methods should be clearly described and fully reported in these trials according to the Consolidated Standards of Reporting Trials (CONSORT). Although human immunodeficiency virus (HIV) infection was first reported in China in 1985, the magnitude of its spread was not evident until the epidemic among former plasma donors across central China was realized. Poor, rural farmers sold plasma to unscrupulous collectors under unsanitary conditions during the early to mid-1990s, resulting in untold numbers of infections . To date, an estimated 740,000 people in China are infected with HIV, most of whom are injecting drug users (IDUs), female sex workers, men who have sex with men, former plasma donors, or blood transfusion recipients. As of Dec 31, 2009, 323,252 people were reported as having HIV in China [The availability of highly active antiretroviral therapy (HAART) has markedly improved the survival rate and quality of life in patients infected with HIV, data from the NFATP show virological suppression, increased CD4+ cell counts, and a pronounced decrease in mortality in patients who have received treatment .Three types of treatment systems are practiced in Chinese society: (a) HAART offered by health care professionals in clinics and hospitals; (b) Buyao, which is over-the-counter popular medicine and includes teas, soups, tablets, herbal preparations, and tonics, which are similar to herb supplements used in some Western countries; and (c) traditional chinese medicine (TCM), provided by trained Chinese herbalists, which incorporates a wide range of theories, therapies, and practices. Many Chinese people use all three types of treatment simultaneously. Generally, people with HIV infection use TCHM for four main reasons: to enhance their immune function, to treat symptoms, to improve their quality of life (QoL), and to reduce side effects related to medications . ComprehWhen HAART is the dominant method of treatment, however, its use is complemented by the presence of complementary and alternative medicine (CAM) . The majThe objective of this paper is to assess the beneficial and harmful effects of TCHM on patients with HIV infection and AIDS compared with no intervention, placebo, or antiretroviral drug.Randomised controlled trials (RCTs) of TCHM in people with HIV infection, HIV-related disease, or AIDS are included irrespective of publication status or language. Observational studies and case series were excluded. TCHM is defined in this paper as herbal Chinese medicine products derived from plants or parts of plants used for the treatment of HIV/AIDS. Controlled intervention can be no treatment, placebo, or antiretrovirals .Cochrane HIV/AIDS Group Trials Register, CENTRAL database, the Cochrane Complementary Medicine Field; MEDLINE, EMBASE, LILACS, Science Citation Index (SCI), China Network Knowledge Infrastructure (CNKI), and the Chinese Biomedical CD-ROM Database, Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS).The following electronic databases were searched (between January 1982 and December 2011):The search terms included HIV, acquired-immunodeficiency-syndrome (AIDS), Chinese-medicine, medicine-Chinese-traditional, medicine-Chinese-herb, herbs, Chinese-herbs.Chinese Journal of Infectious Diseases, Chinese Journal of Dermatovenereology, Journal for China AIDS/STD Prevention and Control, Chinese Journal of Integrated Traditional and Western Medicine, Research of Traditional Chinese Medicine, and Journal of Traditional Chinese Medicine were handsearched from the first publication date onwards to December 2011. Conference proceedings in Chinese were also handsearched.Manufacturers of herbal preparations and experts in relevant fields were contacted for potential trials. The bibliographies of identified trials and review articles were checked in order to find randomised trials not identified by the electronic searches or handsearches.All articles were read, and data were extracted from the articles based on predefined selection criteria by two independent reviewers. To evaluate the methodological quality of the RCTs, the risk of bias was determined using the Cochrane classification for eight criteria: random sequence generation, allocation concealment, patient blinding, assessor blinding, reporting of dropout or withdrawal, intention-to-treat analysis, selective outcome reporting, and other potential biases .We screened 257 relevant articles, and 224 were excluded, leaving us with 33 full-text eligible articles. Of these, 22 more were excluded. The remaining 11 RCTs met our inclusion criteria .Key data from these studies are summarized in Tables The risk of bias in the studies was variable. Nine RCTs had an adequate method for random sequence generation , 20–23, Due to the limited number of trials identified and the variation of participants and herbal preparations, meta-analysis and the prespecified subgroup or sensitivity analyses were not performed.3) for treatment of HIV-related symptoms for duration of 12 weeks [A randomized trial tested a Chinese herbal formulation (IGM-1) composed of 31 Chinese herbs  in 30 HI12 weeks . The stu3) for a treatment period of six months [n = 34) or placebo (n = 34). Over 70% of the patients had received previous antiretroviral therapy, the two groups were comparable regarding sociodemographic characteristics, previous antiretroviral use, viral load, CD4+ cell counts, and other clinical laboratory tests at entry. A total of 53 (78%) patients completed treatment for 6 months, including 24 in the herb group and 29 in the placebo group. Analyses were based on complete data and on intention-to-treat principle in the trial report. After six months, there was no significant difference in CD4+ cell counts, viral load, new AIDS-defining events, number of reported symptoms, psychosocial measurements or QoL between two groups.Interestingly, three years after the above trial was published, the same investigator who prescribed IGM-1 prescribed another Chinese herbal formulation that was tested in a trial in Switzerland . The forx months . The parThe total number of reported adverse events was 46 in the herb group and 20 in the placebo group, and included diarrhea, increased number of daily bowel movements, abdominal pain, constipation, flatulence, and nausea. Hematological or serum chemistry laboratory values showed no evidence of toxicity from the study herbs. Two patients in the herb group died during the study period and causes of death were believed to be due to severe immunodeficiency and pre-enrolment history of severe opportunistic complications, but not related to the study drugs.Compound SH containing five herbs  were comn = 18) or placebo (n = 18). Patients were comparable regarding age, body weight, average duration of drug abuse, and pre trial HIV RNA levels. No intention to treat analyses were applied, the data analyses were based on participants who had completed the trial. Significant decrease in HIV RNA levels was found in herb group than placebo after the end of treatment for 7 months. In this trial, the use of herbs was related to stomach discomfort and diarrhea. No adverse effects were reported from the placebo group. There were no serious adverse events observed.Qiankunning  is a Chi3, while in the placebo group the CD4+ cell counts were decreased by 27.33 ± 85.28 cells/mm3 after treatment for 6 months (P > 0.05). A total of 15 out of 30 patients (6 dropped out) in the ZY-4 group had their CD4 count increased compared with 8 out of 33 patients (3 dropped out) in the placebo group (P < 0.05). The study concludes that ZY-4 is effective in enhancing immunity function based on CD4+ cell counts. However, this study showed no significant difference in body weight or viral load after treatment between ZY-4 and placebo.Chinese herbal medicine zhongyan-4 (ZY-4)  is prepan = 50) received AG+HAART (d4T+ddI+NVP) and Placebo group (n = 50) received placebo + HAART (d4T+ddI+NVP). CD4+ cell counts in the AG group were decreased by 87.65 ± 107.98 cells/mm3, while in the placebo group the CD4+ cell counts were decreased by 156.51 ± 157.04 cells/mm3 after treatment for 11 months (P < 0.05). Significant improvement of symptoms such as fatigue, anorexia, nausea, diarrhea, skin rash was found in AG group. The results showed that patients receiving Chinese herb AG had a lower risk for the decrease of CD4+ cell counts. However, this study showed no significant difference between two groups in viral load after treatment.The Chinese herbal medicine Aining Granule (AG)  was testn = 40) and Nystatin group (n = 40) [A randomized two arms positive-drug controlled open label trial was conducted in 2009 in china, in which 80 AIDS participants with oral candidiasis were included in the Xiaomi Granule  plus Nys(n = 40) . After tn = 58) or Leucogen Tablets plus AZT, ddI, NVP and analogue JC (n = 58) for 6 months [In a double-blind, double-analogue trial, 116 participants with HIV infection and peripheral leucopenia were randomized to receive Jingyuankang Capsule (JC)  plus AZT6 months . The appn = 106) and loperamide capsule plus XC analogue group (n = 52) [P = 0.0029 in 7 days and P = 0.0023 in 14 days) and in diarrhea questionnaire score (P < 0.01 in 14 days). There were no significant differences between groups with respect to stool frequency. No serious adverse events were reported. There was no major difference between XC and placebo in the occurrence of adverse events or in laboratory abnormalities.A randomized, double-blind, double dummy and controlled clinical trial was conducted between 2009 and 2011 in china, in which 158 AIDS-related chronic diarrhea patients were randomized into Xielikang Capsule (XC)  plus lop(n = 52) . The pri3 who were treated with Aikang Capsule  or placebo (n = 88) [In a China phase III clinical muti-center trial conducted between 2002 and 2003, 176 patients with CD4+ cell counts >200 cells/mm Tablets  (n = 88)(n = 88) . PatientThe total number of reported adverse events was 21 in the herb group and 27 in the placebo group, and included diarrhea, cold, abdominal pain, flatulence, and nausea. Hematological or serum chemistry laboratory values showed no evidence of toxicity from the study herbs. Two patients in the placebo group died during the study period and causes of death were believed to be due to severe immunodeficiency and pre-enrolment history of severe opportunistic complications, but not related to the placebo.Due to the limited number of RCTs for included trials, the small sample size of each study, we are not able to draw firm conclusions concerning TCHM therapy in treating patients with HIV infection and AIDS. Compared with placebo, TCHM demonstrated positive effects in improving QoL and symptoms, increasing CD4+ cell counts; however, the quality of studies need to be concerned. Our paper aimed to update and complete the evidence of TCHM treatments for patients with HIV infections and AIDS. Compared to a previous paper , we idenSome studies support the Chinese herb and antiretroviral drug combination therapy , 18. A pThe methodological limitations of the studies reported in this systematic literature review included small sample sizes, non-reporting of followup, insufficient details on sampling, high drop-out rates, lack of intention to treat analysis and lack of blinding. The reporting of studies was also very limited for included papers, with items most commonly missing from the CONSORT checklist including: 1a (identification as RCT in title); 16 ; 6b ; 8, 9, and 10 (details of randomisation procedure); 14b ; and 23 and 24 (registration number and full protocol access) . STRICTAOur paper has a number of important limitations. Although strong efforts were made to retrieve all RCTs on the subject, we cannot be absolutely certain that we succeeded. Moreover, selective publishing and reporting are other major causes for bias, which must be considered. It is conceivable that several negative RCTs remain unpublished. Together, these factors limit the conclusiveness of this systematic review considerably.In conclusion, the results of our systematic review provide limited evidence for the effectiveness of TCHM in treating patients with HIV infection and AIDS. Thus, drawing firm conclusions concerning the effectiveness of CAM therapies remains difficult. Further large and rigorous RCTs are warranted.


The induction immunosuppressive therapy consisted of metilprednisolone and basilixmab; tacrolimus and/or mycofenolic acid were used for maintenance therapy. The therapeutic drug monitoring (TDM) has been performed for the adjusting of both their doses [The HAART reduces the risk of HIV-related renal disease but the incidence of end-stage renal disease (ESRD). Therefore, efficacy and safety of renal transplantation (Tx) is an important resource in the HIV-infected population. We reported the results of kidney Tx in HIV+patients from deceased donors from June 2007 to March 2012 at our institution. The patients had to have CD4+T-cell counts≥200/mm3 (p=0.055). In Figure 1 are reported the CD4+trends of 9 patients with a follow-up of at least 6 months.At the last available point of follow-up , 8 out of the 13 patients (61.6%) without steroid had at least one acute rejection episode, but only 1 patient lost the graft, after 43 months (7.1%) due to chronic rejection associated with infectious and vascular complications. After Tx the median CD4+T-cell count increased from 382.5 (IQR range=233–415) to 434 (IQR range=282–605) cells/mmHIV infection was well controlled, with only 2 (14.3%) cases of virological failure which were promptly resolved after HAART regimen modification. Table 1 shows the observed infectious complications. The skin Kaposi sarcoma has been resolved by switching to immunosuppressive therapy with sirolimus [