Switching subjects with persistently undetectable HIV-1 viremia under antiretroviral treatment (ART) to once-daily tenofovir/emtricitabine (or lamivudine) + nevirapine is a cost-effective and well-tolerated strategy. However, the effectiveness of this approach has not been established.We performed a retrospective study evaluating the rates of treatment failure, virological failure (VF), and variables associated, in all subjects initiating this switch combination in our clinic since 2001. Analyses were performed by a modified intention to treat, where switch due to toxicity equalled failure. The main endpoint was plasma HIV-RNA < 50 copies/mL.341 patients were treated for a median of 176  weeks. At week 48, 306 (89.7%) subjects had HIV-1 RNA <50 copies/mL, 10 (2.9%) experienced VF, and 25 (7.4%) discontinued the treatment due to toxicity. During the whole follow-up 23 (6.7%) individuals  developed VF and treatment modification due to toxicity occurred in 36 (10.7%). Factors independently associated with VF in a multivariate analysis were: intravenous drug use , time with undetectable viral load before the switch , number of prior NRTIs  or NNRTIs , and previous NVP  or efavirenz  unscheduled interruptions. VF was associated with emergence of usual nevirapine mutations , M184V , and K65R (n = 7).The rates of treatment failure at 48 weeks, or long-term toxicity or VF with this switch regimen are low and no unexpected mutations or patterns of mutations were selected in subjects with treatment failure. Many subjects on suppressive antiretroviral therapy (ART) may be considered candidates for long-term regimen simplification towards easier to administer, more tolerable, or more cost-effective regimens –3. TreatNevirapine (NVP) displayed similar rates of efficacy at 12 and 36 months against efavirenz in simplification –13, and Among the newest drugs, only elvitegravir/cobicistat has been evaluated in randomized studies as a switch strategy for subjects receiving NVP . It demoThe combination of once-daily NVP plus TDF/FTC (or 3TC) has been extensively used as a long-term simplification regimen in some European countries, however information about the efficacy and long-term toxicity of this regimen is still scant ;25. FurtTherefore, accurate data on the long-term efficacy and toxicity of NVP plus TDF/FTC (or 3TC) as a switch regimen—with particular focus on the rates of VF or any particular pattern of unexpected mutations—are needed.We performed a retrospective cohort study of HIV-infected patients attending a tertiary University Hospital in Barcelona, Spain since 2001, when all drugs became available. All subjects aged ≥18 years with documented HIV-1 infection were included if they started treatment with NVP plus TDF plus FTC (or 3TC) as a switch from any previous regimen, with an undetectable plasma viral load (pVL), and had at least one subsequent follow-up visit. The inclusion criteria allowed incorporating subjects with early withdrawal of the regimen due to toxicity. Subjects were followed until they stopped the regimen for any reason. The study was approved by the Hospital Research Ethics Committee and conducted in accordance with the Declaration of Helsinki and National standards.Historical follow-up data were extracted from medical records through a systematic database search. No restriction criteria were included in the search. All causes of treatment discontinuation were registered. VF was defined as two consecutive pVL >50 copies/ml.+ cell counts and pVL were collected every 12–24 weeks thereafter, until the last sample available.Baseline characteristics were gathered, including age, gender, risk factor for HIV acquisition, time of HIV infection, number of prior antiretroviral drugs and antiretroviral regimens, prior NRTI mono or dual therapy, time with HIV-1 RNA suppression before the switch, hep B or C co-infection, and reason to initiate the study regimen. CD4The complete previous treatment history was searched, and all previous NNRTI interruptions were recorded, as well as all prior treatment failures.Genotypic resistance tests prior to the initiation of the regimen and the available resistance studies in those patients who failed were collected.Patients’ characteristics were described using medians (IQR) for continuous, non-normal variables and percentages for categorical variables.The primary endpoint was the proportion of subjects with pVL <50 copies/mL at 48 weeks. We based our efficacy and safety analyses on a modified intent-to-treat  exposed or safety populations, which consisted of all patients initiating the regimen with any treatment discontinuation due to toxicity or voluntary treatment discontinuation considered as treatment failure. Subjects substituting 3TC with FTC during the study were not considered failures. Patients lost to follow-up or withdrawing the regimen due to reasons unrelated to toxicity  or efficacy were censored at that time in the analysis, provided they had a pVL <50 c/mL and no toxicity at that visit, considering that this was a retrospective study and subjects were not tied up to an allocated treatment.VF and factors associated with it were also pre-planned analyses. A secondary analysis assessed the percentage of patients remaining on the same regimen with a pVL < 50 copies/mL at the end of follow-up.A relevant list of covariates was included in a multivariate Cox proportional model to determine factors independently associated with VF. The model was adjusted for age, intravenous drug use, hepatitis C co-infection, number of prior NNRTIs received, prior NNRTI treatment interruptions, presence of 3TC (versus FTC) in the regimen, inclusion of NVP in the last regimen, and duration of HIV-1 infection.All variables with a significant association (p<0.05) in the univariate analysis were introduced into the multivariate model. The multivariate analysis was run in the overall cohort and also excluding subjects already on NVP at the time of the switch. The duration of treatment and time to VF were estimated using the Kaplan-Meier method. All statistical analyses were performed using SPSS software for Windows .We identified 367 patients having started a combination including NVP plus TDF plus FTC (or 3TC). Of them, 26 were treatment naïve when they initiated this combination, and were excluded. Cohort demographics of the remaining 341 are shown in The main reasons for initiating the switch regimen were prior drug toxicity , treatment simplification , and pregnancy desire .Overall, 295/341 (86.5%) patients had a pVL <50 copies/mL at 48 weeks , and 10 (2.9%) experienced confirmed VF at 48 weeks. Drug toxicity led to treatment discontinuation in 22 (6.6%) subjects, and 14 (4.0%) experienced a voluntary treatment discontinuation.Toxicity was specifically assessed in all NVP-naïve subjects at the initiation of the study regimen (168 out of 341). Of them, NVP was discontinued in 20 (11.9%), mainly due to early development (most of them at first trimester) of rash or laboratory liver abnormalities. Only 3 (2%) subjects developed grade 4 transaminase increases, none a severe clinical liver event, and none grade 4 rash.In an on-treatment analysis, 96.2% of subjects receiving NVP at 48 weeks had a pVL <50 copies/mL.Patients stayed on the regimen for a median of 176  weeks and 215 (63.5%) patients discontinued the study regimen at any time during the follow-up. The reasons for treatment discontinuation at the last available control were: lost to follow-up , voluntary treatment interruption , recruitment for a randomized clinical trial , toxicity , confirmed VF , subsequent treatment simplification . Among individuals with immune discordance despite a suppressed viremia, 21 (6.1%) received proactive treatment changes . Therefore, only 57 (16.8%) subjects discontinued the treatment due to toxicity or lack of efficacy at 4 years.Hence 156 (45.8%) patients discontinued the study regimen or follow-up in real clinical practice due to reasons unrelated to treatment efficacy. Of the overall cohort, 126 (37.3%) were still on the same regimen and with an HIV-RNA <50 copies/mL in their last control available (median 4 years). The median time to VF and treatment discontinuation are depicted in In a multivariate analysis adjusted for variables described in Population genotypes at failure were available in all 23 subjects (6.7%) experiencing confirmed VF . None ofM184V was selected in 16 (70%) subjects: 12 treated with 3TC and 4 with FTC (p = 0.04). Seven patients had K65R , 5 of them treated with 3TC and 2 with FTC. Six patients selected A62V, with K65R selected in 4 of them, and none with Q151M or T69 insertions. Five patients harboured TAMs. Three subjects harboured major protease mutations , selected in prior failures.The 48-week 2.9%) and long-term (6.7% at 4 years) rates of VF of a switch regimen composed of NVP plus TDF plus FTC (or 3TC) in real clinical practice are low, and similar to those of other common switch strategies seen in similar cohorts and recommended in international guidelines ;2;27;28..9% and lWhilst VF was infrequent, drug resistance mutations against NNRTIs and NRTIs were frequently isolated in patients with VF, in agreement with what has been seen in pivotal trials with NVP in naives, and also with other drugs with a similarly low genetic barrier to resistance  in initial therapy ;33–42. OReassuringly, the frequency and type of mutations seen in our series was concordant with what has been previously seen in other NVP studies, with a potential impact of some of them against the activity of etravirine in subsequent treatments . The mosThe rate of K65R selection was low was, but appeared in approximately one of every three failures, usually with M184V, and more frequently in those treated with 3TC (vs FTC) ;36.1/2 of activated triphosphate 3TC compared to FTC (15 h versus >39 h), a 4- to 10-fold lower antiviral potency of FTC in a range of cell line in vitro passages, and the ability of FTC to inhibit cellular efflux proteins such as the multidrug resistance–associated proteins could account for a lower forgiveness of 3TC, at least when combined with NVP [We observed a significantly higher rate of VF in individuals treated with 3TC instead of FTC, with a significantly higher rate of selection of M184V as well. Nevertheless, these data must be interpreted with caution, as calendar years when subjects received 3TC or FTC were different—as well as the number of pills in the regimen—and unmeasured confounders could exist. However, this is concordant with a double risk of VF  for 3TC vs FTC found in treatment-naives ;45. Somewith NVP ;47–49. TNo subjects selected NRTI resistance mutations without NNRTI ones, thus confirming that NNRTI resistance is selected first, in agreement with previous reports ;51.In an adjusted multivariate analysis, we found an independent association of VF with intravenous drug use, time with undetectable VL, number of prior NRTIs or NNRTIs received, and prior NVP or efavirenz interruptions. Actually, intravenous drug users and higher antiretroviral drug exposure are variables universally associated to increased rates of VF to any switch regimen ;34;52. TTherefore, reinitiation of NVP plus TDF plus FTC (or 3TC) should be discouraged in subjects experiencing unplanned treatment interruptions, even with an undetectable pVL at the time of treatment withdrawal.The main reasons for initiating the regimen in our series were prior toxicity and treatment simplification, which still remain as the main reasons currently.The rates of treatment discontinuation due to adverse events in our cohort  are concordant with rates seen in other NVP or efavirenz studies ;35;36, bHowever, the most frequent reasons for withdrawing the regimen in real clinical practice were not related to toxicity or lack of efficacy, but proactive treatment changes, recruitment for clinical trials, or patients being lost to follow-up, with subjects having suppressed viremia at that time point.Generic substitution is one mechanism of curtailing prescription drug expenditures. Currently available as a generic and with reference pricing, a cost/efficacy assessment done by the Spanish GESIDA Society has shown that NVP plus TDF/FTC (or 3TC) constitutes a cost-effective treatment in Europe despite the availability of many new regimens . It is aThese findings inform regimen management in clinical practice, and would support the long-term maintenance of this strategy in subjects without initial toxicity. Actually, newer antiretroviral drugs have not demonstrated advantages in switch studies in subjects treated with NVP plus TDF/FTC .Our study is subject to the limitation of its retrospective design, which could lead to bias with unmeasured confounding factors such as treatment adherence or channelling prescription by physicians. We specifically made every effort to capture all subjects receiving the first dose of the regimen, to avoid underestimation of toxicity. The study included subjects who changed the whole regimen and subjects who were already receiving NVP and only changed the NRTI backbone. However, both subgroups have been analysed separately in a sensitivity analysis to pinpoint the toxicity of NVP. Nonetheless, the study reports the largest cohort of patients treated with this switch regimen so far, and the results are consistent and robust through adjusted and sensitivity analyses. Important information gleaned from the study includes higher risk of failure with such a switch in a setting for subjects who had previously been exposed to NNRTI and had a history of treatment interruption.In conclusion, a simplification regimen with NVP plus TDF and FTC (or 3TC) in pre-treated subjects maintained virologic suppression with a low risk of short and long-term treatment or VF in subjects without prior NNRTI treatment interruptions, and a low rate of long-term adverse events. The rates of VF are similar to other switch strategies, and no unexpected mutations or patterns of mutations have been selected at failure. These findings do not suggest increased early or late VF rates with this regimen when used as a simplification strategy. However, the rates of discontinuation due to early toxicity were higher. While potentially severe initial toxicity might limit its new initiation in the future, these data support caution against a systematic proactive switch of those subjects successfully treated with this regimen towards newest drugs until clinical advantages to patients are demonstrated in randomised clinical trials.


There are limited data on the failure of second-line antiretroviral therapy (ART) and the use of third-line ART in people living with HIV in resource-limited settings. Since 2011, the Médecins Sans Frontières (MSF) HIV/tuberculosis programme in Mumbai, India, has been providing third-line ART to patients in care.To describe the experiences and programmatic challenges during management of suspected second-line ART failure and third-line ART therapy for patients living with HIV, including the use of HIV viral load (VL) testing.This was a retrospective, observational cohort study of patients with suspected second-line ART treatment failure, who were followed for at least 12 months between January 2011 and March 2014.A total of 47 patients with suspected second-line failure met the inclusion criteria during the study period. Twenty-nine of them (62%) responded to enhanced adherence support, had a subsequent undetectable VL after a median duration of 3 months and remained on second-line ART. The other 18 patients had to be initiated on a third-line ART regimen, which consisted of darunavir–ritonavir, raltegravir, and one or more appropriate nucleoside or nucleotide reverse transcriptase inhibitors, based on the results of HIV genotype testing. Of the 13 patients for whom follow-up VL results were available, 11 achieved virological suppression after a median duration of 3 months on third-line ART (interquartile range: 2.5–3.0). No serious treatment-related adverse events were recorded.With intensive counselling and adherence support in those suspected of failing second-line ART, unnecessary switching to more expensive third-line ART can be averted in the majority of cases. However, there is an increasing need for access to third-line ART medications such as darunavir and raltegravir, for which national ART programmes should be prepared. The cost of such medications and inadequate access to VL monitoring and HIV genotype testing are currently major barriers to optimal management of patients failing second-line ART. India is home to approximately 2.1 million people living with HIV  testing is an indispensable requirement in any ART programme. The World Health Organization (WHO) recommends VL monitoring as the preferred approach to provide an early and more accurate indication of treatment failure, thereby reducing the accumulation of drug-resistance mutations and improving clinical outcomes . HoweverTo date, there are limited data describing experiences of routine VL monitoring in the contexts of patients living with HIV who have suspected second-line ART failure and the use of third-line ART in resource-limited settings. To address this knowledge gap, this study describes the experiences and programmatic challenges during treatment and VL testing of patients living with HIV who are suspected of second-line ART failure and those needing third-line ART in Mumbai within a non-governmental organization (NGO)-run programme that provides ART and VL testing free of charge.This was a retrospective, observational cohort study of patients living with HIV who had suspected failure of second-line ART using data collected under routine programmatic conditions.Since 2006, Médecins Sans Frontières (MSF) has been operating an HIV/tuberculosis (TB) programme in Mumbai, India  and two or three NRTIs (e.g. lamivudine and tenofovir±zidovudine). Third-line ART regimen in the MSF programme included the second-generation PI darunavir boosted with ritonavir (DRV/r) and the integrase inhibitor raltegravir (RAL), together with one or more NRTIs likely to be effective on the basis of HIV genotyping results. As part of routine clinical care, HIV VL and CD4 cell count testing was carried out for each patient every 6 months in the MSF programme. An undetectable VL was defined as a result with fewer than 50 copies/ml. Treatment failure was defined as a VL result >5,000 copies/ml in two consecutive results in a 3-month time frame, as previously recommended by WHO .Patients in the programme were suspected of failing second-line ART if they had received and failed a first-line regimen, were subsequently treated with a second-line regimen for at least three consecutive months, and then had a single VL test result measuring >5,000 copies/ml. All patients suspected of failing second-line ART underwent a thorough assessment, including structured client-centred adherence counselling and repeated VL measurement after 3 months of good adherence. The assessment involved a multidisciplinary team consisting of an HIV physician, psychologist, social worker, and nurse. Each member of the team had special predefined tasks and responsibilities . The timBox 1HIV Physician: Physicians perform a detailed history and examination at the first visit, and they arrange for a number of laboratory tests, including complete blood count, alanine transaminase, serum creatinine, serum bilirubin, blood sugar, serum lipids, Western blot (for HIV-1 and 2), HIV-1 viral load (VL), CD4 count, chest X-ray, abdominal ultrasound, and fundoscopy, as well as a pregnancy test in females. Second-line ART is restarted only after ruling out opportunistic infections. Any treatment-related adverse events are symptomatically managed. Initially, the patient is assessed every two weeks for the first three visits and then monthly. At every visit, adherence is reinforced, and after 2–3 months of good adherence, VL testing is repeated. VL and CD4 count testing are repeated every 6 months. If VL suppression is not achieved, genotyping is performed, and a treatment regimen is designed based on the genotyping results.Psychologist: Every patient is evaluated at baseline, including assessment with the PHQ9 Patient Depression questionnaire. Baseline HIV knowledge is tested using 30 basic HIV questions: a score of <10 is defined as poor knowledge, 11–20 as average knowledge, and 21 or more as good knowledge. Barriers for adherence are identified. The patients see the psychologist every two weeks for the first three visits, and then every month.Social Worker: Every patient receives a social assessment at their first visit, during which social barriers for adherence are identified and solutions discussed with the patient.Nurses: Dosage and timing of all pills are explained to all patients. A pill count is done at every visit, and the percentage of pills taken is entered into a file. Pillboxes are used for patients who have difficulties with timing of their ARVs.The adherence levels of all patients were assessed with patient self-reports. These levels and any adherence concerns were recorded by the team following individual interviews. In patients observed to have adherence issues, the team provided education to the patient about HIV, VL and CD4 testing, and treatment failure. Psychological and emotional support were offered to the patients during treatment, and they were also referred to other NGOs and services as needed.A two-log decrease in the repeat VL measurement 3 months after interventions to support adherence in those suspected of failing a second-line regimen was defined as virological suppression, and these patients were continued on second-line ART.Those patients who failed to achieve virological suppression were investigated for antiretroviral (ARV) resistance using genotyping with the ViroSeq HIV-1 genotyping system method ; the instrument used was the ABI 310 Genetic Analyzer . The Stanford genotypic resistance interpretation algorithm was used to analyse resistance of HIV in these patients. Patients in need of a third-line regimen were prescribed the regimen based on genotyping results.Demographic and clinical information of all patients living with HIV was recorded in patient files. The clinical data that were routinely collected for each patient, including treatment and laboratory data, were entered into an electronic database. A full-time data manager routinely supervised data entry for accuracy and completeness. Data from all patients suspected of second-line failure between January 2011 and March 2014 were included in the analyses. Descriptive statistics were used to analyse the data of these patients using SPSS .The study satisfied the criteria for reports using routinely collected programmatic data set by the MSF independent Ethics Review Board in Geneva, Switzerland. As this was a study of routinely collected monitoring data, informed consent from the patients was not obtained. The named ethics committee specifically approved the study and waived the need for consent.A total of 47 patients living with HIV were suspected to have failed second-line ART during the study period. The median age of patients was 40 years (interquartile range (IQR): 35–46), and almost three-fourths of them (35/47) were male. The median baseline CD4 count for these patients at the time of enrolment was 110 cells/µl (IQR: 47.0–208.8). The monthly family income was less than 7,000 Indian rupees in 27/44 (61.4%) cases, which is less than the cost of second-line ART in a pharmacy in Mumbai . Three pPneumocystis jirovecii pneumonia (PCP).Of the 47 patients suspected of second-line ART failure, 29 patients (62%) responded to enhanced adherence support and had a two-log decrease in their level of HIV on subsequent VL testing . The othAs a result of enhanced adherence support and routine HIV VL monitoring, the majority of patients living with HIV who had suspected second-line ART failure in the MSF programme in Mumbai did not have to be switched to third-line ART. In fact, most of the patients suspected to be failing second-line ART in this study had adherence issues rather than HIV strains that were resistant to the ARV drugs, a finding which is in line with the results of previous studies, including a similar South African cohort and several other programmatic cohorts in resource-limited settings –13.One of the main reasons behind the lack of adherence reported by patients was the high cost of second-line ART (prior to enrolment in the MSF programme). These patients had initially opted to receive their HIV treatment in private facilities rather than public ones, in an effort to reduce HIV-related stigma and discrimination; however, they were eventually no longer able to afford the medications and were forced to stop the treatment. Patients co-infected with HIV and TB had a high pill burden, which has the potential to negatively affect adherence. Additional reasons for poor adherence in our cohort included anxiety, in part due to fear of disclosure of their HIV status, and alcohol abuse.Routine VL monitoring is an important tool to identify poor adherence and ART failure at an early stage, and with proper management this will prevent the accumulation of further resistance mutations and preserve treatment options . RoutineHIV resistance surveillance or genotyping in patients , 17 assiThe small number of patients in the study is one of the limitations, and therefore generalisation of the results may not be possible. However, this study is one of the few reports from resource-limited settings describing operational feasibility and programmatic challenges in relation to management of patients living with HIV who have suspected second-line ART failure and patients requiring third-line ART. There may be additional factors influencing treatment adherence in such patients; however, it would be difficult to comment on these factors on the basis of routine programme data.Early detection of ART failure through routine VL monitoring and HIV resistance surveillance should be prioritised in settings where ART programmes have been successfully established. Adequate adherence support and extensive counselling should be provided to all patients suspected of second-line ART failure since the underlying reason for suspected failure is often not genetic mutation of HIV but improper adherence by patients. HIV viral load testing should be offered after 3 months of enhanced adherence support in all patients with suspected failure based on a single VL measurement.With intensive psychosocial and medical intervention in those suspected to be failing second-line ART, an unnecessary switch to more expensive and often unavailable third-line ART can be averted in the majority of cases. However, there is still an urgent need for improved access to third-line ART regimens in India, for which the national ART programme should be prepared. The cost of such medications and the additional costs of VL monitoring and genotyping are currently major barriers to the optimal management of patients failing second-line ART.


We report interim 24-weeks efficacy data of ATLAS-M trial, a phase IV, multicentre, open-label, randomized study designed to show 48-weeks, non-inferior efficacy (margin of −12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3-drugs ATV/r-based cART.3 for >6 months were eligible. At baseline, patients were randomized to switch to ATV/r+3TC (arm one) or to maintain the original 3-drug regimen (arm two). Primary endpoint: proportion of patients free of TF at week 48. TF was defined as treatment modification for any reason, including virological failure . Enrollment of 266 patients was planned.Subjects on ATV/r+2 NRTIs, without previous treatment failure (TF), with HIV-RNA <50copies/mL for >3 months and CD4>200 cells/mm2 in arm two, p=0.001). No significant differences in bilirubin levels or other laboratory parameters were observed between the two arms.A total of 266 patients  were enrolled. At the time of analysis, 24 weeks data were available for 84 and 87 patients in arm one and two, respectively. At baseline, subjects in the two arms did not differ for the main characteristics. At 24 weeks, at the intention to treat analysis the proportion of patients free of TF was 91.7% (95% CI 85.8–97.6) and 85.1% (95% CI 77.6–92.6) in arm one and two, respectively . VF was observed in two patients randomized to arm one  and one to arm two without resistance mutations. Clinical and laboratory adverse events occurred at similar rates in the two arms. At week 24, patients in arm one showed a greater increase in CD4 . A greater increase in total cholesterol , HDL  and LDL  was also observed in arm one without differences in other lipid parameters. Renal function showed a significant improvement in arm one (mean change in eGFR +5 vs −2 mL/min/1.73mThis interim analysis suggests a 24-weeks non-inferior efficacy of treatment simplification to ATV/rit+3TC as compared to continuation of ATV/rit +2 NRTI in virologically suppressed patients. Follow-up until 48-weeks is scheduled to confirm these data.


Due to drug-drug interactions of HIV- and HCV-specific antivirals when initiating an HCV-therapy, the antiretroviral therapy (ART) often has to be changed. The spectrum of applicable antiretrovirals is small, therefore many patients were switched to raltegravir/truvada (RAL/TVD) in our cohort. Due to the relatively low genetic barrier of RAL, this regimen may be endangered to fail, if the NRTI backbone is not fully active because of pre-existing NRTI resistance. We investigated the long-term follow-up and safety of RAL/TVD in co-infected patients after hepatitis C virus (HCV) therapy was stopped and the protective antiretroviral effect of interferon ended.Twenty patients initiated a direct-acting antiviral (DAA) containing HCV therapy  between 11/2011 and 01/2013. Seventeen were switched to RAL/TVD, three patients were not treated before, but started with the regimen. Diagnosis of HIV infection was dated between 1985 and 2010. The HI-viral suppression was monitored retrospectively to date.Thirteen of the twenty patients (65%) remained on RAL/TVD after finishing HCV treatment, for seven patients, no data about their ART continuation was available, after HCV therapy had stopped. All remaining thirteen patients showed an HI-viral load below detection limit up to date . Only for four patients, historic resistance data were available but none showed NRTI mutations.Switch to RAL/TVD as HIV ART due to initiating HCV therapy was safe for the observed small cohort even in long-term follow-up without switchback or a second ART switch. However, resistance data for the cohort was little, showing no NRTI mutations, indicating a relatively safe setting. Since no further data is available, physicians should keep in mind ART history, historical therapy failure and HIV-resistance while switching ART to treat HCV in co-infected patients. Further investigation in larger cohorts is needed, especially thinking of upcoming interferon-free HCV regimen in heavily pre-treated co-infected patients.


Many analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART).To determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS.3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE).We enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982–2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%.In base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mmThe future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients. The timing of HIV therapy initiation has been controversial, and remains so in resource-limited settings.Accordingly, we developed a model to address how ART initiation recommendations would change with varying assumptions regarding the rates of new drug development, the proportion of new drugs in existing classes versus new mechanistic classes, the patterns of cross-resistance between new and existing mechanistic classes, the efficacy of pipeline drugs compared to existing drugs, and the toxicity of new drugs compared to existing drugs.We adapted the well-validated HIV simulation model of Braithwaite et al.We modified this model by incorporating the arrival of new drugs, both within existing classes of drugs and the development of new classes of antiretroviral agents. This modification allows the simulation to treat patients with more cycles of therapy, and provides increased flexibility for changing to a different drug combination after the development of resistance.In our base case, we simulated a cohort of patients treated under the assumption of the availability of three classes of antiretroviral drugs, without the future development of new drugs, which is a common assumption used by most HIV treatment models.We fit the probability distribution for the arrival of new ART drugs, defined as when the drug was approved by the Food and Drug Administration (FDA), to an exponential distribution using data from the FDA of the approval date of each drug and each new drug class  the arrival process of new classes of drugs, and 2) the arrival process of new drugs belonging to existing classes. We fit the arrival process of drugs to a split Poisson process, meaning that the arrival of new classes is independent from the arrival processes of drugs within an existing class.The development of HIV antiviral resistance is complex, and mutations in the HIV genome that confer resistance to a particular drug may also confer partial resistance to other drugs. Since cross resistance may affect new drugs as it does existing ones, we modeled the probability that new drugs would confer cross resistance. Empirically, cross resistance is substantially more likely in drugs within the same class than between drugs of a different class.The cross resistance of new drugs within a class is assumed to be equal to the distribution of cross-resistance patterns of existing drugs, i.e., if a new drug belongs to the NRTI class, it will follow the resistance pattern of the NRTI class. The probability that a specific mutation will confer resistance to a new drug is estimated by the proportion of drugs in that class for which the mutation is known to confer resistance. For example, in the NRTI class, the M41 mutation confers resistance only to Stavudine and Zidovudine, so the total number of drugs for which M41 confers resistance is 2 out of 7 drugs.The efficacy of a particular drug is represented by its ability to decrease viral load under perfect adherence. Our baseline assumption is that efficacy of new drugs  is equal to the average of viral load decrements observed by drugs in the same class as the new drug, under scenarios of near-perfect adherence. In our base case analysis, we assume that the toxicity of new drugs was similar to the toxicity level of existing drugs within that category. However, in sensitivity analysis we explore scenarios in which the efficacy and toxicity of pipeline drugs are different from existing drugs.3. We considered alternative CD4 thresholds for ART initiation varying from 50 cells/mm3 to 500 cells/mm3, in increments of 50 cells/mm3. In addition, different starting age categories  and baseline viral loads of 104, 104.5, 105 and 105.5 copies/mL were modeled. In each scenario, the optimal CD4 count at which to initiate treatment was identified by finding the CD4 count (up to 500 cell/mm3) that produced the maximum life expectancy. Additionally, in each scenario, we compared increases in life expectancy (LE) and quality-adjusted life expectancy (QALE) that could arise from the expected rate of development of new ARTs.Successive populations of individuals with newly diagnosed chronic HIV infection were considered, each of them starting with CD4 count of 500 cells/mmWe varied several assumptions to assess robustness of model predictions, particularly regarding the pipeline of new ART drugs. Specifically, we varied the inter-arrival time of new drugs, the rate at which new drugs induce resistance mutations, the propensity to adhere with ART overall, the effectiveness of new pipeline drugs compared to existing drugs, and the toxicity level of new pipeline drugs compared to existing drugs. In scenarios in which the efficacy of the new drug is equivalent to the average of the existing drugs, the new drug is added as an extra regimen when the patient has exhausted all existing regimens. However, in sensitivity analysis where the new drug is more effective than existing drugs, we assume the new drug is used after the first regimen has failed.The distribution of inter-arrival times of drugs was satisfied by assuming an exponential distribution with a mean inter-arrival time of 7. 69 months . However, the life expectancy gains to pipeline drugs for most patients remain less than 1%.re small . New ARTOur sensitivity analyses  indicate3, which supports the current WHO recommendations. However, the overall impact of a pipeline of new drugs is not large for most patient groups, with average changes in life expectancy less that 1%, except for patients who are young and have high viral loads, primarily because there are already a large number of regimens available. Our results are supported by intuition, which would suggest that the availability of more drugs would reduce the likelihood of “burning through” existing regimens for patients at highest risk for doing so, in particular patients with higher baseline viral loads.Consistent with current treatment recommendations, the base case model (that does not include the availability of pipeline drugs) supports early treatment in most scenarios. The addition of pipeline drugs raises the CD4 threshold for treatment in several classes of patients, resulting in the optimal CD4 to initiate treatment across virtually all ages and viral loads to be 500 cells/mmOur analysis does indicate that patients will be better served if new HIV drugs are found with lower side effects and toxicities: this remains one of the most important reasons that drug regimens are discontinued, and decreased toxicities and side effects will extend the duration of the regimen.This study has several limitations. Our data are from a cohort that is overwhelmingly male, and thus our results may not apply for women. Cost or cost-effectiveness has not been considered in our analyses, which may have impact on policy recommendations. Our model does not include spreading of resistance patterns in the native viral population. As resistance spreads, some newly infected individuals may be infected with already resistant (non- “wild type”) strains. In addition, our analysis does not consider the impact of pipeline drugs on the epidemic – the model does not represent transmission between individuals. To the extent that new pipeline drugs will lower the VL of some individuals, it would be expected to decrease transmission. However, because the addition of pipeline drugs extends the ability to have effective treatment towards the end of a patient's disease, the effect is expected to be small. Finally, we did not perform subgroup analyses for patient groups likely to have poor adherence , who might be more likely to exhaust existing regimens because of resistance or intolerance, and who therefore would yield disproportional advantages from the development of new drugs. In summary, our results suggest that the rate of development of new ART drugs may not impact the starting threshold for most patient groups, although they may substantially increase benefit for younger patients with higher viral loads. Finally, our sensitivity analyses raise the intriguing prospect that reducing the toxicity profile of new ART drugs may have a greater beneficial impact on health than increasing the supply of new drugs with novel mechanisms or resistance patterns.Appendix S1Contains Figure S1, Basic structure of HIV simulation model. See text for details. Figure S2, Typical patient histories with and without pipeline drugs. See text for details. Figure S3, The Quantile-Quantile plot for pipeline arrival process. Quantile-Quantile plots are used to compare a dataset to a theoretical distribution. It provides an assessment of graphical goodness of fit. If the points lie on the line, the probability distribution is acceptable.(DOCX)Click here for additional data file.


This descriptive, non-interventional study on HIV-1-infected patients treated with DRV/r in the usual clinical setting, with a single-arm prospective observational design, collected data on utilization of darunavir/ritonavir (DRV/r) under the conditions described in marketing authorization in usual clinical practice in Italy to evaluate efficacy and safety of DRV/r-based antiretroviral (ARV) treatment. This analysis focussed on the safety profile of DRV/r in HIV-1 infected patients.Data were analyzed from four cohorts of HIV-1-infected patients treated with DRV/r in the real-world setting, including an ARV-naïve-DRV/r-naïve cohort (Cohort 1), an ARV-experienced-DRV/r-naïve cohort (Cohort 2) and two ARV-DRV/r-experienced cohorts (Cohorts 3 and 4), one of which (Cohort 3) was from the DRV/r Early Access Program. The objective of this analysis was to examine the safety data obtained in these four cohorts in patients enrolled from June 2009 to November 2011 and observed until December 2012 or DRV/r discontinuation.Safety data from 875 patients were analyzed. DRV/r-based treatment was well tolerated, with 36.2% of patients reporting ≥1 adverse event (AE) and very few discontinuations due to study drug-related AEs . The most frequent AEs were diarrhoea (2.7%), reduced bone density (2.6%) and hypercholesterolaemia (2.1%) . RegardiIn HIV-1-infected patients treated with DRV/r in these settings, the tolerability profile was favourable and similar to (or better than) that reported in controlled clinical trials. These data confirm DRV/r to be a safe treatment choice in DRV/r-experienced and naïve patients.


CD4 cell count measurement remains an important diagnostic tool for HIV care in developing countries. Insufficient laboratory capacity in rural Sub-Saharan Africa is frequently mentioned but data on the impact at an individual patient level are lacking. Urban-rural discrepancies in CD4 testing have not been quantified to date. Such evidence is crucial for public health planning and to justify new yet more expensive diagnostic procedures that could circumvent access constraints in rural areas.To compare CD4 testing among rural and urban HIV patients during the first year of treatment.Records from 2,145 HIV positive adult patients from a Médecins sans Frontières (Doctors without Borders) HIV project in Beitbridge, Zimbabwe, during 2011 and 2012 were used for a retrospective cohort analysis. Covariate-adjusted risk ratios were calculated to estimate the effects of area of residence on CD4 testing at treatment initiation, six and 12 months among rural and urban patients.While the proportion of HIV patients returning for medical consultations at six and 12 months decreased at a similar rate in both patient groups, CD4 testing during consultations dropped to 21% and 8% for urban, and 2% and 1% for rural patients at six and 12 months, respectively. Risk ratios for missing CD4 testing were 0.8 (95% CI 0.7-0.9), 9.2 (95% CI 5.5-15.3), and 7.6 (95% 3.7-17.1) comparing rural versus urban patients at treatment initiation, six and 12 months, respectively.CD4 testing was low overall, and particularly poor in rural patients. Difficulties with specimen transportation were probably a major factor underlying this difference and requires new diagnostic approaches. Our findings point to severe health system constraints in providing CD4 testing overall that need to be addressed if effective monitoring of HIV patients is to be achieved, whether by alternative CD4 diagnostics or newly-recommended routine viral load testing. Measurement of absolute cluster of differentiation type 4 (CD4+) cells/μL blood levels is important for initiating and monitoring anti-retroviral therapy (ART) in Human Immunodeficiency Virus (HIV) infected people. WHO guidelines recommend CD4 testing at ART initiation and at six month intervals in settings where viral load measurement is not available . ZimbabwIn Zimbabwe, as in other SSA countries, CD4 testing capacity has not kept up with the continuous ART decentralization process from urban to peripheral health facilities . This isThe effects of these constraints on access to CD4 testing for patients from rural areas in SSA remain poorly understood. The challenges of providing HIV diagnostics and care in rural SSA are frequently reported in the literature, but most often without explicitly comparing rural versus urban areas . StudiesEvidence regarding the existence and magnitude of differences in access to CD4 testing in disadvantaged populations is crucial for public health planning and to support changes in existing service delivery. For instance, alternative diagnostic procedures that could circumvent sample transport constraints such as use of dried blood spots, blood fixatives, point-of-care CD4 enumeration, or CD4 Stabilization Tubes are often associated with higher costs and hence not affordable for many national AIDS programmes. Their introduction would require sound justification. In addition, if routine viral load testing is to become a reality as a treatment monitoring tool in Zimbabwe and other SSA countries soon, it will likely require overcoming similar challenges in specimen transport . Hence tIn a Médecins sans Frontières / Doctors Without Borders (MSF) HIV project in Beitbridge district, Zimbabwe, we compared access to CD4 testing among HIV patients from rural and urban areas at ART initiation, at six and at 12 months of treatment in a retrospective cohort analysis.This study was conducted in Beitbridge district, Matabeleland South province, where MSF maintained an HIV project supporting Ministry of Health and Child Welfare (MoHCW) in prevention, treatment and care of HIV/AIDS between 2009 and 2013. Beitbridge district is located in the south of Zimbabwe bordering South Africa with an estimated population of about 122,000 of which about 34% live in rural areas . HIV preIn close collaboration with MoHCW, MSF offered comprehensive ART services at Beitbridge District Hospital (BDH) and at six rural health centres (RHC) free of charge across the district between 2009 and 2013. BDH laboratory was the only public facility in the district providing comprehensive HIV diagnostic services, including absolute CD4 count measurement using BD Facscount  and Partec Cyflow  cytometers. Collection of blood samples was done using EDTA tubes. The road network in the district is patchy, distances between BDH and RHCs are long, and many roads become impassable during the rainy season.A joint outreach team of MSF and MoHCW nurses regularly visited one RHC per day on an alternating basis to provide HIV care. RHCs were visited once per week on average. At the end of outreach days, patient samples were brought back to BDH for laboratory analysis by the outreach team. Sample transportation on days not coinciding with outreach team visits was erratic due to the limited transport capacity of MoHCW. As such, CD4 testing at RHCs was usually restricted to days when an MSF/MHCW outreach team visited the facility.At BDH and RHCs, medical information of patients was recorded on paper-based patient files during consultations by MoHCW nurses. On an ongoing basis throughout the project, the standard MSF electronic database “Follow Up Care of HIV/Aids” (FUCHIA)  was mainFor this analysis, all records from HIV positive patients above 18 years of age initiated on ART at BDH or any of the six supported RHCs in the MSF HIV project in Beitbridge between January 2011 and December 2012 were considered eligible.Records were sourced from the FUCHIA database and the following variables were included for this analysis: area of residence , whether or not a CD4 test result was recorded at ART initiation, at six and at 12 months (+/-30 days), and baseline characteristics at enrolment . See a priori confounders and included in the adjusted model. Type 1 error margins of 5% were applied throughout. Analysis was conducted between July 2013 and June 2014 using software package STATA v.11 [The exposure of interest was area of residence , and the outcome of interest, whether a patient had a CD4 test result recorded at the different time points. Socio-demographic and clinical patient characteristics were treated as covariates. A bivariate analysis based on chi-square tests was performed to compare the distribution of baseline characteristics between both patient groups. Crude and covariate-adjusted risk ratios including 95% confidence intervals and p-values were calculated using binomial regression models to compare the association between area of residence and whether a CD4 test was done at ART initiation, six and 12 months. All baseline covariates were considered as ATA v.11 .This study is based on existing data from routine project activities that had already been collected under a Memorandum of Understanding between MoHCW and MSF for monitoring and evaluation purposes. Data were analyzed anonymously and only aggregated data without personally identifiable information is presented, hence no individual informed consent was required. Exemption from ethics review was granted by the Medical Research Council of Zimbabwe. This study met the Médecins Sans Frontières’  Ethics Review Board-approved criteria for analysis of routinely-collected programme data. It also satisfied the requirements of the Ethics Advisory Group of the International Union against Tuberculosis and Lung Disease  and meets their approval. This study was conducted in accordance with the principales of the Helsinki Declaration.There were 2,222 records that matched the inclusion criteria. Of these, 77 (3%) were excluded , leaving records of 2,145 patients for the analysis. Patient baseline characteristics are described in Adjusting for socio-demographic and clinical differences between patient groups, the risks for missing CD4 testing were 0.8 (95% CI 0.7–0.9) times lower, 9.2 (95% CI 5.5–15.3) times higher and 7.6 (95% 3.7–17.1) times higher for rural patients compared to urban patients at ART initiation, six months and twelve months, respectively. The inclusion of covariates had no substantial effect on the association between area of residence and CD4 testing .While the proportion of patients accessing medical consultations decreased at six and 12 months of treatment progressively, the rate of decline in visits was similar in rural and urban patients . Of thosAmong all patients initiated on ART, the proportion of patients that received all CD4 tests as recommended during the course of their first year on treatment decreased from 43% and 53% at initiation to 15% and 2% at six months, and to 1% and 0% at 12 months, for urban and rural patients, respectively.This is the first study to compare and quantify differences in CD4 testing between HIV patients from rural and urban areas in a SSA setting during the first year of ART. While our findings show that rural patients among the studied population are much less likely to have CD4 testing done when they should, according to WHO recommendations, at six and 12 months compared to urban patients, we found startlingly low CD4 testing in both patient groups.The main strengths of this study are that i) a large number of patients, enrolled over two years, were included and followed up during their first year of treatment; ii) data were sourced from a standardized and internationally used database; iii) given the low number of excluded records, we are confident that our study sample is representative of the MSF HIV cohort initiated in Beitbridge in 2011 and 2012.A number of limitations are recognized. First, our study only included patients from the six MSF-supported RHCs out of 13 RHCs districtwide, plus BDH. Treatment coverage among ART eligible HIV patients in Beitbridge district was about 35% (MSF project monitoring tool (logframe) 2013). While MSF chose to support RHCs based on remoteness and the intention to have fair geographical coverage, we cannot presuppose representativeness of our cohort for the the district or Zimbabwe as a whole. In fact, we may even underestimate the disparity in CD4 testing between urban and rural areas since MSF offered reliable and comprehensive care at RHCs during outreach days, which might have stimulated uptake of health services in these areas.Second, data were collected for routine reporting purposes and we were unable to cross-check our study data with patient records for this analysis; nonetheless, data are believed to be robust due to built-in data entry checks in FUCHIA.Third, although we controlled for basic demographic and clinical differences between patient groups, we cannot rule out residual confounding by other factors such as socio-economic status, health seeking behavior, number of patient clinic visits, or differences in service provision between urban and rural health facilities. In addition, mobility might have been different, being potentially more cyclical in rural areas depending on farming seasons and more constant in urban areas for commercial activities.Our findings raise a number of important points for discussion:Until now, the disadvantaged situation in rural areas in SSA with regards to CD4 testing had only been explored from a health system or laboratory infrastructure perspective. It had not yet been quantified at a patient level ,13. Our By differentiating between consultations accessed and test results received, we were able to suggest that the reasons for poorer access to CD4 testing in rural compared to urban areas are likely to be within the health care system rather than with the patients. The current EDTA tube based testing method relies on timely specimen transportation and as such, given the transport problems during days when no MSF/MoHCW outreach visits were done, probably explains the bulk of the rural-urban discrepancy. Other explanations could be human resources constraints or lack of phlebotomy equipment. However, since MSF was supplying materials to RHCs during stock-out periods, we think that the latter factors are unlikely to explain much of the observed rural-urban discrepancy. The observed higher proportion of patients receiving CD4 testing at baseline in rural compared to urban areas is striking. A possible explanation for this finding may be related to differences in levels of training between rural and urban health care workers. Rural health care workers often have a lower level of training compared to urban staff, and as such might place greater reliance on the certainty of CD4 testing, instead of clinical assessment, to initiate ART compared to health staff in urban areas. This would lead to a relative increase the proportion of patients initiated on ART who receive CD4 testing at baseline in rural areas.Overall, proportions of being CD4 tested were very low in urban as well as in rural patients, suggesting severe underlying health system constraints in the provision of timely CD4 testing that go beyond transport issues. Parts of the gap might be due to CD4 tests being done outside the precision window of +/-30 days. Patients tested outside this time period who returned within the time window shortly thereafter might not have been re-tested during that subsequent consultation. This implies rational clinical practice, but might have led to an overestimation of the problem in our study. However, given the magnitude of the observed gaps, it is unlikely that this fully explains the extent of our findings. Data capture of CD4 testing into the FUCHIA database was done from returned laboratory result slips in patient files and as such we could not determine where between patient contact and filing of result slip the processing chain broke down. Possible reasons for patients in both areas not receiving effective CD4 testing when they should have (according to WHO recommendations) may have included: patients not being bled during consultations; specimen handling issues in the laboratory; errors in returning of result slips into patient files; stock ruptures of cytometer consumables in the national supply system; or intermittent cytometer breakdowns.The setting of this study—one of the districts in Zimbabwe with the highest HIV prevalence —has a ruTo improve CD4 testing for rural patients, either sample transportation needs to be drastically improved or alternatives to the current testing methods need to be considered . Point-oIn conclusion, this study found low access to CD4 testing at time points recommended by WHO (+/- 30 days) in a high HIV burden district in Zimbabwe. Rural patients were particularly disadvantaged, most likely due to difficulties in specimen transportation, and might benefit from the use of new context-adapted diagnostic methods. However, any innovation will have limited overall impact on the majority of patients without a well-managed health system to support it. Hasty roll out of universal viral load monitoring may face a similar fate as current CD4 testing methods.S1 Table(ZIP)Click here for additional data file.


P = 0.01, 0.001, resp.). An insignificant mean increase of 77 cells/ll occurred in the non-SVR group within month 24 (P = 0.06). Variables associated with greater CD4 gains were higher nadir, lower preinterferon CD4 counts, and lower body mass index (BMI).The long-term impact of pegylated-interferon plus ribavirin treatment outcome on CD4 T cell course in patients coinfected with human immunodeficiency virus and hepatitis C virus is largely unclear in the literature. The aim of this study was to investigate the impact of HCV-RNA clearance by standard anti-HCV therapy on long-term CD4 cells recovery in HIV/HCV patients on successful combined antiretroviral therapy. We retrospectively enrolled HIV/HCV-coinfected patients on HIV medications and treated for hepatitis C. CD4 + T cell counts were registered at baseline and after hepatitis C therapy. Multiple linear regression analysis was performed to identify independent predictors of CD4 + T cell change following the anti-HCV treatment outcome. Of the 116 patients enrolled, 54 (46.6%) reached a sustained virological response. During a follow-up of 24 months, the SVR group showed a mean annual increase in CD4 + T cell from baseline of 84 cells/ll at 1 year and of a further 38 cells/ll within the second year ( With the wave of rapidly evolving treatment of hepatitis C, it behooves us to understand its implications in our coinfected population, where the CD4 (+) T cell recovery after the introduction of an effective combined antiretroviral for HIV treatment is unclear in the literature. Studies have determined that HCV viremia did not affect the CD4 cell count recovery in the HIV patient .Other previous studies have described coinfected patients that had results that implied a fall in the absolute CD4 count at week 24 of HCV treatment when interferon is used and later a subsequent rise to baseline at 24 weeks after the suspension of therapy .Our objective is to revisit the result of sustained viral response (SVR) by previously standard anti-HCV therapy on long-term CD4 cell count recovery in HIV/HCV patients on effective antiretroviral therapy (ART).In short, we are asking the following question: what is the effect of long-term SVR on T cell counts in coinfected patients?Sustained virological response (SVR) was defined by HCV-RNA PCR undetectability 6 months after IFN discontinuation. Now the standard of care defines SVR12 as an undetectable HCV RNA level 12 weeks after treatment discontinuation.Non-SVR is defined by HCV active replication at the same time, independent of the reason .We retrospectively reviewed the charts of coinfected patients treated with pegylated interferon + ribavirin prior to January 1, 2008. Patients were divided into 2 groups based on their SVR24.CD4 T cell modification is calculated as the mean change in CD4 (+) T cell counts from pre-IFN treatment values, which is the anti-HCV definition of response, and was evaluated after 6, 12, and 24 months (up to 60 months) status after IFN-based therapy discontinuation. The plasma HIV-RNA was recorded at the same time points to confirm viral suppression.Subjects were enrolled into the study if (1) they had confirmed HIV and chronic hepatitis C and (2) HIV RNA VL was undetectable for at least 1 year on ART with continuous follow-up documented in our electronic medical records database.Subjects included were treated between 2001 and 2008. CD4 (+) T cell counts were collected at baseline (before treatment), at end of treatment (EOT), then at every 6-month interval, and up to 60 months from therapy discontinuation, having a suppressed HIV virus load throughout the duration of hepatitis C infection therapy and beyond.Multiple linear regression analysis was then implemented to identify independent predictors of CD4 (+) T cell change following the anti-HCV treatment outcome. Repeated linear regression was used to estimate the slope of the CD4 curve .t-test was used to compare continuous variables and Fisher's exact test was used to compare nominal variables. P value was considered significant at <0.05.An independent samples Out of 205 coinfected patients treated, 26 SVR and 20 non-SVR patients were included in the analysis. Baseline characteristics were then constructed, as seen below. Reasons for excluding so many patients from the study were lost to follow-up after treatment, poor nonsuppressed and nonadherence to antiretroviral therapy, or HIV viral load detectability due to resistance.P = 0.772). Thus, graphically, the subjects reached a plateau of their absolute CD4 counts and had no other increases or declines.Time to maximum CD4 count between the two groups did not differ  was significantly different between the two groups: SVR: increase of 83.8 in CD4 count per year  and non-SVR: increase of 44.9 in CD4 count per year (during first 2.2 years), At baseline there were no subjects included in the study who had newly diagnosed diabetes mellitus II, lymphoma, or decompensated liver disease, and the same is true of follow-up. Upon follow-up during the study, there were 3 patients that died and 4 hospital admissions during the study dates. The deaths were due to cardiac causes, one from the SVR group and two from the non-SVR group. The hospitalizations were due to GI bleed, asthma exacerbation, chlamydia pneumonia, and MRSA bacteremia.A plausible explanation for the average of CD4 T cell counts having very little change over long periods of time may be the persistent immune activation and CD4 T cell apoptosis involved with HCV infection . This ac9/liter) × ALT (IU/liter)1/2]13. It demonstrated a gradual increase with the fibrosis stage [A lower nadir of CD4 cell count and higher preinterferon values may negatively affect the CD4 cell count increase after treatment has ended . Due to is stage . IncreasThe nadir of CD4 count prior to the start of treatment of HCV was not included, as it is possible that the nadir CD4 count drawn during treatment may be confounded by IFN induced leukopenia.Greater BMI also gives a negative effect on CD4 cell count rise during the follow-up period . GenotypThe key to understanding the relevance of our study and its applicability is to know the duration of HIV suppression . The lonThe most relevant potential mechanisms that lead to a higher CD4 count when HIV subjects are treated for HCV and achieve SVR include the regression of liver fibrosis that may lead to the prevention of splenomegaly and cirrhosis. This may also be due to the effect of chronic inflammation in the non-SVR group leading to a depressed CD4 count .The achievement of SVR may be associated with a significant immune reconstitution for 2 years after interferon and ribavirin treatment in HIV/HCV coinfected patients, with suppressed HIV viral loads. This phenomenon was not sustained past 2 years. Other factors mentioned should be analyzed to determine evidenced based ways to explain this finding and whether it benefits patients clinically.Attaining SVR may be relevant with the implementation of direct acting agents (DAAs) now that we have very effective treatment and expect more patients to achieve a cure. This strengthens the rationale for treating patients with HCV, specifically coinfected HCV/HIV patients .As we continue to improve our screening capabilities for HCV, we are able to capture HCV patients earlier before much of the hepatic and extrahepatic damage and potentially not allowing the T cell nadir to be as low as it would have been now that the treatments are becoming simpler and shorter than ever.The great majority of the 205 subjects were not included in the analysis for three reasons: they did not have controlled viral loads, they had unacceptable deficits in their data for collection, and there were a number of subjects that were lost to follow-up. The spreadsheets above indicate that all subjects in both groups were confirmed to be taking ART and had an undetectable virus load.Our study is limited by the retrospective manner in which it was designed. Although it added liver histologies that previous studies did not consistently add and we had greater numbers than many of similar quality, more numbers would still be better. As such, even though we included a greater quantity of time after end of treatment was reached than that in many of the previous studies, a longer duration would even be better.


Monotherapy against HIV has undoubted theoretical advantages and has good scientific fundaments. However, it is still controversial and here we will analyze the efficacy and safety of MT with darunavir with ritonavir (DRV/r) on patients who have received this treatment in our hospitals.Observational retrospective study that includes patients from 10 Andalusian hospitals that have received DRV/r in MT and that have been followed over a minimum of 12 months. We carried out a statistical descriptive analysis based on the profile of patients who had been prescribed MT and the efficacy and safety that were observed, paying special attention to treatment failure and virological evolution.3 at 24 weeks.DRV/r was prescribed to 604 patients, of which 41.1% had a CD4 nadir <200/mmc. 33.1% had chronic hepatitis caused by HCV, had received an average of five lines of previous treatment and had a history of treatment failure to analogues in 33%, to non-analogues 22 and protease inhibitors (PI) in 19.5%. 76.6% proceeded from a previous treatment with PI. The simplification was the main criteria for the instauration of MT in the 81.5% and the adverse effects in the 18.5%. We managed to maintain MT in 84% of cases, with only 4.8% of virological failure (VF) with viral load (VL) >200 c/mL and 3.6% additional losses due to VF with VL between 50 and 200 copies/mL. Thirty three genotypes were performed after failure without findings of resistance mutations to DRV/r or other IPs. Only 23.7% of patients presented some blips during the period of exposition to MT. Eighty seven percent of all determinations of VL had <50 copies/mL, and only 4.99% had >200 copies/mL. Although up to 14.9% registered at some point an AE, only 2.6% abandoned MT because of AE and 1.2% because of voluntary decision. Although the average of total and LDL cholesterol increases 10 mg/dL after 2 years of follow-up, so did HDL cholesterol in 3mg/dL and the values of triglycerides (−14 mg/dL) and GPT (−6 UI/mL) decreased. The average count of CD4 lymphocytes increased from 642 to 714/mmIn a very broad series of patients obtained from clinical practice, data from clinical trials was confirmed: MT with DRV as a de-escalation strategy is very safe, it's associated to a negligible rate of adverse effects and maintains a good suppression of HIV replication. VF (with >50 or >200 copies/mL) is always under 10% and in any case without consequences.


Ethiopia is one of the most seriously HIV affected countries in Sub-Saharan Africa. Anemia is a known predictor of disease progression and death among HIV infected patients. In this study, we investigated the magnitude and correlates of anemia among HIV infected patients receiving HAART at a referral hospital in Ethiopia.A retrospective cohort study was conducted from November 2011 to February 2012 in Zewditu Memorial Hospital, Addis Ababa, Ethiopia. Records of 1061 patients on HAART were selected using simple random sampling technique. Socio-demographic and clinical characteristics of the study patients were collected using standardized data extraction instrument. Data were analyzed using STATA version 11.0. Odds ratios with 95% confidence intervals were used to quantify the strength of association between anemia and its potential predictors.3  and 200–350 cells/mm3  were independently associated with the odds of being anemic.The prevalence of anemia at baseline was 42.9%. However, the prevalence significantly decreased to 20.9% at 6 months (p < 0.001) and to 14.3% at 12 months (p = 0.001) after HAART initiation. At baseline, male sex , clinical stage III/IV  and TB co-infection  were independently associated with the odds of being anemic. After 6 months of HAART, male sex , baseline anemia  and TDF-based HAART  were independently associated with the odds of being anemic. Besides, anemia was independently associated with older age at 6 months. After 12 months of HAART, baseline anemia , age group 25–34 years , age group 45–54 years , CD4 count below 200 cells/mmAlthough a remarkable reduction in the prevalence of anemia was observed following initiation of HAART, a significant proportion of HIV patients remained anemic after 12 months of HAART suggesting the need for routine screening and proper treatment of anemia to mitigate its adverse effects. Mycobacterium avium complex, Parvovirus B-19, Cytomegaloviruses, Cryptococcus neoformans and Histoplasma capsulatum were reported to cause abnormalities in blood cell counts , 3% level of precision (d) with 95% confidence interval. Patients transferred in from other health institutions, patients who started ART in the hospital before March 1, 2005 or after November 30, 2010 and patients who were pregnant at baseline or during the follow up visits were excluded from the study.The data was extracted using a standardized instrument by three ART nurses. The collected information includes socio-demographics, clinical characteristics, medication use and immunohematological profile of patients at baseline, 6 and 12 months after initiation of HAART. Hemoglobin (Hgb) values, red blood cell count, white blood cell counts with absolute CD4 cells and CD8 cells, and platelets were determined using the hematology analyzer Cell-Dyn 1800  whereas CD4+ T cells were assayed using the BD FACSCOUNT system . To ensure good quality data, training of data collectors, pre- testing of data extraction instrument and continuous supervision of the data collection process was carried out. Data were checked for missed values and outliers during data management.Data were computerized using Epidata version 3.1 and STATA version 11  was used for data analysis. Anemia was defined based on hematological reference values for adult Ethiopian population . AccordiThe effect of different risk factors on the odds of being anemic were investigated at baseline, at 6 months and at 12 months following initiation of HAART. Odds ratio with 95% confidence interval was used to quantify the strength of association between anemia and its potential predictors. Variables that were found significantly associated with the outcome variable (p < 0.05) in the bivariate analysis as well as variables that were reported to be associated with anemia in previous studies and that were clinically relevant for the occurrence of anemia were included in the multivariable logistic regression model to obtain adjusted effects. Since height was not recorded for the majority of the study participants, missing values for body mass index (BMI) were coded as a separate category before including BMI in multivariable logistic regression so that data from all study participants can be used.Study protocol was approved by the Institutional Review Board of Aklilu Lemma Institute of Pathobiology, Addis Ababa University and Addis Ababa City Administration Health Bureau. Identifiers of the study participants were not collected to maintain confidentiality.3. The mean Hgb value was 12.9 (sd = 2.4 g/dl) while the mean CD4 cell count was 139.8 (sd = 78.8) cells/mm3. Five hundred and forty-four (52.0%) of the study patients were co-infected with different types of opportunistic infections.Demographic and clinical characteristics of the study patients at treatment initiation are presented in Table A total of 455 (42.9%) patients were anemic at baseline of which 360 (34.0%) had mild, 71 (6.7%) had moderate and 24 (2.3%) had severe anemia. The overall prevalence of anemia was higher in males (50.4%) than in females (37.8%) (p < 0.001). Significantly higher proportion of females had moderate and severe forms of anemia compared to males: moderate anemia was 7.9% among females and 4.9% among males (p < 0.001) and severe anemia .3 and 200-350 cells/mm3 are associated with decreased odds of being anemic. In multivariable logistic regression analysis, male sex, clinical stage III/IV and TB co-infection were independently associated with increased odds of being anemic whereas CD4 count <200 cells/mm3 and 200-350 cells/mm3 were independently associated with reduced odds of being anemic in the multivariable analysis.Different factors were observed to be associated with being anemic before HAART initiation Table . In univA total of 980 (92.4%) of the study participants had Hgb measurements at 6 months of HAART initiation. Of these, 970 (99%) had Hgb measurements at baseline. And of the 896 (84.4%) patients who had Hgb measurements at 12 month, 888 (99.1%) had Hgb measurements both at baseline and at 6 months of HAART treatment. Patients with missing Hgb measurements at 6 month (81 patients) were more likely to be those in the age group of 25-34 years, those having a CD4 cell counts of ≥350 cells/mm3, those who were not on co-trimoxazole prophylactic treatment and those who were receiving d4T based HAART regimen. However, there was no statistically significant difference in the sex, BMI values, fluconazole treatment status, TB treatment status and anti-microbial treatment status between patients included and excluded from the study of anemia at the 6 month. During the study period, changes were made to the regimen of 85 patients. Of the 60 patients for whom drug regimen was changed in the first 6 months, 25(41.7%) were those who were anemic at baseline. Treatment regimen was changed for 40 of the patients who were on AZT based regimen (15 (37.5%) were anemic at baseline), for 16 of those on d4T- based regimen (9(56.3%) were anemic at baseline) and for 4 of those on TDF- based regimen (1(25.0%) were anemic at the baseline). After 6 months, 25 patients have changed their treatment regimens of whom 18 (72%) were patients on d4T- based regimen and 7 (28%) were those on AZT- based regimen. The mean (sd) Hgb values of the study patients at 6 and 12 months were 14.0 (2.3) g/dl and 14.4 (1.9) g/dl, respectively.The overall prevalence of anemia significantly decreased after HAART initiation. The prevalence declined from 42.9% at baseline to 20.9% at 6 months p < 0.001) and to 14.3% at 12 months (p = 0.001). There was also a consistent decrease in the prevalence of mild, moderate and severe anemia after treatment with HAART  and 200–350 cells/mm3  were independently associated with increased odds of being anemic.Risk factors for anemia after initiation of HAART are shown in Table In this study, we investigated the prevalence of anemia and its associated factors in a large cohort of HIV infected patients taking HAART over 12 months. A large proportion of our study patients had anemia at baseline and subsequent follow-up time points. The prevalence of anemia before initiation of HAART in this study was comparable with the prevalence reported in other studies ,19. HoweResults from this study show a remarkable reduction in the prevalence of anemia after initiation of HAART. In agreement with our observation, in other studies, the prevalence of anemia in HAART naïve was significantly higher compared to HAART experienced patients ,23. The . However, none of the above studies described the prevalence of anemia according to severity grades. In our study, moderate and severe forms of anemia were higher in females compared to males both before and after 6 months on HAART. The absence of significant difference in the risk of anemia at 12 months on HAART between male and female patients seen in this study may suggest the role of HAART to improve anemia after 12 months.Similar to this study, some studies reported a high prevalence of anemia in males compared to females and attributed it to the fact that lower Hgb level is used to define anemia in women than men ,27. HoweWe observed an increase in the risk of anemia with age. The hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with increasing age and further aging is associated with increased pro-inflammatory cytokine expression many of which contributing to EPO resistance , therebyDifferent studies reported association between increased incidence of low blood cell counts with progressive immunologic deterioration and advanced disease due to HIV ,8,20. ItThe absence of significant association between treatment with AZT and anemia in the current study despite its frequent association with bone marrow suppression has also been previously described ,33. The This study is based on a large cohort of HIV patients on HAART. However, data were collected for routine clinical care, and hence, other important variables, notably viral load are lacking. Moreover, the majority of patients had no data on BMI. Nevertheless, this study highlights the burden of anemia among HIV patients before and after HAART.In conclusion, anemia is a common manifestation of HIV infection both before and after initiation of HAART in the study setting. The treatment of HIV infected patients with HAART has resulted in a remarkable reduction in the prevalence of anemia after 12 months. However, a substantial proportion of patients had anemia after 12 months of HAART, suggesting the need for routine screening of anemia, investigating its causes and instituting appropriate treatment to mitigate the adverse effects of anemia. Considering the high burden even after a prolonged HAART, there is a need for developing a comprehensive screening, treatment and monitoring protocol for anemia.


The 48-week interim analysis of the MODAT study showed that confirmed virologic failure (CVF) was more frequent in patients simplifying to ATV/r monotherapy compared to maintaining ATV/r-based triple therapy. The DSMB recommended stopping study enrollment but continuing follow-up of enrolled patients. We present the 96-week efficacy analysis.Multicentre, randomized, open-label, non-inferiority trial (non-inferiority margin −10%). Treatment failure (TF) was defined as CVF (two consecutive HIV-RNA >50 cp/mL) or discontinuation for any cause. In the monotherapy arm, patients with CVF re-introduced their previous NRTIs and remained in the study if HIV-RNA <50 copies/mL within 12 weeks of re-intensification.101 patients evaluated : 85% malDespite the small sample size, the primary 96-week analysis showed that simplification to ATV/r monotherapy showed inferior efficacy to maintaining ATV/r triple-therapy but appeared to be superior when re-intensification was considered success.