Although a dramatic decrease in AIDS progression has been observed after Highly Active Anti Retroviral Therapy (HAART) in both low- and high-resource settings, few data support that fact in low-resource settings.This study describes the incidence of AIDS-defining illnesses (ADI) after HAART initiation and analyzes their risk factors in a low-resource setting. A focus was put on CD4 cell counts and viral load measurements.404 HIV-1-infected Senegalese adult patients were enrolled in a prospective observational cohort and data censored as of April 2008. A Poisson regression was used to model the incidence of ADIs over two periods and to assess its association with baseline variables, current CD4, current viral load, CD4 response, and virological response.3 and of 61% for patients with a viral load < 1000 cp/mL).ADI incidence declined from 20.5 ADIs per 100 person-years, 95% CI =  during the first year to 4.3, 95% CI =  during the fourth year but increased afterwards. Before 42 months, the decrease was greater in patients with clinical stage CDC-C at baseline and with a viral load remaining below 1000 cp/mL but was uniform across CD4 strata (p = 0.1). After 42 months, 293 patients were still at risk. The current CD4 and viral load were associated with ADI incidence (decrease of 21% per 50 CD4/mmDuring the first four years, a uniform decline of ADI incidence was observed even in patients with low CD4-cell counts at HAART initiation as long as the viral load remained undetectable. An increase was noted later in patients with immunologic and virological failures but also in patients with only virological failure. Since the advent of Highly Active Anti Retroviral Therapy (HAART), a dramatic decrease in AIDS progression has been observed in both developed -5 and deObservational studies have identified the CD4 cell count and the history of AIDS as the strongest predictors of disease progression ,7,11-18.To date, there are few studies about disease progression in low-resource settings and most have short follow-up durations. Nevertheless, as the access to antiretroviral therapy in such settings is scaled up, there is a need for further knowledge on long-term outcomes in patients put on HAART and for evaluation of clinical or biological markers for patient monitoring. The present study describes the incidence and nature of the most common ADI in a low resource setting and examines the relationships between clinical and biological markers and the occurrence of ADI.From August 1998 to April 2002, 404 HIV-1 infected patients aged 15 or more and participating in the "Initiative Sénégalaise d'Accès aux médicaments Antirétroviraux" (ISAARV) were enrolled in an observational cohort after giving written informed consent. The data were censored either at the last visit before April 2008 or at the date of death.The initial antiretroviral therapy regimen was a triple drug combination (two nucleoside reverse transcriptase inhibitors (NRTI) + either one non-nucleoside reverse transcriptase inhibitor (NNRTI) or one protease inhibitor (PI)), except for 18 patients who received only two NRTI until May 2000. Antiretroviral drugs were provided for free starting from December 2003.After comprehensive clinical and biological assessments at inclusion, patients were examined at least every 2 months and had a biological evaluation at least every 6 months. A patient record and a Case Report Form that includes a comprehensive list of various ADIs were made available to the investigator at each patient visit.Patients' monitoring details, characteristics at baseline, antiretroviral treatment efficacy, adherence to treatment, and mortality pattern (early or late) have been previously published -28. The The primary outcome for the present analysis was the occurrence of a new CDC stage C event (ADI) as defined by the CDC revised classification of 1993 . Only ADCD4 cell counts were obtained using the FACSCount System . Plasma viral loads were obtained using either Amplicor HIV-1 1.5 or 2.0 assay  or Bayer bDNA HIV-1 Quantiplex assay 2.0 or 3.0 . All the tests were carried out at Dakar, Senegal.The ADI incidence rate was estimated for each of seven successive periods (year 1 to 6 and rest of follow-up). That rate was defined as the number of new ADIs divided by the number of person-years (PYs) at risk; i.e., the time accrued from the beginning of the period at risk till the end of that period or till censoring. When an ADI occurred, the patient was considered still at risk for occurrence of other ADIs of other types; ADIs of the same type were excluded.3, 200 to 350 cells/mm3, and more than 350 cells/mm3). Then the number of PYs was counted starting from the date of a CD4 cell count till the first event of the following: next CD4 cell count, new ADI, death, or end of follow-up.Incidence rates were also computed for three CD4 cell count categories  that take into account the correlation between multiple events within each individual . All modThe analyses were carried out as follows:In a first step, only demographic variables  and variables measured at baseline  were included in the analysis. In a second step, the association between the incidence rate of ADI and the current values of the biological markers  was assessed. Viral load was considered as a binary covariate using the threshold 1,000 copies/mL. Lastly, covariates that summarize various aspects of the CD4 and virological response over each period were also included in the analysis. More specifically, the achievement of a viral load below 1,000 cp/mL before 12 months for the first period, the achievement of a viral load below 1,000 cp/mL at 42 months for the second period, the duration of follow-up with a viral load below 1,000 cp/mL and the duration with a viral load above 1,000 cp/mL were considered as summary variables for the virological response. The two latter variables were time-dependent. The changes in CD4 cell count over time were modelled independently of the model for ADIs using random-effects regression of CD4 with time . In suchOur analysis focused on the occurrence of ADIs during HAART; thus, the patients were right censored at death. However, death could not be regarded as independent of the occurrence of ADIs because this could lead to biased results . This deThe statistical analyses were done with the open access software R .At HAART initiation, more than half of the patients (55%) had already experienced an ADI. Almost all patients (95%) were antiretroviral-naive, 78% were receiving cotrimoxazole chemoprophylaxis and 169 (44%) started with a PI-containing regimen. The other characteristics of the patients are summarized in Table 3  at baseline to 286 cells/mm3  at 12 months and to 462 cells/mm3  at 72 months.The median CD4 cell count increased from 128 cells/mmAt the end of April 2008, 157 first ADIs were reported. Because of concomitant events, the final number of ADIs considered in the analyses was 155 , tuberculosis (33 cases), recurrent herpetic ulcerations 27 cases) and visceral candidiasis (19 cases)  over the first year to 4.3 ADIs per 100 PYs  over the fourth year, which corresponds to an estimated relative decrease in the incidence rate of 5% per month  .3, the incidence rate of ADIs decreased from 22.0 per 100 PYs  over the first year to 5.7 per 100 PYs  over the fourth year, but increased thereafter to nearly 18 per 100 PYs . In patients with 200 to 350 CD4 cells/mm3, the incidence rate of ADIs decreased from 14.8 events per 100 PYs  to 6.7 events per 100 PYs  over the fourth year, then levelled off. Lastly, in patients with more than 350 CD4 cells/mm3, a steady decrease in the incidence rate of ADIs from 18.3 events per 100 PYs  to 1.3 events per 100 PYs  was observed.The incidence rate of ADIs by current-CD4-cell-count stratum is displayed in Figure During the first period after HAART initiation, the total follow-up accrued to 1,149 PYs and 122 ADIs were observed. The ADI incidence rate was estimated to be as high as 27.4 events per 100 PY at HAART initiation  then decreased linearly by 5% per month .In the multivariate analysis, considering only the baseline covariates, the initial incidence rate was twice as high in patients with CDC-C at baseline than in patients with a clinical stage CDC-A or -B . However, the changes in the ADI incidence rate were negatively associated with the baseline clinical stage .When time dependent variables were introduced in the analysis together with the clinical stage at baseline, the change in the ADI incidence was associated with the duration with a viral load below 1,000 cp/mL . Note here that the rate of decrease in ADI incidence was homogeneous across CD4 strata (p = 0.1).Only 293 patients were followed-up beyond 42 months and therefore included in this analysis. Their follow-up accrued to 932 PYs and 33 new ADIs occurred during this period.At 42 months, 165 (56%) patients had a viral load below 1,000 cp/mL and the median time with viral load persistently below 1000 cp/mL was 12 months .3/month, 95% CI = ) with a large variability in the CD4 slope. Among the 21 patients whose CD4 cell counts decreased below 200 cells/mm3, 16 (75%) had a viral load persistently above 1,000 cp/mL.A linear increase in the CD4 cell count over time was observed  and with a current viral load below 1,000 cp/mL . No significant interaction between these two variables was observed. Of note, the substitution of variable "current viral load" by variable "duration with a viral load below 1,000 cp/mL" led to an equivalent model.In the univariate analysis, the incidence rate of new ADI was associated with the achievement of a viral load below 1,000 cp/mL at the start of the period, the current viral load, the duration with a viral load below 1,000 cp/mL, the current CD4 cell count, and the individual variability in the CD4 slope Table . In the Accurate information on morbidity after HAART initiation in low-resource settings is still needed to improve treatment and monitoring guidelines. The present study presents the incidence of new ADIs in such a setting and the main predictors of ADI occurrence: CD4 cell count and viral load.The ADI incidence rates observed in the Senegalese cohort were consistent with those seen in other low-resource settings ,39 but hA decrease in the ADI incidence rate over the first years after HAART initiation has been observed in other low-resources settings ,10,19,413 and a VL persistently above 1,000 cp/mL. Moreover, after four years on HAART, that decrease persisted only in patients with more than 350 CD4 cells/mm3. These results indicate that the association between the CD4 cell count and the occurrence of ADIs changes with time  and that the CD4 cell count presents an increased predictive value after 4 years on HAART. It should be noted that, during the second period, the current CD4 value was a stronger predictor of ADI than the individual variation in the CD4 slope.Despite the decrease in the ADI incidence rate during the first four years on HAART, an overall increase was observed afterwards, which was mainly due to the high incidence rate of ADIs in patients with less than 200 CD4 cells/mmThe effect of the virological response on the occurrence of new ADIs could be separated into a direct effect independent of the CD4 response and an indirect effect mediated by the effect of the virological response on the CD4 response. This may explain the two-fold decrease in the rate ratio associated with the current viral load between the univariate  and the multivariate  model.The role of the viral load in monitoring AIDS patients after HAART initiation in low-resource settings is still not sufficiently clear or recognized -24. One The present study has several strengths and limitations. Despite its limited size, the study cohort boasts a long follow-up period and few lost to follow-ups. Regular visits with clinical examination allowed frequent information on new ADI occurrence. However, it must be noted that, in our setting, the diagnostic procedures were more limited than in industrialized settings. It is therefore likely that the incidence of some ADIs, such as pneumocystosis, that require advanced diagnostic procedures, could have been underestimated and some misclassification bias introduced. However, those diagnostic procedures did not change over time, protecting from a differential misclassification with time.Another limitation could have been the lack of information on cause-specific mortality. However, the outcome of this study was restricted to the occurrence of ADIs. The dependence between mortality and morbidity could have biased the estimations of the rate ratios but this was taken into account by weighting the models with the inverse probability of surviving.3. During the first four years after HAART initiation, the baseline clinical stage and the current viral load (but not the CD4 cell count) were found to be strong predictors of ADI occurrence. Therefore, as time on HAART extends, regular CD4 cell counts and viral load measurements should find an increasing importance in the monitoring of patients living with AIDS.In this cohort, the incidence rate of ADIs decreased uniformly during the first four years on HAART but increased later, mostly in patients with virological failure and a CD4 cell count of less than 200 cells/mmADIs: AIDS-defining illnesses; BMI: Body Mass Index; HAART: Highly Active Anti Retroviral Therapy; IQR: Interquartile Range; ISAARV: Initiative Sénégalaise d'Accès aux médicaments Antirétroviraux; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor.The authors declare that they have no competing interests.PDB participated to the statistical analysis, interpretation of the results and drafted the manuscript. JFE participated to the data analysis, interpretation of the results and revised critically the article. AD, IN, NG and NK participated to the acquisition of data and revised of the article. PS participated to the conception and design of the study and revised the article. RE participated to the data analysis and revised the article. ED participated to the conception and design of the study and revised critically the article. All the authors have read and approved the version of the article to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/179/prepub


The HCV council 2011 convened 11 leading clinicians and researchers in hepatitis C virus from academic medical centers in the United States to provide a forum for the practical and comprehensive evaluation of current data regarding best practices for integrating new direct-acting antiviral agents into existing treatment paradigms. The council investigated 10 clinical practice statements related to HCV treatment that reflect key topical areas. Faculty members reviewed and discussed the data related to each statement, and voted on the nature of the evidence and their level of support for each statement. In this new era of DAAs, a comprehensive and critical analysis of the literature is needed to equip clinicians with the knowledge necessary to design, monitor, and modify treatment regimens in order to optimize patient outcomes. The 2011 approval of two HCV protease inhibitors, boceprevir and telaprevir, by the U.S. Food and Drug Administration (FDA) represents the most important advances in management of chronic HCV in nearly a decade. These protease inhibitors combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve the rate of sustained viral response (SVR) for all populations evaluated. Although the FDA has provided clear guidance in the labeling requirements for these agents, and new treatment guidelines have been developed . , 8. 7, 810 HCV RNA response after 4 weeks of lead-in demonstrated a 34% SVR compared to 0% in the SOC group with a <1log10 response after 4 weeks.In both trials, previous relapse patients fared exceedingly well with SVR rates ranging from 69% to 88% , 8. In mThe amount of baseline fibrosis was particularly detrimental in the prior null responders. The SVR rate in prior null responders with previously documented cirrhosis was 14% in the pooled telaprevir arms versus 10% in the SOC arm. This is the area of major concern in both prior null responders and patients with cirrhosis—the response rates are not particularly good. Patients with lesser degrees of fibrosis actually did fairly well. This was seen in both prior relapsers, where the response rates were robust across all histologic groups (86% to 84%), and in prior partial responders, who demonstrated a 72% SVR with minimal fibrosis and 56% with bridging fibrosis. However, the SVR rates did drop to 34% in patients with cirrhosis. Relatively few patients with cirrhosis and even fewer with cirrhosis and prior null response were included; thus, there are large confidence intervals around these data.In summary, the panel felt that the data clearly supported the use of triple therapy in treatment-experienced patients when compared to SOC. There are, however, some subgroups of patients with suboptimal response rates, including prior null responders and those with cirrhosis, yet these groups still performed substantially better on triple therapy than with SOC. Since the majority of prior nonresponders and all cirrhotics will require full 48 weeks of therapy, careful consideration to risk : benefit, cost, and future therapeutic options is recommended. Treatment-naïve patients treated with PI/PEG-IFN/RBV regimens.Treatment-experienced patients treated with PI/PEG-IFN/RBV regimens.Response-guided therapy should be utilized in all: The attainment of superior rates of rapid virologic response (RVR) and SVR with the addition of PIs to PEG-IFN/RBV has been accompanied by the capacity to shorten the total duration of therapy in many patients, thereby sparing them unnecessarily protracted exposure to these medications and their side effects. The concept of truncating the duration of therapy in patients who meet criteria for rapid response is known as response-guided therapy (RGT), which was tested extensively in the phase 3 development programs of the PIs. This statement was designed to assess whether RGT is appropriate for the treatment of all patients with HCV. The use of RGT was evaluated for both treatment-naïve  and treaThe results of the phase 3 trials of telaprevir and boceprevir have established a firm foundation for RGT in most treatment-naïve, genotype 1 infected patients . In the In SPRINT-2, the pivotal phase 3 study of boceprevir in treatment-naïve patients, there were 2 arms containing active boceprevir dosing . This reThe phase 3 trial of telaprevir in treatment-experienced patients (the REALIZE study) did not evaluate RGT; patients in all categories were treated with telaprevir + PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV for 48 weeks total , 11. In 10 reduction in HCV RNA at treatment week 12) [The RESPOND-2 study of boceprevir in treatment-experienced patients prospectively included relapsers and partial responders  . If HCV week 12) . 10 HCV RNA reduction after 4 weeks of the PEG-IFN/RBV lead-in, these patients are included among those eligible for boceprevir-based therapy in the product label, but with the stipulation that they receive 48 weeks of treatment including 44 weeks of boceprevir + PEG-IFN/RBV [Prior null responders were not included prospectively in the RESPOND-2 study. Based on the SVR rates in patients with <1log-IFN/RBV . This re-IFN/RBV .Based on these considerations, HCV Council panel members felt that RGT can be recommended for noncirrhotic, treatment-naïve patients who receive PIs, but that 48 weeks of total therapy should be strongly considered in cirrhotics, even if early response has occurred. Although black patients are included among those eligible for RGT, clinicians may choose to extend the duration of therapy on an individualized basis in patients within this group, at least until we have more data on this patient population.For treatment-experienced patients, the panel considered RGT to be appropriate in prior relapsers, though some panelists indicated they might choose to extend therapy in cirrhotics who have relapsed previously. Although RGT is approved for prior partial responders who receive boceprevir, some clinicians may choose to complete a 48-week course of therapy with a PEG-IFN/RBV “tail” if the patient is tolerating treatment well. In prior null responders, no panelist felt that RGT was appropriate at this time. No recommendations about RGT can be made for patient populations in which PI-based therapy currently is unapproved, including HIV-coinfected patients, patients with more advanced cirrhosis, and those who are posttransplant. Results of further studies in these patient populations are pending.IL28B genotype, especially for genotype 1 HCV infection. IL28B genotype also correlates to a patient's response to PI + PEG-IFN/RBV, and this information may be useful to anticipate treatment duration and success. This statement investigates the usefulness of IL28B genotyping in the era of treatment with PIs.Several studies have demonstrated that a patient's likelihood of responding to PEG-IFN/RBV differs according to IL28B genotyping in patients on triple therapy comes from one published randomized controlled trial and multiple look-back investigations of randomized, placebo-controlled trials. The likelihood that PEG-IFN/RBV treatment of HCV infection will result in an RVR or SVR depends on nucleotide sequences near IL28B [IL28B genotype also predicts SVR with PI-based triple therapy [IL28B testing may be considered for its contribution to pretreatment decision-making.Evidence for ar IL28B . Althougar IL28B . Among A therapy –17. Amon therapy . In patiIL28B genotype also is predictive of treatment duration and the likelihood of receiving only 24–28 weeks of therapy for naïve patients. In Caucasian treatment-naïve patients randomized to telaprevir, eRVR was achieved in 64%–78%, 51%–57%, and 45%–50% of patients with CC, CT, and TT genotypes, respectively [In RGT algorithms, ectively . In the ectively . IL28B genotype is a strong predictor of response to PEG-IFN/RBV therapy, and also may provide important response information for patients and providers to make informed decisions regarding use of HCV PIs. Naïve patients with CC genotype may be more likely to initiate therapy knowing that there is a high likelihood of only needing 6 months of therapy. In the treatment-experienced patient, IL28B genotype may be most useful in patients whose prior therapy is not well-characterized. IL28B testing. The biologic basis of this striking association is unknown. In addition, the cost effectiveness of using IL28B testing to withhold HCV PI therapy from persons with favorable genotypes  also is unknown. Moreover, it is not clear to what degree IL28B genotype test results predict response to HCV PI + PEG-IFN/RBV therapy for particular subsets of patients, such as African Americans, HIV-coinfected or posttransplant patients, and those with cirrhosis. Likewise, although further investigation is needed, there may be significantly less predictive value of IL28B testing as more potent HCV regimens emerge, as has been recently suggested by Aerssens and colleagues in the PILLAR trial [However, there are a number of unanswered questions regarding AR trial . The basis of this statement is that prior null responders may have inadequate virologic response to retreatment with PI-based therapy rendering treatment futile, exposing patients to unnecessary risks, and favoring viral resistance. Patients with minimal disease are clinically stable, lack immediate need for treatment, and could benefit from waiting for future, more effective antiviral therapies. 10 drop in HCV RNA by week 4 and <2log10 drop by week 12 during prior treatment with PEG-IFN/RBV. Null responders have been included and evaluated in the telaprevir trials as those with a <2log10 drop by week 12. Poor response, a surrogate for null response, was defined retrospectively by the investigators in the boceprevir trials as those patients who achieved <1log10 drop in HCV RNA by week 4 of a lead-in treatment with PEG-IFN/RBV.Historically, null responders experience <1log10 drop in HCV RNA during lead-in had an SVR rate of 54% (15/28) compared to an SVR of only 15% (6/41) in patients with <1log10 drop in HCV RNA [The design of the REALIZE phase 3 trial utilized 48 weeks of PEG-IFN/RBV for all subjects, which included 144 null responders [ HCV RNA . The rel HCV RNA . Rates o10 decline in HCV RNA, and were classified as “poor responders” to IFN. Rates of SVR in these poor responders were 0%, 33%, and 34% for SOC, RGT, and boceprevir 44 groups, respectively. This “poor responder” lead-in group has been proposed as a potential surrogate for a null population, but as pointed out previously, the lead-in response may not be indicative of a prior null response [In the Phase 3 RESPOND-2 trial, 259 relapsers, 144 partial responders, but no null responders were enrolled , 20. Allresponse .Overall, the likelihood of SVR when null or poor responders to PEG-IFN/RBV are retreated with PI-based triple therapy is 29% to 41%. Although, these rates of SVR are lower than those achievable in treatment-naïve patients (SVR~75%) or relapsers (SVR~80%), the 41% SVR of null responders with METAVIR F0-F2 is similar to the SVR rates that justified widespread use of PEG-IFN/RBV in the treatment of naïve patients with genotype 1 HCV.10 IU/mL (−5.2 to −4.5) [The dilemma for null responders with minimal liver disease is whether to initiate PI-based triple therapy now, or wait for new therapies to emerge. In the INFORM-1 study, 8 null responders (7 infected with HCV genotype 1a) were treated for 13 days with an inhibitor of HCV polymerase  plus an inhibitor of HCV NS3/4A protease (danoprevir), and achieved median HCV RNA decline of −4.9logto −4.5) . Four ofto −4.5) . In the to −4.5) . AdditioMinimal liver disease is characterized by lack of clinical manifestations; normal values for bilirubin, INR, and albumin; normal or only slightly elevated ALT; a METAVIR fibrosis score of F0-F2. In a study of 66 patients with chronic HCV infection who had normal ALT and a mean METAVIR fibrosis score of 0.9 ± 0.8, fibrosis progression was estimated at 0.07 ± 0.07 stage/yr . Given tconsideration of PI-based therapy for null responders with minimal liver disease.An SVR of 41% is sufficient for recommending treatment with triple therapy in prior PEG-IFN/RBV null responders, even those with minimal disease. The alternative to treatment now is to await future, more effective therapies, but these may be years away, and there is no guarantee that minimal liver disease will not progress during that time. Because of this and the ability to utilize early viral stop rules in those patients not responding to triple therapy, the panel recommended While used in combination with PEG-IFN/RBV, PIs demonstrate high rates of SVR. However, treatment failures frequently result in the selection of a population of HCV variants that harbor unique mutations in their genome, which renders the variant less susceptible to the specific agent. Interestingly, prior to treatment with PIs, variants that carry potential resistance mutations can be detected in baseline samples of 5% to 7% of persons; however, the presence of detectable variants has not been strongly linked to treatment failure with combination therapy of a PI + PEG-IFN/RBV . FurtherThe HCV genome is a 10,000-nucleotide positive-strand RNA that encodes for a large polyprotein with structural and functional components. The functional component includes a unique RNA-dependent RNA polymerase that the virus uses to replicate its positive-strand RNA through a negative-strand intermediate and back to multiple copies of the genomic RNA, which then can be packaged into new virions. This polymerase is highly error prone, resulting in the wrong nucleotide being inserted into replicating strands of the HCV genome. It is estimated that 1 error is made for every 10,000 nucleotides. In other words, every strand of new HCV RNA contains at least 1 replaced nucleotide, which may result in a change of the amino acid structure of the protein generated from that strand. This process, coupled with a very high rate of virus production (up to 12 trillion virions/day), ensures that every day the virus randomly creates every possible combination of nucleotide variability . This meSince the PIs and other DAAs are highly targeted molecules designed to fit into the catalytic site of the viral coded functional enzymes, they act to perturb the viral population, leading to a survival advantage to naturally occurring variants that have mutations coding for minor changes in the amino acid, which renders the functional protein more or less able to bind a targeted drug at a specific site . VariantThe amino-acid changes conferring resistance to telaprevir and boceprevir are similar, with the identification of substitutions at positions V36M/A/L, T54A/S, R155K, and A156S/T conferring reduced susceptibility to the DAA ; howeverIn the SPRINT-2 and RESPOND-2 trials, the majority of subjects who did not achieve SVR had one or more specific treatment-emergent NS3-amino-acid substitutions. Detection of these substitutions was most common in subjects with virologic breakthrough or incomplete viral suppression, but it also was detected in persons with on-treatment suppression followed by relapse after discontinuation of therapy . InteresCommercial viral resistance testing has the ability to pick highly targeted sites and report on the nature of the amino acid present at that site. In July 2011, the first commercial PI drug resistance assay was made available in some countries . This asFollowing unsuccessful treatment with a PI-based regimen, virtually all patients have resistance mutations that slowly become undetectable over time, presumably returning to the low prevalence they had at baseline. Since the majority of patients who fail therapy will have detectable variants early after stopping the PI, there is little reason to test for them early after treatment, because they are always present and not informative. For later resistance testing, one must determine if knowing about the presence of these resistant variants at >10% of the total population would preclude treatment with different regimens that might contain a drug in the same class. Presently, there are no data that address this issue in patients with HCV. However, the presence of such variants may be overcome by several strategies. First, the use of the PI at concentrations above the new higher inhibitory concentration may suppress the virus. Second, the use of nonspecific  or other classes of agents  that suppress the virus by a a different mechanism may lower the resistant virus polulation level. Finally, the use of a more potent agent  also has the potential to overcome resistance. As an example of this, prior resistance in HBV due to lamivudine exposure could be overcome by other nucleoside and nucleotide analog polymerase inhibitors . Thus, key data likely will be derived from future studies of re-treatment of patients previously exposed to PIs, either by use of drugs in other classes, other drugs in the same class, or inclusion of drugs used in a failed regimen within a broader therapeutic treatment approach. However, at this time, other anti-HCV drug options are not available, which renders information obtained through resistance testing difficult to utilize, as the presence or absence of detectable variants is not likely to alter current management. Thus, it was agreed by those on the Council that viral resistance testing has no clinical utility in the current management of HCV patients receiving a PI + PEG-IFN/RBV. Two strategies have been approved for the treatment of chronic HCV with PIs in combination with PEG-IFN/RBV: (1) delayed initiation of boceprevir following 4 weeks of treatment with PEG-IFN/RBV (lead-in) and (2) simultaneous initiation of telaprevir with PEG-IFN/RBV. The rationale for the lead-in strategy was based on the hypothesis that lead-in could reduce emergence of drug-resistant mutations by decreasing viral load and allowing PEG-IFN and RBV to reach steady-state pharmacokinetics before adding the PI . AlthougP = 0.057)). Lead-in also allowed the authors to examine PEG-IFN/RBV responsiveness and SVR, which shaped the design of the subsequent boceprevir trials. Those participants experiencing <1.5log10 reduction in viral load during lead-in achieved SVR less frequently and may benefit from longer duration of therapy, as higher SVR rates were seen when participants received boceprevir + PEG-IFN/RBV for 44 weeks (79%–100% compared to 44%–65% with 24 weeks) [Two randomized placebo controlled trials evaluated the role of lead-in and its implications toward prevention of PI resistance-associated variants (RAVs). SPRINT-1, a phase 2 trial, included a 24- and 48-week regimen of therapy both with and without lead-in. The lead-in groups were associated with a modestly lower rate of breakthrough than were the groups with no lead-in (4% compared with 9% (4 weeks) .10 IU/mL decline in viral load at the conclusion of lead-in) experienced SVR less frequently with triple therapy (29%–39% compared to 82% in nonblack cohorts) [10 decline at treatment week 12) were excluded [10 decline in viral load compared to 33%–34%). This was even stronger than historical response to therapy [10 viral load decrease with lead-in) [REALIZE, a phase 3, double-blind, placebo-controlled trial, also evaluated the role of a 4-week PEG-IFN/RBV lead-in prior to the addition of telaprevir in a population of treatment-experienced patients. Lead-in did not have a significant impact on SVR rates (36% without versus 34% with lead-in failed to achieve SVR), virologic failure (20% compared to 17% with lead-in), or relapse rates (10% in both arms) , 20. GivTwo double-blind, randomized, phase 2 trials involving either treatment-naïve patients (SILEN-C1) or patients with prior nonresponse to PEG-IFN/RBV (SILEN-C2) investigated a 3-day PEG-IFN/RBV lead-in prior to the addition of BI201335, a potent HCV NS3/4A protease inhibitor. Surprisingly, both studies found that the 3-day lead-in was associated with decreased viral response .10 reduction in HCV, this reinforces that the patient has IFN responsiveness, which predicts a high probability of SVR. Further, a minority of patients who achieve undetectable HCV RNA at the end of lead-in (RVR) have a high probability of achieving SVR with PEG-IFN/RBV alone. Some experts suggest that persons with an RVR may opt to avoid the addition of a DAA altogether and be treated with PEG-IFN/RBV; however, others argue that patients with an RVR after lead-in qualify for shortened therapy and would benefit from the addition of the DAA by limiting the overall duration of therapy and minimizing viral relapse. Although lead-in was conceptualized to decrease the emergence of RAVs, the data to support this hypothesis are limited. However, the data support that there is a potential use for lead-in to provide valuable information regarding current interferon responsiveness. First, as shown in the above studies, lead-in strongly predicts rates of SVR. In persons who achieve >1log10 decline after 4 weeks of PEG-IFN/RBV) still attained SVR 25%–39% of the time compared to ~5% in the control group. Thus, restricting DAA access to only those patients who are IFN responsive  would deny approximately one-third of patients the potential of obtaining an SVR. As such, lead-in data have limited utility in determining which patients should be treated with PIs. Although lead-in identifies a group with increased risk for resistance, it does so with limited accuracy to predict treatment failure. These data have not been utilized to modulate therapy, and thus one could argue that the lead-in is not necessary. The outcome from lead-in also helps identify those at higher risk for treatment failure and the emergence of resistance. However, the reciprocal relationship  is not accurate enough to discontinue HCV therapy prior to the introduction of a DAA. The design of the RESPOND-2 study included stopping therapy in all patients who still had replicating virus at treatment week 12 , while SHowever, there may be populations in which the risk of resistance is high, and the expected outcome even with triple therapy is low. In the REALIZE study, subjects with prior null response frequently (59%) experienced minimal viral decline with PEG-IFN/RBV lead-in and achieved SVR only 15% of the time . This maLead-in also offers insight into the patient's ability to tolerate and adhere to therapy. This helps identify subjects who are unable to comply with the increased complexity or side effect profile of a DAA. In other words, if the patient is unable to adhere to and/or tolerate 4 weeks of PEG-IFN/RBV, the likelihood of success with the addition of a PI can be expected to be vanishingly low. Additionally, the risk for PEG-IFN and RBV-induced anemia also can be predicted by hemoglobin (Hgb) decline at treatment week 2 . This inGiven the current information available, council members concluded that lead-in with PEG-IFN/RBV has limited impact on patient management and thus it should not influence the decision to initiate a PI, since both good and poor responders to PEG-IFN/RBV lead-in can benefit from the addition of the PI. However, the council also recognized that some clinicians may utilize lead-in as a measure of interferon responsiveness in some specific patient groups  to aid in the decision to start or withhold the PI and save the potential adverse events and cost associated with this therapy. Telaprevir-associated rash was commonly observed in clinical trials, necessitating drug discontinuation in some patients , 39, 40.In the pivotal registration trials of telaprevir, rash/pruritus was reported in 56% of subjects taking telaprevir compared to 34% of those taking only PEG-IFN/RBV , 40, 43.In the clinical trials, a rash-management plan was utilized, which guided the clinical management of telaprevir-associated rash. This plan has been largely incorporated into the FDA-approved prescribing information for telaprevir, with specific strategies recommended based on the severity of the rash . PatientIn the pivotal registration trials of boceprevir, boceprevir-related rash was reported, but these events were uncommon and not clinically severe , 31, 44.IL28B genotypes (CT or TT) [To date, anticonvulsants are the most frequent causative agent for DRESS , but the potential for serious cutaneous AEs may be higher for telaprevir than for previous FDA-approved drugs. However, patients and clinicians are reluctant to stop telaprevir because of its potent antiviral activity and evidence from the ADVANCE trial that indicates that 12 weeks of telaprevir therapy may lead to higher SVR rates than 8 weeks, particularly among patients with unfavorable T or TT) . InteresT or TT) . NeverthT or TT) . In the Prospective studies are needed to demonstrate the safety and efficacy of switching HCV PI drugs during the course of antiviral therapy. Nonetheless, an early (<4 weeks), severe telaprevir rash that necessitates drug discontinuation before the attainment of HCV RNA negativity could jeopardize the likelihood of SVR. Although some of the HCV Council members justified recommending such a switch under extenuating circumstances, the majority indicated that the evidence to support the practice of implementing a switch from telaprevir to boceprevir in patients who stop telaprevir for severe rash does not yet exist. Due to suppression of hematopoiesis due to PEG-IFN and hemolysis due to RBV, anemia occurs frequently in patients undergoing HCV treatment and often leads to symptoms , RBV dose reduction, and/or treatment discontinuation –48. In sDue to differences in the duration of exposure to the HCV PIs , and the use of ESAs during clinical trials with boceprevir but not telaprevir, the management of anemia during HCV treatment is controversial. However, for both HCV PI regimens, there is concern that RBV dose reduction may compromise the antiviral efficacy of the regimen, leading to decreased likelihood of SVR. In addition, considerable uncertainty exists regarding the role of adjuvant ESAs, since the regulatory authorities have issued several advisories on potential AEs related to ESAs, including thrombovascular events and pure red blood cell aplasia –53. ThisP < 0.001). In addition, patients treated with ESAs had an increase in Hgb level and improved symptoms. Several U. S. studies suggest that ESAs have been used in ~15% of patients treated with PEG-IFN/RBV. Since the initial FDA approval of RBV for the treatment of HCV infection in 1998, RBV dose reduction has been recommended in patients with incident anemia, defined as Hgb < 10 g/dL. Subsequently, Hadziyannis and colleagues  found thHowever, the 2009 American Association of the Study of Liver Diseases (AASLD) guidelines state that there are insufficient data to recommend the routine use of ESAs as a means to avoid or ameliorate RBV dose reductions in clinical practice . This poIn the pivotal studies of telaprevir in combination with PEG-IFN/RBV, telaprevir led to an additional decline in Hgb level by 1.0 to 1.5 g/dL compared to PEG-IFN/RBV alone, a trend which appeared to reverse after discontinuation of telaprevir . The incSimilarly, in the pivotal registration trials for boceprevir, anemia (defined as Hgb < 10 g/dL) also was more common in patients treated with boceprevir + PEG-IFN/RBV (52%) compared to the control group (32%) . In addiThe relationships between SVR, RBV dose reduction, and anemia has been evaluated retrospectively in both treatment-naïve and treatment-experienced patients. Focusing on the treatment-naïve study (SPRINT-2), the SVR rate was higher (68%–78%) among patients who developed anemia compared to those who did not develop anemia (58%) . While mDespite confounding of data by the high rate of ESA use, these data suggest that RBV dose reduction was not associated with decreased SVR rates in patients treated with boceprevir + PEG-IFN/RBV. Accordingly, the FDA-approved prescribing information for boceprevir recommends that anemia be managed with standard RBV dose-reduction strategies and, if this approach is not adequate, RBV discontinuation should be considered . The preAnemia develops in approximately half of patients treated with HCV PI-based therapy, representing a significant challenge to the management of these patients. The issue at the center of the discussion is the debate surrounding the impact of RBV dose reduction on SVR. Data from 3023 patients treated in the IDEAL study failed to confirm a negative effect of RBV dose reduction on SVR with PEG-IFN/RBV; indeed, anemic subjects were more likely to achieve SVR than those who did not develop anemia, including those patients who reduced their RBV dose from 1000 or 1200 mg/day to 600 mg/day in one step . This seOn the other hand, the role of ESAs for the management of anemia during HCV treatment is controversial. In earlier randomized controlled trials, ESAs were associated with maintenance of RBV dose, increased Hgb, and improved quality of life in anemic patients treated with PEG-IFN/RBV. In addition, in the retrospective analysis of the IDEAL study, patients who rapidly developed anemia (within 8 weeks of starting PEG-IFN/RBV) achieved higher SVR rates if they received ESAs . This efHowever, the use of ESA also must be tempered by higher costs and the potential for additional AEs. In other patient populations, ESAs have been linked to increased risk of serious cardiovascular events, tumor progression, thrombosis, and death. Additionally, pure red blood cell aplasia due to neutralizing antibodies to native EPO has been reported during HCV treatment. The studies of ESAs during HCV treatment  are difficult to interpret from a safety perspective, as patients were not randomized, and ESA use was open-label. Of note, a randomized controlled trial of the management of anemia with RBV dose reduction alone or with RBV dose reduction plus ESAs is underway, and may shed additional light on the role of ESAs in this setting . Nonethepatients with HCV-HIV coinfectionHCV-transplant populations.PI/PEG-IFN/RBV combinations are first-line therapy in:HCV-infected persons who are coinfected with HIV or who have undergone liver transplantation have a greater risk of liver-related complications due to more rapidly progressive HCV disease and have lower SVR rates following treatment than chronic HCV patients without these conditions –64. NoneOverall, the data to support the use of telaprevir and/or boceprevir in persons who are coinfected with HIV or have undergone liver transplantation are sparse. Key to effective treatment of patients with these conditions is DDI information. Limited DDI studies have been performed with more than 20 antiretroviral drugs as well as with the immunosuppressive agents cyclosporine, tacrolimus, and sirolimus. In terms of efficacy, there are small, phase 2, randomized studies of the HCV PIs in HIV coinfected patients, with only early virologic response data presented publically for one of these agents . No studFurther, there are limited data on the safety and efficacy of telaprevir and boceprevir in cirrhotic patients. The proportion of cirrhotics included in the pivotal registration trials of the PIs was low  and only compensated cirrhotics without severe portal hypertension complications were included. In accordance with recommendations from the Department of Health and Human Services panel, most HIV-infected patients are receiving combination antiretroviral therapy with regimens that incorporate 6 mechanistic classes of drugs and may include pharmacologic boosting with the potent inhibitor of CYP3A, ritonavir . Both teThere are limited studies that assess interactions of the HCV PIs with antiretroviral agents. In healthy volunteer studies, when coadministered, boceprevir increased the concentrations of the NNRTI, efavirenz (an inducer of CYP3A), and the concentration of boceprevir was reduced. Similar interactions were observed with HIV PI, ritonavir, an inhibitor of CYP3A4 . While iMore extensive studies have been presented with telaprevir and antiretroviral agents. In studies of healthy volunteers, telaprevir was combined with the ritonavir-based HIV PIs, atazanavir, darunavir, fosamprenavir, and lopinavir . The resCmax and 430% increase in AUC when boceprevir was coadministered with midazolam [Similar to the situation with antiretroviral agents in HCV-HIVcoinfected patients, HCV-infected transplant recipients must receive immunosuppressive agents. Calcineurin inhibitors (CNIs) and the drug sirolimus are metabolized by CYP34A, and drug interactions with both telaprevir and boceprevir are expected. DDI studies have been conducted with telaprevir and cyclosporine as well as tacrolimus . In a phidazolam , 69. Then = 24) or ritonavir-boosted atazanavir (n = 22) or no antiretroviral therapy (n = 13) [n = 64) to 48 weeks of PEG-IFN/RBV plus placebo (n = 34) [There is a preliminary report from a phase 2a study of 59 HCV-HIVcoinfected patients on antiretroviral therapy with tenofovir/emtricitabine or lamivudine with either efavirenz ((n = 13) . Patient(n = 13) . The pha(n = 34) . To dateThere are data on the treatment of HCV-infected patients with compensated cirrhosis with telaprevir and boceprevir in combination with PEG-IFN/RBV, and these regimens have been approved by the FDA for the treatment of such patients , 6. AmonCmax of the active diastereomer of boceprevir were significantly higher in patients with moderate (Child-Pugh-Turcott (CPT) score of 7–9), and severe (CPT score of 10–12) hepatic impairment relative to subjects with normal hepatic function (32% for moderate and 45% for severe) [Due to safety concerns, treatment of patients with decompensated cirrhosis with PEG-IFN/RBV is relatively contraindicated. Limited efficacy has been observed in the context of carefully conducted studies with, in some cases, gradual dose escalation of PEG-IFN/RBV, known as the LADR protocol (low accelerating dosage regimen). The prospect of the addition of boceprevir and/or telaprevir raises additional safety concerns as well as the potential for altered pharmacokinetics of these agents in the setting of hepatic impairment. After a single-dose of boceprevir in non-HCV infected subjects with decompensated cirrhosis, the mean AUC and  severe) . No dosa severe) .For telaprevir, the steady-state exposure in HCV-negative subjects with mild  and moderate hepatic impairment (CPT class B) was reduced by 15% and 46% compared to healthy subjects [There are no data on the use of telaprevir or boceprevir in combination with PEG-IFN/RBV in this population. Studies will need to be conducted to evaluate the safety and efficacy of both PIs in patients after liver transplant.Although the data are limited and incomplete, telaprevir or boceprevir may be recommended for use in combination with PEG-IFN/RBV for the treatment of chronic HCV infection in carefully selected HIV-infected patients not on antiretroviral therapies or on antiretroviral therapy regimens that are compatible with telaprevir or boceprevir . RecogniIn compensated cirrhotics, SVR rates with PI-based therapy are superior to those with PEG-IFN/RBV alone. Although the small number of patients studied to date limits accurate estimates of safety, tolerability, and efficacy, HCV PI-based therapy is the first-line therapy for this group. In contrast, HCV PIs plus PEG-IFN/RBV therapy are not approved or recommended for use in patients with decompensated cirrhosis. The risk of using PEG-IFN/RBV in this latter group is well established, and this therapy is generally restricted to use in select transplant centers. The addition of an HCV PI to PEG-IFN/RBV is associated with additional toxicity ; the potential for drug resistance in the setting of impending transplantation; and the expectation of low SVR rates. Of note, the use of lead-in therapy with PEG-IFN/RBV, regardless of the HCV PI used, may serve as a useful means of assessing the likelihood of response and establishing tolerability of PEG-IFN/RBV before exposing the patient to the PI (and its associated resistance). Additionally, clinicians need to be aware of the lack of information on telaprevir dosing in Child's B/C cirrhotics. The Council members did not support the routine first-line use of PIs in this patient population; however, this population is clearly of the highest medical need and consideration of treatment in a research setting was supported. The risk oftelaprevir interactions and boceprevir interactions  with CNIs and presumably sirolimus necessitates extreme caution in the use of these drugs in combination. Available data suggest a lesser effect of telaprevir on cyclosporine levels than on tacrolimus levels, so this may be a preferred CNI for patients undergoing PI triple therapy. Close monitoring of CNI levels is essential with the addition of a PI  and removal of a PI . The risks and benefits of undertaking treatment should be carefully considered pending additional data on the optimal dosing of PIs and immunosuppressive drugs. The Council members did not support the routine first-line use of PIs in this population; however, this population also is clearly of the highest medical need and consideration of treatment in a research setting was supported. The new era of DAAs is upon us and offers new hope for HCV-infected patients. The two oral protease inhibitors reviewed here, telaprevir and boceprevir, have completed phase 3 studies and have yielded some consistent early lessons for the protease class. For treatment-naïve, genotype 1 patients, higher cure rates and shorter duration of therapy can be expected, but these benefits are partially offset by new issues of resistance and increased AEs. SVR rates approaching 70%–75% now can be anticipated for treatment-naïve, genotype 1 patients, which should lead to increased treatment opportunities for many HCV populations. In addition, up to two-thirds of patients may be eligible for shorter duration therapy. In the treatment-experienced populations, relapse patients can expect to respond better than previous nonresponders  suggesting that IFN responsiveness is still an important consideration in selecting treatment candidates. Unfortunately, cirrhosis still plays a significant negative factor in response to PI-based triple therapy, especially in those with poor IFN responsiveness. In addition, new issues of viral resistance and increased AEs will increase the importance of close medical management and appropriate patient selection. IL28B polymorphism influences on-treatment virologic responses and has become the most powerful pretreatment predictor of SVR, it is anticipated that this host factor will continue to play a role with new PI-based, IFN-containing regimens. The approval of these new treatment regimens likely will expand the population of patients who will undergo antiviral therapy. However, it is important to understand that these drugs have only been studied extensively in a very homogenous population, which may not translate as well into more challenging populations . Since In conclusion, new DAA-based treatment regimens will offer higher SVR rates and new opportunities to many more of the treatment-naïve and treatment-experienced, genotype 1 populations. However, patient selection will be more important than ever given the complex nature of treatment decisions, monitoring, and side effect management.The purpose of this Council was to critically review the existing body of literature and analyze it in the context of contemporary practice and optimal therapeutic outcomes. Each panel member focused on the existing evidence pertaining to a specific controversy in the management of patients with HCV, and the Council as a whole evaluated and voted on the nature of the existing evidence for each statement. The Council members' evaluations of the evidence with level of support for each statement are shown in the supplemental materials.Click here for additional data file.


For patients on treatment with HIV RNA <50 copies/mL, it is unknown whether the genetic barrier to evolution of resistance is different for DRV/r monotherapy, compared with standard triple combinations of antiretrovirals. Several minor IAS-USA mutations are detected frequently in samples from PI naïve patients.In the MONET trial, 256 patients with no history of virological failure and HIV RNA <50 copies/mL on current HAART (NNRTI based (43%), or PI based (57%) switched to either DRV/r monotherapy (800/100 mg OD) versus DRV/r + 2NRTIs. HIV RNA levels were evaluated at Weeks 2, 12, 24, 36, 48, 60, 72, 84 and 96: all patient samples with HIV RNA above 50 copies/mL were sent for genotypic resistance analysis . Virtual phenotype was also assessed when PI mutations were detected. The percentage of patients with major or minor IAS-USA PI mutations was analysed by treatment arm.Patients were 81% male and 91% Caucasian, with median age 43 years, and median CD4 count of 575 cells/uL. While patients were receiving randomised treatment, HIV RNA was above 50 copies/mL for 47/1051 (4.5%) patient-visits in the DRV/r + 2NRTI arm and 69/1009 (6.8%) patient-visits in the DRV/r monotherapy arm. Of 48 patients with at least one successful genotype , two showed major IAS-USA PI mutations during short-term elevations in HIV RNA (one per treatment arm). Both patients remained phenotypically sensitive to darunavir, with sustained HIV RNA<50 copies/mL during the trial and no change in antiretroviral treatment. The five most common minor IAS-USA mutations detected in the DRV/r mono and DRV/r + 2NRTI arms were L63P , I93L , V77I , I62V  and I64V . These five mutations were also commonly observed in the Stanford HIV database of 7601 samples from PI naive patients. Fourteen patients in the DRV/r monotherapy arm had repeated genotypes during intermittent low-level viraemia — there was no evidence for evolution of minor IAS-USA PI mutations over time in these patients.After 96 weeks of treatment in the MONET trial, there is no evidence for an increased risk of emergence of major or minor IAS-USA PI mutations with DRV/r monotherapy, compared to DRV/r + 2 NRTIs, and no evidence for evolution of PI mutations after repeated genotyping.


Long term maintenance with NRTI-sparing regimens may be preferable for patients with NRTI toxicities, and may offer potential cost savings. Dual ART with once daily darunavir/r and etravirine may be preferable to previous PI/r/NNRTI combinations due to its theoretical higher genetic barrier to resistance and good PK profile. We looked at the use of this regimen within our HIV cohort.Patients prescribed dual ART with darunavir/ritonavir 800mg/100mg QD with etravirine 400mg/day (DRV/r/ETR) until January 2010 were identified by our virtual clinic database. Reason for switch, HIV resistance, viral outcomes were identified.21 patients were switched to DRV/r/ETR with median time on regimen of 51.5 weeks (IQR 33-69 wks). 85% (18/21) where given ETR 400mg QD. 62% (13/21) switched from dual PI/r regimens, 10 combined with efavirenz or nevirapine. 28% (6/21) switched from conventional cART (2 NRTI + PI/r or NNRTI). Patients had a median exposure to 9 ARV drugs prior to switch (IQR 4-11), with 90% (19/21) having previous NNRTI exposure, 7 of which had CNS toxicity with efavirenz. At switch, 57% (12/21) had no previous resistance, 19% (4/21) NRTI mutations only, and 19% (4/21) had NNRTI mutations (K103N (2), Y181C combined with NRTI K65R, M184V mutations (1), prior NNRTI failure (2)). 90% (19/21) had VL<50cps/ml at switch, with 95% (20/21) achieving/maintaining VL<50cps/ml on regimen. Four patients discontinued the regimen, 2 switching to darunavir/r monotherapy, one switching to kivexa/darunavir/r due to non-adherence, and one switching back to previous regimen after 4 weeks. One patient was lost to follow up. Median virological follow of patients remaining on therapy was up 40.8 wks (IQR 32-58 wks). Median CD4 change for the 17/21 who remained on therapy was +101 cells/mm3 (IQR -50-138) with median 39 wks follow up (IQR 31-58 wks). Indications for switch were desire for simplification (9) , and need for NRTI-sparing regimen (12), including previous renal toxicity with tenofovir (4), lipoatrophy (7), peripheral neuropathy (1) and lactic acidosis (2).For patients with VL<50cps/ml, simplification to dual therapy with darunavir/r 800/100mg QD plus etravirine 400mg QD maintains viral suppression and immune reconstitution.


The prognostic role of CD4 response in the first six months of treatment in patients achieving early viral suppression during HIV treatment is unclear.This was a cohort study of HIV-positive adults initiating antiretroviral therapy (ART) between April 2004 and August 2007 who achieved viral suppression (<400 copies/ml) by six months on treatment in South Africa. Immunological response at six months was defined as: (1) absolute CD4 reached (<200 vs. ≥200 cells/ml); (2) absolute CD4 reached ; and (3) CD4 increase from ART initiation . We used Cox regression models to determine the relationship between each definition and both new AIDS-defining condition and death.p=0.01. However, in multivariable analysis, we did not observe any significant differences: aHR: 1.39; 95% CI: 0.98–1.95.A total of 4129 patients were eligible for analysis; 212 (5.1%) of those patients experienced a new AIDS-defining condition and 154 (3.7%) died. Smaller CD4 gains by six months were associated with higher hazards of progression to AIDS : 2.6; 95% CI: 1.2–2.1) and death . A decrease in CD4 count since ART initiation through six months  and smaller CD4 count gains  were also associated with greater risk of progression to AIDS compared to an increase of ≥200 cells/ml. When we examined mortality differences by gender among this virally suppressed cohort, a higher proportion of males died compared to females, 4.7% versus 3.2%, Patients on ART with poor CD4 recovery early in treatment are at greater risk of progression to new AIDS diagnosis or death despite viral suppression. Approaches to managing this sub-group of patients need further investigation. In HIV-positive patients, antiretroviral therapy (ART) has been demonstrated to strongly reduce both morbidity and mortality associated with HIV infection through suppression of HIV viral load and restoration of immune function –4. CD4 cStudies investigating the association of poor CD4 recovery during viral suppression and adverse clinical outcomes amongst patients on ART have shown conflicting results ,22,27–33To understand the impact of CD4 response despite virologic suppression on clinical outcomes, we studied the impact of three definitions of immunological response by six months post-ART initiation amongst patients that achieved viral suppression by six months on treatment in a large cohort in Johannesburg, South Africa. These three definitions focused on: (1) an absolute CD4 count level achieved; (2) categories of CD4 count achieved; and (3) change in CD4 count from ART initiation.The Themba Lethu HIV Clinic in Johannesburg, South Africa is one of the largest HIV care and treatment clinics in South Africa with over 21,000 patients initiated onto ART since 2004. Details of this cohort have been published previously ,35.We conducted a prospective cohort analysis of HIV-positive ART naïve patients ≥18 years of age, who initiated standard first-line ART at Themba Lethu between April 2004 and August 2007 with CD4 counts ≤350 cells/ml. At the time, standard public-sector ART in South Africa consisted of stavudine (d4T) or zidovudine (AZT) with lamivudine (3TC) and either efavirenz (EFV) or nevirapine (NVP). All patients initiating ART with CD4 count less than 200cells/ml were eligible to receive cotrimoxazole prophylaxis . HoweverWe used three specifications of CD4 response at six months post-ART initiation: (1) achieving a CD4 count >200 cells/ml at six months post-ART initiation; (2) CD4 count further categorized  at six months post-ART initiation; and (3) change in CD4 at six months from the ART initiation value . We explored the impact of the varying levels of immunologic response in virally suppressed patients on two outcomes that occurred six months post-ART initiation: progression to a new AIDS-defining condition and death. The revised 2008 US Centers for Disease Control and Prevention AIDS case definition was used to define a new AIDS condition . At ThemFor new-AIDS condition and death, person-time accrued from six months after treatment initiation until the earliest of: (1) new AIDS-defining condition; (2) death; (3) lost to follow-up (defined as four months late for last scheduled clinic visit); (4) transfer; or (5) completion of 24 months of follow-up. For all patients, time zero was the date of viral load suppression (approximately six months after ART initiation). If patients had new-AIDS condition or death, they stopped contributing person-time at the time-point when the new AIDS condition started.p<0.20 in bivariate analyses were included in the multivariate models. All multivariate models were adjusted for age, gender, pregnancy, haemoglobin (Hb) and body mass index (BMI) by six months post-ART initiation. For patients with missing BMI and Hb values at six months, the ART initiation value was carried forward. Person-time accrued from six months after treatment initiation hence this time-point was the study “baseline.” This was to avoid immortal time bias given that the exposure is defined at six months post-ART initiation hence the outcomes under study could not have occurred before then. In additional analyses, we further used Cox proportional hazards models to examine the hazard of progression to new AIDS condition and death after viral suppression by gender. The proportionality assumption was checked ) over time for each covariate) and was not violated. Data were analyzed using STATA version 11 .Patient baseline characteristics were summarized with descriptive statistics. Incidence rates (IR) per 1000 person-years (PY) were computed between 0–6, 6–12, 12–18 and 18–24 months after viral suppression (at six months) to compare the occurrence of study outcomes over follow-up. Kaplan–Meier curves were used to compare progression to AIDS or death stratified by each definitions of immunologic response. We estimated crude and adjusted hazard ratio (aHR) of progression to a new AIDS-defining condition and death using Cox proportional hazards models. Covariates that could plausibly confound the relation between CD4 response and the end-points that had a Use of Themba Lethu Clinic data was approved by the Human Research Ethics Committee of the University of the Witwatersrand and approval for analysis of anonymized data was approved by the Boston University Institutional Review Board.Between April 2004 and August 2007, 4803 ART naïve adult patients initiated standard first-line therapy at Themba Lethu and remained in care for at least six months. Of these, 4473 (93.1%) achieved viral suppression. Among the 4473 patients, 344 (7.7%) did not have CD4 count measures at both ART initiation and six months, leaving 4129 patients eligible for analysis. Patients excluded were similar in baseline characteristics, with the exception that those included were more likely to be unemployed (43.1% vs. 33.4%) and had higher Hb levels at ART initiation  10.1–13 vs. 11.1g/dl; IQR 9.4–12.7). Of those included, the majority were female (64.2%), with a median age of 40 years (IQR: 35–46) and on standard first-line regimen d4T-3TC-EFV (89.2%). The cohort was immunosuppressed at initiation of ART . Over a median follow-up time of 23 months (IQR: 21.5–23.5) per person and 7029 total PY of follow-up, 212 (5.1%) patients experienced a new AIDS-defining condition, 154 (3.7%) died and 555 (13.4%) were lost to follow-up. For the CD4 count categories at initiation, the proportion lost to follow-up decreased roughly monotonically from 14.6% among those with 0–49 cells/ml to 14.0% among those 50–199 cells/ml, and for those with a CD4 count at ART initiation ≥200 cells/ml, 12.3% were lost.n=106; 50%), then extra-pulmonary tuberculosis  and Mycobacterium avium complex . Patients also developed oesophageal candidiasis , extra-pulmonary cryptococcosis , invasive cervical cancer , disseminated mycosis , Kaposi Sarcoma , non-Hodgkin's lymphoma , candidiasis of lungs , herpes simplex pneumonitis or oesophagitis , pneumocystis jirovecii pneumonia  and AIDS Dementia Complex . Among 212 new AIDS-defining conditions, the most common were pulmonary tuberculosis , and declined after that .In Kaplan–Meier analysis a, b, c, In adjusted Cox regression models, an absolute CD4 count <200 cells/ml at six months post-ART initiation was associated with greater risk of progression to a new AIDS condition  versus ≥200 cells/ml . HoweverIn Kaplan–Meier analysis, excess mortality among those with poor CD4 recovery regardless of the definition used was observed. This is shown in In adjusted Cox regression model, the risk for death was again higher for patients failing to achieve an absolute CD4 count ≥200 cells/ml by six months on ART  versus ≥200 cells/ml . A low ap=0.10 . In unadjusted Cox regression models, new AIDS condition rates were also not significantly different between males and females: HR: 1.27; 95% CI: 0.96–1.67 for males versus females . This risk was greatest in the first 6 to 12 months after initiation of ART. These findings demonstrate that in addition to achieving viral suppression during ART, CD4 count recovery soon after ART initiation should be an important treatment goal. Regardless of viral suppression status, monitoring CD4 count recovery during this time period presents an early opportunity to identify patients at risk of poorer prognosis.Though a majority of studies show evidence for an increased risk for progression to AIDS or death among those with poor immune recovery, there have been a few conflicting results. Amongst a multicentre cohort study in Germany, patients with poor immune recovery on ART seemed to remain at increased risk for AIDS despite suppressive ART . SubsequTo date, there is no consensus in current HIV guidelines on the definition of adequate CD4 response. To explore this, we tested varying specifications of CD4 recovery in this cohort to determine their impact on prognosis. First, we defined an adequate response as achieving an increase in CD4 count by six months on ART above a threshold of 200 cells/ml. An absolute CD4 count at six months of <200 cells/ml (Model 1) was the strongest predictor of progression to new AIDS condition and death. This finding supports current recommendations for continued provision of primary prophylaxis against OIs among patients with CD4 count <200 cells/ml including those who are virologically suppressed .et al. where patients with virologic suppression who failed to achieve an increase in CD4 counts of at least 50 cells/ml at six months were three times more likely to develop an AIDS-defining illness or death than complete responders [We observed a trend of higher hazards of death among patients with poorer CD4 responses. Insufficient numbers of deaths in this virally suppressed population may have resulted in some of the wide confidence intervals in these estimates. Our results on the impact of CD4 recovery on risk of death show a trend similar to findings reported previously ,26,28,32sponders . In contsponders . This stet al. demonstrated that reducing time patients spent with lower CD4 count reduced deaths from OIs [In this study, 67.9% of new AIDS conditions were due to tuberculosis (TB). Our data emphasize the burden of TB even among virally suppressed patients. Therefore, strategies that improve CD4 recovery could also reduce the TB-related morbidity and mortality. Lawn from OIs . This sufrom OIs . In addifrom OIs –45. Thisfrom OIs ,47. Intefrom OIs .Studies have shown inconsistent results regarding possible gender-differences disease progression and mortality among HIV-positive patients –55. HoweThe major strength of this study is the homogeneity of our study population. The study population was uniformly viral suppressed at baseline (<400 copies/ml) so that incomplete viral suppression would not explain our findings. In addition we also used routine programme data that commonly reflects limited resource populations. As commonly seen in resource-limited settings, this cohort was immunosuppressed at ART initiation (median CD4 count of 80 cells/ml), all were ART-naïve, and they began standard first-line ART (NNRTI based regimens). Our large sample size and large number of outcome events to draw from is a distinct advantage, in comparison to previous studies, which had lower sample size and fewer events. Our study findings, therefore, add to the body of knowledge of understanding the clinical relevance of poor CD4 responses in the setting of viral suppression.Our findings also should be interpreted in light of the study limitations. First, the setting of this study is mainly an outpatient facility and this may result in underestimation of other serious clinical events, given that sicker patients are more likely to be admitted into hospital care. Second, because we only explored the relation between CD4 count at six months in our analysis, our data cannot be used to comment on the impact of long-term CD4 responses on poor clinical outcomes. The exclusion of patients (7.3%) with missing CD4 and viral load measurements at baseline and six months may have led to some selection bias. However, we expect this bias to be limited, because both excluded and included patients had mostly similar baseline characteristics. Use of cotrimoxazole prophylaxis may be an important confounder in this analysis. A recent systematic review and meta-analysis showed that data from low and middle-income countries did demonstrate that cotrimoxazole significantly increased survival in HIV-positive adults on ART . We, howIn conclusion, our findings show the prognostic role of initial CD4 recovery during ART even among virally suppressed patients. Treatment success of ART should not be solely defined on viral suppression but interpreted as a combination of viral suppression and adequate CD4 response. Early CD4 count recovery regardless of viral suppression could be used as an additional tool used to identify patients who require intensified screening and diagnostic workup for OIs. Furthermore, early initiation of ART would be a major intervention to prevent CD4 count from getting too low and improving CD4 count recovery. Future studies need to focus on interventions that improve CD4 recovery among patients on ART.


Efavirenz (EFV) treatment is associated with a range of neuropsychiatric (NPS) adverse events (AEs), which differ in duration and severity.In this double-blind placebo-controlled trial, 157 treatment-naïve patients with HIV RNA >5000 copies/mL, were randomised 1:1 to either etravirine (ETR) 400mg once daily (n=79), or EFV 600mg once daily (n=78), plus two NRTIs. After 12 weeks of randomised treatment, the type and frequency of NPS AEs was compared between treatment arms.Overall, the patients were 81% male, 85% Caucasian, with a median age of 36 years. Median baseline CD4 Count was 302 cells/uL, median HIV RNA 4.8 log10 copies/mL. In the primary analysis, 13/79 patients (16.5%) in the ETR arm, versus 36/78 (46.2%) in the EFV arm, showed at least one Grade 1-4 treatment-emergent drug-related NPS AE (p<0.001). The most common nervous system was dizziness, reported for 3 patients in the ETR arm versus 15 in the EFV arm. The most common psychiatric adverse events were sleep disorders, reported in 7 patients in the ETR arm versus 25 patients in the EFV arm. The prevalence of Grade 1-4 all cause NPS AEs showed a peak at Week 2 (21.5% in the ETR arm and 43.6% in the EFV arm), but at the Week 12 visit, the percentage with an ongoing Grade 1-4 all cause NPS AE remained different between the arms (21.7% with ETR and 35.7% with EFV). In the ETR arm, 29 all cause NPS adverse events were reported: 20 Grade 1, 7 Grade 2 and 2 Grade 3. In the EFV arm, 93 NPS adverse events were reported: 55 Grade 1, 34 Grade 2 and four Grade 3. New medication for NPS adverse events was started for 7.6% of patients in the ETR arm versus 16.7% of patients in the EFV arm. One patient in the ETR arm and five in the EFV arm discontinued randomized treatment with NPS AE’s.In the SENSE trial, first-line treatment with ETR 400mg once daily +2NRTIs led to significantly fewer NPS AEs, compared with EFV + 2NRTIs. These NPS AEs were mainly Grade 1 or 2 in severity. The difference between the arms emerged at Week 2, but persisted through Week 12.


While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART.ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata.A total of 323 children , including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure  by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r.Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences.NCT00117728ClinicalTrials.gov Identifier:  Studies of sex differences in the course of HIV infection in adults report lower HIV-1 RNA levels and higher CD4 counts in women compared to men, but similar disease progression and clinical outcomes between sexes . ResponsLess is known about sex differences in disease progression and response to ART among children. Differences in CD4 count and HIV-1 RNA between boys and girls have been reported in treatment-naïve HIV-infected children . In treaA better understanding of sex differences in the pathobiology of HIV and its complications would be aided by evaluation of these differences during early childhood when biologic, social, and behavioral differences are less pronounced than in adulthood. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART.In order to assess for sex differences in immunologic, virologic, anthropometric, and other responses to antiretroviral regimens, we performed a secondary analysis of data collected as part of Neverest 2, a clinical trial  assessing the reuse of nevirapine in nevirapine-exposed HIV-infected children conducted from 2005 to 2010 ,25. ChilSocio-demographic information, medical history, weight (kg), height (cm), and blood samples (for CD4 T-cell determination and HIV-1 RNA quantity) were collected at a pretreatment visit. Subsequent visits were scheduled at 2, 4, 8, 12, and every 12 weeks thereafter up to 52 weeks until randomization and at 2, 4, 8, 16, 24, 36, 52, 64, 76 and every 12 weeks thereafter. Blood samples for plasma viral load tests by quantitative HIV-1 RNA PCR  were collected at 4, 16, 24, 36, 52, 64, and 76 weeks post-randomization and for absolute CD4 count and percentages  at 16, 24, 36, 52, 64, and 76 weeks post-randomization, and for both tests at every 12 weeks thereafter until the final study visit. Lopinavir, ritonavir, and nevirapine plasma concentrations were determined using validated LC-MS/MS assays developed in the Division of Clinical Pharmacology, Cape Town, South Africa. An AB Sciex 4000 mass spectrometer was operated at unit resolution in the multiple reaction monitoring mode. The assays were validated over the concentration range of 0.16-20 μg/ml for lopinavir, 0.10-20 μg/ml for nevirapine, and 0.04-5 μg/ml for ritonavir.Non-fasting total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides in mg/dL were measured at pretreatment, time of randomization, and 36, 88, and 136 weeks post randomization . At the final study visit following an overnight fast, total cholesterol, LDL, HDL, triglycerides, C-reactive protein in mg/L, and insulin in mg/dL were measured. Venous blood glucose in mg/dL was measured with a handheld glucometer and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated . ClassifWeight (kg) and height (cm) were measured using a digital scale and stadiometer, respectively. Weight-for-age (WAZ) and height-for-age z-scores (HAZ) were calculated using World Health Organization growth standards . UnderweAll children with HIV-1 RNA >1000 copies/mL were recalled and retested within 4 weeks. Additional counseling was provided if adherence difficulties were detected. Children in the switch group were returned to the LPV/r-based regimen if HIV-1 RNA remained >1000 copies/mL despite enhanced adherence counseling. To evaluate adherence, caregivers were asked to return drug at all scheduled visits. Percentage of medication return was calculated and poor adherence was defined as 20% greater than expected medication return for each drug.p-values are 2-tailed and p-values <0.05 were considered statistically significant. Analyses were performed using SAS version 9.1.3 .All outcomes were compared between sexes within treatment strata as well as between treatment groups within sex strata. Intent-to-treat comparisons were made for treatment groups. Kaplan-Meier methods and log-rank tests were used to describe time to virologic failure. For comparisons between groups at specific time points, we used the Wilcoxon rank-sum test for non-normally distributed continuous variables, t-test for normally-distributed continuous variables, and Chi-square or Fisher exact tests for categorical variables. Generalized estimating equation models were used to compare outcomes with repeated measurements over time using a first order autoregressive correlation structure, adjusting for baseline differences. Tests for interaction between sex and treatment group were performed. All The flow of participants is shown in Figure p = 0.009). Boys also had a lower mean WAZ and HAZ and a greater proportion of boys were underweight and stunted. The pretreatment anthropometric differences remained after adjusting for age at treatment initiation. No differences between sexes were seen in other pretreatment characteristics. In the pre-randomization period, similar proportions of boys and girls died, were lost to follow up, or did not meet criteria for randomization (data not shown). Results were similar if only the 195 children randomized were analyzed, but the mean WAZ of boys and the proportion of boys underweight and stunted were no longer significantly different than girls.The pretreatment characteristics of the 323 children initiating LPV/r-based ART are presented in Table p = 0.747), or the proportion with viral load <50 copies/mL at randomization  when all children were on LPV/r. The probability of virologic failure  by 52 weeks post-randomization was similar between boys and girls who remained on LPV/r  as well as between boys and girls who switched to nevirapine . The probability of virologic failure by 156 weeks was also similar between boys and girls who remained on LPV/r  as well as between boys and girls who switched to nevirapine . Proportions of boys and girls in viremia categories  within treatment groups were similar at all scheduled post-randomization visits.There were no differences between boys and girls in either the proportion who attained viral load suppression to <400 copies/mL by 6 months into the pre-randomization phase , with significantly higher mean CD4 cell counts at 24, 64, and 100 weeks post-randomization  and higher CD4 percentage at 64, 76, and 100 weeks post-randomization  , and girls on LPV/r had a higher mean HOMA-IR than boys on LPV/r  . Upon exp = 0.386). After randomization, boys on LPV/r consistently had a lower WAZ than boys on nevirapine through 148 weeks, but this difference was not statistically significant. There were no sex differences in likelihood of dropping more than one Z score in WAZ before 52 weeks post-randomization.WAZ for boys and girls increased rapidly in the pre-randomization phase Figure ; the meap = 0.473). After randomization, height for boys and girls on both treatment regimens improved through 148 weeks . HAZ stayed lower for boys on nevirapine than girls on nevirapine through 52 weeks post-randomization . The association remained when adjusted for age at initiation of ART , but not when adjusted for pretreatment HAZ .Mean change in HAZ was greater for girls than boys in the pre-randomization phase when all children were on LPV/r, though this difference was not significant . A similar pattern was observed by cumulative skinfold sum, though this difference was not significant . Patterns of fat were similar between boys and girls in both treatment randomization groups  in scheduled post-randomization visits. No significant sex differences in lopinavir concentrations were observed. Of those switched to nevirapine, there were no sex differences in nevirapine concentrations. There were no differences between boys and girls in the proportion of children non-adherent to their drugs at any post-randomization scheduled visits as assessed by medication return percentages.Of those randomized to remain on LPV/r, the plasma concentrations of ritonavir adjusted for WAZ and time since dose was on average 0.115 μg/ml higher in girls than boys -based regimens ,18. A stAlthough studies in adults observe more lipid abnormalities in ART-treated women ,33-36, tSex differences in growth parameters during ART were also detected. Though height remained significantly lower for boys on nevirapine than girls on nevirapine up to 52 weeks post-randomization after adjusting for age at initiation of ART, it was no longer significant when adjusted for pretreatment height. We have previously reported that earlier age of ART initiation can affect growth . Few stuAlthough our study is one of the first to evaluate sex differences in childhood response to potent combination ART, it has limitations. Children in this trial met eligibility criteria for treatment based on South African guidelines in place at the time and only those who attained viral suppression in the first year of therapy were randomized . Thus, oIn this study, we observed no sex differences in viral suppression; however, compared to boys switched to nevirapine, girls switched to nevirapine had a more robust immune recovery. In addition, girls on LPV/r had a more unfavorable lipid profile compared to boys on LPV/r at the final study visit. This study provides a glimpse into early childhood sex differences related to ART. The course and long term consequences of these differences with respect to immunologic and metabolic outcomes is unknown. Future studies of sex differences among HIV-infected children should focus on pharmacokinetics as well as pathophysiologic pathways including chronic inflammation, immune senescence and mitochondrial dysfunction which may influence the therapeutic response and risk of complications. The potential effects of factors such as malnutrition, infections, co-morbidity, viral sub-type, and underlying genetic profiles also warrant further investigation during childhood and adolescence.ALT: Alanine aminotransferase; ART: Antiretroviral treatment; BIA: Bioimpedance analysis; HAZ: Height-for-age z-score; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment of insulin resistance; LPV/r: Ritonavir-boosted lopinavir; LDL: Low-density lipoprotein; NNRTI: Non-nucleoside reverse transcriptase inhibitor; WAZ: Weight-for-age z-score; %BF: Total body fat percent.The authors declare that they have no competing interests.LK, EJA, and AC designed the study. AC, LM, and RS were responsible for data collection. HM, LW, and SM contributed to the pharmacokinetic analysis. SS, SMA, and LK contributed to analysis of data and interpretation of results. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/14/39/prepub


To analyze self-reported adherence to antiretroviral regimens containing ritonavir-boosted protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI), raltegravir, and maraviroc.Overall, 372 consecutive subjects attending a reference center for HIV treatment in Florence, Italy, were enrolled in the study, from December 2010 to January 2012 (mean age 48 years). A self-report questionnaire was filled in. Patients were defined as “non-adherent” if reporting one of the following criteria:<90% of pills taken in the last month, ≥1 missed dose in the last week, spontaneous treatment interruptions reported, or refill problems in the last 3 months. Gender, age, CD4, HIV-RNA, years of therapy, and type of antiretroviral regimen were analyzed with respect to adherence.At the time of the questionnaire, 89.8% of patients had <50 copies/mL HIV-RNA and 14.2% were on their first combined antiretroviral therapy. 57% of patients were prescribed a regimen containing ritonavir boosted protease inhibitors (boosted PI), 41.7% NNRTI, 17.2% raltegravir, and 4.8% maraviroc; 49.5% of the subjects were on bis-in-die regimens, while 50.5% were on once-daily regimens, with 23.1% of these on the single tablet regimen (STR): tenofovir/emtricitabine/efavirenz. The non-adherence proportion was lower in NNRTI than in boosted-PI treatments (19.4% vs 30.2%), and even lower in STR patients (17.4%). In multivariable logistic regression, patients with the NNRTI regimen  and the STR  reported lower non-adherence. Efavirenz regimens were also associated with lower non-adherence , while atazanavir/ritonavir regimens were associated with higher non-adherence. No other relation to specific antiretroviral drugs was found. A higher CD4 count, lower HIV-RNA, and older age were also found to be associated with lower non-adherence, while a longer time on combined antiretroviral therapy was related to higher non-adherence.In conclusion, older age, higher CD4 cell counts, lower HIV-RNA viral loads, and the use of STR are all related to lower non-adherence. In particular, the use of STR maintains an advantage in improving adherence with respect to other cARTs, even with the availability of new, well-tolerated antiretroviral drugs and drug classes in recent years.


Atazanavir (ATV) is a protease inhibitor used in the treatment of HIV infection. It is useful in patients on methadone replacement therapy as its once daily dosing facilitates co-administration with methadone and, unlike the non-nucleoside reverse transcriptase inhibitor, efavirenz, it does not accelerate the metabolism of methadone via induction of cytochrome P450 enzymes . ATV is We performed a single site, retrospective chart review of all patients prescribed ATV at the Mater Misericordiae University Hospital, Dublin between January 2004 and October 2007. Data collected included baseline demographic/lifestyle factors , hepatitis B (HBV) and C (HCV) serology, current and previous antiretroviral therapy, baseline and week-12 routine bloods . The last available bilirubin level for those who discontinued ATV before week-12 was utilised in the analysis.Data was entered into a Microsoft Access database and analyses performed using SAS v9.13. Wilcoxon-Mann–Whitney tests and Spearman’s correlation were used to describe univariate associations between the factors of interest and the change in bilirubin over the first 12 weeks of ATV use. Factors considered in these analyses were: gender; age; ethnicity ; HIV exposure category ; smoking status ; methadone use; AIDS status; CD4+ T-cell count and HIV RNA <50 copies/ml at start of ATV; antiretroviral naïve/experienced at start of ATV; nucleoside reverse transcriptase inhibitor (NRTI) included in regimen  and laboratory parameters , Υ-glutamyl transferase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin (ALB), creatinine) at the time of starting ATV, as well as the pre-ATV bilirubin level itself. Factors that were associated with a change in bilirubin in these analyses (P < 0.2) were then included in forward stepwise multivariable linear regression analyses to identify factors that were independently associated with the change in bilirubin. As the change in bilirubin was skewed, the change value was log-transformed prior to analysis; estimates were back-transformed for presentation for ease of interpretation. Due to the strong co-linearity of HCV antibody positivity, methadone use and IVDU acquisition, it was not possible to include all 3 variables in a single model; therefore the primary model included HCV antibody status and sensitivity analyses were performed after replacing this covariate in the model with IVDU acquisition or methadone use.Ninety-three patients were prescribed ATV. Ten patients were excluded from the analysis due to self-initiated treatment interruption; these patients did not re-attend clinic after the first prescription of ATV. Four subjects discontinued ATV within 12 weeks; of these, one patient had died, one patient discontinued early due to hepatitis secondary to immune reconstitution and 2 patients stopped ATV therapy due to jaundice. 83 patients were included in the final analysis.2. HIV acquisition risk was via IVDU in 61.5%, heterosexual sex in 34.9%, and homosexual sex in 3.6%. Due to the high proportion of IVDU, methadone use (44.6%) and hepatitis C virus co-infection (60.5%) were common. The majority (79 (95.2%)) were co-administered 300 mg ATV with 100 mg ritonavir, with the remainder being administered 400 mg ATV. Just under half of patients (42.2%) started TDF as part of their regimen, with 35 of the remaining 41 patients starting a regimen that contained abacavir (ABC). Median (IQR) CD4 + T-cell count, ALP, ALT and GGT were 165  cells/mm3, 79  IU, 35  IU and 52  IU at baseline, respectively. At baseline, 15 (18.1%) subjects had undetectable HIV RNA (<50 copies/ml) compared to 45 (54.9%) at week 12, while 46 (80.5%) had HIV RNA < 400 copies/ml at week 12.Baseline demographics and clinical factors are shown in Table Bilirubin levels increased from 11  μmol/L at baseline to 27  μmol/L at week-12; the median (IQR) change was 16  μmol/L. Five patients had elevated bilirubin at baseline ; by week 12, all five continued to have elevated bilirubin (Table P = 0.04), GGT  and ALP  at the time of starting ATV were all significantly associated with a smaller increase in bilirubin. Neither BMI nor baseline CD4 + T-cell count significantly correlated with change in bilirubin concentration . Changes in bilirubin were generally but not significantly lower in those with higher pre-ATV levels .Univariate analyses Table  suggesteP < 0.05) were therefore considered for inclusion in a forward stepwise linear regression model: baseline ALP, ALT, GGT, TDF use, Caucasian ethnicity and HCV antibody status. Of these, only baseline ALP and HCV antibody positivity were independently associated with a smaller change in bilirubin , after adjusting for baseline bilirubin. When the analysis was performed with IVDU status replacing HCV antibody positivity, baseline ALP, and TDF use were independently associated with a smaller change in bilirubin concentration . Finally, the exclusion of 2 subjects who discontinued ATV within 4 weeks due to jaundice did not alter our findings appreciably.When sensitivity analyses were performed in which HCV antibody positivity was replaced by methadone use or IVDU status, similar results were obtained. In particular, when HCV antibody positivity was replaced by methadone use, baseline ALP, TDF use and methadone use were independently associated with a smaller change in bilirubin  of plasma ATV in those on concomitant methadone . HoweverWhile our study benefited from the use of longitudinal data and a representative sample of patients , it was limited by its relatively small sample size and its retrospective nature. There was no data regarding compliance although the fact that majority of subjects had an undetectable viral load would suggest adequate adherence. In conclusion, we determined that HCV antibody positivity and higher baseline bilirubin were associated with a smaller increase in bilirubin after initiation of ATV. Ultimately, this data is clinically useful and may reassure prescribing physicians regarding the merit of ATV use for intravenous drug users who are co-infected with HCV, particularly in resource limited settings where regular monitoring of liver function tests may not be feasible. Further research is required to identify clinical predictors that are readily utilisable in everyday practice.ACG has received support, in the form of sponsorship to attend meetings, from Gilead Sciences Ltd., GlaxoSmithKline (Ireland Ltd), Merck, Sharp and Dohme and Bristol-Myers-Squibb Pharmaceuticals. AB, GS & JL None. CAS has received fees for consulting, membership of data safety and monitoring boards/ advisory panels, the development of educational material and speaking engagements as well as support to travel to meetings, from the following companies: Gilead Sciences Ltd., Abbott Pharmaceuticals, Janssen-Cilag, Bristol-Myers-Squibb, Merck, Sharp and Dohme and Glaxo-Smith Kline. PWGM has received support from the following; Molecular Medicine Ireland, Scientific Foundation Ireland, ViiV Healthcare, Gilead Sciences Ltd., GlaxoSmithKline (Ireland Ltd), Abbott, Merck, Sharp and Dohme and Janssen-Cilag.AGC carried out data collection, statistical analysis and drafted the manuscript. AB carried out data collection, data entry and helped draft the manuscript. GS helped draft the manuscript. JL helped draft the manuscript. CAS designed the statistical methods, supervised the statistical analysis and helped draft the manuscript. PWGM conceived the study, supervised the statistical analysis and helped draft the manuscript. All authors read and approved the final manuscript.