HIV positive patients on ritonavir-containing antiretroviral therapy (ART) can develop iatrogenic Cushing syndrome (IACS) and adrenal insufficiency as a result of drug-drug interactions with inhaled or intranasal glucocorticoid therapy. Reports related to epidural triamcinolone injections are relatively uncommon but increasingly reported. We describe a 48-year-old woman with immunologically and virologically well-controlled HIV on ritonavir-based ART, who developed headache, dizziness, and candida and herpes simplex virus (HSV) ulcerative esophagitis 7 days after receiving an epidural triamcinolone injection for cervical radicular pain. Iatrogenic Cushing syndrome and relative adrenal insufficiency were suspected and proven. The patient's ART was changed to a non-HIV protease inhibitor- (PI-) containing program, her symptoms improved, and she did not require hydrocortisone replacement. In this paper, we review the literature on IACS and relative secondary adrenal insufficiency from epidural triamcinolone injections in HIV patients on ritonavir-containing ART regimens. A high index of clinical suspicion is needed for diagnosis. Prevention of drug-drug interactions by taking a thorough medication history for patients on ritonavir-containing ART regimens before prescribing any form of corticosteroid is crucial and effective and sustained interdisciplinary communication in the care of such patients. A 48-year-old HIV positive Caucasian woman, immunologically and virologically well controlled on a ritonavir-boosted protease inhibitor- (PI-) based antiretroviral therapy (ART) regimen, developed iatrogenic Cushing syndrome (IACS) and relative secondary adrenal insufficiency (SAI) following an epidural triamcinolone injection for cervical radicular pain.μL (31%) with a nadir CD4 T-cell count of 524/μL in September 2010. Pretreatment HIV genotyping showed wildtype virus.The patient was diagnosed with HIV in 2008, which was acquired after a sexual assault. Her HIV viral load was 6400 copies/mL at time of diagnosis and CD4 T-cell count was 1125/Screening for coinfections and sexually transmitted infections, including hepatitis C and syphilis, was negative. The HSV serum IgG was positive.The patient had a nine-year history of chronic pain involving her right neck, suboccipital head, shoulder, low back, and lateral hip that had predated her HIV diagnosis. She had been followed by a pain medicine clinic and had received epidural and trochanteric bursa injections periodically for cervical radiculitis and trochanteric bursitis. She also had a history of tobacco use (30 pack years), remote history of illicit drug abuse with last use of IV cocaine in 1983. She had used alcohol heavily in the past but not within the last 10 years. Her psychiatric history included that of anxiety and depression/dysthymic disorder for which she was on low dose fluoxetine. Surgical history only included hysterectomy.The patient had been followed clinically in the HIV clinic and had been in good health with CD4 T-cell count above 500. She was then randomized to be enrolled in the treatment arm of the (START) study—Strategic Timing of Antiretroviral Treatment. After enrollment, she was initiated on ART consisting of tenofovir-emtricitabine 300 mg/200 mg tablet daily, atazanavir 300 mg daily, and ritonavir 100 mg daily in June 2012. CD4 T-cell count was 596 and viral load was 39,500 copies/mL prior to therapy. She tolerated the antiretroviral regimen well; however, she developed a diffuse rash involving her trunk, arms, and thighs ten days after starting the ART program. She was evaluated by dermatology and her physicians in the HIV clinic, and the rash was not felt to be drug related. The rash eventually disappeared with no specific therapy and her HIV regimen was continued unchanged with no return of the rash.The patient had been receiving cervical epidural triamcinolone injections for a year without incident prior to initiating ritonavir. For the six months prior to initiating ritonavir, the patient received two cervical epidural steroid injections and two trochanteric bursa injections with total dose of 60 mg triamcinolone and 6 mg dexamethasone. The last dose was 4 weeks prior to ritonavir initiation. Ten weeks after initiating ritonavir-based ART, the patient received a 40 mg triamcinolone epidural injection at C7-T1 and a 20 mg triamcinolone injection into the right trochanteric bursa to address her chronic neck and leg pain.Seven days after the injection, she developed symptoms of headache, change in taste, and dizziness. She was advised to closely observe her symptoms and report any changes. Nine days later, she developed significant esophageal reflux symptoms despite having no prior history of gastroesophageal reflux disease. She was seen at her primary care internal medicine clinic and advised symptomatic therapy with an over-the-counter antacid.9/L with a normal differential (absolute lymphocyte count of 2150), hemoglobin 13.5 g/dL, platelets 263 × 109/L, sodium 136 mmol/L, potassium 3.8 mmol/L, random glucose of 92 mg/dL, AST 22 U/L, bilirubin 2.6 (direct of 0.3) mg/dL, Cr 0.7 mg/dL, and lipase 30 U/L. An ultrasound of her hepatobiliary tree was normal. She was discharged from the ED with famotidine and aluminum/magnesium hydroxide suspension and advised to follow up with her primary care provider the following day.Due to continued worsening of her symptoms, specifically worse epigastric pain, nausea, and esophageal reflux symptoms, the patient presented to the emergency department (ED) 5 days after developing esophageal reflux symptoms. Diagnostic workup included basic labs: white cell count of 12.2 × 10At the follow-up visit at the primary care internal medicine clinic, an esophagogastroduodenoscopy (EGD) was arranged which revealed significant findings of scattered irregular ulcers 5–10 mm in size, from distal to mid esophagus which were biopsied. The proximal esophagus had scattered diffuse white exudates consistent with candida esophagitis. Ulceration covered 75% of the circumference of the gastroesophageal junction (5-6 mm). The biopsy findings from ulcerated mid and distal esophagus showed hyperplastic squamous esophageal mucosa and gastroesophageal junction-type mucosa with focal active chronic inflammation. The immunohistochemical staining of the mucosal tissue was positive for herpes simplex virus and negative for cytomegalovirus.Four weeks following the epidural steroid injection and one week following the onset of esophageal reflux symptoms, the patient complained of “facial swelling” and insomnia. She had also gained 5 lbs and noted mood changes in the form of increased anxiety.She was started on oral omeprazole and fluconazole therapy for 14 days for esophagitis. Due to ongoing esophageal symptoms, when HSV immunostain from EGD returned positive, a course of oral valacyclovir 1000 mg three times daily for 2 weeks was initiated. The patient's CD4 T-cell count at that time was 745 (25%) and serum HIV RNA viral load was detected but not quantifiable.The patient's constellation of symptoms and normal CD4 T-cell count raised suspicion for IACS from interaction between triamcinolone injection and oral ritonavir therapy which would account for her relative immunodeficiency state despite an adequate CD4 T-cell number. A random morning serum cortisol was 3 mcg/dL (range 7–25 mcg/dL), and for an early morning specimen this signifies a lower serum cortisol value than physiologically expected. The patient began to complain of orthostatic dizziness particularly in the mornings; her orthostatic blood pressure and pulse rate  were normal. She remained euglycemic throughout this time. Follow-up ACTH stimulation test showed an intact response.Following completion of valacyclovir and fluconazole treatment courses, the patient's esophageal symptoms improved by 80% but did not completely resolve. A decision was made to increase the omeprazole dose and due to continued risk of medication interactions, the antiretroviral therapy program was changed to a non-PI based regimen, tenofovir-emtricitabine, and raltegravir.Synthetic glucocorticoid screen did not show detectable triamcinolone levels, and a follow-up 24-hour urine cortisol was measured as 12 mcg/24-hour period 3 weeks following change in the ART program.The score on the Drug Interaction Probability Scale assessing possible interaction between triamcinolone and ritonavir was 8, translating to a probable interaction . No poinThe patient's clinical course slowly improved and returned to baseline approximately 3 months after the triamcinolone injection, without requiring hydrocortisone replacement. She was advised not to have any further epidural triamcinolone injections without proper approval by her HIV specialist or endocrinologist.Our patient had significant morbidity as a result of HIV protease inhibitor and glucocorticoid interactions. We have reviewed the literature and report all available published experience of the interaction between ritonavir and triamcinolone resulting in IACS and secondary adrenal insufficiency.Ritonavir, a potent inhibitor of the cytochrome P450 (CYP) 3 A4 isoenzyme, is used to increase therapeutic levels of other PIs , thereby allowing for lower or less frequent dosing of the active PI. However, this portends numerous drug interactions with medications from various other classes including HMG Co-A reductase inhibitors, phosphodiesterase inhibitors, antiarrhythmics, and corticosteroids [There have been numerous case reports on interaction of inhaled or intranasal fluticasone with ritonavir resulting in IACS and secondary adrenal insufficiency. There have been fewer but increasing number of recent case reports on the interaction between triamcinolone given as an epidural injection and ritonavir.Foisy et al. published a review of 25 cases (15 adult and 10 pediatric) of adrenal suppression and Cushing's syndrome as result of an interaction between ritonavir and inhaled fluticasone . The meaThere are fewer case reports on IACS and secondary adrenal insufficiency in context of triamcinolone and ritonavir. The clinical manifestations of IACS as a result of ritonavir use vary greatly. The symptoms may be as subtle as change in weight distribution/weight gain that may be mistaken for lipodystrophy and the diagnosis may therefore be delayed potentially for months . The morThe presentation of relative secondary adrenal insufficiency may also be variable, ranging from fatigue to overt dizziness and hypotension. A high index of suspicion should be used for any of these symptoms in a patient on ritonavir and receiving any source of corticosteroids and taking a thorough drug history is crucial.When there is a clinical suspicion of HIV PI and glucocorticoid interactions, a patient's adrenal axis needs to be assessed in a systematic manner. An early morning random cortisol level should be obtained as well as an ACTH level. An ACTH stimulation test can be used to confirm adrenal axis suppression from exogenous steroids. A synthetic glucocorticoid screen is also beneficial in demonstrating the source of exogenous excess steroids. These may need to be repeated at more than one time point depending on patient's clinical course, especially if changes to the antiretroviral therapy regimen are made and/or symptoms are not improving with time as expected.Most patients in the literature had spontaneous recovery of symptoms and recovery of adrenal axis in a matter of months, ranging from 2 to 8 months depending on severity of the initial presentation and dose of triamcinolone used once the HIV PI or the glucocorticoid is stopped. Some patients required hydrocortisone replacement during the recovery phase. The need for hydrocortisone replacement appears to depend on the degree of suppression of the hypothalamus-pituitary-adrenal (HPA) axis (based on cosyntropin stimulation test) and is temporary until the HPA axis recovers. Ramanathan et al. showed the elimination half-life of triamcinolone acetonide was prolonged as much as 170-fold when coadministered with ritonavir . RecommeThe first step, however, is to remove the source of exogenous corticosteroids and/or the ritonavir causing the medication interaction.When possible, replacing the ritonavir-boosted PI regimen with another antiretroviral agent with no CYP3A4 inhibition such as a non-nucleoside transcriptase inhibitor, chemokine receptor 5 (CCR5 receptor) antagonist, or an integrase inhibitor , should be considered, as we did with our patient. However, choices may be limited in highly ART treatment experienced patients. In addition, it is not yet known whether cobicistat, currently used to boost elvitegravir concentrations via CYP3A inhibition mechanism, may also have a similar interaction and therefore would not be a good substitution for ritonavir-based regimen with respect to this particular drug-drug interaction.Enteral or parenteral exogenous corticosteroids may be prescribed for various pain conditions across every subspecialty. The management of acute or chronic pain requires patient education as well as coordination of care with those prescribing ritonavir and those who may be offering exogenous corticosteroids. The literature describing the specific ritonavir and triamcinolone interaction is limited and not widely appreciated, but not unique to other corticosteroids. Alternative pain management options should be explored when a patient is on a boosted PI regimen.Cytochrome P450 is a major pathway for drug metabolism via the liver. It is largely responsible for transferring lipid-soluble agents, through a process of oxidation, hydrolysis, or reduction, to water-soluble agents that are easier for the body to eliminate. Ritonavir is known to be a potent inhibitor of a particular isoenzyme of this metabolism pathway, CYP3A4 . CYP3A4 Although drug interactions with ritonavir and PIs are beneficial, the potent inhibition of CYP3A4 by ritonavir can have detrimental effects on other medications, particularly if the interaction potential goes unrecognized. In the case of our patient, an unrecognized interaction between ritonavir and a corticosteroid, triamcinolone, resulted in adrenal suppression. Glucocorticoids, including triamcinolone, undergo metabolism via CYP3A4 .Therefore, use of ritonavir with glucocorticoids can result in increased exposure to the glucocorticoid and increased potential for side effects including HPA axis suppression, osteoporosis, and osteonecrosis.Glucocorticoids differ with regards to potency and elimination half-life –25. As mThe above case illustrates the importance of being cognizant of drug-drug interactions for HIV patients who are on ritonavir-containing regimens. This is particularly important in situations when the medication interactions may not have been well described or medications are administered in nontraditional methods, such as via inhalation or neuraxial injections.In this particular case, the corticosteroid was documented through a separate surgical electronic record compared to other prescribed office based medications including this patient's ART. Also, at that time, this drug-drug interaction between triamcinolone and ritonavir was not as well described and did not appear in drug-interaction databases. Taking a thorough medical and medication (including over-the-counter medications) at each visit with HIV patients is imperative, as well as being vigilant in instances involving chronic pain conditions treated with injectable steroids for potential drug-drug interactions. This drug-drug interaction will not necessarily be readily recognized by the proceduralist administering injectable corticosteroids thus necessitating good communication between providers.A similar concern for glucocorticoid-ART interaction is also present with cobicistat containing ART regimens although there is more evidence in the literature for ritonavir containing ART regimens.Ongoing education of pharmacists, providers involved in care of these patients with emphasis on counselling and interdisciplinary communication between various HIV caregivers, and other specialists as well as patients themselves is important in prevention of such drug-drug interactions and morbidity. A high index of clinical suspicion is needed.Furthermore, use of a universal medication ordering system would help identify such drug interactions, even when the medications were ordered in completely different departments, and prevent these potential complications.If IACS and secondary relative adrenal insufficiency are suspected, as in this illustrative case, prompt assessment of steroid axis is key, as well as consideration of changing ART regimen, when possible, and a multidisciplinary knowledgeable approach to chronic pain for patients on boosted-PI regimens.


Background. Decentralization of antiretroviral therapy (ART) services is a key strategy to achieving universal access to treatment for people living with HIV/AIDS. Our objective was to assess clinical and laboratory outcomes within a decentralized program in Nigeria. Methods. Using a tiered hub-and-spoke model to decentralize services, a tertiary hospital scaled down services to 13 secondary-level hospitals using national and program guidelines. We obtained sociodemographic, clinical, and immunovirologic data on previously antiretroviral drug naïve patients aged ≥15 years that received HAART for at least 6 months and compared treatment outcomes between the prime and satellite sites. Results. Out of 7,747 patients, 3729 (48.1%) were enrolled at the satellites while on HAART, prime site patients achieved better immune reconstitution based on CD4+ cell counts at 12 (P < 0.001) and 24 weeks (P < 0.001) with similar responses at 48 weeks (P = 0.11) and higher rates of viral suppression (<400 c/mL) at 12 (P < 0.001) and 48 weeks (P = 0.03), but similar responses at 24 weeks (P = 0.21). Mortality was 2.3% versus 5.0% (P < 0.001) at prime and satellite sites, while transfer rate was 8.7% versus 5.5% (P = 0.001) at prime and satellites. Conclusion. ART decentralization is feasible in resource-limited settings, but efforts have to be intensified to maintain good quality of care. Nigeria bears the second largest burden of HIV infection in Africa, second only to South Africa. Of the estimated 1.4 million HIV-infected persons needing antiretroviral therapy (ART), only one-third of them were accessing treatment at the end of 2012 [Published reports indicate that ART can be delivered effectively in Africa, with individual biological and immunological responses to ART equivalent to those in high-resource settings –9. NatioConcern has been raised that the rapid expansion of HIV services will reduce the quality of care for individuals within the programs as capacity and resources are stretched . CharactThe AIDS Prevention Initiative in Nigeria (APIN) and Harvard School of Public Health HIV program, supported by a grant from the United States President's Emergency Plan for AIDS Relief (PEPFAR), has supported the provision of treatment and care services to HIV-infected patients at the Jos University Teaching Hospital (JUTH), North Central Nigeria, since 2004. All patients enrolled in the JUTH PEPFAR supported program provided written consent for care; data for those that also consented for use of their information in future analyses were evaluated. The treatment protocol and written consent were approved by the institutional review boards (IRBs) at JUTH and the Harvard School of Public Health. Approval for secondary use of treatment data for this study was also obtained from the IRB at the Harvard School of Public Health.3 and for those individuals with WHO clinical stage 3 or 4 and CD4 counts <350 cells/mm3. Recommended first-line ART included a nonnucleoside reverse transcriptase inhibitor (NNRTI) plus 2 nucleoside reverse transcriptase inhibitors. Once patients were assessed for eligibility, they were asked to return for both group and individual counseling and education sessions to prepare them for ART. During the first year of HAART, all patients had baseline evaluation. This was repeated at 3 and 6 months. Those with detectable viral loads at 6 months had their next evaluation at 9 months. However, those with undetectable viral loads at 6 months had their next evaluation at 12 months, provided that there were no adverse events to warrant more frequent monitoring. Laboratory monitoring for follow-up included hematological indices, biochemical parameters including liver enzymes, serum creatinine, fasting blood sugar, and total cholesterol, and CD4 count and viral load monitoring.This retrospective cohort analysis was performed using routine treatment data from patients enrolled at a tertiary hospital: Jos University Teaching Hospital (JUTH), (prime site or “hub”) and 13 secondary-level health centers (satellite sites or “spoke”) between June 2007 and May 2011. ART eligibility was based on the Nigerian National Adult ART Guidelines , with ARThe study cohort consisted of ART-naive patients ≥15 years of age for whom at least 6 months of treatment follow-up were available.CD4 count measurement was performed using laser-based flow-cytometric enumeration technique . Plasma HIV-1 RNA polymerase chain reaction determination was performed using the Roche Amplicor Monitor assay, version 1.5 . All laboratories participate in regular external quality-control programs for HIV infection diagnosis, CD4+ cell count enumeration, and plasma VL estimation. At the prime site, HBsAg was determined using enzyme immunoassay (EIA)  and HCV antibody was tested using third generation EIA . At the satellites, hepatitis status was determined using rapid test kits .Patient data were collected on standardized clinic forms and entered into a customized electronic record database (FileMaker Pro) by trained data staff at each site. Baseline evaluations included medical history, physical examination, WHO clinical staging, complete blood counts, CD4 count, and plasma VL. These same clinical and laboratory evaluations were performed 3 and 6 months after ART initiation and then approximately every 6 months thereafter unless symptoms required more frequent monitoring.From June 2007, the Harvard PEPFAR/APIN Plus program at JUTH commenced statewide provision of ART services in Plateau State. This was accomplished using the “hub-and-spoke” model . The hubNone of the satellite sites had experience with implementation of comprehensive ART services. However, all of them were providing HCT and single-dose nevirapine based PMTCT services prior to the scale-out process. Each of the secondary-level facility was in turn linked to at least three primary health centers (PHCs).The first step began in 2006 with site assessment and selection. Sites were chosen based on the following criteria: (i) availability of medical doctors/nurses/laboratory scientists/pharmacists and other support staff; most cadres of health care personnel were present at the satellite sites; however, they were present in limited numbers compared to the tertiary site where the absolute numbers of staff were higher; (ii) available HIV testing and counseling (HTC) services; (iii) the presence of adequate counseling and consulting rooms; (iv) capability for safe and secure storage of drugs; and (v) number of patients in need of treatment. Facilities that had adequate patient load but failed to meet the minimum criteria received health systems strengthening and logistical support to operate comprehensive HIV services. The next step involved capacity building and training of health workers using standardized national training tools. In addition to centrally organized trainings, each satellite site received weekly mentorship visits from the satellite team. The team comprised of specialist physicians, an obstetrician, nurse counselors, data personnel, laboratory scientist, and pharmacist. The team visited the sites on their clinic days and provided hands-on training. The third step involved the roll-out and implementation of comprehensive ART services through integration of ART follow-up visits with primary outpatient care services at the satellites. Patients were decentralized for ART follow-up from the prime site to the satellites if they met several criteria: (i) adults or older children on first-line ART  for more than 6 months and stable; (ii) no evidence of active opportunistic infection or drug intolerance; (iii) ART provider's confidence in patient adherence; at enrollment, all patients were given general HIV/ART counseling on one-on-one basis and had at least two contacts with the counselors before commencement of HAART; in addition, adherence was assessed at each clinic visit using patient recall and our electronic pharmacy database; and (iv) patient living closer to satellite than to prime site.The details of the various roles of health care staff at both levels of care are shown in t-tests for continuous variables. We compared immunovirologic outcomes between the prime and satellite sites at 24 and 48 weeks. We also compared change in body weight, hemoglobin levels, and time to HAART initiation (defined as the period between enrollment for care and the pick-up of the first ART prescription) between the sites. Cox proportional hazard model was used to evaluate the relationship between decentralization and the risk of death. In addition, we assessed the risk of virologic failure (VF)  at 12 months of follow-up using a logistic regression model. The 48-week end point viral load data was available for 648 patients  and these were the number of patients analyzed for the VF outcome. Adjustments in multivariate analysis were made for sex, age, clinical stage at initiation, baseline anemia, elevated creatinine, CD4 count, program site, and educational status. Data analysis was performed using Epi Info version 3.5.3  and plots created using the Microsoft Excel graph feature. P values <0.05 were considered significant.Differences between groups were compared using the Chi-square test for categorical variables and P < 0.001). 4712 (60.8%) were married and 1394 (17.8%) reported having no formal education. The median CD4 count at enrollment was 180 cells/mm3 (IQR: 4–1481) and males enrolled for care at a lower CD4 count compared to females . A higher proportion of males (65%) than females (51.2%) (P < 0.001) entered care with CD4 < 200 cells/mm3. There were 2195 (28.3%) patients with advanced WHO disease and the prevalent TB rate for the entire cohort was 10.1%. The details of baseline comparison between patients at the satellite and prime sites are shown in The enrollment of patients by site and flow from recruitment to inclusion in this study is shown in For immunologic outcome, we compared absolute CD4 count as well as median increase from baseline over time points . In spitP < 0.001). There was no significant difference in the weight and hemoglobin levels of the patients at the two sites at the end of the first year of treatment. The details of clinical and laboratory outcomes and follow-up data are shown in Time in care refers to time since enrollment, which encompasses both the pre-ART and ART periods, whereas time on HAART refers only to the period spent on HAART. These two end points differed significantly between the satellites and prime site at the end of one year. Time to ART initiation was significantly longer at the satellite sites, compared with the prime site  become less common and cease to threaten survival in PLHIV. Achieving and maintaining adequate level of CD4 counts is important as many OIs are prevented when CD4 counts rise above 200 cells/mmn Africa –25 have Routine virologic monitoring, though uncommon in HIV treatment programs in resource-limited settings, remains the gold standard for early detection of treatment failure. Recent endorsement by WHO of virologic monitoring for patients on HAART gives the best picture of treatment response, and the ability to maximally suppress viral loads to undetectable levels is a key outcome in ART programs. We found more than half of our patients achieving undetectable viral loads at one year of treatment. Studies –29 have We used time to ART initiation as one of our outcome measures in this study and found that patients at the satellite sites had longer waiting time to commencement of ART compared to patients at the prime site. This may be explained by the fact that the prime site was better resourced and could decide ART eligibility at an earlier rate. Studies reporting delays in ART initiation have cited various factors being responsible for such delays –34. TimeThe treatment model described here, a decentralized program with treatment delivered through the hub-and-spoke model, has allowed rapid scale-up, with an additional 7075 adult patients enrolled for care with 4880 initiating ART in a 4-year period. The rapid increase of ART initiation in the satellite sites is encouraging and suggests that the availability of care at the secondary level reduces the common barriers (travel time and cost) to ART uptake. Other aspects of HIV care, such as pre-ART monitoring and long-term adherence support, will be required to maintain delivery of high quality care as we scale comprehensive HIV services down to secondary and primary levels of care.One of the strengths of this study is that our data originates from operational real-life program information collected as part of routine monitoring and evaluation from a public donor-supported HIV program in a high burden country and may therefore reflect the challenges faced with implementation of public sector programs in many resource-constrained settings. Secondly, we have an electronic medical record system that includes clinical laboratory and pharmacy data, which improved access to longitudinal data for the over 7000 patients included in this analysis. Thirdly, outcomes such as CD4 counts and viral loads required optimal adherence to the APIN ART monitoring protocol. One of our concerns was regarding the accuracy and consistency associated with use of operational data. Differential censoring due to missing data between different levels of care could not be completely discounted. Our mortality estimates may be underestimates because we did not have access to any public registries. However, our program has a tracking unit that routinely generates a list of patients lost to follow-up and this enabled us to document the exact disposition of some patients who may have died outside of the health care setting. Finally, our study is limited by the short follow-up of 12 months and further studies will be required to evaluate differences in health care provision and outcomes beyond the first year of ART, particularly retention and subsequent viral suppression rates.In conclusion, we have shown that rapid scale-up of ART delivery through a decentralized secondary-level care program is feasible in our resource-limited setting and produces outcomes comparable to those reported in other SSA settings. The high rates of detectable viral load in patients on ART at our satellite sites highlight the challenges of program implementation at less well-resourced health centers and efforts have been made to intensify support for medication adherence and to maintain quality of care by health systems strengthening as we scale out to secondary and primary facilities.


Assessing virological response of four-drugs antiretroviral regimen that include raltegravir (RAL) in naïve patients with high viral load  selected from a multicentre Italian database.Naïve patients with HIV RNA>500,000 copies/mL, who began standard antiretroviral regimens either based on non-nucleoside reverse transcriptase inhibitors (NNRTI) or boosted-PI (PI/r), or a standard regimen plus RAL between 2008 and 2013 were analyzed. Observation was censored at 12 months and the percentage of patients who achieved a viral load below the limit of detection (BLD) was calculated. Virological failure was defined as two consecutive viral loads>40 copies/mL.Overall, 179 patients were included (13% with primary HIV infection (PHI), and 42.5% with AIDS diagnosis). Of them, 156 started standard three-drugs antiretroviral regimen , 6 (25%) started a four-drugs antiretroviral regimen containing both RAL and PI/r. Patients’ characteristics were as follows: males 74%, median age 42 years (IQR 35–51), sexually transmission 75.1%, median CD4 count 156 cells/µL (IQR 47–368) and median HIV-RNA 6.1 log10 copies/mL (IQR 5.8–6.4). 91 of 179 patients (50.8%) reached BLD viral load during the twelve months of observation. Three patients (1.7%) who began regimens PI/r-based with three-drugs had virological rebound after reaching BLD viral load. By use of survival analysis, we show that those patients who added RAL to the standard regimen have reached the primary end point faster (mean 8.4 months (95% CI 7.2–9.6) vs 11.4 (95% CI 11.0–11.8) in PI group and 10.3 (95% CI 9.4–11.1) in NNRTI group; p<0.001, Only half of the naïve patients who began antiretroviral therapy having >500,000 copies/mL HIV-RNA had virological success at 12 months. The success was reached faster using the RAL-containing four-drugs regimen, suggesting that strengthening the initial regimen could be an option in patients with very high viral load to improve virological response.


Paediatric antiretroviral treatment (ART) failure is an under-recognized issue that receives inadequate attention in the field of paediatrics and within HIV treatment programmes. With paediatric ART failure rates ranging from 19.3% to over 32% in resource limited settings, a comprehensive evaluation of the causes of failure along with approaches to address barriers to treatment adherence are urgently needed.In partnership with the local Department of Health, a pilot programme has been established by Medecins Sans Frontieres (MSF) in Khayelitsha, South Africa, to identify and support paediatric HIV patients with high viral loads and potential treatment failure. Through detailed clinical and psychosocial evaluations and adherence support with an innovative counselling model, treatment barriers are identified and addressed.Demographic and clinical characteristics from the cohort show a delayed median start date for ART, prolonged viraemia including a large number of patients who have never achieved viral load (VL) suppression, a low rate of regimen changes despite failure, and a high percentage of pre-adolescent and adolescent patients who have not gone through the disclosure process.Stemming this epidemic of paediatric treatment failure requires programmatic responses to high viral loads in children, starting with improved “case finding” of previously undiagnosed HIV-infected children and adolescents. Viral load testing needs to be prioritized over CD4 count monitoring, and flagging systems to identify high VL results should be developed in clinics. Clinicians must understand that successful treatment begins with good adherence, and that simple adherence support strategies can often dramatically improve adherence. Moreover, appropriate adherence counselling should begin not when the child fails to respond to treatment. Establishing good adherence from the beginning of treatment, and supporting ongoing adherence during the milestones in these children's lives is key to sustaining treatment success in this vulnerable HIV-infected patient population. While great progress has been made in the last 15 years in the field of paediatric HIV diagnosis and treatment, a growing problem has emerged that threatens to undermine much of the work that has been done. Paediatric antiretroviral treatment (ART) failure is an under-recognized issue that receives inadequate attention in the field of paediatrics and within HIV treatment programmes. This is in part due to a general absence of viral load (VL) testing in countries with a high burden of disease and limited resources, as well as the long-held belief that immunologic immaturity in children prohibits or prolongs VL suppression. While few studies have fully evaluated cohorts of children with virologic failure, rates of failure in the paediatric age group are reported to range from 19.3% to over 32% in resource limited settings [In Khayelitsha, there is a high HIV burden  –7. CurreIn July 2013, MSF partnered with the Department of Health to develop a pilot programme to identify and support paediatric and adolescent patients with high VLs. The programme consists of a comprehensive evaluation of each patient's medical and psychosocial history, HIV and general paediatric clinical care, structured adherence support through counsellor facilitated support groups, combined clinical/adherence clinician consultations, and home visits when possible by community care workers. Patients aged 0–19 years are eligible for enrolment if their previous VL is >1000 RNA copies/ml or their previous two VLs are >400 RNA copies/ml. Patients come for a series of visits (mostly once a month) and attend group and individual support sessions at each visit. High rates of paediatric virologic failure were observed in a well-established primary care HIV setting, in line with data obtained in previous studies ,2. The mTo stem this epidemic of paediatric treatment failure, programmatic responses to high VLs in children need to be strengthened. First and foremost, improved “case finding” of previously undiagnosed HIV-infected children is urgently needed to prevent the long-term sequelae of untreated HIV infection in young children. Second, VL testing of children should be prioritized over CD4 count monitoring in settings with limited resources; VL monitoring reduces the time failing treatment, increases appropriate switching to second-line ART, and minimizes immunologic decline. To this end, simple flagging systems for high VLs can assist clinics to identify those patients with high VL results and can be instituted with minimal resources in every HIV clinic that treats children. Third, clinicians need to understand that the most important factor in good paediatric HIV care begins with achieving good adherence. Often it is simple adherence support strategies that clinicians can use in busy clinics that greatly improve the quality of patient support that children and their caregivers receive. Lastly, adherence support should not start when the child has a high VL. Appropriate counselling should begin during the process of ART initiation and continue to be re-assessed as the child reaches developmental milestones. Too often, proper basic adherence counselling is only provided once the child has begun failing treatment. Periodic ongoing counselling is essential with paediatric patients since their psychosocial situations frequently changes and new adherence barriers often arise.In summary, one third of children aged 0–19 years were failing antiretroviral therapy in two longstanding primary care HIV clinics, with 33% never achieving viral suppression after initiation of ART. Only by addressing the core deficiencies in paediatric HIV care – insufficient early diagnosis of HIV-infected children, lack of VL monitoring and clinician comfort in how to respond to high VLs, and unstructured and inadequate adherence counselling – will we begin to achieve durable VL suppression in the paediatric HIV population and curb this silent epidemic.


In 2015 South Africa established a national cryptococcal antigenemia (CrAg) screening policy targeted at HIV-infected patients with CD4+ T-lymphocyte (CD4) counts <100 cells/ μl who are not yet on antiretroviral treatment (ART). Two screening strategies are included in national guidelines: reflex screening, where a CrAg test is performed on remnant blood samples from CD4 testing; and provider-initiated screening, where providers order a CrAg test after a patient returns for CD4 test results. The objective of this study was to compare costs and effectiveness of these two screening strategies.We developed a decision analytic model to compare reflex and provider-initiated screening in terms of programmatic and health outcomes  and screening and treatment costs (2015 USD). We estimated a base case with prevalence and other parameters based on data collected during CrAg screening pilot projects integrated into routine HIV care in Gauteng, Free State, and Western Cape Provinces. We conducted sensitivity analyses to explore how results change with underlying parameter assumptions.In the base case, for each 100,000 CD4 tests, the reflex strategy compared to the provider-initiated strategy has higher screening costs  but lower treatment costs , so overall costs of screening and treatment are $17,629 less with the reflex strategy. The reflex strategy saves more lives . Sensitivity analyses suggest that reflex screening dominates provider-initiated screening  or saves additional lives for small additional costs (< $125 per life year) across a wide range of conditions .In countries with substantial numbers of people with untreated, advanced HIV disease such as South Africa, CrAg screening before initiation of ART has the potential to reduce cryptococcal meningitis and save lives. Reflex screening compared to provider-initiated screening saves more lives and is likely to be cost saving or have low additional costs per additional year of life saved. Cryptococcal meningitis (CM) is a leading cause of death among HIV-infected patients with low CD4+ T-lymphocyte (CD4) counts. Further, patients with undiagnosed cryptococcal disease at time of antiretroviral treatment (ART) initiation are at high risk for death from immune reconstitution inflammatory syndrome (IRIS) –3. CryptAs of 2015, the South African government recommended that “HIV-positive adults with a CD4 count <100 cells/μl should be screened for cryptococcal disease before ART is started” . The relIn this paper, we present a decision-analytic model to compare reflex and provider-initiated CrAg screening strategies based on costs (2015 USD), disaggregated into screening, preemptive treatment to avoid hospitalization, hospital, and post-hospital costs, and health outcomes (lives saved and years of life saved using a 3% discount rate). Although prior research has shown that CrAg screening prior to ART initiation is cost effective, alternative strategies for CrAg screening have not been compared systematically. Thus, the focus here is on the difference in costs between the two strategies, the difference in health outcomes achieved, and the incremental cost effectiveness of reflex compared to provider-initiated screening.Of particular interest is the impact of provider and patient adherence to the different strategy protocols. The provider-initiated strategy places responsibility on providers to assess correctly patient eligibility for CrAg screening, while the reflex strategy does not. Both strategies require patients to return for a second visit. High rates of loss-to-follow-up after HIV diagnosis are well documented in South Africa and elsewhere –18, whicWe parameterize the model for a base case using program evaluation data observed during large- scale pilot CrAg screening programs in Gauteng, Free State, and Western Cape Provinces . AdditioReflex and provider-initiated strategies were modeled in two stages: the screening stage and the treatment stage. The screening stage identifies two main categories of patients for the treatment stage: (i) incident CrAg positive patients identified for preemptive treatment; and (ii) incident CrAg positive patients missed by the screening program who also develop CM (discussed in more detail below).In the treatment stage, costs include outpatient fluconazole treatment for patients identified for preemptive treatment in the screening stage. Treatment costs also include hospitalization and post-hospital treatment for patients who develop CM, which includes some patients missed by the screening program and patients identified for preemptive treatment who may still develop CM. A patient’s outcome in the screening stage determines where they enter the treatment stage. The structure of the treatment cost module is the same for both strategies; only the starting numbers of patients in each arm of the model differ (based on the results of the screening program).A key starting point for this analysis is CrAg prevalence in the target population at the time of CD4 count testing. While CrAg prevalence in some populations has been reported in many prior studies , 20, 21,The remainder of this section works through the screening and treatment cost modules. Tables The screening stage for the reflex strategy is described in Figs Under the reflex strategy, 10% of blood samples have a CD4 count < 100 cells/uL; 95% of these are tested for CrAg, with the remaining 5% not tested due to non-adherence to guidelines by lab personnel . In 2014Among the 5% of samples that are not tested, the base case assumption is that 80% are from patients who are pre-ART . This is based on CD4 results from eight Right to Care-supported public clinics in Gauteng Province from 2013. Although the South African CrAg screening guidelines specifically target patients who are not yet on ART, reflex lab screening procedures do not identify patients with low CD4 counts who are on ART. Since patients on ART are not the intended targets for CrAg screening , arm 1, Among those not screened, we use existing program data to estimate that 95.4% are CrAg negative , arm 3, Among these CrAg positive patients who are missed by the screening program, because they were not screened, the base case assumption in Actual data on the proportion of CrAg positive individuals, with low CD4 counts and CSF negative at the time of CD4 testing, who then develop CM does not exist for a large population of HIV-infected patients (whether there is rapid initiation of ART or not). The implications of these assumptions are explored further through sensitivity analysis following the presentation of main results.Among the 95% of reflex samples tested for CrAg , 80% areFor the base case , among tAmong the 60% of pre-ART patients who return ‘quickly enough’ to the clinic for a second visit, 95.4% are CrAg negative, 1.6% are positive and have had prior CM, and 3% are incident CrAg positive patients . The incBased on the model outlined in Figs The logic of the provider-initiated screening module, presented in Figs The first key difference between the two strategies is that, with provider-initiated screening, patients need to return ‘quickly enough’ for their CD4 results, and also then return ‘quickly enough’ to collect CrAg results (two return visits to complete CrAg screening are needed with the provider-initiated policy rather than the one needed for the reflex policy). In A second key difference between the two screening strategies is that provider-initiated screening allows clinicians to target CrAg screening to the intended group of patients: those who are pre-ART and with CD4 count < 100 cells/μl. In A third key difference between the two strategies is provider adherence to screening guidelines. With the reflex policy, 95% of all patients who should be screened for CrAg are screened (in addition to patients who are not the target of the screening program), and CD4 count and CrAg results are available to the clinician simultaneously. With the provider-initiated policy, which depends on provider decision-making, such high levels of adherence to guidelines cannot be assumed. Experience from the Western Cape Province, which implemented the provider-initiated policy, showed low adherence to guidelines, with some modest improvement over time  . AssuminReturning to Of the 48% of patients with CD4 count < 100 cells/μl who return for CD4 results, providers request CrAg tests on 40% of these patients. For the remaining 60% not tested for CrAg, again 3% are incident CrAg positive . As withThe patients actually screened for CrAg need to return quickly enough (their third visit to the clinic within 28 days) to obtain their CrAg results. Data are currently not available to be able to provide a reasonable estimate for this parameter. As a base case, we assume that 80% of these patients return within 28 days, and 20% do not. A high proportion, such as 80%, seems plausible because these are patients who already returned quickly for CD4 results, know their low CD4 results, and are likely to be motivated to return again quickly.Among patients tested for CrAg who do not return quickly enough (20% of those tested), 3.0% are incident CrAg positive with the same structure of outcomes (missed and developed CM) as in Based on the model outlined in Figs Far fewer patients will be screened for CrAg with the provider-initiated policy in part because screening is avoided for patients already on ART. In addition, patients who should be screened are not because they do not return for CD4 results and providers do not order the CrAg test.missed in the screening stage who develop CM . A small number of patients have this endpoint, so the additional treatment costs and health outcomes are essentially irrelevant for a policy comparison.Most patients identified for preemptive treatment initiate treatment (90%). Current guidelines in South Africa for preemptive care of identified CrAg positive patients are 800mg of fluconazole for 2 weeks prior to the initiation of ART, followed by initiation of ART and continuation of daily fluconazole, 400mg for 8 weeks and then 200mg daily for at least 1 year until CD4 counts are > 200 cells/μl., 27 The Some incident CrAg positive patients will also receive a lumbar puncture to assess CSF status, whether symptomatic or asymptomatic, after receiving their CrAg test results, at the same visit or a future visit perhaps to another facility. The costAmong the patients initiated on preemptive fluconazole, some will be treated successfully and some will fail on preemptive treatment and develop CM (or be diagnosed as CSF positive after a lumbar puncture). Among those initiated on preemptive treatment, an estimated 39.7% will fail preemptive treatment, which combines the 33% of patients already CSF positive at time of preemptive treatment initiation as well as a small share (10%) of those CSF negative. The remaining 60.3% initiated on preemptive treatment will not develop CM. Of the patients who develop CM after initiating preemptive treatment, 80% are hospitalized, of whom 68% survive. Of the patients who survive hospitalization, 75% are successful on maintenance fluconazole. The 20% of patients who fail preemptive treatment, but are never hospitalized and die at home, may have failed on preemptive fluconazole due to being CSF positive at time of fluconazole initiation of lack of patient adherence to fluconazole.Parameter assumptions related to the costs of screening and treatment as well as health outcomes are presented in Under the provider-initiated strategy, the CrAg test is completed as a separate test, which requires additional provider time, an additional blood draw, additional transport to lab, additional data entry into electronic data systems, etc. Thus, the unit cost for one CrAg test will be higher with the provider-initiated policy. As a base case, we assume a 25% cost differential between the two strategies for a cost of $6.19 for provider initiated CrAg testing.Patients started on preemptive fluconazole treatment, and who fully adhere to a one-year treatment course, require 533 tablets (200mg each). The cost per 200mg tablet is $0.056, for a total cost of $30.09. The price per tablet is based on the most recent negotiated fluconazole tender in South Africa at the time of this analysis (2015). The cost in USD looks especially low because of the very weak exchange rate in 2015 (ZAR/$15). Not all patients will complete the full year of preemptive treatment. For the base case, partial adherence is defined as taking 66% of the total prescribed annual amount .For patients with CM successfully treated in the hospital (with 14 days of amphotericin B and related services and hotel costs), we use recently published data on hospitalization costs per day in South Africa to estimate the costs of a full 15-day hospital stay at $1950 ($130 per day). Compared to basic hotel costs, the costs of services provided in the hospital  are relatively minor. As an alternative, hospital costs would be slightly lower if we used the detailed information on hospital services and costs reported in Jarvis et al. (see ), and thThose who do not survive the hospital are assumed to require six hospitalized days on average , at a toPatients can have three primary outcomes at the end of the treatment module: survived, died, unknown. In the treatment cost module, patients in For comparing the two screening strategies, health outcomes are based on known lives saved from screening and treatment as well as patients missed by the screening program who do not develop CM. When comparing the two strategies, the difference in this outcome is the additional lives saved from reflex compared to provider-initiated screening. For patients who die from CM, the base case assumption is that the average age of death is between 35–39 years. For this age range, average life expectancy is 32.6 additional years . With a 3% discount rate and 32.6 years of life lost from a death, 21.6 discounted years of life are lost per death, or conversely 21.6 years of life are saved per avoided death.Patients with CM experience serious symptoms and disability whether receiving treatment or not. Thus, in general, the period of time lived disabled due to CM disease prior to and during treatment could be added into the analysis (with disability adjusted life years (DALYs) lost as the combined health outcome). However, the time period for disability for these patients is fairly short (they either respond to treatment or die within one year), so the “years lived disabled” component of DALYs before completion of treatment will be minor for CM compared to the “years of life lost” component .In addition, patients who survive their hospital stay and complete the post-hospital fluconazole treatment could have long-term impairment from CM despite surviving. For example, disability weights for meningitis-related conditions used previously in the Global Burden of Disease estimates are, for example, deafness = 0.229; intellectual impairment = 0.456; and motor deficit = 0.380.[In the base case population of 100,000 patients who receive a CD4 test, 8,000 have a CD4 count <100 cells/μl and are not yet on ART. The goal of screening is to identify the 240 patients out of 8,000 who are not yet on ART, with incident CrAg (no prior CM). In the absence of a screening program, all of these patients are missed. In the presence of a screening program, with the base case assumptions and analysis presented in Figs From From In the base case summarized in In terms of health outcomes, the reflex policy is also estimated to save an additional 30 lives per 100,000 CD4 tests . Note that these are estimates of additional patients “known” to be living at the end of the treatment stage; any patients in the treatment arms with indeterminate final health outcomes (CM relapse) are not included in this estimate, but their treatment costs are included. For reference, there are 21 patients in the reflex policy treatment module and 28 patients in the provider-initiated treatment module with this indeterminate health outcome . We first consider 5 initial scenarios (denoted as SA1-SA5) beyond the base case, and key results are summarized in As noted in Compared to no screening, previous studies have shown that CrAg screening prior to the initiation of ART for patients with baseline CD4 counts < 100 cells/μl is a relatively low cost or cost-saving policy that also saves lives . This will remain true as long as a baseline CD4 count continues to be required prior to the initiation of ART, even if in the future, CD4 thresholds disappear as an eligibility criterion for ART initiation.The question addressed in this analysis is: how best to organize a screening program in a given setting? The model developed for this analysis and the results reported in Tables As with any policy, efficient operational implementation is critical to achieving program targets. In particular, the important first step is to support patients to know their HIV status and present for care when their CD4 count is still well above 100 cells/μL. The second key step is to get patients to return for CD4 results relatively quickly. In South Africa, patients are typically counseled to return in one week, which if adhered to, provides a good opportunity for CrAg-positive patients to benefit from early treatment. Given that NHLS typically completes CD4 tests within 48 hours, opportunities to shorten the return-for-CD4 results period could be evaluated further.Third, screening and provision of preemptive fluconazole treatment must be simultaneously implemented. While a relatively small number of NHLS laboratories provide the bulk of CD4 tests completed in the country, thousands of Primary Health Centers (PHCs) initiate patients on ART. Based on estimates of 200 mg fluconazole tablets needed per 100,000 CD4 tests in As with most modeling analyses, limitations follow from the need to develop model parameters based on data from several sources . As much as possible, parameters for this analysis were generated from a recent evaluation of CrAg screening programs in South Africa . As showBesides the reflex and provider-initiated CrAg screening policies currently included in South Africa’s HIV guidelines, additional strategies have been discussed or may be relevant in the future. First, for example, point-of-care (POC) CrAg screening as part of a provider-initiated approach, using a lateral flow assay (LFA) method when a patient returns for CD4 results, is possible. However, unless paired with a POC CD4 test, this approach does not provide CrAg results to patients any sooner than the reflex policy, but would eliminate the need for a third return visit under a provider-initiated policy. While the CrAg LFA can be performed relatively easily as a POC test, a large scale program of training, quality control, supply chain management, and data systems would need to be developed for POC CrAg screening to be implemented across thousands of PHCs with equivalent quality to current lab-based CrAg screening . The addSecond, in the future quantitative CrAg tests, reporting a CrAg titer to better differentiate disease status, may help target those who should receive preemptive treatment with fluconazole and who should be admitted and treated with amphotericin. While beyond the scope of the current paper, the existing model could be adapted to such strategies for assessing costs and effectiveness.prior to the initiation of ART as is the case for countries considering “test and treat” policies.And third, all patients testing positive for HIV could be prescribed an initial short-course of fluconazole, or perhaps only patients clinically suspected to have a low CD4 cell count based on WHO staging or some other criteria, while awaiting CD4 results. When these patients return for their CD4 result and CrAg result (if CD4 < 100 cells/μl and with reflex screening), those testing CrAg negative would stop fluconazole treatment and immediately initiate ART, while those CrAg positive would continue with preemptive treatment prior to initiating ART. Future research is needed to evaluate the health risks and benefits of such an approach. However, the logic of this third approach becomes more relevant if CD4 test results are not required as long as a baseline CD4 count continues to be included in national guidelines prior to the initiation of ART. Even if all HIV patients are eligible for ART, regardless of CD4 counts, the question remains if a baseline CD4 count will be required prior to initiation of ART or not.CrAg screening prior to the initiation of ART is a relatively low cost or potentially cost saving policy prior to initiation of ART, then a reflex CrAg screening strategy imposes no additional delays on ART initiation for the vast majority of patients. For the relatively few total HIV-infected patients with low CD4 counts who are CrAg positive, appropriate treatment  can still begin prior to initiation of ART.If guidelines under new test-and-treat policies still include baseline CD4 counts and other laboratory tests prior to the initiation of ART becomes more complicated if policies change to same-day ART initiation after an HIV diagnosis . If an immediate test-and-treat approach is implemented as a national policy, CrAg screening before initiation of ART would require both provider-initiated POC CD4 and CrAg testing. Alternatively, CrAg screening after initiation of ART (perhaps implemented discussed above) would need to be evaluated further.However, CrAg screening To date, all analyses of CrAg screening have assumed the presence of CD4 results to target screening. In the absence of such information, future research is needed to compare non-CD4 based strategies for screening, as well as the benefits of CrAg screening for the small proportion of newly-diagnosed HIV-infected patients with low CD4 counts who are incident CrAg positive to the possible costs of delaying ART initiation for the vast majority of all patients (those with CD4 counts > 100 cells/μl and those with low CD4 counts who are CrAg negative).This costing analysis was based on routinely-collected aggregated program data, publically available information, and aggregated results from evaluation studies. No human subjects data were used.S1 Appendix(DOCX)Click here for additional data file.


To investigate the duration of sequential HAART regimens and predictors of first-line regimen discontinuation among HIV-1 vertically infected children and adolescents.Multicentre survey of antiretroviral-naïve patients enrolled in the HIV-Paediatric Cohor,t CoRISpeS-Madrid Cohort, Spain.Patients with a follow-up of ≥1 month spent on HAART, with available baseline CD4 count and HIV-viral load (VL) were included. Time spent on sequential HAART regimens was estimated and multivariable regression was used to identify predictors of time to first-line regimen discontinuation.10 copies/mL. Patients received a mean of 1.9 regimens. Median time on first-line HAART (n = 104) was 64.5 months; second HAART (n = 56) 69.8 months; and third HAART (n = 21) 66.5 months. Eleven (11%) patients were lost to follow-up while on first-line HAART and 54% discontinued . The main predictor of first-line regimen discontinuation was suboptimal adherence to antiretrovirals .104 patients were followed for a median 8 years after starting HAART among 1996–2012; baseline %CD4 was 21.5 (12.3–34.0)and viral load was 5.1 (4.6–5.6) logAdherence to therapy was the main determinant of the duration of the first-line HAART regimen in children. It is important to identify patients at high risk for non-adherence, such as very young children and adolescents, in provide special care and support to those patients. Comunidad Autónoma de Madrid accounted for the 26% of the AIDS cases associated to HIV-1 vertical transmission, most of them now, older children The introduction of highly active antiretroviral therapy (HAART) to medical care for vertically HIV-1-infected children has increased life expectancy and resulted in a substantial decline in AIDS incidence In this study, we evaluate the determinants of first-line HAART discontinuation in a large cohort of HIV-1-infected paediatric patients from Madrid, Spain. The findings of this study provide valuable information for the management of paediatric HIV-1-infection.The study was conducted according to the Declaration of Helsinki and was approved by the Ethical Committees of each participating hospital of the HIV Paediatric Cohort (CoRISpeS-Madrid Cohort) working group. Written informed consent was obtained from all parents or tutors.Comunidad Autónoma de Madrid (CoRISpeS-Madrid Cohort) was established in 1995 as an open cohort of all HIV-1 vertically-infected children identified in a multicentre network of referral paediatric hospitals based in the Comunidad Autónoma de Madrid (see Annex). HIV-1 vertical transmission was assumed to have occurred on the date of birth The HIV Paediatric Cohort of the The present survey was conducted according to the Declaration of Helsinki with the approval of the Institutional Ethics Committee. Patients were selected retrospectively for this survey and were eligible if they had no history of antiretroviral treatment when they initiated their first HAART regimen. The other eligible criteria were: a follow-up of ≥1 month spent on HAART; available baseline CD4 count and HIV-1 RNA viral load (VL). The study period for inclusion of patients was from 1996 to 2012. Individuals were followed from the date of HAART initiation until the date of death, or date of last visit in case of lost to follow-up, or December 31, 2012 (administrative censoring date), which ever occurred first. VL was measured by Amplicor Monitor assay  with a detection limit 50 copies/mL. Several biological samples were provided by the HIV HGM BioBank a priori, because approval of lopinavir/ritonavir could have led to change in treatment management Demographics, clinical, immunological and virological data and HAART use were gathered retrospectively. Clinical classification of AIDS-defining events was based on international guidelines Demographic and baseline characteristics and antiretroviral therapy use are presented using descriptive statistics. The primary endpoint was the time spent on sequential regimens and was estimated by Kaplan-Meier analysis with exact 95% confidence intervals (CI); log-rank test was used to compare survival curves. Time was calculated from the date of HAART initiation until the date of HAART change, or last visit in case of lost to follow-up, or December 31, 2012 (administrative censoring date), whichever occurred first. Univariate proportional hazards regression analyses were performed to identify factors associated with first-line regimen discontinuation, and multivariable proportional hazards regression analysis was performed that included all factors for which the results of univariate analysis were statistically significant (P<0.05) or close to the margin of statistical significance. The variables examined included demographic characteristics, social indicators, baseline laboratory values, HIV-1 subtype, clinical status, provision of antiretroviral prophylaxis to the paediatric patients and calendar period for HAART initiation.To ensure that outcome events could be correctly attributable to the type of regimen, when a substitution of a single drug caused the change from a protease inhibitor (PI)-based to a non-nucleoside reverse transcriptase (NNRTI)-base regimen or vice versa, the type of regimen was re-categorised on the basis of the longest regimen for each patient. Analyses were performed by using SPSS  and 2-tailed P-values <0.05 were considered statistically significant.Of 124 antiretroviral-naïve children who started HAART, 104 were eligible. They initiated HAART between 1997–2012 and had a median time of observation of 101.0 (51.9–139.8) months. At baseline, the majority of children  had VL >100.000 copies/mL and %CD4<25 . Other baseline characteristics are listed in Table S1 in Overall, the mean number of HAART regimens used was 1.9. Eleven (10.6%) children were lost to follow-up while on first-line HAART, 56/104 (53.8%) discontinued their initial regimen, one (1.0%) died of dideoxynucleoside-induced severe lactic acidosis and 36/104 (34.6%) remained under their first-line therapy. Of those, 10/36 (27.8%) had a single-drug substitution within the same class and 2/36 (5.6%) had a class change. Comparison with initial HAART regimen to successive regimens revealed that fewer salvage regimens based on a single PI and more with a boosted PI or four drugs were used (Table S1 in Comunidad Autónoma de Madrid (Spain) as it includes all the cases of vertical HIV-1 transmission that occurred in this area since the dawn of the epidemic in 1982 The availability of HAART has transformed the HIV-1 infection into a chronic and treatable disease. As perinatally-infected children likely require life-long treatment, the assessment of the duration of initial and successive HAART regimens is crucial. This study evaluated the duration of initial and successive HAART regimens and the predictors of therapy discontinuation in HIV-1-infected children of CoRISpeS-Madrid Cohort from 1996 up to 2012. This cohort is highly representative of the paediatric HIV-1 community throughout the Information on the duration of HAART in the paediatric population worldwide is still scarce. High rates of initial HAART change (78%) and an initial HAART duration of only 40 months were observed among children attending a Spanish hospital et al. reported a median duration of only 1.6 years, while the successive regimens were considerably shorter Additional information for the clinical management of HIV-1-infected children and adolescents derives from a limited number of studies that included HIV-1-infected adults. Some observational surveys corroborate our results, showing high rates of initial regimen discontinuation Missing baseline data were a limitation in this study, as did not allow the inclusion of all antiretroviral-naïve children enrolled in the Cohort who initiated HAART. Moreover, data on socio-economic status or specific treatment-related toxicities were available for a subgroup of the study population, thus we were not able to fully capture their effect on therapy discontinuation. Nevertheless, these missing data do not affect the overall HAART duration estimates. Despite the exclusion of some patients from this survey might represent a potential source of bias, it is of note that several characteristics of included and not included patients were comparable. Another limitation of this study is that adherence was not included in the analyses as a time-dependent variable. Notwithstanding these limitations, the long duration of initial HAART represents a relevant and encouraging finding, indicating that the likelihood that effective HAART will last a lifetime is possible. However, enthusiasm for these findings may be dampened by concerns for the risk of suboptimal adherence observed in those patients who might benefit from additional adherence strategies in routine clinical care.Paediatric hospitals of the CoRISpES-Madrid Cohort working group: Hospital Universitario “Doce de Octubre”, Madrid (29 patients); Hospital Universitario “La Paz”, Madrid (14 patients); Hospital Universitario de Getafe, Madrid (13 patients); Hospital Universitario “Carlos III”, Madrid (12 patients); Hospital General Universitario “Gregorio Marañón”, Madrid (12 patients); Hospital Infantil Universitario “Niño Jesús”, Madrid (8 patients); Hospital de Móstoles (7 patients); Hospital Príncipe de Asturias, Alcalá de Henares, Madrid (6 patients); Hospital de Torrejón de Ardoz, Madrid (3 patients).File S1amedian (IQR); bnumber (%); cmedian (95%CI); *C (n = 3), G (n = 2), A1 (n = 1), F1 (n = 1); **recombinant subtypes: CRF01_AE (n = 1), CRF02_AG (n = 10), CRF12_BF (n = 1), CRF13_cpx (n = 1); #3TC/ddI+d4T+NFV ; ##AZT/ABV +3TC+KLT ; ∧d4T+ddI+EFV ; ∧∧AZT +3TC+ABV+NVP ; ∧∧∧AZT +3TC+ddI . CRF, circulating recombinant form; HAART, highly active antiretroviral therapy; MTCT, mother-to-child transmission; PMTCT, antiretroviral prophylaxis of HIV mother-to-child transmission; CMV, cytomegalovirus; HBV, hepatitis B virus; NRTI, nonnucleoside/nucleotide reverse-transcriptase inhibitor; NNRTI, nonnucleoside reverse-transcriptase inhibitor; PI, protease inhibitor. Supporting Information Table S2, Characteristics of included and not included patients. Legend: $Fisher's exact test (2-tailed); $$Mann-Whitney U test (2-tailed). Supporting Information Table S3, Analysis of the cause of discontinuation of first-line HAART according to the type of regimen. Legend: NNRTI, nonnucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; *the underlying cause of death was dideoxynucleoside-induced severe lactic acidosis. Supporting Information Figure S1, Evolution of the percentage of the most frequent antiretroviral drug over time (A) and evolution of viral load (VL), %CD8 and %CD4 over time (B). Legend: Mean of log10 VL (copies/mL), CD8+ T-cell percentage and CD4+ T-cell percentage; bars represent 2 s.e.m. EFV, efavirenz; KLT, kaletra; NFV, nelfinavir.Supporting Information Table S1, Baseline characteristics and antiretroviral therapy use among the study population. Legend: (DOCX)Click here for additional data file.


Since 2004, the government of Tanzania has been rolling out antiretroviral treatment programs all over the country. However, the capacity of the health system to cope with the rapid scale-up of these programs is a major concern, and problems may result in drug stock-outs that force changes in treatment regimens. This study aims to explore stock-outs of antiretroviral drugs and further determine the coping strategies employed to prevent changes in treatment regimens in HIV/AIDS care and treatment clinics in Kinondoni District, Dar es Salaam, Tanzania.A cross-sectional study was conducted in 20 HIV/AIDS care and treatment clinics. Interviews were conducted with the person in charge and a member of the pharmacy staff from each clinic using a pre-tested semi-structured interview guide. Verbal responses were transcribed, coded and analysed by thematic approach. Quantitative data were analysed using Excel spreadsheet .The total number of clients enrolled in the visited clinics was 32,147, of whom 20,831 (64.8%) had already been initiated onto antiretroviral therapies (ART). Stock-out of antiretroviral drugs was reported in 16 out of the 20 clinics, causing 210 patients to change their ART regimens, during the 12 months preceding the survey. Inefficient supply systems, quantification problems and short expiry duration were cited as the main causes of stock-outs. The coping strategies utilised to prevent changes in ART regimens were: shortening of the refill period, borrowing and moving patients to other clinics.Changes in ART regimens due to stock-outs of antiretroviral drugs occurred in a small but significant number of patients. This increases the risk of the emergence of drug-resistant HIV strains. Healthcare workers use various coping strategies to prevent changes in ART regimens but, unfortunately, some of these strategies are likely to increase patient-borne costs, which may discourage them from attending their routine clinics, hence leading to unplanned treatment interruptions. A total of 34 million people were living with HIV/AIDS worldwide and 8 million were already on antiretroviral therapies (ART) by the end of 2011 [Tanzania has a population of about 45 million people , of whomBy the end of December 2012, about 1,176 approved health facilities, both public and private, were providing HIV/AIDS care and treatment services in Tanzania . The MedHIV/AIDS programs are largely funded by donors; some prefer to procure antiretroviral drugs through the MSD, while others use their own agents but rely on the MSD for storage and distribution to the clinics based on their program plans . The MSD3. The default first-line regimen was Zidovudine + Lamivudine + Efavirenz or Nevirapine. Other regimens include: Tenofovir + Emtricitabine + Efavirenz or Nevirapine and Tenofovir + Lamivudine + Efavirenz or Nevirapine [3 [In February 2009, the Ministry of Health and Social Welfare (MoHSW) launched the third edition of its national HIV/AIDS treatment guidelines, which recommended ART to be initiated for all patients with CD4 cell counts less than 200/mmvirapine . In Aprivirapine , followiapine [3 . This cuChanges in ART regimens due to stock-outs of antiretroviral drugs are common, particularly in low-income countries ,17. The This was a cross-sectional study conducted in 20 HIV/AIDS care and treatment clinics located in Kinondoni district in Dar es Salaam region. There were 12 public facilities in the sample, seven were private and one belonged to a parastatal institution. Half were hospitals and the rest were primary healthcare facilities. Five clinics were being used as refill centres for patients who had been initiated onto ART elsewhere.2) with 27 wards which are further subdivided into 127 hamlets. The district hosts about 1.7 million of the 4.5 million people living in Dar es Salaam [daladala with a capacity ranging from 16–35 passengers. During peak hours, usually in the morning and evening, these buses are overcrowded and roads are usually congested.The study was conducted in Kinondoni District, in Dar es Salaam, Tanzania. Dar es Salaam consists of three districts and is the main business city in Tanzania; it also hosts the headquarters of the Medical Store Department. Kinondoni is a typical urban area 531 km1 km2 witThe prevalence of HIV in Dar es Salaam among people aged 15–49 years in 2011–2012 was 6.9% . As of 2008, the municipality hosted 18 approved HIV/AIDS care and treatment clinics [Data was collected from April to May 2011, so this data set is almost three years old; hence the situation may not be the same if a similar study was to be conducted today. Data was mainly collected through in-depth interviews using a pre-tested semi-structured interview guide. Interviews were conducted in the study clinics and recorded by a digital audio recording device.The interview guide was composed of two sections; section one for the in charge of the clinic and section two for pharmacy staff The majority of participants mentioned various components of the pharmaceutical supply management system, such as quantification problems, inefficient distribution and expiration due to short shelf-lives as the main reasons for the stock-outs of antiretroviral drugs in their clinics. They said that many problems originate from the supplier side, as elaborated by one participant, who said the following:Most of the time I would say the problems begin at the Medical Store Department, because at times you place the order and you are told that certain medicines are out of stock. On other occasions they deliver antiretroviral drugs with very short shelf-lives which expire on the shelves shortly after they have arrived at the facility. (Participant from Facility 11)Regarding quantification, the majority of participants said that it is not easy to accurately predict the consumption rate of the medicines as the number of patients initiated onto ART is constantly changing. One participant said:When you want to place the order you need to know exactly how many patients will be initiated on antiretroviral treatments in that period, but if the number of patients keeps changing from time to time it becomes difficult to estimate. And if you order too many doses they may expire since some have a short shelf-life. (Participant from facility 9)Healthcare workers in the clinics which experienced shortages and stock-outs of antiretroviral drugs said that they use various strategies, described below, in attempts to prevent the need for patients to change their ART regimens.The majority of participants said that when they experience shortages of antiretroviral drugs, the first strategy they use is to shorten the refill period. Thus they give patients a smaller number of pills, usually sufficient to keep them on treatment for two weeks rather than a month. Then, after they have replenished their stock, they give them out on a monthly basis. One participant said the following:The major approach we use here when our stock falls is to shorten the refill period; instead of giving them a monthly dose we give them enough for a shorter time so that other patients can also get the medicines. For example, now the refill period for Efavirenz is two weeks instead of one month. If we do it like this every patient will get some pills for some time and if the drugs arrive on time they will receive the usual monthly dose when they come again to refill their prescriptions. (Participant from Facility 7)We learned through the interviews that some clinics place larger orders for antiretroviral drugs than they can use in order to cope with irregular increases in patient numbers or stock-outs at the central level. Therefore, it was not surprising that participants, mostly from clinics with a relatively small number of patients, said that they borrow from other clinics which may have a larger stock of the required antiretroviral drugs. One participant said:We usually borrow from other nearby centres when we are faced with shortages. It is a normal thing to borrow; once we receive our supplies we return the amount we borrowed. We work by helping each other. (Participant from Facility 20)This strategy, although not very common, was also mentioned, especially for those clinics that were established as refill centres in order to minimise congestion at the higher-level facilities. One participant said:This clinic is just a refill centre, patients just come here to refill their prescriptions but all the clinical issues are conducted at the hospital. So at times when they come to refill and we do not have the drugs we tell them to go to the hospital where they usually go for their routine clinical check-up. (Participant from Facility 2)All the participants said that usually they inform patients about the reasons for changing their ART regimens and usually they understand and accept it. They said the change can be permanent or temporary depending on the patient’s experience with the new therapy or the availability of the drugs. One participant said:The new drugs can cause them side-effects they had never experienced before, so when they come to refill, they complain and ask if the drugs they were using previously have arrived. In this kind of a situation we return them to their previous regimens as soon as we can. (Participant from Facility 12)They said, however, that some patients feel more comfortable with their new regimens; hence switching them back becomes impossible.Shortages of antiretroviral drugs leading to changes in ART regimens were common in the surveyed HIV/AIDS care and treatment clinics. The study also reveals that different coping strategies were used to avoid changes in ART regimens, which is important to reduce the risk of the emergence of drug-resistant HIV strains . Drug reShortening of the refill period was a common strategy utilised to cope with the shortages of antiretroviral drugs. This is important to ensure that patients are maintained on their ART regimens; however, this strategy is associated with increased direct and indirect costs borne by patients and their families in accessing treatment . Both diAn inefficient supply system and forecasting challenges were cited as the main factors causing shortages and stock-outs of antiretroviral drugs in the clinics. These findings correlate with a Global Fund report which singled out weak forecasting, accelerated patient enrollment and lengthy procurement processes as the main factors behind antiretroviral drug stock-outs in African countries . Lack ofRecently, the parliamentary committee found large quantities of antiretroviral drugs that had expired at MSD warehouses before being distributed to healthcare facilities, highlighting some of the challenges reported in the facilities. Reliable forecasting, coupled with appropriate inventory management to ensure an uninterrupted supply of antiretroviral drugs, are crucial in the performance of HIV/AIDS care and treatment programs .This study provides a snap-shot evaluation of the performance of the pharmaceutical system, which is under increased pressure due to the scale-up of ART programs in Tanzania. The study employed a purposive sampling method, which limits the generalisation value of its findings since the selected clinics may not give a true representation of all the other HIV/AIDS care and treatment clinics in the country.The data presented in this paper was based on self-reporting by the participating healthcare workers in the selected clinics. We regret that the methodology used in this paper was not sufficient to collect quantitative data for higher-level analysis. Also, we did not interview patients or officials from the MSD, although we strongly believe they possess important information related to the findings of this study. Their views could have strengthened the main conclusion of this study.Changes in ART regimens due to stock-outs of antiretroviral drugs occurred in a small but significant number of patients. This increases the risk of the emergence of drug-resistant HIV strains. Healthcare workers use various coping strategies to prevent changes in ART regimens but, unfortunately, some of these strategies also increase patient-borne costs. This may discourage them from attending their routine clinics, causing unplanned treatment interruptions. Strengthening the supply chain management system is important, otherwise there is a high risk of jeopardising the benefits of antiretroviral treatment programs that have been witnessed in recent years.The interview guide.Click here for file


We evaluated the effectiveness of darunavir (DRV) treatment plus an optimized background regimen in 120 HIV-1 treatment-experienced patients.Retrospective cohort, multicenter study.Adults >16 years with virological treatment failure starting therapy with a DRV-containing regimen were included. Effectiveness was evaluated as the percentage of patients with an undetectable HIV-1 RNA viral load (<50 and <200 copies/mL) after 48 weeks, and changes in CD4+ cell counts. We evaluated the risk factors associated with treatment failure.P < 0.001 vs. baseline). Risk factors associated with poor outcome were age >40 years , use of raltegravir in the regimen , and baseline CD4+ cell count <200 cells/μL .Of the cohort, 83 % were men with a median age of 45 years . They had experienced treatment for a median of 13 years (IQR 9–17) with a median of six previous regimens (IQR 4–7), all using protease inhibitors. After treatment, 82 %  of patients had an HIV-1 RNA viral load <200 copies/mL and 69 % (95 % CI 60–76 %) had <50 copies/mL. The CD4+ cell count increased by 378 cells/μL (IQR 252–559; In this Mexican cohort Darunavir was metabolically safe, well tolerated and achieved high rates of virological suppression in highly treatment-experienced patients infected with HIV-1. TG showed no significant increase from a baseline of 186 mg/dL (135–260 mg/dL) to 197 mg/dL (148–271 mg/dL) at week 24, and it remained not significant at 48 weeks at 220 mg/dL (162–305 mg/dL) , and triglycerides (TG) were measured and are shown below as medians and IQRs. TC showed a significant increase  was also associated with virological failure [OR 3.6 (95 % CI 1.17–11.00); er study .We found that age <40 years was associated with a better response that was attributed to a better adherence in this age group. A meta-analysis showed that older age reduces the risk for nonadherence by 25 % in short-term  and 35 % in longer-term assessments  .This is the first multicenter cohort in Mexico that has evaluated the effectiveness of DRV in highly treatment-experienced patients; a strength of this study was that we could evaluate risk factors for virological treatment failure. By contrast, one of the limitations of this study is that it was a retrospective method to study previously enrolled patients. In addition, we were not able to establish adverse events associated with DRV. Another limitation of this study is that we could not assess adherence to ARV drugs in our population.These results suggest that the use of DRV/r-based regimens for salvage therapy is an effective strategy in the clinical care setting of a developing country. DRV/r in combination with RAL increased the overall success as a regimen for salvage therapy in these highly ARV treatment-experienced HIV-infected patients. Finally, the use of TDF appears to be a good option except for those patients with an SS >35.