Increase In CD4 Cell Count Research Articles

Recent HIV-1 Infection: To Treat or Not to Treat, That Is the Question

The first description of acute human immunodeficiency virus (HIV) infection as a mononucleosis-like syndrome was published in 1985 [1]. Since that time, it has become clear that recent viral infection may be accompanied by a variety of symptoms, at least partly related to the mode of acquisition [2], and may often be asymptomatic [3]. Despite this apparent lack of specificity of clinical presentation, it still remains possible to identify individuals who have acute/early HIV infection by educating healthcare providers and patients alike to consider this diagnosis in the context of a significant systemic illness in an individual with a recent risk exposure. Alternatively, a strategy of repeated testing for infection (using fourth-generation tests detecting the virus as well as the antibody response) in some groups may be employed. The main reason to develop such a strategy would be the availability of an intervention to change the natural history of the disease. An early controlled trial of a 6-month course of zidovudine monotherapy in primary HIV infection showed a clinical effect on minor opportunistic infections over a 15-month period, as well as significant increases in CD4 cell counts [4]. Interestingly, study recruitment was ended prematurely, at least in part because practitioners of the day believed that the correct course of action was to initiate treatment and were unwilling to randomize their patients to observation. In an accompanying editorial, Ho reasoned that the observed benefit related to a marked effect on viral dynamics at a time when viral turnover was at its peak [5]. He further proposed that when more effective treatment modalities were available, the benefit would be even greater. Over time, an immunologic benefit of intervention (the preservation of HIV-specific T-helper cells) was demonstrated to support the rationale for intervention [6]. Since then, enthusiasm for the systematic use of highly active antiviral therapy in this setting has waned, with the benefit of interrupted therapy expected to be modest and without long-term benefit [7]. The current Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-1–Infected Adults and Adolescents states that ‘‘The health care provider and the patient should be fully aware that the rationale for therapy for acute HIV infection is based on theoretical considerations, and the potential benefits should be weighed against the potential risks. For these reasons, treatment of acute HIV infection should be considered optional at this time’’ [8]. It is in this nebulous context that the important work of Hogan and colleagues is published in this issue of the Journal [9]. The Setpoint Study (ACTG A5217) was a randomized clinical trial in which patients who had been infected with HIV in the previous 6 months were assigned to receive a 36-week course of antiretroviral therapy (with tenofoviremtricitabine administered along with lopinavir-ritonavir) or observation. The principal end point was a lowering of the virologic set point at week 72 (thus comparing 36 weeks of therapy followed by 36 weeks of observation with 72 weeks of observation). The secondary end point was the time required to meet eligibility for therapy based on clinical, virologic, and/or immunologic criteria. As with the original trial of zidovudine monotherapy in this setting, the study was discontinued prematurely. The Data Safety Monitoring Board (DSMB) determined that study subjects who did not receive immediate treatment were progressing to require such treatment on clinical grounds at such a rate that an actual comparison of virologic set points between the 2 study groups would not be possible. Of the planned 150 participants, 130 had been enrolled before the closure of Received and accepted 26 September 2011. Correspondence: Brian Conway, MD, FRCPC, Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Downtown ID Clinic, 201-1200 Burrard St, Vancouver, BC V6Z 2C7, Canada (bconway@exchange.ubc.ca). The Journal of Infectious Diseases 2012;205:10–2 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com DOI: 10.1093/infdis/jir702

Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters - a placebo controlled clinical trial in healthy subjects

BackgroundIn Germany, Iscucin® Populi (IP), a preparation from mistletoe growing on the poplar tree, is used in cancer therapy while Viscum Mali e planta tota (VM), a preparation from mistletoe growing on the apple tree, is used in patients with osteoarthritis. Since mistletoe preparations are suspected to induce production of potentially tumor promoting cytokines like interleukin (IL)-6, further studies on the immunological effects are of interest.MethodsIn this 3-armed randomized, double blind clinical trial healthy volunteers received increasing doses of either IP (strength F, 0.0125%, G, 0.25% and H, 5%, each for 4 weeks), or VM (1:1000 [D3], 1:100 [D2] and 2% each for 4 weeks) or placebo (isotonic solution) subcutaneously twice per week over a period of 12 weeks. Physical examination was performed weekly. Routine laboratory parameters and immunological parameters (C-reactive protein (CRP), differential blood count, lymphocyte subsets, immunoglobulins, IL-6 and tumor necrosis factor (TNF)-α) were analysed every 4 weeks.Results71 subjects were included in the study (IP = 30, VM = 21, placebo = 20) of whom 69 concluded it according to protocol. Application of IP strengths G and H caused strong local reactions at the site of injection. In parallel, a distinct eosinophilia (p < 0.001 compared to placebo) occurred. Furthermore, application of all IP concentrations resulted in an increase of CD4 cell counts (p < 0.05) compared to placebo. Stimulation of IL-6 production, CRP or relevant deviations in other laboratory parameters were not observed. Because of local reactions, IP strengths G and H were considered less tolerable than placebo. VM 2% was slightly less tolerable than placebo, caused only mild local reactions and an only small increase in eosinophile counts.ConclusionTreatment with IP results in eosinophilia and an increase of CD4 cells but not in an increase of IL-6 or CRP. No safety concerns regarding the two mistletoe preparations have been raised by this study. EudraCT-Number 2007-002166-35.Trial registrationClinicalTrials.gov: NCT01378702

Efficacy of new antiretroviral drugs in treatment‐experienced HIV‐infected patients: a systematic review and meta‐analysis of recent randomized controlled trials

We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the overall efficacy of new antiretroviral drugs, as well as the factors associated with increased efficacy. We compared CD4 cell count increases associated with chemokine (C-C motif) receptor 5 (CCR5) inhibitors or other new drugs, using indirect comparison. We included RCTs published in 2003-2010 that assessed the 48-week immunological and virological efficacy of adding new antiretroviral drugs vs. placebo to optimized background therapy (OBT) in treatment-experienced subjects. These drugs included maraviroc, vicriviroc, enfuvirtide, raltegravir, etravirine, tipranavir and darunavir. We collected baseline descriptive characteristics, CD4 cell count changes and virological suppression proportions (percentage with HIV RNA <50 HIV-1 RNA copies/mL). We identified 10 studies which included a total of 6401 patients. New drugs were associated with increased virological suppression (pooled odds ratio 2.97) and larger CD4 count increases (pooled nonstandardized difference 39 cells/μL) compared with placebo. OBT genotypic sensitivity scores (GSSs) were also associated with larger differences in virological suppression (P<0.001 for GSS=0,≤1 and ≤2) and CD4 cell count increase (GSS=0, P<0.001; GSS ≤1, P=0.002; GSS ≤2, P=0.015) between the two groups. CCR5 inhibitors were not associated with significant gains in CD4 cell counts (P=0.22) compared with other new drugs. Our study confirmed the overall immunological and virological efficacy of new antiretroviral drugs in treatment-experienced patients, compared with placebo. The main predictive factor for efficacy was the number of fully active drugs. CCR5 inhibitors did not increase CD4 cell count to a greater extent than other new drugs.

Antiretroviral Therapy Initiation and CD4 Progression over time among HIV Infected Adults in Central Africa

International Journal of Medicine and Public Health,2011,1,4,3-11.DOI:10.5530/ijmedph.4.2011.2Published:Oct/2011Type:Original ArticleAntiretroviral Therapy Initiation and CD4 Progression over time among HIV Infected Adults in Central AfricaHrishikesh Chakraborty, Jamie E. Newman, Godfrey Woelk, Jennifer Hemingway-Foday, Iriondo-Perez Jeniffer, Wilfred Akam, Ashu Balimba, Lucien Kalenga, Marc Mbaya, Henri Mukumbi, Théodore Niyongabo, Brigitte MfangamMolu, Robert Ryder, and Robin Huebner Hrishikesh Chakraborty1,2 , Jamie E. Newman2 , Godfrey Woelk2 , Jennifer Hemingway-Foday2 , Iriondo-Perez Jeniffer2 , Wilfred Akam3 , Ashu Balimba4 , Lucien Kalenga5 , Marc Mbaya5 , Henri Mukumbi5, Théodore Niyongabo6, Brigitte MfangamMolu7, Robert Ryder8 and Robin Huebner9 1Department of Epidemiology and Biostatistics, University of South Carolina, USA. 2Statistics and Epidemiology, RTI International, USA. 3Limbé Provincial Hospital, Limbé, Cameroon. 4Hôpital Militaire, Yaoundé, Cameroon. 5AMO-Congo, Democratic Republic of Congo. 6Centre Hospitalo-Universitaire de Kamenge, Bujumbura, Burundi. 7Hôpital Général de Yaoundé, Yaoundé, Cameroon. 8Department of Medicine, University of California San Diego, USA. 9National Institute of Allergy and Infectious Diseases, USA. Abstract:An improved understanding of CD4 progression over time in resource-limited settings may aid in the discussion of when to initiate antiretroviral therapy (ART) and optimal timing for CD4 monitoring. We examined CD4 progression over time among 347 HIV-positive adults from 10 HIV care and treatment programs in Burundi, Cameroon, and the Democratic Republic of Congo (DRC). We applied a mixed model using restricted maximum likelihood to describe CD4 cell count evolution over time following ART initiation and to evaluate the association between other baseline variables and CD4 response over time. Depending on the initial baseline CD4 count, increases in mean CD4 cell count ranged from 24–46 cells/mm 3 from 3 to 6 months after treatment initiation, and from 80–117 from 6 to 18 months after treatment initiation. Females had higher CD4 count at the initiation of treatment than males. Patients with higher CD4 count at ART initiation achieved a higher CD4 count in the following months. We found that higher baseline CD4 cell counts predicted higher CD4 cell counts over time among the patients eligible for this analysis. We also observed increases in mean CD4 cell count from 3 to 18 months after treatment initiation. Keywords:AIDS., ART, CD4 Count, HIVView:PDF (463.95 KB)

Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study

The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44-3·14; p<0·0001) and acquired drug-resistance (2·30, 1·55-3·40; p<0·0001) was increased in participants with pretreatment drug resistance to at least one prescribed drug, but not in those with pretreatment drug resistance and fully active ART. CD4 count increased less in participants with pretreatment drug resistance than in those without (35 cells per μL difference after 12 months; 95% CI 13-58; p=0·002). At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. The Netherlands Ministry of Foreign Affairs.

Disseminated infections due to Immune Reconstitution Inflammatory Syndrome after Highly Active Antiretroviral Therapy - Report of 3 cases from Nigeria

Immune Reconstitution Inflammatory Syndromes (IRIS) are exaggerated pathological inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) due to exuberant immune responses to occult or apparent opportunistic infections or cancers. In view of paucity of studies from Nigeria, we report 3 cases of IRIS presenting as disseminated infections in HIV-1 infected patients initiating HAART. The first case was a previously healthy female who developed disseminated tuberculosis after 4 weeks of regular HAART. Her HAART regimen was continued and she improved after commencement of anti-tuberculosis drugs, with evidence of progressive increase in CD4 cell count. The second case was a HAART-experienced female who stopped her drugs for 4 months. Two months after recommencement of her previous HAART regimen, she developed features of disseminated herpes zoster infection, despite evidence of decrease in viral load by 95%. HAART was continued and she recovered completely after receiving valaciclovir tablets and antibiotics. The third patient was a female student who was commenced HAART on account of chronic cough and weight loss. Three months after regular HAART, she developed features of disseminated Kaposi's sarcoma involving the skin, oropharynx and lungs, despite evidence of 42% increase in CD4 cell count. Unfortunately, she rapidly deteriorated and died during the course of management. Clinicians should be alert to the possibility of IRIS in HIV-infected patients initiated or re-initiated on HAART. There is need for future prospective studies determining risk factors for IRIS in HIV-infected patients from Nigeria.

Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection

To assess efficacy and safety of cobicistat versus ritonavir as pharmacoenhancers for atazanavir when administered with emtricitabine/tenofovir df as initial treatment for HIV-1 infection. Randomized, partially placebo-controlled, double-blind, multicenter study. Antiretroviral treatment-naive adults, screening HIV-1 RNA of at least 5000 copies/ml and CD4 cell count more than 50 cells/μl. Randomized 2 : 1 (stratified by HIV RNA ≤ or >100,000 copies/ml) to receive placebo-blinded once-daily cobicistat 150 mg or ritonavir 100 mg with open-label atazanavir and fixed-dose emtricitabine/tenofovir df. Efficacy and safety at weeks 24 and 48. Eighty-four percent of ATV/co participants and 86% of ATV/r participants suppressed HIV-1 RNA (<50 copies/ ml) at week 24, and 82 and 86% at week 48, respectively, and mean CD4 cell count increased 203 and 199 cells/μl at week 24 and 208 and 177 cells/μl at week 48, respectively. Study treatment discontinuation due to adverse events occurred in 4% ATV/co and in 3% ATV/r participants through 48 weeks. Treatment-related adverse events occurred in 36% ATV/co and 48% ATV/r participants; hyperbilirubinemia occurred in 96 and 100%, and ocular icterus or jaundice occurred in 14 and 17%, respectively. Mean estimated glomerular filtration rate (Cockcroft-Gault, ml/min) decrease occurred in both treatment groups and was evident at week 2 (ATV/co -9, ATV/r -4), reached a nadir by week 24 (-15, -14, respectively), and did not progress further through week 48 (-13, -14). Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with emtricitabine/tenofovir df achieved comparable rates of virologic suppression and CD4 cell count increase with satisfactory safety profiles.

Immune reconstitution inflammatory syndrome following cryptosporidial cholangitis

Immune reconstitution inflammatory syndrome (IRIS) is a frequent complication of HIV-infected patients following initiation of antiretroviral therapy (ART). Although a wide variety of opportunistic pathogens are associated with IRIS, parasites have rarely been reported [1]. We report the first case of IRIS following cryptosporidial cholangitis. A 30-year-old man presented to our emergency room with a long-standing history of severe diarrhea, 25-kg weight loss, as well as epigastric and abdominal pain. He was returning from Turkey where he had drunk contaminated water. Investigation confirmed the presence of Cryptosporidium oocysts in stool; other usual and opportunistic pathogens were absent. HIV-1 serology was positive, CD4 cell count was 120 × 106 cells/l and viral load was 395 160 copies/ml (5.6 log). Renal and hepatic enzymes were normal. An abdominal computed tomography scan showed a 12-mm dilatation of the distal common bile duct. Endoscopic retrograde cholangiopancreatography (ERCP) revealed diffuse mucosal inflammation with fine diffuse nodularities of the duodenum, the common and hepatic bile ducts. Biopsies confirmed the presence of Cryptosporidium oocysts. Sphincterotomy was performed and ART was started with zidovudine, lamivudine and efavirenz. The working diagnosis was HIV-associated cryptosporidial cholangitis. A week later, the patient developed right upper quadrant pain associated with mild cytolysis and cholestasis without associated pancreatitis (Fig. 1). Abdominal studies showed unchanged aspect of the bile ducts and duodenum. This episode was felt to be related to the previous sphincterotomy. Enzymes and symptoms progressively resolved.Fig. 1: Liver enzymes and CD4 cell count over time.Three different entities are presented: cryptosporidial cholangitis on admission (week 0), cholestasis after endoscopic retrogradecholangiopancreatography (weeks 2–4) and immune reconstitution inflammatory syndrome (weeks 8–16). Alk P, alkaline phosphatase; GGT, gamma-glutamyltransferase; SGPT, serum glutamic pyruvic transaminase.Eight weeks after ART initiation, the patient was readmitted with isolated right upper quadrant and epigastric pain with marked elevation of liver enzymes (Fig. 1). Stools samples failed to show Cryptosporidium. The CD4 cell count had markedly increased to 310 × 106 cells/l and viral load decreased to 315 copies/ml (2.5 log). This episode spontaneously resolved during the next 2 months. HIV-associated cholangiopathy is manifested by biliary obstruction due to infection-related strictures [2,3], which historically affected 25% of AIDS patients prior to the advent of ART [4,5]. This entity is usually diagnosed on the basis of clinical features, elevated alkaline phosphatase levels, classic imagery on ERCP [3] and pathogen identification on tissue biopsy (duodenum, ampulla, bile duct or liver). In its acute phase, identification of organisms (Cryptosporidium, Microsporidium, cytomegalovirus or Cyclospora cayetanensis) can be made in approximately 75% of cases [3,6,7] with Cryptosporidium being the most prevalent [6,8]. Disease severity and evolution of biliary cryptosporidiosis in HIV patients largely depends on the immune status of the host. A vulnerable immunity may not efficiently clear a large parasitic burden. For this reason, judicious prescription of ART, instead of antiparasitic therapy, is the preferred initial treatment in cryptosporidiosis. Occasionally, endoscopic sphincterotomy becomes necessary to decompress the biliary system, although the disease can nevertheless progress and become chronic [7,9]. A recent meta-analysis reported a 16.1% incidence of IRIS in HIV-patients starting ART [10]. The following diagnostic criteria for IRIS are generally accepted: HIV patient responding to ART (rapid decrease in plasma viral load by more than 1 log10 or rapid increase in CD4 cell count); atypical inflammatory reaction unexpected in the course of the opportunistic infection; exclusion of others causes that could explain the clinical presentation [11–13]. IRIS can follow any type of opportunistic infection, but has rarely been described with parasites [10,14]. To the author's knowledge, Plasencia et al.[15] reported the only case of an IRIS related to a cryptosporidial infection in an HIV patient with recurring ileitis. Our patient initially presented with a classic case of cryptosporidial cholangitis, confirmed by the presence of Cryptosporidium oocyst on histopathology. The following clinical presentation, 8 weeks after the initial diagnosis, was likely caused by IRIS, as it fits the accepted criteria mentioned earlier: first, the patient had a clear immunologic/virologic response to ART, as confirmed by the quick improvement in CD4 cell count and viral load; second, cryptosporidiosis had resolved completely during that period and was not expected to recur in a HIV patient with markedly improved immunity; third, the timing of the recurrence correlated precisely with the immune reconstitution; and finally, there was no sign of Cryptosporidium or other pathogens on stool sampling. The diagnosis of IRIS is often difficult to pose and was unfortunately delayed in our patient. Had it been suspected earlier, anti-inflammatory drugs or corticosteroids could have been considered. In conclusion, to the authors’ knowledge, this is the first case of IRIS-mediated cholangitis following cryptosporidial infection. Although rare, clinicians should be aware of this possibility following initiation of ART after a documented parasitic infection. Acknowledgements Conflicts of interest There are no conflicts of interest.

Highly active antiretroviral therapy and employment status in Accra, Ghana

This study investigated the immunologic responses and employment history of highly-active antiretroviral therapy (HAART) patients. We interviewed patients and reviewed medical records to collect demographic, clinical, and employment history while on HAART. Demographic characteristics were tested as predictors of immunological response while on HAART using hierarchical linear models. Fevers Unit, Korle-Bu Teaching Hospital, Accra, Ghana Subjects comprised a convenience sample of adult HAART patients receiving therapy for at least 9 months. 270 patients were interviewed. 38 were excluded due to inadequate time on HAART or inability to locate all necessary patient information. This was an observational study. We investigated the change in CD4 cell count and weight since the initiation of therapy, and their ability to maintain or regain employment as well as the reasons for this. The estimated mean ± standard error increase in CD4 cell count from baseline at 6, 12, and 18 months were 102 ± 5, 204 ± 11, and 236 ± 10 cells/µL, respectively. Overall, 147 patients (63.4%) reported remaining employed or obtaining new employment while on HAART. Patients who were asymptomatic at initial presentation were more likely to remain employed or returned to work while on HAART than those who were symptomatic (66.4% vs. 48.8%, P = 0.009). Most patients were employed in the informal sector, which made their economic situation particularly vulnerable to HIV-associated illness. The findings suggest that patients receiving HAART experience good clinical and immunological responses as well as improvement in employment status.

Immune Status at Presentation for HIV Clinical Care in Rio de Janeiro and Baltimore

Late presentation to HIV clinical care increases individual risk for (multiple) clinical events and death, and decreases successful response to highly active antiretroviral therapy (HAART). In Brazil, provision of HAART free of charge to all individuals infected with HIV could lead to increased testing and linkage to care. We assessed the immune status of 2555 patients who newly presented for HIV clinical care between 1997 and 2009 at the Johns Hopkins Clinical Cohort, in Baltimore, Md, and at the Instituto de Pesquisa Clinica Evandro Chagas Clinical Cohort, in Rio de Janeiro, Brazil. The mean change in the CD4 cell count per year was estimated using multivariate linear regression models. Overall, from 1997 to 2009, 56% and 54% of the patients presented for HIV clinical care with CD4 count ≤350 cells per cubic millimeter in Baltimore and Rio de Janeiro, respectively. On average, 75% of the patients presented with viral load >10,000 copies per millimeter. In Rio de Janeiro only, the overall adjusted per year increase in the mean CD4 cell count was statistically significant (5 cells/mm, 95% confidence interval: 1 to 10 cells/mm). We found that, over years, the majority of patients presented late, that is, with a CD4 count <350 cells per cubic millimeter. Our findings indicate that, despite the availability of HAART for more than a decade, and mass media campaigns stimulating HIV testing in both countries, the proportion of patients who start therapy at an advanced stage of the disease is still high.

Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised non-inferiority trial

Scaling up of antiretroviral therapy in low-resource countries is done on the basis of decentralised, integrated HIV care in rural facilities; however, laboratory monitoring is generally unavailable. We aimed to assess the effectiveness and safety of clinical monitoring alone (CLIN) in terms of non-inferiority to laboratory and clinical monitoring (LAB). We did a randomised, open-label, non-inferiority trial in nine rural district hospitals in Cameroon. Eligible participants were adults (≥18 years) infected with HIV-1 group M (WHO disease stage 3-4) who had not previously received antiretroviral therapy, and were followed-up for 2 years by health-care workers in routine activities. We randomly assigned participants (1:1) to CLIN or LAB (counts of HIV viral load and CD4 cell every 6 months) groups with a computer-generated list. The primary outcome was non-inferiority of CLIN to LAB in terms of increase in CD4 cell count with a non-inferiority margin of 25%. We did all analyses in participants who attended at least one follow-up visit. This trial is registered with ClinicalTrials.gov, number NCT00301561. 238 (93%) of 256 participants assigned to CLIN and 221 (93%) of 237 assigned to LAB were eligible for analysis. CLIN was not non-inferior to LAB; the mean increase in CD4 cell count was 175 cells per μL (SD 190, 95% CI 151-200) with CLIN and 206 (190, 181-231) with LAB (difference -31 [-63 to 2] and non-inferiority margin -52 [-58 to -45]). Furthermore, in the predefined secondary outcome of treatment changes, 13 participants (6%) in the LAB group switched to second-line regimens whereas no participants in the CLIN group did so (p<0·0001). By contrast, other predefined secondary outcomes were much the same in both groups-viral suppression (<40 copies per mL; 465 [49%] of 952 measurements in CLIN vs 456 [52%] of 884 in LAB), HIV resistance (23 [10%] of 238 participants vs 22 [10%] of 219 participants), mortality (44 [18%] of 238 vs 32 [14%] of 221), disease progression (85 [36%] of 238 vs 64 [29%] of 221), adherence (672 [63%] of 1067 measurements vs 621 [61%] of 1011), loss to follow-up (21 [9%] of 238 vs 17 [8%] of 221), and toxic effects (46 [19%] of 238 vs 56 [25%] of 221). Our findings support WHO's recommendation for laboratory monitoring of antiretroviral therapy. However, the small differences that we noted between the strategies suggest that clinical monitoring alone could be used, at least temporarily, to expand antiretroviral therapy in low-resource settings. French National Agency for Research on AIDS (ANRS) and Ensemble pour une Solidarité Thérapeutique Hospitalière En Réseau (ESTHER).

Is laboratory monitoring of ART essential worldwide?

In The Lancet Infectious Diseases, Laurent and colleagues report the results of a randomised non-inferiority trial in adults in Cameroon1 with HIV infection receiving antiretroviral therapy (ART). The trial compares the effectiveness and safety of two monitoring strategies: clinical monitoring alone and clinical monitoring plus laboratory monitoring of CD4 cell counts and viral loads. Participants in the laboratory group had increases in CD4 cell counts of more than the 25% threshold in the first 2 years of treatment and therefore non-inferiority of clinical monitoring alone was not shown.

Severe Myelosuppression and MRSA Infection as the Presentation of Perinatal HIV Infection

Severe Myelosuppression and MRSA Infection as the Presentation of Perinatal HIV Infection

Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial

The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725. From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001). Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. Tibotec.

Long-term immunological outcomes in treated HIV-infected individuals in high-income and low-middle income countries

To summarize the recent findings on long-term (at least 3-4 years) immunological responses to combination antiretroviral therapy (cART) and to compare and contrast the findings between cohorts from high-income and low-middle income countries (LMICs). Cohort studies from high-income settings suggest that a majority of treated HIV-infected patients who maintain suppressed HIV viremia experience a gradual increase in CD4 cell counts for several years to normal levels. However, those who start cART at CD4 cell counts less than 200 cells/μl (as opposed to CD4 cell counts>200 cells/μl) spend several more years below the safe CD4 cell count threshold of 500 cells/μl. Cohorts from LMICs also report persistent improvements in CD4+ cell counts over first 4-5 years of follow-up. However, low-CD4 cell counts (<200 cells/μl) at the start of cART, high early mortality, and loss to follow-up in LMICs settings suggest that the observed optimistic responses may be affected by survivorship bias and should be cautiously interpreted as the optimal, rather than an average, response in LMICs populations. LMICs cohorts report similar immunological responses to cART as high-income countries in first 4-5 years of follow-up. Sustaining success in these settings is dependent on timely access to first-line and future cART options, efforts to reduce loss to follow-up, and implementation of treatment guidelines. Cohorts from LMICs are encouraged to continue improving treatment programs and to continue reporting outcomes over the next decade, as surveillance for potential future blunting in responses.

Adult patients’ adherence to anti-retroviral treatment: A survey correlating pharmacy refill records and pill counts with immunological and virological indices

Background Providing anti-retroviral therapy (ART) to patients free of charge enhances their wellbeing, reduces the number of opportunistic infections and enables them to live productive lives, but only if these drugs are taken regularly every day for the rest of their lives. Patients’ ART adherence levels are difficult and expensive to estimate. If simple available measures, such as pharmacy refill records, could be correlated with laboratory test results for improved CD4 counts (indicating immunological recovery) and decreased viral loads (VLs – indicating virological recovery), these could be used as preliminary measures of adherence. Objective The objective was to determine whether the combination of pharmacy refill records and pill counts (including counts for all medications in the HAART regimen) could predict immunological and virologic responses through increased CD4 cell counts and suppressed VL. Results Correlations were compiled for patients’ pharmacy refill records, pill counts, CD4 cell counts, VL counts and self-reported ART adherence at one clinic in Gaborone, Botswana. There was a weak positive, relationship between ART adherence, CD4 cell counts and VL. Pharmacy refills and pill counts adherence measurement methodologies scored high on sensitivity and positive predictive values. Conclusions Pharmacy refill records and pill counts are useful indicators of patients’ ART adherence levels, but should be supplemented with CD4 and VL counts at regular intervals.

Can community health workers improve adherence to highly active antiretroviral therapy in the USA? A review of the literature

Highly active antiretroviral therapy (HAART) has transformed HIV infection into a manageable chronic illness, yet AIDS mortality among ethnic minorities persists in the USA. HAART nonadherence is associated with increased HIV viral load, low CD4 cell count and racial disparities in HIV outcomes. While there is no universal consensus on how to improve medical adherence in HIV-positive populations, the community health worker (CHW) model is emerging as an effective strategy to overcome barriers to HAART adherence. Although utilized in international settings, there is little evidence regarding the effects of CHWs on HIV outcomes in the USA. We performed a comprehensive search from May 2010 to November 2010 to identify studies carried out in the USA that utilized CHWs to improve HAART adherence and measured HIV viral loads and CD4 cell counts to assess intervention effects. Sixteen studies met the inclusion criteria and were reviewed for this article. All studies reported clinical HIV outcomes. Interventions that lasted at least 24 weeks, provided frequent contact with participants, and focused on medication management were associated with improved HAART adherence, as indicated by reduced HIV viral load and increased CD4 cell count. Compared with current standards of care, CHW programmes may offer a practical and cost-effective alternative to improve HAART adherence, which may lead to reduced HIV viral load and increased CD4 cell counts among HIV-positive populations in the USA.

Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients

ODIN (Once-daily Darunavir In treatment-experieNced patients) was a phase III, 48-week, open-label study comparing once-daily vs. twice-daily darunavir/ritonavir (DRV/r) in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients with no DRV RAMs and receiving stable HAART for at least 12 weeks were stratified by HIV-1 RNA (≤ or > 50 000 copies/ml) and randomized to once-daily DRV/r 800/100 mg or twice-daily DRV/r 600/100 mg and an optimized background regimen (≥2 nucleoside reverse transcriptase inhibitors). Primary objective was to demonstrate noninferiority of once-daily vs. twice-daily DRV/r in confirmed virologic response (HIV-1 RNA < 50 copies/ml) at week 48. Five hundred and ninety patients received once-daily (n = 294) or twice-daily (n = 296) DRV/r. Mean baseline HIV-1 RNA was 4.16 log10 copies/ml; median CD4 cell count was 228 cells/μl; and 53.9% had previously used at least one protease inhibitor. At week 48, 72.1% of once-daily and 70.9% of twice-daily patients achieved HIV-1 RNA less than 50 copies/ml (intent-to-treat/time-to-loss of virologic response). The difference in response between once-daily and twice-daily arms was 1.2% (95% confidence interval -6.1 to 8.5%; P < 0.001), establishing noninferiority of once-daily DRV/r versus twice-daily DRV/r. Median CD4 cell count increase was 100 (once-daily) and 94 cells/μl (twice-daily). Virologic failure rate was low and similar for both arms; only one patient (once-daily arm) developed primary protease inhibitor mutations. Once-daily DRV/r had a lower incidence of grade 2-4 triglyceride increases (5.2 vs. 11.0%, P < 0.05). Once-daily DRV/r 800/100 mg was noninferior in virologic response to twice-daily DRV/r 600/100 mg at 48 weeks in treatment-experienced patients with no DRV RAMs, and with a more favorable lipid profile. These findings support use of once-daily DRV/r in this population.

A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial.

Objective:The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen.Design:Multicenter, randomized, open-label, phase III clinical trial.Subjects:Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48.Results:In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48.Conclusions:ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication.

Short Communication: Three Years Follow-Up of First-Line Antiretroviral Therapy in Cambodia: Negative Impact of Prior Antiretroviral Treatment

There are few long-term data on ART-experienced patients in resource-limited settings. We performed a cross-sectional study of HIV-infected patients included in the ESTHER program in Calmette hospital, Phnom Penh, Cambodia, after 36 ± 3 months of cART. Therapeutic, clinical, and immunovirological outcomes were compared between patients who stated they were ART-naive (naive group), dual nucleoside reverse-transcriptase inhibitor (two-NRTI group), or fixed-dose combination of stavudine/lamivudine/nevirapine experienced (three-drug group) at entry to the program. A logistic regression model was used to evaluate the factors associated with virological failure (PCR HIV > 250 copies/ml). Among the 256 patients included in the analysis, 148 (58%) were ART naive while 50 (20%) had previously received two NRTIs and 58 (22%) three drugs. At entry to the program, all the patients received two NRTIs and one nonnucleoside reverse-transcriptase inhibitor (NNRTI). At evaluation, 46 patients (18%) were switched to a protease inhibitor-based regimen (9%, 32%, and 29% of the naive, two-NRTI, and three-drug groups; p < 0.0001). The median CD4 cell count increase was 180/μl overall (IQR: 96-276) and was higher in ART-naive than ART-experienced patients. In the intent-to-treat analysis, virological success was achieved in 83.5%, 67%, and 69% of the naive, two-NRTI, and three-drug groups, respectively (p = 0.002). Factors associated with virological failure were suboptimal previous ART exposure and WHO immunological failure criteria. The long-term efficacy of first-line cART is maintained in Cambodia. In ART-experienced patients, viral load monitoring needs to be available to establish early virological failure and preserve the potency of second line regimens.