Antiretroviral Treatment Guidelines Research Articles

The Incidence and Clinical Characteristics of Acute Serum Creatinine Elevation more than 1.5 mg/dL among the Patients Treated with Tenofovir/Emtricitabine-containing HAART Regimens.

BackgroundThe combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has been the first choice nucleoside reverse transcriptase inhibitor (NRTI) according to many reliable antiretroviral treatment (ART) guidelines because of its high efficacy. However, TDF-related renal toxicity reported in Western countries is a challenging issue regarding clinical use. We conducted this study to evaluate the incidence and characteristics of an acute increase in serum creatinine (Cr) level > 1.5 mg/dL among TDF/FTC-based highly active antiretroviral treatment (HAART)-treated patients.Materials and MethodsWe retrospectively reviewed the medical records of 205 HIV-infected patients treated with TDF/FTC-containing regimens between 1 February 2010 and 30 April 2014. Three groups of TDF/FTC + ritonavir-boosted protease inhibitor (PI/r), TDF/FTC + non-nucleoside reverse transcriptase inhibitor (NNRTI), and TDF/FTC + integrase strand transfer inhibitor (INSTI), and three PI/r subgroups of TDF/FTC + lopinavir (LPV)/r, TDF/FTC + atazanavir (ATV)/r, TDF/FTC + darunavir (DRV)/r were evaluated.ResultsA total 136 patients (91 in the TDF/FTC + PI/r group, 20 in the TDF/FTC + NNRTI group and 25 in the TDF/FTC + INSTI group) were included in the statistical analysis. Four cases (4.9%; all in the TDF/FTC + PI/r group) among 136 patients showed an acute increase in serum Cr more than 1.5 mg/dL, so the overall incidence was 2.8 cases per 100 patient-years. One case was a patient treated with TDF/FTC + LPV/r, and the others were treated with TDF/FTC + ATV/r. No case of an acute increase in serum Cr was observed in the TDF/FTC + DRV/r group. The incidence of serum Cr increase more than 1.5 mg/dL in TDF/FTC + PI/r group was 4.0 cases per 100 patient-years.ConclusionAlthough only a small number of patients were evaluated retrospectively from a single center, the TDF/FTC + PI/r regimen may have been related with relatively higher tendency of increment of serum Cr level. These findings reinforce the importance of close follow-ups of HIV-infected patients treated with the TDF/FTC + PI/r regimens.

The Role of Therapeutic Drug Monitoring and Pharmacogenetic Testing in the Management of HIV Infection: A Review

One of the less acknowledged tools in the international guidelines of combination antiretroviral therapy (cART) for HIV-1 infection is therapeutic drug monitoring (TDM). Yet anywhere there is a Clinical Pharmacology Unit or other facility for measuring plasma drug concentrations, physicians often measure the plasma levels of antiretrovirals as well as of comedications and find it useful. The aim of this article is to provide an overview of how relevant it is for a clinician to assess individual drug levels. Moreover we wanted to investigate to what extent the field is already assisted by web-based tools (i.e.: drug interaction charts). Finally we tried to look how pharmacogenetics may reduce the need for TDM, and whether this diagnostics is cost-effective. We searched PubMed by “drug interactions and HIV”, “drug level and HIV”, “therapeutic drug monitoring”, and we investigated the Liverpool Drug Interaction website, the DHHS Guidelines website, the UCSF website, and the AETC online Guide for HIV/AIDS Clinical care. Furthermore, we assessed the role that the main national and international guidelines for antiretroviral treatment attributed to TDM and searched for the various clinical subsets in which drug monitoring is particularly relevant. Finally, we suggest that cross-sectional studies of subjects failing therapy or experiencing drug-related adverse events, as well as longitudinal studies of particular conditions, may show the importance of problem-targeted rather than routine TDM.

Commentary: The monitoring of adults and children on antiretroviral therapy in the 2013 WHO consolidated ARV guidelines.

The laboratory monitoring of patients on antiretroviral treatment (ART) is an important element of HIV treatment programs, and is one of the cornerstones for ensuring a successful and sustained response to ART. Previous WHO ART guidelines placed greater emphasis on treatment initiation, whereas monitoring was considered optimal but not a prerequisite for the rollout of treatment programs [1]. During the early years of the global AIDS response, this was a decision that was both pragmatic and strategic. Treatment access was a public health emergency, and WHO sought to simplify the approach to ART and thus provide member states with guidance that could be implemented without delay. There is little doubt that this was the right thing to do at the time. Global progress in scaling up HIV care and treatment services has been dramatic and unprecedented; many hundreds of thousands of lives have been saved, and close to 10 million adults and children are now receiving ART [2].

PS-014 One year evaluation of treatment in a cohort of treatment-naive patients: compliance with national and international guidelines?

BackgroundThe DHHS (USA Department of Health and Human Services) Adult Antiretroviral Treatment Guidelines and Portuguese Government HIV Guidelines were updated in 2012/2013. These recommend a non-nucleoside reverse transcriptase inhibitor (NNRTI)...

Using modeling to inform international guidelines for antiretroviral treatment.

Using modeling to inform international guidelines for antiretroviral treatment.

Prevalence of Transmitted HIV-1 Drug Resistance (TDR) Associated Mutations and Predicted Drug Sensitivity in Newly Diagnosed HIV-1 Patient Cohort in a Western New York, 2005-2011

HIV-1 drug resistance associated mutations can be transmitted to persons who are antiretroviral-naive, called Transmitted Drug Resistance (TDR). TDR has the potential to compromise first-line anti-retroviral therapy (ART) in HIV patients and limit the antiretroviral regimens options, which has become an important public health problem. TDR surveillance is an important strategy to monitor the emergence of genetic. TDR has been reported in the United States for many years. Current antiretroviral treatment guidelines recommend drug resistance testing after diagnosis. We did a retrospective analysis of the genotype database of ART-naive patients from our immunodeficiency clinics at the Erie County Medical Center (ECMC) in Buffalo, New York, United States from 2005 to 2011. The prevalence of TDR in the ECMC-US cohort is still high 13.3%. The drug susceptibility is significantly reduced in 10.9% patients. The mutations were mostly “old” drug (such as AZT, D4T, EFV, NVP, SQV/r) related, while most of the “new” drugs (such as TDF, RPV, DRV/r) maintained sensitivity. The introduction of new second, third generation drugs in recent years has not brought down the prevalence of TDR significantly. The TDR prevalence rates in the United States are indicative of the fact that drug resistant mutations were generated before or at the beginning of ART and transmitted down from one generation to the other in ART naive patients, emphasizing that additional management strategies are needed to diagnose HIV infected patients earlier and to effectively treat them timely to further reduce TDR.

Feasibility of Performing Multiple Point of Care Testing for HIV Anti-Retroviral Treatment Initiation and Monitoring from Multiple or Single Fingersticks

BackgroundPoint of Care testing (POCT) provides on-site, rapid, accessible results. With current South African anti-retroviral treatment guidelines, up to 4 fingersticks /patient/clinic visit could be required if utilizing POC. We determined the feasibility and accuracy of a nurse performing multiple POCT on multiple fingersticks followed by simplification of the process by performance of multiple POC on a single fingerstick.Method and FindingsRandom HIV positive adult patients presenting at a HIV treatment clinic in South Africa, for ART initiation/ monitoring, were approached to participate in the study between April-June 2012. Phase I: n=150 patients approached for multiple POCT on multiple fingersticks. Phase II: n=150 patients approached for multiple POCT on a single fingerstick. The following POC tests were performed by a dedicated nurse: PIMA (CD4), HemoCue (hemoglobin), Reflotron (alanine aminotransferase, creatinine). A venepuncture specimen was taken for predicate laboratory methodology. Normal laboratory ranges and Royal College of Pathologists Australasia (RCPA) allowable differences were used as guidelines for comparison. In 67% of participants, ≥3 tests were requested per visit. All POCT were accurate but ranged in variability. Phase I: Hemoglobin was accurate (3.2%CV) while CD4, alanine aminotransferase and creatinine showed increased variability (16.3%CV; 9.3%CV; 12.9%CV respectively). PIMA generated a misclassification of 12.4%. Phase II: Hemoglobin, alanine aminotransferase and creatinine showed good accuracy (3.2%CV, 8.7%CV, 6.4%CV respectively) with increased variability on CD4 (12.4%CV) but low clinical misclassification (4.1%). No trends were observed for the sequence in which POC was performed on a single fingerstick. Overall, PIMA CD4 generated the highest error rate (16-19%).ConclusionsMultiple POCT for ART initiation and/or monitoring can be performed practically by a dedicated nurse on multiple fingersticks. The process is as accurate as predicate methodology and can be simplified using a single fingerstick.

Retrospective study on HIV infected pregnant women and their babies in the Western part of Romania

Results Out of the 104 pregnant women, 94 were known with HIV before getting pregnant, 65.2% of them were under cART by the time they got pregnant. These patients were treated with different cART, based on their antiretroviral treatment history and guidelines. The rest of pregnant women were diagnosed with HIV at delivery or soon after childbirth. We had a total of 115 children born by mothers with HIV, out of them 72 (62.6%) were seroreverters and 17 (14.78%) were children infected with HIV. The rest of 26 children are under 18 months of age and still having positive serology for HIV. All women under cART gave birth to non-infected children. 9 newborns died at delivery or shortly after; their mothers had been diagnosed with HIV during labor (or soon after) or had refused cART. Conclusion In order to prevent MTCT and have healthy babies with surviving mothers, cART taken by the women before getting pregnant is an essential factor. Sustained medical (infectious diseases plus gynecologist) and psychological efforts for caesarian section at week 38, advice for no breastfeeding and administration of pediatric antiretroviral formulas to the newborn remain essential steps in the project to eradicate pediatric HIV infection until 2015.

Structural barriers to antiretroviral treatment: a study using population-based CD4 cell count and linked antiretroviral treatment programme data

BackgroundThe promise of an AIDS-free generation rests on treatment as prevention to reduce HIV incidence. Treatment as prevention depends critically on high antiretroviral treatment (ART) coverage. However, even under current national ART guidelines coverage remains far from universal in sub-Saharan Africa. We examined structural barriers to ART access in a community in rural South Africa, which has a very high adult HIV prevalence (28%) and incidence (approximately three new infections per 100 person-years). MethodsWe did a population-based survey of CD4 cell count among 5000 randomly selected participants in the 2010 round of a longitudinal, population-based HIV surveillance study. The study was carried out by the Africa Centre for Health and Population Studies in the Hlabisa subdistrict of KwaZula-Natal. We identified the people needing ART among the HIV-infected surveillance participants as those who were either enrolled in the local ART programme (ie, people needing and receiving ART) or people who were not enrolled in the programme but had a CD4 cell count below a certain threshold (ie, people needing ART but not yet receiving it). We applied two different CD4 cell count thresholds (≤200 and ≤350 cells per μL), leading to two different samples of people needing ART (n=376 and n=610). We then used logistic regression to explore the effect of socioeconomic factors (sex, age, education, wealth, distance to the nearest ART clinic, urban/rural residence, and migration status) on the binary outcome of ART enrolment in relation to ART need. FindingsART coverage was 72% in the 376 individuals who were either on ART or had a CD4 count of 200 cells per μL or fewer, and 45% in the 610 individuals who were either on ART or had a CD4 count of 350 cells per μL or fewer. Women who needed ART were significantly more likely to receive treatment than were men who needed it (48% vs 34%; p=0·003 for the ≤350 cells per μL threshold). The age pattern of ART coverage increased from approximately 20% at age 20 years to 60% at age 45 years, declining to 40% at age 70 years for the 350 cells per μL or fewer threshold. Controlling for other factors, among those needing ART, women were more than twice as likely to be taking ART than were men (adjusted odds ratio 2·43, 95% CI 1·36–4·33; p=0·003) and every additional km distance from the nearest clinic decreased the likelihood of ART used by approximately 20% (adjusted odds ratio 0·79, 95% CI 0·67–0·94; p=0·007). Education, wealth, and migration did not affect ART access. When we separated women into those who had not been pregnant since inception of the ART programme in 2004, and those who had been pregnant, pregnancy was a significant determinant of ART access, but explained only a small fraction (<10%) of the difference in ART access between women and men. When we used the second sample of 610 individuals, the findings remained essentially the same. InterpretationWorking towards universal coverage goals, ART programmes need to improve access for men, young and old people, and remote populations. Interventions improving geographical accessibility of ART programmes, such as subsidised transport or the opening of more ART clinics in remote areas, are likely to help to overcome important structural barriers to access. FundingThe Africa Centre for Health and Population Studies demographic and HIV surveillance is funded by the Wellcome Trust. TB and FT received financial support from the Wellcome Trust and through 1R01-HD058482-01 from the National Institute of Child Health and Human Development, National Institutes of Health.

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Comparing the effectiveness of efavirenz and nevirapine for first-line antiretroviral therapy in a South African multicentre cohort

Current WHO guidelines for developing countries recommend efavirenz (EFV) and nevirapine (NVP) for first-line antiretroviral treatment (ART). This paper compares the effectiveness of EFV and NVP among ART-naive patients initiating treatment at 56 public health facilities in South Africa between January 2004 and December 2007. Participants were assigned to the EFV or NVP cohorts depending on their baseline ART regimen. Mortality, viral load suppression after 6 months and ART regimen change were compared between the cohorts using Cox proportional hazards models and logistic regression. At initiation, 19 441 (71.1%) patients started EFV and 7909 (28.9%) started NVP treatment. The median follow-up period was 9.5 months (IQR 4.6-17.7). After adjustment, mortality was similar in the two cohorts, (adjusted HR = 1.07, 95% CI 0.89-1.28). Viral load suppression at 6 months was higher in the EFV cohort overall (adjusted odds ratio [AOR] = 1.29, 95% CI 1.05-1.59) and in women aged 16-40 years (AOR = 1.35, 95% CI 1.11-1.63) and women with CD4 counts <25 cells/µL (AOR = 1.95, 95% CI 1.01-3.76). Patients starting on EFV were 47% less likely to change regimen (AOR = 0.53, 95% CI 0.48-0.59). These findings suggest the superior effectiveness of EFV for first-line ART compared with NVP and should be considered during development of future ART guidelines for high-burden regions.

Large Cell Lymphoma: Correlation of HIV Status and Prognosis with Differentiation Profiles Assessed by Immunophenotyping

Diffuse large B cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) represent aggressive non-Hodgkin lymphomas, particularly in the setting of HIV infection. Since the introduction of highly active antiretroviral therapy (HAART), recent studies have documented improved survival outcome in patients with AIDS-related lymphomas. This study contributes a South African perspective by correlating the HIV status and prognosis of DLBCL and PBL with differentiation profiles assessed by immunophenotyping. Analysis of the morphologic, immunophenotypic and clinicopathologic features of 52 cases of DLBCL and 9 cases of de novo PBL was performed. The overall survival of patients with PBL was poorer than that of DLBCL (logrank p value 0.002). Despite HAART, the overall survival with DLBCL and HIV infection was significantly poorer than HIV negative patients with DLBCL (p value <0.001). Profound immunosuppression was evident in the HIV positive group as the mean CD4 count was 151 cells/mm(3) in DLBCL and 61 cells/mm(3) in PBL. HIV positive patients were significantly younger at presentation with greater likelihood of extranodal lymphoma. When Hans' and Muris' algorithmic stratification of DLBCL were applied, no statistical significance was demonstrated (p values 0.188 and 0.399 respectively). However, when Bcl-2 expression occurred in germinal center-type DLBCL (Hans' defined), improved survival was conferred by the germinal center immunophenotype (p value 0.007). The study demonstrates that DLBCL and PBL have significant potential for aggressive behaviour and poor outcome in the setting of profound immunosuppression due to HIV infection. Further studies are required to assess the effect of targeted-immunotherapy (Rituximab) in combination with recent amendment of the South African national antiretroviral treatment guidelines which has created tremendous potential for improved survival in patients with AIDS-related non-Hodgkin B-cell lymphomas.

Genetic Analysis of HIV-1 Integrase Sequences from Treatment Naive Individuals in Northeastern South Africa

Raltegravir, an integrase inhibitor, is not a component of the current South African antiretroviral treatment guidelines, but it could be introduced in the near future as cases of virological failures from current treatment regimens begin to occur. The aim of this study was to analyze the complete HIV integrase gene obtained from individuals at two treatment sites in northeastern South Africa for the presence of Raltegravir associated drug resistant mutations and viral subtypes based on the integrase gene. Examination for mutations against other integrase inhibitors, such as Elvitegravir and Dolutegravir, was also done. Viruses from 127 treatment naive individuals were analyzed. Genetic drug resistance mutations were determined using the Stanford HIV Drug Resistance Interpretation program and the International AIDS society-USA guidelines. Viral subtyping was done by phylogenetic analysis, and recombinants were determined using the REGA, jpHMM and RIP tools. No major resistance mutations were detected. However, 7% of the sequences had minor mutations and polymorphisms. The majority (99%) of the viruses were HIV-1 C. Recombination analysis showed that the polymerase gene of one virus was likely composed of HIV-1 subtype A1 and C sequences. The present study indicates that Raltegravir, Elvitegravir and Dolutegravir resistant mutations may be absent in the study communities and further indicates the presence of recombinant viruses in northeastern South Africa.

Pretreatment antiretroviral exposure from recreational use

The international community has overcome many obstacles in making HIV antiretroviral (ARV) medication available globally, but ARV resistance in treatment-naive individuals remains an implementation challenge. The subject of many recent reports,1-3 worries abound that pretreatment ARV resistance is related to treatment failure and that further increases in the rates of pretreatment ARV resistance might “jeopardise the global HIV response”.1,2 Largely attributed to transmitted resistance, pretreatment ARV exposure such as inadequate treatment outside of sanctioned care networks is believed to be a contributing factor.3 While investigating HIV-risk behaviour in South Africa,4 we learned of a preventable form of pretreatment ARV exposure that has gone largely unreported and may accelerate rates of pretreatment ARV resistance: the recreational use of ARVs referred to by our informants as “whoonga”. Whereas whoonga has received significant media attention since 2010, the first and only report in the medical literature documenting the recreational use of ARVs appeared years earlier from the United States. In discussions with HIV-infected individuals in Miami about prescription drug diversion, Inciardi and colleagues learned that some individuals abuse efavirenz for its “intoxicating” effects and use ritonavir to enhance the effects of illicit drugs such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA/ecstasy).5 Claims about the psychoactive effects of these ARVs are supported by scientific case reports.6,7 Similar ARV abuse patterns in South Africa have been reported in the social science literature and news media. Larkan and colleagues provide an account of individuals smoking efavirenz in Western Cape and summarise media reports that ARVs are combined with illicit drugs such as opiates, methamphetamine, and/or marijuana to make drug cocktails.8 Whoonga, believed to be one such cocktail, brought media attention to the problem of recreational ARV use in Kwazulu-Natal because of its addictive potential, its association with criminal activity, and the challenge it posed to ARV rollout.9 Even local experts who maintain that whoonga is heroin and does not contain ARVs acknowledge that a number of South African drug abusers use ARVs recreationally.10 Although essentially a substance abuse problem, the implications for HIV treatment are broad. For example, diversion of ARVs, in addition to impacting adherence, reduces ARV supply and limits access to treatment. Criminal behaviour related to diversion of ARVs endangers patients and healthcare providers while deterring others from seeking care. Finally, the recreational use of ARVs further stigmatises HIV-infected patients and their communities and may undermine donor willingness to fund ARV treatment.8 In addition to these impacts, when untreated HIV-infected individuals are exposed to ARVs recreationally, they are at risk for acquiring resistance.8 Mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz are among the most common in individuals with pretreatment ARV resistance.1-3 Interestingly, serum concentrations of ARVs including efavirenz have been detected in some HIV-infected individuals with pretreatment ARV resistance who deny prior history of ARV treatment.3 To help explain some of these findings, researchers may wish to inquire specifically about recreational ARV use or use of drug cocktails when assessing pretreatment ARV exposure. Expanding pretreatment ARV resistance screening will help to minimize the risk that this form of pretreatment ARV exposure poses; however, a comprehensive strategy to investigate this problem also involves expanding substance abuse research. Existing substance abuse surveillance methods have not reported on the phenomenon,11,12 and they may need to be improved if we are to understand the extent of pretreatment ARV exposure from recreational ARV use. Systematic research is also needed to explore the chemical makeup of South African street drugs, the abuse liability of ARVs, and the bioavailability and likelihood of developing resistance when ARVs are smoked or otherwise administered inappropriately. Given the high prevalence and complex medical, psychosocial, and political context of HIV in southern Africa, it is important that treatment strategies adapt to emerging issues like recreational ARV use. We may decrease the recreational use of ARVs, decrease drug diversion, and improve adherence to HIV treatment if we avoid ARVs used recreationally when developing ARV treatment guidelines or distribute ARVs to patients in a way that minimizes the potential for misuse. The recreational use of ARVs also serves as a reminder that ARV treatment is not synonymous with HIV treatment and demonstrates the importance of access to effective community-based mental health and substance abuse services.

Programmatic Impact of the Evolution of WHO Pediatric Antiretroviral Treatment Guidelines for Resource-Limited Countries (Tukula Fenna Project, Uganda)

World Health Organization (WHO) recommendations for the initiation of antiretroviral therapy (ART) in children were revised in 2010, but the programmatic impact has had limited study. We used a cohort of 985 Ugandan children followed since 2003 by the Tukula Fenna project to model the differential impact of the 2006, 2008, and 2010 WHO pediatric ART inititation criteria on the proportion of children eligible for ART at enrollment and over time. Using the WHO 2006, 2008, and 2010 ART criteria, 40%, 57%, and 66% of children, respectively, would have been eligible for ART at enrollment and 76%, 84%, and 88% 2 years later. Evaluating the entire cohort followed for 6 years using the 2006, 2008, and 2010 guidelines, the proportion in need of ART was found to be 70%, 82%, and 87%, respectively. Between 2006 and 2008, the proportions of eligible children starting ART within 6 and 12 months were 39% and 50%, respectively; after this, the proportions starting within 6 and 12 months were 50% and 52%. Before 2008, the most common criterion met in children who did not start ART was WHO clinical stage (odds ratio = 2.0, CI 95% = 1.2 to 3.2); after the 2008 recommendations, the most common eligibility criterion in children who did not start ART was age <12 months (odds ratio = 10.5, CI 95% = 3.8 to 31.1). An overall increase of 17% (from 70% to 87%) in children in need of ART was observed in our cohort comparing the 2006 and 2010 guidelines; this increase was primarily driven by the introduction of universal treatment for infants <12 months in 2008.

Compliance with HIV treatment guidelines in the Spanish CoRIS cohort: impact on mortality and immunovirological response

There is little evidence assessing compliance with clinical practice guidelines for antiretroviral treatment and its impact on clinical outcomes. The Spanish national guidelines for antiretroviral treatment are published by the Spanish AIDS Study Group (GeSIDA). The aim of this study was to assess compliance with national guidelines for the treatment of naïve patients from a multicentre Spanish cohort (CoRIS). The specific aims were to evaluate the proportion of patients treated according to the guidelines’ recommendations, to investigate factors associated with the prescription of a non‐recommended treatment, and to assess the impact of non‐recommended treatments on mortality and on virological and immunological response (defined as undetectable viral load and increase of 100 CD4/ml, respectively, after 1 year). Drug combinations were classified as recommended, alternative, or not recommended, according to the guidelines’ “what to start with” recommendations. 6225 naïve patients were included between the years 2004 and 2010. Among 4516 patients who started treatment, 3592 (79.5%), 540 (12%), and 384 (8.5%) started with a recommended, alternative and not‐recommended treatment, respectively. The use of a not‐recommended treatment was significantly associated with CD4 count &gt;500/ml (OR: 2.03, 95% CI: 1.14–3.59), hepatitis B infection (OR: 2.23, 95% CI: 1.50–3.33), treatment in a hospital with &lt;500 beds, and starting treatment in the years 2004 to 2006. There was no significant association of having a not‐recommended treatment with gender, route of transmission, hepatitis C infection, country of origin, education, or viral load. The use of a not‐recommended regimen was significantly associated with mortality (HR: 1.61, 95% CI: 1.03–2.52, p=0.035) and lack of virological response (OR: 0.65, 95% CI: 0.45–0.93, p=0.019), but it was not associated with immunological response (OR: 0.90, 95% CI: 0.75–1.08, p=0.273). In conclusion, compliance with “what to start with” recommendations of Spanish national guidelines was high. The use of not‐recommended regimens was more likely in patients with &gt;500 CD4/ml, hepatitis B infection, and starting treatment in the years 2004–2006 and in small hospitals. Not‐recommended regimens were associated with higher mortality and lack of virological response.

Cost-Effectiveness of Tenofovir Instead of Zidovudine for Use in First-Line Antiretroviral Therapy in Settings without Virological Monitoring

BackgroundThe most recent World Health Organization (WHO) antiretroviral treatment guidelines recommend the inclusion of zidovudine (ZDV) or tenofovir (TDF) in first-line therapy. We conducted a cost-effectiveness analysis with emphasis on emerging patterns of drug resistance upon treatment failure and their impact on second-line therapy.MethodsWe used a stochastic simulation of a generalized HIV-1 epidemic in sub-Saharan Africa to compare two strategies for first-line combination antiretroviral treatment including lamivudine, nevirapine and either ZDV or TDF. Model input parameters were derived from literature and, for the simulation of resistance pathways, estimated from drug resistance data obtained after first-line treatment failure in settings without virological monitoring. Treatment failure and cost effectiveness were determined based on WHO definitions. Two scenarios with optimistic (no emergence; base) and pessimistic (extensive emergence) assumptions regarding occurrence of multidrug resistance patterns were tested.ResultsIn the base scenario, cumulative proportions of treatment failure according to WHO criteria were higher among first-line ZDV users (median after six years 36% [95% simulation interval 32%; 39%]) compared with first-line TDF users (31% [29%; 33%]). Consequently, a higher proportion initiated second-line therapy (including lamivudine, boosted protease inhibitors and either ZDV or TDF) in the first-line ZDV user group 34% [31%; 37%] relative to first-line TDF users (30% [27%; 32%]). At the time of second-line initiation, a higher proportion (16%) of first-line ZDV users harboured TDF-resistant HIV compared with ZDV-resistant viruses among first-line TDF users (0% and 6% in base and pessimistic scenarios, respectively). In the base scenario, the incremental cost effectiveness ratio with respect to quality adjusted life years (QALY) was US$83 when TDF instead of ZDV was used in first-line therapy (pessimistic scenario: US$ 315), which was below the WHO threshold for high cost effectiveness (US$ 2154).ConclusionsUsing TDF instead of ZDV in first-line treatment in resource-limited settings is very cost-effective and likely to better preserve future treatment options in absence of virological monitoring.

Adoption of new HIV treatment guidelines and drug substitutions within first‐line as a measure of quality of care in rural Lesotho: health centers and hospitals compared

In 2007, Lesotho launched new national antiretroviral treatment (ART) guidelines, prioritising tenofovir and zidovudine over stavudine as a backbone together with lamivudine. We compared the rate of adoption of these new guidelines and substitution of first-line drugs by health centers (HC) and hospitals in two catchment areas in rural Lesotho. Retrospective cohort analysis. Patients aged ≥16 years were stratified into a HC- and a hospital-group. Type of backbone at ART-initiation (i), substitutions within first line (ii) and type of backbone among patients retained by December 2010 (iii). A multiple logistic regression model including HC vs. hospital, patient characteristics (sex, age, WHO-stage, baseline CD4-count, concurrent pregnancy, concurrent tuberculosis treatment) and year of ART-start, was used. Of 3936 adult patients initiated on ART between 2007 and 2010, 1971 started at hospitals and 1965 at HCs. Hospitals were more likely to follow the new guidelines as measured by prescription of backbones without stavudine (Odds-ratio 1.55; 95%CI: 1.32-1.81) and had a higher rate of drug substitutions while on first-line ART (2.39; 1.83-3.13). By December 2010, patients followed at health centres were more likely to still receive stavudine (2.28; 1.83-2.84). Health centers took longer to adopt the new guidelines and substituted drugs less frequently. Decentralised ART-programmes need close support, supervision and mentoring to absorb new guidelines and to adhere to them.

Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis

SummaryBackgroundThe emergence and spread of high levels of HIV-1 drug resistance in resource-limited settings where combination antiretroviral treatment has been scaled up could compromise the effectiveness of national HIV treatment programmes. We aimed to estimate changes in the prevalence of HIV-1 drug resistance in treatment-naive individuals with HIV since initiation of rollout in resource-limited settings.MethodsWe did a systematic search for studies and conference abstracts published between January, 2001, and July, 2011, and included additional data from the WHO HIV drug resistance surveillance programme. We assessed the prevalence of drug-resistance mutations in untreated individuals with respect to time since rollout in a series of random-effects meta-regression models.FindingsStudy-level data were available for 26 102 patients from sub-Saharan Africa, Asia, and Latin America. We recorded no difference between chronic and recent infection on the prevalence of one or more drug-resistance mutations for any region. East Africa had the highest estimated rate of increase at 29% per year (95% CI 15 to 45; p=0·0001) since rollout, with an estimated prevalence of HIV-1 drug resistance at 8 years after rollout of 7·4% (4·3 to 12·7). We recorded an annual increase of 14% (0% to 29%; p=0·054) in southern Africa and a non-significant increase of 3% (–0·9 to 16; p=0·618) in west and central Africa. There was no change in resistance over time in Latin America, and because of much country-level heterogeneity the meta-regression analysis was not appropriate for Asia. With respect to class of antiretroviral, there were substantial increases in resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) in east Africa (36% per year [21 to 52]; p<0·0001) and southern Africa (23% per year [7 to 42]; p=0·0049). No increase was noted for the other drug classes in any region.InterpretationOur findings suggest a significant increase in prevalence of drug resistance over time since antiretroviral rollout in regions of sub-Saharan Africa; this rise is driven by NNRTI resistance in studies from east and southern Africa. The findings are of concern and draw attention to the need for enhanced surveillance and drug-resistance prevention efforts by national HIV treatment programmes. Nevertheless, estimated levels, although increasing, are not unexpected in view of the large expansion of antiretroviral treatment coverage seen in low-income and middle-income countries—no changes in antiretroviral treatment guidelines are warranted at the moment.FundingBill & Melinda Gates Foundation and the European Community's Seventh Framework Programme

Prevalence and correlates of alcohol use disorders during antiretroviral treatment in injection-driven HIV epidemics in Vietnam

BackgroundAlcohol use disorders (AUD) negatively affects adherence to and outcomes of antiretroviral treatment (ART) for HIV/AIDS patients. This study determined the prevalence of AUD and identified correlates of alcohol consumption and drinking problems during ART in large injection-driven HIV epidemics in Vietnam. MethodsWe conducted a cross-sectional study of 1016 patients (36.2% women, mean age=35.4) in 7 hospitals in Hanoi, Hai Phong, and Ho Chi Minh City. Alcohol use problems were assessed using the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C). Step-wise multivariate regression analyses determined the correlates of alcohol consumption, hazardous drinking, and binge drinking in HIV/AIDS patients. ResultsThere were 55.0% patients reported ever drinking, 30.1% had positive hazardous drinking and 22.3% had binge drinking. Patients who were male, drug users, working as free-lancers, asymptomatic stage, and poorer immune status were more likely to have severe alcohol consumption, hazardous drinking and binge drinking. Drug users taking both ART and Methadone Maintenance Treatment (MMT), were less likely to report AUD. In non-drug users, the longer duration of ART was also associated with lower alcohol consumption and likelihood of drinking problems. In drug users, those in the 1st year ART were more likely to be at-risk drinking than other patient groups. ConclusionAUD is highly prevalent in HIV/AIDS patients taking ART in large injection-driven HIV epidemics. ART guidelines should include AUD screening and interventions. Expanding the coverage of current services for drug users, including MMT and ART, might contribute to the reduction of AUD.