Related Articles

We systematically reviewed the first-line tenofovir regimens recommended in the 2010 World Health Organization Antiretroviral (ARV) Treatment Guidelines. TDF/3TC/NVP was the least well-studied and appeared the least efficacious. Further study of TDF/3TC/NVP is required before it is widely deployed for initial ARV therapy.

(See the Editorial Commentary by Kuritzkes et al, on pages 876–7.)

We systematically reviewed studies of the virological efficacy of the 4 new tenofovir (TDF)-containing regimens recommended for initial antiretroviral (ARV) therapy in the 2010 World Health Organization ARV Treatment Guidelines. Thirty-three studies assessed the efficacy of 1 or more TDF-containing regimens: TDF/lamivudine (3TC)/nevirapine (NVP) (n = 3), TDF/ emtricitabine (FTC)/NVP (n = 9), TDF/3TC/efavirenz (EFV) (n = 6), and TDF/FTC/EFV (n = 19). TDF/3TC/NVP was the least well-studied and appeared the least efficacious of the 4 regimens. In 2 comparative studies, TDF/3TC/NVP was associated with significantly more virological failure than AZT/3TC/NVP; a third study was terminated prematurely because of early virological failure. TDF/FTC/NVP was either equivalent or inferior to its comparator arms. TDF/3TC/EFV was equivalent to its comparator arms. TDF/FTC/EFV was equivalent or superior to its comparator arms. Possible explanations for these findings include the greater antiviral activity of EFV versus NVP and longer intracellular half-life of FTC-triphosphate versus 3TC-triphosphate. Further study of TDF/3TC/NVP is required before it is widely deployed for initial ARV therapy.

Background

Although tenofovir (TDF) is a common component of antiretroviral therapy (ART), recent evidence suggests inferior outcomes when it is combined with nevirapine (NVP).

Methods

We compared outcomes among patients initiating TDF+emtricitabine or lamivudine (XTC)+NVP, TDF+XTC+efavirenz (EFV), zidovudine (ZDV)+lamuvidine (3TC)+NVP, and ZDV+3TC+EFV. We categorized drug exposure by initial ART dispensation, by a time-varying analysis that accounted for drug substitutions, and by predominant exposure (>75% of drug dispensations) during an initial window period. Risks for death and program failure were estimated using Cox proportional hazard models. All were regimens were compared to ZDV+3TC+NVP.

Results

Between July 2007 and November 2010, 18,866 treatment-naïve adults initiated ART: 18.2% on ZDV+3TC+NVP, 1.8% on ZDV+3TC+EFV, 36.2% on TDF+XTC+NVP, and 43.8% on TDF+XTC+EFV. When exposure was categorized by initial prescription, patients on TDF+XTC+NVP (adjusted hazard ratio [AHR]:1.45; 95%CI:1.03–2.06) had a higher post-90 day mortality. TDF+XTC+NVP was also associated with an elevated risk for mortality when exposure was categorized as time-varying (AHR:1.51; 95%CI:1.18–1.95) or by predominant exposure over the first 90 days (AHR:1.91, 95%CI:1.09–3.34). However, these findings were not consistently observed across sensitivity analyses or when program failure was used as a secondary outcome.

Conclusion

TDF+XTC+NVP was associated with higher mortality when compared to ZDV+3TC+NVP, but not consistently across sensitivity analyses. These findings may be explained in part by inherent limitations to our retrospective approach, including residual confounding. Further research is urgently needed to compare the effectiveness of ART regimens in use in resource-constrained settings.

Background

We and others have shown that subtype C HIV-1 isolates from patients failing on a regimen containing stavudine (d4T) or zidovudine (AZT) exhibit thymidine-associated mutations (TAMs) and K65R which can impair the efficacy of Tenofovir (TDF) at second line. Depending on the various studies, the prevalence of K65R substitution as determined by the Sanger method ranges from 4 to 30%. Our aim was to determine whether ultra-deep pyrosequencing (UDPS) could provide more information than the Sanger method about selection of K65R in this population of patients.

Methods

27 subtype C HIV-1 isolates from treated patients failing on a regimen with d4T or AZT plus lamivudine (3TC) plus nevirapine (NVP) or efavirenz (EFV) and who had been sequenced by Sanger were investigated by UDPS at codon 65 of the reverse transcriptase (RT). 18 isolates from naïve patients and dilutions of a control K65R plasmid were analysed by Sanger plus UDPS.

Results

Analysis of Sanger sequences of subtype C HIV-1 isolates from naïve patients exhibited expected polymorphic substitutions compared to subtype B but no drug resistance mutations (DRMs). Quantitation of K65R variants by UDPS ranged from <0.4% to 3.08%. Sanger sequences of viral isolates from patients at failure of d4T or AZT plus 3TC plus NVP or EFV showed numerous DRMs to nucleoside reverse transcriptase inhibitors (NRTIs) including M184V, thymidine-associated mutations (TAMs) plus DRMs to non- nucleoside reverse transcriptase inhibitors (NNRTIs). Two K65R were observed by Sanger in this series of 27 samples with UDPS percentages of 27 and 87%. Other samples without K65R by Sanger exhibited quantities of K65R variants ranging from <0.4% to 0.80%, which were below the values observed in isolates from naïve patients.

Conclusions

While Sanger sequencing of subtype C isolates from treated patients at failure of d4T or AZT plus 3TC plus NVP or EFV exhibited numerous mutations including TAMs and 8% K65R, UDPS quantitation of K65R variants in the same series did not provide any more information than Sanger.

To estimate the incidence of adverse drug reactions (ADRs) in Human immune deficiency virus (HIV) patients on highly active antiretroviral therapy (HAART). To identify the risk factors associated with ADRs in HIV patients. To analyze reported ADRs based on various parameters like causality, severity, predictability, and preventability. Retrospective case-control study. An 18-month retrospective case-control study of 208 patients newly registered in ART center, RIMS hospital, Kadapa, were intensively monitored for ADRs to HAART. Predictability was calculated based on the history of previous exposure to drug. Multivariate logistic regressions were used to identify the risk factors for ADRs. Data were analyzed using the chi-square test for estimating the correlation between ADRs and different variables. All statistical calculations were performed using EpiInfo version 3.5.3. Monitoring of 208 retrospective patients by active Pharmacovigilance identified 105 ADRs that were identified in 71 patients. Skin rash and anemia were the most commonly observed ADRs. The organ system commonly affected by ADR was skin and appendages (31.57%). The ADRs that were moderate were 90.14% of cases. The incidence of ADRs (53.52%) was higher with Zidovudine + Lamivudine + Nevirapine combination. CD4 cell count less than <250 cells/μl were 80.28%, male gender were observed to be the risk factors for ADRs. Our study finding showed that there is a need of active pharmaceutical care with intensive monitoring for ADRs in Indian HIV-positive patients who are illiterate, of male and female gender, with CD4 count ≤250 cells/mm3 with comorbid conditions.

Background

Spontaneous adverse drug reaction (ADR) reporting is the cornerstone of pharmacovigilance. ADR reporting with Yellow Cards has tremendously improved pharmacovigilance of drugs in many developed countries and its use is advocated by the World Health Organization (WHO). This study was aimed at investigating the knowledge and attitude of doctors in a teaching hospital in Lagos, Nigeria on spontaneous ADR reporting and to suggest possible ways of improving this method of reporting.

Methods

A total of 120 doctors working at the Lagos State University Teaching Hospital (LASUTH), in Nigeria were evaluated with a questionnaire for their knowledge and attitudes to ADR reporting. The questionnaire sought the demographics of the doctors, their knowledge and attitudes to ADR reporting, the factors that they perceived may influence ADR reporting, and their levels of education and training on ADR reporting. Provision was also made for suggestions on the possible ways to improve ADR reporting.

Results

The response rate was 82.5%. A majority of the respondents (89, 89.9%) considered doctors as the most qualified health professionals to report ADRs. Forty (40.4%) of the respondents knew about the existence of National Pharmacovigilance Centre (NPC) in Nigeria. Thirty-two (32.3%) respondents were aware of the Yellow Card reporting scheme but only two had ever reported ADRs to the NPC. About half (48.5%) of the respondents felt that all serious ADRs could be identified after drug marketing. There was a significant difference between the proportion of respondents who felt that ADR reporting should be either compulsory or voluntary (χ2 = 38.9, P < 0.001). ADR reporting was encouraged if the reaction was serious (77, 77.8%) and unusual (70, 70.7%). Education and training was the most recognised means of improving ADR reporting.

Conclusion

The knowledge of ADRs and how to report them are inadequate among doctors working in a teaching hospital in Lagos, Nigeria. More awareness should be created on the Yellow Card reporting scheme. Continuous medical education, training and integration of ADR reporting into the clinical activities of the doctors would likely improve reporting.

Objective

To describe the safety and efficacy of highly active antiretroviral therapy (HAART) in pregnant women treated in an integrated antenatal antiretroviral programme (ANC ARV).

Methods

A retrospective analysis was performed on patients attending the ANC ARV from August 2004 through February 2007.

Results

Data was collected on 689 treatment-naïve pregnant women initiated on HAART. The mean age was 29.2 years. The mean baseline CD4+ count was 154 cells/uL and mean baseline HIV viral load was 101,561 copies/ml. Tuberculosis was the most prevalent presenting opportunistic infection (7.7%). Stavudine, lamivudine, and nevirapine were initiated in 82% of women with the most frequent adverse drug reaction being nevirapine-associated skin rash (3.5%). Mean gestational age at HAART initiation was 27 weeks. Among women with follow-up data, 80% gained 50 or more CD4 cells/uL, and 80.5% achieved viral suppression to <1000 copies/ml. Of 302 mother/infant pairs who completed postnatal follow-up, the HIV transmission rate was 5%. In women who received more than seven weeks of HAART during pregnancy, transmission was 0.3%.

Conclusions

Within the ANC ARV programme, initiating pregnant women on HAART was feasible, safe, and effective. Advanced gestational age at treatment initiation and loss to follow-up emerge as important challenges in this population.

Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6–15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden.

Background

During stavudine phase-out plan in developing countries, tenofovir is used to substitute stavudine. However, knowledge regarding whether there is any difference of the frequency of renal injury between tenofovir/lamivudine/efavirenz and tenofovir/lamivudine/nevirapine is lacking.

Methods

This prospective study was conducted among HIV-infected patients who were switched NRTI from stavudine/lamivudine to tenofovir/lamivudine in efavirenz-based (EFV group) and nevirapine-based regimen (NVP group) after two years of an ongoing randomized trial. All patients were assessed for serum phosphorus, uric acid, creatinine, estimated glomerular filtration rate (eGFR), and urinalysis at time of switching, 12 and 24 weeks.

Results

Of 62 patients, 28 were in EFV group and 34 were in NVP group. Baseline characteristics and eGFR were not different between two groups. At 12 weeks, comparing mean ± SD measures between EFV group and NVP group were: phosphorus of 3.16 ± 0.53 vs. 2.81 ± 0.42 mg/dL (P = 0.005), %patients with proteinuria were 15% vs. 38% (P = 0.050). At 24 weeks, mean ± SD phosphorus and median (IQR) eGFR between the corresponding groups were 3.26 ± 0.78 vs. 2.84 ± 0.47 mg/dL (P = 0.011) and 110 (99-121) vs. 98 (83-112) mL/min (P = 0.008). In NVP group, comparing week 12 to time of switching, there was a decrement of phosphorus (P = 0.007) and eGFR (P = 0.034). By multivariate analysis, 'receiving nevirapine', 'old age' and 'low baseline serum phosphorus' were associated with hypophosphatemia at 24 weeks (P < 0.05). Receiving nevirapine and low baseline eGFR were associated with lower eGFR at 24 weeks (P < 0.05).

Conclusion

The frequency of tenofovir-associated renal impairment was higher in patients receiving tenofovir/lamivudine/nevirapine compared to tenofovir/lamivudine/efavirenz. Further studies regarding patho-physiology are warranted.

Summary

In July 2010, the World Health Organization (WHO) released new guidelines entitled, “Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Towards universal access.” Previewed in November 2009 in abridged form, the completed document highlights the key WHO recommendations for antiretroviral treatment (ART) and prophylaxis in pregnant women, and contains substantial changes from the 2006 guidelines. Of note, the new guidelines recommend ART for all pregnant women with a CD4 cell count (CD4) less than 350 cells/mm3, regardless of their clinical stage; includes tenofovir (TDF) as an acceptable alternative component of an ART regimen in pregnant and breastfeeding women; encourages initiation of both ART and antiretroviral (ARV) prophylaxis early in pregnancy; eliminates single-dose nevirapine (sdNVP) per se as a prophylaxis option; lists three-drug ARV prophylaxis as an option for women who do not need ART for their own health; and introduces extended daily infant nevirapine (ED-NVP) as a strategy for prevention of breast milk transmission of HIV. This article reviews these new recommendations and their rationale, and highlights key implications and challenges to their implementation in the Zambian context.

Background

Multidrug antiretroviral (ARV) regimens including HAART and short-course dual antiretroviral (sc-dARV) regimens were introduced in 2004 to improve Prevention of Mother-to-Child Transmission (PMTCT) in Cameroon. We assessed the effectiveness of these regimens from 6–10 weeks and 12 months of age, respectively.

Methodology/Findings

We conducted a retrospective cohort study covering the period from October 2004 to March 2008 in a reference hospital in Cameroon. HIV-positive pregnant women with CD4 ≤350 cells/mm3 received first-line HAART [regimen 1] while the others received ARV prophylaxis including sc-dARV or single dose nevirapine (sd-NVP). Sc-dARV included at least two drugs according to different gestational ages: zidovudine (ZDV) from 28–32 weeks plus sd-NVP [regimen 2], ZDV and lamuvidine (3TC) from 33–36 weeks plus sd-NVP [regimen 3]. When gestational age was ≥37 weeks, women received sd-NVP during labour [regimen 4]. Infants received sd-NVP plus ZDV and 3TC for 7 days or 30 days. Early diagnosis (6–10 weeks) was done, using b-DNA and subsequently RT-PCR. We determined early MTCT rate and associated risk factors using logistic regression. The 12-month HIV-free survival was assessed using Cox regression. Among 418 mothers, 335 (80%) received multidrug ARV regimens (1, 2, and 3) and MTCT rate with multidrug regimens was 6.6% [95%CI: 4.3–9.6] at 6 weeks, without any significant difference between regimens. Duration of mother's ARV regimen <4 weeks [OR = 4.7, 95%CI: 1.3–17.6], mother's CD4 <350 cells/mm3 [OR = 6.4, 95%CI: 1.8–22.5] and low birth weight [OR = 4.0, 95%CI: 1.4–11.3] were associated with early MTCT. By 12 months, mixed feeding [HR = 8.7, 95%CI: 3.6–20.6], prematurity [HR = 2.3, 95%CI: 1.2–4.3] and low birth weight were associated with children's risk of progressing to infection or death.

Conclusions

Multidrug ARV regimens for PMTCT are feasible and effective in routine reference hospital. Early initiation of ARV during pregnancy and proper obstetrical care are essential to improve PMTCT.

Objective

To determine if differences in short-term virologic failure among commonly used ART regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART.

Design

Observational cohort study of patients initiating ART between January 2000 and December 2005.

Setting

The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States.

Subjects, participants

A total of 13,546 antiretroviral-naïve HIV-positive patients initiating ART with efavirenz (EFV), nevirapine (NVP), lopinavir/ritonavir (LPV/r), nelfinavir (NFV), or abacavir (ABC) as third drugs in combination with a zidovudine and lamivudine NRTI backbone.

Main outcome measures

Short-term (24-week) virologic failure (>500 copies/mL) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes).

Results

Compared with EFV as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; NVP (adjusted odds ratio=1.87, 95%CI=1.58,2.22), LPV/r (1.32, 95%CI=1.12–1.57), NFV (3.20, 95%CI=2.74,3.74), and ABC (2.13, 95%CI=1.82,2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with NVP (adjusted hazard ratio for composite outcome measure 1.27, 95%CI=1.04,1.56) and ABC (1.22, 95%CI=1.00,1.48).

Conclusions

Among antiretroviral-naïve patients initiating therapy, between-ART regimen differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

Objective

The World Health Organization (WHO) recently changed its first-line antiretroviral treatment guidelines in resource-limited settings. The cost-effectiveness of the new guidelines are unknown.

Design

Comparative effectiveness and cost-effectiveness analysis using a model of HIV disease progression and treatment.

Methods

Using a simulation of HIV disease and treatment in South Africa, we compared the life expectancy, quality-adjusted life expectancy, lifetime costs, and cost-effectiveness of five initial regimens. Four are currently recommended by the WHO: tenofovir/lamivudine/efavirenz; tenofovir/lamivudine/nevirapine; zidovudine/lamivudine/efavirenz; and zidovudine/lamivudine/nevirapine. The fifth is the most common regimen in current use: stavudine/lamivudine/nevirapine. Virologic suppression and toxicities determine regimen effectiveness and cost-effectiveness.

Results

Choice of first-line regimen is associated with a difference of nearly 12 months of quality-adjusted life expectancy, from 135.2 months (tenofovir/lamivudine/efavirenz) to 123.7 months (stavudine/lamivudine/nevirapine). Stavudine/lamivudine/nevirapine is more costly and less effective than zidovudine/lamivudine/nevirapine. Initiating treatment with a regimen containing tenofovir/lamivudine/nevirapine is associated with an incremental cost-effectiveness ratio of $1,045 per quality-adjusted life year compared with zidovudine/lamivudine/nevirapine. Using tenofovir/lamivudine/efavirenz was associated with the highest survival, fewest opportunistic diseases, lowest rate of regimen substitution, and an incremental cost-effectiveness ratio of $5,949 per quality-adjusted life year gained compared with tenofovir/lamivudine/nevirapine. Zidovudine/lamivudine/efavirenz was more costly and less effective than tenofovir/lamivudine/nevirapine. Results were sensitive to the rates of toxicities and the disutility associated with each toxicity.

Conclusion

Among the options recommended by WHO, we estimate only three should be considered under normal circumstances. Choice among those depends on available resources and willingness to pay. Stavudine/lamivudine/nevirapine is associated with the poorest quality-adjusted survival and higher costs than zidovudine/lamivudine/nevirapine.

Background

Self-initiation to antiretroviral treatment (ART) exposes the patient to the risk of drug toxicity, poor adherence to treatment, and escalates the development of drug resistance.

Objectives

To determine the sources of antiretroviral (ARV) drugs by unregistered human immunodeficiency virus (HIV)-infected patients and the extent of ARV self-medication.

Methods

Simulated clients were used to investigate availability and ARV dispensing practice in the private pharmacies in Dar Es Salaam, Tanzania. A total of 480 HIV-infected patients qualifying to start ART were interviewed to find out their previous use of ARV drugs prior to visiting the HIV clinics. Venous blood (2 mL) was collected from each patient who indicated not to have used ARVs in the past (n = 450). Blood samples were analyzed for the presence and levels of nevirapine (NVP).

Results

Only 5.1% (23/451) of pharmacies were found stocking ARVs drugs, among which 4.0% were retail. Drug dispensers in nearly all (15/18) retail pharmacies which stocked ARVs were willing to sell ARVs without prescription. Out of 450 enrolled patients, only 2.7% (12) stated that they had been receiving ARV drugs from HIV clinics but interrupted the ART treatment due to various reasons. From 450 patients, only 10% had quantifiable NVP concentrations in the blood, despite stating in an interview that they had not recently used ARVs.

Conclusion

Prior use of ARV drugs outside HIV clinics was rare among patients attending those centers. However, the results show that some patients could access and use ARV drugs from private pharmacies without undergoing ART eligibility assessment in HIV clinics.

A combined manual and computer search of the literature on the Canadian experience with adverse drug reactions (ADRs) to prescribed drugs yielded a total of 23 articles. The risk of developing an ADR, factors influencing that risk, the incidence of ADRs, ADRs as a cause of hospitalization, case fatality ratios, whether ADRs increase hospitalization time, and the drugs that are most commonly implicated in ADRs were analyzed.

Objective

To assess effectiveness and safety of a generic fixed-dose combination of tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) among HIV-1-infected patients in Western India.

Methods

Antiretroviral (ARV)-naive and experienced (thymidine analog nucleoside reverse transcriptase inhibitor [tNRTI] replaced by TDF) patients were started on a regimen of 1 TDF/FTC/EFV pill once a day. They were followed clinically on a periodic basis, and viral loads and CD4 counts were measured at 6 and 12 months. Creatinine clearance was calculated at baseline and at 6 months and/or as clinically indicated. Effectiveness was defined as not having to discontinue the regimen due to failure or toxicity.

Results

One hundred forty-one patients who started TDF/FTC/EFV before 1 June 2007 were eligible. Of these, 130 (92.2%) and 44 (31.2%) had 6- and 12-months follow-up, respectively. Thirty-five percent of the patients were ARV-naive. Eleven patients discontinued treatment (4 for virologic failure, 1 for grade 3–4 central nervous system disturbances, 4 for grade 3–4 renal toxicity, and 2 for cost). Ninety-six percent of patients were virologically suppressed at 6 months. Frequency of TDF-associated grade 3–4 renal toxicity was 2.8%; however, 3 of these patients had comorbid conditions associated with renal dysfunction.

Conclusion

A fixed-dose combination of generic TDF/FTC/EFV is effective in ARV-naive and experienced patients. Although frequency of severe renal toxicity was higher than has been reported in the literature, it was safe in patients with no comorbid renal conditions.

Thomas Campbell and colleagues report findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing.

Background

Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.

Methods and Findings

1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.

An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007).

Conclusion

EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.

Trial Registration

www.ClinicalTrials.gov NCT00084136

Please see later in the article for the Editors' Summary.

Editors' Summary

Background

Despite the enormous gains in reducing HIV-related illness and death over the past decade, there are still considerable challenges to meeting the global goal of universal access to highly active antiretroviral treatment—a combination of effective drugs that attack the HIV virus in various ways—to everyone living with HIV/AIDS who could benefit from treatment. In recognition of the related financial, technical, and system obstacles to providing universal access to HIV treatment, in 2010 the UN agency responsible for HIV/AIDS—UNAIDS—launched an ambitious plan called Treatment 2.0, which aims to simplify the way HIV treatment is currently provided. One of the main focuses of Treatment 2.0 is to simplify drug regimes for the treatment of HIV and to make treatment regimes less toxic. In line with Treatment 2.0, the World Health Organization currently recommends that antiretroviral regimens for the initial treatment of HIV should include two nucleoside reverse transcriptase inhibitors (zidovudine or tenofovir disoproxil fumarate [DF] with lamivudine or emtricitabine) and a non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine.)

Why Was This Study Done?

Most of the evidence about the safety and effectiveness of clinical trials come from clinical trials in high-income countries and thus is not generally representative of the majority of people with HIV. So in this study, the researchers conducted a randomized controlled trial in diverse populations in many different settings to investigate whether antiretroviral regimens administered once daily were as effective as twice-daily regimens and also whether a regimen containing the drug atazanavir administered once daily was as safe and effective as a regimen containing efavirenz—data from previous studies have suggested that atazanavir has characteristics, such as its side effect profile, which may make it more suitable for low income settings.

What Did the Researchers Do and Find?

The researchers recruited eligible patients from centers in Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand, the United States, and Zimbabwe—almost half (47%) were women. Then the researchers randomly assigned participants to one of three regimens: efavirenz 600 mg daily plus co-formulated lamivudine-zidovudine 150 mg/300 mg twice daily (EFV+3TC-ZDV); or atazanavir 400 mg once daily, plus didanosine-EC 400 mg once daily, plus emtricitabine 200 mg once daily (ATV+DDI+FTC); or efavirenz 600 mg once daily plus coformulated emtricitabine-tenofovir-DF 200 mg/300 mg once daily (EFV+FTC-TDF). During the study period ATV+DDI+FTC was found to be inferior to EFV+3TC-ZDV, so the Multinational Data Safety Monitoring Board ordered this arm of the trial to stop. Then a year later, due to the low number of treatment failures (deaths, severe HIV disease, or serious opportunistic infections) in the remaining two arms, the board advised the trial to stop early. So the researchers analyzed the data obtained up to this point and pooled the results from all of the centers.

The researchers found that during an average of 184 weeks of follow-up, there were 95 treatment failures (18%) among 526 participants taking EFV+FTC-TDF compared to 98 failures among 519 participants taking EFV+3TC-ZDV. During an average 81 weeks follow-up, there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV. As for safety, 243 (46%) participants assigned to EFV+FTC-TDF reached a safety endpoint (grade 3 disease, abnormal lab measurement, or the need to change drug) compared to 313 (60%) in the EFV+3TC-ZDV group. Importantly, the researchers found that there was greater risk of safety events for women assigned to EFV+3TC-ZDV and also that the atazanavir-based regimen had a higher relative efficacy in women compared to men.

What Do These Findings Mean?

These findings suggest that in diverse populations, EFV+FTC-TDF is as effective as EFV+3TC-ZDV but importantly, the once-daily dosing of EFV+FTC-TDF makes this regimen useful for the initial treatment of HIV, especially in low-income countries. Therefore, as per the guidance in Treatment 2.0, EFV+FTC-TDF in a single combination tablet that can be taken once a day is an attractive option. These findings also indicate that as ATV+DDI+FTC was found to be inferior to the other regimens, this combination should not be used in the initial treatment of HIV. These findings also add to the evidence that antiretroviral efficacy and safety can differ between women and men and support further development of sex-specific recommendations for antiretroviral regimen options.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001290.

The UNAIDS website has more information about Treatment 2.0; and the WHO website provides technical information

For an introduction to the treatment of HIV/AIDS see http://www.avert.org/treatment.htm; the AVERT site also has personal stories from women living with HIV/AIDS

AIDSmap provides information for individuals and communities affected by HIV/AIDS

The ACTG website provides information about research to improve treatment of HIV and related complications

ABSTRACT

Background

Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV).

Methods and Findings

Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs.

Conclusion

NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.

Comparison of two commonly prescribed non-nucleoside reverse transcriptase inhibitors shows that patients on nevirapine have better blood lipid profiles

Objective

To compare the safety/tolerability of abacavir and nevirapine in HIV-infected adults starting antiretroviral (ARV) therapy in Uganda.

Methods

Twenty-four-week randomized double-blind trial conducted with 600 symptomatic ARV-naive adults with CD4 <200 cells/mm3 allocated to zidovudine/lamivudine plus 300 mg abacavir (A) and nevirapine placebo (n = 300) or 200 mg nevirapine (N) and abacavir placebo (n = 300) twice daily. The primary endpoint was any serious adverse event (SAE) definitely/probably or uncertain whether related to blinded nevirapine/abacavir. Secondary endpoints were adverse events leading to permanent discontinuation of blinded nevirapine/abacavir, and grade 4 events.

Results

Seventy-two per cent participants were women; 19% had WHO stage 4 disease; the median age was 37 years (range 18–66); the median baseline CD4 count was 99 cells/mm3 (1–199). Ninety-five per cent completed 24 weeks: 4% died and 1% were lost to follow-up. Thirty-seven SAEs occurred on blinded drug in 36 participants. Twenty events [6 (2.0%) abacavir, 14 (4.7%) nevirapine participants] were considered serious adverse reactions definitely/probably/uncertain whether related to blinded abacavir/nevirapine [HR = 0.42 (95% CI 0.16–1.09) P = 0.06]. Only 2.0% of abacavir participants [six patients (0.7–4.3%)] experienced a suspected hypersensitivity reaction (HSR). In total 14 (4.7%) abacavir and 30 (10.0%) nevirapine participants discontinued blinded abacavir/nevirapine (P = 0.02): because of toxicity (6A, 15N; P = 0.07, all rash/possible HSR and/or hepatotoxicity), anti-tuberculosis therapy (6A, 13N), or for other reasons (2A, 2N).

Conclusions

There was a trend towards a lower rate of serious adverse reactions in Ugandan adults with low CD4 starting ARV regimens with abacavir than with nevirapine. This suggests that abacavir could be used more widely in resource-limited settings without major safety concerns.

Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.

Background

Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.

Methods and Findings

All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).

Conclusions

Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.

Trial Registration

ClinicalTrials.gov NCT00146380

Please see later in the article for the Editors' Summary

Editors' Summary

Background

Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.

Why Was This Study Done?

More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.

What Did the Researchers Do and Find?

In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.

What Do These Findings Mean?

These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.

The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study

Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS

HIV InSite has comprehensive information on HIV/AIDS

Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)

UNICEF also has information about children and HIV and AIDS (in several languages)

The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT

Background

Cutaneous adverse drug reactions (cADRs) can cause significant morbidity and distress in patients especially in the HIV infected population on antiretroviral therapy. Adverse Drug Reaction monitoring and ascertaining causality in resource limited settings still remains a challenge. This study was carried out to evaluate causality and measure incidence of cADRs in HIV infected patients on highly active antiretroviral therapy. The study was also designed to test a 3-step approach in the monitoring and evaluation of ADRs in resource limited settings.

Methodology

A retrospective patient medical records review was carried out at the Parirenyatwa Family Care Centre, (Harare, Zimbabwe). Cases of cADRs were reported to the Medicines Control Authority of Zimbabwe (Drug regulating body in Zimbabwe) for assessment and causality classification.

Results

Two hundred and twenty-one patient records were randomly selected and reviewed to determine if any diagnosis of cADRs was made by clinicians. Causality assessment revealed 13.1% of cADRs which were due to an offending agent in the antiretroviral therapy against an initial incidence of 17.6% which had been determined by the physicians.

Conclusions

cADRs had an incidence of 13.1% within the population under study due to non nucleoside reverse transcriptase inhibitors (NNRTIs). Most reactions were due to the NNRTIs which contributed 72.4 % of all cADRs. A panel of experts from the drug regulatory authority can be used as an implementation based mechanism in ascertaining causality objectively in settings where resources are constrained.

Objectives:

Antimalarial drugs are commonly prescribed for the treatment of malaria and suspected cases of malaria in India. The recent trend is to prescribe ACT and the incidence of adverse reactions to this therapy is notwell-documented in Indian population. Therefore, this study was designed to assess ADR pattern of antimalarial drugs particularly ACT in India.

Materials and Methods:

Over a period of 1 year, 500 patients who were administered antimalarial drugs were enrolled in the study. The World Health Organization causality assessment scale was used for classifying the ADR.

Results:

In this study out of 500 patients, 251 complained of ADRs. The sex-wise difference in reporting of ADRs was statistically not significant (P=0.0943). The most common ADRs reported were nausea, anorexia and vomiting. ADRs were most commonly reported when chloroquine was coprescribed.

Conclusions:

This study indicates that ACT was commonlyused in the treatment of malaria. Results of the analysis suggest that all the ADRs were of moderate intensity and no serious ADR was observed. This baseline information will be useful to implement the ACT in India.

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV+ pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.

Background

Concomitant use of antiretrovirals (ARV) and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate (DMPA) among women on ARV.

Study Design

HIV-infected women on selected ARV regimens or no ARV were administered DMPA 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation.

Results

Seventy evaluable subjects were included, 16 on nucleoside only or no ARV, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens, and 16 on nevirapine-containing regimens. Nine grade 3 or 4 adverse events occurred in 7 subjects; none were judged related to DMPA. The most common findings possibly related to DMPA were abnormal vaginal bleeding (9, 12.7%), headache (3, 4.2%), abdominal pain, mood changes, insomnia, anorexia, and fatigue, each occurring in 2 (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred.

Conclusions

The clinical profile associated with DMPA administration in HIV-infected women, most on ARV, appears similar to that seen in HIV-uninfected women. DMPA prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published DMPA/ARV interaction data, these data suggest that DMPA can be used safely by HIV-infected women on the ARV studied.

HIV-infected breastfeeding infants acquired multi-class drug resistance (MCR) after their mothers started highly active antiretroviral therapy (HAART). MCR was more frequent in infants whose mothers started HAART by 6 months post-partum or were exclusively breastfeeding when they reported HAART use.

Background. The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)–infected lactating women with CD4+ cell counts <350 cells/μL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis.

Methods. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests.

Results. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P = .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P = .003).

Conclusions. postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.

Background

Epidemiologic information on time trends of Adverse Drug Reactions (ADR) and ADR-related hospitalizations is scarce. Over time, pharmacotherapy has become increasingly complex. Because of raised awareness of ADR, a decrease in ADR might be expected. The aim of this study was to determine trends in ADR-related hospitalizations in the older Dutch population.

Methodology and Principal Findings

Secular trend analysis of ADR-related hospital admissions in patients ≥60 years between 1981 and 2007, using the National Hospital Discharge Registry of the Netherlands. Numbers, age-specific and age-adjusted incidence rates (per 10,000 persons) of ADR-related hospital admissions were used as outcome measures in each year of the study. Between 1981 and 2007, ADR-related hospital admissions in persons ≥60 years increased by 143%. The overall standardized incidence rate increased from 23.3 to 38.3 per 10,000 older persons. The increase was larger in males than in females. Since 1997, the increase in incidence rates of ADR-related hospitalizations flattened (percentage annual change 0.65%), compared to the period 1981–1996 (percentage annual change 2.56%).

Conclusion/Significance

ADR-related hospital admissions in older persons have shown a rapidly increasing trend in the Netherlands over the last three decades with a temporization since 1997. Although an encouraging flattening in the increasing trend of ADR-related admissions was found around 1997, the incidence is still rising, which warrants sustained attention to this problem.