The aim of this assignment is tocritically appraise an entry from the Paediatric Infectious Disease Journal,titled Virologic Response to First-line Efavirenz- orNevirapine- based Antiretroviral Therapy in HIV-infected African Children (Kekitiinwaet al.
(2017)). This critical appraisal will be done to examine how validthe results or the trial are, the results themselves and how useful there arein justifying the research. The study compared drug discontinuation and viralload in HIV-infected African children following Nevirapine or Efavirenz-basedantiretroviral therapy. Human Immunodeficiency Virus (HIV) is aLentivirus within the family of Retroviridae and is thought to have entered thehuman population between 1920-1940. The genome consists of two identical single-strandedRNA molecules that are enclosed within the core of the virus particle. ProviralDNA is generated by the reverse transcription of the viral RNA genome into DNA,degradation of the RNA and integration of the double stranded HIV DNA into thehuman genome (Blood, 2016).
HIV is transmitted via bodily fluids,predominantly blood and semen, with sexual intercourse being the most commonmethod of transmission worldwide, accounting for approximately 80% ofinfections (Askew and Berer, 2003). Itis because of this, that preventative methods such as practising safe sex byusing condoms and abstaining from sharing needles are vital in the prevention ofHIV spread. The treatment of HIV-1 infection wasrevolutionised in the mid-1990s by the development of inhibitors of the reversetranscriptase and protease and the introduction of drug regimens that combinedthese agents to enhance overall efficacy and durability of therapy (Arts et al, 2012). Antiretroviraltherapy (ART) has been highly effective in reducing morbidity and mortality ofHIV-patients. There are three classes of antiretroviral drugs;nucleoside-reverse transcriptase inhibitors (NRTI), non-nucleoside reversetranscriptase inhibitors (NNRTI) and protease inhibitors. Efavirenz (EFV) and Nevirapine (NVP), both NNRTIs, are two of the mostcommonly used medications in first line ART (Mbuagabw et al, 2016).
In both developed and developing countries,combination ART has become one of the most widely used methods of HIVtreatment. Despite an increase in global funding for HIV/AIDS, and considerablereductions in drug prices, resource limited countries still struggle tomaintain long term therapy options. NNRTI-based ART has been the mostaffordable regimen for HIV-infected patients in resource limited countries (Loubiere et al, 2010). SECTION ADid the trial address a clearly focussedissue?Previous literature has noted that NVPhas poorer virologic response in adult and paediatric studies when compared toEFV, therefore the researchers of this study examined virologic response in 836previously untreated ART-naïve children aged 3-17 from Uganda and Zimbabwe.
Theyfound that short term VL suppression favoured EFV, but that long term relativeperformance was age dependent, with better suppression in older children withNVP. The trial aimed to compare viral load(VL) response and drug discontinuation in ART-naïve Ugandan/Zimbabwean children3-17 years of age initiating ART with clinician chosen EFV or NVP in the ARROWtrial (an open-label randomised trial evaluating two strategic approaches formanagement of ART). Predictors of suppression <80, ><400 and ><1000 copies/mL at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (P = 0.
1). Results: A total of 445 (53%) children received efavirenz and 391 (47%) nevirapine. Children receiving efavirenz were older (median age, 8.6 vs. 7.5 years nevirapine, P ><80,<400, <1000 copies/mL at 36, 48 and 144 weeks were identified usingmultivariable logistic regression with backwards elimination (P=0.
1). The trial compares a continuous firstline ART regimen consisting of two nucleoside reverse transcriptase inhibitors(NRTI) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI), withinduction with four drugs (two classes) followed by maintenance with threedrugs. The second randomisation involves childrenreceiving two NRTIs – abacavir (ABC) and lamivudine (3TC), plus an NNRTI,either EFV or NVP. The control arm(A) will continue this three drug ART regimen for the duration of first linetherapy. Children assigned to arms B and C will receive a fourth drug, the NRTIzidovudine (ZDV) for the first 36 weeks. After 36 weeks, children in arm B willstop taking ZDV and children in arm C will stop taking NNRTI (both arms willreduce to 3 drugs for the remainder of their first line ART). Was the assignment of patients to treatmentsrandomised?Children were randomised 1:1:1 to openlabel lamivudine (3TC) + abacavir (ABC) + NNRTI continuously (Arm A; control,no zidovudine (ZDV)); induction maintenance with 4-drug 3TC + ABC + NNRTI + ZDVfor 36 weeks, then 3TC + ABC + NNRTI (Arm B; short term ZDV) or 3TC + ABC + NNRTIfor 36 weeks + ZDV (Arm C; long term ZDV).
The NNRTI (EFV/NVP) was chosen byclinicians, both were available in all centres throughout the trial for initialART substitutions. Children were randomised 1:1 in a factorial design toclinically driven monitoring versus laboratory plus clinical monitoring fortoxicity and efficacy. After 36 weeks, eligible children taking lamivudine +abacavir twice daily were randomised to continue twice daily or move to once daily.ARROW is a randomised controlledclinical trial designed to assess two different management strategies forgiving first line anti-HIV medicines. Were all of the patients who entered thetrial properly accounted for at its end?445 children received EFV and theremaining 391 received NVP.
Four of the children initiated on an EFV-basedregimen and 18 children receiving an NVP-based regimen died before week 36. Theinitial NNRTI was permanently discontinued before week 36 in 8 initiating EFV(2 adverse events, 4 voluntary and 2 pregnancy related) and 22 initiating NVP(9 adverse events and 13 tuberculosis related). A further 13 EFV and 7 NVP diedafter week 36, and the initial NNRTI was permanently discontinued in 37children initiating EFV and 41 initiating NVP. Overall, Arm-A/B childreninitiating EFV or NVP spent 94.4% and 88.9% follow-up time through their lastclinic visit (median, 4 years follow up) on EFV or NVP-containing ART respectively. Over total follow up, the initial NNRTIwas permanently discontinued because of adverse effects in 7/445 initiating EFVand 9/391 initiating NVP.
Were patients, health workers and studypersonnel blind to treatment?The allocation of participants to treatmentgroups was randomised, however participants, study personnel and health workerswere not blind to treatment options. Though patients were randomised in a 1:1:1ratio, children were not randomised to EFV or NVP, however potentialconfounders were considered for inclusion in models in order to eliminate bias.EFV was given to older children (median 8.6 years old) which a higher CD4%(12%) whereas NVP was given to younger children (median 7.5 years old) with alower CD4% (10%). None of the children who were coinfected with tuberculosis initiatedan NVP-based regimen as EFV has been used to treat HIV/TB in other trials, sothis may be a reason for the nonrandomization of children to EFV and NVP. Were the groups similar at the start ofthe trial?445 (53%) of children, 242 of which weremale, received EFV and 391 (47%), 176 of which were male received NVP. Themedian ages differ from 8.
6 years of age receiving EFV and 7.5 years of agereceiving NVP. Asidefrom the experimental intervention, were the groups treated equally? SECTION BHow large was the treatment effect?One of the key measures within thisstudy was drug discontinuation in response to adverse effects and toxicity, howeverarguably more important when comparing EFV against NVP is the measure viralload (number of copies of HIV’s genetic material (RNA) per millilitre) followingcombination ART with either NNRTI. As well as this, other factors considered tobe potential confounders included CD4%, weight/height ratio and gender. Between 36–48 weeks, virologicsuppression < 80 copies/mL was superior with efavirenz, particularly inchildren with higher pre-ART VL (P =0.0004); longer-term suppression was superior with nevirapine in older children(P = 0.05).
Early suppression waspoorer in the youngest and oldest children, regardless of NNRTI (P = 0.02); longer-term suppression waspoorer in those with higher pre-ART VL regardless of NNRTI (P = 0.05). Results were broadly similarfor <400 and <1000 copies/ml. The initial NNRTI was permanentlydiscontinued for adverse effects in 7 of 445 (2%) children initiating EFVcompared with 9 in 391 (2%) initiating NVP. How precise was the estimate of thetreatment effect?The confidence interval reflects theprecision of study results. The wider the confidence interval, the lessprecision exists in the result.
When the 95% CI does not include 1, thedifference is significant at the usual 0.05 level. At 36 weeks, VL per log10 was 1.01(0.58-1.76) and 0.29 (0.15-0.
56) for EFV and NVP respectively. At 48 weeks, VLwas 0.76 (0.39-1.
49) and 0.33 (0.13-0.86) for EFV and NVP respectively. At week 144, older children/adolescentshad poorer suppression <80 copies/ml on EFV (adjusted odds ratio (aOR) peryear older = 0.79 95% CI: 0.
69 – 0.90, P= 0.001), but suppression was independent of age on NVP (aOR = 0.94 0.79-1.11,P = 0.46).
Effect sizes were similar for<400 copies/ml (EFV: aOR per year older = 0.74 0.64-0.87, P=0.001); (NVP: aOR = 0.88 0.
72-1.08 P = 0.23 and <1000 copies/ml (EFV:aOR = 0.72 0.61-0.85) P = 0.001;nevirapine: aOR = 0.
85 (0.69–1.06) P = 0.14.
SECTION CCan the results be applied in your context?(or to the local population?)With ART being a leading method of HIVtreatment, it is used not only by those in Sub-Saharan Africa, but globally. Itremains a leading treatment in developing countries due to its costeffectiveness, however studies have shown that use of EFV and NVP as first lineART has been prevalent in North and South America, Australia, Europe, South Africaand Thailand (van Leth et al, 2004)and that it is not age restrictive, being suitable for use in children, adolescentsand adults. Were all clinically important outcomes considered?Is there any other information you wouldlike to have seen?Although VL suppression and drug discontinuationare valid means of comparing EFV and NVP, the article briefly touches upon CD4%being a potential confounder, however fails to go into any elaborate detail. For each year of age during follow-up,three values of CD4 cell count were estimated (every four months) and thelowest value of the year was classified in the following categories: ? 500/mm3,350 to 499/mm3, 200 to 349/mm3 or <200/mm3 .
Death rates and SMRs were estimated for the cumulated time period spent within each category of CD4 cell count. ><200mm3.The level of CD4 cell count is known as a strong prognostic factor for theoccurrence of AIDS-defining events and death. (Lewdenet al, 2007) A study by Faal et al hypothesised thatproviding immediate CD4 count results at HIV testing could improve ARTinitiation, and found that providing CD4 results at HIV diagnosis increased thelikelihood of patients reporting for ART initiation (Faal et al, 2011). Are the benefits worth the harms and costs?The major benefit of using EFV and NVPas the chosen NNRTI in combination ART is that they are cheap and readily availableacross pharmacies in both developed and developing countries. The article statesthat both EFV and NVP have favourable toxicity profiles, however cliniciansshould be aware of possible hypersensitivity reactions with either drug. Publications exploring similar researchquestions have stated that adverse effects of NVP can include liver damage anda rash, and that EFV may also cause a rash, impair mental function and causefoetal malformations (Mbuagbaw et al,2016). The article briefly touches upon some participants reporting adversecentral nervous system effects, though a plausible explanation for this is theparticipants taking more unreported treatment interruptions and missed doses.
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