The infection was revolutionised in the mid-1990s

The aim of this assignment is to
critically appraise an entry from the Paediatric Infectious Disease Journal,
titled Virologic Response to First-line Efavirenz- or
Nevirapine- based Antiretroviral Therapy in HIV-infected African Children (Kekitiinwa
et al. (2017)). This critical appraisal will be done to examine how valid
the results or the trial are, the results themselves and how useful there are
in justifying the research. The study compared drug discontinuation and viral
load in HIV-infected African children following Nevirapine or Efavirenz-based
antiretroviral therapy.

Human Immunodeficiency Virus (HIV) is a
Lentivirus within the family of Retroviridae and is thought to have entered the
human population between 1920-1940. The genome consists of two identical single-stranded
RNA molecules that are enclosed within the core of the virus particle. Proviral
DNA 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 the
human genome (Blood, 2016).

HIV is transmitted via bodily fluids,
predominantly blood and semen, with sexual intercourse being the most common
method of transmission worldwide, accounting for approximately 80% of
infections (Askew and Berer, 2003). It
is because of this, that preventative methods such as practising safe sex by
using condoms and abstaining from sharing needles are vital in the prevention of
HIV spread.

The treatment of HIV-1 infection was
revolutionised in the mid-1990s by the development of inhibitors of the reverse
transcriptase and protease and the introduction of drug regimens that combined
these agents to enhance overall efficacy and durability of therapy (Arts et al, 2012). Antiretroviral
therapy (ART) has been highly effective in reducing morbidity and mortality of
HIV-patients. There are three classes of antiretroviral drugs;
nucleoside-reverse transcriptase inhibitors (NRTI), non-nucleoside reverse
transcriptase inhibitors (NNRTI) and protease inhibitors. Efavirenz (EFV) and Nevirapine (NVP), both NNRTIs, are two of the most
commonly 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 HIV
treatment. Despite an increase in global funding for HIV/AIDS, and considerable
reductions in drug prices, resource limited countries still struggle to
maintain long term therapy options. NNRTI-based ART has been the most
affordable regimen for HIV-infected patients in resource limited countries (Loubiere et al, 2010).

SECTION A

Did the trial address a clearly focussed
issue?

Previous literature has noted that NVP
has poorer virologic response in adult and paediatric studies when compared to
EFV, therefore the researchers of this study examined virologic response in 836
previously untreated ART-naïve children aged 3-17 from Uganda and Zimbabwe. They
found that short term VL suppression favoured EFV, but that long term relative
performance was age dependent, with better suppression in older children with
NVP.

The trial aimed to compare viral load
(VL) response and drug discontinuation in ART-naïve Ugandan/Zimbabwean children
3-17 years of age initiating ART with clinician chosen EFV or NVP in the ARROW
trial (an open-label randomised trial evaluating two strategic approaches for
management 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 using multivariable logistic regression with backwards elimination (P=0.1).   The trial compares a continuous first line ART regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI), with induction with four drugs (two classes) followed by maintenance with three drugs.   The second randomisation involves children receiving 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 line therapy. Children assigned to arms B and C will receive a fourth drug, the NRTI zidovudine (ZDV) for the first 36 weeks. After 36 weeks, children in arm B will stop taking ZDV and children in arm C will stop taking NNRTI (both arms will reduce to 3 drugs for the remainder of their first line ART).   Was the assignment of patients to treatments randomised? Children were randomised 1:1:1 to open label lamivudine (3TC) + abacavir (ABC) + NNRTI continuously (Arm A; control, no zidovudine (ZDV)); induction maintenance with 4-drug 3TC + ABC + NNRTI + ZDV for 36 weeks, then 3TC + ABC + NNRTI (Arm B; short term ZDV) or 3TC + ABC + NNRTI for 36 weeks + ZDV (Arm C; long term ZDV). The NNRTI (EFV/NVP) was chosen by clinicians, both were available in all centres throughout the trial for initial ART substitutions. Children were randomised 1:1 in a factorial design to clinically driven monitoring versus laboratory plus clinical monitoring for toxicity 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 controlled clinical trial designed to assess two different management strategies for giving first line anti-HIV medicines.   Were all of the patients who entered the trial properly accounted for at its end? 445 children received EFV and the remaining 391 received NVP. Four of the children initiated on an EFV-based regimen and 18 children receiving an NVP-based regimen died before week 36. The initial 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 died after week 36, and the initial NNRTI was permanently discontinued in 37 children initiating EFV and 41 initiating NVP. Overall, Arm-A/B children initiating EFV or NVP spent 94.4% and 88.9% follow-up time through their last clinic visit (median, 4 years follow up) on EFV or NVP-containing ART respectively.   Over total follow up, the initial NNRTI was permanently discontinued because of adverse effects in 7/445 initiating EFV and 9/391 initiating NVP.   Were patients, health workers and study personnel blind to treatment? The allocation of participants to treatment groups was randomised, however participants, study personnel and health workers were not blind to treatment options. Though patients were randomised in a 1:1:1 ratio, children were not randomised to EFV or NVP, however potential confounders 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 a lower CD4% (10%). None of the children who were coinfected with tuberculosis initiated an NVP-based regimen as EFV has been used to treat HIV/TB in other trials, so this may be a reason for the nonrandomization of children to EFV and NVP.   Were the groups similar at the start of the trial? 445 (53%) of children, 242 of which were male, received EFV and 391 (47%), 176 of which were male received NVP. The median ages differ from 8.6 years of age receiving EFV and 7.5 years of age receiving NVP.     Aside from the experimental intervention, were the groups treated equally?   SECTION B How large was the treatment effect? One of the key measures within this study was drug discontinuation in response to adverse effects and toxicity, however arguably more important when comparing EFV against NVP is the measure viral load (number of copies of HIV's genetic material (RNA) per millilitre) following combination ART with either NNRTI. As well as this, other factors considered to be potential confounders included CD4%, weight/height ratio and gender.   Between 36–48 weeks, virologic suppression < 80 copies/mL was superior with efavirenz, particularly in children with higher pre-ART VL (P = 0.0004); longer-term suppression was superior with nevirapine in older children (P = 0.05). Early suppression was poorer in the youngest and oldest children, regardless of NNRTI (P = 0.02); longer-term suppression was poorer in those with higher pre-ART VL regardless of NNRTI (P = 0.05). Results were broadly similar for <400 and <1000 copies/ml.     The initial NNRTI was permanently discontinued for adverse effects in 7 of 445 (2%) children initiating EFV compared with 9 in 391 (2%) initiating NVP.   How precise was the estimate of the treatment effect? The confidence interval reflects the precision of study results. The wider the confidence interval, the less precision exists in the result. When the 95% CI does not include 1, the difference 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, VL was 0.76 (0.39-1.49) and 0.33 (0.13-0.86) for EFV and NVP respectively.   At week 144, older children/adolescents had poorer suppression <80 copies/ml on EFV (adjusted odds ratio (aOR) per year 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 C Can the results be applied in your context? (or to the local population?) With ART being a leading method of HIV treatment, it is used not only by those in Sub-Saharan Africa, but globally. It remains a leading treatment in developing countries due to its cost effectiveness, however studies have shown that use of EFV and NVP as first line ART has been prevalent in North and South America, Australia, Europe, South Africa and Thailand (van Leth et al, 2004) and that it is not age restrictive, being suitable for use in children, adolescents and adults.   Were all clinically important outcomes considered? Is there any other information you would like to have seen? Although VL suppression and drug discontinuation are 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 the lowest 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 the occurrence of AIDS-defining events and death.  (Lewden et al, 2007)   A study by Faal et al hypothesised that providing immediate CD4 count results at HIV testing could improve ART initiation, and found that providing CD4 results at HIV diagnosis increased the likelihood 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 NVP as the chosen NNRTI in combination ART is that they are cheap and readily available across pharmacies in both developed and developing countries. The article states that both EFV and NVP have favourable toxicity profiles, however clinicians should be aware of possible hypersensitivity reactions with either drug.   Publications exploring similar research questions have stated that adverse effects of NVP can include liver damage and a rash, and that EFV may also cause a rash, impair mental function and cause foetal malformations (Mbuagbaw et al, 2016). The article briefly touches upon some participants reporting adverse central nervous system effects, though a plausible explanation for this is the participants taking more unreported treatment interruptions and missed doses.   The results of the study confirm the generally favourable toxicity profiles of both EFV and NVP, with only 2 and 8 hypersensitivity reactions respectively, and only 2% of patients permanently discontinuing each NNRTI due to adverse effects where clinicians may not discontinue the drug despite toxicity if it is not life-threatening. Permanent discontinuations following non-adverse effects were more prevalent in NVP, particularly with tuberculosis treatment, making EFV more favourable for children at high risk of tuberculosis following ART initiation.       References Arts, E. J., & Hazuda, D. J. (2012). HIV-1 antiretroviral drug therapy. Cold Spring Harbor perspectives in medicine, 2(4), a007161.   Askew, I., & Berer, M. (2003). The contribution of sexual and reproductive health services to the fight against HIV/AIDS: A review. Reproductive health matters, 11(22), 51-73. Blood, G. A. C. (2016). Human Immunodeficiency Virus (HIV). Transfusion Medicine and Hemotherapy, 43(3), 203.   Faal, M., Naidoo, N., Glencross, D. K., Venter, W. D., & Osih, R. (2011). Providing immediate CD4 count results at HIV testing improves ART initiation. JAIDS Journal of Acquired Immune Deficiency Syndromes, 58(3), e54-e59. Kekitiinwa, A., Szubert, A. J., Spyer, M., Katuramu, R., Musiime, V., Mhute, T., ... & ARROW Trial Team. (2017). Virologic Response to First-line Efavirenz-or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children. The Pediatric infectious disease journal, 36(6), 588-594.   Lewden, C., Chêne, G., Morlat, P., Raffi, F., Dupon, M., Dellamonica, P., ... & Leport, C. (2007). HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. JAIDS Journal of Acquired Immune Deficiency Syndromes, 46(1), 72-77.   Loubiere, S., Meiners, C., Sloan, C., Freedberg, K. A., & Yazdanpanah, Y. (2010). Economic evaluation of ARTs in resource-limited countries. Current Opinion in HIV and AIDS, 5(3), 225. Mbuagbaw, L., Mursleen, S., Irlam, J. H., Spaulding, A. B., Rutherford, G. W., & Siegfried, N. (2016). Efavirenz or nevirapine in three?drug combination therapy with two nucleoside or nucleotide?reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral?naïve individuals. The Cochrane Library. van Leth, F. R. A. N. K., Phanuphak, P., Ruxrungtham, K., Baraldi, E., Miller, S., Gazzard, B., & Johnson, M. A. (2004). Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. The Lancet, 363(9417), 1253-1263.