Nonnucleoside Reverse Transcription Inhibitor Research Articles

Molecular genetic characterization analysis of a novel HIV-1 circulating recombinant form (CRF156_0755) in Guangdong, China.

The characteristic of human immunodeficiency virus type 1 (HIV-1) is its susceptibility to erroneous replication and recombination, which plays a crucial role in the diverse and dynamic variation of HIV-1. The spread of different subtypes in the same population often leads to the emergence of circulating recombination forms (CRFs). At present, the main recombinant subtypes of HIV-1 in China are CRF07_BC, CRF01_AE, CRF08_BC and B' subtypes, while CRF55_01B has become the fifth major epidemic strain in China after rapid growth in recent years since it was first reported in 2013. In this study, we obtained five nearly full-length genomes (NFLGs) and one half-length genome from five different cities in Guangdong. Here, we focused on analyzing their characteristics, parental origin and drug resistance. Plasma samples were collected from six HIV-1 infected patients in Guangdong Province who had no epidemiological association with each other. The NFLGs of HIV-1 were amplified in two overlapping segments by the near-terminal dilution method. The positive products were sequenced directly to obtain genomic sequences. The recombinant patterns and breakpoints of the NFLGs were determined using the Simplot software and confirmed by the maximum likelihood trees for segments using the IQ-TREE and BEAST software. The genotypic resistance profiles of the protease reverse transcriptase and integrase were resolved by the Stanford HIV drug resistance database. The six genomes shared highly similar recombinant pattern, with the CRF55_01B backbone substituted by CRF07_BC segments, therefore assigned as CRF156_0755. The evolutionary analysis of the segments showed that CRF07_BC segments were not clustered with the Chinese MSM variants in the CRF07_BC lineage. All the five NFLGs were identified with the non-nucleoside reverse-transcription inhibitors (NNRTIs) resistance mutation V179E. With the accumulation and evolution of recombination between CRF55_01B and CRF 07_BC, the prevalence of more recombinant strains of CRF55_01B and CRF 07_BC may occur. Therefore, it is necessary to strengthen the identification and monitoring of the recombination of CRF55_01B and CRF 07_BC.

Investigation of Drug-resistance substitutions in HIV-1 RT Protein in Iranian HIV Infected Patients

Abstract: 
 Background:
 Currently, more than 37 million people are living with human immunodeficiency virus type 1. Reverse transcription (RT) is a main part in the life cycle of retroviruses which is responsible for synthesis of DNA complementary to an RNA or DNA template. Recently several inhibitors have been introduced to target RT protein; however, drug resistance is one of the greatest challenges in the improvement of effective treatment for human immunodeficiency virus (HIV) infection. Here, we determined the resistance mutations in the RT gene in treatment failure patients and searched for the dominant subtype among them. 
 Methods:
 HIV viral load and a reverse transcriptase nested polymerase chain (RT-nested PCR) reactions were performed in 15 patients with treatment failure to amplify the RT gene. Drug resistance mutations, as well as the viral subtypes, were analyzed using by using several bioinformatics software and online tools.
 Results: 
 The frequency of RT related drug-resistance mutations in patients was 33.3%, among which the major mutation consisted of 20% of all those occurring in codon 184. Moreover, the results showed 6.6% and 26.6% of patients were resistant to Non-Nucleoside RT Inhibitor (NNRTIs) and Nucleoside RT Inhibitors (NRTIs), respectively. In addition, the vast majority of samples (12 patients of 15) belonged to subtype CRF35-AD.
 Conclusions:
 The present study reports updates on the mutations related to RT resistance in Iranian HIV patients receiving treatment, show that 20% of the samples had a high-level of resistance to Lamivudine, and Emtricitabine which should be confirmed for further antiretroviral (AVR) regimens for HIV infected patients. Also, two new mutations related to resistance to Nevirapine, Doravirine, Zidovudine, and Stavudine were introduced in this investigation.
 The present results could be used as predictive information on the response to anti-RT, and also highlight the importance of considering the periodic monitoring of HIV resistance test in HIV infected patients.

Evolution of HIV-1 Surveillance Drug Resistance Mutations Over 10 Years in New South Wales, Australia.

New South Wales has the greatest burden of HIV in Australia, with 2012 and 2013 recording the highest rates of new diagnoses in 20 years. Concurrently, there has been significant changes in antiretroviral treatments and testing paradigms. We compiled a statewide resistance database to characterize changes in HIV-1 resistance mutations over time. Genotypic antiretroviral resistance testing (GART) was performed on request at three reference laboratories using commercial and in-house methods. In total, 7629 HIV-1 polymerase sequences obtained from GART from 2004 to 2013 were retrospectively collated, reformatted, de-identified, and analyzed using Stanford HIVdb program 7.0 and the 2009 World Health Organization (WHO) surveillance drug resistance mutations (SDRMs). Analyses were performed on subgroups of known treatment naives, treatment experienced, and seroconverters. There has been a decrease in overall rates of prevalent drug resistance mutations from 57.8% in 2004 to 21% in 2013. Dual and triple class resistance mutations have decreased from 32.7% in 2004 to 5.8% in 2013 and 16.4% to 1.2%, respectively. In treatment-naive individuals (n = 450), the frequency of protease inhibitor (PI) mutations remains low at 2.7%. In seroconverters, rates of transmitted drug resistance (TDR) are 6.6%, 3%, 3%, and 1.5% for overall, PI, non-nucleoside reverse transcription inhibitor (NNRTI), and NRTI, respectively. In treatment experienced, rates remain stable with 36.0%, 18.9%, 29.1%, and 6.4% for overall, NNRTI, NRTI, and PI mutations. The most common mutations in treatment experienced occurred at position M184, T215 (NRTI); K103 (NNRTI); I54 (PI). Apparent decreases in prevalent SDRMs can be attributed to changes in GART testing indications over time. In treatment-naive and -experienced subgroups, rates have been stable with low rates of TDR in seroconverters.

937. Factors Associated with Metabolic Syndrome in People with HIV under 40 Years in Guatemala

BackgroundHIV infection and antiretroviral therapy (ART) can lead to metabolic abnormalities associated with increased cardiovascular disease risk, some of these abnormalities (central obesity, elevated fasting glucose, triglycerides, and blood pressure and low HDL cholesterol) are in metabolic syndrome (MetS). The prevalence of MetS increases with age. Currently, the status of MetS in people with HIV (PWH) Guatemala is unknown. We assessed the prevalence of MetS and potential predictors in PWH participating in prospective cohort study at Hospital Roosevelt in Guatemala City.MethodsWe performed a cross-sectional analysis of PWH under 40 years old receiving ART for at least 6 months from July 2019 to March 2020. The harmonized criteria for MetS and the cut-off for waist circumference recommended by the Latin American Diabetes Association were used. Association between MetS and gender, place of residency, ethnicity, educational level, baseline and current CD4 count, smoking, alcohol consumption, physical activity, viral load, body mass index (BMI) and ART exposure was assessed in bivariate analysis. Potential predictors (p-value < 0.1) were included in a multivariate binary logistic regression model.ResultsOf total cohort of 757 participants enrolled390 (51.5%) were younger than 40 years. Of those under < 40 years, 150 (38.5%) were women, 59 (15.1%) Mayan, median age was 32 years (IQR 27, 37). 93 (23.8%) had MetS. Between group differences in Table 1. Of those with Met, 51 (54.8%) had elevated waist circumference, 87 (93.5%) elevated triglycerides, 83 (89.2%) low HDL-c, 56 (60.2%) elevated blood pressure and 35 (37.6%) elevated fasting glucose. Body mass index (BMI) ≥ 25 kg/m2 or higher and 2 years or more of cumulative non-nucleoside reverse transcription inhibitors (NNRTI) where more common in those < 40 years with MetS compared to those without MetS. On multivariable regression, MetS was associated with current CD4 count < 200 (OR 3.1; IC 1.51, 6.34; p-value < 0.01) and BMI ≥ 25 kg/m2 (OR; 6.53; IC 3.64, 11.73; p-value < 0.01).Table1. Between group differences (No MetS vs MetS) ConclusionNearly one in every four PWH under 40 years old in our cohort was affected by MetS. Dyslipidemia (elevated triglycerides and low HDL-c) was the main driver of MetS. Lower CD4 count and overweight were predictors for MetS in PWH under 40.Disclosures Andrej Spec, MD, MSCI, Astellas (Grant/Research Support)Mayne (Consultant)Scynexis (Consultant)

Chiral Separation of Non-Nucleoside Reverse Transcription Inhibitor Efavirenz by HPLC on Cellulose-Based Chiral Stationary Phase

A stereospecific HPLC method for the separation of efavirenz (EFZ) enantiomers in bulk drug and formulations was developed and validated on a normal-phase cellulose derivatized chiral column. The effect of organic modifiers, namely, 2-propanol, ethanol and trifluoroacetic acid in mobile phase was optimized to obtain the best enantiomeric separation. The retention times of (R)-EFZ and (S)-EFZ were observed to be 7.5 and 9.2 min, respectively. The calibration curve was found to be linear over the concentration range of 200 - 6210 ng/mL with a determination coefficient (R 2 ) of 0.9999 for the (R)-isomer. The limit of detection (LOD) and limit of quantification (LOQ) were calculated to be 66 ng/mL and 200 ng/mL, respectively. The proposed method was found to be accurate, precise and suitable for the separation and quantification of unwanted (R)-EFZ in active pharmaceutical ingredients (API). The analytical results were supported by statistical parameters. The proposed method could be successfully applied to the enantiomeric purity analysis of EFZ in bulk drug samples and formulations.

Treatment Experience and Repeat Pregnancy Impact the Effectiveness of Non-Nucleoside Reverse Transcription Inhibitor-Highly Active Antiretroviral Therapy for the Prevention of Mother to Child Transmission of Human Immunodeficiency Virus.

Non-nucleoside reverse transcription inhibitor (NNRTI)-containing antiretroviral therapy (ART) for the prevention of mother to child transmission (PMTCT) of human immunodeficiency virus (HIV) has led to dramatic reductions in perinatal HIV infection in resource-constrained settings. Nonetheless, PMTCT programs are complicated by repeat pregnancies, in which long-term or repeat exposures to PMTCT regimens over time may lead to the acquisition of HIV drug resistance mutations, and consequent treatment failure. In this study, we retrospectively assessed the effectiveness of the NNRTI-based PMTCT protocol from 2008 to 2010 in The Bahamas National HIV/AIDS Program. We show that women who had been in repeat pregnancies and those who were already prescribed ART at conception were at increased risk of virologic failure, relative to treatment-inexperienced women and primigravida, respectively (AOR 3.1, 95% CI: 1.3-7.1, p = .008 and AOR 5.0, 95% CI: 1.8-14.1, p = .002). In addition, women undergoing treatment at conception were more likely to possess HIVDR mutations relative to treatment-naive women (AOR 447.1, 95% CI: 17.9-11,173.5, p = .001). Therefore, individual treatment history is a key metric determining the effectiveness of current and future PMTCT interventions. The implications of this to PMTCT programmatic success in light of the most recent WHO guidelines are discussed.

Regorafenib therapy for hepatocellular carcinoma in a HIV‐1‐infected patient: A case report

Regorafenib therapy for hepatocellular carcinoma in a HIV‐1‐infected patient: A case report

Changes in Body Fat Distribution in Antiretroviral-Naive HIV-Positive Individuals Initiating Current ART Regimens.

To describe the changes in body fat distribution (BFD) occurring over 60 months in a group of antiretroviral therapy (ART)-naive individuals starting different antiretroviral regimens. A prospective ongoing fat change assessment including clinical evaluation and dual X-ray absorptiometry scan is being conducted in all consecutive patients initiating ART from January 2008. Arm, leg, trunk, and total fat as well as fat mass ratio were determined. A total of 146 patients were included (80% male, 40% MSM). Mean age was 44 years, HIV-1 RNA was 4.98 log10 copies/mL, and CD4 count was 254 cells/μL. The most common initial antiretroviral combination included non-nucleoside reverse transcription inhibitor (NNRTI) drugs followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI)-based regimens. At month 36, an increase was seen in the body mass index (BMI), total fat, trunk fat, and limb fat. The fat mass ratio (FMR) also showed a significant increase in both men and women (P = 0.001). In patients receiving NNRTI- or INSTI-based regimens (but not PIs), there was a marginal but statistically significant increase in the FMR (0.10 and 0.07, respectively; P = 0.01). Sixty-two subjects completed 60 months of follow-up. FMR showed a significant increase even in the PI group at this time point (P < 0.03). We observed a significant increase in the fat and lean body mass in all compartments and treatment groups over 36 and 60 months. Clinically irrelevant differences were found in fat distribution regardless of the treatment group and baseline characteristics. The data suggest that current antiretroviral regimens have little impact on BFD during the first years of treatment.

The small-molecule 3G11 inhibits HIV-1 reverse transcription.

The small-molecule 6-(tert-butyl)-4-phenyl-4-(trifluoromethyl)-1H,3H-1,3,5-triazin-2-one (3G11) inhibits HIV-1 replication in the human T cell line MT-2. Here, we showed that 3G11 specifically and potently blocks HIV-1 infection. By contrast, 3G11 did not block other retroviruses such as HIV-2, simian immunodeficiency virus (SIVmac ), bovine immunodeficiency virus, feline immunodeficiency virus, equine infectious anemia virus, N-tropic murine leukemia virus, B-tropic murine leukemia virus, and Moloney murine leukemia virus. Analysis of DNA metabolism by real-time PCR revealed that 3G11 blocks the formation of HIV-1 late reverse transcripts during infection prior to the first-strand transfer step. In agreement, an in vitro assay revealed that 3G11 blocks the enzymatic activity of HIV-1 reverse transcriptase as strong as nevirapine. Docking of 3G11 to the HIV-1 reverse transcriptase enzyme suggested a direct interaction between residue L100 and 3G11. In agreement, an HIV-1 virus bearing the reverse transcriptase change L100I renders HIV-1 resistant to 3G11, which suggested that the reverse transcriptase enzyme is the viral determinant for HIV-1 sensitivity to 3G11. Although NMR experiments revealed that 3G11 binds to the HIV-1 capsid, functional experiments suggested that capsid is not the viral determinant for sensitivity to 3G11. Overall, we described a novel non-nucleoside reverse transcription inhibitor that blocks HIV-1 infection.

Longer duration of combination antiretroviral therapy reduces the risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans

BackgroundHodgkin lymphoma (HL) incidence has increased since combined antiretroviral therapy (cART) introduction. It is unclear how different cART classes (e.g., protease inhibitors (PI), non-nucleoside reverse transcription inhibitors (NNRTI)) influence HL. This study aimed to determine the effects of cART duration on HL incidence among HIV-infected veterans. MethodsWe performed a retrospective cohort study utilizing the Veterans Affairs HIV Clinical Case Registry (1985–2010). HL cases were identified using ICD-9 codes (201.4-9). cART, PI, and NNRTI duration was the aggregate number of treatment days delivered. Incidence rates (IR) and rate ratios (IRR) were calculated from Poisson regression models to examine the effects of cART duration on HL. Results31,576 cART users contributed 288,736 person-years (PY) and 211 HL cases (IR=7.3/10,000 person-years). HL incidence decreased from 25.1/10,000 PY (95%CI=18.9–33.4) within the first year of cART to 0.6/10,000 PY (95%CI=0.3–1.6) after ≥10 years. In multivariable models, each additional year of cART was associated with decreased HL incidence (IRR=0.80; 95%CI=0.75–0.86); similar effects were observed in models assessing HL incidence by PI and NNRTI. ConclusionOur findings indicate long-term cART of any class is associated with decreased HL risk. High HL incidence directly following cART initiation supports a potential immune reconstitution mechanism in HIV-related HL. Further research is needed to evaluate the interaction between early cART, immune reconstitution, and HL.

The nonnucleoside reverse transcription inhibitor MIV-160 delivered from an intravaginal ring, but not from a carrageenan gel, protects against simian/human immunodeficiency virus-RT Infection.

We previously showed that a carrageenan (CG) gel containing 50 μM MIV-150 (MIV-150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p>0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, >80% protection was observed (p<0.03). MIV-160 is a related NNRTI with a similar IC(50), greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV-160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo.

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Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors

New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC50=0.015μg/mL; 0.046μM, SI >1667) and (EC50=0.025μg/mL; 0.086μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC50=1.01μg/mL; 3.27μM, SI >25).

Long-Term Efficacy, Safety, and Tolerability of Rilpivirine (RPV, TMC278) in HIV Type 1-Infected Antiretroviral-Naive Patients: Week 192 Results from a Phase IIb Randomized Trial

TMC278-C204 (NCT00110305), a 96-week trial of the nonnucleoside reverse transcription inhibitor (NNRTI) rilpivirine (RPV, TMC278) in 368 HIV-1-infected, treatment-naive patients, was extended to investigate long-term safety and efficacy. Week 192 analysis results are presented. This was a long-term follow-up of a Phase IIb, randomized trial. No significant RPV dose-response relationships with respect to the primary endpoint (composite ITT-TLOVR algorithm) were observed at week 48 or 96. All RPV-treated patients were switched to open-label 75 mg qd at week 96 and then to 25 mg qd, the Phase III dose, at approximately week 144 as it gave the best benefit-risk balance. All control patients continued receiving open-label efavirenz (EFV) 600 mg qd. At week 192, 59% of RPV- and 61% of EFV-treated patients maintained confirmed viral load <50 copies/ml (ITT-TLOVR algorithm). The mean changes from baseline in CD4 cell count were similar in both groups (RPV: 210 cells/mm(3) vs. EFV: 225 cells/mm(3)). No new safety concerns were noted between week 48 and 192. In the week 192 analysis, RPV compared with EFV was associated with a lower overall incidence of grade 2-4 adverse events (AEs) at least possibly related to treatment, including rash (p<0.001) and neurologic AEs (p<0.05 Fisher's exact test, post hoc analyses) Incidences of serious AEs, grade 3 or 4 AEs, and discontinuations due to AEs were similar across groups. Increases in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were significantly lower with RPV than with EFV. RPV continued to show sustained efficacy similar to EFV at week 192 with a generally more favorable safety profile.

Drug Resistance Prevalence in Human Immunodeficiency Virus Type 1 Infected Pediatric Populations in Honduras and El Salvador During 1989–2009

Emergence of viral resistance is a major obstacle for antiretroviral treatment (ART) effectiveness. Human immunodeficiency virus type-1 (HIV-1) variants and drug-resistance mutations were identified in naive and antiretroviral drug-experienced children with virologic failure, in Honduras and El Salvador. Dried blood spots (DBS) from 80 individuals (54 from Honduras, 26 from El Salvador) infected during their childhood between 1989 and 2009 were collected in 2009. The HIV pol region was amplified and sequenced to identify antiretroviral-resistant mutations according to the 2009 International AIDS Society. The genotypic drug resistance interpretation was performed using the Stanford algorithm. HIV-1 variants were characterized by phylogenetic analysis and subtyping tools. HIV-1 protease and reverse transcription sequences were obtained from DBS specimens in 71 and 66 patients, respectively, of the 80 patients. All children were native Central Americans carrying subtype B, with a mean age of 9 years, most were male (65%), perinatally infected (96%), with moderate/severe AIDS symptoms (70%), and receiving first line ART at the time of sequencing (65%). Diagnostic delay was frequently observed. Infected children from Honduras presented longer ART experience and clinical outcomes, and more frequent severe symptoms. Resistant variants infected 1 of 11 naive children from El Salvador but none of the perinatally infected naive children from Honduras. Resistance was higher among ART-exposed individuals in both countries and similar for protease inhibitors (16%), nucleoside reverse transcription inhibitors (44%-52%), and nonnucleoside reverse-transcription inhibitors (66.7%). One in 10 pretreated children in each country was infected with resistant viruses to the 3 drug families. Our data support the need for continued surveillance of resistance patterns using DBS at national levels among naive and pretreated children to optimize the ART regimens.

Predictors of Virologic Failure and Genotypic Resistance Mutation Patterns in Thai Children Receiving Non-Nucleoside Reverse Transcriptase Inhibitor–Based Antiretroviral Therapy

Nonnucleoside reverse transcription inhibitor (NNRTI)-based antiretroviral therapy (ART) has been widely used as a first-line regimen for the treatment of HIV. This study aimed to determine the rate and predictors of virologic failure and describe patterns of resistance mutation. The inclusion criteria were children who were <18 years and receiving NNRTI-based ART. Plasma HIV-1 RNA and CD4 were monitored every 6 months. Virologic failure was defined as plasma HIVRNA >1000 copies/mL. Forty (20%) of 202 children had virologic failure, of whom 33 (16%) failed in the first year of therapy. By multivariate analysis, the children who received nevirapine were 3.7 times more likely to develop virologic failure than those receiving efavirenz (P = 0.006). The prevalence's of patients with >or=1 major mutations conferring drug resistance to nucleoside reverse transcription inhibitors (NRTIs) and NNRTIs were 89% and 97%, respectively. The common NNRTI mutations were Y181C/I (58%) and K103N (34%). The NRTI mutations were M184V/I (84%), K65R (11%), Q151M (5%), and >or=3 TAMs (3%). The virologic failure rate in children was high and mostly occurred in the first year of treatment. The most common resistance mutations were those conferring resistance to NNRTIs and lamivudine. There were few instances of multiNRTI resistance. Early detection of virologic failure might allow more options for second-line regimens.

Pattern and Predictors of Immunologic Recovery in Human Immunodeficiency Virus-Infected Children Receiving Non-Nucleoside Reverse Transcriptase Inhibitor-Based Highly Active Antiretroviral Therapy

Non-nucleoside reverse transcription inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) is the recommended first-line regimen for children in Thailand. This study was aimed to assess pattern and predictors of immune recovery in antiretroviral-naive Thai children starting NNRTI-based HAART. Records were extracted from clinical databases of 2 treatment cohorts in Thailand. The inclusion criteria were HIV-infected naive children who initiated NNRTI-based HAART when CD4 <25%. Immune recovery was defined as achieving a target CD4% of 25. The impact of age, gender, baseline clinical category, CD4 and HIV RNA titer, and regimen on immune recovery to weeks 96 was assessed using multiple logistic regression. There were 274 patients (52% females) with a median baseline age of 7 (Interquartile range [IQR]: 4-9) years and a median CD4% of 5 (IQR: 1-12) who started treatment with nevirapine (66%) or efavirenz (34%) based HAART. Median duration of follow-up was 168 (IQR: 120-192) weeks. The median CD4% increase from baseline was 7% (IQR: 5-11) and 18% (IQR: 12-23) at weeks 24 and 96, respectively. The probability of reaching target CD4% was 51% (95% confidence interval: 45%-57%) by week 96. The predictors of immune recovery at week 96 were younger age, female gender, higher baseline CD4%, and sustained virologic suppression after week 24. In this cohort of children with low baseline CD4, half achieved immune recovery after 96 weeks of HAART. The predictors for immune recovery are younger children, female gender, high baseline CD4%, and long-term virologic suppression.

Two-Year Outcomes of Children on Non-Nucleoside Reverse Transcriptase Inhibitor and Protease Inhibitor Regimens in a South African Pediatric Antiretroviral Program

Few data exist on the efficacy of the limited regimens for children with HIV, which are available in sub-Saharan Africa. Retrospective cohort study to evaluate the clinical and laboratory outcomes of 391 children who received protease inhibitor (PI) or non-nucleoside reverse transcription inhibitor (nNRTI)-containing highly active antiretroviral regimens (HAART) from a Cape Town clinic. Endpoints included CD4% and count, viral loads, weight-for-age Z score (WAZ), survival, drug changes, and loss to follow-up over 24 months. A generalized estimating equation population-averaged model was used to identify associations with virological suppression, and a log-rank test explored associations with survival. Overall, this cohort achieved a sustained doubling of median CD4% from baseline, steady increase of median WAZ, and survival of 91%, despite only 49% virologic suppression at 24 months. However, when analyzed according to regimen, PI-containing regimens had better virologic suppression at all time points. There were no differences in immunologic and growth endpoints between regimens or in survival. In a multivariate model predicting virologic suppression at any duration up to 24 months and adjusting for baseline CD4%, regimen, age, baseline WAZ, duration of HAART, and year of HAART initiation, nNRTI-based regimens (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.19-0.77) and length of time on HAART were inversely associated with virologic suppression. Age (OR: 1.23 per year; 95% CI: 1.09-1.39) was positively associated with virologic suppression. The benefits of HAART are substantial in this setting, although PI regimens achieved greater virologic suppression than nNRTIs. Further exploration of regimens and dosing of antiretrovirals for children in these settings is needed.

Human Immunodeficiency Virus-Infected Boy With Stevens-Johnson Syndrome Caused by Nevirapine

To the Editors: We read with interest the recent case report by Oberdorfer et al1 published in the June edition of the journal, entitled “Human immunodeficiency virus-infected boy with Stevens-Johnson syndrome caused by nevirapine.” However, we believe that certain aspects of the report require further clarification for readers. Following an initial report by Warren et al2 in 1998, nevirapine-induced Stevens-Johnson syndrome (SJS) is now a well-recognized and -documented phenomenon. Although data in children are relatively limited, to our knowledge the first description of this particular complication in children was in a report by Pollard et al in 1998.3 That report summarized the early experience with nevirapine in adults, as well as children (pediatric investigational trials BI 892, ACTG 180, and ACTG 245), focusing primarily on adverse events. Interestingly, the authors described 2 cases of SJS in the pediatric population and estimated the overall incidence of this complication to be approximately 0.3%. Further pediatric cases of SJS related to nevirapine therapy have since been described.4,5 Oberdorfer et al's case adds to these previous reports. Human immunodeficiency virus (HIV) infection alone is a significant risk factor for SJS and toxic epidermal necrolysis (TEN). In a recent, large European multicenter study (EuroSCAR study) on SJS/TEN, HIV-infected individuals had an estimated 12-fold increased risk of developing SJS/TEN compared with healthy controls.6 The mechanisms involved are not fully understood, although it has been postulated that immune dysregulation resulting from HIV infection plays a contributory role. Notably, the EuroSCAR study also reported a strong association between the administration of nevirapine and the development of SJS/TEN (relative risk: greater than 22), with the majority of cases occurring within the first 28 days of therapy. We would like to remind readers of the most commonly used terminology in relation to SJS/TEN originally proposed by Bastuji-Garin et al.7 In brief, SJS is defined as involvement of 2 or more mucosal areas and less than 10% of the body surface area. Epidermal necrolysis of greater than 30% of the body surface area is classified as TEN; cases with 10–30% involvement are referred to as overlap syndrome SJS/TEN. A patient with 60% body surface area involvement is therefore better described as TEN, although arguably the distinction between syndromes is somewhat arbitrary. Nevirapine is the only non-nucleoside reverse transcription inhibitor (NNRTI) recommended for use in children younger than 3 years, and is therefore an integral component of first-line NNRTI-based antiretroviral regimens in infants and young children. Liquid preparations of protease-inhibitors are generally unpalatable and thus used less commonly in this age group. Consequently, nevirapine remains invaluable in the treatment of HIV in children, despite the association with potentially serious side effects, which in addition to SJS/TEN include fulminant hepatitis and other variants of hypersensitivity reactions.8 Marc Tebruegge Nicole Ritz Tom Connell Nigel Curtis Department of Paediatrics The University of Melbourne Infectious Diseases Unit/ Department of Medicine Murdoch Children's Research Institute Royal Children's Hospital Melbourne Parkville, Victoria, Australia

Initial Antiretroviral Drugs

To the Editors: We have read with great interest the recent clinical case published in your journal by Cruz and Palazzi.1 The patient was finally diagnosed with underlying human immunodeficiency virus (HIV) infection and superimposed bacterial pneumonia. Because his CD4 count was <350/mm3 and his HIV viral load was high, HAART (Highly Active Antiretroviral Therapy) was initiated, the authors explain, based on current guidelines on the use of antiretroviral therapy in HIV-infected adolescents. HAART was initiated with a nucleoside analog (NRTI), a protease inhibitor (PI), and a non-nucleoside reverse transcription inhibitor (NNRTI). We agree that the adolescent needs to start treatment, but we think that the treatment they used is not based on current guidelines. In the American Pediatric Guidelines2 and the European Pediatric Guidelines3 the recommended antiretroviral regimens of choice for initial therapy for HIV-infected children contain 1 NNRTI or 1 PI combined with a 2-drug NRTI backbone. There are insufficient data to recommend regimens containing agents from 3 drug classes, with the exception of efavirenz plus nelfinavir plus 1 or 2 NRTIs, which has been shown to be safe and effective in HIV-infected children.4 Nevertheless, this option should be considered only in special circumstances, as an alternative option, as there are more disadvantages than with preferred regimens. The American Adults and Adolescents Guidelines5 also clearly state that triple-class regimens are included in the not recommended strategies for the antiretroviral-naive patient. Pablo Rojo, PhD Maria Isabel Gonzalez-Tome, MD Department of Pediatrics Hospital 12 de Octubre Madrid, Spain Jose Tomas Ramos, MD Department of Pediatrics Hospital de Getafe Madrid, Spain