Reverse Transcriptase Inhibitor-based Antiretroviral Therapy Research Articles

Study APV20002: Safety and Efficacy Results Through Week 684 for Pediatric Participants Living with HIV-1 Treated with Ritonavir-Boosted Fosamprenavir Oral Solution-Based Antiretroviral Therapy.

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4+ cell count was 1,235 cells/mm3 [n = 51] at baseline, 1,690 cells/mm3 (n = 41) at Week 48, and 1,280 cells/mm3 (n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

HIV-1 Treatment Failure, Drug Resistance, and Clinical Outcomes in Perinatally Infected Children and Adolescents Failing First-Line Antiretroviral Therapy in Western Kenya.

Long-term impact of drug resistance in perinatally infected children and adolescents living with HIV (CALWH) is poorly understood. We determined drug resistance and examined its long-term impact on failure and mortality in Kenyan CALWH failing first-line non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART). Academic Model Providing Access to Healthcare, western Kenya. Participants were enrolled in 2010-2013 (timepoint 1) and a subsample re-enrolled after 4-7 years (timepoint 2). Viral load (VL) was performed on timepoint 1 samples, with genotyping of those with detectable VL. Primary endpoints were treatment failure (VL >1000 copies/mL) at and death before timepoint 2. Multinomial regression analysis was used to characterize resistance effect on death, failure, and loss-to-follow-up, adjusting for key variables. The initial cohort (n = 480) was 52% (n = 251) female, median age 8 years, median CD4% 31%, 79% (n = 379) on zidovudine/abacavir + lamivudine + efavirenz/nevirapine for median 2 years. Of these, 31% (n = 149) failed at timepoint 1. Genotypes at timepoint 1, available on n = 128, demonstrated 93% (n = 119) extensive resistance, affecting second line. Of 128, 22 failed at timepoint 2, 17 died, and 32 were lost to follow-up before timepoint 2. Having >5 resistance mutations at timepoint 1 was associated with higher mortality [relative risk ratio (RRR) = 8.7, confidence interval (CI) 2.1 to 36.3] and loss to follow-up (RRR = 3.2, CI 1.1 to 9.2). Switching to second line was associated with lower mortality (RRR <0.05, CI <0.05 to 0.1) and loss to follow-up (RRR = 0.1, CI <0.05 to 0.3). Extensive resistance and limited switch to second line in perinatally infected Kenyan CALWH failing first-line ART were associated with long-term failure and mortality. Findings emphasize urgency for interventions to sustain effective, life-long ART in this vulnerable population.

LB9. The Effect of Initiating Integrase Inhibitor-based vs. Non-Nucleoside Reverse Transcriptase Inhibitor-based Antiretroviral Therapy on Progression to Diabetes among North American Persons in HIV Care

BackgroundIntegrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been implicated in greater weight gain than other regimens among people with HIV, but there is little evidence about its role in serious clinical outcomes proximal to weight gain. We therefore examined the impact of initial ART regimen class/drug on incident diabetes mellitus (DM) in a large North American HIV cohort.MethodsTreatment-naïve adults (≥18 years) initiating INSTI-, protease inhibitor (PI)-, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART from January 2007 to December 2016 in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included. Individuals were followed until date of incident DM (HgA1c >6.5%, diabetes-specific medication, DM diagnosis along with diabetes-related medication, or random glucose measure ≥200 mg/dL), virologic failure, regimen core switch, cohort close (through December 2016), death date, or loss to follow-up (≥12 months with no contact before cohort close). Cox regression stratified by site and adjusting for age, sex, race, HIV transmission risk, year of ART initiation, and baseline weight, CD4+ cell count, and HIV-1 RNA yielded adjusted hazard ratios (HR) and 95% confidence intervals (CI) for incident DM by ART class and INSTI drug.ResultsAmong 21,516 eligible ART initiators, 10,553 (49%) started NNRTIs, 6,677 (31%) PIs, and 4,286 (20%) INSTIs, with median follow-up of 3.0, 2.4, and 1.6 years, respectively. Among INSTI initiators, 21% started dolutegravir (DTG), 28% raltegravir (RAL), and 51% elvitegravir (EVG). Overall, 669 (3%) developed DM. Patients differed by all characteristics except baseline body mass index and HIV-1 RNA. Those starting INSTIs vs. NNRTIs had increased risk of incident DM (HR = 1.22; CI: 0.95–1.57) similar in magnitude as for PI vs. NNRTI initiators (HR = 1.25; CI: 1.05–1.49) (figure). Among INSTIs, starting RAL- vs. NNRTI-based ART was associated with a 50% increased risk of DM (HR = 1.50, CI: 1.11–2.03).ConclusionInitiating ART with INSTI- or PI- vs. NNRTI-based regimens may confer increased risk of incident DM, though risk is heterogeneous among INSTIs. Further research is needed to determine whether this elevated risk can be attributed to weight gain. DisclosuresKassem Bourgi, MD, Gilead Sciences (Grant/Research Support), Joseph J. Eron, MD, Gilead Sciences (Consultant, Grant/Research Support), Janssen (Grant/Research Support), Merck (Consultant), ViiV Healthcare (Consultant, Grant/Research Support), M. John Gill, MB, ChB, MSc, Gilead (Board Member), Merck (Board Member), Viiv (Board Member), Michael Silverberg, PhD, MPH, Gilead (Grant/Research Support). Other Authors: No reported disclosures.

Clinically relevant thresholds for ultrasensitive HIV drug resistance testing: a multi-country nested case-control study

Implementation of ultrasensitive HIV drug resistance tests for routine clinical use is hampered by uncertainty about the clinical relevance of drug-resistant minority variants. We assessed different detection thresholds for pretreatment drug resistance to predict an increased risk of virological failure. We did a case-control study nested within a prospective multicountry cohort. Our study included patients from 12 clinical sites in Kenya, Nigeria, South Africa, Uganda, and Zambia. We defined cases as patients with virological failure (ie, those who had either viral load ≥400 copies per mL at 12 months or had switched to second-line antiretroviral therapy [ART] as a result of virological failure before 12 months) and controls as those with viral suppression (viral load <400 copies per mL at 12 months) on first-line non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. We assessed pretreatment drug resistance with Illumina MiSeq next-generation sequencing, using the International Antiviral Society (IAS)-USA mutation list or the Stanford HIV Drug Resistance Database (HIVDB) genotypic sensitivity score. We calculated diagnostic accuracy measures and assessed the odds of virological failure using conditional logistic regression for 1%, 5%, and 10% pretreatment drug resistance detection thresholds, compared with the conventional 20% or more used in Sanger-based sequencing. Paired viral load results before ART and at month 12 of follow-up were available from 1896 participants. We identified 178 patients with virological failure and selected 338 matched controls. We excluded 117 patients from pretreatment drug resistance analysis; therefore, 152 cases of virological failure and 247 controls were included in the final analysis. With the IAS-USA mutation list, at a detection threshold of 20% or more in patients with pretreatment drug resistance, the adjusted odds ratio (OR) for virological failure was 9·2 (95% CI 4·2-20·1) compared with those without pretreatment drug resistance. Lowering the threshold resulted in adjusted ORs of virological failure of 6·8 (95% CI 3·3-13·9) at the 10% threshold, 7·6 (3·4-17·1) at the 5% threshold, and 4·5 (2·0-10·2) at the 1% threshold. Lowering the detection threshold from 20% improved the sensitivity (ie, ability to identify cases) from 12% (n=18) to 13% (n=19) at detection threshold 10%, to 15% (n=23) at detection threshold 5%, and to 17% (n=26) at detection threshold 1%, but caused a slight reduction in specificity (ie, ability to identify controls) from 98% (n=241) to 96% (n=238) at the 10% threshold, 96% (n=236) at the 5% threshold, and a larger reduction to 92% (n=227) at the 1% threshold. Diagnostic ORs were 5·4 (95% CI 2·1-13·9) at the 20% threshold, 3·8 (1·7-8·6) at the 10% threshold, 3·8 (1·8-8·1) at the 5% threshold, and 2·3 (1·2-4·2) at the 1% threshold. Use of the Stanford HIVDB genotypic sensitivity scores yielded similar ORs for virological failure, sensitivities, specificities, and diagnostic ORs. Ultrasensitive resistance testing for pretreatment drug resistance improved identification of people at risk of virological failure; however, this came with a reduction in our ability to identify people with viral suppression, especially at very low thresholds. Further modelling is needed to estimate the optimal trade-off for the 5% and 20% thresholds, balancing improved case finding against unnecessary regimen switching. The Netherlands Ministry of Foreign Affairs, IrsiCaixa, and European Union.

Adverse fetal and infant outcomes among HIV-infected women who received either nonnucleoside reverse transcriptase inhibitor-based or protease inhibitor-based antiretroviral therapy for prevention of mother-to-child transmission.

For HIV-infected pregnant and breastfeeding women, antiretroviral therapy (ART) is known to reduce the mother's risk of passing the infection to her child. However, concerns remain about possible associations between various components of different ART regimens and adverse fetal and infant outcomes. As part of a clinical trial in western Kenya for the prevention of mother-to-child transmission (PMTCT) of HIV, pregnant women received one of two different ART regimens. The original PMTCT study conducted in Kenya enrolled 522 HIV-infected, ART-naive pregnant women. These women were assigned to receive an ART regimen that included either nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), or nelfinavir, a protease inhibitor. This substudy involves 384 women from the original study who had baseline CD4 cell counts at least 250 cells/μl, and compares the risks of adverse fetal and infant outcomes between the two ART regimens. There were 386 live births (including multiples) and 7 (1.8%) stillbirths. Among live births, there were 67 preterm deliveries, 37 low-birth weight infants, and 14 infant deaths by 6 months. There were no statistically significant differences between the two ART regimens for any of the reported adverse outcomes. Although these data do not show significant differences between the NNRTI-based or protease inhibitor-based regimens in serious adverse fetal and infant outcomes, more studies need to be done and careful vigilance is needed to ensure infant safety.

Anemia in people on second line antiretroviral treatment in Lilongwe, Malawi: a cross-sectional study

BackgroundAnemia is common among people living with HIV infection and is frequently associated with poor quality of life and poor prognosis. It has been well described in antiretroviral naïve individuals and those on non-nucleoside reverse transcriptase inhibitor-based first line antiretroviral therapy (ART) regimens. However there is limited information on anemia for ART experienced individuals on protease inhibitor-based second line ART regimens in resource limited settings. Our objective was to describe the prevalence and risk factors of anemia in this ART experienced population in Malawi.MethodsWe conducted a cross-sectional study using routine facility data at two HIV clinics in Lilongwe, Malawi. The analysis included individuals receiving protease inhibitor-based second line ART. Clinical and laboratory data were collected at routine clinic visits. We used descriptive statistics, two-sample t-tests and multivariate logistic regression for data analysis.ResultsThree hundred seventy-seven records were included in this analysis (37% male, median age 41 years, median CD4 count 415 cells/μL). The prevalence of anemia was 125/377 (33.2%) − mild, moderate and severe anemia was 17.5%, 13.8%, and 1.9% respectively. Female participants had a higher prevalence than male participants (43.6% vs. 15.7%, p < 0.001). In multivariate logistic regression, female sex (adjusted odds ratio (aOR) 5.3; 95% CI 2.9–9.5) and a CD4 count <200 cell/ul (aOR 3.1; 95%CI 1.6–6.0) were associated with increased risk of having anemia while a BMI ≥30 kg/m2 (aOR 0.8; 95% CI 0.6–1.0) and being on ART for more than 10 years (aOR 0.4; 95% CI 0.2–0.9) were associated with reduced risk of anemia. Being on a zidovudine- containing ART regimen was not associated with anemia.ConclusionAnemia is common in people on second line ART in Lilongwe, Malawi. Screening for anemia in this population would be a useful strategy; especially for female patients, those who are underweight and have a low CD4 cell counts.

Effectiveness of Protease Inhibitor/Nucleos(t)ide Reverse Transcriptase Inhibitor-Based Second-line Antiretroviral Therapy for the Treatment of Human Immunodeficiency Virus Type 1 Infection in Sub-Saharan Africa: A Systematic Review and Meta-analysis.

In sub-Saharan Africa, 25.5 million people are living with human immunodeficiency virus (HIV), representing 70% of the global total. The need for second-line antiretroviral therapy (ART) is projected to increase in the next decade in keeping with the expansion of treatment provision. Outcome data are required to inform policy. We performed a systematic review and meta-analysis of studies reporting the virological outcomes of protease inhibitor (PI)-based second-line ART in sub-Saharan Africa. The primary outcome was virological suppression (HIV-1 RNA <400 copies/mL) after 48 and 96 weeks of treatment. The secondary outcome was the proportion of patients with PI resistance. Pooled aggregate data were analyzed using a DerSimonian-Laird random effects model. By intention-to-treat analysis, virological suppression occurred in 69.3% (95% confidence interval [CI], 58.2%-79.3%) of patients at week 48 (4558 participants, 14 studies), and in 61.5% (95% CI, 47.2%-74.9%) at week 96 (2145 participants, 8 studies). Preexisting resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) increased the likelihood of virological suppression. Major protease resistance mutations occurred in a median of 17% (interquartile range, 0-25%) of the virological failure population and increased with duration of second-line ART. One-third of patients receiving PI-based second-line ART with continued NRTI use in sub-Saharan Africa did not achieve virological suppression, although among viremic patients, protease resistance was infrequent. Significant challenges remain in implementation of viral load monitoring. Optimizing definitions and strategies for management of second-line ART failure is a research priority. CRD42016048985.

Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060

Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060

Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals.

BackgroundClinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown.MethodsWe measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL).ResultsThere was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient −0.04, P = 0.021), supporting our previous findings in vitro.ConclusionsTogether, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0288-6) contains supplementary material, which is available to authorized users.

Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment

This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

Sensitive Assessment of the Virologic Outcomes of Stopping and Restarting Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy

BackgroundNon-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.MethodsResistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.ResultsFour weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).ConclusionsDetection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.

Effect of Nonnucleoside Reverse Transcriptase Inhibitor–Based Antiretroviral Therapy on Dysglycemia and Insulin Sensitivity in South African HIV-Infected Patients

Data on the prevalence of the complications of antiretroviral therapy (ART) (diabetes, central fat accumulation, peripheral fat wasting, and dyslipidemia) in sub-Saharan Africa are sparse. We examined the prevalence and associated risk factors of dysglycemia and insulin sensitivity in HIV-infected South Africans. HIV-infected patients, on nonnucleoside reverse transcriptase inhibitor-based ART or ART-naive, had oral glucose tolerance tests and clinical anthropometry. Insulin sensitivity and β-cell function were assessed. The prevalence of dysglycemia in 406 ART-naive patients and 443 patients on ART was 25.7% and 21.9% (P = 0.193), respectively. Dysglycemic patients on ART had a similar body mass index (P = 0.440), greater waist circumference (P = 0.047), and smaller calf skinfold thickness (P = 0.015) than dysglycemic ART-naive patients but no difference in β-cell function or insulin sensitivity. Normoglycemic patients on ART had a greater body mass index (P = 0.0009), waist circumference (P = 0.0001), and abdominal skinfold thickness (P = 0.040), similar calf skinfold thickness (P = 0.079), and reduced β-cell function [lower insulinogenic index (P = 0.027) and oral disposition index (D(o), P = 0.020)] compared with normoglycemic ART-naive patients. In multivariate analysis, older age [odds ratio (OR): 1.04, 95% confidence interval (CI): 1.02 to 1.06], male gender (OR: 1.96, 95% CI: 1.28 to 2.99), higher CD4 count (OR: 1.0, 95% CI: 1.00 to 1.02) and use of efavirenz (OR: 1.70, 95% CI: 1.19 to 2.45) were associated with dysglycemia. The prevalence of dysglycemia in ART-naive and ART patients was similar. Peripheral fat wasting was more common in dysglycemic patients on ART. The association of efavirenz with dysglycemia is important because first-line ART regimens in the developing world include nonnucleoside reverse transcriptase inhibitors, and increasingly, efavirenz is selected because of its perceived lower toxicity than nevirapine.

Microbial Translocation: A Marker of Advanced HIV-1 Infection and a Predictor of Treatment Failure?

To the Editor—We agree that the issue of whether microbial translocation (MT) is a cause or consequence of human immunodeficiency virus type 1 (HIV-1) disease progression is an important question that can only be addressed through longitudinal analyses of natural history cohorts such as the study by Redd et al [1]. A timely and definitive answer to this question will depend on the availability of archived specimens that have been well characterized and properly stored. Specimen banks of this nature are relatively rare in Africa. However, there are issues of equal importance, namely, whether microbe-associated immune activation persists during highly active antiretroviral therapy (HAART) and whether this has an adverse effect on therapeutic outcome. There is already a growing body of evidence indicating that HAART-treated patients have elevated levels of bacterial DNA and plasma lipopolysaccharide (LPS) for at least 2 years after starting therapy [2], with one North American study showing decreased levels of LPS and CD4 T cell cycling after >5 years of maximally suppressive HAART [3]. There is also increasing evidence that elevated levels of LPS are associated with monocyte-macrophage activation and disease pathology, not only in HIV-1-infected patients with dementia [4] and hepatitis C–related liver disease [5], but also in HIV-1–negative patients with tuberculosis [6] and inflammatory bowel disease [7]. LPS has also been linked to T cell activation and proliferation [3], presumably via secretion of proinflammatory mediators by monocyte-macrophages. However, as emphasized by Redd et al, MT does not account for all aspects of immune activation in patients with late-stage disease. We examined the relationship between plasma LPS, HIV-1 viral load, and immune activation, before and after 1 year of nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART), in Africans with advanced HIV-1 disease and CD4 counts <200 cells/μL [8]. We found that some aspects of monocyte activation (CCL2, CXCL10, the frequency of CD14+CD16+ monocytes) were associated with high levels of HIV-1 RNA, whereas others (tumor necrosis factor [TNF], soluble CD14 [sCD14]) were more closely linked to plasma concentrations of LPS or the presence of opportunistic co-infections (interleukin 6). In addition to being independent of HIV-1 replication, LPS-associated activation, as measured by sCD14 and TNF, was independent of T cell activation and was only partially curtailed after 1 year of successful ART. These findings may help explain the results of Rempel et al [9]. Similar to our study, these investigators found that LPS and sCD14 remained elevated in HAART-treated patients. They also found that monocytes isolated from patients with high levels of residual viremia exhibited different patterns of gene expression after in vitro stimulation with LPS and interferon (IFN)–α. IFN-α activation resembled that observed in patients, while the LPS pattern differed from that normally induced following activation with whole bacteria (interleukin 10) or Fc/complement receptor–mediated phagocytosis (interleukin 6, interleukin 1β), leading to the conclusion that these monocytes were not responsive to LPS. However, LPS induced the up-regulation of a large number of genes (n = 992), a finding that is consistent with the ability of LPS to induce 5 different signaling cascades [10]. Whether these altered LPS patterns are due to a superimposed (or counterbalancing) effect of HIV-1 on monocyte activation or a defect in endotoxin tolerance remains to be determined. Additional studies should include HAART-treated patients with undetectable viremia and be performed using whole bacteria and LPS/LPS-binding protein (LBP) in addition to monomeric LPS. To rule out activation during positive selection with anti-CD14 antibodies, monocytes should be isolated using negative as well as positive selection methods. Additional studies are also needed to unravel the relationships between LPS, sCD14, and immune activation. CD14 binds and presents LBP-bound LPS to its signaling complex, lymphocyte antigen 96 (MD-2)/toll-like receptor 4 (TLR4), triggering monocyte-macrophage activation and the release of sCD14 [11]. sCD14 contributes to cell activation by transferring monomeric LPS to membrane CD14 (mCD14), or directly to the MD-2/TLR4 complex in cells that lack mCD14. However, sCD14 can also induce endotoxin tolerance by removing LPS from mCD14 and diverting it to plasma lipoproteins [11], a process that may decrease CD14 shedding. This is further complicated by studies showing that HIV-1 RNA can enhance TLR4-mediated response to LPS, causing dysregulation of endotoxin tolerance [12]. The complex relationships between HIV-1, MT, and immune activation are likely to depend on the integrity of gastrointestinal epithelium, the level of HIV-1 replication, plasma concentrations of LPS-binding protein and endotoxin core antibody, and the presence/absence and type of opportunistic co-infections, as well as the combined effects of these infections on TLR signaling cascades. Understanding these interactions may be critical to the design of strategies aimed at enhancing therapeutic efficacy in Africa where treatment is often delayed until CD4 counts drop to <200 cells/μL.

Reversal of Growth Failure in HIV-Infected Thai Children Treated with Non-Nucleoside Reverse Transcriptase Inhibitor–Based Antiretroviral Therapy

Growth failure is a common problem in HIV-infected children. The extent to which this growth failure could be reversed after the children receive antiretroviral therapy (ART) is not known. This study assessed the incidence of growth failure in HIV-infected Thai children, impact of ART on growth, and the predictors of growth reversal after initiating ART. Growth parameters and other characteristics were extracted from the database of a prospective cohort of HIV-infected children (age <or=15 years) who were enrolled to initiate non-nucleoside reverse transcriptase inhibitor-based ART between August 2002 and May 2007. Body weight and height measurements, CD4 cell counts, plasma HIV RNA levels were collected at baseline and 24-week intervals. A total of 225 HIV-infected children were included, 116 (51%) were males. The median age at baseline was 7.4 years (interquartile range [IQR] 5.2-9.8). Fifty-three percent were in Centers for Disease Control and Prevention (CDC) category C and 54% had CD4 percentage 5 or less. The mean (standard deviation [SD]) of baseline weight-for-age (WAZ) and height-for-age (HAZ) z-scores were -2.02 (1.17) and -2.22 (1.51). The median follow-up time was 216 weeks (IQR 120-240). The cumulative probability of growth reversal among the 179 subjects with growth failure at entry was 58% (95% confidence interval [CI] 49-67) at week 240. In a multivariate Cox regression model, higher entry WAZ (p < 0.001) and HAZ (p < 0.001), use of a nevirapine-based regimen (compared to efavirenz, p = 0.027) and larger CD4% gains to week 48 (p < 0.001) were significant predictors of growth reversal after initiating ART. NNRTI-based ART leads to a substantial improvement in growth of HIV-infected children. Initiation of ART before the children developed growth failure should be encouraged.

Clinical impact of patient population differences and genomic variation in efavirenz therapy

Guidelines for use of antiretroviral agents presently recommend first-line treatments with nonnucleoside reverse transcriptase inhibitor-based regimens. Efavirenz is the standard-of-care comparator for nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. As with many antiretroviral medications, efavirenz is subject to interindividual variation in metabolism, effectiveness, and tolerability. Demographic factors such as age, sex, and ethnicity have been demonstrated to influence this variability, but other underlying factors such as genetics, disease state, and concomitant drug use can also play a role. The clinical impactions of these factors are only beginning to be understood. Although significant advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of efavirenz, providers should not withhold treatment of HIV infection with an efavirenz-based regimen on the basis of racial or ethic categorizations.

Second-line antiretroviral therapy in resource-limited settings: the experience of Médecins Sans Frontières

To describe the use of second-line protease-inhibitor regimens in Médecins Sans Frontières HIV programmes, and determine switch rates, clinical outcomes, and factors associated with survival. We used patient data from 62 Médecins Sans Frontières programmes and included all antiretroviral therapy-naive adults (> 15 years) at the start of antiretroviral therapy and switched to a protease inhibitor-containing regimen with at least one nucleoside reverse transcriptase inhibitor change after more than 6 months of nonnucleoside reverse transcriptase inhibitor first-line use. Cumulative switch rates and survival curves were estimated using Kaplan-Meier methods, and mortality predictors were investigated using Poisson regression. Of 48,338 adults followed on antiretroviral therapy, 370 switched to a second-line regimen after a median of 20 months (switch rate 4.8/1000 person-years). Median CD4 cell count at switch was 99 cells/microl (interquartile ratio 39-200; n = 244). A lopinavir/ritonavir-based regimen was given to 51% of patients and nelfinavir-based regimen to 43%; 29% changed one nucleoside reverse transcriptase inhibitor and 71% changed two nucleoside reverse transcriptase inhibitors. Median follow-up on second-line antiretroviral therapy was 8 months, and probability of remaining in care at 12 months was 0.86. Median CD4 gains were 90 at 6 months and 135 at 12 months. Death rates were higher in patients in World Health Organization stage 4 at antiretroviral therapy initiation and in those with CD4 nadir count less than 50 cells/microl. The rate of switch to second-line treatment in antiretroviral therapy-naive adults on non-nucleoside reverse transcriptase inhibitor-based first-line antiretroviral therapy was relatively low, with good early outcomes observed in protease inhibitor-based second-line regimens. Severe immunosuppression was associated with increased mortality on second-line treatment.

HIV-1 genotype after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and virological response after resumption of the same regimen

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a longer half-life than nucleoside reverse transcriptase inhibitor (NRTIs). Simultaneous interruption of all drugs exposes the patients to NNRTI monotherapy. This study evaluated HIV-1 genotype after treatment interruption (TI) of NNRTI-based antiretroviral therapy (ART) and virological response after resumption of the same ART regimen. A prospective study was conducted in HIV-1-infected patients who enrolled into a CD4-guided TI study. All patients continued dual NRTIs for a further 7-10 days at NNRTI TI. HIV-1 genotypic assay was performed prior to resumption of the same ART regimen. Forty-three patients required ART resumption after TI from NNRTI-based regimens. Mean age was 42.7 years; 44% were men. Median CD4 and HIV-1 RNA at the time of ART resumption were 178 cell/mm(3) and 5.78 log copies/mL, respectively. HIV-1 genotype revealed no mutations contributed to NRTI or NNRTI resistance. Of all, 56% and 100% patients achieved undetectable HIV-1 RNA at three and six months, respectively. Median CD4 were 386 and 419 cells/mm(3) at the corresponding periods. In conclusion, continuation of dual NRTIs for 7-10 days after TI of NNRTI-based regimens can minimize the risk of acquired NNRTI resistance. With this strategy, the same regimen can be used for resumption and also yield good virological and immunological outcomes.

Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy

Highly active antiretroviral therapy (HAART) has recently been implemented in Thailand. Its long-term effects have not been clearly evaluated. The objective of this study was to estimate the prevalence of lipodystrophy (LD) and other metabolic changes in HIV-infected children receiving HAART. Ninety children who began HAART (either nevirapine or efavirenz, together with lamivudine and stavudine) were prospectively followed. LD was assessed by waist-to-hip ratio and LD checklist. Hypercholesterolaemia was defined as total cholesterol > 200 mg/dl and low-density lipoprotein cholesterol > 130 mg/dl. Low levels of high-density lipoprotein cholesterol (HDL-c), hypertriglyceridaemia and hyperglycaemia were defined as HDL-c < 40 mg/dl, triglyceride > 200 mg/dl and plasma glucose > 110 mg/dl, respectively. The mean age at entry was 7.6 (SD 2.9) years. Fifty-three children received nevirapine- and 37 received efavirenz-based HAART. The prevalence of LD was 9%, 47% and 65% at 48, 96 and 144 weeks after HAART initiation, respectively. Patterns of LD at week 144 were central lipohypertrophy (46%), peripheral lipoatrophy (20%), and combined type (34%). A higher prevalence of LD was found among females (61% versus 39%; P = 0.04) and those with more advanced disease (CDC category B or C) at baseline (73% versus 51%; P = 0.04). There was no difference in prevalence of LD between the two regimens. At 144 weeks, fasting hypertriglyceridaemia was detected in 12%, hypercholesterolaemia in 11%, and increased plasma glucose in 4% of children. Low HDL-cholesterolaemia decreased from 94% at baseline to 12% at week 144 (P < 0.01). More than half of the children developed LD at 144 weeks after HAART. Dyslipidaemia occurred in 11-12% of children.

Discontinuation of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy: clinical implications in patients on CD4 T-cell-guided treatment interruption

Ruiz and colleagues [1] found the frequent de novo selection of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance in the group in their study on guided treatment interruptions (GTI) probably to be driven by the simultaneous interruption of all drugs in patients receiving NNRTI-containing regimens. They discouraged the inclusion of any drug with long plasma or low genetic barriers into GTI regimens because of the risk of the de novo selection of resistant mutations. Both United States and United Kingdom HIV treatment guidelines ackowledge the difficulty of knowing the exact duration of antiretroviral therapy cover required after stopping NNRTI, and the optimal interval between stopping efavirenz or nevirapine and other antiretroviral drugs is unknown. Their prolonged half-life leads to the detection of these drugs for 1–3 weeks after discontinuation [2,3], and the simultaneous interruption of all antiretroviral drugs in a regimen containing these agents may therefore result in functional monotherapy with the NNRTI. This in turn increases the risk of the selection of NNRTI-resistant mutations. Therefore some experts recommend stopping NNRTI while continuing other antiretroviral drugs for 5–7 days [4,5]. We describe our experience in eight patients who simultaneously interrupted all antiretroviral drugs (including NNRTI) during CD4 T-cell GTI and obtained a rapid return of plasma viraemia to undetectable levels after restarting the same regimen. A total of 46 white European patients were enrolled in the clinical study of CD4 T-cell GTI. Of these, 22 were on NNRTI-based antiretroviral therapy. The criteria used to stop antiretroviral therapy were a CD4 T-cell count of 500 cells/μl or greater and a plasma HIV-RNA level of less than 50 copies/ml for at least 3 years. Patients underwent laboratory evaluations 4 and 12 weeks after stopping antiretroviral therapy and then every 3 months. The criteria for restarting HAART were: (i) acute retroviral syndrome; (ii) patient's choice, independent of the CD4 T-cell count; (iii) pregnancy; (iv) the onset of HIV-related systemic symptoms (acute retroviral syndrome) or of opportunistic infections; (v) a CD4 T-cell count decline to less than 250 cells/μl. Four weeks after discontinuation, an antiretroviral genotyping test (TruGene HIV-1 genotyping assay) was performed to assess the presence of NNRTI-related point mutations. Fifteen patients restarted ART; eight of them (five women, median age 42 years, range 37–55) were on NNRTI (five on efavirenz and three on nevirapine). Four patients were antiretroviral naive and four antiretroviral experienced. Table 1 give details of the antiretroviral regimens, the date and length of interruption, and months of undetectable viral load reached after the reintroduction of the same regimen. Viraemia was undetectable again in all patients within 3 months of the reintroduction of antiretroviral therapy, and continues to be so.Table 1: Antiretroviral regimens, date and months of interruption, and time length of undetectable viral load after reintroduction of the same regimen.Genotypic resistance tests failed to reveal mutations conferring resistance to NNRTI in all patients (100%). Few data are available on the discontinuation of NNRTI-based therapy in order to avoid a monotherapy state and the potential evolution of drug-resistant variants. Two studies have documented how the duration of detectable levels of these drugs after discontinuation ranges from less than one week [4] to over 3 weeks [5], and the authors suggested continuing the nucleoside reverse transcriptase inhibitor backbone for a minimum of 5 days to a maximum of 14 days after the discontinuation of NNRTI in order to avoid the emergence of resistance. Some authors have also shown that certain host genetic polymorphisms, more common among African-American and Hispanic individuals [6,7], result in slower rates of clearance of these drugs. The optimal time sequence for staggered component discontinuation has, however, not been still determined. Our results, in a small number of individuals, indicate that white European patients with high CD4 T-cell numbers and undetectable plasma HIV-RNA levels can simultaneously discontinue all components of their antiretroviral regimen without developing point mutations conferring resistance to NNRTI. We hypothesized that the 4–7 day delay in viral rebound after therapy interruption, as shown by Neumann et al. [8], could explain our results. Perhaps the risk of developing NNRTI resistance when stopping all antiretroviral drugs simultaneously is more common when cessation occurs with a detectable plasma viraemia, as suggested by others [4].

Rapid CD4 decline after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy in a resource-limited setting

BackgroundNon-nucleoside reverse transcriptase inhibitor (NNRTI) with stavudine and lamivudine is widely used as the first-line antiretroviral therapy (ART) in resource-limited settings. Lipodystrophy is common and options for switching ART regimen are limited; this situation can lead to patients' poor adherence and antiretroviral resistance. Treatment interruption (TI) in patients with high CD4 cell counts, lipodystrophy, and limited options may be an alternative in resource-limited settings. This study aimed to determine time to resume ART after TI and predictors for early resumption of ART in a resource-limited setting.MethodsA prospective study was conducted in January 2005 to December 2006 and enrolled HIV-infected patients with HIV-1 RNA <50 copies/mL, CD4 > 350 cells/mm3, and willing to interrupt ART. CD4 cell count, HIV-1 RNA, lipid profile, and lipodystrophy were assessed at baseline and every 3 months. ART was resumed when CD4 declined to <250 cells/mm3 or developed HIV-related symptoms. Patients were grouped based on ART regimens [NNRTI or protease inhibitor (PI)] prior to TI.ResultsThere were 99 patients, 85 in NNRTI group and 14 in PI group. Mean age was 40.6 years; 46% were males. Median duration of ART was 47 months. Median nadir CD4 and baseline CD4 were 151 and 535 cells/mm3, respectively. Median CD4 change at 3 months after TI were -259 (NNRTI) and -105 (PI) cells/mm3 (p = 0.038). At 13-month median follow-up, there was no AIDS-defining illness; 38% (NNRTI) and 29% (PI) of patients developed HIV-related symptoms. ART was resumed in 51% (NNRTI) and 36% (PI) of patients (p = 0.022). By Kaplan-Meier analysis, median time to resume ART was 5.5 (NNRTI) and 14.2 (PI) months (log rank test, p = 0.026). By Cox's regression analysis, NNRTI-based ART (HR 4.9; 95%CI, 1.5–16.3), nadir CD4 <100 cells/mm3 (HR 2.7; 95%CI 1.4–5.3) and baseline CD4 <500 cells/mm3 (HR 1.6; 95%CI, 1.2–3.1) were predictors for early ART resumption.ConclusionTI of NNRTI-based ART leads to rapid CD4 decline and high probability of early ART resumption and should be avoided. It is necessary to scale-up the options for HIV-infected patients with lipodystrophy in resource-limited settings.