Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV‐1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short‐term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long‐term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first‐ and second‐line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.     

The effect of antiretroviral therapy provision on all‐cause,AIDS and non‐AIDS mortality at the population level – a comparative analysis of data from four settings in Southern and East Africa

Objective To provide a broad and up‐to‐date picture of the effect of antiretroviral therapy (ART) provision on population‐level mortality in Southern and East Africa. Methods Data on all‐cause, AIDS and non‐AIDS mortality among 15–59 year olds were analysed from demographic surveillance sites (DSS) in Karonga (Malawi), Kisesa (Tanzania), Masaka (Uganda) and the Africa Centre (South Africa), using Poisson regression. Trends over time from up to 5 years prior to ART roll‐out, to 4–6 years afterwards, are presented, overall and by age and sex. For Masaka and Kisesa, trends are analysed separately for HIV‐negative and HIV‐positive individuals. For Karonga and the Africa Centre, trends in AIDS and non‐AIDS mortality are analysed using verbal autopsy data. Results For all‐cause mortality, overall rate ratios (RRs) comparing the period 2–6 years following ART roll‐out with the pre‐ART period were 0.58 (5.9 vs. 10.2 deaths per 1000 person‐years) in Karonga, 0.79 (7.2 vs. 9.1 deaths per 1000 person‐years) in Kisesa, 0.61 (6.7 compared with 11.0 deaths per 1000 person‐years) in Masaka and 0.79 (14.8 compared with 18.6 deaths per 1000 person‐years) in the Africa Centre DSS. The mortality decline was seen only in HIV‐positive individuals/AIDS mortality, with no decline in HIV‐negative individuals/non‐AIDS mortality. Less difference was seen in Kisesa where ART uptake was lower. Conclusions Falls in all‐cause mortality are consistent with ART uptake. The largest falls occurred where ART provision has been decentralised or available locally, suggesting that this is important.     

Does use of antiretroviral therapy regimens with high central nervous system penetration improve survival in HIV‐infected adults?

Objectives

The aim of the study was to determine whether combination antiretroviral therapy (cART) with high central nervous system penetration‐effectiveness (CPE) rank (neurocART) is associated with increased survival benefit compared with non‐neurocART.

Methods

Prospective data were examined for HIV‐positive patients in the Asia Pacific HIV Observational Database who had commenced cART. CPE rank was calculated using the 2010 rankings process. NeurocART status was assigned to regimens with a CPE rank of 8 or more. Survival was analysed using Cox proportional hazards models with covariates updated at changes in cART regimen and with deaths up to 90 days after regimen cessation attributed to that regimen. Sensitivity analyses were conducted to examine the robustness of analysis assumptions.

Results

Among 5882 patients, 308 deaths occurred. The hazard ratio (HR) for neurocART use was 0.89 (P=0.35) when data were stratified by cohort and adjusted for age, mode of HIV exposure, hepatitis B virus coinfection, AIDS‐defining illness, CD4 count (cells/μL) and regimen count. Sensitivity analyses showed similar nonsignificant results. We also examined a composite endpoint of AIDS‐defining illness or death (HR=0.93; P=0.61), baseline regimen as neurocART (HR=0.95; P=0.69), CPE category (P=0.71) and prior neurocART duration (P=0.16). No association between CD4 cell count and neurocART use was observed (P=0.52).

Conclusions

Our findings do not show a significant overall survival benefit associated with neurocART compared with cART. The potential benefit associated with neurocART in terms of prevention of neurocognitive impairment did not translate into an improvement in overall survival in this population. These findings were limited by the low incidence of associated mortality. Further studies and more extensive data are needed to address these limitations.     

Antiretroviral therapy uptake and coverage in four HIV community cohort studies in sub‐Saharan Africa

Objective To compare socio‐demographic patterns in access to antiretroviral therapy (ART) across four community HIV cohort studies in Africa. Methods Data on voluntary counselling and testing and ART use among HIV‐infected persons were analysed from Karonga (Malawi), Kisesa (Tanzania), Masaka (Uganda) and Manicaland (Zimbabwe), where free ART provision started between 2004 and 2007. ART coverage was compared across sites by calculating the proportion on ART among those estimated to need treatment, by age, sex and educational attainment. Logistic regression was used to identify socio‐demographic characteristics associated with undergoing eligibility screening at an ART clinic within 2 years of being diagnosed with HIV, for three sites with information on diagnosis and screening dates. Results Among adults known to be HIV‐infected from serological surveys, the proportion who knew their HIV status was 93% in Karonga, 37% in Kisesa, 46% in Masaka and 25% in Manicaland. Estimated ART coverage was highest in Masaka (68%) and lowest in Kisesa (2%). The proportion of HIV‐diagnosed persons who were screened for ART eligibility within 2 years of diagnosis ranged from 14% in Kisesa to 84% in Masaka, with the probability of screening uptake increasing with age at diagnosis in all sites. Conclusions Higher HIV testing rates among HIV‐infected persons in the community do not necessarily correspond with higher uptake of ART, nor more equitable treatment coverage among those in need of treatment. In all sites, young adults tend to be disadvantaged in terms of accessing and initiating ART, even after accounting for their less urgent need.     

COVID‐19 research: an opinion piece

The unprecedented global scale of COVID‐19 globally has triggered a race to discover interventions to reduce associated morbidity and mortality and rapid release of research findings prior to any degree of critical review. As with previous novel infection outbreaks, antiretrovirals are just one drug class that has been held up as a potential strategy for prophylaxis and treatment with scant evidence and risk of harm. Here we summarize the evidence for antiretrovirals to treat COVID‐19 and, as a drug that has also been studied in HIV, hydroxychloroquine, and flag some of the pitfalls of using therapies that have not been evaluated robustly.     

Effect of antiretroviral agents on carbohydrate metabolism in HIV-1 infected pregnant women

BACKGROUND: Despite the correlation between the use of protease inhibitors (PI) and adverse metabolic glycemic events, no prospective study has examined these parameters in pregnant women who use these drugs. METHODS: A prospective study was conducted on 57 pregnant women to investigate the effect of antiretroviral drugs (ARV) on the carbohydrate metabolism during pregnancy. The women were divided into three groups: ZDV Group, 20 HIV-1 infected women taking ZDV; TT Group, 25 patients on triple antiretroviral treatment (ZDV + 3TC + NFV); and Control Group, 12 pregnant women. Blood samples were obtained during the first visit for the determination of fasting plasma glycemia, when the patients were also submitted to a 75 g oral glucose test (OGTT-75g). These procedures were performed four times along pregnancy. RESULTS: The median values of the area under the glycemia curve (AUC) determined over a period of 120 min between the 33rd and 38th week were 11 685 mg/dL for the Control Group, 13 477 mg/dL for the ZDV Group, and 13 650 mg/dL for the TT Group (p = 0.049). There was an increase in the AUC along pregnancy for all three groups studied, regardless of the treatment used, although this increase was significant only in the TT Group (p = 0.001). The antiretroviral agents had no deleterious effects on prematurity, low birth weight, intrauterine growth restriction rates, or on Apgar score. CONCLUSION: An association was detected between the use of PI and the development of carbohydrate intolerance during pregnancy. The antiretroviral agents had no deleterious effects on perinatal prognosis.     

Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Objectives

The aim of the study was to evaluate the long‐term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)‐, darunavir/ritonavir (DRV/r)‐, and lopinavir/ritonavir (LPV/r)‐containing regimens.

Methods

Data were analysed for 5678 EuroSIDA‐enrolled patients starting a DRV/r‐, ATZ/r‐ or LPV/r‐containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART‐naïve subjects (8%) at ritonavir‐boosted protease inhibitor (PI/r) initiation; (2) ART‐experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV‐1 RNA copies/mL; and (3) ART‐experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r‐based regimen. The main analysis was performed with intention‐to‐treat (ITT) ignoring treatment switches.

Results

The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log‐rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART‐naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment‐experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r‐based ART.

Conclusions

Although confounding by indication and calendar year cannot be completely ruled out, in ART‐experienced subjects the long‐term effectiveness of DRV/r‐containing regimens appears to be greater than that of ATZ/r and LPV/r.

     

Prevention of mother‐to‐child transmission of HIV in Denmark, 1994–2008

Objectives

The aim of this study was to describe trends in the management of pregnancies in HIV‐infected women and their outcomes over a 14‐year period in Denmark on a national basis.

Methods

The study was a retrospective cohort study of all HIV‐infected women in Denmark giving birth to one or more children between 1 June 1994 and 30 June 2008.

Results

We identified 210 HIV‐infected women with 255 pregnancies, ranging from 7 per year in 1995 to 39 per year in 2006. Thirty per cent of the women were Caucasian and 51% were Black African. Knowledge of HIV status before pregnancy increased from 8% (four of 49) in 1994–1999 to 80% (164 of 206) in 2000–2008. Only 29% (53 of 183) of the women chose to consult an infectious disease specialist when planning pregnancy, while 14% (27 of 199) received assistance with fertility. The proportion of women on antiretroviral therapy (ART) increased from 76% (37 of 49) in 1994–1999 to 98% (201 of 206) in 2000–2008. Vaginal deliveries ranged from 0 in 2003 to 35% of pregnancies in 2007. Mother‐to‐child transmission (MTCT) of HIV decreased from 10.4% in 1994–1999 to 0.5% in 2000–2008. All women giving birth to an HIV‐positive child were diagnosed with HIV during or after delivery and did not receive prophylactic ART.

Conclusions

The annual number of HIV pregnancies increased fivefold during this 14‐year period and substantial changes in pregnancy management were seen. No woman treated according to the national guidelines, i.e. ART before week 22, intravenous zidovudine (ZDV) during labour, neonatal ZDV for 4 to 6 weeks and no breastfeeding, transmitted HIV to her child.     

Predictors of bacterial pneumonia in Evaluation of Subcutaneous Interleukin‐2 in a Randomized International Trial (ESPRIT)

Background and Objectives

Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin‐2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin‐2 (rIL‐2) with cART vs. cART alone (control arm) in HIV‐infected adults with CD4 counts ≥300 cells/μL, offered the opportunity to explore associations between bacterial pneumonia and rIL‐2, a cytokine that increases the risk of some bacterial infections.

Methods

Baseline and time‐updated factors associated with first‐episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected.

Results

IL‐2 cycling was most intense in years 1–2. Over ≈7 years, 93 IL‐2 [rate 0.67/100 person‐years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570 cells/μL (IL‐2 arm) and 463 cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log₁₀ higher VL 1.28; 95% CI 1.11, 1.47; P<0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/μL higher 0.94; 95% CI 0.89, 1.0; P=0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL‐2 was received <180 days previously (HR 1.66; 95% CI 1.07, 2.60; P=0.02) vs.≥180 days previously (HR 0.98; 95% CI 0.70, 1.37; P=0.9). Compared with the control group, pneumonia risk in the IL‐2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3–4, 5–6 and 7, respectively.

Conclusions

Bacterial pneumonia rates in cART‐treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL‐2 receipt and/or detectable HIV viraemia warrants further exploration.     

Short‐term antiretroviral therapy to prevent mother‐to‐child transmission is safe and results in a sustained increase in CD4 T‐cell counts in HIV‐1‐infected mothers*

Background

Short‐term antiretroviral therapy (START) to prevent mother‐to‐child transmission (MTCT) is currently recommended for all HIV‐1‐infected pregnant women. The objective of this study was to assess the effect on CD4 cell counts and viral load dynamics the withdrawal of START after birth could generate.

Methods

This was a 5‐year cohort study involving HIV‐1‐infected pregnant women who presented with CD4 counts >300 cells/μL and had received START to prevent MTCT.

Results

Seventy‐five pregnancies were assessed. In 24 cases, there was a history of antiretroviral therapy prior to prophylaxis. The median baseline CD4 count was 573 cells/μL. In 75% of cases, prophylaxis was started after 26.6 weeks of gestation. The median CD4 cell count increase over baseline during prophylaxis was 24.5%. In only five cases did HIV‐1 viral load remain detectable during prophylaxis. After START, CD4 cell counts did not drop significantly, and the HIV‐1 viral load plateau was near the baseline level. The estimated mean time for CD4 count to fall below 300 cells/μL was 3.5 years and was directly associated with high baseline CD4 cell count, as well as with CD4 increase after prophylaxis, whereas it was negatively correlated with previous use of antiretroviral (ARV) drugs and persistence of detectable HIV‐1 viral load during prophylaxis.

Conclusions

A potent, well‐tolerated prophylactic ARV regimen can improve CD4 cell counts during and after START. In women receiving such prophylaxis, there is a remarkable time interval for CD4 cell counts to drop to levels that indicate treatment.     

Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of β chemokines and RNases

T-cell-derived soluble factors that inhibit both X4 and R5 HIV are recognized as important in controlling HIV. Whereas three β chemokines, regulated-on-activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1α, and MIP-1β, account for the suppression of R5 HIV by blockade of HIV entry, the major components responsible for the inhibition of X4 HIV strains have not been identified previously. We identify these factors primarily as a mixture of three β chemokines [macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC), and I-309] and two RNases (angiogenin and RNase 4) of lesser potency and show that in a clade B population, some correlate with clinical status and are produced by both CD4(+) and CD8(+) T cells (chemokines, angiogenin) or only by CD8(+) T cells (RNase 4). The antiviral mechanisms of these HIV X4-suppressive factors differ from those of the previously described HIV R5-suppressive β chemokines.