Efficacy of highly active antiretroviral therapy in HIV-1 infected children

Although the reduction in HIV-1-related deaths with highly active antiretroviral therapy (HAART) is similar in adults and children, the extent of the changes in two important surrogate markers HIV-1 RNA levels and CD4+ T cell counts, differs widely. In most paediatric studies virological response rates to HAART are inferior to those in adults. This review provides an overview of the paediatric clinical studies using HAART and seeks to improve the understanding of factors that may contribute to success or failure of HAART in children. An overview of all current articles on paediatric clinical trials using HAART is provided. 23 papers were available. HIV-1 RNA loads and CD4+ T cell counts were used as primary outcome measures. Virological response rates were highly variable, both among the different antiretroviral drugs but also among different studies using the same medication. Four studies in which dosages of the administrated protease inhibitor (PI) were adjusted after pharmacokinetic evaluation had superior virological response rates compared with those in which fixed dosages were used. Immunological response rates were more uniform than virological responses. In almost all studies increases of CD4+ T cell counts are reported independent of the extent of the virological response. Side-effects of HAART were generally mild, transient, and of gastrointestinal origin. Significant percentages of patients with serum lipid abnormalities were reported in three paediatric studies. However, signs of clinical lipodystrophy were not observed. The inferior virological response rates, which have been reported in HIV-1 infected children treated with HAART form a reflection of the challenges that are encountered in the treatment of these children. Difficulties with adherence and with the pharmacokinetics of PIs in children require an intensive, child-adjusted approach. A practical approach to therapy in institutions without tertiary care facilities may be induction therapy with a lopinavir containing regimen (lacking a need for therapeutic drug monitoring), to reduce high viral load levels followed by an easily tolerated maintenance regimen, for example containing abacavir or nevirapine.     

Mortality and progression to AIDS after starting highly active antiretroviral therapy

OBJECTIVES: To examine survival and progression to AIDS among HIV-infected patients after starting highly active antiretroviral therapy (HAART). METHODS: The study population consisted of 3724 patients from the ATHENA observational cohort who initiated HAART. We considered progression to either an AIDS-defining disease or death, distinguishing HIV-related and non-related (including therapy-related) deaths. A time-dependent multivariate hazards model was fitted to the patient data and 5-year survival probabilities under various therapy scenarios estimated. RESULTS: A total of 459 patients developed AIDS and 346 died during 12 503 person-years of follow-up. HIV-related mortality decreased from 3.8 to 0.7 per 100 person-years between 1996 and 2000 whereas non-HIV-related mortality did not change (0.4 and 0.9, respectively, P = 0.25). For asymptomatic and symptomatic therapy naive patients younger than 50 years with CD4 counts above 10 x 10(6) and 150 x 10(6) cells/l, respectively, predicted 5-year survival probabilities were above 90% when HAART was used continuously. This limit was 450 x 10(6) cells/l when HAART was used during 20 weeks in each 24 week-period of follow-up, and 110 x 10(6) cells/l when patients delayed initiation of HAART for 1 year after becoming eligible for treatment. CONCLUSIONS: Survival probabilities were high among HIV-infected patients initiating HAART at an early stage of infection. The best therapy strategy is therefore to start HAART at this stage of infection. However, deferring HAART in patients with high CD4 cell counts may be clinically more appropriate given toxicity and adherence problems. The lack of any change in non-HIV-related mortality suggests that toxicity has not yet become a major risk factor for death.     

Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy

OBJECTIVE: To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of < 500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). RESULTS: HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a > or = 50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a > or = 50 cells/microL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. CONCLUSIONS: HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus.     

High rates of active hepatitis B and C co-infections in HIV-1 infected Cameroonian adults initiating antiretroviral therapy

Objectives

To investigate the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA in HIV‐infected patients initiating antiretroviral therapy in Cameroon.

Methods

Baseline blood samples from 169 patients were tested retrospectively for hepatitis B surface antigens (HBsAg), anti‐hepatitis B core (anti‐HBc), anti‐HCV and – if HBsAg or anti‐HCV result was positive or indeterminate – for HBV DNA or HCV RNA, respectively, using the Cobas Ampliprep/Cobas TaqMan quantitative assay (Roche Diagnostics GmbH, Mannheim, Germany).

Results

HBV DNA was detected in 14 of the 18 patients with positive or indeterminate HBsAg results [8.3% of the total study population, 95% confidence interval (CI) 4.6–13.5]. The median HBV viral load was 2.47 × 10⁷ IU/mL [interquartile range (IQR) 3680–1.59 × 10⁸; range 270 to >2.2 × 10⁸]. Twenty‐one patients (12.4%, 95% CI 7.9–18.4) were found with HCV RNA (all with positive HCV serology). The median HCV viral load was 928 000 IU/mL (IQR 178 400–2.06 × 10⁶; range 640–5.5 × 10⁶). No patient was co‐infected with HBV and HCV. In multivariate analysis, HCV co‐infection was associated with greater age [≥45 years vs. <45 years, odds ratio (OR) 11.89, 95% CI 3.49–40.55, P<0.001] and abnormal serum alanine aminotransferase level [≥1.25 × upper limit of normal (ULN) vs. <1.25 × ULN, OR 7.81, 95% CI 1.54–39.66, P=0.01]; HBV co‐infection was associated with abnormal serum aspartate aminotransferase level (OR 4.33, 95% CI 1.32–14.17, P=0.02).

Conclusions

These high rates of active HBV and HCV co‐infections in HIV‐positive Cameroonian patients requiring antiretroviral therapy underline the need to promote: (i) screening for HBV and HCV before treatment initiation; (ii) accessibility to tenofovir (especially in HBV‐endemic African countries); and (iii) accessibility to treatment for HBV and HCV infections.     

HAART治疗20例艾滋病患者疗效评估

目的评价高效抗逆转录病毒疗法(Highly active antiretroviral therapy,HAART)对我国艾滋病(AIDS)患者的疗效。方法对20例接受免费HAART治疗1~2年(平均18个月)的HIV-1感染的晚期患者进行横断面调查,检测HIV-RNA病毒载量、CD4 T淋巴细胞绝对计数、HIV特异性细胞毒性T淋巴细胞(CTL)应答、常规生化检验和临床指标观察。结果所有观察对象在HAART治疗1~2年(平均18个月)后,临床症状明显改善:大部分患者病毒复制得到有效抑制,80%患者血浆中HIV-RNA载量在检测水平以下,CD4 T淋巴细胞绝对计数平均356.9±155.7/mm3,其中8例(40%)大于400/mm3;CTL应答频率和效应在每个蛋白区都有应答,对Nef蛋白应答较为突出。结论HAART治疗对我国HIV/AIDS患者疗效显著,能提高HIV-1感染者的生活质量,降低机会性感染,并使部分免疫功能重建,具有较高的安全性和耐受性。     

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

OBJECTIVE: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). METHODS: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). RESULTS: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads.No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). CONCLUSION: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.     

The effect of hepatitis C on progression to AIDS before and after highly active antiretroviral therapy

OBJECTIVES: To assess the effect of infection with hepatitis C virus (HCV) on the progression of human immunodeficiency virus (HIV) disease, before and after the introduction of highly active antiretroviral therapy (HAART). METHODS: We used data from a multi-centre prospective study of HIV seroconverters. Survival analyses were performed to compare the progression to AIDS by HCV serostatus in the period before HAART (i.e. June 1991-May 1996) and in the HAART era (i.e. June 1996-June 2001), controlling for duration of HIV infection. RESULTS: Among the 1052 persons enrolled, 595 (56.6%) were co-infected; the median follow-up time was 9.7 years. Adjusting for demographic variables (age at HIV seroconversion and gender), HCV infection had no effect on the progression to AIDS in the pre-HAART era [relative hazard (RH) = 0.84; 95% confidence interval (CI), 0.63-1.11], whereas it increased the risk in the HAART era (RH = 1.77; 95% CI, 1.15-2.73). In the HAART era, the proportion of person-time spent on HAART out of the total time at risk was significantly lower among co-infected persons (30 versus 40% for non-co-infected persons; P-value = 0.001); no significant difference was found for dual-therapy (29 versus 25%, respectively; P-value = 0.205); a significant difference was found for mono-therapy (15 versus 8%, respectively; P-value < 0.001). CONCLUSIONS: HCV infection was not a determinant of HIV disease progression in the pre-HAART era, whereas since the introduction of HAART, co-infected individuals seem to have had a faster disease progression. This may in part be explained by differences in person-time spent on different antiretroviral regimens.     

Immunological response to highly active antiretroviral therapy in children with clinically stable HIV-1 infection

We studied changes in 60 immunological parameters after the administration of highly active antiretroviral therapy (HAART) in 192 clinically stable antiretroviral drug-experienced HIV-1-infected children 4 months-17 years old. The studied immunological parameters included standard lymphocyte subsets and lymphocyte surface markers of maturation and activation. The most significant changes during the 48-week study period were seen for CD8(+), CD8(+)CD62L(+)CD45RA(+), CD8(+)CD38(+)HLA-DR(+), and CD4(+) T cell percentages (P < .0001 for all parameters). These changes suggest that significant decreases in the expression of activation markers and increases in the expression of naive markers in the CD8(+) T cell population may be related to better virologic control in these HIV-1-infected children, who had relatively stable immune function at the initiation of HAART. At week 44 of HAART, the major immunological parameters in these HIV-1-infected children moved from baseline values to about halfway to two-thirds of the way toward the values in healthy, uninfected children.     

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients

Background

We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV‐1.

Methods

A multicentre retrospective study of 23 multidrug‐resistant paediatric patients (five children and 18 adolescents) enrolled in the study from 1 September 2007 to 28 February 2010 was carried out. We performed a longitudinal analysis of immunological, virological and clinical data.

Results

The median age of the patients was 14.2 years [interquartile range (IQR) 12.5–15.8 years]. At baseline, the median HIV‐1 RNA was 29 000 (4.5 log₁₀) HIV‐1 RNA copies/mL (range 4300‐83 000 copies/mL), the median CD4 T‐cell count was 445 cells/μL (range 221–655 cells/μL) and the median CD4 percentage was 19.6% (IQR 13.0‐31.0). Remarkably, 16 of 23 patients (70%) harboured one or more etravirine‐associated resistance mutations. The backbone regimen included at least two fully active drugs in 91% of patients. After etravirine‐based therapy, 20 patients (87%) achieved HIV‐1 RNA<400 copies/mL and 18 of 23 (78%) achieved HIV‐1 RNA<50 copies/mL: three (13%) within the first month, seven (30%) within the first 4 months, and six (26%) between the 5th and 8th months. CD4 T‐cell recovery was observed in 19 patients (83%). The median follow‐up time was 48.4 weeks (IQR 35.7–63.4 weeks); four patients (17%) were exposed to etravirine for >120 weeks. Three mild/short‐term and two moderate skin rashes were observed in the adolescents. Laboratory abnormalities included hypercholesterolaemia (11 of 23 patients), hypertriglyceridaemia (eight of 23 patients), and reduced high‐density lipoprotein cholesterol (10 of 23 patients). Adherence was complete in seven patients (30%). No patients showed complete resistance to etravirine after follow‐up. However, three of 21 patients (14%) who initially showed intermediate resistance interrupted etravirine treatment because of virological failure.

Conclusions

We observed a sustained antiviral response and improved immunological parameters in multidrug‐resistant paediatric patients, most of whom had received etravirine as part of salvage regimens with at least two fully active drugs.