Stephanie Shiau

Incident fractures in HIV-infected individuals: a systematic review and meta-analysis

Objective(s):Some but not all studies indicate that individuals with HIV infection are at an increased risk of fracture. We systematically reviewed the literature to investigate whether incidence of fracture (both overall and fragility) differs between individuals with and without HIV. Design:A systematic review and meta-analysis. Methods:Medline, Scopus and the Cochrane Library databases for all studies ever published up to 28 September 2012 and electronically available conference abstracts from CROI, ASBMR, IAS and AIDS were searched. All studies reporting incidence of all fracture and fragility fracture in HIV-infected adults were included. A random effects model was used to calculate pooled estimates of incidence rate ratios (IRRs) for studies that presented data for HIV-infected and controls. For all studies, incidence rates of fracture and predictors of fracture among HIV-infected individuals were summarized. Results:Thirteen eligible studies were analysed, of which seven included controls. Nine studies reported all incident fractures and 10 presented incident fragility fractures. The pooled IRR was 1.58 [95% confidence interval (CI) 1.25–2.00] for all fracture and 1.35 (95% CI 1.10–1.65) for fragility fracture. Smoking, white race and older age were consistent predictors for fragility fractures. Conclusion:Our results indicate that HIV infection is associated with a modest increase in incident fracture. Future research should focus on clarifying risk factors, designing appropriate interventions and the long-term implications of this increased risk for an ageing HIV-infected population.

Metabolic abnormalities and body composition of HIV-infected children on Lopinavir or Nevirapine-based antiretroviral therapy

Background Few studies have assessed metabolic and body composition alterations in perinatally HIV-infected African children on antiretroviral therapy (ART). We compared metabolic profiles and regional fat of children on ritonavir-boosted lopinavir (lopinavir/ritonavir), lamivudine and stavudine to those switched to nevirapine, lamivudine and stavudine. Methods This study evaluated metabolic and body composition outcomes in 156 HIV-infected children completing a randomised trial that assessed the continued use of lopinavir/ritonavir-based ART or switch to nevirapine-based ART in Johannesburg, South Africa (2005–2010). Fasting total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides total and regional body fat (BF) were measured. A clinical assessment for lipodystrophy (LD) was conducted. Results 156 children (mean age 5.1±0.8 years, mean duration of treatment 4.2±0.7 years, mean time since randomisation 3.4±0.7 years) were enrolled. 85 were randomised to the lopinavir/ritonavir group and 71 to the nevirapine group. The lopinavir/ritonavir group had lower mean HDL (1.3±0.4 vs 1.5±0.4 mmol/l, p<0.001) and higher mean TC (4.4±1.0 vs 4.1±0.8 mmol/l, p=0.097), LDL (2.6±0.9 vs 2.3±0.7 mmol/l, p=0.018) and triglycerides (1.1±0.4 vs 0.8±0.3 mmol/l, p<0.001). The lopinavir/ritonavir group had more total BF by mean skinfold sum (43±11.1 vs 39±10.1 mm, p=0.031) and BF% by bioelectrical impedance analysis (17.0±7.0 vs 14.1±8.0%, p=0.022). Thirteen (8.4%) met criteria for LD. Conclusions Unfavourable alterations in lipid profile and triglycerides, and differences in fat are detectable in young HIV-infected South African children receiving lopinavir/ritonavir-based regimens versus those switched to nevirapine-based regimens. Interventions to mitigate these alterations are warranted to reduce long-term cardiovascular disease risk.

Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis.

Objective:There is growing evidence that fracture risk is increased in individuals with HIV and/or hepatitis C virus (HCV) infection. We systematically reviewed the literature to determine whether prevalence of osteoporosis and incidence of fracture is increased in HIV/HCV-coinfected individuals. Design:A systematic review and meta-analysis. Methods:A search was performed of Medline, Scopus and the Cochrane Library databases, as well as of abstracts from annual retroviral, liver and bone meetings (up to 2013) for studies with bone mineral density (BMD) or bone fracture data for HIV/HCV-coinfected individuals. Osteoporosis odds ratios (ORs) and fracture incidence rate ratios (IRRs) were estimated from studies with data on HIV-monoinfected or HIV/HCV-uninfected comparison groups. Results:Of 15 included studies, nine reported BMD data and six reported fracture data. For HIV/HCV-coinfected, the estimated osteoporosis prevalence was 22% [95% confidence interval (95% CI) 12–31] and the crude OR for osteoporosis compared with HIV-monoinfected was 1.63 (95% CI 1.27–2.11). The pooled IRR of overall fracture risk for HIV/HCV-coinfected individuals was 1.77 (95% CI 1.44–2.18) compared with HIV-monoinfected and 2.95 (95% CI 2.17–4.01) compared with uninfected individuals. In addition to HIV/HCV-coinfection, older age, lower BMI, smoking, alcohol and substance use were significant predictors of osteoporosis and fractures across studies. Conclusion:HIV/HCV coinfection is associated with a greater risk of osteoporosis and fracture than HIV monoinfection; fracture risk is even greater than uninfected controls. These data suggest that HIV/HCV-coinfected individuals should be targeted for fracture prevention through risk factor modification at all ages and DXA screening at age 50.

Initiation of Antiretroviral Therapy Before 6 Months of Age is Associated with Faster Growth Recovery in South African Children Perinatally Infected with Human Immunodeficiency Virus

OBJECTIVE To describe the effects of age at antiretroviral therapy (ART) initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation. STUDY DESIGN This secondary analysis describes anthropometric changes in children infected with HIV in Johannesburg, South Africa who initiated ritonavir-boosted lopinavir-based ART before 24 months of age and were randomized to continue ritonavir-boosted lopinavir or to receive nevirapine after achieving and maintaining virologic suppression. Weight, height, and head circumference were measured at visits over 48 months post-ART initiation. Growth patterns including weight-for-age z-scores (WAZs), height-for-age z-scores, body mass index-for-age z-scores, and head circumference for age z-score were compared between children initiating ART<6 months, 6-12 months, and 12-24 months of age. RESULTS A total of 195 children (mean±SD age 10.7±5.9 months), including 54 (27.7%)<6 months, 69 (35.4%) 6-12 months, and 72 (36.9%) 12-24 months of age at ART initiation, were evaluated. In the first 12 months on treatment, children<6 months of age at ART initiation experienced more rapid improvement in WAZ (1.98 vs 1.44, P=.084) and head circumference for age z-score (1.24 vs 0.45, P=.004) than children who initiated ART between 12-24 months of age. By 48 months on ART, growth outcomes were similar, regardless of age at ART initiation. WAZ approached population norms by 12 months on ART. Although improving, height-for-age z-scores remained on average 1.0 z-score below population norms at 48 months of therapy. CONCLUSIONS Initiation of ART before 6 months of age results in more rapid growth recovery in children infected with HIV. These data provide further evidence for the importance of prompt diagnosis and early initiation of ART for infants infected with HIV.

Risk Factors for Invasive Cryptococcus neoformans Diseases: A Case-Control Study

Background Cryptococcus neoformans is a ubiquitous environmental fungus that can cause life-threatening meningitis and fungemia, often in the presence of acquired immunodeficiency syndrome (AIDS), liver cirrhosis, diabetes mellitus, or other medical conditions. To distinguish risk factors from comorbidities, we performed a hospital-based, density-sampled, matched case-control study. Methods All new-onset cryptococcal meningitis cases and cryptococcemia cases at a university hospital in Taiwan from 2002–2010 were retrospectively identified from the computerized inpatient registry and were included in this study. Controls were selected from those hospitalized patients not experiencing cryptococcal meningitis or cryptococcemia. Controls and cases were matched by admission date, age, and gender. Conditional logistic regression was used to analyze the risk factors. Results A total of 101 patients with cryptococcal meningitis (266 controls) and 47 patients with cryptococcemia (188 controls), of whom 32 patients had both cryptococcal meningitis and cryptococcemia, were included in this study. Multivariate regression analysis showed that AIDS (adjusted odds ratio [aOR] = 181.4; p < 0.001), decompensated liver cirrhosis (aOR = 8.5; p = 0.008), and cell-mediated immunity (CMI)-suppressive regimens without calcineurin inhibitors (CAs) (aOR = 15.9; p < 0.001) were independent risk factors for cryptococcal meningitis. Moreover, AIDS (aOR = 216.3, p < 0.001), decompensated liver cirrhosis (aOR = 23.8; p < 0.001), CMI-suppressive regimens without CAs (aOR = 7.3; p = 0.034), and autoimmune diseases (aOR = 9.3; p = 0.038) were independent risk factors for developing cryptococcemia. On the other hand, diabetes mellitus and other medical conditions were not found to be risk factors for cryptococcal meningitis or cryptococcemia. Conclusions The findings confirm AIDS, decompensated liver cirrhosis, CMI-suppressive regimens without CAs, and autoimmune diseases are risk factors for invasive C. neoformans diseases.

Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa: A Randomized Clinical Trial.

IMPORTANCE Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission. OBJECTIVE To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization. INTERVENTIONS Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148). MAIN OUTCOMES AND MEASURES Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points. RESULTS The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ∞) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to ∞). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group. CONCLUSIONS AND RELEVANCE Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01146873.

Young age at start of antiretroviral therapy and negative HIV antibody results in HIV-infected children when suppressed

Background:Negative results on standard HIV antibody tests have been described among HIV-infected children suppressed on antiretroviral therapy (ART) started early in life. Here, we describe the frequency and predictors of this phenomenon in a well characterized cohort of treated children. Methods:We selected samples from 103 HIV-infected children who started ART 14 months of age or less and from 122 children who started 6 months of age or less followed as part of two sequential clinical trials in Johannesburg, South Africa. Children had attained viral suppression on ART and had received ART for between 3 and 6.4 years (mean 4.3 years) when tested for HIV antibody using a standard ELISA (Genescreen HIV1/2 version 2; Bio-rad). Results:Only children 6 months of age or less when ART was started had negative antibody results when tested after suppression on ART several years later. Negative or low-positive antibody results were observed in 40.0, 37.0 and 27.8% of children starting ART less than 2 months of age, or starting during month 2 or 3, respectively. This dropped to 5.9, 3.5 and 5.3% if ART was started during month 4, 5 and 6, respectively. Higher CD4+ percentage prior to ART initiation and no recorded intermittent viremia also predicted negative antibody results. Conclusion:Testing negative on standard HIV antibody tests occurs fairly commonly among HIV-infected children who started ART 3 months of age or less and are virally suppressed. It would be prudent in clinical practice to avoid HIV antibody tests among virally suppressed, early-treated children to prevent unnecessary confusion.

Bone Health in HIV-Infected Children, Adolescents and Young Adults: A Systematic Review

BACKGROUND Children and adolescents, who either acquire HIV infection perinatally, from contaminated blood products or via sexual transmission early in life, have the greatest cumulative exposure to the negative direct and indirect effects of HIV infection and ART on bone, which may lead to increased lifetime risk for osteoporosis and fracture. We conducted a systematic review to evaluate the literature on bone health in children and adolescents with HIV. METHODS We performed a comprehensive search of the Medline, Scopus, and Cochrane Library databases (up to April 1, 2014) for studies that reported on bone imaging or bone fractures in HIV-infected children, adolescents, or young adults. RESULTS A total of 32 publications met our inclusion criteria. Seventeen studies were cross-sectional and 15 were longitudinal. The majority of studies were conducted in high-income countries, three in middle-income countries and none in low-income countries. Overall, the studies we reviewed indicate that measures of bone mass are reduced, with increased prevalence of low BMD in children and adolescents with HIV. However, the studies are highly variable with respect to comparison sources, measurement methods, adjustment techniques for body size or growth retardation, and highlighted risk factors, including aspects related to medication exposures as well as the effects of HIV infection per se. CONCLUSION HIV infection appears to be associated with decreased bone accrual throughout childhood and adolescence. Initial studies indicate that sub-optimal bone accrual may be persistent and result in reduced peak bone mass, an important determinant of future risk of osteoporosis and fracture. Important areas for future research include evaluation of bone mass, bone quality and fracture risk across the life course among those with early-life infection with HIV, particularly in resource-limited settings where the majority of children with HIV live.

Antiretroviral treatment in HIV-infected infants and young children: novel issues raised by the Mississippi baby

The recent case report of an HIV-infected child in Mississippi with viral control post-antiretroviral therapy (ART) interruption has sparked interest in the possibility of ‘functional cure’ in infants if they initiate ART very soon after birth. The ‘Mississippi baby’ also raises many new questions around the clinical care of HIV-infected infants and young children, including when treatment should be initiated, why treatment should be initiated, what treatment should be initiated, and how to identify infants early enough to treat them adequately. Here, we review research conducted before the report of the ‘Mississippi baby’ highlighting the important new issues that now need to be taken into consideration.

Switching to Efavirenz Versus Remaining on Ritonavir-boosted Lopinavir in Human Immunodeficiency Virus-infected Children Exposed to Nevirapine: Long-term Outcomes of a Randomized Trial

Background We previously demonstrated the noninferiority of switching to efavirenz (EFV) versus remaining on ritonavir-boosted lopinavir (LPV/r) for virologic control in children infected with human immunodeficiency virus (HIV) and exposed to nevirapine (NVP) for prevention of mother-to-child transmission. Here we assess outcomes up to 4 years post-randomization. Methods From 2010-2013, 298 NVP-exposed HIV-infected children ≥3 years of age were randomized to switch to EFV or remain on LPV/r in Johannesburg, South Africa (Clinicaltrials.gov NCT01146873). After trial completion, participants were invited to enroll into observational follow-up. We compared HIV RNA levels, CD4 counts and percentages, lipids, and growth across groups through four years post-randomization. Results HIV RNA levels 51-1000 copies/mL were less frequently observed in the EFV group than the LPV/r group (odds ratio [OR] 0.67, 95% confidence interval [CI]: 0.51-0.88, P = .004), as was HIV RNA >1000 copies/mL (OR 0.52 95% CI: 0.28-0.98, P = .04). The probability of confirmed HIV RNA >1000 copies/mL by 48 months was 0.07 and 0.12 in the EFV and LPV/r groups, respectively (P = .21). Children randomized to EFV had a reduced risk of elevated total cholesterol (OR 0.45 95% CI: 0.27-0.75, P = .002) and a reduced risk of abnormal triglycerides (OR 0.42, 95% CI 0.29-0.62, P < .001). Conclusions Our results indicate that the benefits of switching virologically suppressed NVP-exposed HIV-infected children ≥3 years of age from LPV/r to EFV are sustained long-term. This approach has several advantages, including improved palatability, reduced metabolic toxicity, simplified cotreatment for tuberculosis, and preservation of second line options. Clinical Trials Registration NCT01146873.