Virological failure and HIV drug resistance among adults living with HIV on second-line antiretroviral therapy in the Asia-Pacific.

OBJECTIVES: To assess second-line antiretroviral therapy (ART) virological failure and HIV drug resistance-associated mutations (RAMs), in support of third-line regimen planning in Asia. METHODS: Adults > 18 years of age on second-line ART for ≥ 6 months were eligible. Cross-sectional data on HIV viral load (VL) and genotypic resistance testing were collected or testing was conducted between July 2015 and May 2017 at 12 Asia-Pacific sites. Virological failure (VF) was defined as VL > 1000 copies/mL with a second VL > 1000 copies/mL within 3-6 months. FASTA files were submitted to Stanford University HIV Drug Resistance Database and RAMs were compared against the IAS-USA 2019 mutations list. VF risk factors were analysed using logistic regression. RESULTS: Of 1378 patients, 74% were male and 70% acquired HIV through heterosexual exposure. At second-line switch, median [interquartile range (IQR)] age was 37 (32-42) years and median (IQR) CD4 count was 103 (43.5-229.5) cells/µL; 93% received regimens with boosted protease inhibitors (PIs). Median duration on second line was 3 years. Among 101 patients (7%) with VF, CD4 count > 200 cells/µL at switch [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.17-0.77 vs. CD4 ≤ 50) and HIV exposure through male-male sex (OR = 0.32, 95% CI: 0.17-0.64 vs. heterosexual) or injecting drug use (OR = 0.24, 95% CI: 0.12-0.49) were associated with reduced VF. Of 41 (41%) patients with resistance data, 80% had at least one RAM to nonnucleoside reverse transcriptase inhibitors (NNRTIs), 63% to NRTIs, and 35% to PIs. Of those with PI RAMs, 71% had two or more. CONCLUSIONS: There were low proportions with VF and significant RAMs in our cohort, reflecting the durability of current second-line regimens.

Adverse bone health and abnormal bone turnover among perinatally HIV-infected Asian adolescents with virological suppression.

OBJECTIVES: This study aimed to determine the prevalence of low bone mass and assess its relationship with abnormal bone turnover among HIV-infected Asian adolescents. METHODS: A multicentre, cross-sectional study was conducted at four paediatric HIV centres in Thailand and Indonesia. Perinatally HIV-infected adolescents aged 10-18 years receiving antiretroviral therapy (ART) with virological suppression (HIV RNA < 400 copies/mL) were enrolled. Study assessments included lumbar spine (L2-L4) dual-energy X-ray absorptiometry and measurement of bone turnover markers. Bone mineral density (BMD) and bone mineral apparent density (BMAD) Z-scores were calculated based on Thai normative age- and sex-matched references. Low bone mass was defined as BMD or BMAD Z-scores ≤ -2. RESULTS: Of 396 participants, 57% were female. The median age was 15.0 [interquartile range (IQR) 13.3-16.9] years, and 73% were in Tanner stage 3-5. At enrolment, the median CD4 T-cell count was 734 (IQR 581-907) cells/µL, and 37% were on protease inhibitor (PI)-based regimens. The overall prevalence of lumbar spine BMD and BMAD Z-scores ≤ -2 were 16.4% and 8.3%, respectively. Z-scores were lower with older age, female sex, body mass index (BMI) <5th percentile, boosted PI exposure and CD4 T-cell percentage < 15% before ART initiation. Increased bone turnover markers were inversely associated with BMD and BMAD Z-scores. CONCLUSIONS: Low bone mass was linked to older age, female sex, low BMI, boosted PI exposure, and poor immunological status before ART commencement in our cohort of perinatally HIV-infected Asian adolescents. Dysregulation of bone turnover was associated with bone demineralization. Screening for low bone mass should be implemented to identify individuals who might benefit from interventions to preserve bone health.

Chronic hepatitis C infection and liver disease in HIV-coinfected patients in Asia.

Data on markers of hepatitis C virus (HCV) disease in HIV-HCV-coinfected patients in resource-limited settings are scarce. We assessed HCV RNA, HCV genotype (GT), IL28B GT and liver fibrosis (FibroScan® ) in 480 HIV-infected patients with positive HCV antibody in four HIV treatment centres in South-East Asia. We enrolled 165 (34.4%) patients in Jakarta, 158 (32.9%) in Bangkok, 110 (22.9%) in Hanoi and 47 (9.8%) in Kuala Lumpur. Overall, 426 (88.8%) were male, the median (IQR) age was 38.1 (34.7-42.5) years, 365 (76.0%) reported HCV exposure through injecting drug use, and 453 (94.4%) were on combination antiretroviral therapy. The median (IQR) CD4 count was 446 (325-614) cells/mm3 and 208 (94.1%) of 221 patients tested had HIV-1 RNA <400 copies/mL. A total of 412 (85.8%) had detectable HCV RNA, at a median (IQR) of 6.2 (5.4-6.6) log10 IU/mL. Among 380 patients with HCV GT, 223 (58.7%) had GT1, 97 (25.5%) had GT3, 43 (11.3%) had GT6, eight (2.1%) had GT4, two (0.5%) had GT2, and seven (1.8%) had indeterminate GT. Of 222 patients with IL28B testing, 189 (85.1%) had rs12979860 CC genotype, and 199 (89.6%) had rs8099917 TT genotype. Of 380 patients with FibroScan® , 143 (37.6%) had no/mild liver fibrosis (F0-F1), 83 (21.8%) had moderate fibrosis (F2), 74 (19.5%) had severe fibrosis (F3), and 79 (20.8%) had cirrhosis (F4). One patient (0.3%) had FibroScan® failure. In conclusion, a high proportion of HIV-HCV-coinfected patients had chronic HCV infection. HCV GT1 was predominant, and 62% of patients had liver disease warranting prompt treatment (≥F2).

Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virological failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study.

BACKGROUND: Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen. METHODS: We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463. FINDINGS: We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal. INTERPRETATION: The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy. FUNDING: University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research.

Prognostic significance of the interval between the initiation of antiretroviral therapy and the initiation of anti-tuberculosis treatment in HIV/tuberculosis-coinfected patients: results from the TREAT Asia HIV Observational Database.

OBJECTIVES: We evaluated the effect of the time interval between the initiation of antiretroviral therapy (ART) and the initiation of tuberculosis (TB) treatment on clinical outcomes in HIV/TB-coinfected patients in an Asian regional cohort. METHODS: Adult HIV/TB-coinfected patients in an observational HIV-infected cohort database who had a known date of ART initiation and a history of TB treatment were eligible for study inclusion. The time interval between the initiation of ART and the initiation of TB treatment was categorized as follows: TB diagnosed while on ART, ART initiated ≤ 90 days after initiation of TB treatment ('early ART'), ART initiated > 90 days after initiation of TB treatment ('delayed ART'), and ART not started. Outcomes were assessed using survival analyses. RESULTS: A total of 768 HIV/TB-coinfected patients were included in this study. The median CD4 T-cell count at TB diagnosis was 100 [interquartile range (IQR) 40-208] cells/µL. Treatment outcomes were not significantly different between the groups with early ART and delayed ART initiation. Kaplan-Meier analysis indicated that mortality was highest for those diagnosed with TB while on ART (3.77 deaths per 100 person-years), and the prognoses of other groups were not different (in deaths per 100 person-years: 2.12 for early ART, 1.46 for delayed ART, and 2.94 for ART not started). In a multivariate model, the interval between ART initiation and TB therapy initiation did not significantly impact all-cause mortality. CONCLUSIONS: A negative impact of delayed ART in patients coinfected with TB was not observed in this observational cohort of moderately to severely immunosuppressed patients. The broader impact of earlier ART initiation in actual clinical practice should be monitored more closely.

Atherosclerotic cardiovascular disease screening and management protocols among adult HIV clinics in Asia.

OBJECTIVES: Integration of HIV and non-communicable disease services improves the quality and efficiency of care in low- and middle-income countries (LMICs). We aimed to describe current practices for the screening and management of atherosclerotic cardiovascular disease (ASCVD) among adult HIV clinics in Asia. METHODS: Sixteen LMIC sites included in the International Epidemiology Databases to Evaluate AIDS - Asia-Pacific network were surveyed. RESULTS: Sites were mostly (81%) based in urban public referral hospitals. Half had protocols to assess tobacco and alcohol use. Protocols for assessing physical inactivity and obesity were in place at 31% and 38% of sites, respectively. Most sites provided educational material on ASCVD risk factors (between 56% and 75% depending on risk factors). A total of 94% reported performing routine screening for hypertension, 100% for hyperlipidaemia and 88% for diabetes. Routine ASCVD risk assessment was reported by 94% of sites. Protocols for the management of hypertension, hyperlipidaemia, diabetes, high ASCVD risk and chronic ischaemic stroke were in place at 50%, 69%, 56%, 19% and 38% of sites, respectively. Blood pressure monitoring was free for patients at 69% of sites; however, most required patients to pay some or all the costs for other ASCVD-related procedures. Medications available in the clinic or within the same facility included angiotensin-converting enzyme inhibitors (81%), statins (94%) and sulphonylureas (94%). CONCLUSION: The consistent availability of clinical screening, diagnostic testing and procedures and the availability of ASCVD medications in the Asian LMIC clinics surveyed are strengths that should be leveraged to improve the implementation of cardiovascular care protocols.

Cervical cytological abnormalities and HPV infection in perinatally HIV-infected adolescents.

BACKGROUND: Behaviourally HIV-infected adolescent females are at higher risk for abnormal cervical cytology and HPV infection compared to those who are uninfected, but data on perinatally HIV-infected adolescent females are lacking. METHODS: Cervical cytology, HPV infection and E6/E7 mRNA were assessed in sexually active 12-24-year-old adolescent females: perinatally HIV-infected (group 1, n = 40), behaviourally HIV-infected (group 2, n = 10), and HIV-uninfected (group 3, n = 10). RESULTS: Median age was lower in group 1 (18 years) than in groups 2 (24 years) and 3 (20.5 years) (P < 0.001), and median time since sexual debut was shorter: 2 vs 5 vs 4 years (P < 0.001). More trial participants in group 1 than group 2 were on antiretrovirals (90% vs 70%; P <0.001). Abnormal cervical cytology (atypical squamous cells of undetermined significance and higher) was observed in 30% (group 1), 40% (group 2) and 30% (group 3) (P = 0.92), whereas high-risk HPV infection was observed in 45%, 45% and 40%, respectively (P = 1.00). Positive E6/E7 mRNA was found in 28% of group 1, but not in other groups. High-risk HPV infection predicted abnormal cytology in all groups [OR 6.77, 95% confidence interval (CI) 1.99-23.0; P = 0.001). Additionally, plasma HIV RNA ≥50 copies/mL (OR 13.3, 95% CI 1.16-153.06; P = 0.04) predicted abnormal cytology in HIV-infected adolescent females. CONCLUSIONS: Despite the younger age and shorter time since sexual debut, cervical cytological abnormalities and HPV infection were as common in perinatally HIV-infected as in behaviourally infected and uninfected adolescents. HPV vaccination, pre-cancer screening and antiretroviral treatment in HIV-infected female adolescents should be implemented to minimise the risk of cervical cancer.

Program overview: the reality check sessions at the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections.

The 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections provided a unique forum to assess opinions regarding current infection control controversies. The "Reality Check" sessions were a special portion of the conference where attendees expressed their opinions on these issues and heard varying viewpoints from noted experts. Using an Audience Response System (ARS), individual audience members cast their votes during seven different sessions. Although systems such as the ARS have been used during other conferences, there are no published accounts to date describing audience viewpoints on infection control topics. An overview of the "Reality Check" sessions follows.

Reality check: should we try to detect and isolate vancomycin-resistant enterococci patients?

Antimicrobial resistance, including vancomycin resistance in enterococci (VRE), is a growing problem in healthcare facilities. This "Reality Check" session focused on the question of whether we should try to detect and isolate patients colonized or infected with VRE.

Reality check: should we use vancomycin for the prophylaxis of intravascular catheter-associated infections?

The use of intravascular catheters is associated with increased risk of bloodstream infections, principally caused by coagulase-negative staphylococci. This "Reality Check" session, held at the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections, focused on the question of whether, and in what manner, vancomycin should be used for the prophylaxis of these infections

Should we routinely use mupirocin to prevent staphylococcal infections?

Routine use of mupirocin to prevent staphylococcal infections is controversial. We assessed attitudes and practices of healthcare professionals attending the Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections regarding mupirocin prophylaxis. Eighty percent of participants did not use mupirocin routinely. At the end of the session, 58% indicated they would consider increased use of mupirocin.

Reality check: how should we control antimicrobial use? Current practices and controversies.

The infectious diseases community shares a wide consensus about the need for control of antimicrobial use. However, current practices toward this goal remain controversial. This "Reality Check" session assessed attendees of the 4th Decennial Conference regarding their knowledge and practices about control of antimicrobial use in hospitals.

Management of occupational exposures to hepatitis C virus: current practice and controversies.

Unlike hepatitis B virus and human immunodeficiency virus, there currently are no immunization or chemoprophylactic interventions available to prevent infection after an occupational exposure to hepatitis C virus (HCV). A "Reality Check" session was held at the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections to gather information on current practices related to management of occupational exposures to HCV, generate discussion on controversial issues, and identify areas for future research. Infection control professionals in attendance were knowledgeable in most issues addressed regarding the management of occupational exposures to HCV. Areas of controversy included the use of antiviral therapy early in the course of HCV infection and the appropriate administrative management of an HCV-infected healthcare worker.

Infection control dogma: top 10 suspects.

As infection control evolved into an art and science through the years, many infection control practices have become infection control dogmas (principles, beliefs, ideas, or opinions). In this "Reality Check" session of the 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections, we assessed participants' perceptions of prevalent infection control dogmas. The majority of participants agreed with all dogmas having evidence of efficacy, except for the dogma on the frequency of changing mechanical-ventilator tubing. In contrast, the majority of participants disagreed with dogmas not having evidence of efficacy, except for the dogma on perineal care, umbilical cord care, and reminder signs for isolation precaution. As for controversial dogmas, many of the responses were almost evenly distributed between "agree" and "disagree." Infection control professionals were knowledgeable about evidence-based infection control practices. However, many of the respondents still believe in some of the non-evidence-based dogmas.

Evaluation of a successful vancomycin-resistant Enterococcus prevention intervention in a community of health care facilities.

BACKGROUND: In April 1997, vancomycin-resistant enterococci (VRE) emerged in several health care facilities in the Siouxland region and a VRE Task Force was formed. From 1997 through 1999, an evaluation of VRE prevalence at 30 facilities was performed. METHODS: In 1999, we conducted a survey and focus groups of health care workers to address initial reactions to VRE, feasibility of the Task Force recommendations, and lessons learned. RESULTS: Personnel at 29 (97%) facilities surveyed completed the questionnaire, and 15 health care workers from 11 facilities participated in 5 focus groups. The outcomes of expanded education and improved awareness of VRE for patients and health care workers were ranked the No. 1 priority overall and by long-term care facility personnel. Respondents agreed that Task Force recommendation adherence had significantly improved infection control (83%) and that the Task Force was an appropriate mechanism to coordinate infection control efforts (90%). Focus groups commented that it was most difficult to educate family members about VRE; they expressed concern about variation between VRE policies, especially between acute care and long-term care facilities, and about the quality of life of isolated patients. CONCLUSIONS: Our data illustrate that this intervention has been far-reaching and include the development of a health care infrastructure that may be used as a model to address additional health care issues (eg, emerging pathogens or biological threats).

The calgary youth clinic.

This is a report of the findings gathered from the study of youthful patients presenting at a clinic set up in response to the need felt after a rock festival was held in Calgary. The clinic was staffed by volunteers, and the response was so good that some volunteers had to be turned away. One night per week was found to be sufficient time to meet the demand. Findings were assessed according to age and place of residence.

Prevalence of nosocomial infections in neonatal intensive care unit patients: Results from the first national point-prevalence survey.

OBJECTIVES: Patients admitted to neonatal intensive care units (NICUs) are at high risk of nosocomial infection. We conducted a national multicenter assessment of nosocomial infections in NICUs to determine the prevalence of infections, describe associated risk factors, and help focus prevention efforts. STUDY DESIGN: We conducted a point prevalence survey of nosocomial infections in 29 Pediatric Prevention Network NICUs. Patients present on the survey date were included. Data were collected on underlying diagnoses, therapeutic interventions/treatments, infections, and outcomes. RESULTS: Of the 827 patients surveyed, 94 (11.4%) had 116 NICU-acquired infections: bloodstream (52.6%), lower respiratory tract (12.9%), ear-nose-throat (8.6%), or urinary tract infections (8.6%). Infants with infections were of significantly lower birth weight (median 1006 g [range 441 to 4460 g] vs 1589 g [range 326 to 5480 g]; P <.001) and had longer median durations of stay than those without infections (88 days [range 8 to 279 days] vs 32 days [range 1 to 483 days]; P <.001). Most common pathogens were coagulase-negative staphylococci and enterococci. Patients with central intravascular catheters (relative risk = 3.81, CI 2.32-6.25; P <.001) or receiving total parenteral nutrition (relative risk = 5.72, CI 3.45-9.49; P <.001) were at greater risk of bloodstream infection. CONCLUSIONS: This study documents the high prevalence of nosocomial infections in patients in NICUs and the urgent need for more effective prevention interventions.

Control of vancomycin-resistant enterococcus in health care facilities in a region.

BACKGROUND: In late 1996, vancomycin-resistant enterococci were first detected in the Siouxland region of Iowa, Nebraska, and South Dakota. A task force was created, and in 1997 the assistance of the Centers for Disease Control and Prevention was sought in assessing the prevalence of vancomycin-resistant enterococci in the region's facilities and implementing recommendations for screening, infection control, and education at all 32 health care facilities in the region. METHODS: The infection-control intervention was evaluated in October 1998 and October 1999. We performed point-prevalence surveys, conducted a case-control study of gastrointestinal colonization with vancomycin-resistant enterococci, and compared infection-control practices and screening policies for vancomycin-resistant enterococci at the acute care and long-term care facilities in the Siouxland region. RESULTS: Perianal-swab samples were obtained from 1954 of 2196 eligible patients (89 percent) in 1998 and 1820 of 2049 eligible patients (89 percent) in 1999. The overall prevalence of vancomycin-resistant enterococci at 30 facilities that participated in all three years of the study decreased from 2.2 percent in 1997 to 1.4 percent in 1998 and to 0.5 percent in 1999 (P<0.001 by chi-square test for trend). The number of facilities that had had at least one patient with vancomycin-resistant enterococci declined from 15 in 1997 to 10 in 1998 to only 5 in 1999. At both acute care and long-term care facilities, the risk factors for colonization with vancomycin-resistant enterococci were prior hospitalization and treatment with antimicrobial agents. Most of the long-term care facilities screened for vancomycin-resistant enterococci (26 of 28 in 1998 [93 percent] and 23 of 25 in 1999 [92 percent]) and had infection-control policies to prevent the transmission of vancomycin-resistant enterococci (22 of 25 [88 percent] in 1999). All four acute care facilities had screening and infection-control policies for vancomycin-resistant enterococci in 1998 and 1999. CONCLUSIONS: An active infection-control intervention, which includes the obtaining of surveillance cultures and the isolation of infected patients, can reduce or eliminate the transmission of vancomycin-resistant enterococci in the health care facilities of a region.