Patricia A. Cane

British HIV Association guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals 2011.

1.u2002Levels of evidence 1.1u2002Reference 2.u2002Introduction 3.u2002Auditable targets 4.u2002Table summaries 4.1u2002Initial diagnosis 4.2u2002Assessment of ART‐naïve individuals 4.3u2002ART initiation 4.4u2002Initial assessment following commencement of ART 4.5u2002Routine monitoring on ART 4.6u2002References 5.u2002Newly diagnosed and transferring HIV‐positive individuals 5.1u2002Initial HIV‐1 diagnosis 5.2u2002Tests to determine whether acquisition of HIV infection is recent 5.3u2002Individuals transferring care from a different HIV healthcare setting 5.4u2002Communication with general practitioners and shared care 5.5u2002Recommendations 5.6u2002References 6.u2002Patient history 6.1u2002Initial HIV‐1 diagnosis 6.2u2002Monitoring of ART‐naïve patients 6.3u2002Pre‐ART initiation assessment 6.4u2002Monitoring individuals established on ART 6.5u2002Assessment of adherence 6.6u2002Recommendations 6.7u2002References 7.u2002Examination 7.1u2002Recommendations 8.u2002Identifying the need for psychological support 8.1u2002References 9.u2002Assessment of immune status 9.1u2002CD4 T cell counts 9.2u2002CD4 T cell percentage 9.3u2002References 10.u2002HIV viral load 10.1u2002Initial diagnosis/ART naïve 10.2u2002Post ART initiation 10.3u2002Individuals established on ART 10.4u2002Recommendations 10.5u2002References 11.u2002Technical aspects of viral load testing 11.1u2002References 12.u2002Viral load kinetics during ART and viral load ‘blips’ 12.1u2002References 13.u2002Proviral DNA load 13.1u2002References 14.u2002Resistance testing 14.1u2002Initial HIV‐1 diagnosis 14.2u2002ART‐naïve 14.3u2002Post treatment initiation 14.4u2002ART‐experienced 14.5u2002References 15.u2002Subtype determination 15.1u2002Disease progression 15.2u2002Transmission 15.3u2002Performance of molecular diagnostic assays 15.4u2002Response to therapy 15.5u2002Development of drug resistance 15.6u2002References 16.u2002Other tests to guide use of specific antiretroviral agents 16.1u2002Tropism testing 16.2u2002HLA B*5701 testing 16.3u2002References 17.u2002Therapeutic drug monitoring 17.1u2002Recommendations 17.2u2002References 18.u2002Biochemistry testing 18.1u2002Introduction 18.2u2002Liver function 18.3u2002Renal function 18.4u2002Dyslipidaemia in HIV‐infected individuals 18.5u2002Other biomarkers 18.6u2002Bone disease in HIV‐infected patients 18.7u2002References 19.u2002Haematology 19.1u2002Haematological assessment and monitoring 19.2u2002Recommendations 19.3u2002References 20.u2002Serology 20.1u2002Overview 20.2u2002Hepatitis viruses 20.3u2002Herpes viruses 20.4u2002Measles and rubella 20.5u2002Cytomegalovirus (CMV) 20.6u2002References 21.u2002Other microbiological screening 21.1u2002Tuberculosis screening 21.2u2002Toxoplasma serology 21.3u2002Tropical screening 21.4u2002References 22.u2002Sexual health screening including anal and cervical cytology 22.1u2002Sexual history taking, counselling and sexually transmitted infection (STI) screening 22.2u2002Cervical and anal cytology 22.3u2002Recommendations 22.4u2002References 23.u2002Routine monitoring recommended for specific patient groups 23.1u2002Women 23.2u2002Older age 23.3u2002Injecting drug users 23.4u2002Individuals coinfected with HBV and HCV 23.5u2002Late presenters 23.6u2002References Appendix

Respiratory Syncytial Virus Infection and Disease in Infants and Young Children Observed from Birth in Kilifi District, Kenya

BACKGROUNDnIn developing countries, there are few data that characterize the disease burden attributable to respiratory syncytial virus (RSV) and clearly define which age group to target for vaccine intervention.nnnMETHODSnSix hundred thirty-five children, recruited during the period 2002-2003, were intensively monitored until each experienced 3 epidemics of RSV infection. RSV infection was diagnosed using immunofluorescence of nasal washing specimens collected at each episode of acute respiratory infection. Incidence estimates were adjusted for seasonality of RSV exposure.nnnRESULTSnFor 1187 child-years of observation (CYO), a total of 409 (365 primary and 82 repeat) episodes of RSV infection were identified. Adjusted incidence estimates of lower respiratory tract infection (LRTI), severe LRTI, and hospital admission were 90 cases per 1000 CYO, 43 cases per 1000 CYO, and 10 cases per 1000 CYO, respectively, and corresponding estimates among infants were 104 cases per 1000 CYO, 66 cases per 1000 CYO, and 13 cases per 1000 CYO, respectively. The proportion of cases of all-cause LRTI, and severe LRTI and hospitalizations attributable to RSV in the cohort was 13%, 19%, and 5%, respectively. Fifty-five percent to 65% of RSV-associated LRTI and severe LRTI occurred in children aged >6 months. The risk of RSV disease following primary symptomatic infection remained significant beyond the first year of life, and one-quarter of all reinfections were associated with LRTI.nnnCONCLUSIONSnRSV accounts for a substantial proportion of the total respiratory disease in this rural population; we estimate that 85,000 cases of severe LRTI per year occur in infants in Kenya. The majority of this morbidity occurs during late infancy and early childhood--ages at which the risk of disease following infection remains significant. Disease resulting from reinfection is common. Our results inform the debate on the target age group and effectiveness of a vaccine.

The level and duration of RSV-specific maternal IgG in infants in Kilifi Kenya

Background Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined. Methods A birth cohort (nu200a=u200a635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated. Results The half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (Pu200a=u200a0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb. Conclusion Maternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider.

Incidence and Severity of Respiratory Syncytial Virus Pneumonia in Rural Kenyan Children Identified through Hospital Surveillance

BACKGROUNDnAlthough necessary for developing a rationale for vaccination, the burden of severe respiratory syncytial virus (RSV) disease in children in resource-poor settings remains poorly defined.nnnMETHODSnWe conducted prospective surveillance of severe and very severe pneumonia in children aged <5 years admitted from 2002 through 2007 to Kilifi district hospital in coastal Kenya. Nasal specimens were screened for RSV antigen by immunofluorescence. Incidence rates were estimated for the well-defined population.nnnRESULTSnOf 25,149 hospital admissions, 7359 patients (29%) had severe or very severe pneumonia, of whom 6026 (82%) were enrolled. RSV prevalence was 15% (20% among infants) and 27% during epidemics (32% among infants). The proportion of case patients aged 3 months was 65%, and the proportion aged 6 months was 43%. Average annual hospitalization rates were 293 hospitalizations per 100,000 children aged <5 years (95% confidence interval, 271-371 hospitalizations per 100,000 children aged <5 years) and 1107 hospitalizations per 100,000 infants (95% confidence interval, 1012-1211 hospitalizations per 100,000 infants). Hospital admission rates were double in the region close to the hospital. Few patients with RSV infection had life-threatening clinical features or concurrent serious illnesses, and the associated mortality was 2.2%.nnnCONCLUSIONSnIn this low-income setting, rates of hospital admission with RSV-associated pneumonia are substantial; they are comparable to estimates from the United States but considerably underestimate the burden in the full community. An effective vaccine for children aged >2 months (outside the age group of poor responders) could prevent a large portion of RSV disease. Severity data suggest that the justification for RSV vaccination will be based on the prevention of morbidity, not mortality.

The Natural History of Respiratory Syncytial Virus in a Birth Cohort: The Influence of Age and Previous Infection on Reinfection and Disease

This study aimed to quantify the effect of age, time since last infection, and infection history on the rate of respiratory syncytial virus infection and the effect of age and infection history on the risk of respiratory syncytial virus disease. A birth cohort of 635 children in Kilifi, Kenya, was monitored for respiratory syncytial virus infections from January 31, 2002, to April 22, 2005. Predictors of infection were examined by Cox regression and disease risk by binomial regression. A total of 598 respiratory syncytial virus infections were identified (411 primary, 187 repeat), with 409 determined by antigen assay and 189 by antibody alone (using a “most pragmatic” serologic definition). The incidence decreased by 70% following a primary infection (adjusted hazard ratio = 0.30, 95% confidence interval: 0.21, 0.42; P < 0.001) and by 59% following a secondary infection (hazard ratio = 0.41, 95% confidence interval: 0.22, 0.73; P = 0.003), for a period lasting 6 months. Relative to the age group <6 months, all ages exhibited a higher incidence of infection. A lower risk of severe disease following infection was independently associated with increasing age (P < 0.001) but not reinfection. In conclusion, observed respiratory syncytial virus incidence was lowest in the first 6 months of life, immunity to reinfection was partial and short lived, and disease risk was age related.

Persistence of HIV-1 Transmitted Drug Resistance Mutations

There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.

Development and optimization of an internally controlled dried blood spot assay for surveillance of human immunodeficiency virus type-1 drug resistance

OBJECTIVESnWe present the evaluation of a methodology for the genotypic assessment of human immunodeficiency virus type-1 (HIV-1) drug resistance, optimized for use with dried blood spots (DBS).nnnMETHODSnThe ability to generate HIV-1 protease (PR) and reverse transcriptase (RT) contiguous amplicons and nucleotide sequences from DBS was evaluated. Different collection matrices and extraction methodologies were compared. The relative subtype sensitivity of the amplification strategy was assessed using a comprehensive panel of plasmids representing A-H subtypes. A panel of DBS and plasma specimens was subjected to HIV genotyping. Sequences generated from each sample type were compared.nnnRESULTSnExtensive replicate testing revealed most sensitivity with the use of 903 filter paper and silica/guanidine extraction, which had an estimated 95% inclusivity endpoint of 1542 proviral copies/mL, as compared with 21 573 proviral copies/mL for the FTA system. All HIV-1 group M subtypes analysed-with the exception of subtypes A2, AE, AG, F and H-had a relative sensitivity of </=10 plasmid copies/PCR reaction. The PCR was multiplexed to include amplification of a human housekeeping gene to monitor the integrity of the human genomic DNA. Using a panel of clinical samples, we demonstrated the ability to amplify and sequence from 83% (n = 10) in the PR region and 100% (n = 12) in the RT region, of samples with detectable viral load. All specimens with an HIV-1 RNA load >/=1000 copies/mL were successfully amplified and sequenced. Twelve specimens had pol genotyping from both plasma and DBS samples. Sequence analysis and drug resistance interpretation revealed that 10 (83%) provided concordant drug resistance interpretation.nnnCONCLUSIONSnOur results demonstrate that the technique is appropriate for surveillance of drug resistance in untreated individuals and those with virological failure on therapy.

Factors associated with increased risk of progression to respiratory syncytial virus-associated pneumonia in young Kenyan children*

Objectivesu2002 To identify factors associated with developing severe respiratory syncytial virus (RSV) pneumonia and their commonality with all‐cause lower respiratory tract infection (LRTI), in order to isolate those risk factors specifically associated with RSV‐LRTI and identify targets for control.

Genetic Relatedness of Infecting and Reinfecting Respiratory Syncytial Virus Strains Identified in a Birth Cohort From Rural Kenya

Background.u2003Respiratory syncytial virus (RSV) reinfects individuals repeatedly. The extent to which this is a consequence of RSV antigenic diversity is unclear. Methods.u2003Six-hundred thirty-five children from rural Kenya were closely monitored for RSV infection from birth through 3 consecutive RSV epidemics. RSV infections were identified by immunofluorescence testing of nasal washing samples collected during acute respiratory illnesses, typed into group A and B, and sequenced in the attachment (G) protein. A positive sample separated from a previous positive by ≥14 days was defined as a reinfection a priori. Results.u2003Phylogenetic analysis was undertaken for 325 (80%) of 409 identified infections, including 53 (64%) of 83 reinfections. Heterologous group reinfections were observed in 28 episodes, and homologous group reinfections were observed in 25 episodes; 10 involved homologous genotypes, 5 showed no amino acid changes, and 3 were separated by 21–24 days and were potentially persistent infections. The temporal distribution of genotypes among reinfections did not differ from that of single infections. Conclusions.u2003The vast majority of infection and reinfection pairs differed by group, genotype, or G amino acid sequence (ie, comprised distinct viruses). The extent to which this is a consequence of immune memory of infection history or prevalent diversity remains unclear.

Time trends in drug resistant HIV-1 infections in the United Kingdom up to 2009: multicentre observational study.

Objective To evaluate whether the prevalence of HIV-1 transmitted drug resistance has continued to decline in infections probably acquired within the United Kingdom. Design Multicentre observational study. Setting All UK public laboratories conducting tests for genotypic HIV resistance as a part of routine care. Participants 14u2009584 patients infected with HIV-1 subtype B virus, who were first tested for resistance before receiving antiretroviral therapy between January 2002 and December 2009. Main outcome measure Prevalence of transmitted drug resistance, defined as one or more resistance mutations from the surveillance list recommended by the World Health Organization. Results 1654 (11.3%, 95% confidence interval 10.8% to 11.9%) patients had one or more mutations associated with transmitted HIV-1 drug resistance; prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P=0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P=0.24) and protease inhibitors (1.5% to 2.1%, P=0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively). Conclusions The previously observed decline in the prevalence of transmitted drug resistance in HIV-1 infections probably acquired in the UK seems to have stabilised. The continued high prevalence of thymidine analogue mutations suggests that the source of this resistance may be increasingly from patients who have not undergone antiretroviral therapy and who harbour resistant viruses. Testing of all newly diagnosed HIV-1 positive people should be continued.