Background We describe a child who was identified shortly after birth as infected with the human immunodeficiency virus type 1 (HIV-1), but whose infection appears to have completely cleared. Asymptomatic HIV-1 infection was diagnosed in the mother during the fourth month of pregnancy. The infant was delivered vaginally at 36 weeks, received no blood products, and was not breast-fed. Methods and Results HIV-1 was detected by culture of the infant's peripheral-blood mononuclear cells at 19 and 51 days of age. Plasma from the infant was also culture-positive for HIV-1 at 51 days of age by DNA polymerase chain reaction (PCR). Nucleotide-sequence analysis of HIV-1 DNA showed extremely close homology of the cultures obtained 32 days apart, and forensic markers of genetic identity for the two cultures were identical. Hence, inadvertent viral contamination or error in the collection of specimens was highly unlikely. At 12 months of age the infant was seronegative for HIV-1, and numerous subsequent cultures and t...

Clearance of HIV Infection in a Perinatally Infected Infant

Background The specificity of nucleic acid amplification tests (NAATs) used for early infant diagnosis (EID) of HIV infection is <100%, leading some HIV-uninfected infants to be incorrectly identified as HIV-infected. The World Health Organization recommends that infants undergo a second NAAT to confirm any positive test result, but implementation is limited. Our objective was to determine the impact and cost-effectiveness of confirmatory HIV testing for EID programmes in South Africa. Method and findings Using the Cost-effectiveness of Preventing AIDS Complications (CEPAC)–Pediatric model, we simulated EID testing at age 6 weeks for HIV-exposed infants without and with confirmatory testing. We assumed a NAAT cost of US$25, NAAT specificity of 99.6%, NAAT sensitivity of 100% for infants infected in pregnancy or at least 4 weeks prior to testing, and a mother-to-child transmission (MTCT) rate at 12 months of 4.9%; we simulated guideline-concordant rates of testing uptake, result return, and antiretroviral therapy (ART) initiation (100%). After diagnosis, infants were linked to and retained in care for 10 years (false-positive) or lifelong (true-positive). All parameters were varied widely in sensitivity analyses. Outcomes included number of infants with false-positive diagnoses linked to ART per 1,000 ART initiations, life expectancy (LE, in years) and per-person lifetime HIV-related healthcare costs. Both without and with confirmatory testing, LE was 26.2 years for HIV-infected infants and 61.4 years for all HIV-exposed infants; clinical outcomes for truly infected infants did not differ by strategy. Without confirmatory testing, 128/1,000 ART initiations were false-positive diagnoses; with confirmatory testing, 1/1,000 ART initiations were false-positive diagnoses. Because confirmatory testing averted costly HIV care and ART in truly HIV-uninfected infants, it was cost-saving: total cost US$1,790/infant tested, compared to US$1,830/infant tested without confirmatory testing. Confirmatory testing remained cost-saving unless NAAT cost exceeded US$400 or the HIV-uninfected status of infants incorrectly identified as infected was ascertained and ART stopped within 3 months of starting. Limitations include uncertainty in the data used in the model, which we examined with sensitivity and uncertainty analyses. We also excluded clinical harms to HIV-uninfected infants incorrectly treated with ART after false-positive diagnosis (e.g., medication toxicities); including these outcomes would further increase the value of confirmatory testing. Conclusions Without confirmatory testing, in settings with MTCT rates similar to that of South Africa, more than 10% of infants who initiate ART may reflect false-positive diagnoses. Confirmatory testing prevents inappropriate HIV diagnosis, is cost-saving, and should be adopted in all EID programmes.

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The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis

Background 
Early infant HIV diagnosis (EID) coverage and uptake remains challenging. Point-of-care (POC) testing may improve access and turn-around-times, but, while several POC technologies are in development there are few data on their implementation in the field.


Methods 
We conducted an implementation study of the Alere q Detect POC system for EID at two public sector health facilities in Cape Town. HIV-exposed neonates undergoing routine EID testing at a large maternity hospital and a primary care clinic received both laboratory-based HIV PCR testing per local protocols and a POC test. We analysed the performance of POC versus laboratory testing, and conducted semi-structured interviews with providers to assess acceptability and implementation issues.


Results 
Overall 478 specimens were taken: 311 tests were performed at the obstetric hospital (median child age, 1 days) and 167 six-week tests in primary care (median child age, 42 days). 9.0% of all tests resulted in an error with no differences by site; most errors resolved with retesting. POC was more sensitive (100%; lower 95% CI, 39.8%) and specific (100%, lower 95% CI, 98%) among older children tested in primary care compared with birth testing in hospital (90.0%, 95% CI, 55.5–99.8% and 100.0%, lower 95% CI, 98.4%, respectively). Negative predictive value was high (>99%) at both sites. In interviews, providers felt the device was simple to use and facilitated decision-making in the management of infants. However, many wanted clarity on the cause of errors on the POC device to help guide repeat testing.


Conclusions 
POC EID testing performs well in field implementation in health care facilities and appears highly acceptable to health care providers.

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Field evaluation of HIV point-of-care testing for early infant diagnosis in Cape Town, South Africa.

Objective 
To describe factors associated with mother-to-child HIV transmission (MTCT) in Kenya and identify opportunities to increase testing/care coverage.


Design 
Cross-sectional analysis of national early infant diagnosis (EID) database.


Methods 
365,841 Kenyan infants were tested for HIV from January 2007-July 2015 and results, demographics, and treatment information were entered into a national database. HIV risk factors were assessed using multivariable logistic regression.


Results 
11.1% of infants tested HIV positive in 2007–2010 and 6.9% in 2014–2015. Greater odds of infection were observed in females (OR: 1.08; 95% CI:1.05–1.11), older children (18–24 months vs. 6 weeks-2 months: 4.26; 95% CI:3.87–4.69), infants whose mothers received no PMTCT intervention (vs. HAART OR: 1.92; 95% CI:1.79–2.06), infants receiving no prophylaxis (vs. nevirapine for 6 weeks OR: 2.76; 95% CI:2.51–3.05), and infants mixed breastfed (vs. exclusive breastfeeding OR: 1.39; 95% CI:1.30–1.49). In 2014–2015, 9.1% of infants had mothers who were not on treatment during pregnancy, 9.8% were not on prophylaxis, and 7.0% were mixed breastfed. Infants exposed to all three risky practices had a seven-fold higher odds of HIV infection compared to those exposed to recommended practices. The highest yield of HIV-positive infants were found through targeted testing of symptomatic infants in pediatric/outpatient departments (>15%); still, most infected infants were identified through PMTCT programs.


Conclusion 
Despite impressive gains in Kenya’s PMTCT program, some HIV-infected infants present late and are not benefitting from PMTCT best practices. Efforts to identify these early and enforce evidence-based practice for PMTCT should be scaled up. Infant testing should be expanded in pediatric/outpatient departments, given high yields in these portals.

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Mother-to-child transmission of HIV in Kenya: A cross-sectional analysis of the national database over nine years

Background In Kenya, access to early infant diagnosis and viral load monitoring services for HIV patients on ART is significantly hampered by sample transportation challenges and long turnaround times. Near patient care testing technologies have the potential to obviate such constraints. The Cepheid GeneXpert was launched in 2010 as a TB assay and in 2014 as a potential point of care HIV viral load assay. Whereas it is widely is used for TB in Kenya, its utility for HIV testing has not been evaluated. Objective To investigate the performance and usability characteristics of the GeneXpert HIV-1 qualitative and quantitative assay. Methods This was a cross sectional study among 911 HIV Exposed infants and 310 HIV positive adults. Existing machines used for routine TB diagnosis were used in this study. The diagnostic accuracy of the qualitative assay was assessed using Roche CAP/CTM while the quantitative assay was assessed using with Abbott m2000 as the reference assays respectively. Statistical analysis was done using Stata/MP Version 14 for Mac. Concordance values and misclassification were calculated at the clinical cutoff of 1000 cp/ml. Results The sensitivity, specificity and accuracy of the GeneXpert HIV-1 qualitative assay were 99.23% (95% CI 97.24-99.90%), 98.91% (95% CI 97.76-99.55%) and 99.00% respectively. For the quantitative assay, they were 92.50% (95% CI 79.61-98.43%), 100.00% and 97.00% respectively. All 30 (100%) users reported that the GeneXpert machine was easy to use, workflow was simple and TB diagnosis was not negatively affected. In our hands, the median turn-around time for an individual qualitative and quantitative test was 90 minutes. A total of 58 (4.34%) errors and 28 (2.10%) invalid outcomes were experienced; 44 (3.29%) tests did not run to completion due to power outages. Conclusion GeneXpert HIV-1 qualitative and quantitative assay is an accurate test for the diagnosis of HIV in infants and for viral load monitoring. At the point of care, the GeneXpert machine's simple work flow, ease of use and short test turnaround time present the potential to improve access to HIV testing and viral load monitoring. To integrate HIV diagnosis into the existing GeneXpert platforms for TB Diagnosis, there is need to scale up the infrastructure and to change the way work is done.

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Performance and usability of Cepheid GeneXpert HIV-1 qualitative and quantitative assay in Kenya.

BACKGROUND In Kenya, the availability of a cheap diagnostic service for HIV-exposed infants has helped scale-up access to treatment, and provided a means by which programs that support Prevention of Mother to Child Transmission of HIV can be evaluated. As expected for any large testing program, discrepant and indeterminate results present a significant challenge. METHODS Dried Blood Spots were collected from health centers countrywide and couriered to four laboratories for tests. Results were dispatched either by email, telephone, GSM SMS printer or courier. Between 2006 and 2009, tests were conducted with the Manual Roche v. 1.5 Assay. In 2010 the labs switched fully to the Cobas® AmpliPrep/ Cobas® TaqMan® HIV-1 Qual automated Roche Test. RESULTS Between 2006 and 2010, the KEMRI CVR EID Lab conducted 64 591 HIV tests in on children <18 months of age. HIV tests (38 834) used the manual assay, while 17 133 tests used the automated assay. Overall, 10.7% (6915) of the samples tested positive, while 86.6% (55 967) tested negative. A total of 1.6% (1041) tested indeterminate and required a re-bleed of the infant. Two hundred positive tests by the manual assay were retrieved randomly and retested using the automated assay. Among them, 192 (96%) remained positive, 5 (2.5%) were negative while 3 (1.5%) failed. A total of 160 negative samples by the manual assay were retrieved and retested with the automated assay. Among them, 154 (96.24%) remained negative, 3 (1.88%) tested positive while 3 (1.88%) failed. A total of 215 samples that gave indeterminate results by the manual assay were retested using the automated system. Among them, 62 (28.8%) gave positive results, 144 (66.97%) negative and 6 (2.8%) samples still gave discrepant results. Three (1.4%) did not amplify successfully. A few infants who were apparently positive appeared to test HIV negative with age. CONCLUSIONS Indeterminate results are a significant challenge for HIV diagnostic services, as seen in the Kenyan EID Program. In our experience, they are more often negative than they are positive. False positive and false negative results can arise from clerical error, contamination and limitations of the technologies available. To forestall the consequences of such outcomes, the sensitivity and specificity of available assays must be further improved. All HIV positive samples should be retested for confirmation, and if confirmed, a new sample must be drawn and tested for DNA at the time the infant receives their initial results or starts antiretroviral therapy. Viral clearance is a phenomenon that requires further studies.

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Discrepant test findings in early infant diagnosis of HIV in a national reference laboratory in Kenya: challenges and opportunities for programs.

Results: A total of 32,671 infant samples were tested between January 2010 and March 2012. 29,571 (91.5%) infants were HIV negative and 2,666 (8.3%) were HIV positive. The odds of being seropositive were higher in females (OR 1.15, p=0.0010) overall, and were also higher than for males in most age categories. The odds of positivity associated with exclusive breastfeeding before 6 months were 0.48 (p = 0.0000), exclusive replacement feeding before 6 months 0.77 (p = 0.0393), mixed feeding before 6 months 1.88 (p= 0.0000), breastfeeding after 6 months 2.14 (p= 0.0000), and not breastfeeding after 6 months 1.66 (p= 0.0000). The odds of seropositivity were 2.54 (p=0.0000) in the absence of maternal prophylaxis and 2.96 (p= 0.0000) without infant prophylaxis. All other prophylactic approaches were associated with lower odds of seropositivity. Babies who received no prophylaxis and breastfed beyond six months, whose mothers received no prophylaxis, faced the highest seropositivity odds (OR 2.11, p = 0.0086).

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Elizabeth Nyambura

Papers

Discrepant test findings in early infant diagnosis of HIV in a national reference laboratory in Kenya: challenges and opportunities for programs.

Factors associated with mother to child transmission of Human Immunodeficiency Virus in Kenya