Of the 1084 HIV-infected infants, 320 (29.5%) were traced to an ART clinic and 764 confirmed infected children were not linked to care. Among children arriving at the Baylor COE, nearly 72% were identified as outpatients, with the remainder inpatients at the time of referral (Table 3). Infants referred from outpatient clinics were diagnosed and enrolled into care at significantly younger ages than infants referred while hospitalized. Overall, the median age at diagnosis was 3.0 months for all patients, 2.0 months for infants referred from outpatient facilities, and 10.2 months for inpatient referrals (Table 3). Outpatient referrals enrolled into ART clinics a median of 1.4 (0.8-2.5) months after diagnosis.
As of December 2008, only about half of the 221 infants who we successfully traced to the Baylor COE had initiated ART, a median of 2.5 months after clinic registration (Table 3). The median duration on ART was 7.4 months. Outpatient referrals began treatment at a younger age compared with inpatient referrals; 8.3 versus 12.7 months. Although we observed a reduction in the delay to ART initiation each year, the proportion of infants starting ART did not increase (Table 4). ART initiators were not significantly younger than noninitiators at diagnosis (5.1 versus 6.9 months, P = 0.062), however, they were younger at enrollment (6.4 versus 8.7 months, P = 0.010).
Sixty-nine HIV-infected infants in care at the COE died or were lost to follow-up (34.2%) by December 2008, with slightly more than one third of these events (34.8%) occurring within the first 3 months (Fig. 2). Antiretroviral therapy increased the likelihood of survival 7-fold (odds ratio, 7.1; 95% confidence interval, 3.68 to 13.70; P < 0.0001). We did not find significant associations between survival and age at diagnosis, time from diagnosis to enrollment, time from enrollment to ART initiation, or advanced WHO stage at presentation. The findings were similar in our sensitivity analysis that censored for “LTFU” and “Transfer Out” (data not shown).
Large numbers of HIV-exposed infants in Lilongwe, Malawi, did not access HIV testing. Among HIV-infected infants, only 29.5% successfully enrolled into facilities providing pediatric HIV services, with mortality rates remaining high despite successful linkage to a care facility. Overall, this suggests PMTCT, EID, and pediatric ART services are not sufficiently integrated, resulting in high default rates, elevated levels of vertical HIV transmission, late infant HIV diagnosis, delayed pediatric ART initiation, and high HIV-infected infant mortality.
Other studies evaluating PMTCT programs have previously reported high attrition rates after initial maternal HIV diagnosis.21-23 Our findings expand on this by highlighting key components of PMTCT care from the infant's perspective, and the high mortality rate of ART-naive HIV-infected infants.24,25 It is important to note that our results likely underestimate infant mortality as we reported only the outcome of patients who enrolled in HIV care facilities.
We only traced 320 HIV-infected infants to a pediatric ART clinic, with a majority found at the Baylor COE, likely due to the gradual uptake of pediatric ART services at health centers during this period. The high attrition can be partly attributed to the absence of one facility providing the full spectrum of maternal and infant HIV services on a daily basis, along with the relative cost of transportation for a mostly impoverished patient population. HIV-infected mothers may receive ANC and maternity at 1 location, yet pediatric services at Baylor COE were on a different campus. Prior studies have demonstrated the cost of transport as a barrier to the retention of HIV-infected patients in care, and it is likely that it similarly impedes infant HIV test result follow-up and subsequent program attrition, particularly when care for the mother and infant are not at the same facility.26,27,8 The lack of consistent patient identification, coupled with the disjointed, multifacility provision of HIV services detrimentally affects retention. Suboptimal referral systems prevented tracing across the facilities and determining drop-out points. For example, verbal referral systems prevented determining if patients failed to collect PCR results or failed to report to clinic after being provided with results.
The identified patients are likely representative of HIV-infected Malawian infants who enter care in Lilongwe, as this study was generated from operational data from all sites implementing service during this period. We acknowledge that some additional infants may have been tested or arrived to care and were not captured due incompatible patient identification numbers and suboptimal referral documentation. Missing infant test records, lost results, and illegible referral forms challenged data collection efforts, overall program monitoring, and patient and healthcare provider navigation of the maternal-child healthcare system. Additionally, our data sources were not robust enough to identify women who may have had HIV seroconversion after their first ANC visit. Our findings may not be representative of areas with lower HIV prevalence such as more rural locations or those with less partner support. The additional activities support by the BAN study and the Baylor community outreach programs likely increased the number of children accessing services.
At the time of our evaluation, EID was only available in 7 sites nationally. Currently, EID has expanded to 14 of 28 districts covering 24% of PMTCT sites. However, given there are only 3 PCR laboratories which still rely on manual techniques, the results of dried blood spot DNA PCR testing are only available after 1 month. With expansion of the program, delays of 4 months have been observed (HIV unit, MOH). We observed inefficiencies in the EID system that affected test result availability, notably the unreliable transportation of test results from the central laboratory to the clinical facility. Point of care infant HIV testing, including rapid DNA PCR assays, bed-side p24 antigen testing, and quantitative reverse transcriptase activity analyses27-30 could dramatically improve EID systems by facilitating the immediate referral of HIV-infected infants, eliminating the need for a separate visit to receive results. Alternatively, the novel use of cell phones to transmit results from central labs to external clinics may improve communication of laboratory results in Malawi.31
Although ART improved infant survival, we noted delays in ART initiation by several months after enrollment. The delay in ART initiation was influenced by the treatment guidelines of the period, which recommended ART initiation for all HIV-infected infants based upon clinical and/or immunologic criteria.19 The WHO and MOH modified their recommendations for ART eligibility to include all HIV-infected infants younger than 12 months in mid-2008 after data demonstrated efficacy of this strategy.20,32 This policy change likely reduced the time to ART initiation that we observed in our cohort. Importantly, our findings of high mortality in patients not initiating ART further support these guidelines.
Delays in ART initiation may also stem from Baylor affiliated HIV clinics pre-ART education requirements. Although the Malawi ART program requires only a single pre-ART education, 1 guardian and an understanding of the implications of ART,19 the Baylor COE requires 2 pre-ART education sessions for caregivers and identification of a second caregiver before initiating infant ART. Although ART adherence education is a critical component of successful pediatric ART treatment,33 it must be balanced with the importance of timely ART initiation.
Although the integration of PMTCT, EID, and pediatric HIV care programs has been a common challenge throughout resource-limited settings,34,17 our findings suggest that the following 5 recommendations may improve PMTCT and pediatric HIV services.
ART initiation in infants should be treated as medically urgent, given the rapid disease progression and high mortality observed within this age group in the absence of ART. Following the WHO guidelines, all HIV-infected infants younger than 12 months of age should begin ART as soon as is feasible, with referral and care systems taking the necessary steps to accommodate this urgency. Combining HIV education and ART adherence training into enrollment visits or during hospitalization may allow ART initiation to occur earlier with well-adjusted and informed guardians.
In lieu of restructuring the delivery of maternal and infant HIV services into 1 facility, we recommend that a universal patient identification system be nationally implemented to allow tracing of mother-infant pairs between PMTCT, EID, and pediatric HIV facilities. Combined with standardized documentation within health passports, a universal identification system would facilitate communication between PMTCT, EID, and pediatric HIV sites and could help confirm arrival of referred patients. Moreover, such a system would benefit tuberculosis control, immunization, and other national health programs. Novel tracing strategies may ensure that mother-infant pairs are receiving the full continuum of HIV services. One example is the Baylor Tingathe outreach program which uses community health workers to track mother-infant pairs starting from the mother's diagnosis at antenatal care until there is either a definitive negative diagnosis for the infant or positive diagnosis and confirmed entry into clinical care with ART initiation. Preliminary results from this program have demonstrated improved utilization of services and a dramatic decrease in loss-to-follow-up of mothers and infants.35,36
We recommend routine provider-initiated infant HIV antibody testing at all immunization visits, starting at the sixth week of life in settings where HIV exposure documentation does not exist or tracking mother-infant pairs is not feasible. Although high proportions of Malawian women deliver outside of formal health care facilities, most infants routinely access immunization clinics.33 Using a strategy of HIV antibody screening of all infants attending the 6-week immunization visit, followed by DNA PCR testing of those with positive HIV antibody test results, has been demonstrated to be high yield, feasible, and acceptable in South Africa.37,38 The expansion of this strategy would be an effective utilization of an existing well functioning health care service to provide early postnatal identification of HIV-exposed infants.
Routine inpatient pediatric HIV testing provides another critical avenue for the identification of HIV-exposed and HIV-infected children who may have been missed in the early postnatal period or who acquired HIV later in infancy via breastfeeding. This strategy has been demonstrated as a highly productive, viable, and acceptable approach in Malawi,16 Zambia,39 and Uganda.40 Furthermore, this is an effective strategy to diagnose previously unidentified HIV-infected mothers and re-identify defaulted HIV-exposed and HIV-infected children.16
Infant HIV DNA PCR test results should be reported in 2 weeks or less if ART initiation hinges on the result to prevent excessive infant mortality. Where DNA PCR testing is not yet available or results are severely delayed, we recommend utilizing a clinical diagnostic algorithm to determine ART eligibility in HIV antibody-positive infants. Development of a valid rapid point of care assay for infant HIV infection remains a high priority for PMTCT and pediatric treatment programs.
Although these recommendations should be interpreted within the context of national PMTCT, EID, and pediatric HIV treatment programs, and in light of current PMTCT regimens,42 they can likely be generalized given the HIV epidemiologic and program similarities between sub-Saharan African countries. The implementation of these recommendations would therefore represent a significant advancement for pediatric HIV prevention and care programs throughout generalized HIV epidemic resource-limited settings.
This study demonstrated a high attrition rate of HIV-exposed and HIV-infected infants between maternal and infant HIV care services, elevated levels of mother-to-child transmission, delayed diagnosis and late ART initiation in HIV-infected infants, and high subsequent mortality rates in HIV-infected ART-naive infants enrolled into pediatric HIV care in urban Malawi. Our findings suggest that establishing integrated PMTCT, EID, and pediatric HIV care services along with implementing strategies to improve patient retention and access to earlier infant testing and ART initiation would greatly improve outcomes for HIV-infected infants in generalized epidemic resource-constrained settings.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
Africa; antiretroviral therapy; early infant diagnosis; HIV testing; pediatric HIV; Malawi; prevention of mother-to-child transmission