Abstract
Sickle cell disease (SCD) is a genetic disorder resulting from a mutation in the hemoglobin (Hb) gene. Sickle cell disease results in chronic anemia and a variety of acute and chronic complications that can lead to early mortality. A child with both SCD and HIV presents a management challenge, particularly in a resource-limited setting. In this case report, we describe the case of an 18-month-old Kenyan girl with SCD and HIV who developed a severe hypersensitivity reaction to first-line antiretroviral therapy (ART). Selecting an appropriate drug substitute for a child with SCD and HIV presents a management dilemma when the available options have problematic side effect profiles or are inaccessible or inappropriate according to national guidelines. The challenges in choosing an appropriate ART regimen for a child with SCD and HIV highlight the lack of data and scarcity of treatment options for pediatric patients.
Introduction
Both HIV and sickle cell disease (SCD) are conditions that occur predominantly in sub-Saharan Africa (SSA), affecting mainly people of African descent. The World Health Organization (WHO) estimates that 23.5 million of the world’s 34 million people living with HIV/AIDS live in SSA, and 90% of the world’s 3.4 million HIV-infected children live in SSA. Seventy-five percent of children affected by SCD also live in SSA. 1,2 Both SCD and HIV cause significant pediatric mortality. Sickle cell disease causes 5% of the deaths in children less than 5 years old in African countries, including more than 9% of deaths in children less than 5 years in West Africa and up to 16% in individual West African countries. More than 50% of HIV-infected children die within the first 2 years of life without antiretroviral therapy (ART). 1,3
Given the high burden of both HIV and SCD in this region, there is a high probability of comorbidity within the same population although SCD seems to reduce the risk of HIV infection. 4 These conditions have been extensively studied individually; however, there is little information describing patients with both HIV and SCD or the appropriate management of this comorbidity, particularly for children. Patients with comorbid HIV and SCD may be even more susceptible to opportunistic infections, given how both conditions increase susceptibility to infections with encapsulated organisms. Medication management may become a particular challenge, with overlapping side effect profiles between certain antiretroviral (ARV) medications and both the medications and complications for SCD. 5,6
In this case report, we highlight the challenges in managing pediatric patients with SCD and HIV in a resource-limited setting, drawing attention to special medical management considerations and the existing data on this comorbidity.
Case Presentation
An 18-month-old African girl with SCD and perinatal HIV infection was enrolled in HIV care at a rural clinic in Kenya. Both conditions were diagnosed following admission at the nearby health facility where she was managed for pneumonia and anemia. She was initiated on first-line ART based on the Kenyan National guidelines, 7 starting a regimen that included abacavir (ABC), lamivudine (3TC), and nevirapine (NVP). She was also given daily cotrimoxazole prophylaxis. Two weeks later, she developed features of a severe hypersensitivity reaction; these included generalized rash, diarrhea, vomiting, and abdominal pain. Her ART was subsequently discontinued, and she remained on cotrimoxazole only. The girl’s symptoms promptly resolved, and within 3 weeks she was asymptomatic. Designing a new regimen for this child proved challenging as all the available ART options have adverse potential side effects for children and particularly for a child with this comorbidity.
The national guidelines for ART in Kenya indicate that in the case of a child with a severe hypersensitivity reaction, the drugs most likely to cause the reaction would be ABC, followed by NVP. 7 The guidelines specify that, in a severe reaction, the drugs must be stopped and not rechallenged because of the risk of fatality. Alternative drugs should be used once the reaction is controlled. For the case described, it was not possible to identify whether the ABC or NVP was responsible for the hypersensitivity reaction. Therefore, drug substitutions should be made for both the nucleoside reverse transcriptase inhibitor (NRTI; in this case, ABC) and the nonnucleoside reverse transcriptase inhibitor (NNRTI; in this case, NVP).
The NRTI options available included zidovudine (ZDV), stavudine (d4T), and tenofovir (TDF). Each of these potential options had significant drawbacks for the case described. The side effects of ZDV include bone marrow suppression, 7 which would compound the problem of anemia for a patient with SCD. Zidovudine has also been described to induce reversible pure red cell aplasia 5 and may potentially predispose an aplastic crisis. Furthermore, the national guidelines indicate ZDV should only be used in patients with baseline Hb greater than 9 g/dL, 7 which is unlikely in a patient with SCD for whom chronic anemia is a norm. Although d4T was available, neither the WHO nor the Kenya National AIDS and Sexually Transmitted Infection Control Programme (NASCOP) recommend the use of d4T due to its long-term, cumulative, irreversible side effects. 7,8 Although the US Food and Drug Administration recently approved the use of TDF in children aged 2 to 18 years, 9 NASCOP in Kenya has not yet approved its use, nor are formulations for the pediatric population available locally.
The choice of a replacement for NVP, the NNRTI, was also a challenge. The available NNRTI, efavirenz (EFV), has cross-reactivity in side effects with NVP. 10 Moreover, EFV is contraindicated in children less than 3 years or 10 kg. 7 Therefore, the NNRTI class was to be replaced with a protease inhibitor (PI), a coformulation of lopinavir/ritonavir (LPV/r; Table 1).
Investigations Done in the Period of Follow-Up—Year 2012.
Abbreviations: ELISA, enzyme-linked immunosorbent assay; MCV, mean corpuscular volume.
After multidisciplinary consultations involving pediatric, hematology, and pharmacy departments, a regimen comprising ZDV, 3TC, and LPV/r was chosen. Cotrimoxazole was also continued. Given the possibility of worsening anemia or an aplastic crisis with the patient’s underlying SCD, initiating this regimen was to be done with close monitoring of her Hb level. Her caregiver was counseled about the unique situation and about signs and symptoms of concern. Two weeks had elapsed between the patient’s hypersensitivity reaction and the point at which the HIV care team was ready to reinitiate ART. At this time, the patient was asymptomatic and clinically stable and had not had a crisis in the past month.
On the day prior to initiation, the patient was admitted at the nearby district hospital. She had been unwell for 2 days, presenting with cough and fever. Examination revealed a sick-looking patient who was pale, febrile, and tachypneic; her other examination findings were normal. A blood smear for malaria was negative. She was severely anemic with Hb of 6 g/dL. The patient was admitted to the district hospital, where she was diagnosed with pneumonia and started on intravenous penicillin and gentamycin. Unfortunately, she died 7 hours after arrival at the hospital. Cause of death was recorded as pneumonia in a patient with HIV and SCD.
Discussion
This case highlights a special group of pediatric patients for whom management is not covered within published protocols or guidelines and for whom we need more multidisciplinary input and careful attention. Patients with comorbid conditions, such as SCD and HIV, present a particular challenge in resource-limited settings where treatment options are restricted, and clinicians may not have training that extends to more complicated cases. The published literature on patients with comorbid SCD and HIV is scarce.
Separately, both SCD and HIV have been extensively studied, and they are both associated with high rates of morbidity and mortality in children, especially in settings where care is delayed. 1,3,11,12 Although 75% of the burden of SCD is found among children in SSA, the morbidity and mortality often go unacknowledged. In 1994, a prospective 10-year study in which more than 3764 patients were enrolled from birth to 66 years of age at 23 clinical centers across the continental United States was conducted. The study identified risk factors for early death in patients with SCD. 11 The risk factors included more symptomatic disease, elevated white blood cell count >15 000 cells/µL, and low Hb <7.1 g/dL. The patterns of mortality showed that the peak incidence of death among children with SCD occurred between 1 and 3 years of age and was predominantly caused by pneumococcal sepsis. It was anticipated that universal newborn screening and early administration of prophylactic penicillin would significantly reduce this mortality. This has now been proved in the developed world.
Patients with SCD in resource-limited settings continue to have very high mortality. A hospital-based, prospective cohort study conducted in Dar es Salaam, Tanzania, over the period of 2004 to 2009 found a high mortality rate among patients with SCD of 1.9 per 100 person-years of observation, and the mortality rate was highest in children under 5 years (7.3 [4.8-11]), adjusting for dates of birth and study enrollment. 12 The independent risk factors predicting death in patients with SCD were low Hb <5 g/dL and high total bilirubin >102 µmol/L.
Historically, studies have shown that the most common cause of death in children with SCD is bacteremia, with
The limited data describing patients with comorbid HIV and SCD reveal risks related to more complicated hospitalizations and treatment challenges. 18 A 10-year, retrospective study from 1994 to 2003 describing hospital use patterns among US children with comorbid SCD and HIV found that the average length of stay for children was longer in comorbid patients with both SCD and HIV than those with SCD alone (8.0 days versus 4.3 days, respectively). The mean charges were also higher for comorbid patients (US$18 291 versus US$9584). Compared with patients with SCD without HIV, HIV infection conferred a higher risk of hospitalization for bacterial infection and sepsis (odds ratio [OR] 2.75; 95% confidence interval [CI] 1.66-4.6) but lower risk of vasoocclusive crises (OR 0.32; 95% CI 0.22-0.44). In the United States, inpatient case fatality rate for children with comorbid SCD and HIV was not different from that of children with SCD alone, but it was lower than that of children with HIV infection. In 2002, Lowe described a case report of a 50-year-old African woman in the Netherlands who had recurrence of sickle cell bone crises after initiation of ART. 6 The patient experienced 5 bone crises without clear cause within a year of initiating d4T, didanosine (ddI), and nelfinavir (NFV)/EFV, whereas her previous bone crises had been occasional and associated with clear provocative factors. It was suggested that ART played a role in the increased bone crises, either directly or indirectly. A cross-sectional study done in the United States examining comorbidities of SCD and HIV infection found that the frequency of HIV infection was significantly lower in patients with SCD than in those without SCD (1.5% versus 3.3%). 4 In contrast, SCD was associated with a higher risk of hepatitis C and hepatitis B virus infection. This led to the speculation that SCD might make it more difficult to become infected with HIV or alter the progression of HIV infection. The impact of SCD on HIV transmission to children has not been studied, and research is also still needed on the prospective implications for adults.
An estimated 3.4 million children were living with HIV at the end of 2011. However, only 28% (25%-31%) of these children have access to ART, compared with 54% (51%-59%) access for adults. 2 There is a limited availability of pediatric ART formulations especially in palatable liquid and fixed-dose combination tablets. 19 These ARV medications are also significantly more costly than that of adult formulations, resulting in delays in supply chain and slow transition to newer options in developing countries. The cold chain requirement for LPV/r syrup storage is yet another challenge in resource-limited settings. All of these issues with limited pediatric formulations and drug access contributed to the management dilemma in this case. In summary, the child with comorbid SCD and HIV in SSA faces myriad challenges.
Conclusion
Both children with HIV and children with SCD face significant threats to their survival. A child with comorbid HIV and SCD, particularly in the resource-limited settings where both diseases are most prevalent, presents a complex management challenge for clinicians. Maximizing regimen efficacy and minimizing potential side effects are challenging, especially due to the complications brought about by both diseases as well as the limited availability of pediatric regimens. Moreover, there are few data to inform clinicians on the risks and best practices for such patients in resource-limited settings. Research to understand how these comorbid conditions impact children in these settings is much needed.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported in part by the USAID-AMPATH Partnership from the US Agency for International Development as part of President's Emergency Plan for AIDS Relief (PEPFAR). Dr Vreeman was also supported by National Institute for Mental Health (NIMH) 1K23MH087225-01.