Without intervention, rates of mother-to-child HIV transmission range from 15% to 45%.1 With advances in antiretroviral therapy (ART) for HIV-infected women and exposed infants, transmission rates in resource-rich countries have been reduced to 1% to 2%.2 In certain parts of the world, however, rates of HIV infection among pregnant women are high; for example, they are 20% to 40% in southern Africa.3 Thus, despite prevention of mother-to-child HIV transmission interventions, a substantial number of neonates will acquire HIV infection.
A review published in Expert Review of Clinical Pharmacology in 2017 focused on treatment goals associated with ART in this population.4 “These goals have expanded beyond reduction of morbidity and mortality, which is conventionally associated with ART, to include aiming to facilitate HIV remission,” the investigators wrote. In addition, they discussed the distinct rationale and evidence supporting each of these goals.
Rationale for Early ART
Since 2009, treatment guidelines for infants have recommended that ART be initiated immediately. “Treatment of infants as soon as diagnosed, regardless of symptoms or immune status, has long been recommended because of the rapid disease progression that occurs in HIV-infected neonates,” review coauthor Louise Kuhn, PhD, professor of epidemiology at Columbia University’s Mailman School of Public Health in New York City, told Infectious Disease Advisor. This recommendation is primarily based on findings from the Children with HIV Early Antiretroviral Therapy (CHER) study, which found clear benefits for immediate vs deferred initiation of ART.5 “Thus, timely therapy initiation for neonates is essential to prevent morbidity and mortality.”
HIV progression occurs more rapidly in infants compared to adults, and mortality is high, at up to 50% in the first 2 years of life, in the absence of ART.6 “This aggressive disease course makes an intuitive case for the need for rapid intervention with ART,” as noted in the review. In addition, although CD4 count has been effectively used to identify adults at highest risk for progression, and thus in need of ART, this marker is less discriminating in infants, as most have normal CD4 counts.
Identification and Overlapping Goals
There are several challenges, largely related to cost and logistics, in identifying HIV-infected neonates. “Ideally, neonates should be tested at birth, but since there is inevitable turnaround time on the diagnostic tests, neonates and their mothers are generally discharged by this time and will need to be recalled for treatment initiation,” Dr Kuhn explained. “Testing at birth will also miss the infections acquired intrapartum.”
The authors also examined the overlap between prophylaxis and treatment regimens, noting that recommendations for each are nearly identical in some programs. “Using therapy as prophylaxis or prophylaxis as therapy may seem a perfect solution for the problem of when to start…. But this approach raises the new problem of when to stop,” they wrote. Although continuing therapy is the clear choice when infection is confirmed, all other cases present complications.
For example, although prophylaxis should be continued for at least 6 weeks in nonbreastfed infants to rule out intrapartum infections, a longer course may be required for breastfed infants. There is concern, however, that a negative polymerase chain reaction result may not rule out infection in this context of antiviral saturation from prophylaxis.
Antiretroviral Drugs for Neonates
In clinical trials, nevirapine-based treatment was found to be inferior to lopinavir/ritonavir-based therapy for infants and children.7,8 However, nevirapine is the favored drug for initial ART in this population, mainly because of the FDA black box warning against the use of lopinavir/ritonavir during the first 2 weeks of life as a result of reported adverse events such as cardiac abnormalities and death.9
Nevirapine is highly effective for prevention of mother-to-child HIV transmission, has been widely used in neonates, and has a good safety profile. “The downside of nevirapine as [prevention of mother-to-child HIV transmission] is that it almost invariably selects resistance mutations in infected infants who acquire infection despite prophylaxis,” according to the paper. “This raises concern about use of nevirapine-based regimens as treatment for these infants since single-point mutations confer resistance to [non-nucleoside reverse transcriptase inhibitors].”
As a result, it is typically recommended that nevirapine-based treatment be limited to short periods vs the months-long course used for prophylaxis. For the nucleoside reverse transcriptase backbone drugs, zidovudine and lamivudine are the only practical options for neonates. Integrase inhibitors are now favored for HIV treatment in adults and will likely be eventually used in neonates once the appropriate doses and formulations become available.
The Remission Hypothesis
“The added impetus for neonatal treatment is the hypothesis that initiation of ART within hours of birth may facilitate HIV remission in at least some infants,” said Dr Kuhn. “In other words, early therapy may reduce the viral reservoir to such an extent that these infants may be able to control HIV without therapy at some later point.”
This possibility was first highlighted by a case in Mississippi in which an infant who received ART within 30 hours after birth showed undetectable viral levels for 12 months after ART was discontinued.10 Although viral rebound ultimately occurred in this child, as detected 27.6 months after discontinuing ART, there are 3 newer cases of early-treated perinatally infected children who appear to be in remission years after ART was discontinued.11-13
“The many different components of this hypothesis need to be carefully investigated,” Dr Kuhn concluded. She and her coauthors anticipate that during the next 5 years, further developments in this area may lead to interventions that can facilitate remission.
- Mother-to-child transmission of HIV. http://www.who.int/hiv/topics/mtct/en/. Geneva: World Health Organization. Accessed January 12, 2018.
- Siegfried N, van der Merwe L, Brocklehurst P, Sint TT. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev. 2011;(7):CD003510.
- AIDSinfo Online Database. http://aidsinfo.unaids.org/. Geneva: UNAIDS. Accessed January 12, 2018.
- Kuhn L, Shiau S. The pharmacological treatment of acute HIV infections in neonates. Expert Rev Clin Pharmacol. 2017;10:1353-1361.
- Violari A, Cotton MF, Gibb DM, et al; CHER Study Team. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359:2233-2244.
- Sutcliffe CG, Scott S, Mugala N, et al. Survival from 9 months of age among HIV-infected and uninfected Zambian children prior to the availability of antiretroviral therapy.Clinical Infect Dis. 2008;47:837-844.
- Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure.N Engl J Med. 2010;363:1510-1520.
- Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavirboosted lopinavir for HIV-infected children.http:N Engl J Med. 2012;366:2380-2389.
- FDA drug safety communication: serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution [news release]. https://www.fda.gov/Drugs/DrugSafety/ucm246002.htm. Silver Spring, MD: US Food and Drug Administration. Published March 8, 2011. Accessed January 12, 2018.
- Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child.N Engl J Med. 2015;372:786-788.
- Frange P, Faye A, Avettand-Fenoel V, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016;3:e49-54.
- McMahon JH, Chang J, Tennakoon S, et al. Post-treatment control in an adult with perinatally acquired HIV following cessation of antiretroviral therapy. AIDS. 2017;31:1344-1346.
- Violari A, Cotton MF, Kuhn L, et al. Viral and host characteristics of a child with perinatal HIV-1 following a prolonged period after ART cessation in the CHER trial. Presented at: IAS 2017; June 23-26, 2017; Paris, France. Poster TUPDB0106LB.