Management of HIV Infection

Nucleoside and Nucleotide Analog Reverse Transcriptase Inhibitors

The nucleoside-analog reverse transcriptase inhibitors (NRTIs) were the first class of ARVs available for the treatment of HIV infection. NRTIs inhibit the HIV reverse transcriptase enzyme, which is responsible for the reverse transcription of viral RNA into DNA. The nucleotide-analog reverse transcriptase inhibitor (NtRTI) tenofovir competitively inhibits viral reverse transcriptase, but because it already possesses a phosphate molecule, it bypasses the initial phosphorylation step that is required for activation of NRTIs.

NRTIs/NtRTIs (N[t]RTIs) are the backbone of ART. In general, two of these agents are used with a protease inhibitor (PI), non-nucleoside analog reverse transcriptase inhibitor (NNRTI), or integrase strand transfer inhibitor (INSTI) as first-line therapy. Fixed-dose combinations of N(t)RTIs are available to simplify dosing. With subsequent regimens, one or more of the N(t)RTIs used in an earlier regimen are often used again to take advantage of a favorable resistance profile.

Unusual but serious toxicities that can occur with the use of N(t)RTIs include lactic acidosis, hepatic steatosis, cardiomyopathy, and rapidly ascending muscular weakness. However, these toxicities are more commonly seen with the use of the older, less frequently used NRTIs (didanosine (ddI), stavudine (d4T), zidovudine (ZDV)), rather than the more commonly used lamivudine (3TC), abacavir (ABC), and tenofovir. Tenofovir appears to cause fewer mitochondrial toxicities, but concerns about its deleterious effects on bone and kidneys limit its use in children; studies in adults suggest that tenofovir alafenamide (TAF), a different oral form of tenofovir, can achieve therapeutic activity with less risk of bone and kidney toxicity than the original oral form, tenofovir disoproxil fumarate (TDF). TAF is US Food and Drug Administration (FDA)-approved for children >25 kg and is available in fixed-dose combinations.

Non-Nucleoside Analog Reverse Transcriptase Inhibitors

The NNRTIs have specific activity against HIV-1 but not HIV-2 or other retroviruses. NNRTIs noncompetitively bind to and disrupt the catalytic site of reverse transcriptase. Because drug resistance to NNRTIs requires a single mutation that does not appear to affect viral fitness, resistance can develop rapidly after initiation of NNRTI in a non-suppressive regimen. Cross-resistance occurs readily between the NNRTIs efavirenz (EFV), nevirapine (NVP), and rilpivirine (RPV); cross-resistance is less common with etravirine (ETR) and doravirine (DOR). In adults, NNRTI-based ART regimens are at least as effective as PI-based regimens in achieving durable viral suppression; however, in children under age 3 years, the NNRTI NVP is inferior to the PI lopinavir (LPV)/ritonavir (RTV). ^, NNRTIs appear to be associated with less long-term toxicity than PIs.

NNRTIs are associated with several types of hepatic toxicity, including asymptomatic elevation in transaminases, clinical hepatitis, and hypersensitivity reactions with hepatitis. However, serious liver dysfunction appears to occur much less commonly in children receiving NVP than in adults.

Hypersensitivity reactions are reported more commonly with NNRTIs (especially NVP) than with other antiretroviral agents. Effects of EFV on the central nervous system (CNS) include confusion, hallucinations, and nightmares. Concern about an increased risk of neural tube defects with EFV led to avoidance of this drug in early pregnancy, but more recent evidence has been reassuring. The FDA continues to recommend against the use of EFV in women who may become pregnant and during early pregnancy, but the DHHS Guidelines and the World Health Organization (WHO) assessment is that EFV is a safe component of ART at any time in pregnancy. ETR has been approved for children 2 years or older; it is typically used in combination with PIs and other ARVs in children for whom other ART regimens have failed. RPV is approved for use in children >12 years and 35 kg. DOR, the newest NNRTI, is not currently approved for use in children, though studies in children 12 years and older are ongoing.

Protease Inhibitors

PIs inhibit the HIV protease enzyme, which is required to cleave viral polyprotein precursors and generate functional viral proteins. PIs have a potent antiretroviral effect, especially when used in combination with N(t)RTIs and/or NNRTIs. Because resistance to PIs requires multiple mutations, some of which reduce viral fitness, PI resistance usually develops slowly. However, compared with NNRTIs, PIs are associated with more long-term toxicity, such as fat redistribution, lipodystrophy syndrome, hyperlipidemia, diabetes mellitus, and hyperglycemia. In children, most PIs require coadministration with a pharmacologic enhancer, usually RTV, because cobicistat (COBI) is not yet approved for use in children. The pharmacologic enhancer inhibits cytochrome P450 (CYP) 3A4 enzymes and increases the concentrations of other PIs. RTV is no longer used in therapeutic doses for anti-HIV activity. The most commonly used PI in children is a coformulation of LPV and RTV known as LPV/r. Other PIs co-administered with a pharmacologic enhancer include atazanavir (ATV) and darunavir (DRV). Fosamprenavir (FPV) and tipranavir (TPV) are less frequently used. All PIs are metabolized by and/or inhibit enzymes in the CYP system; therefore, attention to potential drug–drug interactions is required.

Integrase Inhibitors

The drugs in this class—raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), and bictegravir (BIC)—inhibit the viral integrase, preventing the strand transfer step that is necessary for the integration of the viral genome into the host cell genome. RAL is approved for use from birth in infants who are full term and weigh at least 2 kg. EVG is available only in coformulation with other drugs in convenient single-pill, once-daily regimens but only for children weighing at least 25 kg. Both RAL and EVG have a relatively low barrier to resistance. Once-daily DTG has a high barrier to resistance and the 50 mg adult tablet can be used in children weighing at least 20 kg. The FDA approved a pediatric DTG formulation and dosing for children >4 weeks of age and 3 kg in 2020. The newest INSTI, BIC, has a barrier to resistance similar to that of DTG. It is approved for pediatric patients >25 kg and is available only as a co-formulated tablet.

In May 2018, FDA warned that women taking DTG around conception might have a higher risk of potential neural tube defects in their infants based on a study in Botswana (where there is no fortification of food with folate). Additional results from that ongoing study have been less concerning, leading the US guidelines to recommend DTG as a preferred agent in pregnancy, irrespective of gestational age.

Cabotegravir is an investigational, long-acting antiretroviral administered intramuscularly. Studies in adolescents are ongoing.

Other Classes

Enfuvirtide (T-20), the only FDA-approved fusion inhibitor, which prevents viral entry, requires twice-daily subcutaneous injections. Maraviroc (MVC), an entry inhibitor, binds to and alters the structure of the CCR5 chemokine receptor, preventing it from being used by HIV as a coreceptor. Because some strains of HIV also can infect cells by using the CXC chemokine receptor type 4 (CXCR4) molecule as a coreceptor, MVC is ineffective in individuals who harbor CXCR4-tropic HIV or dual-tropic virus (i.e., able to bind to both CCR5 and CXCR4). These two drugs are seldom used in children.

Ibalizumab is a monoclonal antibody administered via infusion, which acts as a CD4-directed post-attachment inhibitor, blocking HIV from binding to the CCR5 and CXCR co-receptors. It is approved for use in treatment-experienced adults with multidrug-resistant HIV infection. There is no experience or trial in children.

Fostemsavir was approved by the FDA in 2020 for treatment-experienced adults with multidrug-resistant HIV infection. It is a gp120 attachment inhibitor, which interferes with virus attachment to the CD4 receptor. There is no experience or trial in children.