Antiretroviral Treatment of HIV Infection

Multiple classes of antiretrovirals are used in ART. Two classes inhibit HIV entry, and the others inhibit one of the 3 HIV enzymes needed to replicate inside human cells; 3 classes inhibit reverse transcriptase by blocking its RNA-dependent and DNA-dependent DNA polymerase activity.

• Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and terminate synthesis of DNA chains.

• Nucleotide reverse transcriptase inhibitors (nRTIs) competitively inhibit the HIV reverse transcriptase enzyme, as do NRTIs, but do not require initial phosphorylation.

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind directly to the reverse transcriptase enzyme.

• Protease inhibitors (PIs) inhibit the viral protease enzyme that is crucial to maturation of immature HIV virions after they bud from host cells.

• Entry inhibitors (EIs), sometimes called fusion inhibitors, interfere with the binding of HIV to CD4+ receptors and chemokine co-receptors; this binding is required for HIV to enter cells. For example, CCR-5 inhibitors block the CCR-5 receptor.

• Post-attachment inhibitors bind to the CD4 receptor and prevent HIV (that also binds to the CD4 receptor) from entering the cell.

• Integrase strand transfer inhibitors prevent HIV DNA from being integrated into human DNA.

• Attachment inhibitors bind directly to the viral envelope glycoprotein 120 (gp120), close to the CD4+ binding site, which prohibits the conformational change necessary for initial interaction between the virus and the surface receptors on CD4 cells, thereby preventing attachment and subsequent entry into host T cells and other immune cells.

• Capsid inhibitors interfere with the protein shell (HIV capsid) that protects HIV's genetic material and enzymes required for replication.

Combinations of 2, 3, or 4 medications from different classes are usually necessary to fully suppress replication of wild-type HIV. The specific drugs are chosen based on the following:

• Anticipated adverse effects

• Simplicity of regimen

• Concomitant conditions (eg, hepatic or renal dysfunction)

• Other drugs being taken (to avoid drug interactions)

To maximize adherence, clinicians should choose an affordable, well-tolerated regimen that uses once/day (preferable) or twice-a-day dosing. Guidelines from expert panels for initiating, selecting, switching, and interrupting therapy and special issues concerning treatment of women and children change regularly and are updated on the U.S. Department of Health and Human Services website, HIVinfo.NIH.gov.

Tablets containing fixed combinations of ≥ 2 medications are now widely used to simplify regimens and improve adherence.

Tablets containing fixed combinations of one medication with cobicistat, which is a pharmacokinetic enhancer devoid of anti-HIV activity to increase the amount of medicine with HIV activity in the blood, can be used.

Adverse effects with combination tablets are the same as those for the individual drugs included.

This regimen consists of 2 antiretrovirals with a long-acting suspension formulation: rilpivirine, an NNRTI (non-nucleoside reverse transcriptase inhibitor), and the integrase inhibitor cabotegravir. The regimen can be administered as an intramuscular injection every 2 months. Patients with HIV infection who wish to consider this injectable regimen must be adults who are on a stable regimen and who are virologically suppressed (HIV-1 viral load rilpivirine or cabotegravir. Patients with activehepatitis B infectionare often excluded, because this regimen does not have treatment spectrum against hepatitis B. Patients often start their treatment with oral cabotegravir and rilpivirine for 4 weeks to assess how well they tolerate the drug. Common adverse effects are injection site pain, low-grade fever, and headaches. Hypersensitivity post-injection reactions are rare. This long-acting injectable regimen is still of limited use in parts of the world with the highest HIV burden.

Interactions between antiretrovirals may increase or decrease efficacy.

For example, efficacy can be increased by combining a subtherapeutic dose of ritonavir (100 mg once/day) with another protease inhibitor (PI) (eg, darunavir, atazanavir). Ritonavir inhibits the hepatic enzyme that metabolizes the other PI. By slowing clearance of the therapeutically dosed PI, ritonavir increases the other medication’s levels, maintains the increased levels longer, decreases the dosing interval, and increases efficacy. Another example is lamivudine (3TC) plus zidovudine (ZDV). Use of either drug as monotherapy quickly results in resistance, but the mutation that produces resistance in response to 3TC increases the susceptibility of HIV to ZDV. Thus, when used together, they are synergistic.

Conversely, combining certain antiretrovirals (eg, ZDV and stavudine [d4T]) may decrease the efficacy of each medication. However, these combinations are not used in clinical practice anymore.

Combining medications often increases the risk that either medication will have an adverse effect. Possible mechanisms include the following:

• Hepatic metabolism of PIs by cytochrome P-450: The result is decreased metabolism (and increased levels) of other medications.

• Additive toxicities: For example, combining first-generation NRTIs, such as stavudine (d4T) and didanosine (ddI), increases the chance of adverse metabolic effects and peripheral neuropathy. Also, using a tenofovir disoproxil fumarate (TDF) in a ritonavir-boosted regimen increases the plasma levels of tenofovir disoproxil and, in susceptible patients with certain comorbidities, causes renal dysfunction.

Many medications may interfere with antiretrovirals. Coformulated bictegravir is contraindicated when co-administering with a tuberculosis treatment containing rifampin or rifabutin. The levels of bictegravir fall too much due to the presence of the inducer effect of rifampin/rifabutin and predispose to the risk of HIV viral failure. Interactions with herbs or supplements may also occur, for example,St. John's wort can enhance metabolism of PIs and NNRTIs and thus decrease plasma PI and NNRTI levels. Thus, interactions should always be checked before any new medication is started (see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions).

Antiretrovirals can have serious adverse effects. Some of these effects, notably anemia, hepatitis, renal insufficiency, pancreatitis, and glucose intolerance, can be detected by blood tests before they cause symptoms. Patients should be screened regularly, both clinically and with appropriate laboratory testing (complete blood count; blood tests for hyperglycemia, hyperlipidemia, hepatic and pancreatic damage, and renal function; urinalysis), especially after new drugs are started or unexplained symptoms develop.

Metabolic effects consist of interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Subcutaneous fat is commonly redistributed from the face and extremities to the trunk, neck, breasts, and abdomen—a cosmetic effect (called lipodystrophy) that can stigmatize and distress patients. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial.

Weight gain, central obesity, hyperlipidemia, and insulin resistance, which together constitute the metabolic syndrome, increase the risk of myocardial infarction, stroke, and dementia.

Antivirals from all classes appear to contribute to these metabolic effects, but PIs are the most clearly involved. Some older ART drugs, such as ritonavir and d4T, commonly have metabolic effects. Others, such as tenofovir disoproxil fumarate, etravirine, atazanavir or darunavir (even when combined with low-dose ritonavir), raltegravir, and maraviroc, appear to have small to minimal effects on lipid levels.

Mechanisms for metabolic effects appear to be multiple; one is mitochondrial toxicity. Risk of metabolic effects (highest with PIs) and mitochondrial toxicity (highest with NRTIs) varies by medication class and within medication classes (eg, among NRTIs, highest with d4T).

Metabolic effects are dose-dependent and often begin in the first 1 to 2 years of treatment. Lactic acidosis is uncommon but can be lethal.

Nonalcoholic fatty liver disease is being increasingly recognized among patients with HIV. Certain early-generation ART medications caused steatosis, and as their use decreased, incidence of steatosis decreased. Nonetheless, even with newer-generation ART drugs, there appears to be a risk of steatosis.

Long-term effects and optimal management of metabolic effects are unclear. Lipid-lowering medications (statins) and insulin-sensitizing medications (glitazones) may help. Patients should be counseled about maintaining a healthy diet and regular physical activity as ways to help promote health. (See also the recommendations of the HIV Medicine Association of the Infectious Diseases Society of America and the Adult AIDS Clinical Trials Group: Guidelines for the Evaluation and Management of Dyslipidemia in HIV-infected Adults Receiving Antiretroviral Therapy.)

Bone complications of ART include asymptomatic osteopenia and osteoporosis, which are common. Uncommonly, osteonecrosis of large joints such as the hip and shoulder causes severe joint pain and dysfunction. Mechanisms of bone complications are poorly understood.

Lipodystrophy (Lipoatrophy) in HIV

Lipodystrophy (Lipoatrophy) in HIV (1)

These images show clinical signs of lipodystrophy and lipoatrophy. The left panel shows the accumulation of fat tissue in the posterior cervical areas known as “buffalo hump” (red arrow). The right panel shows increased abdominal fat. The abdominal fat that people with HIV experience is deep inside the organ cavity (visceral fat). The right panel also shows the loss of fat under the skin in the arms and legs, known as lipoatrophy.

... read more

Image courtesy of Dr. Edward R. Cachay.

Lipodystrophy (Lipoatrophy) in HIV (2)

With use of antiretroviral medications, body fat can be redistributed from the face and extremities (left panel) to the trunk, breasts, and abdomen (center panel) and neck (right panel).

... read more

© Springer Science+Business Media

Lipodystrophy (Lipoatrophy) in HIV (1)

These images show clinical signs of lipodystrophy and lipoatrophy. The left panel shows the accumulation of fat tissue in the posterior cervical areas known as “buffalo hump” (red arrow). The right panel shows increased abdominal fat. The abdominal fat that people with HIV experience is deep inside the organ cavity (visceral fat). The right panel also shows the loss of fat under the skin in the arms and legs, known as lipoatrophy.

... read more

Image courtesy of Dr. Edward R. Cachay.

Lipodystrophy (Lipoatrophy) in HIV (2)

With use of antiretroviral medications, body fat can be redistributed from the face and extremities (left panel) to the trunk, breasts, and abdomen (center panel) and neck (right panel).

... read more

© Springer Science+Business Media

Patients beginning ART sometimes deteriorate clinically, even though HIV levels in their blood are suppressed and their CD4 count increases, because of an immune reaction to subclinical opportunistic infections or to residual microbial antigens after successful treatment of opportunistic infections (see immune reconstitution inflammatory syndrome for a more detailed discussion).

Interruption of ART is usually safe if all drugs are stopped simultaneously, but levels of slowly metabolized medications (eg, nevirapine) may remain high and thus increase the risk of resistance. Interruption may be necessary if intervening illnesses require treatment or if medication toxicity is intolerable or needs to be evaluated. After interruption to determine which medication is responsible for toxicity, clinicians can safely restart most medications as monotherapy for up to a few days.

NOTE: The most important exception is abacavir; patients who had fever or rash during previous exposure to abacavir may develop severe, potentially fatal hypersensitivity reactions with reexposure. Risk of an adverse reaction to abacavir is 100-fold higher in patients with HLA-B*57:01, which can be detected by genetic testing.