Drug Treatment of HIV Infection

Multiple classes of antiretrovirals are used in ART (see table Antiretroviral Drugs Antiretroviral Drugs ). 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.

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

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, AIDSinfo.

Tablets containing fixed combinations of ≥ 2 drugs are now widely used to simplify regimens and improve adherence. Common combination tablets include

Tablets containing fixed combinations of one drug 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. These combinations include

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

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 drug’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, interactions between antiretrovirals may decrease the efficacy of each drug. One drug may increase elimination of another drug (eg, by inducing hepatic cytochrome P-450 enzymes responsible for elimination). Another, poorly understood effect of some NRTI combinations (eg, ZDV plus stavudine [d4T]) results in decreased antiretroviral activity without increasing drug elimination. This later combination is rarely used in clinical practice anymore.

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

Many drugs may interfere with antiretrovirals (see Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents: Drug-Drug Interactions); thus, interactions should always be checked before any new drug is started.

In addition to drug interactions, the following influence activity of some antiretroviral drugs and should be avoided:

Antiretrovirals can have serious adverse effects (see table Antiretroviral Drugs Antiretroviral Drugs ). 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, hyperlidemia, 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 that can stigmatize and distress patients called lipodystrophy. Treating the resulting deep facial grooves with injected collagen or polylactic acid can be beneficial.

Central obesity, hyperlipidemia, and insulin resistance, which together constitute the metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia. Causes... read more , 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 or 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 drug class and within drug 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 Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more is being increasingly recognized among patients living with HIV. Certain early-generation ART drugs 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 drugs (statins) and insulin-sensitizing drugs (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.

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. IRIS usually occurs in the first months of treatment but is occasionally delayed. IRIS can complicate virtually any opportunistic infection and even tumors (eg, Kaposi sarcoma) but is usually self-limited or responds to brief regimens of corticosteroids.

IRIS has two forms:

Paradoxical IRIS typically occurs during the first few months of treatment and usually resolves on its own. If it does not, corticosteroids, given for a short time, are often effective. Paradoxical IRIS is more likely to be severe when ART is started soon after treatment of an opportunistic infection is started. Thus, for some opportunistic infections, ART is delayed until treatment of the opportunistic infection has reduced or eliminated the infection.

In patients with unmasked IRIS, the newly identified opportunistic infection is treated with antimicrobial drugs. Occasionally, when the symptoms are severe, corticosteroids are also used. Usually, when unmasked IRIS occurs, ART is continued. An exception is cryptococcal meningitis. Then ART is temporarily interrupted until the infection is controlled.

Determining whether clinical deterioration is caused by treatment failure, IRIS, or both requires assessment of the persistence of active infections with cultures and can be difficult.

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