Antiviral agents

While further study is needed, data are accumulating regarding pharmacokinetic interactions among the various antiretroviral agents, especially those involving the HIV protease inhibitors and NNRTIs, and the need for dosage adjustments as a result of these interactions. While some pharmacokinetic interactions between antiretroviral agents can be used for therapeutic advantage (e.g., use of low-dose ritonavir to boost plasma concentrations of some other HIV protease inhibitors), other interactions can result in suboptimal drug concentrations and reduced therapeutic effects and should be avoided. The pharmacokinetic interaction between ritonavir and other HIV protease inhibitors is now used for therapeutic advantage in various antiretroviral regimens.

The fact that hyperglycemia, new-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and diabetic ketoacidosis have occurred in HIV-infected individuals receiving HIV protease inhibitors should be considered when these drugs are used during pregnancy. Because pregnancy is itself a risk factor for hyperglycemia and it is not known whether use of an HIV protease inhibitor exacerbates this risk, glucose concentrations should be monitored closely in pregnant women receiving these drugs and these women should be advised about the warning signs of hyperglycemia and diabetes (e.g., increased thirst and hunger, unexplained weight loss, increased urination, fatigue, dry or itchy skin).

Since most occupational exposures to HIV do not result in transmission of the virus, the potential toxicity of PEP regimens must be considered carefully and, whenever possible, prophylaxis should be implemented in consultation with clinicians who have expertise in antiretroviral therapy and HIV transmission. Modification of the recommended regimens may be appropriate based on factors such as whether the source patient is known or suspected of being infected with drug-resistant strains of HIV; the local availability of antiretroviral agents; and the medical condition, concurrent drug therapy, and drug toxicity in the exposed health-care worker. A decision to offer such prophylaxis should be individualized taking into account the likelihood of HIV transmission occurring, the potential benefits and risks of such prophylaxis, and the interval between the exposure and initiation of therapy.

Safety and efficacy of zidovudine in pregnant women have been established and the drug appears to be well tolerated during pregnancy. In addition to zidovudine, data are available from clinical trials in pregnant women for didanosine, lamivudine, and stavudine; data regarding use of abacavir or tenofovir disoproxil fumarate (a nucleotide reverse transcriptase inhibitor) are not available to date. Follow-up of uninfected children born to women enrolled in study PACTG 076 (from birth to a median age of 4.2 years) has not revealed any difference in growth, neurodevelopment, or immunologic status among infants born to women who received zidovudine for prevention of maternal-fetal transmission of HIV compared with those born to women who received placebo.

Recommendations for use of antiretroviral agents for the treatment of HIV infection in pregnant HIV-infected women generally are the same as those for nonpregnant HIV-infected adults, and women should receive optimal antiretroviral therapy regardless of pregnancy status. Although zidovudine is the only antiretroviral agent currently labeled for use in pregnant women, most clinicians do not consider pregnancy a contraindication for multiple-drug antiretroviral therapy when such therapy is indicated, especially during the second or third trimester.

The same general principles of antiretroviral therapy that apply to HIV-infected adults also apply to HIV-infected pediatric patients; however, the treatment of HIV-infected neonates, children, and adolescents involves unique pharmacologic, virologic, and immunologic considerations. In 1993, the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children, a panel convened by the National Pediatric and Family HIV Resource Center (NPHRC), the Health Resources and Services Administration (HRSA), and the National Institutes of Health (NIH) first issued guidelines for the use of antiretroviral agents in the treatment of HIV-infected children. At that time, monotherapy with zidovudine or didanosine was considered an appropriate regimen for initial therapy in HIV-infected pediatric patients.

A review of the agents that the patient already has received is essential. Resistance testing (performed while the patient is still receiving the old regimen) is useful in maximizing the number of active drugs in the new regimen. Viral resistance is an important, but not the only, reason for treatment failure.

The optimal time to initiate antiretroviral therapy in asymptomatic patients is unclear. A decision to initiate antiretroviral therapy in an HIV-infected adult or adolescent who is asymptomatic should be made after considering the patient’s willingness to begin antiretroviral therapy.

Antiretroviral therapy in HIV-infected adults who are treatment naive (have not previously received antiretroviral therapy) should be initiated with a potent multiple-drug regimen. Treatment should be aggressive with the goal of maximal suppression of viral load to undetectable levels.

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine, zidovudine).