The guidelines contain updated recommendations in several areas, including diagnosis of HIV in infants, start of antiretroviral therapy, selection of antiretrovirals, and adherence to antiretroviral therapy in children and teenagers.

The guidelines now also include a rating system to indicate the strength of each recommendation, and formatting changes have been implemented to improve readability. For example, a section on drug side effects in children that includes information on risk factors, symptoms, preventative measures, and treatment options is now presented in a table format for ease of use.

The guidelines are intended for use by doctors and other health care professionals when treating HIV-positive children and teens.

Key updates to various sections of the guidelines are summarized below.

Diagnosis Of HIV In Infants

The guidelines now recommend HIV testing at birth for infants who are at high risk for contracting the virus. This includes babies born to HIV-positive mothers who did not receive prenatal care or prenatal antiretroviral therapy, or who had HIV viral loads (amount of virus in the blood) greater than 1,000 copies per milliliter near the time of delivery.

HIV infection in adults is usually diagnosed by looking for antibodies – proteins made by the immune system to help identify and fight bacteria and viruses. In infants, however, tests for HIV antibodies may lead to false-positive results, as children of this age group often still carry their mothers’ HIV antibodies.

To avoid a false diagnosis, the guidelines continue to recommend tests that detect the virus itself to determine HIV status in infants younger than 18 months. This includes HIV DNA PCR assays and HIV RNA tests, both of which can detect the HIV virus directly.

The guide also continues to recommend that babies be tested for HIV at 14 to 21 days after birth, age 1 to 2 months, and 4 to 6 months of age.

Start Of Antiretroviral Therapy

Suggestions for when to initiate antiretroviral therapy vary according to age group.

Antiretroviral therapy is now recommended for children older than 12 months who have normal CD4 (white blood cell) counts but HIV viral loads of 100,000 copies per milliliter of blood or higher, even if their symptoms are mild or nonexistent.

For children under the age of 12 months, the guidelines continue to recommend starting antiretroviral therapy regardless of CD4 count, viral load, or the presence or absence of symptoms. Several studies have shown that starting therapy early in children of this age significantly reduces the chances a child will progress to AIDS or die.

In children with normal CD4 counts whose HIV viral loads are less than 100,000 copies per milliliter, and who have mild or no symptoms, initiation of treatment can be either considered or deferred.

Selection Of Antiretroviral Drugs For Treatment Naïve Patients

As with adults, all HIV-positive children should be treated using combination therapy that includes at least three different antiretroviral drugs from two different classes.

However, the updated guidelines now indicate that non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy is not recommended for children younger than 3 years of age who have been exposed to single dose Viramune (nevirapine).

Viramune is often used to prevent mother-to-child transmission. Babies who have been exposed to Viramune before birth have a higher risk of drug resistance to Viramune after birth. They may also have a higher chance of treatment failure with NNRTI-based antiretroviral therapy.

For children under 3 years of age who have been exposed to Viramune, the preferred treatment is a Kaletra (lopinavir/ritonavir)-based regimen.

In addition, Viramune is not recommended in girls after puberty who have CD4 counts of 250 cells per microliter or higher, and Sustiva (efavirenz) is not recommended in sexually active teenage girls unless contraception can be reliably guaranteed.

Other antiretrovirals that are not recommended are Viracept (nelfinavir) for children under 2 years of age, Sustiva in children under 3 years of age, and unboosted Prezista (darunavir), Invirase (saquinavir mesylate), or Aptivus (tipranavir).

Drugs that should not be combined in children include Epivir (lamivudine) plus Emtriva (emtricitabine), zidovudine (Retrovir) plus stavudine (Zerit), or dual NNRTI regimens.

The guidelines also recommend against once daily (rather than twice daily) dosing of Kaletra, boosted Prezista, and boosted or unboosted Lexiva (fosamprenavir) in children. Although once-daily doses of these antiretrovirals have been approved in adults, the effectiveness of once-daily dosing versus twice-daily dosing has not been shown in children.

The guide continues to recommend that treatment naïve patients (patients who have never received antiretroviral therapy) complete antiretroviral drug resistance testing before choosing which drugs to use for treatment.

Adherence To Antiretroviral Therapy

Adherence to therapy can often be difficult for children and teenagers. Ensuring that patients follow their treatment regimens is important because missing doses can cause HIV to develop resistance to treatment, leading to treatment failure.

The guidelines now recommend that at least one method to monitor adherence, such as self-reporting of missed doses or pharmacy refill checks, be used in addition to viral load tests.

The updated guidelines also suggest prescribing once-daily antiretroviral therapy when possible rather than twice-daily dosing, since studies in adults have shown once-daily dosages promote better adherence.

For more information, please see the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (pdf).

The guidelines include updates on preferred regimens for prevention of HIV transmission during pregnancy.

According to the report, fewer than 200 children are now born with HIV in the United States each year, as a result of efforts to limit mother-to-child transmission.

Transmission of HIV from a pregnant woman to her baby can occur during pregnancy, labor, or while breastfeeding after the baby is born. To prevent this, women are usually treated with antiretrovirals throughout the pregnancy and are told not to breastfeed their babies.

In this latest report, the NIH now recommends that pregnant women with HIV who are not already taking antiretrovirals start taking them sooner than previously suggested. The NIH suggests initiating treatment after the first trimester, and no later than 28 weeks into the pregnancy.

The guidelines also recommend pregnant women take a combination regimen consisting of at least three drugs, preferably two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor.

The recommended NRTI regimen is Combivir (zidovudine/lamivudine), based on clinical trials demonstrating its effectiveness.

The recommended NNRTI is Viramune (nevirapine), although only in women with CD4 cell counts of less than 250 cells/mm3 unless the benefits outweigh the risk of potential liver toxicity. Women already taking Viramune may continue during pregnancy.

The recommended protease inhibitor regimen is Kaletra (lopinavir/ritonavir). Alternative protease inhibitors include Norvir (ritonavir) in combination with Invirase (saquinavir), Crixivan (indinavir) or Reyataz (atazanavir).

Several treatments are not recommended for part or all of the pregnancy:

• The combination of stavudine (Zerit) and didanosine (Videx) are not recommended since they may cause serious side effects, including liver failure, in pregnant women.

• Sustiva (efavirenz) should not be taken in the first trimester of pregnancy because of possible harm to the baby. Sustiva is also an ingredient in Atripla (efavirenz/emtricitabine/tenofovir).

• Viread (tenofovir) should only be used when there is intolerance or resistance to zidovudine (Retrovir) or if the pregnant woman has hepatitis B because it may harm the baby. Viread is also an ingredient in Atripla and Truvada (emtricitabine/tenofovir).

• There is not yet enough data on Intelence (etravirine), Prezista (darunavir), Lexiva (fosamprenavir), Aptivus (tipranavir), Fuzeon (enfuvirtide), Selzentry (maraviroc), or Isentress (raltegravir) to recommend their use in pregnancy, although in some cases they may be used if other drugs are not well tolerated.

Prevention of mother-to-child transmission in HIV-positive women with hepatitis B (HBV) is also discussed. Treatment options depend on whether the mother requires anti-HIV treatment for her own health, anti-HBV treatment, or both.

The NIH also reaffirmed its recommendation that HIV-positive women should avoid breastfeeding. Although clinical trials in Africa have shown that antiretrovirals reduce the chances of transmitting HIV through breastfeeding, there is still a risk.

Since women in the U.S. have a safe, viable alternative to breastfeeding – formula feeding – the NIH strongly discourages HIV-positive women from breastfeeding.

After the baby is born, antiretroviral treatment of the infant is usually continued to ensure infection does not occur. The recommended treatment is zidovudine for six weeks after birth. In the new guidelines, the NIH warns that combining zidovudine with other treatments is not well-studied and should be done with caution.

Both Norvir and Kaletra have been associated with heart block, a problem with the heart’s electrical system, in babies, and therefore require especially close monitoring if used in infants.

Finally, food pre-chewed by HIV-positive caregivers should not be given to infants since this potentially increases the risk of HIV transmission.

The NIH welcomes feedback on the guideline revisions. Comments should be sent to ContactUs@aidsinfo.nih.gov with the subject line “Perinatal Comments” by June 7, 2010.

For more information, please see the complete guidelines at the NIH (pdf) website.

Protease inhibitors are a class of antiretroviral drugs that prevent HIV from replicating by blocking a necessary protein called protease.

Drugs in this class include Aptivus (tipranavir), Crixivan (indinavir), Invirase (saquinavir mesylate), Kaletra (lopinavir/ritonavir), Lexiva (fosamprenavir), Norvir (ritonavir), Prezista (darunavir), Reyataz (atazanavir), and Viracept (nelfinavir).

Although some of the drug interactions had been known for specific protease inhibitors, the added information will affect all currently approved drugs in this class.

Drugs that should be avoided by individuals taking protease inhibitors include:

• Revatio (sildenafil), used to treat pulmonary arterial hypertension, a condition in which blood pressure in the arteries of the lungs is abnormally high. Protease inhibitors tend to increase concentrations of Revatio in the bloodstream, which could cause a dangerously low drop in blood pressure.
• Uroxatral (alfuzosin), which is used to treat men who have an enlarged prostate. Protease inhibitors increase the risk of severe low blood pressure in men taking Uroxatral.

The active ingredient in Revatio, sildenafil, is also the active ingredient in Viagra. Pfizer, which makes Viagra, recommends that men taking protease inhibitors should take no more than 25 mg of Viagra in a 48-hour period.

The FDA also listed several drugs that should not be given at the same time as protease inhibitors, including:

• Salmeterol (Serevent), which is used in asthma treatment. Protease inhibitors can lead to an increased risk of heart problems when given with salmeterol.
• Tracleer (bosentan), another drug for treatment of pulmonary arterial hypertension. Tracleer should not be given with Reyataz unless Norvir is also prescribed. Cotreatment with Tracleer and Reyataz without Norvir may result in higher blood concentrations of Tracleer, increasing both its activity and side effects.
• Colchicine, a natural product often used to treat gout, and which should not be given at the same time as protease inhibitors in patients with liver or kidney problems. Protease inhibitors may slow the rate at which the intestine and liver process colchicine.

Finally, several drugs were found to need dosing adjustments if administered with protease inhibitors. These include:

• Adcirca (tadalafil), another treatment for pulmonary arterial hypertension. Protease inhibitors can affect the amount of Adcirca in the body, so dosages should be monitored carefully.
• Colchicine for all patients taking protease inhibitors, when prescribed for the treatment of familial Mediterranean fever and gout or gout prevention.

Patients taking protease inhibitors should speak to their physicians before beginning or ending any drug regimens, and should tell doctors about all medications they are taking.

For more information on protease inhibitor drug-drug interactions, please see the FDA website.

GSK, the drug’s manufacturer, has updated existing prescribing information to include the potential for Lexiva to increase cholesterol levels, which is known to raise the risk of heart attacks.

GSK recommends testing triglycerides and cholesterol levels in patients, both initially and at set intervals throughout the course of therapy.

Evidence for this increased risk comes from a French case-controlled study, which found a positive correlation between Lexiva use and heart attack incidence.

Lexiva is a type of antiretroviral drug known as a protease inhibitor that is indicated for use in combination therapy with other antiretroviral drugs. Protease inhibitors work by disabling protease, a protein that HIV needs in order to replicate. In general, GSK noted that protease inhibitors tend to be associated with higher levels of cholesterol and other lipids in the blood.

Lexiva is not the first HIV drug to be associated with cardiovascular disease. Ziagen (abacavir) has also been associated with increased risk of heart problems (see related AIDS Beacon news).

HIV infection itself is also associated with lipid disorders and ischemic heart disease, a disease in which the heart’s blood supply is reduced. In a recent study conducted in Italy, scientists show that without antiretroviral treatment, HIV-infected individuals have an increased risk of cardiovascular disease (see related AIDS Beacon news).

For more information, please see the press release on the FDA Web site, which also provides a link to GSK’s letter (pdf) to all health professionals.