The US Department of Health and Human Services (DHHS) convened an expert panel on Clinical Practices for Treatment of HIV Infection in January 1997, composed of researchers, clinicians and HIV-positive treatment advocates. The panel first published Guidelines for the use of Antiretroviral Agents in HIV-infected Adults and Adolescents in 1997. The Health and Human Services guidelines are now regularly updated and available on at http://www.aidsinfo.nih.gov/guidelines/.

The DHHS guidelines originally endorsed treatment in asymptomatic people with CD4 counts below 500 cells/mm³. However, significant changes were made to the recommendations in February 2001. These changes brought this major United States protocol closer to the British HIV Association guidelines.

The most recent version of the DHHS guidelines was published in May 2006.

Starting treatment

The guidelines state that viral load testing should be carried out at the time of diagnosis and every three to four months in asymptomatic people. CD4 cell count should also be measured at diagnosis and subsequently every three to four months.

Therapy is recommended for any person with symptomatic HIV infection, regardless of CD4 cell count, as well as for patients with CD4 cell counts below 200 cells/mm³. For patients with CD4 cell counts between 200 and 350 cells/mm³, treatment should be offered, as it should for those with CD4 cell counts above 350 cells/mm³ with viral loads above 100,000 copies/ml. However, the precise time of treatment initiation in these patients depends on their readiness to begin therapy, including the risk of side-effects and the likelihood of their adhering to the treatment combination.

The goals of treatment are:

• To reduce HIV-related morbidity and mortality.
• To improve quality of life.
• To restore or preserve immune system function.
• To suppress viral load as much and for as long as possible.

The guidelines emphasise that the following tools are important in achieving these goals:

• Selection of an appropriate drug combination.
• Preservation of future treatment options.
• Drug resistance resting before treatment.
• Rational sequencing of drugs.
• Maximal adherence, which may be affected by social issues, susbstance abuse or depression.

Choice of treatment

The guidelines recommend an antiretroviral regimen that is expected to suppress HIV viral load, produce a sustained increase in CD4 cell count, and delay progression to AIDS and death. At least three antiretroviral drugs should be used in any regimen. The guidelines provide charts on the advantages and disadvantages of various class-sparing regimens including drug interactions and side-effects. Consideration of antiretroviral potency, pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile should inform the choice of three-drug or four-drug regimen for each individual.

The latest version of the guidelines recommend that resistance testing is carried out before treatment in all patients, in order to guide choice of drugs, as well as following treatment failure, when viral loads are above 1000 copies/ml.

The May 2006 guidelines recommend several 'preferred regimens' in previously untreated patients, and then suggests acceptable alternatives.

For patients who have not taken antiretroviral therapy before, the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen is efavirenz (Sustiva) with either 3TC (lamivudine, Epivir) or FTC (emtricitabine, Emtriva) and either AZT (zidovudine, Retrovir) or tenofovir (Viread). The preferred protease inhibitor-based regimen is ritonavor-boosted lopinavir (Kaletra) with either 3TC or FTC and AZT. This differs from current British guidelines, which do not recommend AZT due to the risks of the development of fat loss.

Several alternative regimens are offered. These include combinations including nevirapine (Viramune), atazanavir (Reyataz), fosamprenavir (Telzir) with or without ritonavir (Norvir) boosting, ritonavir-boosted indinavir (Crixivan), nelfinavir (Viracept) and ritonavir-boosted saquinavir (Invirase), together with two nucleoside or nucleotide reverse transcriptase inhibitors. A triple NRTI combination of abacavir (Ziagen), AZT and 3TC is recommended only for patients who cannot take NNRTIs or protease inhibitors.

Assessment and management of treatment failure

The management of patients whose anti-HIV treatment combination has failed receive substantial attention in the guidelines.

Treatment failure is defined as viral load above 400 copies/ml after 24 weeks of treatment, above 50 copies/ml after 48 weeks, or repeated viral loads above 400 copies/ml after prior viral suppression.

The guidelines state that the evaluation of antiretroviral treatment failure should include assessing the severity of HIV disease of the patient, antiretroviral treatment history, including the duration, drugs used, antiretroviral potency, adherence history, and drug intolerance and toxicity, and the results of current and prior drug resistance testing. The causes of treatment failure should also be investigated, including adherence, drug interactions, drug intolerance and drug resistance. Although therapeutic drug monitoring can assess levels of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors in the blood to guide patient management, the guidelines point out that their interpretation is complex, and that an expert clinical pharmacologist should be consulted.

The goal of treatment with limited or intermediate prior drug exposure and drug resistance is to re-establish maximal virologic suppression. However, the guidelines point out that assessing and managing patients with extensive treatment experience and drug resistance is complex and requires expert advice.

In general, the guidelines recommend that doctors use the treatment history and past and current resistance test results to identify active agents, ideally three, to design a new regimen. If three active agents cannot be identified, boosting protease inhibitors with ritonavir (Norvir) or re-using other prior antiretroviral agents should be considered. Adding a drug with a new mechanism of action, such as T-20 (enfuvirtide, Fuzeon) to an optimised background antiretroviral regimen can add significant antiretroviral activity.

In general, one active drug should not be added to a failing regimen because drug resistance is likely to develop quickly. However, in patients with advanced HIV disease and higher risk of clinical progression, adding one active agent to an optimised background regimen may provide clinical benefits and should be considered.

Interrupting therapy

The guidelines point out that treatment interruptions may enable patients to minimise drug toxicity and cost, but that there are risks involved. For example, patients taking breaks from treatment may be at risk of disease progression and the development of drug resistance.

Short-term breaks, for example during surgical operations or when a patient has gastroenteritis, are sometimes necessary. In these cases, all drugs should be stopped at the same time, with the exception of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which should usually be stopped before other drugs in the regimen.

Longer treatment interruptions are not recommended outside clinical trials, following recent findings that these can lead to increased risks of disease progression and death.

Acute HIV infection

Whether treatment of acute HIV infection results in long-term virologic, immunologic, or clinical benefit is unknown, so the guidelines recommend that treatment should be considered optional at this time. Therapy should also be considered optional for patients in whom HIV seroconversion has occurred within the previous six months.

If the clinician and patient elect to treat acute HIV infection with antiretroviral therapy, treatment should be implemented with the goal of suppressing plasma viral loads, with viral load and CD4 cell count testing as in patients with established HIV infection. Resistance testing may be useful in optimising the choice of drugs and treatment response.

Special groups

The guidelines also deal with HIV treatment in special groups, including adolescents, intravenous drug users, pregnant women and people co-infected with hepatitis B or C viruses or tuberculosis.

Adolescent patients should generally be treated in similar ways to adults, although some dose modifications may be required for patients at earlier stages of puberty. Adolescents often have adherence difficulties for a range of psychological reasons, leading the guideline's authors to suggest that this group need substantial support in adhering to their drug regimens.

Injection drugs users often experience problems with co-infections, side-effects of drugs, drug interactions and adherence, for medical and social reasons. The guidelines recommend collaboration between susbtance abuse programmes and HIV treatment providers, as well as close support for HIV-positive drug users. The susbtitution therapy methadone interacts with many antiretrovirals, resulting in dose modifications in the construction of successful antiretroviral drug combinations.

The treatment of pregnant women is covered in separate guidelines. However, the treatment guidelines contain a brief summary of these, including the need to initiate treatment not only when it is needed for the the health of a woman of reproductive age, but also to prevent mother-to-child transmission of HIV. Efavirenz (Sustiva) should be avoided by women who wish to become pregnant or who does not use contraception effectively and consistently, due to the risk of congenital abnormalities if taken in the fisrt trimester of pregnancy.

The guidelines summarise treatment of patients co-infected with hepatitis B, pointing out that FTC (emtricitabine, Emtriva), 3TC (lamivudine, Epivir) and tenofovir (Viread) are active against HIV and hepatitis B virus. In treating either infection, care should be taken not to expose either virus to only one active drug, because of the risk of resistance.

In patients with hepatitis C co-infection, the guidelines recommend that ribavirin not be given alongside ddI (didanosine, Videx / VidexEC) or AZT (zidovudine, Retrovir), and that patients taking antiretroviral therapy have liver function tests carried out regularly.

Finally, the guidelines recommend that HIV-positive patients with tuberculosis should receive the same treatment for tuberculosis as HIV-negative patients, with acute tuberculosis requiring immediate treatment. They recommend delaying antiretroviral therapy for four to eight weeks after starting tuberculosis treatment, with appropriate dose adjustments of rifamycin as necessary. Patients with CD4 cell counts below 100 cells/mm³ should receive tuberculosis treatment three times per week, rather than once or twice.