Viral load measurement

Testing for the amount of HIV in plasma by measuring viral RNA has become a standard component of the management of HIV-infected patients.²³ There are important prognostic implications for the amount of viral load in persons with HIV disease.²⁴ In patients with higher viral loads, disease progression is more rapid, both immunologically, in terms of the rate of CD4 cell count decline, and clinically, in terms of development of AIDS-defining illness. In addition, the plasma levels in HIV-positive pregnant women directly correlate with the risk of perinatal transmission.²⁵ Viral load is an important useful marker for judging the effectiveness of various antiretroviral drug interventions.^26,27

There are several assays available for testing HIV for resistance to antiretroviral agents. Genotype or phenotype testing is used to determine whether the virus has mutated. The results of genotype or phenotype testing provide important information about resistance to specific antiretroviral drugs. If a mutant form is resistant to a particular antiretroviral drug, the HAART regimen may be altered so that the potential for viral suppression is maximized. Changes in the drug combinations used for HAART to respond to viral resistance are referred to as salvage therapy. Like genotypic testing, phenotypic testing may not detect small subpopulations of resistant HIV.²⁸

Researchers continue to work on developing effective HAART components and vaccines. The primary goal of antiretroviral therapy is to achieve prolonged suppression of HIV replication.^23,29 At this time, there are six classes of HIV medications. Two classes of drugs, receptor site inhibitors and fusion inhibitors (FIs), work to prevent HIV from successfully entering the cell. CCR5 inhibitors (CIs) include maraviroc (Selzentry), a CCR5 co-receptor antagonist (receptor site inhibitor). Receptor site inhibitors are the most recently approved class of drugs. FIs such as enfuvirtide (Fuzeon) or T-20 act outside the T cells by blocking the entry of HIV into the cell. T-20 is often used as part of salvage therapy; it is a twice-daily injectable drug with a cost of more than $25,000 per year.

The four other classes of drugs work within the cell by interfering with one of three enzymes that are involved with the replication process: reverse transcriptase, integrase, and protease. These classes include nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors (INIs), and protease inhibitors (PIs). In 1987, zidovudine (AZT), an NRTI, was first approved by the U.S. Food and Drug Administration. Since that time, several more NRTI drugs have been approved.³⁰ Other drugs, such as nevirapine and efavirenz, also inhibit the reverse transcriptase enzyme, but they are not nucleoside analogs. These NNRTIs bind to the enzymatic binding pocket of the reverse transcriptase gene and block binding by the nucleosides.³¹ Like reverse transcriptase, integrase is an enzyme that is active in the early stages of the replication process, and INIs can be used to interrupt its function by preventing the integration of the virus in the host cell’s DNA.³² INIs, such as elvitegravir or raltegravir (Isentress), are one of the most recently approved classes of drugs. Another drug target for anti-HIV agents is the protease enzyme. The PI drugs are structurally different from other drugs and include agents such as ritonavir, indinavir, nelfinavir, and saquinavir.³³

HAART may be NNRTI or PI based (i.e., NNRTI and PI drugs are used in combination with an NRTI such as AZT). There has been a gradual evolution of pharmacology that has allowed for multiple drugs to be combined into one pill. Thus the number of pills required per day as well as the administration schedule have become increasingly more manageable over recent years. However, drugs from different classes (NRTI, NNRTI, and PI) are typically included in HAART. The current recommendation from the Department of Health and Human Services for a treatment-naïve patient is either one NNRTI and two NRTIs or a PI (boosted with ritonavir) and two NRTIs.²² Because of the rapidly evolving nature of HAART, the reader is advised to consult with the CDC for the most current clinical practice guidelines.

Side effects and toxicities are common with drugs used to treat HIV disease. Purported side effects of NRTIs include peripheral neuropathy, myopathy, anemia, gastrointestinal (GI) disturbances, hepatomegaly, and pancreatitis. NNRTIs may cause rash, liver dysfunction, cognitive problems, and lactic acidosis. PIs may cause lipodystrophy, peripheral neuropathy, GI intolerance, hyperlipidemia, hyperglycemia, and liver toxicity. Injection site reactions are common with T-20. This list of side effects is cursory, and the full impact of these and other HIV drugs on the various systems of the body is a continually emerging area. Occasionally an individual’s HAART regimen is modified to mitigate the side effects that may occur with specific drugs.

Current medication regimens can significantly reduce the HIV level not only in the peripheral blood but also in the lymphoid tissue and the central nervous system (CNS).³⁴ The goal of HAART is to reduce HIV viral load to undetectable levels in serum. The greatest challenge with HAART is resistance to one drug in a class of agents, which may induce partial or complete resistance with other agents, depending on the specific mutations involved.^28,35 In a field that is rapidly changing, specific recommendations for antiretroviral therapy are best made by an infectious disease specialist with experience in the management of patients with HIV disease. The major therapeutic decisions include (1) when to initiate therapy, (2) what drugs to prescribe, (3) when to change therapy, and (4) which drugs to change to. When PIs were introduced as a complement to already existing NRTI and NNRTI drugs, the mortality rate of HIV-infected patients and the incidence of opportunistic infections decreased, most likely as a result of the increased use of combination HAART.³⁶ The role of drugs with immunomodulating activity in combination with HAART is also undergoing extensive research.^37,38 Drug regimens for HIV disease are dynamic, and clinical practice guidelines are consistently updated; many changes in the approach to drug interventions can be expected as HIV infection continues to be a chronic disease.³⁹

Vaccines

HIV-positive individuals respond less well than do uninfected persons to most vaccines. The degree of immunodeficiency present at the time of vaccination has an impact on the response to hepatitis A or B, pneumococcal, and influenza A and B vaccines.⁴⁰ Patients with a CD4 count of more than 200 cells/mcL have a more successful response to the vaccine. Patients should be informed that the extent and duration of the protective efficacy of these vaccines are still uncertain.

Vaccination for HIV has the potential to prevent or control disease progression. The development of an effective preventative vaccine for HIV is an area of continuing research. The first human immunizations with the potential AIDS vaccine took place in 1986 in healthy seropositive volunteers in France and Zaire. Low levels of both humoral and cell-mediated immune responses resulted. One conclusion of this study is that booster vaccinations could be effective.⁴¹ Several vaccine candidates have been developed and tested in human phase 1 or 2 trials. To date, at least 13 vaccine candidates have been created with use of different forms of recombinant proteins that target the HIV envelope. Research has found that the vaccine candidates introduced antibodies that rarely neutralized HIV progression, as evidenced by assessment of patient blood counts (i.e., CD4 counts). Furthermore, these recombinant proteins rarely produced a cellular response that would target and destroy cells already infected with HIV.⁴² Currently there is no evidence of a vaccine that produces extended, high-titer neutralization across a variety of HIV strains.⁴² The most recent clinic trial, the Thai Phase III HIV vaccine trial (also known as RV 144), was completed in September 2009. The study incorporated two vaccines, a prime vaccine (ALVAC-HIV) and a booster vaccine (AIDSVAX B/E), which were based on strains found in Thailand, where the clinical trial was conducted. The clinical trial involved over 16,000 volunteers who received either the vaccine combination or a placebo. The clinical trial found that the vaccine regimen was safe and modestly effective, demonstrating that the vaccine combination lowered the HIV infection rate by 31.2% compared with the placebo. The study also found that the vaccine had no effect on the viral load of those volunteers who became infected during the clinical trial.⁴³

Genetic mutation of the virus further complicates attempts to disable it. Genetically similar but distinguishable strains of HIV can exist in one individual. Furthermore, drug-resistant strains of HIV have been identified.⁴⁴ Yet another difficulty with vaccination development is a lack of animal models. Chimpanzees replicate simian immunodeficiency virus, a similar but not identical disease. In addition, an average of 12 years and $231 million is required for a new drug to gain Food and Drug Administration approval. Many major pharmaceutical companies seem wary of the immense research expenses and potential liability risks linked to vaccine development. The result is that smaller biotechnology companies with fewer resources are assailing the complicated problems of HIV infection.¹³ Recent advancements and plans for future clinical trials are largely supported by military or government programs. Researchers are optimistic that the vaccine will induce both humoral and cellular immune responses and have no toxic effects. It will protect against initial infection and retard disease onset in infected individuals.

In summary, as of July 2011 no HIV vaccines have been approved for use; there are clinical trials in process and research in this area is ongoing.