HIV/AIDS Medication - Understanding for patients

Human immunodeficiency virus (HIV) is a retrovirus that was formally identified in 1983(1) and causes acquired immune deficiency syndrome (AIDS). HIV binds to the CD4 receptors on T-lymphocytes, monocytes, neural cells and macrophages, migrating to the lymphoid tissue where the virus then replicates and infects new CD4-positive cells. As the infection spreads further the depleted function of the CD4 cells result in a greater predisposition to immune dysfunction.

How is HIV managed and treated?

Recent developments in the management and treatment of HIV have revolutionised the way in which the disease is perceived. The success of antiretroviral therapy (also known as ART, or HAART), has resulted in far fewer patients developing AIDS, with HIV now widely considered more as a chronic condition in which progress to AIDS becomes increasingly rare. The function of ART is to decrease patient burden of HIV, prevent opportunistic infections that can lead to death as a result of immune dysfunction, and maintain the successful functioning of the immune system.

The management of patients with HIV/AIDS is often complex, requiring the ongoing monitoring and treatment of any particular drug treatment as well as any specific complications that arise as a result of HIV infection. Treatment regimen will often depend on the particular stage that each patient is at.

ART is recommended for all patients:

• with established HIV infection and a CD4 cell count of ≤350 cells/mm3
• any patients with a CD4 cell count between 351-500 cells/mm3 if they have a low CD4 percentage, or a high risk of developing cardiovascular disease (2).
• Patients with late stage HIV, although not when there is a co-infection with TB and CD4 levels >350 cells/mm3

The use of ART is often complicated by co-infection with other diseases. Co-infection is particularly prevalent in underdeveloped countries with weak health systems. Co-infections with diseases such as hepatitis and tuberculosis constitute a very small percentage of patients in developed countries. In the event of treating co-infection with hepatitis, ART choice must take into consideration pre-existing liver conditions and be monitored closely and regularly in patients with end stage liver disease.

Although ART has revolutionised the care available for HIV/AIDS patients, it can cause a number of different symptoms including insulin resistance, dyslipidaemia (an abnormal amount of lipids in the blood), and fat redistribution. Most ART is often offered in combination, with preferred first line treatments usually three particular drugs (efavirenz and tenofovir or abacavir, as well as lamivudine or emtricitabine).

What are the different functions of ART drugs? Are there different classifications?

ART drugs are broadly classified by the phase of the retrovirus lifecycle that they have been designed to inhibit, with five different classes often used in combination to treat HIV infection.

Entry inhibitors (also occasionally known as fusion inhibitors) block the targets of the HIV-1 virus to prevent its binding, fusion and entry onto cells. At present, the most commonly used drugs in this category are enfuvirtide and maraviroc.

Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) function by inhibiting the reverse transcription of the HIV virus from RNA into DNA, and include a number of commonly used drugs such as abacavir, lamivudine, tenofovir, and zidovudine (3).

Non-Nucleoside reverse transcriptase inhibitors (NNRTI) act to inhibit reverse transcriptase by binding onto the allosteric site of each enzyme, and include drugs such as rilpivirine and etravirine.

Integrase inhibitors, such as elvitegravir and dolutegravir, inhibit the viral enzyme integrase and prevent the integration of viral DNA into the DNA of a HIV infected cell.

Protease inhibitors prevent the binding of the virus to precursor proteins, and include some of the most commonly recognised ART drugs such as nelfinavir, amprenavir, ritonavir, and atazanavir. As many of the protease inhibitors have been in development since the beginning of ART treatment, there is some resistance to some drugs that are currently on the market. The pharmaceutical market has responded to this, and there are a range of second generation drugs that have been evidenced to be effective against HIV variants that are otherwise resistant (4).

Are there any dangers associated with the misuse of ART drugs?

When used improperly, multi-drug resistant strains of HIV can become the dominant genotype very quickly and pose significant challenges for the management and treatment of the virus. Prior to multiple drug classification in 1997, and the standardised use of ART treatment globally, the misuse and serial prescribing of reverse transcriptase inhibitors such as stavudine, lamivudine, and zidovudine lead to the emergence of a wide range of multi-drug resistant mutations (5). As a result, a number of ART drugs are now used in combination, creating obstacles for further HIV replication as much as possible.

Pharmaceutically many combination drugs are now available in a single pill, which has also been evidenced to significantly improve adherence to medical treatment (6). This has a number of benefits, improving individual outcomes for patients with HIV and reducing wider population level incidence of drug resistance. Combination drugs in a single pill are commonly referred to as fixed dose combinations.

What is the evidence regarding the optimal time for administering ART treatment to patients with HIV?

In the first six months after HIV infection, many patients have a viral load that tends to be elevated and results in them being more symptomatic. There is some evidence to suggest that treatment administered during this time period can significantly reduce the viral load, with the SPARTAC trial comparing 48 weeks and 12 weeks of ART finding that that the 48 week treatment schedule significantly reduced viral load and CD4 count for up to a year after the treatment had stopped (7).

The treatment of children with HIV can be very complicated, with evidence from trials investigating the impact of a single dose of nevirapine at birth to reduce mother-baby transmission showing a high risk of NNRTI resistance (8). ART administered to mothers carrying HIV during pregnancy has been evidenced to substantially reduce the risk of transmission (9), as has the method by which the baby is delivered, with planned caesarean sections having a much lower risk than vaginal deliveries or emergency C-sections.

References

1. Sharp PM, Hahn BH (2011) Origins of HIV and the AIDS pandemic Harb Perspect Med doi: 10.1101/cshperspect.a006841
2. Guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy (2012) British HIV Association
3. Das K, Arnold E (2013) HIV-1 reverse transcriptase and antiviral drug resistance. Part 1 Virology 3(2): 111–8
4. Wensing AM, van Maarseveen NM, Nijhuis,M (2010) Fifteen years of HIV protease inhibitors: Raising the barrier to resistance  Antiviral Research 85(1): 59–74 doi:10.1016/j.antiviral.2009.10.003
5. Schmit JC, Cogniaux J, Hermans P et al (1996) Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain Jour Infect Dis 174(5):962-8
6. Adherence-resistance relationships to combination HIV antiretroviral therapy (2007) Curr HIV/AIDS Rep 4(2): 65–72
7. Short-Course Antiretroviral Therapy in Primary HIV Infection NEJM 368(3): 207–217
8. Response to Nonnucleoside Reverse Transcriptase Inhibitor-Based Therapy in HIV-Infected Children with Perinatal Exposure to Single-Dose Nevirapine (2009) AIDS Research and Human Retroviruses 25(10): 989–996
9. Mother-to-Child Transmission of HIV Infection in the Era of Highly Active Antiretroviral Therapy Clin Infect Dis 40(3): 458–46