2.2: Literature Review
2.2.1 HIV Infection and Transmission
The Human Immunodeficiency Virus (HIV) is an enveloped retrovirus that belongs to the genus of lentiviridae. It’s further broken down in two classes; HIV-1, most common globally, and HIV-2, a less pathogenic variant concentrated in West Africa. HIV-1 has been divided into four distinct genetic groups: M, N, O and P (Fonjungo et al., 2000). Group M is responsible for over 90% of HIV-1 infections globally. Natural genetic variation has led to the sub-classification of HIV-1 group M into nine subtypes (A-D, F-H, J, and K) and numerous circulating recombinant forms (Robertson et al., 2000). Subtype B is most prevalent in Europe, North America and Australia. In sub-Saharan Africa, HIV-1 subtype C is responsible for 56% of infections, mainly in southern and east Africa, whereas smaller proportions of infections are caused by subtypes A, D and G (Hemelaar, Gouws, Ghys, ; Osmanov, 2011).
HIV is transmitted sexually, through parenteral exposure to blood and its products, or from mother to child during pregnancy, birth or breast-feeding. The virus primarily targets CD4+ T-lymphocytes and macrophages. The acute infection is characterized by a burst of viral replication and immune activation (Daar, Moudgil, Meyer, ; Ho, 1991) and it’s followed by a symptom-free period of eight to ten years in majority of the individuals. During chronic infection, the number of CD4+ T-lymphocytes gradually declines. Without ART, cell-mediated immunity will eventually be lost and the immunodeficient HIV-infected person has an increased risk of developing opportunistic infections and neoplasms. The last stage is AIDS, and finally death if an individual does not start treatment (ART).
2.2.2 Antiretroviral treatment
ART reduces HIV-related morbidity and mortality by lowering of the viral load to minimum levels. This allows the immune system of the infected individual to recover thus preventing opportunistic infections (Williams et al., 2010). Although ART cannot completely eliminate HIV from the body of those individuals infected, the advent of ART has changed the perception of HIV from a death sentence to a manageable chronic illness. Ever since ART became available in public health facilities in 2004, HIV no longer inevitably leads to AIDS and death.
ART regimens
First line regimens: The Uganda National ART Guidelines recommend a combination of TDF and3TC is the preferred NRTI backbone for adults and adolescents aged ten years and above. This includes pregnant and breastfeeding women. AZT and ABC are also part of the first line ART recommendations but only in situations where the preferred combination is deemed unfit. Due to cost ABC use in adult patients in is only reserved for individuals with contraindications to the preferred options. With regard to the NNRTI choice, EFV is preferred. NVP is the only NNRTI for clients who cannot tolerate EFV or in circumstances were EFV is contraindicated (Ministry of Health, 2016).
Second line regimens: Second line ART regimens are developed mainly for patients failing first line regimen. However, a number of individuals might be started on second line ART due to toxicities or co-morbidities in which the use of drugs used as second line ART (PIs) are usually associated with a better outcome, for example karpos’ sarcoma. The formation of the second line regimen usually depends on the ARVs that were used during the first line ART. For example, individuals who were on AZT during their first line ART are changed to TDF while those who were on TDF for first line are changed to AZT or ABC (Ministry of Health, 2016). This guidance originates from the fact that when on TDF, the viral mutation K65R increases the viral susceptibility to AZT and TDF does not accumulate Thymidine Analogue mutations (TAMs) which render other thyminide analogues ineffective (Stephan et al.).
The National Guidelines for treatment of HIV recommend the NNRTI in first line regimen to be changed to a PI. ATV/r combination is the preferred PI because it offers an opportunity of once daily dosing hence lowering the pill burden and secondly, it has a better GI tolerability as compared to LPV/r. Furthermore, ATV/r is more affordable than LPV/r. If the patient is intolerant to ATV/r or circumstance where it’s contraindicated, LPV/r can be used instead (Ministry of Health, 2016). Patients who may not be able to tolerate the above standard second line regime may be put on a non-standard second line regimen.
Third line Regimen: Not all ART treatment centre have third line ART. When a patient on 2nd line ART is confirmed to be failing following clinical or virological criteria, the recommendation is to refer the patient to the nearest treatment center providing third line ART. Before anyone is switched onto 3rd Line ART, they should have a resistance profiling test done to confirm PI resistance and to determine the most optimal treatment regimen. The recommended 3rd line regimen will include boosted Darunavir, an integrase inhibitor with an option of adding 2 NRTIs. The DRV/r would be 600mg twice daily, as compared to 800mg once daily in clients with no prior exposure to PIs (Ministry of Health, 2016).