Artículo 2. Neuromuscular excercise in children with Down Syndrome. A systematic review

The clinical stages of HIV infection progress from an initial acute phase, associated with primary infection, to an asymptomatic state and from that, to an advanced state of infection (Vajpayee, Kaushik, Sreenivas, Wig, & Seth, 2005). The asymptomatic stage is also called

―clinical latency‖ and is accompanied by persistent viral replication in the lymph nodes.

During this phase, the number of CD4+ T-lymphocytes decreases continuously, until the patient‘s immune system is no longer capable of controlling opportunistic pathogens (Sierra, et al., 2005). Thus; the viral load can reflect progression, whereas a CD4 count is associated

18 with the risk of developing opportunistic infections. Ideally, a patient would possess a low viral load and a high CD4+ T cell level, and it is recommended that both the viral load and CD4 counts be examined when determining disease progression (Anderson, 2006; Holodniy

& Miller, 2002).

2.2.5 2.2.4.1 Classification of HIV infection

Two main classifications of HIV infection have been described; one comes from the Centre for Disease Control and Prevention (CDC) and the other from the WHO.

CDC classification for HIV infection

In 1993 the CDC revised its 1981 classification. This was the first time the HIV infection had been classified, and where the CD4+ T- lymphocyte count was identified as a marker for HIV-related immune suppression. The current CDC classification categorises PLWH on the basis of CD4+T-lymphocyte counts and the clinical conditions associated with HIV infection.

Three categories of CD4+ T-lymphocyte and also three categories of clinical condition associated with the disease have been identified (Buehler & Berkelman, 1992). The following are the categories for CD4+T-lymphocyte counts: (1) category1; CD4+ T- lymphocyte count is greater than or equal to 500 cells/ul; (2) category2; CD4+T- lymphocyte count ranges between 200-499 cells/ul; (3) category3; CD4+T-lymphocyte count is less than 200 cells/ul (Buehler & Berkelman, 1992).

With regard to the clinical conditions associated HIV disease; the following are the relevant categories: (1) category A (Asymptomatic HIV infection); this includes acute (primary) HIV infection and persistent generalised lymphadenopathy. (2) Category B (symptomatic HIV infection). It includes conditions such as bacillary angiomatosis, candidiasis vulvovaginal, (persistent, frequent, or unresponsive to therapy), cervical dysplasia (moderate or

severe)/cervical carcinoma. It includes constitutional symptoms, such as fever (38.5 C) or diarrhoea lasting for longer than one month, and herpes zoster, involving at least two distinct episodes or more than one dermatome, as well as peripheral neuropathy (Buehler &

Berkelman, 1992).

(3) Category C: it includes conditions that are indicators for AIDS: once a person has experienced one of the conditions; he or she will remain in the C category. This includes conditions such as candidiasis of bronchi, trachea, or lungs , oesophagus , cervical cancer, cryptococcosis (extrapulmonary) , diarrhoea (for longer than one month), encephalopathy,

19 herpes simplex( chronic ulcer(s) for longer than one month), bronchitis, pneumonitis,

oesophagitis , Kaposi's sarcoma, Burkitt's Lymphoma, mycobacterium tuberculosis (pulmonary or extrapulmonary), pneumocystis carinii pneumonia, pneumonia (recurrent), progressive multifocal leukoencephalopathy, salmonella septicemia, recurrent ,

toxoplasmosis of brain and wasting syndrome due to HIV (Buehler & Berkelman, 1992).

WHO classification for HIV infection

The WHO classification has undergone several revisions (most recently in 2005). This classification was based on the stages of the clinical conditions associated with HIV, with or without access to CD4+ T-lymphocyte counts. However CD4+ testing is still considered useful to determine the degree of immunosuppression and to support clinical decision-making. For example, it helps to determine the need for antiretroviral treatment and other therapies. The system is intended to improve the management, treatment monitoring and surveillance of PLWH (World Health Organisation (WHO), 2005a).

Clinical staging of HIV/AIDS for adults and adolescents includes the following stages:

primary HIV infection is asymptomatic and acute retroviral syndrome. Clinical stage 1 is asymptomatic with persistent generalized lymphadenopathy. Clinical stage 2 involves moderate unexplained weight loss (<10% of presumed or measured body weight), recurrent respiratory tract infections (sinusitis, bronchitis, otitis media, pharyngitis), herpes zoster, angular cheilitis, recurrent oral ulcerations, papular pruritic eruptions, seborrhoeic dermatitis and fungal nail infections of the fingers (World Health Organisation (WHO), 2005a).

Clinical stage 3 involves conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations. The indicators include severe weight loss (>10% of presumed or measured body weight), unexplained chronic diarrhoea for longer than one month, unexplained persistent fever (intermittent or constant for longer than one month), oral candidiasis, oral hairy leukoplakia, pulmonary tuberculosis (TB) diagnosed in the two

previous years, severe presumed bacterial infections (e.g. pneumonia, pyomyositis, bone or joint infection, meningitis, bacteraemia), acute necrotizing ulcerative stomatitis, gingivitis or periodontitis. It also involves conditions where confirmatory diagnostic testing is necessary, including unexplained anaemia (< 8 g/dl), and/or neutropenia (<500/mm3) and or

thrombocytopenia (<50 000/ mm3) for more than one month (World Health Organisation (WHO), 2005a).

20 Clinical stage 4 involves conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations. The indicators include HIV wasting syndrome, pneumocystis pneumonia, recurrent severe or radiological bacterial pneumonia, chronic herpes simplex infection (orolabial, genital or anorectal of more than one month‘s duration), oesophageal candidiasis, extrapulmonary TB, Kaposi‘s sarcoma, central nervous system (CNS) toxoplasmosis, etc. This also involves conditions where confirmatory diagnostic testing is necessary, such as extrapulmonary cryptococcosis (including meningitis), disseminated non-tuberculous mycobacteria infection, candida of the trachea, bronchi or lungs, visceral herpes simplex infection, cytomegalovirus (CMV) infection (retinitis or of an organ other than the liver, spleen or lymph nodes), recurrent non-typhoidal salmonella septicaemia lymphoma (cerebral or B cell non-Hodgkin), and invasive cervical carcinoma (World Health Organisation (WHO), 2005a) .

The World Health Organisation (WHO) (2005a) immunological staging of HIV infection includes the following stages: no significant immunosuppression: >500/mm3; mild immunosuppression: 350-499/mm3; advanced immunosuppression: 200 −349/mm3; and severe immunosuppression: <200/mm3.

2.2.6 Antiretroviral treatment

HIV encodes at least three types of enzymes: protease, reverse transcriptase and endonuclease (Aymard, Legrand, Trichereau, & Diquet, 2000). In order to inhibit reproduction of the virus in the human body; pharmaceutical scientists have produced antiretroviral drugs, which are described as a treatment for people infected with HIV.

Following advanced research on this treatment, scientists have introduced the highly active antiretroviral treatment. This consists of a triple combination of drugs, and significantly assists the suppression of HIV replication (Miranda et al., 2007); it results in reconstitution and augmentation of the CD4 count. Unfortunately, due to the persistence of viral reservoirs, highly active antiretroviral treatment does not eradicate HIV (Mahungu, et al., 2009).

There are three main types of antiretroviral drugs: the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) (Aymard, et al., 2000). NRTIs include Abacavir, Didanosine, Dideoxycytidine, Lamivudine, Stavudine and Zidovudine etc. The NNRTIs include Delavirdine, Efavirenz and Nevirapine etc. The PIs include Amprenavir, Indinavir,

21 Nelfinavir, Ritonavir and Saquinavir etc. Therapeutic strategy regimens are based on a

combination of these antiretroviral drugs (Aymard, et al., 2000).

World Health Organisation (WHO) (2006b) recommends that the first-line treatment regimen for adults and adolescents should contain two NRTIs plus one NNRTI. It has been found that this combination is efficacious, less expensive and has generic formulations. The following NRTIs are considered preferable as a first-line regimen: Zidovudine (AZT) or Stavudine (D4T), Lamivudine (3TC) or Emtricitabine (FTC), Tenofovir (TDF) or Abacavir (ABC). If the choice is NNRTI, then Efavirenz (EFV) and Nevirapine (NVP) are preferable. The PIs are reserved for the second-line treatment regimen and are combined with an NRTI (Gilks et al., 2006; World Health Organisation (WHO), 2006b).

The antiretroviral treatment regimen in Rwanda follows the WHO recommendations, so the usual combinations comprise two NRTIs plus one NNRTI or two NRTIs plus one PI (MoH-Rwanda, 2011a). As it is shown in Table 1, in (MoH-Rwanda, there are four combinations of drugs recommended for the first-line regimen (Ministry of Health (MoH) Rwanda, 2011a).

Table 1: Antiretroviral drugs combination recommended for the first line regimen, in Rwanda

NRTI NNRTI

Tenofovir (TDF) + Lamivudine (3TC) or FTC Efavirenz (EFV) Tenofovir (TDF) + Lamivudine (3TC) or FTC Nevirapine (NVP) Abacavir (ABC) + Lamivudine (3TC) or FTC Efavirenz (EFV) Abacavir (ABC) + Lamivudine (3TC) or FTC Nevirapine (NVP)

(Ministry of Health (MoH) Rwanda, 2011a) 2.2.5.1 Antiretroviral treatment side effects

Various side effects of antiretroviral treatment as a result of toxicity have been observed and these can vary in severity from mild to severe and may sometimes be life-threatening.

Kumarasamy et al. (2008), in a prospective study, found that over half of PLWH developed at least one treatment-associated adverse event and this contributed to the need to change or discontinue the initial regimens. However, at times it might be difficult to distinguish between the complications of the HIV infection and the side-effects of antiretroviral

22 treatment toxicity. The common side effects are shown in Table 2 (World Health

Organisation (WHO), 2006b).

Table 2: Antiretroviral drugs first line treatment regimen side effects Antiretroviral drug Common associated side effects

ABC Hypersensitivity reaction

AZT Severe anaemia or neutropenia

Severe gastrointestinal intolerance (example of symptoms may be persistent nausea and vomiting)

Lactic acidosis

D4T Lactic acidosis

Lipoatrophy/ metabolic syndrome Peripheral neuropathy

TDF Renal toxicity (renal tubular dysfunction)

EFV Persistent and severe central nervous system toxicity

Potential teratogenicity (first trimester of pregnancy or women not using adequate contraception)

NVP Hepatitis

Hypersensitivity reaction

Severe or life-threatening rash (Stevens-John syndrome). Severe rash with desquamation or sometimes with other health problems such as;

fever, oral lesions, blistering, facial oedema or conjunctivitis (World Health Organisation (WHO), 2006b)

The World Health Organisation (WHO) (2006b) has suggested that countries select and keep a considerable stock of first-line treatment regimen drugs; they should also have a limited quantity of second-line regimen drugs available. Despite the side effects or toxicity of the

23 antiretroviral treatment; the majority of PLWH who are able to access and adhere to

antiretroviral treatment can expect an improvement in their CD4 count and a decreased viral load (Heaton et al., 2011; Howard et al., 2002), a reduction in the occurrence of opportunistic infections and an overall reduction in disease-related morbidity and mortality (Heaton, et al., 2011; Russell et al., 2007).