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#### **Chapter 2 Provisional chapter**

#### **HIV-Associated Vasculopathy HIV-Associated Vasculopathy**

Ashraf Alqaqa Ashraf Alqaqa

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42 HIV/AIDS - Contemporary Challenges

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66655

#### **Abstract**

HIV vasculopathy is a wide range of clinical spectrum related to HIV infection. Increasing longevity of HIV-infected individuals secondary to antiretroviral therapy advancements has resulted in increasing the number of patients with HIV-related vasculopathy. Clinicians need to be aware of the different types of HIV vasculopathy to be able to diagnose and manage the pathology and improve patient care.

**Keywords:** HIV vasculopathy, vascular disease, carotid disease, aortic aneurysm, peripheral arterial disease, cerebral vasculopathy

## **1. Introduction**

Human immunodeficiency virus (HIV) reduces the immunity of a body, making it vulnerable to opportunistic diseases. HIV was first reported in the USA in 1981, in young homosexual men. The young men were said to have severe opportunistic infections [1]. Two years later the virus was labeled as HIV and acquired immune deficiency syndrome (AIDS), if advanced [2]. A patient is diagnosed with AIDS when their immune system is significantly low, and their CD4 count is <200 cells/μl. The areas most affected with HIV/AIDS-infected persons are the Sub-Saharan regions of Africa. More than 72% of the world's population with HIV live in Africa. According to the 2007 report on HIV/AIDS, the world's total population living with this infection is about 33 million [3]. The burden of the worldwide epidemic of HIV infection continues to increase, especially in the developing world. Third World countries experience a vast financial burden of managing and treating HIV-infected and affected persons with scarce resources. The new advancement of potent antiretroviral therapies has, however, made it possible for more patients to live longer, allowing healthcare providers to witness new clinical manifestations of the chronic HIV infection.

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There have been major improvements in novel clinical management in a bid to manage HIV [2]. For instance in 1987, HIV was for the first time linked to vasculopathy, impulsive arteriovenous fistula and arterial occlusive disease or aneurysmal infection [4]. The prevalence of symptomatic vasculitis in HIV patients is about 1% according to recent studies [5]. The chief objective of this review will be to describe the HIV-associated vasculopathies in various parts of the body.

Pathogenecity of HIV, which is associated with vasculopathy, is rather complex and hence not fully comprehended. The complexity is a result of several factors such as inflammatory and immunological response to HIV infections. These factors lead to deleterious and dynamic effects on the endothelial and smooth muscle cells of the blood vessels.

HIV infection results in several interleukins and tumor necrosis factor-α (TNF-α) in response to production of viral proteins by the virus. The HIV-transactivator of transcription protein (*tat*) and viral envelope glycoprotein component (gp120) are believed to induce and mediate the inflammatory responses to vessels. This inflammation consequently results in the production of cytokines and adhesion molecules that interfere with endothelial function. In essence, the viral protein accesses the smooth muscle component of the media layer through CD4 surface receptor. Ultimately, this results into abnormal proliferation of the smooth muscle, and abnormal activation of the coagulation cascade [6–10].

Histological studies show an infiltration of the large vessels surrounded by different inflammatory cells including neutrophils, lymphocytes, monocytes and plasma cells in HIV-infected persons. The infiltration of those cells results in obliterate endarteritis, which is an occlusion of the vessels supplying the vasa vasorum, and leads to ischemia, and necrotic changes of the vessel wall are induced [7–11]. Studies of the biopsy and culture of those aneurysms, however, fail to reveal infectious pathogens.

A murine AIDS model has helped investigate pathogenesis of acquired AIDS. In this model the murine leukemia virus (MuLV) is injected into mice. The mice characteristically develop hypergammaglobulinemia, splenomegaly, lymphadenopathy, T-cell and B-cell functional abnormality. The mice also become highly susceptible to opportunistic infections. The murine AIDS and human AIDS have a lot of similarities regarding immune function alterations. Further clinical progression based on this model and vessel wall animal models has suggested a link between endothelial dysfunction and vasculopathy. It has been found that aortas from infected mice have increased concentrations of ICAM-1 and VCAM-1. Moreover, decrease in their contractile responses and impairment in the endothelium-dependent relaxation are observed.

Pathological findings, conversely, have indicated the thinning of the media layer as a result of the viral infection. In addition, they have indicated a direct viral invasion of the aortic fibroblasts at the level of the adventitia. It has therefore been postulated that an autoimmune destructive process can happen as a result of the similarity in the DNA sequence of the viral glycoprotein and a component of the matrix of the vessel wall. Important to note is that, no strong evidence has been found to support this theory.

It has been postulated that an autoimmune destructive process is possible where there is a DNA sequence of the viral glycoprotein, and a component of the matrix of the vessel wall. This, however, is not fully agreeable as there is lack of strong evidence to support the theory [8–12].

To diagnose HIV-associated vasculopathy, other causes of arterial occlusions and aneurysms have to be eliminated. These are mycotic aneurysms caused by syphilis and tuberculosis. Second, arterial occlusions caused by Takayasu's arteritis, vasculitis, and systemic lupus erythematosus (SLE) and Behcet's disease. Finally, elimination of antiphospholipid antibody syndrome-related aneurysms which make close differentials [13–15].

Recent studies indicate that various symptoms of HIV disease have been affecting almost all body organs. For example, studies in radiological, clinical and postmortem indicated cerebral, cardiac, renal and peripheral vascular pathologies in HIV-infected persons. This chapter will look at different HIV-associated vasculopathies affecting the main organ systems in a body.

## **2. HIV-associated large vessel aneurysm**

There have been major improvements in novel clinical management in a bid to manage HIV [2]. For instance in 1987, HIV was for the first time linked to vasculopathy, impulsive arteriovenous fistula and arterial occlusive disease or aneurysmal infection [4]. The prevalence of symptomatic vasculitis in HIV patients is about 1% according to recent studies [5]. The chief objective of this review will be to describe the HIV-associated vasculopathies in various parts of the body. Pathogenecity of HIV, which is associated with vasculopathy, is rather complex and hence not fully comprehended. The complexity is a result of several factors such as inflammatory and immunological response to HIV infections. These factors lead to deleterious and dynamic

HIV infection results in several interleukins and tumor necrosis factor-α (TNF-α) in response to production of viral proteins by the virus. The HIV-transactivator of transcription protein (*tat*) and viral envelope glycoprotein component (gp120) are believed to induce and mediate the inflammatory responses to vessels. This inflammation consequently results in the production of cytokines and adhesion molecules that interfere with endothelial function. In essence, the viral protein accesses the smooth muscle component of the media layer through CD4 surface receptor. Ultimately, this results into abnormal proliferation of the smooth muscle, and

Histological studies show an infiltration of the large vessels surrounded by different inflammatory cells including neutrophils, lymphocytes, monocytes and plasma cells in HIV-infected persons. The infiltration of those cells results in obliterate endarteritis, which is an occlusion of the vessels supplying the vasa vasorum, and leads to ischemia, and necrotic changes of the vessel wall are induced [7–11]. Studies of the biopsy and culture of those aneurysms, how-

A murine AIDS model has helped investigate pathogenesis of acquired AIDS. In this model the murine leukemia virus (MuLV) is injected into mice. The mice characteristically develop hypergammaglobulinemia, splenomegaly, lymphadenopathy, T-cell and B-cell functional abnormality. The mice also become highly susceptible to opportunistic infections. The murine AIDS and human AIDS have a lot of similarities regarding immune function alterations. Further clinical progression based on this model and vessel wall animal models has suggested a link between endothelial dysfunction and vasculopathy. It has been found that aortas from infected mice have increased concentrations of ICAM-1 and VCAM-1. Moreover, decrease in their contractile

Pathological findings, conversely, have indicated the thinning of the media layer as a result of the viral infection. In addition, they have indicated a direct viral invasion of the aortic fibroblasts at the level of the adventitia. It has therefore been postulated that an autoimmune destructive process can happen as a result of the similarity in the DNA sequence of the viral glycoprotein and a component of the matrix of the vessel wall. Important to note is that, no

It has been postulated that an autoimmune destructive process is possible where there is a DNA sequence of the viral glycoprotein, and a component of the matrix of the vessel wall. This, however, is not fully agreeable as there is lack of strong evidence to support the theory [8–12].

responses and impairment in the endothelium-dependent relaxation are observed.

effects on the endothelial and smooth muscle cells of the blood vessels.

abnormal activation of the coagulation cascade [6–10].

strong evidence has been found to support this theory.

ever, fail to reveal infectious pathogens.

44 HIV/AIDS - Contemporary Challenges

The large arteries' condition in HIV-infected persons is not very researched, as it is a rare occurrence. Its pathology is different from atherosclerosis and mycotic aneurysm. It is considered a distinct clinical and pathological entity. It is non-infective vasculopathy, where the microbiological cultures of blood, aneurysm wall and thrombus are negative. Furthermore, the patients with atherosclerotic aneurismal disease are older in comparison to patients with aneurysms related to HIV. HIV-related aneurysm is commonly found in young patients in their 30s [10–14].

While the condition stands to affect any large artery, aneurysms typically affect superficial femoral, carotid and popliteal artery. Aneurysms are not uncommonly found to be multiple and have primarily pseudoaneurysm-like focal saccular transformations. Medical practitioners are therefore advised to screen patients for multiplicity using ultrasound or CT scan with contrast. Leukocytoclastic vasculitis of the vasa vasorum and periadventitial vessels is an important mechanism which weakens the wall of the vessel, and leads to focal disruption of the wall at the position of transmural necrosis. This mainly causes the false impression of aneurysm [9, 10, 13, 14]. The symptoms associated with the aneurysm depend on its location and size. It might be that compressive symptoms in an adjacent organ or structure result in life-threatening hemodynamic instability in case of a rupture. Thromboembolic and venous thrombosis are also likely complications of the aneurysm which have often been reported.

Majority of HIV-infected persons with associated aneurysm have advanced immunosuppressed state. This is usually indicated by abnormally reversed CD4:CD8 ratio. Such patients illustrate an abnormally low CD4 count (a median of about 400 cells/μl only). In addition, if such patients have high globulin level, they exhibit low serum albumin consistently [9–13].

While deciding the management approach of HIV-infected persons with asymptomatic aneurysm, it's important to take into consideration their clinical condition and nutrition status. With this in mind, symptomatic aneurysm lesions should be treated according to the standard guidelines, rules and open surgery standard therapy. The use of endovascular therapy has also gained popularity over the past years. HIV-infected patients should be optimized according to standard practice such as an earlier intervention. Conservative treatment on the other hand would be the best option for patients with advanced HIV/ AIDS. Low albumin (<35 g/l) and CD4 count are both indicators of poor operative outcome. Clinical management should, however, maintain a consistency in administering antiretroviral therapy regardless of CD4 level. This is because such prevalence is indicator of an advanced phase of the condition [8–11, 13, 14].

## **3. Cerebral vasculopathy**

Cerebral vasculopathy in HIV-infected patients is infrequently observed. The disease is believed to be under-diagnosed in most cases according to recent reports. HIV vasculopathy of the central nervous system affects small- to medium-sized blood vessels. The HIVassociated aneurysmal disease is frequently of a fusiform type, and occurs in young adults. This type of aneurysm affects carotids and extracranial vessels mainly. On the other hand, the intracranial aneurysm is a rare discovery and is often observed in children. Some reports have linked the low CD4 counts to increased chances of intracerebral vasculopathy occurrence [11, 12, 15, 16].

The primary pathogenesis of intracerebral vasculopathy is not known. However, various studies have shown that postmortem histological examination indicates damage of the interior elastic lamina and fibrosis. This histological examination has also shown interference of the media along with intimal hyperplasia. The resulting aneurysmal and occlusive patterns of this disease tend to lead to ischemic and/or hemorrhagic complications [10–14].

The pathogenesis of HIV-associated cerebral aneurysms has also been postulated to be a result of immune response to the HIV protein. This occurs, according to various researches, inside the endothelial cell. It has been suggested that the use of antiretroviral therapy may exacerbate the vasculopathy because it can lead to immune reconstitution inflammatory syndrome (IRIS) [15, 16].

A similar theory suggested that an abnormal and significant change in the vascular response to blood flow, which occurs due to changes in circulating cytokines and growth factors, can lead to vascular remodeling. These changes are thought to play a main role in aneurismal dilatation. The production of cytokines and growth factors is believed to be caused by opportunistic infections, which involve the blood vessel endothelial wall, allowing it to abnormally increase. Such repeated infections contribute to an amplified production of elastase, which increases the thickness and fragmentation of the internal elastic lamina. Such changes in the lamina are associated with development of fusiform aneurysms. Because of this suggested association, patients with cerebral aneurysm should be investigated for underlying opportunistic infections [11–13].

## **4. Carotid disease in HIV patients**

Carotid intima-media thickness (IMT) measurement by B-mode high-resolution ultrasound is a noninvasive method of assessing atherosclerosis. It is also a strong predictor of cardiovascular events. IMT is considered in HIV persons to evaluate cardiovascular risk.

The prevalence of carotid atherosclerosis in HIV population varies, and correlates with Framingham risk score (FRS). The higher the FRS, the higher the prevalence. The prevalence is estimated to be 26.6% in the very low-risk group and 76.5% in high-risk group. The carotid IMT of individuals with HIV infection was, on average, 0.04 mm thicker (95% confidence interval; and 0.02–0.06 mm, p < 0.001) than that of individuals without HIV infection. Carotid plaque also has been found to be 1.5-fold more frequent in HIV patients in comparison to non-infected persons.

It is believed that the traditional CVD risk factors, in addition to HIV infection factors, play a role in this pathology. However, the role of ART is still not clearly confirmed. There are several studies that have suggested the use of ART as a significant and an independent risk associated with carotid atherosclerosis in HIV-infected patients. Moreover, it has been found that there is a moderate independent association between HIV immunological marker and increased carotid IMT and plaque presence [16, 17].

## **5. HIV-associated vascular thrombosis**

should, however, maintain a consistency in administering antiretroviral therapy regardless of CD4 level. This is because such prevalence is indicator of an advanced phase of the condition

Cerebral vasculopathy in HIV-infected patients is infrequently observed. The disease is believed to be under-diagnosed in most cases according to recent reports. HIV vasculopathy of the central nervous system affects small- to medium-sized blood vessels. The HIVassociated aneurysmal disease is frequently of a fusiform type, and occurs in young adults. This type of aneurysm affects carotids and extracranial vessels mainly. On the other hand, the intracranial aneurysm is a rare discovery and is often observed in children. Some reports have linked the low CD4 counts to increased chances of intracerebral vasculopathy occurrence [11,

The primary pathogenesis of intracerebral vasculopathy is not known. However, various studies have shown that postmortem histological examination indicates damage of the interior elastic lamina and fibrosis. This histological examination has also shown interference of the media along with intimal hyperplasia. The resulting aneurysmal and occlusive patterns of

The pathogenesis of HIV-associated cerebral aneurysms has also been postulated to be a result of immune response to the HIV protein. This occurs, according to various researches, inside the endothelial cell. It has been suggested that the use of antiretroviral therapy may exacerbate the vasculopathy because it can lead to immune reconstitution inflammatory syn-

A similar theory suggested that an abnormal and significant change in the vascular response to blood flow, which occurs due to changes in circulating cytokines and growth factors, can lead to vascular remodeling. These changes are thought to play a main role in aneurismal dilatation. The production of cytokines and growth factors is believed to be caused by opportunistic infections, which involve the blood vessel endothelial wall, allowing it to abnormally increase. Such repeated infections contribute to an amplified production of elastase, which increases the thickness and fragmentation of the internal elastic lamina. Such changes in the lamina are associated with development of fusiform aneurysms. Because of this suggested association, patients with cerebral aneurysm should be investigated for underlying opportu-

Carotid intima-media thickness (IMT) measurement by B-mode high-resolution ultrasound is a noninvasive method of assessing atherosclerosis. It is also a strong predictor of cardiovascu-

lar events. IMT is considered in HIV persons to evaluate cardiovascular risk.

this disease tend to lead to ischemic and/or hemorrhagic complications [10–14].

[8–11, 13, 14].

12, 15, 16].

drome (IRIS) [15, 16].

nistic infections [11–13].

**4. Carotid disease in HIV patients**

**3. Cerebral vasculopathy**

46 HIV/AIDS - Contemporary Challenges

Even though women comprise the highest population of HIV-infected persons in Africa, their male counterparts are said to be more likely to have primary arterial thrombosis. In addition, they are likely to present with late advanced limb ischemia. The pathophysiology of this disease is not well comprehended. Several causes of primary HIV infection-associated thrombosis have been documented. The levels of total proteins and the von Willebrand factor have been found to be increased in such patients. This suggested that endothelial cell dysfunction may play a role, as a predisposing factor for primary thrombosis. Hypercoagulable states associated with the HIV infection, including antiphospholipid antibody syndrome, deficiencies in free protein S, protein C, and antithrombin III, could predispose patients to arterial thrombosis [18, 19].

What is unique about HIV-associated vascular thrombosis is the normality of the arterial tree proximal to the thrombosed arteries by duplex ultrasonography, angiography and macroscopic appearance. Second is the thrombosis of all distal vessels with no demonstrable runoff. Duplex ultrasonography also showed hyperechoic 'spotting' in the arterial wall, the 'string of pearls sign', which has also been observed in patients with HIV-associated arterial aneurysms. Both endothelial dysfunction and coagulation abnormality of the HIV patients were found to correlate with the state of immunosuppression [19, 20].

When managing HIV-associated occlusive vasculopathy, the vascular surgical rules should be followed. Patients having less CD4 count should not be excluded from surgical intervention, since surgical findings show that its success does not depend on CD4 levels. The treatment for primary arterial thrombosis includes surgical thrombectomy with or without thrombolysis. The use of corticosteroid post thrombectomy has been considered previously, although it did not decrease the rethrombosis rate. The treatment modality available unfortunately did not significantly alter the level of amputation. The rate of limb salvage in such cases is about 27%. According to therapy researches, it is clear that therapies do not address the underlying ongoing processes. It's important to note that such studies are only but a few; they are sporadic and reflect individual experiences [19–24].

Venous thrombosis is reported as a complication in HIV-infected patients. It is believed to be a result of disturbance of coagulation process. It is estimated that deep vein thrombosis in HIVinfected patients of up to 5% is attributable to a process of thrombophilia. In addition, protein anticardiolipin antibodies and protein C deficiency have been reported in such patients [25–29].

## **6. HIV-associated peripheral arterial disease**

Peripheral arterial disease is a significant clinical management issue in HIV-infected patients. The disease creates a risk of cardiovascular disease, and is associated with increased morbidity and mortality rate. HIV-infected individuals are believed to have higher prevalence and more severe forms of PAD. Measuring ankle-brachial index (ABI) is the initial noninvasive test to diagnose PAD. It usually correlates to obstructive disease and more than 50% stenosis by angiography in the lower extremity arterial system, if abnormal. Moreover, post-exercise ABI measurement could be used to uncover milder diseases.

Low ABI and high ABI readings have been linked to atherosclerosis and increased cardiovascular events. The exact prevalence of PAD in HIV population is still under-studied and not clearly defined. The studies are not numerous and the existing ones show contradicting results. However, the prevalence is believed to be higher than in normal population and in the range of 9.8–13.9%. High ABI prevalence in HIV patients has risen and is estimated to be in the range of 13.3–19.7%. However, none of the classical vascular risk factors were associated with ABI measurements.

Post-exercise ABI measurement change is suggestive of PAD in HIV-infected patients. It has been reported to range from 10.9% to 26.5%, depending on the criteria used. The exercise test was performed to symptomatic versus asymptomatic HIV-patients. Interestingly, the postexercise changes in ABI are not associated with traditional atherosclerosis risk factors such as diabetes mellitus, hypertensive disorder and dyslipidemia. Screening for subclinical PAD using post-exercise measurement is encouraged in HIV-infected patients, even when they do not depict symptoms of PAD. PAD has a frequent occurrence in young HIV population and coexists with critical limb ischemia. In HIV-infected patients, there is growing evidence suggesting a high prevalence of PAD and a higher risk of developing severe and accelerated atherosclerosis. PAD in HIV patients is six-fold more than in HIV-negative patients [30–33].

The antiretroviral protease inhibitor induces dyslipidemia, making HIV infection a risk factor for atherosclerosis. HIV causes direct injury to the arterial wall, resulting in the initiation of the inflammatory process. Such inflammations contribute to the development of premature atherosclerosis. Endothelial dysfunction in HIV-infected patients is associated with increasing levels of soluble adhesion molecules, cytokines and procoagulant proteins. The effect of the HIV-associated proteins gp(120 )on endothelium have been suggested to cause endothelial dysfunction [25–28, 32, 33]. In addition, PAD in HIV-infected patients can occur even in undetectable viral levels or in absence of severely suppressed immune system. This can be explained by the chronic inflammatory state in HIV patients. PAD, in addition, does not correlate to Framingham risk score in the HIV-infected population [34].

## **7. HIV and atherosclerotic coronary artery disease**

Venous thrombosis is reported as a complication in HIV-infected patients. It is believed to be a result of disturbance of coagulation process. It is estimated that deep vein thrombosis in HIVinfected patients of up to 5% is attributable to a process of thrombophilia. In addition, protein anticardiolipin antibodies and protein C deficiency have been reported in such patients [25–29].

Peripheral arterial disease is a significant clinical management issue in HIV-infected patients. The disease creates a risk of cardiovascular disease, and is associated with increased morbidity and mortality rate. HIV-infected individuals are believed to have higher prevalence and more severe forms of PAD. Measuring ankle-brachial index (ABI) is the initial noninvasive test to diagnose PAD. It usually correlates to obstructive disease and more than 50% stenosis by angiography in the lower extremity arterial system, if abnormal. Moreover, post-exercise

Low ABI and high ABI readings have been linked to atherosclerosis and increased cardiovascular events. The exact prevalence of PAD in HIV population is still under-studied and not clearly defined. The studies are not numerous and the existing ones show contradicting results. However, the prevalence is believed to be higher than in normal population and in the range of 9.8–13.9%. High ABI prevalence in HIV patients has risen and is estimated to be in the range of 13.3–19.7%. However, none of the classical vascular risk factors were associated

Post-exercise ABI measurement change is suggestive of PAD in HIV-infected patients. It has been reported to range from 10.9% to 26.5%, depending on the criteria used. The exercise test was performed to symptomatic versus asymptomatic HIV-patients. Interestingly, the postexercise changes in ABI are not associated with traditional atherosclerosis risk factors such as diabetes mellitus, hypertensive disorder and dyslipidemia. Screening for subclinical PAD using post-exercise measurement is encouraged in HIV-infected patients, even when they do not depict symptoms of PAD. PAD has a frequent occurrence in young HIV population and coexists with critical limb ischemia. In HIV-infected patients, there is growing evidence suggesting a high prevalence of PAD and a higher risk of developing severe and accelerated atherosclerosis. PAD in HIV patients is six-fold more than in HIV-negative patients [30–33]. The antiretroviral protease inhibitor induces dyslipidemia, making HIV infection a risk factor for atherosclerosis. HIV causes direct injury to the arterial wall, resulting in the initiation of the inflammatory process. Such inflammations contribute to the development of premature atherosclerosis. Endothelial dysfunction in HIV-infected patients is associated with increasing levels of soluble adhesion molecules, cytokines and procoagulant proteins. The effect of the HIV-associated proteins gp(120 )on endothelium have been suggested to cause endothelial dysfunction [25–28, 32, 33]. In addition, PAD in HIV-infected patients can occur even in undetectable viral levels or in absence of severely suppressed immune system. This can be explained by the chronic inflammatory state in HIV patients. PAD, in addition, does not cor-

**6. HIV-associated peripheral arterial disease**

ABI measurement could be used to uncover milder diseases.

relate to Framingham risk score in the HIV-infected population [34].

with ABI measurements.

48 HIV/AIDS - Contemporary Challenges

HIV-infected patients live longer since the introduction of ART. It is believed that the risk of atherosclerosis in HIV patients is increased because of associated metabolic disturbances. The coronary disease in such infected individuals is considered distinctive. It is usually more diffuse and is associated with circumferential-intimal thickening, atherosclerotic plaques and abnormal proliferation of the smooth muscle. The muscles with luminal protrusions share several similarities with cardiac transplant vasculopathy [34–38]. Reports have suggested that the most common initial presentation of the HIV patient with CAD is acute myocardial infarction and its mortality can go as high as 24%. In addition, more than 40% test positive to triple vessel disease [39–41].

Coronary artery disease (CAD) is commonly observed in patients who are on ART. During a study conducted on this, HIV-infected patients who were not using ART showed a slight risk of ischemic heart disease. The risk was slightly higher in HIV-infected persons who were on ART. However, during the post-ART period there was a significant increase in the risk of ischemic cardiac disease in the HIV-infected population. The 3-year risk for myocardial infarction was 3.6-fold higher in patients on ART in comparison to those who were not [34, 38–43].

There are numerous metabolic changes that are associated with ART (protease inhibitor in particular). They include impaired glucose metabolism and lipodystrophy as a result of increased insulin insensitivity, and they tend to accelerate the atherosclerosis process. The data regarding nucleoside reverse transcriptase inhibitors, as a risk for CAD, are not very clear. In a D.A.D study, abacavir and didanosine were found to be associated with increased risk of myocardial infarction. Consequently, abacavir has been linked to higher cardiovascular events in first 6 months of the infection. Conversely, other studies could not establish a similar relationship, especially after controlling the traditional cardiovascular risk factors. Furthermore, no link was established in non-nucleoside reverse transcriptase inhibitors and integrase inhibitors as an association with cardiovascular events [20, 44–47].

On one hand, HIV infection has been postulated to independently increase the risk of premature CAD. The mechanism by which the virus can accelerate atherosclerosis is multifactorial and complex. This mechanism involves the activation of inflammatory cells, which changes the immune response in HIV patients. This leads to exposure to a variety of xenoantigens from HIV infection and other viral and bacterial infections. These infections result in the ignition of a continuous inflammatory condition that speeds up atherosclerosis [21, 30, 34].

Endothelial dysfunction is an early marker of atherosclerosis. Endothelial dysfunction has been found in young HIV-infected individuals and has been attributed to increased viral load. HIV affects directly the endothelium function and results in increased levels of prothrombotic plasma markers such as von Willebrand factor, b2 microglobulin and thrombomodulin. In addition, it leads to increased levels of the circulating inflammatory molecules, interleukin 6 and D-dimer.

Prevention of CAD is a cornerstone in clinically managing HIV-infected patients. Careful cardiac screening of individuals who are receiving ART is important. Patients with a history in cardiovascular risk factors stand to benefit from such screening as they are at a higher risk. Identification of asymptomatic atherosclerotic diseases of the coronaries would help to maximize patients' therapy. By the use of risk stratification tests such as coronary artery calcium score, high sensitivity C-reactive protein and carotid intima-medial thickness, HIV patients with higher risk of cardiovascular events can be identified. This will protect such patients from aggressive risk factors through modification and preventive measures.

Interruption of chronic ART therapy is highly discouraged as it could lead to increase in cardiovascular-associated morbidity and mortality. The SMART study has shown that the risk of cardiovascular morbidity and mortality has increased significantly. This is in patients who were assigned to a CD4 cell count guided therapy arm, as compared to their counter parts with continuous therapy arm. However, no studies or theories support an association of CD4 count and CAD [34, 43].

The conventional cardiovascular risk factors are found to be higher in HIV patients. Patients with smoking habits particularly, experience increased risk of atherosclerosis and increase the prothrombotic state [38, 39]. Controlling and modifying the risk factors and comorbidities is important in managing atherosclerosis. The fasting lipids should be checked before starting ART, and followed up to adjust therapy according to the lipids' value changes. If statin therapy is needed to treat high low-density lipoprotein (LDL) levels, the dose to be used should be identified carefully. This is because the risk of statin drug interaction and possible rhabdomyolysis is higher in HIV patients. PI, ritonavir and some antimicrobial agents inhibit specific cytochrome P450 enzymes, which are important in metabolizing several statins. This is because such agents could increase the toxicity of those drugs. Pravastatin (20–40 mg), low-dose atorvastatin (10 mg) and rosuvastatin (5–10 mg) have been suggested as safe if used with protease inhibitors. Ezetimibe can also be added to statin therapy to achieve target levels of LDL. Fibrates are used to control hypertriglyceridemia, if the concentration is above 500 mg/dL.

## **8. Pulmonary arterial hypertension**

HIV-related pulmonary arterial hypertension (PHT) is estimated to occur in 0.5% of the HIV population. It is usually present with nonspecific symptoms such as dyspnea on exertion, lower extremity edema and fatigue. PHT is considered a poor prognostic finding and it is said to lead to right ventricular dysfunction, therefore significantly increasing the mortality rate.

The pathogenesis of HIV-related PHT is complex and still not very well understood. Factors that are believed to participate in the pathogenesis are related to the viral infection in patients. It is believed that the HIV virus stimulates an immune response, which leads to the release of different cytokines and growth factors. This may include the potent vasoconstrictors, endothelin-1, interleukin 6, tumor necrosis factor and platelet-derived growth factor. These immunological responses result in endothelial damage, intimal fibrosis, and stimulate the proliferation of the smooth muscle and fibroblast of the arterioles. Eventually, the pathological structural changes lead to the formation of plexiform lesion. The lesion is quite similar to those found in PaHTN caused by other factors. More recent evidence suggests that the patient's immunologic response, virus HIV-negative factor (Nef), HIV-transactivator of transcription (Tat) accessory proteins and human herpes virus-8 coinfection, may play an important role to cascade events.

Its prognosis is poor and the reported mortality rate is said to be high. PaHTN in HIV population is an independent predictor of mortality with 1-year survival rate reported to range from 51% to 88%. The severity of HIV infection and CD4 cell count has no apparent correlation with this complication. The effect of highly active antiretroviral therapy regimens on the clinical course is still not well defined and is presently being investigated. However, it has been suggested that long-duration treatment with HAART might reduce mortality rate. Currently the treatment of HIV-PaHTN is similar to that of idiopathic pulmonary arterial hypertension patients. There have been reports of the use of diuretics, anticoagulation, phosphodiesterase V inhibitors and calcium channel blockers to treat HIV-PaHTN. HAART prostacyclin analogs (e.g.epoprostenol and endothelin) and receptor inhibitors (such as bosentan) were found to be effective in reducing the pulmonary arterial pressure in HIV patients. Heart-lung transplantation is the last treatment option in this subgroup of patients [21, 22, 34].

## **9. Conclusion**

Identification of asymptomatic atherosclerotic diseases of the coronaries would help to maximize patients' therapy. By the use of risk stratification tests such as coronary artery calcium score, high sensitivity C-reactive protein and carotid intima-medial thickness, HIV patients with higher risk of cardiovascular events can be identified. This will protect such patients

Interruption of chronic ART therapy is highly discouraged as it could lead to increase in cardiovascular-associated morbidity and mortality. The SMART study has shown that the risk of cardiovascular morbidity and mortality has increased significantly. This is in patients who were assigned to a CD4 cell count guided therapy arm, as compared to their counter parts with continuous therapy arm. However, no studies or theories support an association of

The conventional cardiovascular risk factors are found to be higher in HIV patients. Patients with smoking habits particularly, experience increased risk of atherosclerosis and increase the prothrombotic state [38, 39]. Controlling and modifying the risk factors and comorbidities is important in managing atherosclerosis. The fasting lipids should be checked before starting ART, and followed up to adjust therapy according to the lipids' value changes. If statin therapy is needed to treat high low-density lipoprotein (LDL) levels, the dose to be used should be identified carefully. This is because the risk of statin drug interaction and possible rhabdomyolysis is higher in HIV patients. PI, ritonavir and some antimicrobial agents inhibit specific cytochrome P450 enzymes, which are important in metabolizing several statins. This is because such agents could increase the toxicity of those drugs. Pravastatin (20–40 mg), low-dose atorvastatin (10 mg) and rosuvastatin (5–10 mg) have been suggested as safe if used with protease inhibitors. Ezetimibe can also be added to statin therapy to achieve target levels of LDL. Fibrates are used to control hypertriglyceridemia, if the concentration is above 500 mg/dL.

HIV-related pulmonary arterial hypertension (PHT) is estimated to occur in 0.5% of the HIV population. It is usually present with nonspecific symptoms such as dyspnea on exertion, lower extremity edema and fatigue. PHT is considered a poor prognostic finding and it is said to lead to right ventricular dysfunction, therefore significantly increasing the mortality rate. The pathogenesis of HIV-related PHT is complex and still not very well understood. Factors that are believed to participate in the pathogenesis are related to the viral infection in patients. It is believed that the HIV virus stimulates an immune response, which leads to the release of different cytokines and growth factors. This may include the potent vasoconstrictors, endothelin-1, interleukin 6, tumor necrosis factor and platelet-derived growth factor. These immunological responses result in endothelial damage, intimal fibrosis, and stimulate the proliferation of the smooth muscle and fibroblast of the arterioles. Eventually, the pathological structural changes lead to the formation of plexiform lesion. The lesion is quite similar to those found in PaHTN caused by other factors. More recent evidence suggests that the patient's immunologic response, virus HIV-negative factor (Nef), HIV-transactivator of tran-

from aggressive risk factors through modification and preventive measures.

CD4 count and CAD [34, 43].

50 HIV/AIDS - Contemporary Challenges

**8. Pulmonary arterial hypertension**

HIV-associated vascular diseases is not a common occurrence, even though it is considered to be of significant clinical importance. A comprehensive screening for possible etiology such as co-infections, lymphoproliferative disease, and autoimmune disorders, before other pathological attributions to HIV infection is important for appropriate patients' management. HIVassociated vascular disease can be manifested either as aneurysms or occlusive forms. The two forms of diseases can lead to hemorrhagic or ischemic life-threatening complications, respectively.

## **Author details**

Ashraf Alqaqa

Address all correspondence to<EMAIL_ADDRESS>
Tennova Healthcare, Tennessee, USA

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#### **Anti-Retroviral–Based HIV Pre-Exposure Prophylaxis for Women: Recent Advances and Next Steps Anti-Retroviral–Based HIV Pre-Exposure Prophylaxis for Women: Recent Advances and Next Steps**

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Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67163

#### **Abstract**

There is a daunting challenge to prevent human immunodeficiency virus (HIV) acquisition in women at high risk of acquiring HIV. Of the 37 million people globally living with HIV, more than half are women. Women account for nearly 60% of adults with HIV in sub-Saharan Africa, where unprotected heterosexual sex is the primary driver of the epidemic. While male condoms are effective, they are not always used, and this is not something women can control. Women urgently need prevention tools they can decide to use, independent of a husband or partner. Pre-exposure prophylaxis (PrEP), in which HIV-uninfected persons with ongoing HIV risk use antiretroviral (ARV) medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy. We review recent advances in the development of new biomedical HIV prevention interventions with a highlight of findings from pivotal clinical trials, as well as a discussion on future generation strategies for women.

**Keywords:** HIV, women, tenofovir, dapivirine, pre-exposure prophylaxis

## **1. Introduction**

In 2015, 2.1 million people became newly infected with Human Immuno Deficiency Virus (HIV) and 1.1 million died from Acquired Immuno Deficiency Syndrome (AIDS) related illnesses [1]. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) Global Report, 70 percent of the 37 million people estimated to be living with HIV reside in sub-Saharan Africa [1]. In this setting, where unprotected heterosexual sex is the primary driver of the epidemic, women account for nearly 60 percent of adults with HIV.

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

While existing HIV-1 prevention interventions including behavior change, use of male and female condoms, treatment of sexually transmitted infections (STIs), male circumcision, and uptake of antiretroviral (ARV) treatment to reduce the infectiousness of persons with HIV-1 have gone a long way in controlling the spread of HIV-1 infection [2–6], HIV-1 rates in young women in resource limited settings remain unacceptably high [1]. This is in part, because many HIV-1 prevention methods require the participation or consent of a male partner. Women urgently need prevention tools they can decide to use, independent of a husband or partner [7]. Developing HIV prevention options that women can use therefore remains a global concern, given the soaring rates of HIV infection among women. Preexposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a promising new HIV prevention strategy [8–11].

## **2. HIV prevention biomedical interventions**

#### **2.1. Microbicides**

#### *2.1.1. CAPRISA 004*

Tenofovir gel was the first ARV-based microbicide to be tested in an effectiveness trial. CAPRISA 004 was a phase 2B microbicide study that tested peri-coitally applied 1% TDF vaginal gel among 889 South African women conducted from May 2007 to March 2010. The trial found a 39% (95% CI, 6–60%; p = 0.017) lower HIV infection rate in women using 1% tenofovir gel as compared to the women using placebo gel when used in a coitally dependent regimen [12]. Tenofovir gel was shown to be safe when used up to 12 h before sex and again within 12 h after sex (BAT), for a maximum of two doses in 24 h. The drug was found to be 54% effective among women who were the highest adherers (gel adherence > 80%). Participants who adhered to the dosing regimen in more than 80% of sex acts were the least likely to acquire HIV (54% lower risk of infection).

#### *2.1.2. FACTS 001*

FACTS 001 was a phase III safety and effectiveness double-blind, randomised, placebo-controlled trial of pericoital tenofovir 1% gel for HIV prevention in 18–30 year Women at nine sites in South Africa [17]. The study evaluated the safety and effectiveness of pericoital TFV 1% gel when using the BAT-24 regimen (before and after sex; no more than 2 doses in 24 h) among women at nine sites in South Africa. A total of 2059 women were randomized to tenofovir 1% gel or to placebo and instructed women to apply the gel 12 h before and within 12 h after sex, the same schedule used in CAPRISA 004. The study was conducted between Oct 2011 and Aug 2014. In 3036 person-years of observation accrued, 123 HIV infections occurred (HIV incidence: 4.0/100 women years); 61 in the TFV arm and 62 in the placebo group (incidence rate ratio [IRR], 1.0; 95% CI: 0.7–1.4). In a nested case-cohort sub-study (n = 214) that examined TFV drug levels in quarterly cervicovaginal lavage (CVL) samples in HIV seroconverters vs controls, high TFV in CVL was significantly associated with a reduction in HIV acquisition (HR, 0.52; 95% CI, 0.27–0.99; p = 0.04).

Considering all adherence data, the FACTS 001 team calculated that women used gel for an average of 50–60% of sex acts. Majority of participants were not able to achieve sufficiently high levels of gel coverage required for protection which underscores the need for a range of HIV prevention options for young women which may be easier to integrate into their lives.

## **2.2. Oral PrEP**

While existing HIV-1 prevention interventions including behavior change, use of male and female condoms, treatment of sexually transmitted infections (STIs), male circumcision, and uptake of antiretroviral (ARV) treatment to reduce the infectiousness of persons with HIV-1 have gone a long way in controlling the spread of HIV-1 infection [2–6], HIV-1 rates in young women in resource limited settings remain unacceptably high [1]. This is in part, because many HIV-1 prevention methods require the participation or consent of a male partner. Women urgently need prevention tools they can decide to use, independent of a husband or partner [7]. Developing HIV prevention options that women can use therefore remains a global concern, given the soaring rates of HIV infection among women. Preexposure prophylaxis (PrEP), in which HIV uninfected persons with ongoing HIV risk use antiretroviral medications as chemoprophylaxis against sexual HIV acquisition, is a prom-

Tenofovir gel was the first ARV-based microbicide to be tested in an effectiveness trial. CAPRISA 004 was a phase 2B microbicide study that tested peri-coitally applied 1% TDF vaginal gel among 889 South African women conducted from May 2007 to March 2010. The trial found a 39% (95% CI, 6–60%; p = 0.017) lower HIV infection rate in women using 1% tenofovir gel as compared to the women using placebo gel when used in a coitally dependent regimen [12]. Tenofovir gel was shown to be safe when used up to 12 h before sex and again within 12 h after sex (BAT), for a maximum of two doses in 24 h. The drug was found to be 54% effective among women who were the highest adherers (gel adherence > 80%). Participants who adhered to the dosing regimen in more than 80% of sex acts were the least

FACTS 001 was a phase III safety and effectiveness double-blind, randomised, placebo-controlled trial of pericoital tenofovir 1% gel for HIV prevention in 18–30 year Women at nine sites in South Africa [17]. The study evaluated the safety and effectiveness of pericoital TFV 1% gel when using the BAT-24 regimen (before and after sex; no more than 2 doses in 24 h) among women at nine sites in South Africa. A total of 2059 women were randomized to tenofovir 1% gel or to placebo and instructed women to apply the gel 12 h before and within 12 h after sex, the same schedule used in CAPRISA 004. The study was conducted between Oct 2011 and Aug 2014. In 3036 person-years of observation accrued, 123 HIV infections occurred (HIV incidence: 4.0/100 women years); 61 in the TFV arm and 62 in the placebo group (incidence rate ratio [IRR], 1.0; 95% CI: 0.7–1.4). In a nested case-cohort sub-study (n = 214) that

ising new HIV prevention strategy [8–11].

**2.1. Microbicides**

56 HIV/AIDS - Contemporary Challenges

*2.1.1. CAPRISA 004*

*2.1.2. FACTS 001*

**2. HIV prevention biomedical interventions**

likely to acquire HIV (54% lower risk of infection).

## *2.2.1. Partner's PrEP*

The Partners PrEP Study was a three-arm phase III, randomized, double-blind, placebo-controlled, 3-arm trial of daily oral TDF & FTC/TDF PrEP for the prevention of HIV acquisition by HIV seronegative partner in heterosexual HIV serodiscordant partnerships. It was one of the two land marker studies that provided evidence to support US Food and Drug Administration approval for FTC-TDF PrEP. The study demonstrated PrEP HIV protective effectiveness against HIV infection of 67% (95% CI 44–81%, p < 0.0001) for TDF and 75% (95% CI 55–87%, p < 0.0001) for FTC/TDF [13] compared to person receiving placebo. The HIV protection effects of TDF and FTC/TDF were in women and men. For TDF, efficacy among women was 71% and was 63% among men; for FTC/TDF, efficacy was 66% in women and 84% in men—all were statistically significant. In a follow-on open-label demonstration project of integrated delivery of ART and PrEP for prevention in HIV sero-discordant couples, the investigators observed virtual elimination of incident HIV [13].

## *2.2.2. FEM-PrEP Study*

The FEM-PrEP Study was a phase 3, randomized, placebo-controlled, trial that assessed of the effectiveness of daily oral FTC/TDF for HIV prevention among HIV-uninfected women 18–35 years in Kenya, South Africa and Tanzania [14]. The trial was stopped early by Independent Data Monitoring Committee due to futility at the time of study stop. No significant safety concerns were noted. Adherence by self-report and pill counts was high, but plasma drug levels revealed that only 15–26% of samples from seroconverters had TDF detected and only 26–38% of non-seroconverting controls. Thus, the investigators concluded that PrEP adherence was too low to assess PrEP's HIV protection. Less than 40% of the HIV-uninfected women in the TDF–FTC group had evidence of recent pill use at visits that were matched to the HIVinfection window for women with seroconversion.

## *2.2.3. TDF2 study*

The TDF2 study was a phase 2B study that assessed the safety, adherence and efficacy of daily oral FTC/TDF in 1200 (45.7% women) HIV-uninfected heterosexual male and female participants aged 18–39 years conducted in Botswana [15]. After a 1563 person-years of observation (median, 1.1 years; maximum, 3.7 years), FTC/TDF PrEP resulted in a 62.6% reduction in HIV acquisition for participants assigned to FTC/TDF compared to placebo (HR, 0.37; CI, 21.5– 83.4, p = 0.013). As treated analysis provided protective efficacy of 77.9% (95% CI, 41.2–93.6; p = 0.01) for FTC/TDF versus placebo, overall, and 75.4% (23.7, 94.4; p = 0.02) for women. No significant safety concerns were noted, though participants randomized to the FTC/TDF arm did experience more nausea, vomiting and dizziness than those randomized to placebo.

## *2.2.4. MTN-003/Vaginal and Oral Interventions to Control the Epidemic (VOICE)*

Was a phase 2B safety and effectiveness study of tenofovir 1% gel, tenofovir disoproxil fumarate tablet and emtricitabine/tenofovir disoproxil fumarate tablet for the prevention of HIV infection in women [16]. The primary aim of the VOICE trial was to estimate the safety and effectiveness of daily treatment with vaginal TFV gel, as compared with placebo gel, and of oral TDF and oral TDF-FTC, as compared with oral placebo, in preventing sexually acquired HIV-1 infection in women.

A total of 5029 were enrolled in the study were followed up monthly and assessed for HIV seroconversion. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was −49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97–2.29), −4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73–1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61–1.21). Adherence to study product among those in the active arms was generally very low. TFV was detectable in 30%, 29%, and 25% of random plasma samples from participants in the TDF, TDF-FTC, and TFV gel arms of the study, and an inverse correlation was demonstrable between detection of TFV in plasma and characteristics predictive of HIV-1 acquisition.

#### *2.2.5. Partner's demonstration project*

OLE projects have been called for as part of the pathway to scale-up of PrEP. Previous studies like the Partner's PrEP that assessed effectiveness of oral truvada and tenofovir for HIV prevention among sero-discordant couples in Kenya and Uganda have shown that when participants are given the active product through open-label access projects, even those with previous poor adherence during the clinical trial are now more likely to use product when they know they are now using the active product [13]. From a protection level of about 73% in the partner's PrEP, researchers have reported substantially reduced HIV risk of up to 95% when used with high adherence [17], **Figure 1**.

## **2.3. Vaginal rings**

#### *2.3.1. MTN-020— A Study to Prevent HIV Infection with a Ring with Extended ring (ASPIRE)*

Intravaginal rings offer a strategy to deliver antiretroviral PrEP medications with lesser opportunities for adherence challenges than for daily oral pills or vaginal gels [18]. ASPIRE was a phase III study conducted among 2629 sexually active HIV-negative women ages 18–45 at 15 clinical research sites in Malawi, Uganda, South Africa and Zimbabwe to determine whether a vaginal ring containing the ARV drug dapivirine is a safe and effective method for protecting against the sexual transmission of HIV when used by women for a month at a time. The study found HIV risk was reduced by 27% overall—for women group assigned to use the dapivirine ring compared placebo ring group—and 37% in a planned second analysis that excluded data from two sites with less than ideal retention and adherence. Notably high protection (56%) was observed in women >21 years, who also appeared to use the ring most consistently, **Figure 2** [10].

**Figure 1.** HIV incidence in Partner's PrEP demonstration project [17].

(median, 1.1 years; maximum, 3.7 years), FTC/TDF PrEP resulted in a 62.6% reduction in HIV acquisition for participants assigned to FTC/TDF compared to placebo (HR, 0.37; CI, 21.5– 83.4, p = 0.013). As treated analysis provided protective efficacy of 77.9% (95% CI, 41.2–93.6; p = 0.01) for FTC/TDF versus placebo, overall, and 75.4% (23.7, 94.4; p = 0.02) for women. No significant safety concerns were noted, though participants randomized to the FTC/TDF arm did experience more nausea, vomiting and dizziness than those randomized to placebo.

Was a phase 2B safety and effectiveness study of tenofovir 1% gel, tenofovir disoproxil fumarate tablet and emtricitabine/tenofovir disoproxil fumarate tablet for the prevention of HIV infection in women [16]. The primary aim of the VOICE trial was to estimate the safety and effectiveness of daily treatment with vaginal TFV gel, as compared with placebo gel, and of oral TDF and oral TDF-FTC, as compared with oral placebo, in preventing sexually acquired

A total of 5029 were enrolled in the study were followed up monthly and assessed for HIV seroconversion. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was −49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97–2.29), −4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73–1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61–1.21). Adherence to study product among those in the active arms was generally very low. TFV was detectable in 30%, 29%, and 25% of random plasma samples from participants in the TDF, TDF-FTC, and TFV gel arms of the study, and an inverse correlation was demonstrable between detection of TFV in plasma and characteristics predictive of HIV-1 acquisition.

OLE projects have been called for as part of the pathway to scale-up of PrEP. Previous studies like the Partner's PrEP that assessed effectiveness of oral truvada and tenofovir for HIV prevention among sero-discordant couples in Kenya and Uganda have shown that when participants are given the active product through open-label access projects, even those with previous poor adherence during the clinical trial are now more likely to use product when they know they are now using the active product [13]. From a protection level of about 73% in the partner's PrEP, researchers have reported substantially reduced HIV risk of up to 95%

*2.3.1. MTN-020— A Study to Prevent HIV Infection with a Ring with Extended ring (ASPIRE)*

Intravaginal rings offer a strategy to deliver antiretroviral PrEP medications with lesser opportunities for adherence challenges than for daily oral pills or vaginal gels [18]. ASPIRE was a phase III study conducted among 2629 sexually active HIV-negative women ages 18–45 at 15 clinical research sites in Malawi, Uganda, South Africa and Zimbabwe to determine

*2.2.4. MTN-003/Vaginal and Oral Interventions to Control the Epidemic (VOICE)*

HIV-1 infection in women.

58 HIV/AIDS - Contemporary Challenges

*2.2.5. Partner's demonstration project*

**2.3. Vaginal rings**

when used with high adherence [17], **Figure 1**.

**Figure 2.** Age and HIV-1 protection in ASPIRE [10].

A summary of the outcomes of recent HIV prevention trials among women is provided in **Table 1**.

**Table 1.** Outcomes of recent HIV prevention trials involving women.

#### *2.3.2. MTN-025—HIV open-label prevention extension (HOPE)*

HOPE is an open-label study of vaginal ring for preventing HIV among former ASPIRE participants. Women who took part in ASPIRE, a trial that found a vaginal ring containing an antiretroviral (ARV) drug called dapivirine was safe and helped protect against HIV, are now being offered the opportunity to use the ring as part of a new study called HOPE. HOPE builds on the results of ASPIRE by gathering additional information on the ring's safety, how women use the ring knowing that it can help reduce their risk of HIV and the relationship between adherence and HIV protection. Women who participated in a similar study called the RING study by the international partnership for microbicides (IPM) are being followed up under the dapivirine ring extended access and monitoring (DREAM OLE) protocol.

#### **2.4. Discussion**

High HIV incidence among young women in Africa [1] highlights the need for female-controlled HIV prevention. Social, structural and economic disparities perpetuate vulnerabilities of women. The lower social and economic power of women makes it difficult for them to negotiate safe sex [18]. In stable partnerships, condom use is low, and women are often unaware of their partner's HIV status [19]. Therefore, a need exists for HIV prevention methods that women can initiate themselves. Scaling up of proven biomedical technologies for women at high risk is therefore a high priority. Daily oral tenofovir-based PrEP, dapivirine vaginal ring and antiretroviral treatment as prevention are some of the promising biomedical technologies for prevention options for women.

A summary of the outcomes of recent HIV prevention trials among women is provided in

Women 889 39% [CI = 6–60]

Men and women 1200 62% [CI = 22–83]

Serodiscordant couples 4758 67% [CI = 44–81] efficacy

Women 1950 Futility of daily oral FTC/

Women 2629 27% [CI= 1–46]

2499 44% [CI = 15–63]

effectiveness of coitallydependent vaginal TFV gel

effectiveness of daily oral

effectiveness of daily oral

75% [CI = 55–87] efficacy daily oral FTC/TDF

effectiveness of dapivirine

FTC/TDF

FTC/TDF

TDF

daily oral TDF

6% [CI = −52 to 41]

vaginal ring

**Study Study population Sample size Results**

Gay men, other MSM, transgender women

HOPE is an open-label study of vaginal ring for preventing HIV among former ASPIRE participants. Women who took part in ASPIRE, a trial that found a vaginal ring containing an antiretroviral (ARV) drug called dapivirine was safe and helped protect against HIV, are now being offered the opportunity to use the ring as part of a new study called HOPE. HOPE builds on the results of ASPIRE by gathering additional information on the ring's safety, how women use the ring knowing that it can help reduce their risk of HIV and the relationship between adherence and HIV protection. Women who participated in a similar study called the RING study by the international partnership for microbicides (IPM) are being followed up

under the dapivirine ring extended access and monitoring (DREAM OLE) protocol.

High HIV incidence among young women in Africa [1] highlights the need for female-controlled HIV prevention. Social, structural and economic disparities perpetuate vulnerabilities of women. The lower social and economic power of women makes it difficult for them to negotiate safe sex [18]. In stable partnerships, condom use is low, and women are often unaware of their partner's HIV status [19]. Therefore, a need exists for HIV prevention methods that

*2.3.2. MTN-025—HIV open-label prevention extension (HOPE)*

**Table 1.** Outcomes of recent HIV prevention trials involving women.

**Table 1**.

CAPRISA 004 *South Africa* (Tenofovir Gel)

TDF2 Study *Botswana* (Oral Tenofovir)

FEM-PrEP

ASPIRE

Partners PrEP Study *Kenya, Uganda*

(Oral Truvada/Tenofovir)

*Kenya, S Africa, Tanzania* (Oral Truvada)

*Uganda, Malawi, South Africa, Zimbabwe*

*Brazil, Ecuador, Peru, South Africa, Thailand, US* (Oral Truvada)

60 HIV/AIDS - Contemporary Challenges

iPrEx

**2.4. Discussion**

Multiple studies of PrEP have shown that oral ARVs, when used consistently, reduce the risk of HIV infection in people who are at high risk by up to 92% including among women [5]. Currently, FTC-TDF is the medication with a label indication as PrEP against HIV acquisition recommended by the World Health Organization (WHO) and the United States Centers of Diseases Control and Prevention [20, 21]. Consequently, recent landmark approvals in sub-Saharan Africa, including South Africa [22] and Kenya [23], and commitment from large-scale funding partners (including PEPFAR) are leading to accelerated rollout of TDF-based PrEP for high-risk populations. TDF alone or TDF with lamivudine are other as an alternative to suggested by WHO [24]. Importantly, other new oral PrEP drugs (e.g. maraviroc) are currently being evaluated [25]. Although some PrEP trials in African women did not show effectiveness against HIV [14, 16, 26], follow-on analyses from those two studies have consistently provided strong evidence of very low adherence to PrEP in those studies [16, 27].

Prevention technologies such as vaginal ring containing ARV provide tremendous promise for the HIV prevention field as they provide HIV prevention options that fit in women's lives. The recent demonstration of moderate HIV protection conferred by monthly vaginal ring containing medication dapivirine is a step in right direction. An important feature of the dapivirine ring is its high level of safety [28]. This excellent safety profile also suggests that minimal medical monitoring would be needed, potentially making it both a practical and cost-effective option in under-resourced settings. The next step is to ensure that the vaginal ring is safe for all women at risk of HIV acquisition including pregnant and breastfeeding women.

For HIV uninfected women in known serodiscorant partnership, initiation and sustained use of ART by their infected male patterns are another highly effective prevention options for couples [5]. Women who want to conceive or with HIV positive partners who have not yet initiated ART, PrEP as bridge to ART prevention strategy is an attractive and highly effective HIV option. In PrEP as a bridge to ART strategy, PrEP is offered to HIV-uninfected person as a 'bridge' to ART in the discordant partnership—that is, until ART initiation by the HIVinfected partner and for the first 6 months after ART is started or viral suppression. This strategy demonstrated nearly elimination of HIV transmission within serodiscordant couples in Uganda and Kenya [29].

A robust pipeline of new PrEP drugs and formulations is not only important for advancing demonstrated success of products but also for addressing limitations of current biomedical technologies with the ultimate goal of prevention options that fit women's needs to ensure they will be used at scale. The current pipeline of ARV-based prevention products includes oral pills (miravorac), vaginal rings (tenofovir), vaginal and rectal gels, vaginal films, long-acting injectable ARVs (rilpivirine, cabotegravir) and multipurpose technologies that could combine ARV to reduce women's risk of HIV and STIs while providing effective contraception.

## **3. Summary**

Oral PrEP trials have demonstrated a decrease in HIV infection rates of between 44 and 77%. But it is now proven that with good adherence, Truvada, a once-a-day pill can reduce HIV infection rates by at least 92%. Because of high level of effectiveness, oral PrEP has been licensed for high-risk populations in the US, Canada, Kenya and South Africa. Efforts to have the dapivirine vaginal ring licensed for HIV prevention among women are currently underway. The process is an important one that takes time. It's anticipated that regulatory approvals could be received by 2018 in some countries in Africa. Results of the ASPIRE and RING studies are a boost to efforts focused on developing and evaluating next generation products, such a 3-month ring (just four rings would provide a woman a full year of protection), and combination rings that can provide protection against HIV, other STIs and unintended pregnancy. A vaginal ring could offer an important option as part of combination strategies or as a stand-alone method for women unable or not willing to use other strategies like medical male circumcision, condoms and oral PrEP.

## **Author details**

Flavia Matovu Kiweewa1,2,\*, Kenneth K. Mugwanya1,3 and Francis Kiweewa1,4

\*Address all correspondence to<EMAIL_ADDRESS>
1 Makerere University School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda

2 University of Witwatersrand, Johannesburg, South Africa

3 University of Washington, Seattle, United States

4 Makerere University-Walter Reed Project, Kampala, Uganda

## **References**

[5] Cohen MS, McCauley M, Gamble TR. HIV treatment as prevention and HPTN 052. Current Opinion in HIV and AIDS. 2012;7(2):99.

**3. Summary**

62 HIV/AIDS - Contemporary Challenges

circumcision, condoms and oral PrEP.

\*Address all correspondence to<EMAIL_ADDRESS>
3 University of Washington, Seattle, United States

2 University of Witwatersrand, Johannesburg, South Africa

4 Makerere University-Walter Reed Project, Kampala, Uganda

[1] UNAIDS. Report on the global AIDS epidemic 2015.

exposure prophylaxis. The Lancet HIV. 2015;2(6):e228.

**Author details**

**References**

Sciences, Kampala, Uganda

2007;369(9562):657–66.

Oral PrEP trials have demonstrated a decrease in HIV infection rates of between 44 and 77%. But it is now proven that with good adherence, Truvada, a once-a-day pill can reduce HIV infection rates by at least 92%. Because of high level of effectiveness, oral PrEP has been licensed for high-risk populations in the US, Canada, Kenya and South Africa. Efforts to have the dapivirine vaginal ring licensed for HIV prevention among women are currently underway. The process is an important one that takes time. It's anticipated that regulatory approvals could be received by 2018 in some countries in Africa. Results of the ASPIRE and RING studies are a boost to efforts focused on developing and evaluating next generation products, such a 3-month ring (just four rings would provide a woman a full year of protection), and combination rings that can provide protection against HIV, other STIs and unintended pregnancy. A vaginal ring could offer an important option as part of combination strategies or as a stand-alone method for women unable or not willing to use other strategies like medical male

Flavia Matovu Kiweewa1,2,\*, Kenneth K. Mugwanya1,3 and Francis Kiweewa1,4

1 Makerere University School of Public Health, Makerere University College of Health

[2] Seidman D, Weber S, Aaron E, Cohan D, Grant R. The FACTS about women and pre-

[3] Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. The Lancet.

[4] Weiss HA, Halperin D, Bailey RC, Hayes RJ, Schmid G, Hankins CA. Male circumcision

for HIV prevention: from evidence to action? AIDS. 2008;22(5):567–74.

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[18] Langen TT. Gender power imbalance on women\'s capacity to negotiate self-protection against HIV/AIDS in Botswana and South Africa. African Health Sciences.

[19] Wagner GJ, Holloway I, Ghosh-Dastidar B, Ryan G, Kityo C, Mugyenyi P. Factors associated with condom use among HIV clients in stable relationships with partners at vary-

[20] Centers for Disease Control and Prevenion. Preexposure prophylaxis for the prevention of HIV infection in the United States-2014: A clinical practice guideline. [Accessed on February 9, 2017];2014 :1–67. http://www.cdc.gov/hiv/pdf/prepguidelines2014.pdf. [21] World Health Organization. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. http://apps.who.int/iris/bitstream/10665/186275/

[22] Bekker L-G, Rebe K, Venter F, Maartens G, Moorhouse M, Conradie F, et al. Southern African guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring HIV-1 infection. Southern African Journal of HIV Medicine. 2016;17(1):1–11.

[23] http://emtct-iatt.org/wp-content/uploads/2016/09/Guidelines-on-Use-of-Antiretroviral-Drugs-for-Treating-and-Preventing-HI....pdf Guidelines on Use of Antiretroviral Drugs for Treating and Preventing HIV Infection in Kenya 2016 Edition Accessed October 2016.

[24] World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection—recommendations for a public health approach, second edition, 2016. Geneva, Switzerland: World Health Organization, 2016.

[25] Abraham BK, Gulick R. Next generation oral PrEP: beyond tenofovir. Current Opinion

[26] Rees H, Delany-Moretlwe S, Lombard C, editors. FACTS 001: a multi-centred phase III randomised, double-blind, placebo-controlled tiral of periocoital tenofovir 1% gel for HIV prevention in Women. Conference on Retroviruses and Opportunistic Infections;

[27] Corneli AL, Deese J, Wang M, Taylor D, Ahmed K, Agot K, et al. FEM-PrEP: adherence patterns and factors associated with adherence to a daily oral study product for pre-exposure prophylaxis. JAIDS Journal of Acquired Immune Deficiency Syndromes.

[28] Baeten, Jared M., et al. "Antiretroviral prophylaxis for HIV prevention in heterosexual

[29] Heffron R, Pintye J, Matthews LT, Weber S, Mugo N. PrEP as peri-conception HIV pre-

men and women." *New England Journal of Medicine* 367.5 (2012): 399-410.

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64 HIV/AIDS - Contemporary Challenges

## **Three Decades of HIV/AIDS Pandemic: Challenges Faced by Orphans in Tembisa, South Africa Three Decades of HIV/AIDS Pandemic: Challenges Faced by Orphans in Tembisa, South Africa**

Pius Tangwe Tanga, Princess Khumalo and Priscilla Gutura Priscilla Gutura Additional information is available at the end of the chapter

Pius Tangwe Tanga, Princess Khumalo and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66652

#### **Abstract**

This paper was extracted from a broader study conducted on the effectiveness of social support mechanisms provided to human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) orphans in Tembisa, Gauteng Province. Using a qualitative research design, an interview guide was designed for in‐depth interviews, which were conducted with 12 HIV‐ and AIDS‐affected and ‐infected orphans. In addition, a focus group discussion was run with 13 children's caregivers and two social workers were interviewed as key informants. Nevertheless, this paper discusses the challenges faced by orphans of HIV and AIDS. Maslow's hierarchy of needs was used as the theoretical framework of the study. The findings indicate that the death of a parent signifies the disruption of the basic pattern of a child's life living in the urban area where the role of extended families does not exist as compared to rural areas where a child belongs to the whole village. There are challenges that are impacting on the daily lives of the HIV/AIDS‐ affected and ‐infected orphans. Notably, the participants' narratives suggested that there were challenges in terms of health, shelter, education and food. It is concluded therefore that the war against the impacts of HIV and AIDS is still far from being achieved.

**Keywords:** HIV and AIDS, social support, challenges, orphans, caregivers, social workers

## **1. Introduction**

Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) is one of the major public health challenges and it is a pandemic worldwide [1]. Statistics released by Statistics South Africa showed that the population of the country was estimated at 54.96 million by mid‐2015 with approximately 48% being male and 52% female [2]. Furthermore,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Statistics SA showed that the estimated overall HIV prevalence rate is approximately 11.2% of the total South African population. The total number of people living with HIV is estimated at approximately 6.19 million in 2015. For adults aged 15–49 years, an estimated 16.6% of the population is HIV positive [2].

Further, HIV/AIDS has increased the number of orphans enormously to the extent that the United Nations in 2000 defines an orphan as a child who has lost one parent. This is because, when the first parent is killed by the disease, the next one follows within a short period of time. The death of both parents leads the child to be called a double orphan [3]. However, in most African nations, the fact of the matter is that the burden of parental death from AIDS is the greatest with 12.3 million children under the age of 15 having lost one or both parents to AIDS [4]. There is an estimation that 12 million children aged 17 and younger in the sub‐ Saharan Africa have lost one or both parents mainly due to HIV/AIDS [5]. This sordid truth is not far‐fetched even in the Southern African region. Then, it was concluded that these children are often left in the care of caregivers who have limited resources and abilities to care and provide for their psychosocial needs [6].

The General Household Survey in 2007 identified approximately 3.7 million orphans (children without both parents) living in South Africa. This survey also indicated that the number of children who had lost both parents had increased over the previous 5 years (2002–2006) and of further interest was that during 2006, 77% of all orphans were of school‐going age—7 years and above.

Substantially, there are international articles that place primary responsibility of the welfare of children on parents or guardians and extended families. These are the Convention of the Rights of the Child (CRC) (Article 5) and the African Charter on the Rights and Welfare of the Child (AC) (Articles 9 (3) and 18). However, the African norms and values just like the aforementioned articles also articulate such child‐welfare values. Even Kawewe [6] argues that in many African traditions the extended family is part and parcel of child rearing with the villagers and community members playing a role as the child is viewed as belonging to everyone. He further concludes that the AIDS pandemic defies the concept of the analogy 'it takes a village to raise a child' as many communities can no longer cope with those in need of care. As a result, children are left without caregivers. Some are left in alternative care such as adoption, non‐relative care or institutionalization.

South Africa is a signatory to the Declaration of Commitment of the United Nations General Assembly Special Session on Children held in 2002 (UNGASS). One of the articles of the Declaration states that

By 2003 develop, and by 2005 implement national policies and strategies to:

Build and strengthen governmental family and community capacities to provide supportive environments for orphans and boys and girls infected and affected by HIV and tAIDS including by providing appropriate counselling and psycho‐social support, ensuring their enrolment in school and access to shelter, good nutrition, health and social services on an equal basis with other children, to protect orphans and vulnerable children from all forms of abuse, violence, exploitation, discrimination, trafficking and loss of inheritance. (Article 65)

In the past few years of the post‐apartheid regime, profound political and social changes have been seen in South Africa, with the government taking the lead in introducing significant social welfare policy changes [7]. Major objectives of social welfare policies in South Africa are alleviating poverty and enabling the previously disadvantaged communities to have access to basic social services [8]. The social security system (mainly social grants) is the government's chief initiative in tackling poverty and inequality through which, according to [9], it has over 16 million beneficiaries accessing the social grants provided for by the government. Among these grants is a grant for children known as the Foster Care Grant.

Statistics SA showed that the estimated overall HIV prevalence rate is approximately 11.2% of the total South African population. The total number of people living with HIV is estimated at approximately 6.19 million in 2015. For adults aged 15–49 years, an estimated 16.6% of the

Further, HIV/AIDS has increased the number of orphans enormously to the extent that the United Nations in 2000 defines an orphan as a child who has lost one parent. This is because, when the first parent is killed by the disease, the next one follows within a short period of time. The death of both parents leads the child to be called a double orphan [3]. However, in most African nations, the fact of the matter is that the burden of parental death from AIDS is the greatest with 12.3 million children under the age of 15 having lost one or both parents to AIDS [4]. There is an estimation that 12 million children aged 17 and younger in the sub‐ Saharan Africa have lost one or both parents mainly due to HIV/AIDS [5]. This sordid truth is not far‐fetched even in the Southern African region. Then, it was concluded that these children are often left in the care of caregivers who have limited resources and abilities to care

The General Household Survey in 2007 identified approximately 3.7 million orphans (children without both parents) living in South Africa. This survey also indicated that the number of children who had lost both parents had increased over the previous 5 years (2002–2006) and of further interest was that during 2006, 77% of all orphans were of school‐going age—7

Substantially, there are international articles that place primary responsibility of the welfare of children on parents or guardians and extended families. These are the Convention of the Rights of the Child (CRC) (Article 5) and the African Charter on the Rights and Welfare of the Child (AC) (Articles 9 (3) and 18). However, the African norms and values just like the aforementioned articles also articulate such child‐welfare values. Even Kawewe [6] argues that in many African traditions the extended family is part and parcel of child rearing with the villagers and community members playing a role as the child is viewed as belonging to everyone. He further concludes that the AIDS pandemic defies the concept of the analogy 'it takes a village to raise a child' as many communities can no longer cope with those in need of care. As a result, children are left without caregivers. Some are left in alternative care such as

South Africa is a signatory to the Declaration of Commitment of the United Nations General Assembly Special Session on Children held in 2002 (UNGASS). One of the articles of the

Build and strengthen governmental family and community capacities to provide supportive environments for orphans and boys and girls infected and affected by HIV and tAIDS including by providing appropriate counselling and psycho‐social support, ensuring their enrolment in school and access to shelter, good nutrition, health and social services on an equal basis with other children, to protect orphans and vulnerable children from all forms of abuse, violence, exploitation, discrimination, trafficking and loss of inheritance.

By 2003 develop, and by 2005 implement national policies and strategies to:

population is HIV positive [2].

68 HIV/AIDS - Contemporary Challenges

and provide for their psychosocial needs [6].

adoption, non‐relative care or institutionalization.

years and above.

Declaration states that

(Article 65)

The Foster Care Grant is also used to provide support for children orphaned by HIV and AIDS; it is orphans who have lost both parents who are the most likely to be receiving the grant, providing that children remain in the care of foster parents [10]. Partially reflecting the effects of a deepening HIV and AIDS pandemic, since 10 years ago, when HIV‐related orphaning rates started rising rapidly, the use of the Foster Care Grant changed. The number of Foster Care Grant beneficiaries rose from 43,000 in 1997 to 300,000 in 2006 [11]. As of 30 April 2016, approximately 545,000 children were receiving the Foster Care Grant [9].

The Sowetan reported that the Social Development Minister Bathabile Dlamini, in Gugulethu, had highlighted that caregivers were reported to be misusing social grants [12]. According to the government, these social assistance grants are to assist caregivers to give orphans (in this case, HIV and AIDS orphans) a better life, a chance to be respectable members of the community and reduce poverty. However, a number of studies carried out so far have indicated that child poverty is still exceedingly high [13, 14]. According to UNICEF's report on the level of child poverty, it was clearly indicated that poverty was deepening in various parts of South Africa [4].  They also noted that previous inequalities in education, health care and basic infrastructure have also contributed to the backlog in present services [7]. The vulnerability of children, especially those living in poor areas, is compounded by HIV and AIDS.

A number of researchers [15, 16] have indicated that the HIV and AIDS pandemic is one of the greatest threats to the realization of child rights in South Africa and sub‐Saharan Africa. Research by the Children's Institute demonstrates some of the multiple vulnerabilities faced by children before the death of caregivers [17]. Children often take on the responsibility of caring for sick adults and are unable to attend school or study because of the difficulties at home. In short, children's experiences of orphanhood and its compounded vulnerabilities begin long before the death of a significant adult. It is not surprising that many of the subsequent experiences of children who have been orphaned are poverty‐related—such as an inability to afford school fees and school uniforms, prolonged experiences of hunger, inadequate housing and poor access to water [17]. On the other hand, Meintjes and Hall [18] reported that although the government and civil society have expressed concern about the growing number of children living in child‐headed households, there is little evidence to support this fear.

The Department of Social Development provides care and support to orphans and vulnerable children and their caregivers and these include child‐care forums, community‐based drop‐ins, home‐based care centres, early childhood development programmes, among others. For the purpose of this study, support mechanisms refer to all social support given to HIV and AIDS orphans in Tembisa Child and Family Welfare Society Organization. This assistance might be from social workers, care workers or givers and other members of society, offering support to orphans affected and infected with HIV and AIDS. The need for continuing social welfare policy reform processes and providing support mechanisms for responding to orphans and vulnerable children in South Africa is critical for policymakers. This research therefore evaluated the social support provided to HIV and AIDS orphans in Tembisa, Gauteng. A huge emphasis is placed on the challenges faced. The study focused more on the challenges faced by female caregivers as they form the bulk of Tembisa Child and Family Welfare Society's caseloads and the HIV and AIDS orphans in their care.

## **2. The research problem**

The AIDS epidemic has affected many children in South Africa leaving them either affected or infected [19]. These children are left behind with the greatest challenge of all which is figuring out how to survive, they are left with responsibilities way beyond their capacities, and they lack financial, emotional, physical, mental and material support to care for themselves. In addition, they are left under the care of people who are financially, emotionally, physically or mentally incapable to care for them [20]. The government has put forward means to assist these children to cope with the difficulties of life, but regardless of these there is still a need to determine how effective the measures put forward are assisting.

The majority of orphans and vulnerable children in South Africa are left in the care of old and weak women or sickly caregivers. The government has made recommendable success in combating abject poverty and hunger through social assistance programme [21]. Even after such measures, issues such as fraud still hover around and most caregivers and orphans are still battling with meeting challenges of day‐to‐day living. However, [21] continues to argue that the high prevalence of HIV and AIDS among caregivers has worsened the challenges of child poverty. The government in 2005 enacted the Children's Act 38 of 2005 which provided under Section 155 and 156 for the orphans of whatever nature to be associated with Foster Care Grants. The grant was to assist foster parents put the orphaned children through school, clothe them and shelter them. Due to the backlogs in many organizations assisting with the application of these grants and the misuse of such grants by some foster parents, the survival of HIV and AIDS orphans is still a struggle far from being won. The previous inequalities in education, health care and basic infrastructure have highly contributed in caregivers being unable to care for orphans and orphaned children [21].

## **3. Theoretical framework**

This study is anchored on Maslow's theory of human needs [22]. Maslow's theory of human needs depicts the hierarchy in a manner where needs in the lower level should be met before an individual can progress and satisfy the needs in the next level. This theory has five levels of needs, the lowest being the most basic need that a body cannot survive without and the top of the pyramid the least basic human need [23]. The lowest level of the pyramid is physiological needs, safety and security needs, love and belonging needs; at the top of the pyramid are esteem needs and self‐actualization. Once a need is satisfied an individual will be able to go to the next need [24].

This theory is relevant in this study as HIV/AIDS orphans have needs that should be met in order to fulfil their responsibilities. Orphans are driven by several factors to strive to satisfy the bottom need, and then move on up the hierarchy. Therefore, through understanding their challenges as AIDS orphans, ways of motivating them to fulfil their lives can be developed and implemented.

## **4. Research area and methodology**

orphans in Tembisa Child and Family Welfare Society Organization. This assistance might be from social workers, care workers or givers and other members of society, offering support to orphans affected and infected with HIV and AIDS. The need for continuing social welfare policy reform processes and providing support mechanisms for responding to orphans and vulnerable children in South Africa is critical for policymakers. This research therefore evaluated the social support provided to HIV and AIDS orphans in Tembisa, Gauteng. A huge emphasis is placed on the challenges faced. The study focused more on the challenges faced by female caregivers as they form the bulk of Tembisa Child and Family Welfare Society's

The AIDS epidemic has affected many children in South Africa leaving them either affected or infected [19]. These children are left behind with the greatest challenge of all which is figuring out how to survive, they are left with responsibilities way beyond their capacities, and they lack financial, emotional, physical, mental and material support to care for themselves. In addition, they are left under the care of people who are financially, emotionally, physically or mentally incapable to care for them [20]. The government has put forward means to assist these children to cope with the difficulties of life, but regardless of these there is still a need to

The majority of orphans and vulnerable children in South Africa are left in the care of old and weak women or sickly caregivers. The government has made recommendable success in combating abject poverty and hunger through social assistance programme [21]. Even after such measures, issues such as fraud still hover around and most caregivers and orphans are still battling with meeting challenges of day‐to‐day living. However, [21] continues to argue that the high prevalence of HIV and AIDS among caregivers has worsened the challenges of child poverty. The government in 2005 enacted the Children's Act 38 of 2005 which provided under Section 155 and 156 for the orphans of whatever nature to be associated with Foster Care Grants. The grant was to assist foster parents put the orphaned children through school, clothe them and shelter them. Due to the backlogs in many organizations assisting with the application of these grants and the misuse of such grants by some foster parents, the survival of HIV and AIDS orphans is still a struggle far from being won. The previous inequalities in education, health care and basic infrastructure have highly contributed in caregivers being

This study is anchored on Maslow's theory of human needs [22]. Maslow's theory of human needs depicts the hierarchy in a manner where needs in the lower level should be met before an individual can progress and satisfy the needs in the next level. This theory has five levels of needs, the lowest being the most basic need that a body cannot survive without and the top of the pyramid the least basic human need [23]. The lowest level of the pyramid is physiological

caseloads and the HIV and AIDS orphans in their care.

determine how effective the measures put forward are assisting.

unable to care for orphans and orphaned children [21].

**3. Theoretical framework**

**2. The research problem**

70 HIV/AIDS - Contemporary Challenges

Data presented in this paper were collected from Tembisa and the participants included HIV/AIDS orphans and their caregivers and social workers. The purpose was to get views from both the orphans themselves and the people who cared for these orphans. It is believed that once the researcher has developed an understanding of the rationale behind the choice of engaging in any form of research (either qualitative or quantitative), he designs the study [25]. Therefore, a qualitative research design was selected for this study. The goal of this method was to learn about the phenomenon and get in‐depth information and feelings of the participants.

The study was conducted in Tembisa Township in the East Rand of the Gauteng province in South Africa. The township is just a few kilometres outside the Kempton Park and the second largest township in Gauteng after Soweto. Its population is estimated to be a little over 500,000. The township came about during the apartheid era as a beacon of hope to the black families who were evicted from their homes. Many people live in poverty and in shacks or the recently built houses from the government (Reconstruction and Development Programme). Tembisa Child and Family Welfare Society provides social services to the township, especially for HIV/AIDS orphans and their caregivers.

This study was only limited to HIV and AIDS orphans being serviced by Tembisa Child and Family Welfare Society and also residing there. The study also targeted the caregivers of the orphans and the social workers who were servicing them. Therefore, this research made use of 13 caregivers, two social workers and 12 orphans. For the purpose of this study, the non‐ probability procedure in the form of purposive sampling was utilized to select the sample. The orphans were selected purposefully from the database of HIV and AIDS orphans receiving services from Tembisa Child and Family Welfare Society. The samples were drawn from the caseloads of social workers.

The study used semi‐structured interviews with the aid of interview guides. The interview guide consisted of non‐directive unstructured questions which were written in English, but the interviews were conducted in both English and Zulu. The questions on the research guide were meant to guide the researcher to keep to the objectives of the study. The interviews conducted were recorded with an audio recorder to make it easy to capture all the data and also to avoid misquoting the participants.

Focus groups were also used as a method of collecting data and they targeted care givers. Focus groups are a means of understanding how people feel or think about an issue [26] and can help understand how people feel about the issue being studied. Participants in the focus groups were allowed to share their perceptions, points of views, experiences and wishes without any pressure. An environment that is tolerant and non‐threatening to all participants was created. Once the research reached a point of saturation [27], the data collection process was concluded.

Qualitative data analysis was used. Data analysis was explained as the process of bringing order, structure and meaning to a mass of data collected [26]. Qualitative data analysis according to Ref. [26] is a search for general statements about relationships in different categories of data. The researchers went through the transcripts of the collected data with the use of a translator. Data analysis was done through the process of thematic analysis. Through reading the transcripts, the researcher came up with the underlying meanings of the information gathered. This process was repeated until a list of topics was acquired. Topics were then clustered together into baskets and were labelled as 'major topics', 'unique topics' and 'leftovers'. Data were then categorized into themes after finding the most descriptive wording for the topics [26].

In line with the ethical requirements of research, the researchers consulted with relevant authorities to gain access to research components. In order to gain access to the participants, the researchers firstly gained permission from the university in the form of an ethical clearance certificate. Other ethical procedures, including informed consent, anonymity and confidentiality, as well as participant debriefing were put into place during and after data collection. Potential respondents were verbally informed at the start of the study that their participation was completely voluntary and verbal consent of their participation was obtained. Caregivers provided verbal consent for themselves and their children. The children themselves gave consent for their participation and child‐friendly language was used.

## **5. Results**

This section provides the findings of the study, according to the themes that emerged. Firstly, the biographical information of the participants is laid out. Thereafter, the challenges faced by orphans, caregivers and social workers are presented.

## **5.1. Biographical characteristics of participants**

Interviews were held with 12 orphans within the age range of 10–18 (both affected and/infected with HIV and AIDS). In terms of gender, these children were proportionately selected, that is, they consisted of six males and six females. A total number of eight children interviewed were both affected and infected with HIV and AIDS and four indicated that they were affected only. Seven of the orphans were maternal orphans with unknown fathers, two were paternal orphans with unknown mothers and three of them were double orphans.

The population of orphaned children in Tembisa is very high with Tembisa Child and Family Welfare Society recording a number of more than 3000 families every year. The average dependency ratio in most of these families is 1:3. In all cases reported to the organization, of every 10 children, eight are orphans affected or infected by HIV and AIDS. Furthermore, amongst 13 participants who were in the focus group discussions, there were three child‐care workers and 10 caregivers. All of the participants were female black Africans. The participants' ages ranged from the age of 21–65 years. Two social workers were also interviewed as key informants.

## **5.2. Challenges faced by HIV and AIDS orphans**

The study aimed at investigating the challenges that were being faced in the provision of psychosocial support to HIV and AIDS orphans and the results of these are highlighted in this section.

## *5.2.1. Theme one: poor health*

Focus groups were also used as a method of collecting data and they targeted care givers. Focus groups are a means of understanding how people feel or think about an issue [26] and can help understand how people feel about the issue being studied. Participants in the focus groups were allowed to share their perceptions, points of views, experiences and wishes without any pressure. An environment that is tolerant and non‐threatening to all participants was created. Once the research reached a point of saturation [27], the data collection process was

Qualitative data analysis was used. Data analysis was explained as the process of bringing order, structure and meaning to a mass of data collected [26]. Qualitative data analysis according to Ref. [26] is a search for general statements about relationships in different categories of data. The researchers went through the transcripts of the collected data with the use of a translator. Data analysis was done through the process of thematic analysis. Through reading the transcripts, the researcher came up with the underlying meanings of the information gathered. This process was repeated until a list of topics was acquired. Topics were then clustered together into baskets and were labelled as 'major topics', 'unique topics' and 'leftovers'. Data were then categorized into themes after finding the most descriptive wording

In line with the ethical requirements of research, the researchers consulted with relevant authorities to gain access to research components. In order to gain access to the participants, the researchers firstly gained permission from the university in the form of an ethical clearance certificate. Other ethical procedures, including informed consent, anonymity and confidentiality, as well as participant debriefing were put into place during and after data collection. Potential respondents were verbally informed at the start of the study that their participation was completely voluntary and verbal consent of their participation was obtained. Caregivers provided verbal consent for themselves and their children. The children themselves gave con-

This section provides the findings of the study, according to the themes that emerged. Firstly, the biographical information of the participants is laid out. Thereafter, the challenges faced by

Interviews were held with 12 orphans within the age range of 10–18 (both affected and/infected with HIV and AIDS). In terms of gender, these children were proportionately selected, that is, they consisted of six males and six females. A total number of eight children interviewed were both affected and infected with HIV and AIDS and four indicated that they were affected only. Seven of the orphans were maternal orphans with unknown fathers, two were paternal

The population of orphaned children in Tembisa is very high with Tembisa Child and Family Welfare Society recording a number of more than 3000 families every year. The average

orphans with unknown mothers and three of them were double orphans.

sent for their participation and child‐friendly language was used.

orphans, caregivers and social workers are presented.

**5.1. Biographical characteristics of participants**

concluded.

72 HIV/AIDS - Contemporary Challenges

for the topics [26].

**5. Results**

HIV and AIDS has in the past presented a continuum of complex health issues that ranged from protecting personal health to ensuring that societies have adequate supplies of health care. In Tembisa, the main hospital (Tembisa Hospital) has a facility specifically for children infected with HIV and AIDS. All the children participating in the study who were on anti‐retro viral medication or immune boosters claimed to attend *check‐ups* at the hospital (Masakhane clinic). Child F stated:

I started taking Anti Retro Viral treatment at the age of 5 (now 15 years old). It has been a routine for me and they are now like a part of me. My aunt usually takes me to the clinic for my check‐up, but when she is not available to do so I go on my own…

Caregivers reported to understand the need to keep the children under constant monitoring to ensure that they did not default on their medication. It was, however, an agreement with most of the participants in the focus group that keeping track of what the children ate and did during school hours was difficult.  They eat these things behind the caregivers' backs. Such defaults only come to light when the children's viral loads spiral after hospital check‐up.

Furthermore, the caregivers mentioned that they could not afford nutritious food to give the children. The two social workers who were interviewed also highlighted that the health of orphans deteriorated at times because of lack of nutritious food to eat which is required by those who were living with the virus. One of the social workers said:

When we send the children for assessments to our doctor or the nurses here, we usually find out that the child's health would have deteriorated in terms of their CD4 count. This is usually caused by the children not eating the right food they are supposed to eat for example vegetables and fruits. (Social Worker 1)

## *5.2.2. Theme two: inadequate shelter*

Of all the children in the study, five reported to be residing in either '*shacks*' or as tenants in outside rooms. Four children reported to be staying in their parental homes and three reported that they lived in the homes of extended family members and that their parents never owned houses of their own. One child stated that:

I live with my three siblings in my grandmother's house.  Lucky for us, we are the only family my grandmother has now. (Child D)

For most of these children, though the case is quite different and another child highlighted that:

My aunt has four children of her own and they are girls. She and my mother stayed together in our shack from the time I was born. The shack is two roomed and had one bedroom which my aunt and cousins sleep in. Two of my cousins now have children… there is hardly any space… (Child H).

## *5.2.3. Theme three: poor school performance*

The loss of a parent due to any disease is not easy for a child. Losing a parent to HIV and AIDS is not easy for most children as they suffer from psychosocial effects and often lose concentration at school. Seven of the children interviewed were aware that their parents died of HIV and AIDS and two of these witnessed the illness and death of their parents. Child B reported:

I was twelve and the eldest. I would help to wash and dress my mother. She was very sick but did not want to go to the hospital until it was too late… She passed away at home in my presence (sobs)…

The child reported that during the time her mother was sick, she went to school occasionally so as to help look after her. Her performance at school dropped a lot that she had to repeat some grades.

In all the interviews, the children indicated that when their parents had the HIV‐ and AIDS‐ related sicknesses, their performances in school were affected. Four of the participants suffered through absenteeism from school and hence missed out on some lessons and important tests. Others (six) had to drop out of school after the death of their parents and re‐start at a later stage in a new school with present caregivers. Some (two) because of family circumstances were forced to enter into the system and be institutionalized, hence resulting in stigmatization by other learners in those schools. These and other factors have resulted in lower performance by most HIV and AIDS orphans as well as the overburden placed on caregivers to address their needs.

The caregivers also highlighted that the children's performance at school were poor. One caregiver mentioned that:

At one point I was called by the principal of the school because of the poor performance of my sister's child I am staying with. The principal mentioned that the child was so brilliant but after the death of her mother her grades were getting lower and lower (Caregiver AA)

#### *5.2.4. Theme four: food insecurity*

Health and nutrition statuses tend to decline as less money is often available to properly feed the household. One caregiver reported that the greatest challenge they had with caring for the orphans was that it was not easy having an extra mouth to feed with the present day economy. She stated that:

I have five children of my own and when my brother died, his three children came to stay with me as his wife died too and I am the only family left. Two of his children are attending school and the youngest is at crèche… my salary was not enough to feed and clothe my children (Caregiver BB)

Through the organization's Family Preservation programme, many community children find a source of food security from the food parcels handed out every month. Normally, family preservation is meant to work with a family for at least 6 months and discharge afterwards. One social worker stated this:

Some of our clients are placed on family preservation as a temporary measure whilst we work on processing their foster care applications which normally take longer than a year (Social Worker 2).

Tembisa is not an agrarian region; hence farming for food is not an option for many caregivers. None of the community members in the focus groups reported to have a backyard garden in their homes as they claimed that space was taken up by outside rooms which they used as a source of income.

Child B reported that she and her siblings stayed with their parents in the rural areas of Limpopo where life was simple and much cheaper. After the death of their mother, they had to move to Tembisa to stay with their maternal aunt as she was the only surviving family they knew. She described life in Gauteng (Tembisa to be precise) as very expensive as their aunt had to put food on the table every day, clothe them, pay bills and school fees. When asked how they survived, one care giver said that, 'We wait a long time to have foster care grants paid out and most of us are unemployed and survive on part time jobs that give us less than R500.00 a month…'

Another caregiver also highlighted that, '… if it were not for the outside rooms I built from a loan I got from the bank last year, life would be very hard for us… Rental money from tenants helps us…'. For most orphans, the loss of parents meant no more income in the house.

## **6. Discussion**

I live with my three siblings in my grandmother's house.  Lucky for us, we are the only family my grandmother

For most of these children, though the case is quite different and another child highlighted

My aunt has four children of her own and they are girls. She and my mother stayed together in our shack from the time I was born. The shack is two roomed and had one bedroom which my aunt and cousins sleep in. Two of my cousins now have children… there

The loss of a parent due to any disease is not easy for a child. Losing a parent to HIV and AIDS is not easy for most children as they suffer from psychosocial effects and often lose concentration at school. Seven of the children interviewed were aware that their parents died of HIV and AIDS and two of these witnessed the illness and death of their parents. Child B reported:

I was twelve and the eldest. I would help to wash and dress my mother. She was very sick but did not want to go to the hospital until it was too late… She passed away at home in

The child reported that during the time her mother was sick, she went to school occasionally so as to help look after her. Her performance at school dropped a lot that she had to repeat some grades. Four years later, she still remembered the death of her mother like it

In all the interviews, the children indicated that when their parents had the HIV‐ and AIDS‐ related sicknesses, their performances in school were affected. Four of the participants suffered through absenteeism from school and hence missed out on some lessons and important tests. Others (six) had to drop out of school after the death of their parents and re‐start at a later stage in a new school with present caregivers. Some (two) because of family circumstances were forced to enter into the system and be institutionalized, hence resulting in stigmatization by other learners in those schools. These and other factors have resulted in lower performance by most HIV and AIDS orphans as well as the overburden placed on caregivers to address their needs.

The caregivers also highlighted that the children's performance at school were poor. One

At one point I was called by the principal of the school because of the poor performance of my sister's child I am staying with. The principal mentioned that the child was so brilliant but after the death of her mother her grades were getting lower and lower (Caregiver AA)

Health and nutrition statuses tend to decline as less money is often available to properly feed the household. One caregiver reported that the greatest challenge they had with caring

has now. (Child D)

74 HIV/AIDS - Contemporary Challenges

is hardly any space… (Child H).

*5.2.3. Theme three: poor school performance*

my presence (sobs)…

caregiver mentioned that:

*5.2.4. Theme four: food insecurity*

was yesterday.

that:

The aim of the paper was to explore the challenges faced by HIV and AIDS orphans in Tembisa. The data obtained in the study is aligned with the literature which portrays orphan‐related challenges which are impacting on the daily lives of the HIV/AIDS‐affected and ‐infected orphans. Notably, the participants' narratives suggested that there were challenges in terms of health, shelter, education and food. According to [27], the death of a parent signifies the disruption of the basic pattern of a child's life. With death comes the challenge of meeting the child's basic needs.

The study highlights that the HIV/AIDS pandemic leaves a trajectory of orphans under the care of overloaded elderly women to assume an inexplicably major role in societal provisions, while undermining their engagement in civil society. This relates to what was outlined that many orphans are being cared for by the already structurally marginalized women, particularly elderly grandmothers often living in destitution [1].

The extended family network that has traditionally existed in Africa and South Africa is finding itself increasingly under strain because of HIV/AIDS [28]. The Department of Social Development in 2012 outlined that the HIV and AIDS pandemic has disrupted family, community and social structures, and has led to a marked increase in the number of orphans and other vulnerable children. The findings of the study strongly support the available literature that argues that children orphaned by HIV and AIDS depend mainly on their extended families to meet their basic needs.