Chapter 1: Introduction: Research background and rationale
Chapter 2: Study objectives
Chapter 3: Study design and methodology
Chapter 4: Results
Chapter 5: Sensitivity Analysis
Chapter 6: Conclusions and discussion
Chapter 1: Introduction: Research background and rationale
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since 1981, and about 33 million people (most of them living in low- and middle-income countries) are now infected with human immunodeficiency virus (HIV) .
As one of the major treatments against HIV/AIDS, highly active antiretroviral therapy (ART) became available in 1996 but was extremely expensive in developing countries. Lack of ART in developing countries was a problem and was declared as a global health emergency in 2003, since then governments, international agencies, and funding bodies began to implement plans to increase ART coverage in low and mid-income countries. In 2009, more than a third of people who needed ART were receiving it .
HIV destroys immune system cells such as CD4 T-cells, leaving infected individuals susceptible to other infections. The CD4 T-cell count (CD4 count) is the major laboratory indicator of immune function in patients who have HIV infection, and it is one of the key factors in determining urgency of ART initiation. For most low and mid-income countries, CD4 count measurements play an important role in determining eligibility for ART . In 2013, World Health Organization released a more aggressive guideline compared to previous guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, which encouraged early treatment for patients with a CD4 cell amount less than 500 cells per cubic millimeter (cells/μL).  This is also known as “early treatment”, which defined as therapy initiated when the CD4+ T-cell count ranged from 350 to 500 cells/μL.
The reason why WHO released a more aggressive ART guideline was because the median baseline CD4 count at which people initiate ART has been suggested to be risen during the past decade by a lot of research evidence [4-10]. In 2003 Velasco-Hernandez and colleagues were the first to propose that treatment could potentially be used to eliminate HIV epidemics. Different from early treatment, “test and treat” is a more aggressive strategy and predicted by the modeling that if everyone is tested regularly and all infected persons are put on ART regardless of CD4 level, HIV/AIDS can be eliminated from society .
The reasons for the decline of HIV/AIDS prevalence in some “test and treat” modeling [5-10] are: (1) Clinical trial findings demonstrates that probability of HIV transmission was reduced under “test and treat” strategy [5-8], since initiation of ART at early stages of the disease can reduce the plasma viral load by up to six orders of magnitude . (2) Evidence suggests that testing HIV positive causes dramatic reductions in sexual activity levels, which also reduces HIV transmission probability [9, 10]. But others also find that benefits from expanded ART use are counterbalanced by modest increases in risky sexual behavior [11–13].
As for the degree of the decline of HIV/AIDS prevalence, existing mathematical models that simulate the impact of scaling up “test-and-treat” policies show mixed results. Some find significant gains in averting new HIV infections for more aggressive treatment strategies [14-16], whereas others find only modest effects [17–18].
Instability of the models and the discrepancy in model findings in “test and-treat” outcomes reflect the sensitivity of assumptions about HIV prevalence and other population parameters. This highlights the need to calibrate mathematical models to mimic the real world HIV prevalence trends .
Actually, the potential benefits of “test and treat” strategy are not limited to the reduction of AIDS epidemic. Recent economic analysis found that investment in antiretroviral therapy is cost-effective and may also result in cost savings [20-21]. The cost savings of HIV/AIDS treatment is very important to the world, since the spending in HIV/AIDS prevention and treatment is tremendous. In 2011, an estimated US$16.8 billion was spent on HIV/AIDS, compared to US$ 300 million in 1996. This is also an 11 percent increase on the money spent on HIV and AIDS in 2010 . The spending is still estimated to be increasing. In Hecht R’s modeling, without a serious change in approach, AIDS will still be a major pandemic and the funding required in resource-poor countries could reach an estimated $35 billion annually by 2031, which is two times more than the current level . It is important to include costing into the model when conducting analysis for different HIV treatment and prevent strategies. Also, for public health officials and policy makers in general to make a determination about the validity and feasibility of a “test and treat” strategy, biomedical findings must be linked to costing.
The reason why “test and treat” could be cost-saving is that investment in HIV treatment could increase employment and productivity and also avert future expenses for medical expenditure. . Cost-effectiveness studies have been done around cost-effectiveness of “test and treat” strategies. Some are focusing on impact of “test” , and some are only focusing on expanding treatment to larger population . One cost-effectiveness of HIV testing and treatment model in South Africa showed that increasing the length of the survival time, although beneficial to individuals, reduces the probability of eliminating HIV and decreases the cost-effectiveness of using universal “test and treat” strategies .
The studies of cost-effectiveness analysis for “test and treat” strategies are limited. There are some cost-effectiveness analysis for early ART. One early ART in persons infected with HIV in serodiscordant couples was conducted in South Africa and India settings, using a computer simulation of the progression of HIV infection. The results show that early ART is very cost-effective over a lifetime under most modeled assumptions in the two countries . Another cost-effectiveness of early ART used multiple independent mathematical models to evaluate the potential health impact, costs, and cost-effectiveness on different adult ART eligibility criteria. The study is from a health system perspective with results projected over 20 years in four settings—South Africa, Zambia, India, and Vietnam. And results show earlier ART eligibility can be very cost-effective in low and middle-income settings .
However, drug resistance is an issue that could potentially counterbalance the cost savings. Velasco-Hernandez and colleagues also noted that the emergence of highly transmissible resistant strains of HIV can significantly reduce the benefits of early ART . Baggaley et al also found that early treatment is ineffective as a measure to control sub-Saharan African HIV epidemics, as increasing the proportion on treatment increases the emergence and spread of multiple-drug-resistant HIV (MDR) .
Potential effects of MDR under “test and treat” strategy can be further divided into two parts. The first part is the effect of higher coverage of ART. Expanding eligibility for use of ART will result in higher coverage of ART in HIV-infected population, which could cause more patients generate MDR due to poor adherence especially in developing countries. This treatment failure will bring more cost burden, since more patients will move from first-line treatment to second-line treatment, and in some African countries, the price of second line drugs could be much more expensive than the first line drugs . The second part is the effect of higher prevalence of MDR. Sood et al’s mathematical modeling indicated that “test and treat” could lead to even a near doubling of the prevalence of MDR (9.06% compared to 4.79%) in 10 years under ‘test and treat” policy . Higher rates of MDR will counterbalance the benefit of HIV infections averted by “test and treat” strategy.
 UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2013, 2013.http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/UNAIDS_Global_Report_2013_en.pdf. Accessed by April 20th, 2014.
 http://www.avert.org/funding-hiv-and-aids.htm#sthash.nZW6cOOe.dpuf Accessed by April 20th, 2014.
 WHO. Supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach.
 Kilby JM, Lee HY, Hazelwood JD, et al. Treatment response in acute/early infection versus advanced AIDS: equivalent fi rst and second phases of HIV RNA decline. AIDS 2008; 22: 957–62.