PubMed was searched with the broad terms of “HIV and antiretroviral therapy” with filters of research articles, clinical trials, reviews, meta-analyses in adults, and the English language to identify a large collection of potential articles for this Seminar. Papers deemed most relevant to this Seminar were selected, focusing on those as recent as possible, apart from important early work. Emphasis was placed on larger trials and cohorts and longer periods of treatment or observation. An
SeminarAntiretroviral therapy and management of HIV infection
Introduction
Advances in understanding of HIV biology and pathogenesis, and in application of that knowledge to reduce morbidity and mortality, rank among the most impressive accomplishments in medical history. No example since penicillin rivals the development of antiretroviral drugs in controlling a previously fatal infection. Antiretroviral therapy nowadays is potent, convenient, and typically well tolerated. Treatment initiated before advanced disease stage reduces plasma HIV RNA concentrations to undetectable values in most motivated patients who have access to these drugs.1, 2 Although the degree of immunological recovery varies in treated people, most who begin therapy before the onset of advanced immunodeficiency—eg, a CD4 T-cell count lower than 200 cells per μL—show robust and sustained CD4 T-cell gains.3, 4, 5
Despite the unquestioned success of modern treatment, many challenges remain. For reasons still being investigated, antiretroviral therapy does not fully restore health. HIV-infected people on such treatment have a shorter life expectancy than their do uninfected peers.6, 7, 8 This short life expectancy is especially true for patients who initiate therapy during advanced stages of their disease,6 but might even be true for optimally treated patients.9 Many patients continue to have long-term toxic effects from drugs that were once widely used in resource-rich parts of the world, and these effects are expected to become a major disease burden in the many regions where these drugs are still used. Many patients cannot maintain the high levels of adherence necessary for virus control, and, worldwide, large populations do not have continuous access to treatment. International programmes providing antiretroviral drugs to resource-limited countries are reaching only a proportion of those needing care and are threatened by the present economic downturn and changes in political will. There also remains the real possibility that recently developed drugs, currently assumed to be safe, will show novel side-effects after long-term use. Finally, many HIV-infected people remain unaware of their HIV infection, continue to transmit HIV to others, and when diagnosed have very advanced and often difficult-to-treat late-stage disease. These concerns are especially relevant to the most marginalised communities who are disaproportionately affected, even in resource-rich countries such as the USA.10
This Seminar briefly reviews the natural history and pathogenesis of antiretroviral untreated and treated HIV disease, the drugs used to treat the infection, and the tests used to monitor care. The unmet treatment needs are discussed in detail. Although the primary focus is on care in settings in which economics slightly constrain resources, the unique needs and challenges associated with the worlwide roll-out of antiretroviral drugs are also addressed.
Section snippets
Initial epidemic and early response
The simian version of HIV was probably transmitted from its natural host, the chimpanzee, to man in the early to middle years of the 20th century in the west central African countries of Cameroon and Gambia.11 The spread of HIV in man was initially slow and focal, but became explosive because of rapid urbanisation in the post-colonial era. Shortly after gaining a deeper hold in African cities, HIV rapidly spread worldwide, appearing in at-risk individuals in most regions by the mid-to-late
Natural history of untreated HIV infection
HIV infection follows sexual or parenteral exposure to HIV-containing fluids. In vaginal exposure, HIV attaches to target cells that carry it to regional lymph nodes in which it replicates and quickly establishes a productive and permanent infection.15 Once infection is systemic, HIV preferentially targets CCR5 CD4 memory T lymphocytes in the gastrointestinal tract, a crucial element in host defence in the gut.16, 17 By contrast with peripheral blood CD4 cell counts, which decline slowly in
Antiretroviral drugs and laboratory monitoring
Antiretroviral drugs are classed by the viral life-cycle step they inhibit (figure 1), and in some cases, by their chemical structure. Although many drugs might target a single enzyme, these drugs have unique side-effect profiles, drug-drug interactions, and potency. For those reasons, most formularies allow access to all drugs, but this practice might change once generic drugs become available and the cost differences between therapeutic options become more substantial.
A detailed description
CD4 testing
The average CD4 T-cell count in uninfected adults is typically more than 500 cells per μL. Most opportunistic infections and cancers occur as the CD4 T-cell count falls below 200 cells per μL. Recent guidelines use the threshold of 350 cells per μL as a strong indicator for beginning antiretroviral therapy.34, 35, 36 This threshold was selected, in part, because it was midway between the lower limit of normal (500 cells per μL) and the threshold often used to define AIDS (200 cells per μL).
Quantitative viral load testing
Quantitative viral load, or concentrations of plasma HIV RNA, is measured with PCR or related methods. Chronic established HIV infection is often associated with a stable set point, which varies widely between individuals. The viral load set point is associated with the rate of CD4 T-cell decline and with the risk of AIDS and death.39, 40 Both virus and host factors contribute to the viral load set point,41, 42 but the precise mechanism for these effects remains to be defined. The reasons for
Drug resistance testing
Antiretroviral drug-resistance mutations will almost invariably emerge if HIV is allowed to replicate in the presence of antiretroviral drug concentrations insufficient to exert complete suppression. The common resistance mutations for all drugs have been well characterised and their detection with reproducible commercial assays is straightforward, as long as the plasma viral load is at least 500–1000 copies per mL.46, 47 Each antiretroviral drug, and to some degree each drug class, varies in
Chemokine receptor tropism and HLA-B* testing
HIV enters its preferred target cells by binding to one or both of the chemokine receptors CCR5 and CXCR4 (figure 1). Nearly all patients with primary HIV infection harbour a virus that binds to CCR5 (R5 virus), thus termed R5 virus. For unclear reasons, as the disease progresses over time, many, if not most, untreated individuals develop a virus that also binds to CXCR4 (X4 virus).61 Since one therapeutic drug class specifically targets CCR5 (table), testing is needed to define which tropism
Basics of antiretroviral management: when to start treatment
Antiretroviral therapy is best managed by physicians with HIV expertise. The following section outlines generally the state-of-the-art of the most common clinical questions, such as when therapy should be recommended, which drugs should be used first, and when the initial regimen might need changes.
When is the best time to start antiretroviral therapy? Few issues in the clinical management of HIV infection have generated as intense or extended debates as this question. Such controversy is not
What treatment to start
What drugs should be used in an initial antiretroviral regimen? Several well tolerated and highly effective regimens are available for treatment-naive patients. The differences in terms of virological outcomes for the available regimens are often subtle and need very large studies to discern them.62, 72, 74, 93 Convenience, pill burden, tolerability, and long-term toxic effects are now the most important factors to consider when decisions between the various therapeutic options have to be made.
When to switch treatment
When should therapy be changed and what should be given after the first-line antiretroviral drug regimen? Initial HIV therapy is expected to succeed. Most treatment modifications result from toxic effects and to identify and replace the drug that is causing the unwanted side-effect is generally straightforward.94 Although uncommon, more serious versions of treatment failure can happen and the various types of therapeutic failure have their own causes and consequences.
Virological treatment
Present translational research themes
The last 15 years of HIV clinical research have largely focused on development of effective strategies for suppression of HIV replication in a durable and safe manner. The clinical research agenda is now shifting toward addressing a new set of questions, as outlined below and in the panel.
What explains the variable outcomes in patients given antiretroviral drugs? The goal of therapy is to reduce plasma HIV RNA concentrations to below values that are detectable with commercially available
Conclusion
HIV is now a chronic illness in patients with continued treatment access and excellent long-term adherence. Similar success is being realised in even desperately poor settings. Although the success of therapy is unquestioned, many issues persist. Since cure is not yet possible, treated people have to maintain lifelong adherence and face the risk of delayed drug toxic effects. Even treated HIV infection might cause chronic low-level inflammation with its potential for harm, incompletely restored
Search strategy and selection criteria
References (146)
- et al.
Risk of extensive virological failure to the three original antiretroviral drug classes over long-term follow-up from the start of therapy in patients with HIV infection: an observational cohort study
Lancet
(2007) - et al.
Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study
Lancet
(2007) - et al.
Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load
Blood
(2004) - et al.
Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies
Lancet
(2002) - et al.
Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial
Lancet
(2009) - et al.
Heterosexual HIV-transmission after initiation of antiretroviral therapy: a prospective cohort analysis
Lancet
(2010) - et al.
Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model
Lancet
(2009) - et al.
Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial
Lancet
(2007) - et al.
Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study
Lancet
(2004) - Gill VS, Lima VD, Zhang W, et al. Improved virological outcomes in British Columbia concomitant with decreasing...