Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-Limited Settings

Background The potential impact of pre-exposure chemoprophylaxis (PrEP) on heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. Methodology/Principle Findings A deterministic mathematical model was used to simulate the effects of antiretroviral PrEP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic, neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC = −0.94), level of coverage (PRCC = 0.92), and time to achieve target coverage (PRCC = −0.82). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even with a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%–62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%–75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (≤50%). Conclusions/Significance Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averted in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (≤50%).

[1]  R M May,et al.  The Influence of Different Sexual‐Contact Patterns between Age Classes on the Predicted Demographic Impact of AIDS in Developing Countries , 1989, Annals of the New York Academy of Sciences.

[2]  Shandir Ramlagan,et al.  South African National HIV Prevalence, HIV Incidence, Behaviour and Communication Survey, 2005 , 2008 .

[3]  Lynn Morris,et al.  Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration , 2005, PLoS medicine.

[4]  Mike Wood,et al.  December, 2006 , 2007, The Lancet.

[5]  C. Charpentier,et al.  Role of Minority Populations of Human Immunodeficiency Virus Type 1 in the Evolution of Viral Resistance to Protease Inhibitors , 2004, Journal of Virology.

[6]  C. Watts,et al.  Shifts in condom use following microbicide introduction: should we be concerned? , 2003, AIDS.

[7]  Bikram Chakraborty,et al.  Diminished Replicative Fitness of Primary Human Immunodeficiency Virus Type 1 Isolates Harboring the K65R Mutation , 2005, Journal of Clinical Microbiology.

[8]  J. Garcia-Calleja,et al.  National population based HIV prevalence surveys in sub-Saharan Africa: results and implications for HIV and AIDS estimates , 2006, Sexually Transmitted Infections.

[9]  K. Überla,et al.  Antiretroviral Therapy during Primary Immunodeficiency Virus Infection Can Induce Persistent Suppression of Virus Load and Protection from Heterologous Challenge in Rhesus Macaques , 2000, Journal of Virology.

[10]  Lincoln E. Moses,et al.  AIDS: sexual behavior and intravenous drug use. , 1989 .

[11]  R. May,et al.  The transmission dynamics of human immunodeficiency virus (HIV). , 1988, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[12]  N. Pedersen,et al.  Prophylactic and Therapeutic Benefits of Short-Term 9-[2-(R)-(Phosphonomethoxy)Propyl]Adenine (PMPA) Administration to Newborn Macaques following Oral Inoculation with Simian Immunodeficiency Virus with Reduced Susceptibility to PMPA , 2000, Journal of Virology.

[13]  O. Laeyendecker,et al.  Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. , 2005, The Journal of infectious diseases.

[14]  R. Anderson,et al.  Strategies for limiting the spread of HIV in developing countries: conclusions based on studies of the transmission dynamics of the virus. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[15]  G. Guyatt,et al.  Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis. , 2006, JAMA.

[16]  Richard J. Beckman,et al.  A Comparison of Three Methods for Selecting Values of Input Variables in the Analysis of Output From a Computer Code , 2000, Technometrics.

[17]  J. Orem,et al.  Survival by AIDS defining condition in rural Uganda , 2000, Sexually transmitted infections.

[18]  Sally Blower,et al.  Calculating the contribution of herpes simplex virus type 2 epidemics to increasing HIV incidence: treatment implications. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  P. Ghys,et al.  Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004 , 2006, AIDS.

[20]  S. Wilson.  Methods for the economic evaluation of health care programmes , 1987 .

[21]  C. Mahé,et al.  HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries? , 2002, AIDS.

[22]  R. Anderson,et al.  Factors controlling the spread of HIV in heterosexual communities in developing countries: patterns of mixing between different age and sexual activity classes. , 1993, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[23]  A. Telenti,et al.  Infrequent Transmission of HIV-1 Drug-Resistant Variants , 2003, Antiviral therapy.

[24]  Simon D W Frost,et al.  Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population. , 2003, The Journal of infectious diseases.

[25]  Bluma G. Brenner,et al.  Persistence and Fitness of Multidrug-Resistant Human Immunodeficiency Virus Type 1 Acquired in Primary Infection , 2002, Journal of Virology.

[26]  G. Garnett,et al.  Has global HIV incidence peaked? , 2006, The Lancet.

[27]  John P. Moore,et al.  Promote HIV Chemoprophylaxis Research, Don't Prevent It , 2005, Science.

[28]  J. Coffin,et al.  HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy , 1995, Science.

[29]  Sarah Palmer,et al.  Selection and persistence of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 in patients starting and stopping non-nucleoside therapy , 2006, AIDS.

[30]  J. Moatti,et al.  Access to antiretroviral treatment and sexual behaviours of HIV‐infected patients aware of their serostatus in Côte d'Ivoire , 2003, AIDS.

[31]  A. Blanc.  Demographic and health surveys , 1991 .

[32]  J. M. Arribas,et al.  Perirenal fat diameter measured by echography could be an early predictor of lipodystrophy in HIV type 1-infected patients receiving highly active antiretroviral therapy. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  N. Padian,et al.  Effectiveness of HIV prevention strategies in resource-poor countries: tailoring the intervention to the context , 2006, AIDS.

[34]  R M May,et al.  Age-dependent choice of sexual partners and the transmission dynamics of HIV in Sub-Saharan Africa. , 1992, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[35]  W. Heneine,et al.  Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques , 2006, Journal of Virology.

[36]  R Hoh,et al.  Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. , 2001, The New England journal of medicine.

[37]  M. Eigen,et al.  The Hypercycle: A principle of natural self-organization , 2009 .

[38]  Nicholas C. Grassly,et al.  Modelling emerging HIV epidemics: the role of injecting drug use and sexual transmission in the Russian Federation, China and India , 2003 .

[39]  M. Eigen,et al.  Emergence of the Hypercycle , 1979 .

[40]  Peter Schuster,et al.  A principle of natural self-organization , 1977, Naturwissenschaften.

[41]  James O Lloyd-Smith,et al.  The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa , 2006, PLoS medicine.

[42]  R. Anderson,et al.  Balancing sexual partnerships in an age and activity stratified model of HIV transmission in heterosexual populations. , 1994, IMA journal of mathematics applied in medicine and biology.

[43]  M. Wainberg,et al.  Diminished Representation of HIV-1 Variants Containing Select Drug Resistance-Conferring Mutations in Primary HIV-1 Infection , 2004, Journal of acquired immune deficiency syndromes.

[44]  J. Pape,et al.  Heterosexual Transmission of HIV in Haiti , 1996, Annals of Internal Medicine.

[45]  K. V. Van Rompay,et al.  Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. , 2001, The Journal of infectious diseases.

[46]  E. Rosenberg,et al.  Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  P. Das.  XVI International AIDS Conference. , 2006, The Lancet. Infectious diseases.

[48]  James E. Campbell,et al.  An Approach to Sensitivity Analysis of Computer Models: Part I—Introduction, Input Variable Selection and Preliminary Variable Assessment , 1981 .

[49]  M. Mouroux,et al.  Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. , 2001, AIDS.

[50]  G. Garnett,et al.  The Epidemiological Impact of an Hiv/Aids Vaccine in Developing Countries , 2002 .

[51]  G. Garnett,et al.  Modeling the impact of HIV chemoprophylaxis strategies among men who have sex with men in the United States: HIV infections prevented and cost-effectiveness , 2008, AIDS.

[52]  R. Grant,et al.  Prevention of SIV Infection in Macaques by (R)-9-(2-Phosphonylmethoxypropyl)adenine , 1995, Science.

[53]  R. Anderson,et al.  Potential Impact of Antiretroviral Therapy on HIV-1 Transmission and AIDS Mortality in Resource-Limited Settings , 2006, Journal of acquired immune deficiency syndromes.

[54]  Hadi Dowlatabadi,et al.  Sensitivity and Uncertainty Analysis of Complex Models of Disease Transmission: an HIV Model, as an Example , 1994 .

[55]  M. Alvarez,et al.  Evolution of human immunodeficiency virus type 1 populations after resumption of therapy following treatment interruption and shift in resistance genotype. , 2002, The Journal of infectious diseases.

[56]  Rebecca Hoh,et al.  Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. , 2005, The Journal of infectious diseases.

[57]  W. Heneine,et al.  The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions , 2006, Journal of Virology.

[58]  Jacques Izopet,et al.  Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy , 2001, Journal of Virology.

[59]  Roy M. Anderson,et al.  The Transmission Dynamics of Human Immunodeficiency Virus (HIV) , 1988 .

[60]  M. D. Miller,et al.  In Vitro Human Immunodeficiency Virus Type 1 Resistance Selections with Combinations of Tenofovir and Emtricitabine or Abacavir and Lamivudine , 2006, Antimicrobial Agents and Chemotherapy.

[61]  M. Wainberg,et al.  HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture , 2006 .

[62]  E. Asamoah-odei,et al.  HIV prevalence and trends in sub-Saharan Africa: no decline and large subregional differences , 2004, The Lancet.

[63]  S. Aral,et al.  Behavioral aspects of sexually transmitted diseases: core groups and bridge populations. , 2000, Sexually transmitted diseases.

[64]  P. Kaye.  Infectious diseases of humans: Dynamics and control , 1993 .

[65]  L. Naeger,et al.  Molecular Mechanisms of Resistance to Human Immunodeficiency Virus Type 1 with Reverse Transcriptase Mutations K65R and K65R+M184V and Their Effects on Enzyme Function and Viral Replication Capacity , 2002, Antimicrobial Agents and Chemotherapy.

[66]  W. Heneine,et al.  Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infection , 2007, Retrovirology.

[67]  B. M. Flynn,et al.  Containment of Simian Immunodeficiency Virus Infection: Cellular Immune Responses and Protection from Rechallenge following Transient Postinoculation Antiretroviral Treatment , 2000, Journal of Virology.

[68]  Ronald L. Iman,et al.  Assessing hurricane effects. Part 1. Sensitivity analysis , 2002, Reliab. Eng. Syst. Saf..

[69]  Charles L. Robertson,et al.  The International Herald Tribune , 1987 .

[70]  M. Hudgens,et al.  Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. , 2006, The Journal of infectious diseases.

[71]  R. Hayes,et al.  Commercial sex and the spread of HIV in four cities in sub-Saharan Africa , 2001, AIDS.

[72]  M. Eigen,et al.  The hypercycle. A principle of natural self-organization. Part A: Emergence of the hypercycle. , 1977, Die Naturwissenschaften.

[73]  J. Salomon,et al.  The Global Impact of Scaling Up HIV/AIDS Prevention Programs in Low- and Middle-Income Countries , 2006, Science.

[74]  Jon C. Helton,et al.  An Approach to Sensitivity Analysis of Computer Models: Part II - Ranking of Input Variables, Response Surface Validation, Distribution Effect and Technique Synopsis , 1981 .

[75]  B Ferry,et al.  Comparison of key parameters of sexual behaviour in four African urban populations with different levels of HIV infection , 2001, AIDS.

[76]  M. Wainberg,et al.  High Prevalence of the K65R Mutation in Human Immunodeficiency Virus Type 1 Subtype C Isolates from Infected Patients in Botswana Treated with Didanosine-Based Regimens , 2006, Antimicrobial Agents and Chemotherapy.

[77]  Joseph A. C. Delaney.  Sensitivity analysis , 2018, The African Continental Free Trade Area: Economic and Distributional Effects.

[78]  A. Cheng,et al.  K65R development among subtype C HIV-1-infected patients in tenofovir DF clinical trials. , 2007, AIDS.