Working Paper No.6 HIV/AIDS Technologies: A review of progress to date and current prospects COMMISSIONED BY: aids2031 Science and Technology Working Group AUTHORED BY: KEITH ALCORN NAM Publications Disclaimer: The views expressed in this paper are those of the author(s) and do not necessarily reflect the official policy, position, or opinions of the wider aids2031 initiative or partner organizations aids2031 Science and Technology working group A review of progress to date and current prospects October 2008 Acronyms 3TC lamivudine ANRS Agènce Nationale de Récherche sur la Sida ART Antiretroviral therapy ARV Antiretroviral AZT azidothymidine or zidovudine bDNA branched DNA CDC US Centers for Disease Control CHER Children with HIV Early Antiretroviral therapy (study) CTL Cytotoxic T-lymphocyte D4T stavudine DSMB Data and Safety Monitoring Board EFV Efavirenz ELISA Enzyme Linked Immunosorbent Assay FDC Fixed-dose combination FTC Emtricitabine HAART Highly Active Antiretroviral Therapy HBAC Home-based AIDS care HCV Hepatitis C virus HPTN HIV Prevention Trials Network HSV-2 Herpes simplex virus type 2 IAVI International AIDS Vaccine Initiative IL-2 Interleukin-2 LED Light-emitting diode LPV/r Lopinavir/ritonavir MIRA Methods for Improving Reproductive Health in Africa trial MSF Médecins sans Frontières MSM Men who have sex with men MVA Modified vaccinia Ankara NIH US National Institutes of Health NRTI Nucleoside reverse transcriptase inhibitor NNRTI Non-nucleoside reverse transcriptase inhibitor OBT Optimised background therapy PCR Polymerase chain reaction PEPFAR President’s Emergency Plan for AIDS Relief PEP Post-exposure prophylaxis PrEP Pre-exposure prophylaxis SIV Simian immunodeficiency virus SMART Strategies for Management of Antiretroviral Therapy TAG Treatment Action Group VOICE Vaginal and Oral Interventions to Control the Epidemic trial ii 1 Contents 1 Contents .................................................................................iii 2 Introduction.............................................................................1 3 Prevention technologies ........................................................3 3.1.1 ‘Combination prevention’ ........................................................................................................... 4 3.1.2 A new lexicon for biomedical HIV prevention? ............................................................................ 4 3.1.3 Future questions for biomedical prevention trials........................................................................ 5 3.1.4 Challenges in biomedical HIV prevention trials ........................................................................... 6 3.1.5 Behavioural prevention ................................................................................................................ 7 3.2 Male condoms.................................................................................................................................. 8 3.3 Harm reduction for injecting drug users .........................................................................................11 3.3.1 Future research questions......................................................................................................... 12 3.4 Circumcision................................................................................................................................... 12 3.4.1 Projected effect on the HIV epidemic ........................................................................................ 13 3.4.2 Circumcision technologies ......................................................................................................... 14 3.4.3 Future research questions......................................................................................................... 16 3.5 Microbicides ................................................................................................................................... 17 3.5.1 How they work ........................................................................................................................... 18 3.5.2 The “first generation” of microbicides: surfactants..................................................................... 19 3.5.3 The “second-generation” of microbicides: non-specific entry inhibitors .................................... 19 3.5.4 The “next generation” of microbicides: specific inhibitors.......................................................... 20 3.5.5 Enhancers of natural defences.................................................................................................. 22 3.5.6 Combination microbicides.......................................................................................................... 22 3.5.7 Rectal microbicides.................................................................................................................... 23 3.5.8 Future research questions......................................................................................................... 23 3.6 Other female-initiated barrier methods ..........................................................................................24 3.6.1 Female condoms ....................................................................................................................... 25 3.6.2 Future research questions......................................................................................................... 25 3.7 Antiretroviral prevention: Pre-exposure prophylaxis (PrEP) .......................................................... 26 3.7.1 Premature halting of early studies ............................................................................................. 27 3.7.2 Public health implications of PrEP............................................................................................. 28 3.7.3 Future research questions......................................................................................................... 28 3.8 Antiretroviral prevention: Post-exposure prophylaxis .................................................................... 29 3.8.1 Effectiveness of post-exposure prophylaxis .............................................................................. 30 iii 3.8.2 Drawbacks of post-exposure prophylaxis.................................................................................. 30 3.8.3 Guidelines for post-exposure prophylaxis ................................................................................. 30 3.8.4 Future research questions......................................................................................................... 30 3.9 Antiretroviral prevention: Antiretroviral treatment of index partners .............................................. 31 3.9.1 Future research questions......................................................................................................... 32 3.10 Prevention of mother-to-child transmission (PMTCT).................................................................... 32 3.10.1 Antiretroviral therapy and prophylaxis ................................................................................ 33 3.10.2 Infant feeding......................................................................................................................... 34 3.11 Sexually transmitted infection treatment........................................................................................37 3.11.1 HSV-2 suppression ...............................................................................................................37 3.11.2 Future research questions..................................................................................................... 39 3.12 Vaccines......................................................................................................................................... 40 3.12.1 Future research questions..................................................................................................... 41 3.12.2 Current investments in vaccine development ....................................................................... 42 4 Antiretroviral treatment........................................................46 4.1 Existing drug classes ..................................................................................................................... 47 4.1.1 Developmental products in existing/emerging classes.............................................................. 48 4.2 Longer-term class developments................................................................................................... 50 4.3 Formulation developments............................................................................................................. 51 4.3.1 Fixed-dose co-formulations ....................................................................................................... 51 4.3.2 Fixed-dose combinations: Paediatric formulations.................................................................... 52 4.3.3 Extended-release products........................................................................................................ 52 4.3.4 Dose reduction........................................................................................................................... 53 4.3.5 Nanotechnology and therapeutics (improved delivery methods) .............................................. 53 4.4 Immunotherapy .............................................................................................................................