What’s in the Pipeline: New HIV Drugs, Vaccines, Microbicides, HCV and TB Therapies in Clinical Trials
By Rob Camp, Richard Jefferys, Tracy Swan & Javid Syed
Edited by Bob Huff
August 2006
From the Forword:
Twenty-five years into the global HIV pandemic, 40 million people are living with the virus and some 25 million have died. According to UNAIDS, five million people were newly infected last year and 3.1 million died. By the end of 2005, according to the World Health Organization, about 1.3 million HIV-infected persons in developing countries were receiving antiretroviral therapy (ART)—a fourfold increase in just two years, with the most dramatic increase (800%) in sub-Saharan Africa. However, WHO recognizes that roughly 6.5 million people are in danger of dying from HIV/AIDS in the next two years, which means some 5 million in desperate need of ART are still unable to access it. A recent letter in The Lancet suggests that far more may currently need treatment; “Applying the WHO guidelines would then give…a total of 11.7 million who should be eligible.” (England 2006)
If current guidelines on when to start ART are revised to recommend ART initiation at higher CD4 levels, then the number of people who need ART will increase further.
ART is working very well where it is available. A recent international collaboration compared 18 ART programs in Africa, Asia, and South America with 12 HIV studies from Europe and North America by looking at first-year mortality among 4,810 and 22,217 persons starting ART in the two settings. While complete follow-up data were available on all patients from Europe/North America, just 57% (2,725) of “patients from low-income settings were actively followed up and included in survival analyses.” Results were encouraging, though patients initiating therapy in low-income settings were sicker, had lower baseline CD4 cell counts and higher early mortality:
Compared with high-income countries, patients starting HAART in low-income settings had lower CD4 cell counts … were more likely to be female … and more likely to start treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI). At 6 months, the median number of CD4 cells gained…and the percentage of patients reaching HIV-1 RNA levels below 500 copies/mL…were similar. [Note: In many lowincome countries viral load is not available.] Mortality was higher in low-income settings than in high-income settings. The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3 (95% CI 1.6-11.8) during the first month to 1.5 (CI 0.7-3.0) during months seven through twelve. The provision of treatment free of charge in low-income settings was associated with 77% lower mortality (adjusted HR 0.23, 95% CI 0.08-0.61). (ART-LINC and ART-CC 2006)
A recent modeling exercise calculated the survival benefits of AIDS treatment (PCP and MAC prophylaxis, increasingly potent and tolerable ART, and prevention of mother-to-child transmission). The authors concluded that:
Treatment for patients with AIDS in care in the United States since 1989 yielded a total survival benefit of 2.8 million years. [Prevention of mother-to-child transmission] averted nearly 2,900 infant infections, equivalent to 137,000 additional years of survival benefit… At least 3.0 million years of life have been saved in the United States as a direct result of care of patients with AIDS. (Walensky 2006)
Research and activism have been the twin engines driving progress against the pandemic. Politics, prejudice, and scientific hurdles remain the three chief obstacles to its control. The response to HIV/AIDS around the world has been dramatically transformed since 1996, when highly active antiretroviral therapy arrived. Death rates in developed countries from HIV/AIDS have declined by twothirds. Since the Durban AIDS conference in 2000, the advent of cheap generic antiretroviral combinations in 2001, the formation of the Global Fund to Fight AIDS, TB and Malaria (GFTAM) in 2002, the establishment of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) in 2003, and the WHO ‘3×5’ initiative and subsequent efforts at global scale up, world leaders have grudgingly come to declare a commitment to:
Pursue all necessary efforts to scale up nationally driven, sustainable and comprehensive responses to achieve broad multisectorial coverage for prevention, treatment, care and support, with full and active participation of people living with HIV, vulnerable groups, most affected communities, civil society and the private sector, towards the goal of universal access to comprehensive prevention programs, treatment, care and support by 2010. (UN General Assembly 2006)
According to UNAIDS, annual resources for scale-up towards universal access must triple by 2008 to $20-23 billion per year, yet the Global Fund lacks committed resources beyond the current round six. In Moscow last month, G8 leaders tepidly reaffirmed their commitment to Universal Access, as well as to The Global Plan to Stop TB and to expanded efforts to control malaria, avian influenza, and other emerging epidemics. Just how these commitments will be realized remains unclear (G8 2006).
In the first ten years of AIDS drug development, the FDA approved seven drugs: five nucleoside analogue reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, 3TC) and one protease inhibitor, Roche’s saquinavir. Since the beginning of 1996, the FDA has approved three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, efavirenz), three new nucleotide or nucleoside analogues (abacavir, tenofovir, 3TC), ten protease inhibitors (ritonavir, indinavir, nelfinavir, saquinavir soft gel capsules now withdrawn, amprenavir, lopinavir/r, atazanavir, fosamprenavir, tipranavir, and darunavir) and one entry/fusion inhibitor (T-20) (see table). FDA has also approved an increasing number of two- and threedrug fixed-dose combinations such as Combivir (AZT/3TC), Trizivir (AZT/3TC/ABC), Epzicom (ABC/3TC), Truvada (3TC/TDF) and recently, Atripla, a once-daily triple combination of 3TC/TDF/efavirenz. FDA has also approved a number of generic FDC products for sale internationally but not in the U.S. Unfortunately progress in treatment research over the past twenty years has not been matched by progress in establishing safe and effective preventive interventions such as microbicides, pre-exposure prophylaxis (PrEP) or vaccines.
TAG’s 2006 Pipeline Report focuses on a key part of the product development pipeline for biomedical interventions to prevent or treat HIV and its two most common deadly global co-infections: tuberculosis (TB) and hepatitis C virus (HCV) infection.