# Presentation: 933594

## Research Advances in           HIV Care

- Joel E. Gallant, MD, MPH
- Johns Hopkins University School of Medicine

## Slide 2

## Cellular Reservoirs of HIV-1 Replication and Persistence

**Cellular Reservoirs of HIV-1 Replication and Persistence**

- M. Stevenson, Nature Medicine. 2003

## Frequency of Latently Infected CD4 

- 0.00001

- 0.0001

- 0.001

- 0.01

- 0.1

- 1

- 10

- 100

- 1000

- 10000

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

**Time on ****HAART**** (years)**

**Frequency**
** ****(IUPM)**

**Frequency of Latently Infected CD4 **
**Cells as a Function of Time on HAART**

**Siliciano R, et al.**

**Notes:**
Decay of latently infected cells in patients with prolonged suppression of viremia on HAART
Black lines show 95% confidence intervals on slope

## Lipoatrophy

**Lipoatrophy**

## Fat Accumulation

## Will We Return to Earlier Therapy?

- Availability of better, easier, less toxic regimens
- 2 pills qd without food restrictions
- No known long-term toxicity
- Long-term data may begin to demonstrate benefit with earlier therapy
- Risk of prolonged HIV exposure independent of CD4?
- e.g. dementia, NHL, PML
- Reduced transmission
- Potential for intermittent therapy

## Intermittent CD4-Guided TherapyThe BASTA Study

**Maggiolo F, *****et al. 43******rd****** ICAAC,***** Chicago, September 2003, H-448**

- 18/76 (24%) restarted HAART at least once
- 95% in STI group have maintained CD4 >400 at 20 months of follow-up
- Only nadir CD4 <350 cells/mm3 predicted time to restart HAART
- Cost of care in STI group decreased by ~€300/month

**Notes:**
Enrollment started 12/2001; recruitment in 2002-03
7 days on, 7 days off therapy:
VL does not rise immediately after stopping therapy; if interruption short enough patients should never be viremic (no fall in CD4 counts, no increase in contagiousness)
Jan 02: planned interim analysis after enrolment of 150 patients (50 each arm)
Week on/week off (WOWO) arm to be stopped if failure rate significant >10%; analysis on all patients with follow up of at least 8 weeks; n=112, of which 36 are in WOWO arm.
19/36 (53%) evaluable patients have had virological failures  (2 VL> 500 c/mL) in the WOWO arm versus 2/37 failed in the continuous treatment and 0/39 in CD4 guided arm.
Discontinuation of the WOWO arm, continues with the CD4-guided and continuous treatment arms.

NOTE – this is not the HIV-NET study.

##  Pulse Therapy

- CD4 Count

**CD4 Treatment threshold**

- = on HAART

- Time

**Treatment interruption (mos-yrs)**

## Stopping Drugs with Different Half-Lives 

**0**

**24**

**48**

**36**

**12**

**Time (hours)**

**Drug concentration**

**IC****90**

**IC****50**

**Last Dose **

**Day 1**

**Day 2**

*MONOTHERAPY*

**Zone of potential  replication**

**Taylor S, *****et al. 11******th****** CROI,***** San Francisco, 2004, #131**

**Notes:**
Key Points
Considerations of forgiveness are critical for ensuring “coverage” if a dose is missed

## Response to therapy in women receiving single-dose NVP for MTCT

- 255 women started d4T, 3TC, NVP postpartum
- 213 NVP-exposed, 42 not NVP-exposed intrapartum
- Genotype postpartum (median 12 days [range 10−14])
- K103N (21%)
- G190A (9%)
- Y181C (2%)
- 61 patients had detectable NVP levels up to 24 days postpartum

**Jourdain G, *****et al*****. *****11******th****** CROI*****, San Francisco 2004, #41LB**

**Subsequent response to triple therapy (<50 c/mL)**

**Notes:**
Mothers exposed to SD-NVP for PMTCT experienced a lower virological success rate of subsequent NNRTI-based therapy compared to non-exposed mothers. However, a clinically meaningful proportion of women still achieved virological success at 6 months even in the presence of mutations. Importantly, later initiation of therapy after NVP exposure was associated with an improved virological response. These results suggest that drug-resistance mutations that arise following SD-NVP exposure have an effect on the efficacy of subsequent NNRTI-based therapies. 
Strategies which maximize benefit of subsequent antiretroviral therapy for the mother while preserving the remarkable achievements of potent antiretroviral therapy for PMTCT need to be developed. 

## Drug Resistance Among Treatment-Naive Patients

**Little S, et al. 8th CROI; 2001; Chicago.  Abstract 756.**

**Patients With >10-Fold Resistance***** *****(*****N *****= 408)**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**20**

**Any ARV**

**NRTI**

**NNRTI**

**PI**

**MDR**

**Isolates With >10-Fold Reduced****Susceptibility (%)**

**1995-1998**

**1999-2000**

***P *****= .001**

***P *****= .03**

***P *****= .007**

***P *****= .0001**

***P *****= .002**

**Notes:**
ARV-naive patients from 8 North American cities were assessed for resistance mutations (N = 408)
Relative to patients with sensitive virus
Patients with >10-fold resistance to 1 drug showed a longer time to viral suppression (P = .05)
Patients with >2.5-fold resistance to 1 drug showed a trend to earlier virologic failure
These data suggest that inadequate adherence, among other factors, may lead to increasing rates of transmission of drug-resistant HIV.  Hence, adherence at the patient level may have public health consequences

## Targets for Antiretroviral Therapy

**Targets for Antiretroviral Therapy**

**Reverse Transcriptase Inhibitors**

**Protease Inhibitors**

**Integrase Inhibitors**

**Entry****Inhibitors**

**Various PI**

**NRTIs,**
**NNRTIs**

**T-20**

## Antiretroviral Agents Approved in the U.S.(May 2004)

| NRTIs | NNRTIs | PIs |
| --- | --- | --- |
| zidovudine (AZT) – Retrovir | nevirapine (NVP) – Viramune | saquinavir (SQV) – Invirase, Fortovase |
| didanosine (ddI) – Videx, Videx EC | delavirdine (DLV) – Rescriptor | indinavir (IDV) – Crixivan |
| zalcitabine (ddC) – Hivid | efavirenz (EFV) - Sustiva | ritonavir (RTV) – Norvir |
| stavudine (d4T) – Zerit | Nucleotide RTIs | nelfinavir (NFV) – Viracept |
| lamivudine (3TC) – Epivir | tenofovir DF (TDF) -Viread | amprenavir (APV) – Agenerase |
| abacavir (ABC) – Ziagen | Fusion Inhibitors | lopinavir/ritonavir (LPV/r) - Kaletra |
| emtricitabine (FTC) - Emtriva | enfuvirtide (ENF, T20) - Fuzeon | atazanavir (ATV) - Reyataz |
|  |  | fosamprenavir (FPV) - Lexiva |

## Recommended regimens fortreatment-naïve patients: DHHS 3/04

**Preferred regimens**

- *EFV safety in pregnancy not established – avoid in pregnant women or women with pregnancy potential
- **Only when an NNRTI- or a PI-based regimen cannot or should not be used as first-line therapy

**Alternative regimens**

**Triple NRTI****
**ABC + 3TC + (ZDV or d4T)**

**www.aidsinfo.nih.gov**

- TDF _*or*_
- ddI _*or*_
- (ABC)

- EFV _*or*_
- ATV _*or*_
- ATV/RTV _*or*_
- FPV/RTV

- Current Options for                        Once Daily Therapy

- 3TC _*or*_
- FTC

- +

- +

## The Move Toward Simpler Regimens

- _1996: _
- _3-drug regimen_: ddI + d4T + SQV
- 	- 22 pills per day:
- 	-SQV: 6 q8h with food
- 	-ddI:  1 pill bid 1⁄2 hr ac or 2 hrs pc
- 	-d4T: 1 pill bid

- _2004?_:
- _3-drug regimen_: TDF/FTC or ABC/3TC + EFV
- 2 pills qd

## Efavirenz Toxicity:Neuropsychiatric Effects

- Dizziness, dreams, insomnia, impaired concentration
- _Management_: Pre-treatment counseling, reassurance, altered dosing, short-term benzodiazepines, change drugs if persistent (e.g. > 2-3 weeks)
- Depression, hallucinations, psychosis
- _Management_: Change drugs

## Slide 19

## Slide 20

## Slide 21

## Slide 22

## Slide 23

## Slide 24

## The AIDS pandemicAdults and children living with HIV/AIDS, end 2003

- 5 M new HIV infections in 2003
- 3 M deaths due to HIV/AIDS in 2003
- 40 M living with HIV/AIDS; 50% females

**North America**
**790,000−1.2 M**

**Caribbean**
**350,000−590,000**

**Latin America**
**1.3−1.9 M**

**North Africa**
**& Middle East**
**470,000−730,000**

**Sub-Saharan Africa**
**25−28.2 M**

**East Asia **
**& Pacific**
**700,000−1.3 M**

**S & SE Asia**
**4.6−8.2 M**

**Australia**
**& New Zealand**
**12,000−18,000**

**Western **
**Europe**
**520,000−680,000**

**Eastern Europe**
**& Central Asia**
**1.2−1.8 M**

- Source: UNAIDS

**Prevalence**
** **

**(increase since 2002)**

**Source: UNAIDS**

## Lifetime Risk of AIDS Death:15-Year-old Boys Infected with HIV

**Current level of risk maintained**

**Risk halved over next 15 years**

**UNAIDS. Report on the global HIV/AIDS epidemic. June 2000; ****Source: Zaba B, 2000 (unpublished data)**

**Risk of dying of AIDS (%)**

**Current adult HIV prevalence rate (%)**

**Cambodia**

**Côte d’Ivoire**

**Kenya**

**South Africa**

**Zambia**

**Zimbabwe**

**Botswana**

**Burkina Faso**

**Cambodia**

**Côte d’Ivoire**

**Kenya**

**South Africa**

**Zambia**

**Zimbabwe**

**Botswana**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**5**

**10**

**15**

**20**

**25**

**30**

**35**

**40**

**0**

**Burkina **
**Faso**

**Lifetime Risk of AIDS Death:****15-Year-old Boys Infected with HIV**

## Classification of HIV 

- Genetic composition differs, allowing assessment of the geographic distribution
- Viruses may combine, creating circulating recombinant forms (CRFs)
-  HIV-1 is most common, but HIV-2 now circulating outside Africa, especially India
-        * Most infections due to Group M viruses
-        ** Clade B: 98–99% USA, 90% Europe

- McCutchan F. *2**nd** IAS*, Paris 2003, #23; Peeters M*. ibid*, #24

**Notes:**
HIV-2 mostly confined to West Africa (8-10% of infections in Guinea Bissau); prevalence stable or declining in most areas.  Less pathogenic and less transmissible than HIV-1.
HIV-1 is the predominant strain of HIV globally.
Group O viruses restricted to W. Africa – first recognized ~1990 in Cameroon.  Serologic data indicates group O virus dates from early 1960s or before (was isolated from blood of Norwegian sailor).  Increasing recognition of dual infections with group O and group M viruses.
Group N viruses very rare (only about 10 cases total); closely related to SIV.  Found only in Cameroon.
Timing of viral emergence estimated to be:
M strains ~ 1930
HIV-2 ~ 1940

## A global view of HIV-1 infection 50% of all new HIV-1 cases worldwide are caused by HIV-1 subtype C 

**HIV-1 group M (main) viruses includes several**** ****subtypes**** ****A through K**

## VaxGen B/B Phase III: Preliminary results 

|  | All | Vaccine | Placebo |
| --- | --- | --- | --- |
| Total | 5009 | 191/3330 (5.7%) | 98/1679 (5.8%) |
| Men | 4741 | 190/3155 (6.3%) | 94/1586 (5.9%) |
| Women | 268 |       1/175 (0.6%) |       4/93 (4.3%) |
| White | 4185 | 211/2994 (5.4%) | 98/2994 (6.0%) |
| Black* | 314 |       4/203 (2.0%) |     9/111 (8.1%) |
| Men | 168 |       4/111 (3.6%) |       5/57 (7.5%) |
| Women | 146 |         0/93 (0.0%) |       4/53 (7.5%) |
| Hispanic | 326 |     11/212 (5.2%) |     6/114 (5.3%) |
| Asian | 73 |         2/53 (3.8%) |      2/20 (10.0%) |
| Other | 111 |        6/71 (8.5%) |      6/40 (15.0%) |

**VaxGen B/B Phase III: Preliminary results **

- _Multivariate analysis_: No differences seen after controlling for age, education, geographic region, and risk behavior.

- Graham BS. *43**rd** ICAAC*, Chicago, September 2003, #637b; Popovic V. *ibid*, #H-1942

- _Univariate analysis_: Vaccine effectiveness statistically higher in blacks and women

- **p*<0.01

## Obstacles to HIV vaccine development

- Enormous clade and sequence variability
- Natural immune response to HIV infection is <5% effective
- Promising animal vaccine approaches with homologous sequences have completely failed (e.g., SIV 239)
- Naturally controlled infections do not protect against pathogenic superinfection (reinfection with different HIV strain)

- Desrosiers R*. 11**th* *CROI, *San Francisco 2004, #109

**Notes:**
The fact that a vaccine that contains a genetic sequence identical (homologous) to the genetic sequence of the virus with which the animals are challenged fails to protect against infection, illustrates how difficult it will be to develop vaccines that protect against heterologous challenges.

## SIV in nonhuman primatesPotential for new strains of HIV

- HIV-1 and -2 crossed species from nonhuman primates
- Assay of meat derived from 17 species of butchered primates for SIV-type viruses (>1000 samples)
- 14/17 species found to contain SIV-like viruses
- Potential for human exposure and resulting in HIV-3, HIV-4, HIV-5...

- Peeters M, *et al.* *2**nd** IAS, *Paris 2003, #24

- © Karl Ammann _[http://karlammann.com](http://karlammann.com/)_

**Notes:**
Increased exchange of people between urban and rural areas - more people in contact with primates, conditions for dissemination of new disease are increasing.